Shaping the Future of Research - Herbert Wertheim College of ...

SUMMARY REPORT: 

Shaping the Future of Research 

A Strategic Plan for the National Heart, Lung, and Blood Institute

SUMMARY REPORT: 


A Strategic Plan for the National Heart, Lung, and Blood Institute 

NIH Publication No. 07-6149 

September 2007

Welcome from the Director 

I am delighted to present the Strategic 

Plan of the National Heart, Lung, and 

Blood Institute. This plan refl ects the 

intellectual energy of over 600 individuals 

representing an international spectrum 

of expertise in areas of relevance to 

the Institute’s mission. We are proud 

of the important role that the Institute 

has played historically in shaping the 

prevention and treatment of heart, lung, 

and blood diseases worldwide. We look 

forward with great enthusiasm to building 

upon this tradition and broadening our 

impact in the years to come. We invite 

you to join us in this grand adventure. 

With best wishes, 

Elizabeth G. Nabel, M.D. 

Director 

| 3

4 | Strategic Plan Summary | National, Heart, Lung, and Blood Institute

Introduction 

The National Heart, Lung, and Blood Institute (NHLBI) provides global leadership 

for a research, training, and education program to promote the prevention 

and treatment of heart, lung, and blood diseases and enhance the health of all 

individuals so that they can live longer and more fulfi lling lives. 

The breadth of the Institute’s programs refl ects its mandate, which includes three of 

the four leading causes of death in the United States. To achieve its vision, the NHLBI 

stimulates basic discoveries about the causes of disease, speeds the translation of basic 

discoveries into clinical practice, fosters training and mentoring of emerging scientists 

and physicians, and communicates research advances to the public. The NHLBI also 

collaborates with international organizations to help reduce the burden of heart, lung, 

and blood diseases worldwide. 

Heart, lung, and blood research can be expected to change dramatically over the 

next several decades in response to major drivers of research activity—information 

technologies that link scientists and their fi ndings globally and instantaneously; 

accelerating health care costs; an aging population of baby boomers who can expect 

to live longer, more productive lives, even in the face of chronic diseases; and the 

development of increasingly sophisticated research tools and databases. 

This strategic plan is intended to provide the NHLBI with a guide for its research 

and training programs over the next 5 to 10 years. It consists of a set of goals that 

refl ects the successive movement of scientifi c discovery from “form to function,” 

“function to causes,” and “causes to cures.” The goals focus on questions and 

processes that are broadly applicable to the Institute’s mandate, rather than on any 

specifi c disease or condition. 

The plan refl ects the wisdom, advice, and judgment of more than 600 individuals, 

including researchers, representatives of patient advocacy groups and professional 

societies, and other members of the scientifi c and lay communities. We are indebted to 

all participants for their commitment to the excellence and productivity of the Institute. 

Their further participation in the strategic plan will ensure its successful implementation 

and its continued evolution in response to new challenges and discoveries. 

| 5

Goal 1: To increase understanding 

of the molecular and physiological 

basis of health and disease and 

use that understanding to improve 

diagnosis, treatment, and prevention. 

Modern science offers outstanding opportunities to probe the innermost 

workings of the human body and to understand how events at the 

subcellular and molecular levels infl uence the functioning and integrity of 

the individual as a whole. Powerful new research approaches promise to 

unlock nature’s fundamental mysteries and shed light on where healthy 

processes go awry and how they can be corrected. 

Key research questions include 

the following: 

What processes help us maintain health 

throughout life? 

Processes of great interest include the steps 

involved in organ development; the mechanisms 

of tissue repair and regeneration; and the 

roles played by growth factors, intercellular 

communications, and connective tissue. Research 

in these areas will facilitate understanding of 

critical physiological mechanisms that operate 

from embryonic development to old age and will, 

thereby, enable progress in the development of 

cell-based therapeutics. 

6 | Strategic Plan Summary | National, Heart, Lung, and Blood Institute 

How do cells receive and process 

instructions? 

Complex networks of biological molecules allow 

cells to receive and process the instructions 

needed to carry out normal functions. When 

the networks are disrupted, disease can occur. 

Research using new technologies will enhance 

understanding of how environmental factors, 

drugs, and even a person’s own genes affect 

how well cellular pathways function. This work 

should facilitate the identifi cation of approaches 

that support the proper functioning of cellular 

pathways as well as the environmental, genetic, 

and other factors that disrupt them.

What genetic factors account for 

susceptibility or resistance to disease? 

Most common diseases have a complex cause 

that involves multiple genetic risk factors. 

Moreover, the severity may vary greatly among 

affected individuals depending on the presence 

of genes that either enhance or suppress disease 

manifestations. New tools are available to enable 

researchers to identify gene variants and modifi ers 

that affect an individual’s risk of developing a 

particular disease and its range of manifestations 

as well as the person’s response to medications 

and other interventions—key elements in the 

development of personalized medicine. 

How does the body respond to 

environmental factors? 

Environment in this context includes not just toxic 

exposures but also diet, physical activity, sleep 

deprivation, and psychosocial infl uences, all of 

which may combine to alter the predisposition 

for developing a disease, the rapidity and degree 

of its progression, and the response to therapy. 

Determining the mechanisms by which such 

factors disrupt normal biology and interact with 

genetic susceptibility is an important objective of 

future research. 

Can we differentiate between various 

subtypes of a disease? 

Traditional diagnostic criteria may not reveal subtle 

differences in the features of a given disease that 

can have important prognostic or therapeutic 

implications. Biomarkers—measurable physical, 

functional, or biochemical indicators—can be 

used to subdivide related diseases into clinically 

meaningful classes to achieve early diagnosis, to 

predict disease progression or regression, and to 

anticipate the occurrence of desirable or adverse 

therapeutic outcomes. Moreover, the biomarkers 

may themselves serve as effective targets for 

drug development. 

Can we fi nd new ways to observe 

and investigate disease processes in 

living people? 

The same knowledge base that will provide new 

insights into disease mechanisms and enable 

identifi cation of potential therapeutic targets 

will also enable the design of new molecular 

imaging probes and provide an impetus for the 

development of new methods to visualize disease. 

Advances in imaging technology may enhance 

understanding of the natural history of disease 

and may lead to more powerful, specifi c, and 

timely treatments. 

Genetics and Genomics 

The NHLBI is investing substantial resources to 

identify genetic susceptibility factors for common and 

rare diseases and to uncover ways of applying the 

new knowledge to develop innovative approaches 

for diagnosis, prevention, and treatment. For 

example, the Institute is developing genetic data 

from long-standing groups of study participants, 

linking it with data about participants’ characteristics 

and health indicators, and making it available—with 

appropriate privacy safeguards—to investigators in 

the community. This is just one step in a sequence of 

activities that will lead us from gene identifi cation to 

functional studies and genomic clinical trials 

and, ultimately, to personalized medicine.

Goal 2: To improve understanding 

of the clinical mechanisms of disease 

and thereby enable better prevention, 

diagnosis, and treatment. 

Remarkable progress is being made in understanding the molecular, 

genetic, and cellular origins of disease, and opportunities now exist to 

uncover practical uses for this new knowledge, particularly in the realm of 

personalized medicine. The application of a fundamental understanding of 

biological processes to the prevention and management of disease requires 

creative insights by investigators from diverse scientifi c fi elds. Further 

research is needed to identify, measure, and validate targets and pathways 

that have been detected in basic studies and then to develop new clinical 

applications and rigorously evaluate their effectiveness and safety. 



Can we repair old body parts or build 

new ones? 

Cell-based therapeutic approaches, including those 

involving the use of stem cells, offer great promise 

for treating heart, lung, and blood diseases. 

However, many questions remain concerning 

how to select, propagate, and administer cells 

and, most important, how to ensure that they 

remain viable and contribute safely to healing 

and function. Similarly, tissue engineering offers 


the possibility of restoring normal function in 

many diseases through the creation of durable, 

functional, and biocompatible implants. 

Can we harness the potential of genomics, 

imaging, and nanotechnology to develop 

new diagnostic and therapeutic strategies? 

For example, nanotechnology (engineering on 

an ultra-small scale) can be expected to play 

a key role in such areas as drug delivery and 

therapeutics, molecular imaging, diagnostics 

and biosensors, and tissue engineering and 

biomaterials. Although clinical testing of 

nanoparticles and nanodevices awaits future

developments, less-invasive applications (e.g., 

diagnostic blood tests) could become available 

much sooner, if preclinical and clinical studies 

establish their safety and utility. 

Is it possible to detect abnormalities 

and pathologies long before they cause 

symptoms and illness? 

Many disease processes relevant to the NHLBI 

mission are known to progress silently over the 

course of decades. The use of rapidly evolving 

imaging technologies could shed light on 

mechanisms of disease initiation, progression, 

and reversal; detect “subclinical” disease before 

symptoms develop; and potentially identify targets 

for effective interventions. 

Can we improve our ability to diagnose 

disease, track its progress, and predict 

the success of treatments? 

Biomarker discovery and validation have already 

yielded benefi ts for subgroups of patients identifi ed 

as being at risk for a wide variety of disorders. 

Studies to associate genes with disease characteristics 

are expected to uncover many new biomarkers that 

may prove useful for evaluating risk and individual 

responsiveness to treatments in populations and, 

ultimately, for identifying new therapeutic targets. 

Such work could potentially transform clinical 

Clinical Networks 

Since the early 1990s, the NHLBI has been a pioneer in developing 

networks to support and facilitate clinical research on a variety of 

diseases, including childhood and adult asthma, pediatric heart 

disease, heart failure, chronic obstructive pulmonary disease 

(COPD), thalassemia, and sickle cell disease. Recently established 

networks are addressing cell therapies, surgical interventions, 

community-based care, and resuscitation outcomes for patients 

with cardiovascular diseases. The NHLBI networks enable a timely 

response to new scientifi c developments by providing clinical and 

administrative expertise, access to patients, standardization of 

treatment protocols, and rapid dissemination of research fi ndings 

to health care professionals and the public. 

decision-making and enhance the participation of 

patients in health-promoting behaviors. 

How can we personalize our approach to 

disease prevention and treatment? 

Personalized medicine is based on the concept 

that all individuals have unique characteristics 

as defi ned by their genome and that human 

variability in health and disease is determined 

by genetic makeup in combination with 

developmental and environmental exposures 

(e.g., diet, exercise, sleep, psychosocial infl uences). 

Exploration of the interactions between genetic 

and environmental factors has now become 

essential to explain the development, progression, 

and outcome of many diseases and to identify 

the best interventions for a given patient. As 

the vision of personalized medicine becomes a 

reality, clinicians will be able to select effective 

medications and dosages and avoid adverse 

reactions, thereby improving outcomes and 

potentially reducing health care costs. 

What are “best practices” for the 

medicine of today and tomorrow? 

The NHLBI will continue its long and distinguished 

tradition of excellence in conducting clinical trials to 

ensure that clinical practice guidelines for disease 

detection, management, and prevention are based 

on rigorous standards of scientifi c evidence. 

| 9

Goal 3: To translate research 

into practice for the benefi t of 

personal and public health. 

To realize its public health objective, the NHLBI must fi nd ways to extend the full 

benefi ts of scientifi c advances to all of the diverse populations that constitute 

the American public. Many evidence-based approaches to prevent and treat 

heart, lung, and blood diseases have not been uniformly applied in clinical and 

community practice. Further understanding of the translation process itself 

is needed to expedite and expand the adoption of biomedical advances into 

clinical practice and individual health behaviors. Focused behavioral and social 

science research may help uncover effective new approaches for communicating 

research fi ndings to the public and for motivating and empowering individuals 

and communities to take charge of their health. 



How can we move proven therapeutic 

and preventive approaches into 

everyday practice? 

Integrating behavioral and social sciences research 

with clinical research is crucial for developing 

successful strategies to improve medical practice. 

A better understanding of the factors that 

infl uence patient, provider, and health care system 


behaviors may facilitate the development of new 

methods to reduce the “quality gap” between 

what is currently being done and what can 

potentially be accomplished. Research is needed 

to evaluate factors that are associated with caredelivery 

patterns; to document the benefi ts, risks, 

and costs of interventions; and to identify patientcentered 

approaches to clinical decision-making. 

How can we ensure that medical practice is 

based on up-to-date scientifi c evidence? 

The NHLBI plays a pivotal international 

role in continually assessing the available

evidence, serving as a knowledge broker for 

the development of clinical practice guidelines, 

and identifying areas that need additional 

research to support clinical decision-making. 

Systems approaches are needed to speed the 

implementation of knowledge in health care and 

community settings; to foster partnerships among 

practitioners, patients, family members, community 

organizations, and community health workers; 

and to create environments that support healthy 

choices and reduce known risk factors. 

How can we reach high-risk 

communities? 

Substantial evidence indicates that health, 

socioeconomic status, and psychosocial factors 

are inextricably linked and that disparities in 

health status are complex problems that demand 

multifaceted solutions. In particular, new 

approaches that can accommodate nontraditional 

family patterns and immigrant status are needed. 

Community groups and local health providers 

who share an appreciation of psychosocial 

issues and cultural beliefs must be involved in 

efforts to promote community acceptance of 

science-based health information. Partnerships 

and linkages will be supported that enhance 

understanding of the contributions of individual 

health behaviors, community-based organizational 

and environmental policies, and health systems 

innovations to reducing health disparities. 

How can we engage individuals as full 

participants in their health care and 

disease prevention? 

Despite widespread recognition of the importance of 

health behaviors, only a relatively small percentage 

of adults and children regularly follow relevant 

prevention and treatment recommendations. 

Infl uences on health behaviors are diverse—they 

include personal knowledge and motivation, familial 

expectations and role models, and environmental 

factors such as workplace and school policies. 

Accordingly, emphasis should be placed on 

developing and evaluating approaches within the 

context of complex real-world environments. 

How can we communicate research 

advances effectively to the public? 

The NHLBI will continue to develop public education 

programs as needed, partnering with professional 

societies, patient-advocacy groups, community 

organizations, and Federal entities to ensure 

that uniform health messages are disseminated. 

In addition to encouraging individuals and 

communities in health promotion and disease 

prevention efforts, the Institute will stress the 

importance of their involvement in the research 

process by emphasizing that new health-related 

information can be generated only with their 

cooperation and participation. 

Prevention 

The NHLBI places great emphasis on the 

translation and dissemination of research fi ndings 

to health professionals, patients, and the public 

so that timely information can be integrated 

into health care practice and individual health 

behavior. Disease prevention through awareness 

and the modifi cation of risk factors is a subject 

that receives considerable attention. For instance, 

The Heart Truth campaign urges women to take 

steps to lower their risk of developing coronary 

heart disease. WeCan! is helping households 

and communities around the country to prevent 

obesity in youngsters and to encourage lifelong 

habits of healthy eating and exercise. 

| 11

Next Steps 

The NHLBI Strategic Plan provides a broad vision of challenges that the 

Institute will be addressing over the next few years. A detailed strategy 

for its implementation will be developed by the Institute in consultation 

with the National Heart, Lung, and Blood Advisory Council and with other 

representatives from the research community and the public. 

A time-honored way to advance knowledge and 

explore new horizons is for researchers to apply 

their expertise and insight to intriguing scientifi c 

questions. We anticipate that much of the plan 

will be realized through such investigator-initiated 

research, and we are disseminating the plan widely 

in the research community in the expectation that 

it will generate highly meritorious proposals. 

NHLBI-initiated investments guided by this plan 

will be directed largely toward programs that 

either enable or complement investigator-initiated 

activities. They will call for a variety of strategies 

to facilitate the conduct of research; enhance 

interdisciplinary work; speed early-stage translation 

of basic discoveries; ensure the cross-fertilization 

of basic, clinical, and epidemiological discoveries; 

and maximize the resultant public health benefi ts. 

The Institute will use the following key strategies in 

fulfi lling the objectives of the plan. 

• Develop and facilitate access to scientifi c 

research resources. 

• Develop new technologies, tools, and resources. 

• Increase the return from NHLBI populationbased 

and outcomes research. 

• Establish and expand collaborative resources 

for clinical research. 

• Extend the infrastructure for clinical research. 

• Support the development of multidisciplinary 

teams. 

• Develop and retain human capital. 

• Establish knowledge networks to bridge the 

gap between research and practice. 

The NHLBI also will explore ways to increase its 

programmatic involvement in global health issues 

related to chronic diseases in the developing world. 

As the challenges identifi ed in this plan are met 

and as new ones emerge, the NHLBI will identify 

and embrace new strategies. The Institute will 

also continue to look to its Advisory Council and 

to the larger research community for guidance 

to ensure that the plan continues to refl ect the 

rapidly changing environments of research and 

public health issues. 

| 13


Information and Resources 

NHLBI Resources 

NHLBI Home Page 

http://www.nhlbi.nih.gov 

NHLBI Strategic Plan 

http://apps.nhlbi.nih.gov/strategicplan/ 

NHLBI Information for Researchers 

http://www.nhlbi.nih.gov/resources/index.htm 

NHLBI Information for Health Professionals 

http://www.nhlbi.nih.gov/health/indexpro.htm 

NHLBI Information for Patients and the Public 

http://www.nhlbi.nih.gov/health/index.htm 

NHLBI Clinical Trial Database 

http://apps.nhlbi.nih.gov/clinicaltrials/ 

NHLBI Funding Training and Policies 

http://www.nhlbi.nih.gov/funding/index.htm 

NHLBI Training and Career Development Web Site 

http://www.nhlbi.nih.gov/funding/training/ 

NHLBI Research and Policy Update Listserv 

http://www.nhlbi.nih.gov/resources/listserv/index.htm 

NHLBI Fact Book 

http://www.nhlbi.nih.gov/about/factpdf.htm 

NIH Resources 

NIH Home Page 

http://www.nih.gov 

NIH Center for Scientifi c Review 

http://cms.csr.nih.gov/ 

NIH Forms and Applications 

http://grants.nih.gov/grants/forms.htm 

NIH Grants and Funding Opportunities 

http://grants1.nih.gov/grants/index.cfm 

NIH Public Involvement 

http://www.nih.gov/about/publicinvolvement.htm 

For More Information 

The National Heart, Lung, and Blood Institute (NHLBI) Health 

Information Center is a service of the NHLBI of the National 

Institutes of Health. The NHLBI Health Information Center 

provides information to health professionals, patients, and 

the public about the treatment, diagnosis, and prevention 

of heart, lung, and blood diseases and sleep disorders. For 

more information, contact: 

NHLBI Health Information Center 

P.O. Box 30105 

Bethesda, MD 20824-0105 

Phone: 301-592-8573 

TTY: 240-629-3255 

Fax: 301-592-8563 

Web site: http://www.nhlbi.nih.gov 

| 15


Discrimination Prohibited 

Under provisions of applicable public laws enacted by Congress 

since 1964, no person in the United States shall, on the grounds 

of race, color, national origin, handicap, or age, be excluded 

from participation in, be denied the benefits of, or be subjected 

to discrimination under any program or activity (or, on the basis 

of sex, with respect to any education program and activity) 

receiving Federal financial assistance. In addition, Executive 

Order 11141 prohibits discrimination on the basis of age by 

contractors and subcontractors in the performance of Federal 

contacts, and Executive Order 11246 states that no federally 

funded contractor may discriminate against any employee or 

applicant for employment because of race, color, religion, sex, 

or national origin. Therefore, the National Heart, Lung, and 

Blood Institute must be operated in compliance with these laws 

and Executive Orders.


September 2007


A Strategic Plan for the National Heart, Lung, and Blood Institute


A Strategic Plan for the National Heart, Lung, and Blood Institute 


September 2007

II | A Strategic Plan for the National Heart, Lung, and Blood Institute

Welcome from the Director 

I am delighted to present the Strategic Plan of 

the National Heart, Lung, and Blood Institute. 

This plan reflects the intellectual energy of over 

600 individuals representing an international 

spectrum of expertise in areas of relevance to 

the Institute’s mission. We are proud of the 

important role that the Institute has played 

historically in shaping the prevention and 

treatment of heart, lung, and blood diseases 

worldwide. We look forward with great 

enthusiasm to building upon this tradition and 

broadening our impact in the years to come. 

We invite you to join us in this grand adventure. 

With best wishes, 


Director 

| III

IV | A Strategic Plan for the National Heart, Lung, and Blood Institute

Table of Contents 

Introduction 1 

Executive Summary 3 

The NHLBI, Past and Present 7 

Goals and Challenges 9 

Goal 1 

Goal 2 

Goal 3 

To improve understanding of the molecular and physiological basis of health and disease, and to 

use that understanding to develop improved approaches to disease diagnosis, treatment, and prevention. 

To improve understanding of the clinical mechanisms of disease and thereby enable better prevention, 


To generate an improved understanding of the processes involved in translating research into practice and 

use that understanding to enable improvements in public health and to stimulate further scientific discovery. 

Strategies 25 

Strategy 1 Develop and facilitate access to scientific research resources. 26 

Strategy 2 Develop new technologies, tools, and resources. 26 

Strategy 3 Increase the return from NHLBI population-based and outcomes research. 27 

Strategy 4 Establish and expand collaborative resources for clinical research. 28 

Strategy 5 Extend the infrastructure for clinical research. 28 

Strategy 6 Support the development of multidisciplinary teams. 29 

Strategy 7 Develop and retain human capital. 30 

Strategy 8 Bridge the gap between research and practice through knowledge networks. 31 

Appendix 32 

Participants 32 

NIH Participants 39 

Information and Resources 44 

10 

14 

18 

| V

Introduction 

The National Heart, Lung, and Blood Institute (NHLBI) has a distinguished record of 

supporting and guiding seminal advances in heart, lung, and blood research that have 

yielded unprecedented improvements in the Nation’s health. Building on the Institute’s 

numerous accomplishments, we now have an opportunity to develop a heart, lung, and 

blood research agenda for the United States that will lead to even greater successes. This is our 

challenge—and our obligation, as stewards of Federal research dollars. 

Heart, lung, and blood research can be expected to change dramatically over the next several decades 

in response to the major drivers of research activity: information technologies that link scientists and 

their fi ndings globally and instantaneously; accelerating health care costs; an aging population of baby 

boomers who can expect to live longer, more productive lives, even in the face of chronic diseases; and 

the development of increasingly sophisticated research tools and databases. 

This strategic plan is intended to provide the NHLBI with a guide for its research and training programs 

over the next 5 to 10 years. It is not intended to provide a detailed implementation plan to address 

the challenges it identifi es—that will be developed by the Institute over the life of the strategic 

plan in consultation with the National Heart, Lung, and Blood Advisory Council (NHLBAC) and with 

representatives from the research community and the public—and it is not intended to address 

matters that are beyond the scope of the Institute’s mandate. We expect that implementation of 

the plan will require the Institute to continue to develop and explore effective ways to collaborate 

with other agencies of the Federal government; with other governmental agencies, both domestic 

and foreign; and with nongovernmental organizations, both public and private. Our success in 

implementing the plan will be evaluated on an ongoing basis by the Institute with advice and guidance 

provided by the NHLBAC. 

This strategic plan refl ects the wisdom, advice, and judgment of more than 600 individuals who 

participated in its preparation, all of whom are identifi ed in the Appendix. We are indebted to 

them and to the scientifi c communities they represent for their commitment to the excellence and 

productivity of the Institute. Their further participation in the strategic plan will ensure its successful 

implementation and its continued evolution in response to new challenges and discoveries. We are 

also indebted to the many individuals and organizations that contributed their insights to the plan 

during the time that it was open for public comment. 

Introduction | 1

2 | A Strategic Plan for the National Heart, Lung, and Blood Institute

Executive Summary 

The National Heart, Lung, and Blood Institute provides global leadership for a research, training, 

and education program to promote the prevention and treatment of heart, lung, and blood diseases 

and to enhance the health of all individuals so that they can live longer and more fulfi lling lives. 

The breadth of the Institute’s programs refl ects the breadth of its mandate, which includes three of 

the four leading causes of death in the United States. To achieve its vision, the NHLBI stimulates 

basic discoveries about the causes of disease, speeds the translation of basic discoveries into clinical 

practice, fosters training and mentoring of emerging scientists and physicians, and communicates 

research advances to the public. 

This strategic plan is intended to provide the NHLBI with a guide for its research and training programs 

over the next 5 to 10 years. Investigator-initiated research has long constituted the largest share of the 

NHLBI research portfolio, and it is our intention to maintain that historical commitment. In fact, we 

expect that much of the plan will be realized through our investment in investigator-initiated research. 

Institute investments guided by this plan will be directed largely toward programs that either will 

enable or complement investigator-initiated activities. 

The plan consists of a set of goals that refl ects the successive movement of scientifi c discovery from 

“form to function” (Goal 1), “function to causes” (Goal 2), and “causes to cures” (Goal 3), with research 

challenges identifi ed for each of the goals and a set of strategies to address the plan as a whole. 

Executive Summary | 3

The goals are as follows: 

Goal 1: To Improve Understanding of the Molecular and 

Physiological Basis of Health and Disease, and To Use 

That Understanding To Develop Improved Approaches to 

Disease Diagnosis, Treatment, and Prevention. 

Challenge 1.1: To delineate mechanisms that relate 

molecular events to health and disease. 

1.1.a. Develop a detailed understanding of the molecular, 

cellular, and physiological mechanisms that maintain health 

from embryonic development to the end of the human lifespan. 

1.1.b. Identify intracellular targets of key signaling and 

transcriptional pathways in normal and pathological states. 

1.1.c. Determine key genetic variants that are associated with 

specific diseases and delineate the molecular mechanisms that 

account for susceptibility or resistance to disease. 

1.1.d. Define molecular, cellular, and organ-specific responses 

to environmental challenges and the mechanisms by which 

heritable and non-genetic factors interact in disease initiation 

and progression and in therapeutic response. 

1.1.e. Determine the role of systemic pathological processes, 

such as inflammation, immunity, and infection, in the 

development and evolution of disease. 

Challenge 1.2: To discover biomarkers that differentiate 

clinically relevant disease subtypes and that identify 

new molecular targets for application to prevention 

and diagnosis—including imaging, and therapy. 

1.2.a. Identify molecular signatures that allow complex disease 

phenotypes to be stratified into clinically relevant categories. 

1.2.b. Develop in vivo molecular imaging methods and 

probes for investigating the biology of disease processes. 

4 | A Strategic Plan for the National Heart, Lung, and Blood Institute 

Goal 2: To Improve Understanding of the Clinical 

Mechanisms of Disease and Thereby Enable Better 

Prevention, Diagnosis, and Treatment. 

Challenge 2.1: To accelerate the translation of basic 

research findings into clinical studies and trials 

and to promote the translation of clinical research 

findings back to the laboratory. 

2.1.a. Integrate advances in regenerative biology to develop 

clinically feasible applications. 

2.1.b. Apply discoveries in nanotechnology to the 

development of new diagnostic and therapeutic strategies. 

2.1.c. Integrate, analyze, and share extant and emerging 

genotypic and phenotypic data. 

Challenge 2.2: To enable the early and accurate risk 

stratification and diagnosis of cardiovascular, lung, 

and blood disorders. 

2.2.a. Exploit noninvasive imaging methods to detect and 

quantify subclinical disease. 

2.2.b. Apply new discoveries in biomarkers to improve risk 

assessment, diagnosis, prognosis, and prediction of response 

to therapy. 

Challenge 2.3: To develop personalized preventive 

and therapeutic regimens for cardiovascular, lung, 

and blood diseases. 

2.3.a. Improve the understanding of interactions between 

genetic and environmental factors that influence disease 

development and progression and response to therapy. 

2.3.b. Identify and evaluate interventions to promote health 

and treat disease in genetically defined patient subgroups by 

altering developmental or environmental exposures including 

drugs, diet and exercise, sleep duration and quality, and 

infectious agents and allergens. 

Challenge 2.4: To enhance the evidence available 

to guide the practice of medicine, and improve 

public health.

Goal 3: To Generate an Improved Understanding of the 

Processes Involved in Translating Research into Practice and 

Use That Understanding To Enable Improvements in Public 

Health and To Stimulate Further Scientific Discovery. 

Challenge 3.1: To complement bench discoveries 

and clinical trial results with focused behavioral and 

social science research. 

3.1.a. Develop and evaluate new approaches to implement 

proven preventive and lifestyle interventions. 

3.1.b. Develop and evaluate policy, environmental, and other 

approaches for use in community settings to encourage and 

support lifestyle changes. 

3.1.c. Develop and evaluate interventions to improve patient, 

provider, and health care system behavior and performance in 

order to enhance quality of care and health outcomes. 

Challenge 3.2: To identify cost-effective approaches 

for prevention, diagnosis, and treatment. 

3.2.a. Evaluate the risks, benefits, and costs of diagnostic tests 

and treatments in representative populations and settings. 

3.2.b. Develop research designs, outcome measures, and 

analytical methods to assess prevention and treatment 

programs in community and health care settings across 

populations and lifespan. 

Challenge 3.3: To promote the development and 

implementation of evidence-based guidelines in 

partnership with individuals, professional and 

patient communities, and health care systems and 

to communicate research advances effectively to 

the public. 

3.3.a. Establish evidence-based guidelines for prevention, 

diagnosis, and treatment and identify gaps in knowledge. 

3.3.b. Develop personalized and community- and health care 

system-oriented approaches to increase the use of evidencebased 

guidelines by individuals, communities, health care 

providers, public institutions, and, especially, by populations 

that experience a disproportionate disease burden. 

3.3.c. Communicate research advances effectively to the public. 

The strategies that will be used to address the preceding 

goals and challenges are listed below: 

Strategy 1: Develop and facilitate access to 

scientific research resources. 

Strategy 2: Develop new technologies, tools, and 

resources. 

Strategy 3: Increase the return from NHLBI 

population-based and outcomes research. 

Strategy 4: Establish and expand collaborative 

resources for clinical research. 

Strategy 5: Extend the infrastructure for clinical 

research. 

Strategy 6: Support the development of 

multidisciplinary teams. 

Strategy 7: Develop and retain human capital. 

Strategy 8: Bridge the gap between research and 

practice through knowledge networks. 

Executive Summary | 5


The NHLBI, Past and Present 

The National Heart Institute was established in 1948 through the National Heart Act, with a mission 

to support research and training in the prevention, diagnosis, and treatment of cardiovascular diseases. 

Twenty-four years later, through the National Heart, Blood Vessel, Lung, and Blood Act, Congress 

directed the Institute to increase and coordinate its activities to improve understanding and reduce 

the public health burden of heart, blood vessel, lung, and blood diseases. As a result, the Institute 

expanded its scientifi c areas of interest, intensifi ed its efforts related to research on diseases within its 

purview, and re-emphasized its commitment to training the next generation of investigators in heart, 

lung, and blood research. It also assumed responsibility for the conduct of educational activities, 

including the development and dissemination of materials for health professionals and the public, with 

an emphasis on prevention. During the 1990s, the Institute was directed to expand its mandate to 

encompass sleep disorders through its administration of the National Center on Sleep Disorders Research 

and was charged with administering the Women’s Health Initiative. 

Today, the NHLBI provides global leadership for research, training, and education programs to promote 

the prevention and treatment of heart, lung, and blood diseases and enhance the health of all individuals 

so that they can live longer and more fulfi lling lives. The breadth of the Institute’s programs refl ects the 

breadth of its mandate, which includes three of the four leading causes of death in the United States. 

While necessarily focusing considerable effort and resources on diseases that affect large numbers of 

people, the Institute also recognizes its obligation to address those conditions that do not themselves 

constitute a major public health burden but do impose serious health burdens on affected individuals. 

To achieve its vision, the NHLBI stimulates basic discoveries about the causes of disease, speeds the 

translation of basic discoveries into clinical practice, fosters training and mentoring of emerging scientists 

and physicians, and communicates research advances to the public. The NHLBI creates and supports 

a robust, collaborative research infrastructure in partnership with private and public organizations, 

including academic institutions, industry, and government agencies. The NHLBI collaborates with 

patients, families, health care professionals, scientists, professional societies, patient advocacy groups, 

community organizations, and the media to maximize the use of research results and leverage resources 

to address the public health needs of the Nation. 

All activities of the NHLBI are conducted in a spirit of public service and with a commitment to 

excellence, innovation, integrity, respect, compassion, and open communication. 

The NHLBI, Past and Present | 7


Goals and Challenges 

The structure of this plan refl ects a successive movement of scientifi c discovery from “form to function,” 

“function to causes,” and “causes to cures.” Although research priorities are provided for each of the 

plan’s major goals, the NHLBI recognizes that the relevant fi elds, available technologies, and emerging 

biological principles are evolving rapidly. As a result, the NHLBI is committed to remaining vigilant in 

identifying—and nimble in embracing—critical research opportunities as they arise. The Institute will 

continue to look to the NHLBAC and to the larger research community for guidance and assistance in 

implementing the plan and ensuring that it is updated as needed to refl ect the latest scientifi c advances. 

The Institute also will continue to look to the larger research community to develop the ideas and 

conduct the studies that will advance our knowledge of heart, lung, and blood diseases and will 

enable its application in ways that will improve public health. Investigator-initiated research has long 

constituted the largest share of the NHLBI research portfolio, and it is our intention to maintain that 

historical commitment. In fact, we expect that much of the plan will be realized through our investment 

in investigator-initiated research and, especially, through those innovative investigator-initiated research 

projects that entail a high risk but offer the promise of especially high returns. Institute investments 

guided by this plan will be directed largely toward programs that will either enable or complement 

investigator-initiated activities. 

…we expect that much of the plan will be realized through 

our investment in investigator-initiated research… 

Goals and Challenges | 9

Goal 1: To Improve Understanding 

of the Molecular and Physiological Basis 

of Health and Disease, and To Use That 

Understanding To Develop Improved 

Approaches to Disease Diagnosis, 

Treatment, and Prevention. 

To enhance understanding of the molecular and physiological basis of health and disease, 

the NHLBI has identified two priority objectives. The first is to delineate normal and 

pathological biological mechanisms. The second is to exploit the emerging understanding 

of these mechanisms to identify biomarkers of disease. The second challenge provides a 

natural link to the clinical and translational objectives that are considered subsequently in 

this plan because the goal of biomarker discovery is to identify markers that can be used 

to stratify diseases into distinct and clinically relevant molecular subtypes, monitor disease 

initiation and progression, and uncover potential therapeutic targets. 

Challenge 1.1: To delineate mechanisms 

that relate molecular events to health 

and disease. 

Recent technological advances offer new opportunities for 

investigating the molecular events associated with health and 

disease. The developing field of systems biology, for example, 

allows scientists to identify mechanistic relationships among 

the numerous individual molecules that constitute larger 

systems of cells, tissues, and organs and to generate predictive 

models of molecular, cellular, and physiological processes 

based on these mechanistic relationships. The models allow 

scientists not only to understand but also to anticipate the 

consequences of specific perturbations of molecular events. 

Such systems-level approaches have numerous applications to 

heart, lung, and blood investigations. 


Since pathology and drug therapy represent medically relevant 

perturbations of normal biology, systems-level approaches are 

ideally suited for investigating and providing unique solutions 

to biomedical problems. Although already widely used in basic 

studies of health and disease, the combination of “-omics” 

technologies and integrative computational methods will 

increasingly play a major role in efforts to obtain a systemslevel 

understanding of health and disease. 

While a systems approach clearly will be important for pursuing 

Goal 1, many biological functions still are best studied using 

biochemical and biophysical methods applied at the level of 

individual or small numbers of molecules rather than at the 

systems level. Thus, if a complete understanding of normal and 

pathobiological conditions is to be achieved, future mechanistic 

investigations must strike a balance between highly reductionist 

and systems-level approaches, and integrate the two strategies 

to obtain a holistic view of health and disease.

In fact, no single strategy—however comprehensive—will be 

able to address every problem of biomedical interest to heart, 

lung, and blood investigators. More likely, investigational 

approaches will have to be customized based on the 

biological process or disease to be studied. Development and 

dissemination of new technologies throughout the research 

community will allow investigators the flexibility to draw on 

core experimental and computational methods that are suited 

to multiple applications. 

1.1.a. Develop a detailed understanding of 

the molecular, cellular, and physiological 

mechanisms that maintain health from embryonic 

development to the end of the human lifespan. 

Developing a comprehensive understanding of the mechanisms 

involved in maintaining human health will require research 

approaches that are more multidisciplinary and integrative than 

those relied upon in the past. Scientists currently working in 

separate fields, such as tissue engineering and gene therapy, 

will need to work collaboratively to achieve an integrated 

understanding of relevant biological processes. Processes 

of interest to NHLBI investigators include tissue repair and 

regeneration; organ development (with an emphasis on stem 

cell biology, model organism genetics, and human congenital 

disorders); intrinsic and extrinsic mechanisms underlying 

the proliferation, differentiation, maturation, survival, and 

trafficking of stem and progenitor cells in different contexts; 

and roles played by growth factors, extracellular matrix, and 

cell-cell contact. The resulting information will be critical for 

understanding physiological mechanisms and applying the 

information to the development of cell-based therapies. 

1.1.b. Identify intracellular targets of key signaling 

and transcriptional pathways in normal and 

pathological states. 

Research in model organisms and human systems has 

demonstrated that signaling and transcriptional pathways 

intersect to form higher order regulatory networks. Because 

the disruption of individual pathways may have adverse 

consequences that are manifested as disease, detailed 

characterization of regulatory networks at cellular, tissue, and 

whole-organism levels is essential. Research must progress 

beyond an understanding of static molecular relationships to 

the development of dynamic, quantitative models that are 

capable of predicting how subtle environmental or genetic 

perturbations alter normal function. Such models will help 

researchers to identify potential targets for therapeutic 

interventions and to anticipate not only the benefits but 

also the potential adverse effects of specific interventions. 

The new models also are expected to provide insights into 

variations among individuals in the response to interventions, 

a central goal of personalized medicine. Research to meet 

the challenge will require the use of emerging technologies 

such as high-throughput small-molecule gene and protein 

expression profiling, high-density genotyping, ribonucleic 

acid interference (RNAi) and chemical screening, protein 

interaction mapping, and computational methods that allow 

the integration and interrogation of disparate data sets 

relevant to heart, lung, and blood experimental systems. 

1.1.c. Determine key genetic variants that are 

associated with specifi c diseases and delineate 

the molecular mechanisms that account for 

susceptibility or resistance to disease. 

Most common diseases—including those of the cardiovascular, 

pulmonary, and hematopoietic systems—have a complex 

etiology that involves multiple genetic risk factors. Disease 

severity may vary greatly among affected individuals depending 

on the presence of genes that either enhance or suppress 

a disease phenotype. Researchers now are able to identify 


disease susceptibility, resistance, and modifier loci using the 

completed human haplotype map in conjunction with new 

genomic mapping technology that permits cost-efficient 

detection of common polymorphic variants on a genome-wide 

scale in thousands of affected individuals and healthy controls. 

The NHLBI currently supports genetic association studies for 

a number of common heart, lung, and blood diseases and 

recognizes the importance of continuing its commitment to 

this promising area of research. However, conducting an 

association study is only the first step in identifying a disease 

gene. Researchers must independently replicate findings from 

an initial association study in a second cohort and then perform 

additional fine-mapping studies to select the causative gene 

from the possible candidates that maps to a chromosomal 

region of interest. Once researchers have determined that a 

gene variant contributes to disease susceptibility or resistance, 

additional research is required to determine its mechanism of 

action. Investigations that address mechanisms will intersect 

with other objectives of this strategic plan, notably those 

focused on gene and protein functions in health and disease. 

Finally, while some of the genetic variants associated with 

diseases relevant to the NHLBI mandate will be found at 

high frequency among affected individuals, rare variants also 

could be informative for understanding disease pathogenesis 


and for developing new treatments. The discovery of 

rare variants awaits the development of less expensive 

technology for high-throughput deoxyribonucleic acid (DNA) 

sequencing, and the NHLBI must be prepared to encourage 

the adoption of such technology as it becomes available. 

Similar genetic and genomic approaches also must be applied 

to pharmacogenomics—the study of individual variations in 

responses to particular drug therapies—a key element in the 

development of personalized medicine. 

1.1.d. Defi ne molecular, cellular, and organ-specifi c 

responses to environmental challenges and the 

mechanisms by which heritable and non-genetic 

factors interact in disease initiation and progression 

and in therapeutic response. 

Environmental influences can affect disease susceptibility 

and phenotypic heterogeneity through their interactions with 

genes and their effects on proteins and protein metabolites. 

Environment in this context includes not just toxic exposures 

but also diet, physical activity, sleep deprivation, psychosocial 

factors, and—in the case of the developing fetus—maternal 

factors, all of which may converge to alter the predisposition 

for developing a disease, the rapidity and degree of its 

progression, and the response to therapy. Determining 

the mechanisms by which non-genetic factors perturb 

normal biology and interact with genetic susceptibility is an 

important objective of future research. Suitable experimental 

systems that recapitulate adverse environmental effects and 

gene-environment interactions are needed for the study of 

disease development and evolution. 

1.1.e. Determine the role of systemic pathological 

processes, such as infl ammation, immunity, 

and infection, in the development and evolution 

of disease. 

Systemic processes reflect an integration of genetic, 

infectious, toxic, ischemic, and metabolic insults in acute 

and chronic disease. Understanding how this integration 

of multiple stimulants contributes to disease initiation and 

progression remains an important challenge. Research in 

this area has the potential to profoundly alter approaches to 

disease prevention, diagnosis, and treatment.

Challenge 1.2: To discover biomarkers 

that differentiate clinically relevant 

disease subtypes and that identify new 

molecular targets for application to 

prevention and diagnosis—including 

imaging, and therapy. 

Broadly defined, biomarkers encompass any characteristic 

that is objectively measured and evaluated as an indicator of 

genotype, normal biological processes, pathological processes, 

or responses to therapeutic intervention. Investigations 

addressing Challenge 1.1 will expand the list of known 

biological components in numerous cellular and physiological 

contexts. More important, they will associate the components 

with specific context-dependent functions and will identify 

previously unrecognized interactions among individual genes 

and proteins. Finally, research addressing Challenge 1.1 

will pinpoint molecules, pathways, and networks that are 

perturbed by particular disease processes. Collectively, the 

findings will enable the extension of basic science discoveries 

to the identification of markers with predictive, diagnostic, 

and prognostic power; to the validation of therapeutic targets; 

and to the characterization of pathways that are amenable to 

molecular imaging. 

1.2.a. Identify molecular signatures that allow 

complex disease phenotypes to be stratifi ed into 

clinically relevant categories. 

Traditional diagnostic criteria—including physical examination 

findings, gross and microanatomical features of affected 

tissues, or the combined results of conventional laboratory and 

radiological testing—may not reveal subtle differences among 

subtypes of a given disease. Because such distinctions can 

have important prognostic or therapeutic implications, more 

refined methods are needed to characterize what historically 

have been considered to be homogeneous disorders. It is 

becoming increasingly apparent that small sets of molecular 

markers can be used to subdivide related diseases into clinically 

meaningful classes. They also can be used to diagnose disease 

at an early stage, to predict disease progression or eventual 

regression, and to anticipate the occurrence of desirable or 

adverse therapeutic outcomes. Moreover, the biomarkers may 

themselves serve as effective drug targets or may be useful for 

monitoring and even titrating the response to specific therapies 

or prophylactic measures. Thus, the identification of new 

biomarkers forms an essential foundation for the development 

of personalized medicine. 

1.2.b. Develop in vivo molecular imaging methods 

and probes for investigating the biology of 

disease processes. 

The same knowledge base that will provide new insights 

into disease mechanisms and enable the identification of 

potential therapeutic targets also will enable the design of 

new molecular imaging probes and provide an impetus for 

the development of new imaging modalities. After initial 

development and testing in animal models, promising new 

imaging methods and reagents must be adapted for use 

in human subjects. Advances in imaging technology may 

enhance understanding of the natural history of disease and 

may have subsequent translational applications in routine 

clinical settings. 


Goal 2: To Improve Understanding 

of the Clinical Mechanisms of Disease 

and Thereby Enable Better Prevention, 

Diagnosis, and Treatment. 

To increase understanding of the clinical mechanisms of disease initiation and progression 

and to improve prevention, diagnosis, and treatment, the NHLBI has identifi ed four priority 

objectives. The fi rst is to enhance the transmission of knowledge between basic and 

clinical research so that fi ndings in one arena rapidly inform and stimulate research in the 

other. The second is to apply new approaches and technologies to develop more precise 

methods of risk-stratifi cation and diagnosis. The third is to advance the nascent fi eld 

of personalized medicine. The fourth is to enhance the evidence available to guide the 

practice of medicine and improve public health. 

Challenge 2.1: To accelerate the translation 

of basic research fi ndings into clinical 

studies and trials and to promote the 

translation of clinical research fi ndings 

back to the laboratory. 

Remarkable advances have been made in understanding 

the molecular, genetic, and cellular bases of heart, lung, 

and blood diseases, and opportunities now exist to uncover 

practical uses for this new knowledge. The application of 

the fundamental understanding of biological processes to 

prevention and management of disease requires creative 

insights into possible relationships and implications. It 

will be necessary to identify, measure, and validate targets 

and pathways that have been detected in basic studies. 


Improved animal models and new analytic approaches that 

bridge basic and clinical investigations will be needed to 

move this work along. 

2.1.a. Integrate advances in regenerative biology 

to develop clinically feasible applications. 

Allogeneic and autologous stem cells and cell-based 

therapies hold great potential for treating heart, lung, 

and blood diseases. Advances in hematopoietic stem cell 

biology and in the ability to manipulate such cells in vitro, 

including gene transfer, have moved the field closer to 

clinical application. Research is needed on the selection 

of cells and their propagation, production, dose, timing 

and method of administration; adjunctive pharmacology; 

viability after delivery; and effects on organ function, 

healing, and microvascular perfusion. Much work must

e done to define and overcome genetic and immunologic 

barriers to successful allogeneic stem cell transplantation. 

The feasibility of organ, tissue, blood vessel, and blood 

regeneration/restoration with xenogeneic and allogeneic 

cells also is ripe for further exploration. 

Tissue engineering offers the possibility of improving 

function and host response in many heart, lung, and blood 

vessel diseases through the creation of durable, functional, 

biocompatible implants. Considerable basic research (e.g., 

the development of artificial scaffolds and other tissue 

constructs or the manipulation of growth factors to generate 

an adequate supply of blood vessels and nerves) has brought 

the field to a point where testing in humans may be feasible. 

2.1.b. Apply discoveries in nanotechnology to 

the development of new diagnostic and 

therapeutic strategies. 

Drug delivery and therapeutics, molecular imaging, diagnostics 

and biosensors, and tissue engineering and biomaterials 

are all areas in which nanotechnology is expected to play 

a key role in the future. Of relevance to the NHLBI is the 

potential application of nanotechnology to the diagnosis and 

treatment of vulnerable plaque; tissue repair, engineering, and 

remodeling for the restoration of blood vessels and heart and 

lung tissue; the diagnosis, treatment, and prevention of lung 

inflammatory diseases; the development of multifunctional 

devices to monitor the body for the onset of thrombotic or 

hemorrhagic events and precisely regulate the release of 

therapeutic drugs; and the development of in vivo sensors 

to monitor patients for sleep apnea. Clinical testing of 

nanoparticles and nanodevices is not likely to begin for 5 

to 10 years, and another 5 years will probably be needed 

before materials could be used in clinical practice. However, 

applications of nanotechnology that are less invasive (e.g., 

diagnostic blood tests) could become available much sooner. 

Success in bringing nanotechnology to the bedside will depend 

on collaborations among biologists and physicians, materials 

scientists, physicists, and engineers. Particular emphasis 

should be placed on conducting the necessary preclinical and 

clinical studies to assess the potential health risks associated 

with nanotechnologies. 

2.1.c. Integrate, analyze, and share extant and 

emerging genotypic and phenotypic data. 

Biomedical research already has generated volumes of data 

from advances in “-omic” technologies and biomedical 

imaging, and an overwhelming amount of new information 

can be expected from such developments as affordable 

individual genome sequencing, real-time metabolomics, and 

electronic medical records. Realizing the full potential of these 

data will require a significant partnership between biomedical 

researchers, mathematicians, systems engineers, statisticians, 

and computer scientists. The NHLBI expects to play a key role 

in developing and supporting an information infrastructure 

that embodies comprehensive standards for biomedical 

information related to heart, lung, and blood diseases and 

sleep disorders, including controlled vocabularies, ontologies, 

data models, and data representation formats; that facilitates 

the integration of data from the molecular level to the systems 

level in health and disease; and that encourages and enables 

the broad sharing and use of research data with appropriate 

attention to privacy. 

Challenge 2.2: To enable the early and 

accurate risk stratifi cation and diagnosis of 

cardiovascular, lung, and blood disorders. 

Over the past several decades, multiple observational and 

intervention studies supported by the NHLBI have identified 

and refined the definition of risk factors for heart, lung, and 

blood disorders. Opportunities now exist to improve the 

precision of risk estimates across the lifespan for individuals 

and populations, to identify abnormalities before disease is 


clinically evident, and to develop strategies for preventing the 

development or progression of subclinical disease. Progress 

in this area hinges on the identification, measurement, and 

validation of biological pathways and targets for intervention. 

2.2.a. Exploit noninvasive imaging methods to 

detect and quantify subclinical disease. 

Many disease processes relevant to the NHLBI mission— 

plaque formation in atherosclerosis, destruction of alveoli 

in emphysema—are known to progress silently over the 

course of decades. The use of sensitive imaging technology 

would shed light on mechanisms of initiation, progression, 

and reversal of disease and would enable the measurement 

of the clinical outcomes of interventions. For example, a 

pressing need exists for advances in noninvasive imaging 

that can accurately assess risk for myocardial infarction 

before and after therapeutic intervention. Such advances not 

only could be of immediate benefit to patients but also could 

shorten the time required to test new therapeutic agents by 

reducing the need for clinical trials that rely on clinical end 

points. Similarly, better methods for imaging an evolving 

thrombus would markedly improve the diagnosis of patients 

with arterial and venous thrombosis. To make the most of 

opportunities in this area, magnetic resonance imaging, 


computerized tomography, the rapidly evolving techniques 

of molecular imaging, and other imaging modalities may be 

integrated with genomic technologies and biomarkers and 

validated in clinical trials. 

2.2.b. Apply new discoveries in biomarkers to 

improve risk assessment, diagnosis, prognosis, 

and prediction of response to therapy. 

As noted in Challenge 1.2, biomarkers are broadly defined 

to encompass any characteristic that is objectively measured 

and evaluated as an indicator of genotype, normal biological 

processes, pathological processes, or responses to therapeutic 

intervention. Biomarkers are needed in clinical medicine to 

detect early tissue injury and document disease progression. 

They may prove particularly valuable in providing clues to 

disease etiology. Focused and rapid biomarker discovery 

and validation have already yielded significant benefits for 

subgroups of patients identified as being at risk for a wide 

variety of disorders. Association studies using “-omic” 

technologies are expected to uncover many new biomarkers 

that may become useful tools for evaluating risk and 

individual responsiveness to interventions in populations 

and, ultimately, for identifying new therapeutic targets. An 

improved ability to detect subclinical diseases and monitor 

disease progression could potentially transform clinical 

decision-making and enhance the participation of patients in 

lifestyle choices and behaviors that affect clinical outcomes. 

Challenge 2.3: To develop personalized 

preventive and therapeutic regimens for 

cardiovascular, lung, and blood diseases. 

Personalized medicine is based on the concept that all 

individuals have unique characteristics defined by their 

genome and that human variability in health and disease 

is determined by genetic makeup in combination with 

environmental exposures. If the vision of personalized 

medicine becomes a reality, it will enable clinicians to select 

appropriate medications and dosages to achieve high 

efficacy and avoid adverse reactions, thereby improving 

outcomes and potentially reducing health care costs. More 

efficient drug development is also likely to result: testing 

new drugs only in patients likely to experience a benefit 

could speed the process of getting drugs to market.

2.3.a. Improve the understanding of interactions 

between genetic and environmental factors that 

infl uence disease development and progression 

and response to therapy. 

Over the past 50 years, great advances have been made in 

understanding the roles of such environmental influences 

as diet, exercise, sleep, psychosocial factors, socioeconomic 

status (SES), and air and water quality on the development 

of disease. Environmental and lifestyle or behavioral factors 

are known to contribute to the initiation or progression 

of many common disorders of the heart, lungs, and blood. 

Even single-gene disorders are now acknowledged to have 

complex genetic and environmental modifiers of expression 

and severity. Exploration of the interactions between genetic 

and environmental factors has now become essential to 

explain the development, progression, and outcome of many 

diseases. Key to success in this area will be the development 

of more precise measures of environmental exposures and 

more robust definitions of clinical phenotypes. 

The NHLBI will capitalize on its rich resource of studies that 

enable the association of whole-genome single-nucleotide 

polymorphisms with clinical phenotypes. The identification of 

such associations will enhance the understanding of complex 

traits and will permit investigators to explore the relationship 

between genetic variants, gene expression, and gene 

function. The application of these “-omic” approaches may 

lead to more sophisticated analyses of risk and individual 

responsiveness to interventions in populations. 

2.3.b. Identify and evaluate interventions to 

promote health and treat disease in genetically 

defi ned patient subgroups by altering 

developmental or environmental exposures 

including drugs, diet and exercise, sleep duration 

and quality, and infectious agents and allergens. 

Disease development and progression are influenced not 

only by genetic factors but also by developmental and 

environmental exposures. In recent years, researchers have 

focused on identifying, measuring, and understanding 

the effects of such exposures to provide a basis for the 

development of new interventions. Systems biology 

approaches for modeling the complex interactions between 

genetic and environmental factors provide valuable 

information for identifying potential interventions. Basic 

researchers are developing in vivo systems and tools for 

preclinical testing of new therapies. They are also developing 

new cell and animal models based on knowledge of 

susceptibility genotypes and relevant exposures. Large cohort 

studies that include measures of exposure to drugs, allergens, 

and infectious agents, as well as information about diet, 

exercise, sleep duration and quality, and psychosocial factors, 

offer a wealth of information for generating hypotheses. In 

the future, the value of data from basic, clinical, and cohort 

studies will be enhanced by the standardization of definitions 

of phenotypes, diseases, exposures, and outcomes. In addition, 

the creation of shared databases with information from 

multiple studies will facilitate the integration and analysis of 

results. Clinical testing of new interventions will be informed 

not only by epidemiological and basic studies of the effects 

of particular exposures but also by results of genetic and 

genomic studies that allow researchers to sort patients into 

genetically defined subgroups. Such clinical tests are expected 

to enable developmental and environmental interventions that 

are tailored to individuals. 

Challenge 2.4: To enhance the evidence 

available to guide the practice of 

medicine, and improve public health. 

The NHLBI will continue to build upon a long and distinguished 

tradition of excellence in the conduct of clinical trials to 

generate new knowledge to improve the prevention, diagnosis, 

and treatment of heart, lung, and blood diseases. Many of the 

current rigorous standards of evidence upon which practice 

guidelines are based derive from NHLBI-supported randomized 

clinical trials. The Institute remains committed to continuing 

to generate new evidence that will inform disease prevention, 



Goal 3: To Generate an Improved 

Understanding of the Processes Involved 

in Translating Research into Practice 

and Use That Understanding To Enable 

Improvements in Public Health and To 

Stimulate Further Scientifi c Discovery. 

To realize its public health objective, the Institute must fi nd ways to extend the full benefi ts 

of scientifi c advances to all of the diverse populations that constitute the American public. 

Many evidence-based approaches to prevent and treat heart, lung, and blood diseases have 

not been uniformly applied in clinical and community practice. Further research is needed on 

the translation process itself to expedite and expand the adoption of biomedical advances 

into clinical practice and individual health behaviors. The NHLBI will evaluate new ways 

to disseminate and implement proven prevention and treatment approaches to improve 

public health. Research to address issues that are directly relevant to clinical and community 

practice, such as how best to apply what is already known to be effective, is a priority. 


Opportunities exist for the NHLBI to collaborate 

with community-based practice networks to 

conduct multidisciplinary research that would 

address important behavioral issues and facilitate 

the evaluation of new approaches to prevent, 

diagnose, and treat disease. The new Clinical 

and Translational Science Awards (CTSAs) of 

the National Institutes of Health (NIH) and the 

Practice-Based Research Networks of the Agency 

for Healthcare Research and Quality both offer 

the potential for leveraging Institute resources.

Challenge 3.1: To complement bench 

discoveries and clinical trial results 

with focused behavioral and social 

science research. 

Behavioral and psychosocial factors are known to play 

an important role in the development and progression of 

heart, lung, and blood diseases. For example, diet and 

physical activity are critically involved in the development 

of cardiovascular disease risk factors, such as hypertension, 

dyslipidemia, obesity, diabetes, and untreated sleep apnea 

and reduced sleep duration, are risk factors for obesity, 

hypertension, and diabetes. The success of many therapeutic 

regimens, even highly effective ones, depends on patient 

adherence. Stress and depression are other behavioral 

factors known to be associated with cardiovascular disease 

risk and progression. 

Despite widespread recognition of the importance of 

health behaviors, only a relatively small percentage of 

adults regularly follow relevant recommendations. Because 

influences on health behaviors are diverse, ranging from 

individual (e.g., knowledge and motivation), to familial 

(e.g., expectations and role models), to environmental (e.g., 

workplace and school policies, social and cultural norms, 

and physical environments), they are best studied in complex 

environments. In the clinical setting, a widely acknowledged 

“quality gap” exists in which proven effective preventive 

and therapeutic strategies are not consistently followed, a 

function of both patient behavior and provider practice. The 

gap is greater among Americans with limited resources and 

minority groups. 

If research findings are to improve the public’s health, they 

must be translated into practice. Because it is often not clear 

how best to do so, the translation process itself needs study. 

Methods especially are needed to adapt interventions to 

address the needs of minority populations. 

3.1.a. Develop and evaluate new approaches 

to implement proven preventive and lifestyle 

interventions. 

Although research has uncovered a number of preventive 

and lifestyle interventions that are effective in small, 

controlled studies, it is often not clear how to implement 

them on a larger scale. Family- and community-based 

approaches offer particular promise for reaching much of 

the population. Although major life events (e.g., school 

transitions, entry into the workforce, retirement) often result 

in increased risk, they also may present opportunities to 

implement effective preventive strategies. Research also is 

needed to evaluate the extent to which risk stratification 

and application of personalized approaches can improve 

effectiveness. 

3.1.b. Develop and evaluate policy, environmental, 

and other approaches for use in community settings 

to encourage and support lifestyle changes. 

The successful national effort to reduce tobacco use illustrates 

the efficacy of policy and environmental approaches to 

promote healthy lifestyles. Environmental factors may also 

affect health behaviors. Examples include the influence of 

public policy decisions on physical activity, nutrition (e.g., 

portion sizes, marketing practices, retail food choices), and 

adequate sleep in students and workers. Research is needed 

to identify factors that are important influences on behavior 

and health and to determine how they can be changed in a 

cost-effective way. 


3.1.c. Develop and evaluate interventions to 

improve patient, provider, and health care system 

behavior and performance in order to enhance 

quality of care and health outcomes. 

Integrating behavioral and social sciences research with 

clinical research is crucial for developing successful strategies 

to improve health care. An improved understanding of the 

factors that influence patient, provider, and health care system 

behaviors may facilitate the development of new approaches 

to reduce the “quality gap.” A range of such interventions as 

economic incentives and performance measures for providers 

could be evaluated. Wide-scale adoption of electronic health 

records could enable tracking of the delivery and outcome of 

medical innovations, evaluation of factors that are associated 

with care-delivery patterns, and testing of new interventions. 

Studies are needed to identify and evaluate “patient-centered” 

approaches, such as incorporating patient preferences into 

clinical decision-making, and to reduce the inappropriate use 

of diagnostic tests and treatments. 


Challenge 3.2: To identify cost-effective 

approaches for prevention, diagnosis, 

and treatment. 

To achieve a substantial improvement in the health of the 

Nation, more cost-effective approaches to prevent, diagnose, 

and treat heart, lung, and blood diseases are needed. 

Research on community applications of evidence-based 

clinical practices will be undertaken to document current 

practice patterns and factors associated with high-quality 

clinical care; identify the relative contributions of secular 

trends and interventions; integrate data from rare diseases 

and newly emerging data on prevalent diseases to develop, 

evaluate, and revise evidence-based clinical best practices; 

and translate findings into educational messages for 

providers, patients, and the general public and assess their 

effects on behaviors and health status. 

3.2.a. Evaluate the risks, benefi ts, and costs of 

diagnostic tests and treatments in representative 

populations and settings. 

Surveillance systems that allow for the rapid analysis and 

communication of health status can provide data on the 

effectiveness of community-based and population-based 

interventions. Dissemination of results is the most critical 

part of the research effort, yet much remains to be learned 

about how to do so effectively. New disciplines such as 

bioinformatics may transform established public health 

education approaches. Social marketing approaches and 

diffusion-of-innovation models may provide insights that can 

help refine preventive and therapeutic efforts. The NHLBI 

will initiate collaborations and public-private partnerships to 

facilitate evaluations of new treatment approaches. The new 

CTSAs are models of interdisciplinary teams and streamlined, 

non-redundant core facilities that may transform translational 

research. Industry—including health plans, disease 

management companies, and purchasers—is a rich source of 

data and will be included in the research enterprise. Research 

on health services and outcomes can evaluate clinically 

feasible interventions to improve the delivery of evidencebased 

preventive and therapeutic approaches.

3.2.b. Develop research designs, outcome measures, 

and analytical methods to assess prevention and 

treatment programs in community and health care 

settings across populations and lifespan. 

New approaches are needed that can accommodate 

nontraditional family patterns, low SES, and immigrant 

status. The “microculture” of immigrant families, including 

their eating, drinking, and sleeping patterns, health literacy, 

and responses to major life events, can influence not only 

their interactions with the health care system but also their 

health. Successes over several decades have enabled people 

with congenital diseases to live beyond childhood, but too 

often inadequate data are available to guide their treatment 

as adults. Data systems that can characterize patient 

demographics, including SES, access to health care, patterns 

of health care use, family structure, work roles, quality of life, 

and clinical health status, could be used to identify clinical 

best practices and educate providers. Research designs and 

analytic methods are needed to enable valid analyses of 

interventions delivered at a “group” level (e.g., at worksites 

or in clinical practices) and to assess the efficacy of preventive 

interventions that seek to achieve long-term public health 

improvements through small individual changes. Evaluations 

of the cost-effectiveness of interventions require methods that 

are relevant to society as a whole and consider all relevant 

costs as well as quality of life. 

Challenge 3.3: To promote the 

development and implementation of 

evidence-based guidelines in partnership 

with individuals, professional and 

patient communities, and health care 

systems and to communicate research 

advances effectively to the public. 

Too often, evidence-based guidelines that distill the best 

available scientific knowledge into recommended actions 

for individuals, communities, and health care systems to 

improve health outcomes are not fully adopted into practice. 

Addressing this challenge will require efforts to promote the 

implementation of evidence-based guidelines by individuals, 

communities, health care providers, and public institutions; 

to influence public policy by promoting and implementing 

evidence-based guidelines; and to reduce health disparities 

with attention to personalized, community, and health 

system-oriented approaches to increase the use of proven 

preventive interventions among vulnerable subgroups. 


3.3.a. Establish evidence-based guidelines for 

prevention, diagnosis, and treatment and identify 

gaps in knowledge. 

The NHLBI will continue to exert national leadership in the 

development of evidence-based guidelines and promote 

the concept of integrated guidelines that comprehensively 

address the known, modifiable risk factors associated with a 

disease. The NHLBI will continue to take a leadership role in, 

or serve as a knowledge broker for, guideline development 

efforts and support ongoing efforts to make the most current 

scientific evidence publicly available so that professional 


organizations can develop appropriate guidelines. The 

Institute will continually assess the nature of the available 

evidence and identify areas that need additional research to 

support clinical decision-making. 

3.3.b. Develop personalized and community- 

and health care system-oriented approaches to 

increase the use of evidence-based guidelines by 

individuals, communities, health care providers, 

public institutions, and, especially, by populations 

that experience a disproportionate disease burden. 

Systems approaches will be developed to speed the 

implementation of knowledge in health care and community 

settings; foster partnerships among practitioners, patients, 

family members, community organizations, and community 

health workers; and create environments that support 

healthy choices and reduce known risk factors. Linkages 

among interested groups that previously operated 

independently will be encouraged to realize efficiencies 

through cooperation. As appropriate, the NHLBI will work 

with other government agencies and with private-sector 

organizations to encourage reliance on evidence-based 

guidelines in setting policies that affect health behaviors 

and care. Policy changes (e.g., regarding reimbursement 

practices, performance measures, and accreditation 

standards) can be highly effective in stimulating the 

development and implementation of evidence-based 

guidelines and influencing the behaviors of providers, 

patients, and health systems. School and worksite 

environments can foster improvements in lifestyle behaviors 

and risk factor screening practices. 

Substantial evidence indicates that health, SES, and 

psychosocial factors are inextricably linked and that health 

disparities exist even among individuals at the same SES 

level who are from different population groups. Efforts to 

raise the health of minority groups to the level enjoyed by 

the majority population must recognize that discrimination in 

living conditions, educational systems, health care systems, 

and work settings can adversely influence health. Because 

they share an understanding of their local environment,

including an appreciation of prevalent psychosocial factors 

and cultural beliefs, community groups and local health 

providers must be involved in efforts to promote community 

acceptance of science-based health information. Outcomes 

from community health promotion and evaluation projects 

can inform the development of new dissemination models 

at the personalized/individual, community, and health care 

system levels. The Institute will support partnerships and 

linkages that enhance the understanding of contributions of 

individual health behaviors, community-based organizational 

and environmental policies, and health systems innovations 

to reducing health disparities. 

3.3.c. Communicate research advances effectively 

to the public. 

The objective of all NHLBI public education activities is to 

motivate the audience to become active users of health 

information. The Institute will continue to investigate 

and evaluate new communication and social-marketing 

approaches to communicate research advances with the goal 

of engaging all interested parties. They include members 

of the research community who generate new knowledge; 

governmental agencies, national voluntary and professional 

organizations, credentialing bodies, and foundations that 

translate and disseminate knowledge; individuals engaged 

in clinical practice and in community programs who apply 

the science to improve health outcomes and share their 

experiences with others; and workers in the knowledge 

technology field who develop and implement new systems 

that can link various knowledge communities and promote 

performance-focused and science-based approaches. 

The Institute will continue to develop public education 

programs, as needed, to address areas of major public health 

concern, such as heart failure, partnering with professional 

societies, patient-advocacy groups, community-based 

organizations, and Federal entities to ensure that uniform 

health messages are disseminated. In addition to encouraging 

individuals and communities in health promotion and disease 

prevention efforts, the Institute will stress the importance of 

their involvement in the research process by emphasizing that 

new health-related information can be generated only with 

their cooperation and participation. 



Strategies 

Implementation of this plan will require a diversity of approaches to address the scientifi c challenges 

previously identifi ed that will enable sharing of both knowledge and resources. This section presents 

the strategies that the NHLBI intends to employ to facilitate the conduct of research; enhance 

interdisciplinary work; speed early stage translation of basic discoveries; ensure cross-fertilization of 

basic, clinical, and epidemiologic discoveries; and maximize the resultant public health benefi t of the 

information created. As the challenges identifi ed in this plan are met and as new ones emerge, the 

NHLBI will identify and embrace new strategies. The Institute also will continue to look to the NHLBAC 

and to the larger research community for guidance to ensure that these strategies are updated as 

needed to refl ect the rapidly changing environments of research and public health issues. 

As the challenges identifi ed in this plan are met and as 

new ones emerge, the NHLBI will identify and embrace 

new strategies. 

Strategies | 25

Strategy 1: Develop and facilitate access 

to scientifi c research resources. 

Lack of access to costly technologies often limits what 

individual investigators can accomplish. It is not practical for 

every laboratory, department, or even institution to develop 

many technical capabilities involving expensive equipment, 

scarce materials, large amounts of space, and specialized 

technical expertise. Such services can be more efficiently 

provided by centralized facilities that are dedicated to a 

single activity or a set of related functions and can ensure 

appropriate quality control oversight and realize economies 

of scale. Centralized facilities can also significantly enhance 

the productivity of individual investigators by allowing them to 

focus on pursuing hypothesis-driven scientific questions rather 

than on obtaining the resources needed to address them. 

Support will be provided for core genomics, proteomics, 

chemical, and RNAi screening; small-animal imaging; and 

other technologies as they become available or are requested 


by the research community. Adoption of new and cheaper 

DNA sequencing methods for large-scale re-sequencing 

projects is one example of a need that is likely to arise in the 

very near future. 

The Institute will strategically support tissue and animal 

repositories, databases, and information systems dedicated 

to the support of NHLBI projects. In creating such resources, 

careful attention will be paid to center capacity, regional 

distribution, and standardization of methods so that quality 

services are made available expeditiously to all who require 

them. Formal mechanisms will be established to ensure 

equitable access to the resources without imposing onerous 

requirements on investigators. 

Strategy 2: Develop new technologies, 

tools, and resources. 

In addition to making existing technologies widely available, 

the NHLBI will continue to invest in the development of 

new methods for laboratory investigations. Areas requiring 

attention include genomics; proteomics; metabolomics; 

bioinformatics (especially integrative computational 

tools); imaging probes and modalities (for studies at the 

level of whole animals, cells, and individual molecules); 

nanotechnology; tissue engineering; gene knock-out, knockdown, 

and knock-in methods in whole animals; and gene 

and cell-based therapies. 

Animal models are a critical resource. Support is required 

for efforts to create new animal models that closely emulate 

the pathology of human disorders and that can be used not 

only for mechanistic investigations but also for evaluations 

of new therapies. The need for new animal models is certain 

to expand rapidly, as additional human disease susceptibility 

genes are discovered in genome-wide association studies. 

To accommodate the increased need, new experimental 

approaches for qualitatively and quantitatively perturbing 

model organism orthologs and for studying interacting 

genetic and non-genetic factors will be required. 

Given that the new technologies, tools, and resources needed 

by NHLBI investigators also will be used by investigators who 

are supported by other funding sources, opportunities for their 

development through partnering arrangements—with other 

NIH components as well as with other government agencies 

and with private sector organizations—will be explored. 

The NHLBI also will undertake projects that complement and 

extend other resource development efforts, as exemplified by

such existing programs as the Pharmacogenetics Research 

Network and the Knockout Mouse Project, and perhaps 

enable the development of new collaborative networks or 

other approaches to stimulate preclinical efforts. By seeking 

involvement in additional research opportunities of this type, 

the NHLBI can both enhance community-wide activities 

and provide valuable resources for the benefit of its own 

investigators, thereby yielding benefits for all interested parties. 

Strategy 3: Increase the return from NHLBI 

population-based and outcomes research. 

The NHLBI has made extensive and highly productive 

investments in population-based and outcomes research 

that have not only addressed specific scientific questions but 

also provided real-world perspectives on disease burden, 

risk factors, and the effectiveness of medical care. If the full 

value of these studies is to be realized, however, the Institute 

must address several critical needs. 

The Institute will take a leadership role in developing national 

standards for nomenclature and informatics to facilitate the 

sharing of phenotypic data. Common collection methods, 

definitions, and exchange formats for data are needed to 

enable linkages among studies of complex diseases. Data 

from studies that are not large enough individually to 

examine gene-environment interactions, risks and benefits of 

interventions, or risk factor associations in subgroups could 

be pooled to address those issues. Nomenclature standards 

that are easily implemented, universally accessible, broadly 

applicable, and yet flexible enough to accommodate advances 

in technology and science (e.g., newly identified risk factors 

and disease end points) are needed. Data repositories that 

include informatics tools for data analysis and promote 

data-sharing (while ensuring data security and participant 

confidentiality) are needed. 

The Institute will selectively complement ongoing 

surveillance of local and national incidence, prevalence, 

practice patterns, and outcome measures in diverse 

populations. Up-to-date figures are critical for detecting 

important scientific and public health trends, and they also 

can be used to uncover health disparities and monitor 

efforts to reduce them. Documentation of the influence 

of sociocultural environments, psychosocial traits and 

stressors, lifestyles, economic resources, access to health 

care, and other factors can reveal pathways that contribute 

to disease burden and therapeutic response. Surveillance 

of practice patterns can enable assessment of the effects of 

clinical guidelines on physician prescribing practices and can 

facilitate the identification of barriers to implementing best 

practices. Efforts will focus on enhancing and combining 

data from existing data collection systems, partnering 

with public and private organizations that collect and use 

electronic health information (e.g., insurers, large health care 

systems, other government agencies), and developing new 

approaches to capture data in diverse populations. 

The value of existing studies could be enhanced by adding 

new genetic, social, environmental, and psychological 

measures. Because even such well-defined environmental 

exposures as smoking have been difficult to measure, this 

effort may call for new technologies to enable accurate 

assessments of risk. New analytic methods are needed to 

integrate the large volumes of data obtained in population 

research to permit examinations of gene-environment and 

gene-gene interactions and of reversible heritable changes in 

gene function. Population studies can provide an appropriate 

context for evaluating and translating new technologies 

for imaging and “-omics” into clinical applications. The 

introduction of “-omics” technologies into population studies 

will require interactions among epidemiologists, geneticists, 

clinicians, bioinformaticians, statisticians, and “-omics” 

scientists and the creation of new resources to be shared 

with the scientific community in a manner consistent with 

participant consent. Large-scale “-omics” studies are likely to 

require new paradigms, including public-private partnerships. 

Strategies | 27

Strategy 4: Establish and expand 

collaborative resources for clinical research. 

Coordinated resources are needed to facilitate the conduct 

of disease-oriented studies and speed the application of 

basic science observations to clinical problems. The network 

approach to translational and clinical research has been 

successful and will be expanded to additional areas of science. 

Disease-oriented Internet portals could enable access to 

information and tools for use in research and patient care. 

They would serve not only as an essential resource for 

integrative understanding of heart, lung, and blood disorders 

but also as a stimulus for community-wide collaborations. 

To be effective, portals must be interoperable with other 

data and information resources to allow users to develop 

a comprehensive understanding of relevant diseases, 

particularly multi-system and multi-organ syndromes. They 

also will facilitate the sharing and linking of disparate data 

types (e.g., sequences, single nucleotide polymorphisms, 

phenotypes, disease mechanisms) and the development of 

data-management tools, strategies for analysis, and datavisualization 

approaches. 

The new NIH network of CTSAs offers great promise for 

investigators interested in conducting research in community 

settings, affording them access to an integrated and organized 

resource. A serious challenge for the NHLBI continues to 

be the delay typically experienced between the time that an 


intervention is shown to be effective and when it is broadly 

adopted by health practitioners, patients, and the public. One 

potential way to reduce the delay would be to encourage 

broader community involvement in research to increase the 

general awareness of ongoing studies and increase interest 

in research outcomes. The Institute views the CTSAs as an 

important resource for stimulating community involvement in 

clinical research whenever appropriate. 

Strategy 5: Extend the infrastructure for 

clinical research. 

The NHLBI will develop a comprehensive process for 

establishing priorities for large clinical trials. As part of 

the process, advice will be solicited from a broad range 

of interested parties, including individual investigators, 

expert panels, industry, other Federal agencies (e.g., 

Centers for Medicare and Medicaid Services, Food and 

Drug Administration), patients, and nonacademic medical 

practitioners through their professional societies. Also 

needed are explicit criteria to be used in deciding among 

proposed trials to ensure that the most pressing questions 

are addressed. Establishing standards for the design, 

conduct, and interpretation of clinical studies and trials will 

ensure that the answers are scientifically valid and applicable 

to diverse populations. 

The process of initiating and conducting clinical trials will 

be refined. Templates and educational materials will be 

developed to guide clinical trial investigators as they pursue 

a research idea from study design to implementation. 

Standardized definitions of end points and adverse events, 

streamlined reporting procedures of adverse events, and 

improved methods for analyzing data from early-phase trials 

are also needed. Controlled vocabularies, ontologies, data 

models, and data representation formats will be developed 

for major areas within the Institute’s mission to enable 

data sharing and study comparisons. NHLBI-supported 

researchers will be encouraged to adopt the same Federal 

standards already used by clinical systems in order to 

facilitate the research use of data stored in clinical databases 

within health care organizations. In addition, the NHLBI will 

work with other components of the NIH and the Department 

of Health and Human Services toward facilitating clinical 

research by reducing the regulatory burden associated with 

the initiation and conduct of clinical studies.

The scientific return from the Institute’s substantial 

investments in time and resources represented by large-scale 

clinical trials can be increased by facilitating important 

ancillary studies. In addition to providing mechanisms for the 

timely funding of ancillary studies not included in the original 

trial protocol, efficiency may be gained by incorporating 

substudies of known broad interest and applicability into the 

initial funding action. Ancillary studies to validate imaging 

findings and biomarkers with clinical outcomes, studies that 

establish repositories for use by the research community, and 

biostatistical methodology development will be included in 

the initial design of trials whenever possible. The Institute 

also recognizes the value of community- and practice-based 

research and their potential for further increasing the return 

on its clinical trial investments, and it will continue to 

encourage and support such efforts. 

Strategy 6: Support the development of 

multidisciplinary teams. 

Interdisciplinary collaborations are becoming ever more 

critical to all areas of research related to the mission of the 

NHLBI. Increasingly, clinicians and biologists are requiring the 

expertise of individuals in quantitative disciplines, including 

computer science, mathematics, physics, and engineering. 

The NHLBI encourages this trend by including in research 

initiatives, wherever appropriate, a requirement that diverse 

groups of scientists be assembled to work together on a 

common problem. The Institute will consider supporting 

“virtual centers” to enable collaborations that are focused 

on expertise and are independent of geography. Given the 

currently available electronic and Web-based communication 

technologies, geography is no longer a barrier. 

Development of multidisciplinary teams will require greater 

recognition in the research community, and especially in 

universities and medical schools, of the accomplishments 

of groups rather than individuals. It will also likely entail 

collaborations on research programs among the various 

Institutes and Centers of the NIH. To facilitate the transition to 

and acceptance of this new research paradigm, the NHLBI and 

other funding agencies will have to work closely with academic 

institutions to ensure that proper recognition is accorded to all 

participants. Acknowledging the value and appropriateness of 

a co-principal investigator in individual research project grants 

is a good start, but more needs to be done. 

One approach to promoting interdisciplinary research is for 

the NHLBI to establish seed funding for Research Centers 

of Excellence. By providing infrastructure support, Centers 

can serve as a focal point within an institution for research 

in heart, lung, and blood diseases as well as attract the 

interest of investigators who are unaffiliated with the Center 

but who have potentially related skills and expertise. To 

ensure the greatest return on Research Centers of Excellence, 

eligibility could be limited to institutions that have been 

selected for the CTSA, with NHLBI funding provided to 

enhance the CTSA in areas relevant to the Institute’s mission. 

Consideration will be given to limiting the period of NHLBI 

support for a Center, to requiring recipient institutions to 

provide some level of matching funds for the entire award 

term, and to requiring the institutions to present a plan for 

transition to continue funding of the Center beyond the 

period of NHLBI Center support. 

Strategies | 29

Strategy 7: Develop and retain 

human capital. 

The NHLBI and the heart, lung, and blood research 

community have experienced increasing challenges in the 

recruitment of young scientists. The Institute is committed to 

extending the reach of its educational efforts to elementary 

and high school students, and it will continue to expand 

its support of science education in the schools to ensure a 

steady supply of enthusiastic and creative young scientists. 

To ensure the continued advance of knowledge related to 

heart, lung, and blood diseases, the NHLBI must enable 

a constant renewal of the research workforce. To that 

end, the NHLBI supports training and career development 


opportunities for scientists at all career stages. Scientists 

today are called upon to master increasingly complex 

technologies, including quantitative methods that may not 

have been part of their training. The Institute not only will 

encourage inclusion of courses in statistics and other types of 

mathematical analysis in postdoctoral training for scientists 

in biomedical disciplines but also will enable hands-on 

training experiences in relevant quantitative areas. To avoid 

extending what is already a lengthy training experience for 

most scientists, the added materials will be accompanied 

by measures to shorten the overall training period, such as 

providing incentives to both mentors and trainees who meet 

certain milestones. 

To afford scientists with expertise in quantitative and 

analytical areas the opportunity to contribute to biomedical 

research, the Institute will offer programs to enable them 

to acquire relevant basic biomedical knowledge. One way 

of doing so would be to foster reciprocal cross-training 

during the postdoctoral years for individuals with predoctoral 

training in biomedical disciplines and quantitative disciplines. 

This could also serve as a stimulus for interdisciplinary 

studies among the next generation of scientists. 

New investigators face the challenge of obtaining a first 

individual research project grant (R01) in competition 

with applications from more experienced individuals. The 

NHLBI will continue its policy of giving new investigators 

an advantage by funding them at higher pay scales and 

ensuring expedited re-review of applications that are highly 

meritorious but do not receive funding on first submission. 

The NHLBI recognizes the critical role of mentoring to 

ensure success in research careers and will work with host 

institutions to develop new approaches to foster mentoring 

for young faculty members. The Institute also recognizes that 

initial funding for a new investigator is often not sufficient 

to establish a research career; the first competing renewal 

is critical. Partial bridge funding, perhaps in a cost-sharing 

mechanism with host institutions, might provide adequate 

support for an unsuccessful applicant to maintain a research 

program, while a revised application is pending. 

The Institute recognizes its obligation to established scientists. 

They often are required to develop new skills to respond to 

changes in research directions and new scientific opportunities. 

Training programs of “continuing biomedical education” and 

support for mini-sabbaticals are two possible approaches to 

aid established investigators in acquiring needed expertise.

Strategy 8: Bridge the gap between 

research and practice through 

knowledge networks. 

The NHLBI has a long history of establishing and maintaining 

networks to fulfill its mandate to translate science-based 

information into clinical practice and public health behavior. 

The Institute will explore new network approaches to promote 

collaborations among researchers that enable them to develop 

evidence-based initiatives to improve public health. 

The NHLBI will create individual knowledge networks focused 

on disease priorities—based on their burden to society—to 

connect researchers to health practitioners by facilitating 

interaction among those who generate new knowledge, those 

who translate and disseminate it, and those who use it. The 

networks will provide an avenue for identifying knowledge 

gaps that need to be addressed by future research and 

for speeding translation into practice through use of more 

effective approaches to synthesizing and organizing evidence. 

It is expected that knowledge networks will constitute a public 

resource that will enable research and prevention programs 

internationally as well as domestically. Development of a 

Cardiovascular Knowledge Network (CKN) is the first step. 

The knowledge network concept can then be expanded to 

encompass other diseases based on the lessons learned in the 

first 3 years of operation of the CKN. 

The CKN will require a new informatics infrastructure that 

supports knowledge-sharing and rapid interaction between 

researchers and practitioners as well as close surveillance 

of cardiovascular health data to guide research and 

development of preventive efforts, particularly for selected 

populations. Other important aspects include community 

strategies that pool resources to create environments that 

support healthy choices and reduce known risk factors over 

the entire lifespan, incentives to stimulate the adoption of 

beneficial behaviors, personalized health care strategies 

that address individual needs, and social marketing 

communication strategies to promote social norms that 

improve cardiovascular health. 

Broad scientific literacy is essential to enable full public 

participation in policy decisions posed and informed by 

scientific advances and full individual participation in the 

active maintenance and management of their own health. 

Citizens, patients, family members, and investors must be 

able to critically evaluate new information, assess areas of 

ambiguity, and appreciate the implications of personal and 

public decisions related to health. The NHLBI will participate 

in improving science education in elementary and secondary 

schools and in improving higher education for nonscientists 

as well as scientists. 

Strategies | 31

Appendix—Participants 

Edward Abraham, M.D. 

University of Alabama at 

Birmingham 

Michael Acker, M.D. 

University of Pennsylvania 

Christine M. Albert, M.D. 

Brigham and Women’s Hospital 

Jean-Pierre Allain, M.D. 

University of Cambridge 

Laura Almasy, Ph.D. 

Southwest Foundation for 

Biomedical Research 

Garnet Anderson, Ph.D. 

Fred Hutchinson Cancer 

Research Center 

Margaret Anderson 

The Center for Accelerating 

Medical Solutions 

Mark E. Anderson, M.D., Ph.D. 

University of Iowa 

Derek C. Angus, M.D. 

University of Pittsburgh 

Elliot Antman, M.D. 


Lawrence J. Appel, M.D., M.P.H. 

Johns Hopkins University 

Andrea Apter, M.D., M.Sc. 


Donna Arnett, Ph.D. 

University of Alabama at Birmingham 

Bruce J. Aronow, Ph.D. 

Cincinnati Children’s Hospital 

Medical Center 

Mara G. Aspinall, M.B.A. 

Genzyme Genetics 

Larry Atwood, Ph.D. 

Boston University 

James AuBuchon, M.D. 

Dartmouth-Hitchcock 


Grover C. Bagby, Jr., M.D. 

Oregon Health and 

Science University 

Raymond D. Bahr, M.D. 

St. Agnes Healthcare System 

James Baker, M.D. 

University of Michigan 

H. Scott Baldwin, M.D. 

Vanderbilt University 

Christie Ballantyne, M.D. 

Baylor College 

Tom Baranowski, Ph.D. 

Baylor College of Medicine 

Barbara E. Barnes, M.D. 


Ted Barrett, Ph.D. 

Lovelace Respiratory Research Institute 

William A. Baumgartner, M.D. 


Dan Beard, Ph.D. 

Medical College of Wisconsin 

Michael J. Becich, M.D., Ph.D. 


John Belperio, M.D. 

University of California, Los Angeles 

Emelia J. Benjamin, M.D., Sc.M. 


Ivor J. Benjamin, M.D. 

University of Utah 

Susan Bennett, M.D. 

George Washington University 

Raymond L. Benza, M.D. 


Gordon R. Bernard, M.D. 


Donald Berry, Ph.D. 

University of Texas 

Ronald Bialek, M.P.P. 

The Public Health Foundation 

Celso Bianco, M.D. 

America’s Blood Centers 

Joyce Bischoff, Ph.D. 

Children’s Hospital Boston 

Peter B. Bitterman, M.D. 

University of Minnesota 

Henry R. Black, M.D. 

Rush University 

Henry W. Blackburn, M.D. 


Judith Blake, Ph.D. 

The Jackson Laboratory 

Bruce Q. Blazar, M.D. 


David A. Bluemke, M.D., Ph.D. 


Neil Blumberg, M.D. 

University of Rochester 


Eric Boerwinkle, Ph.D. 


Roberto Bolli, M.D. 

University of Louisville 

Robert Bonow, M.D. 

Northwestern University 

Jeffrey Borer, M.D. 

Cornell University 

Richard Boucher, M.D. 

University of North Carolina at 

Chapel Hill 

Janice Bowie, Ph.D., M.P.H. 


Eugene Braunwald, M.D. 

Harvard University 

Bruce E. Bray, M.D. 


Paul Bray, M.D. 

Jefferson Medical College 

Malcolm K. Brenner, M.D., Ph.D. 


Patrick Breysse, Ph.D. 


James Bristow, M.D. 

Joint Genome Institute 

Michael Bristow, M.D., Ph.D. 

University of Colorado 

V. Courtney Broaddus, M.D. 

University of California, San Francisco 

Colleen Brophy, M.D. 

Arizona State University 

Ronald T. Brown, Ph.D. 

Temple University 

Hal E. Broxmeyer, M.D., Ph.D. 

Indiana University 

George Buchanan, M.D. 

University of Texas Southwestern 

Esteban E. Burchard, M.D. 


Julie Buring, M.D. 


Gregory C. Burke, M.D., M.Sc. 

Wake Forest University 

John C. Burnett, Jr., M.D. 

Mayo Clinic 

Helen Burstin, M.D., M.P.H. 

Agency for Healthcare Research 

and Quality 

Michael Busch, M.D., Ph.D. 

Blood Centers of the Pacific 

William W. Busse, M.D. 

University of Wisconsin Hospital 

Robert Byington, Ph.D. 


Michael Cabana, M.D. 


Robert M. Califf, M.D. 

Duke University 

Blase A. Carabello, M.D. 

Michael E. DeBakey Veterans Affairs 


James Casella, M.D. 


Margaret O. Casey, R.N., M.P.H. 

National Association of Chronic 

Disease Directors 

Patricia Casey 

Kaiser Permanente Medical Group 

C. Thomas Caskey, M.D. 

University of Texas Health 

Science Center 

Mario Castro, M.D. 

Washington University 

Oswaldo Castro, M.D. 

Howard University 

Sule Cataltepe, M.D. 


Juan Celedon, M.D., Dr.P.H. 


David M. Center, M.D. 


Aravinda Chakravarti, Ph.D. 


Peng-Sheng Chen, M.D. 

Cedars-Sinai Medical Center 

Linzhao Cheng, Ph.D. 


Kenneth R. Chien, M.D., Ph.D. 

Richard B. Simches Research Center 

Aram V. Chobanian, M.D. 


David C. Christiani, M.D., M.P.H. 


Douglas B. Cines, M.D. 


William Clarke, M.D., M.Sc. 

Cellectar, LLC

Alexander W. Clowes, M.D. 

University of Washington 

Thomas D. Coates, M.D. 

Children’s Hospital Los Angeles 

Thomas M. Coffman, M.D. 


Alan R. Cohen, M.D. 

Children’s Hospital of Philadelphia 

Larry Cohen 

Prevention Institute 

Barry S. Coller, M.D. 

Rockefeller University 

Alfred F. Connors, M.D. 

Case Western Reserve University 

Richard S. Cooper, M.D. 

Loyola University 

Janet M. Corrigan, Ph.D. 

The National Quality Forum 

Maria R. Costanzo, M.D. 

Edward Cardiovascular Institute 

Shaun R. Coughlin, M.D., Ph.D. 

University of California, 

San Francisco 

Allen W. Cowley, Jr., Ph.D. 


James Crapo, M.D. 

National Jewish Medical and 


Michael H. Criqui, M.D., M.P.H. 

University of California, San Diego 

Jose Cruz, D.Sc. 

Pan American Health Organization 

Ronald G. Crystal, M.D. 


Ann B. Curtis, M.D. 

University of South Florida 

William C. Cushman, M.D. 

Memphis Veterans Administration 


A. Jamie Cuticchia, Ph.D. 


Mark Daly, Ph.D. 

Whitehead Institute 

Stephen R. Daniels, M.D., Ph.D. 


Martha L. Daviglus, M.D., Ph.D. 


Barry Davis, M.D., Ph.D. 


Ron Davis, Ph.D. 

Stanford University 

Robin L. Davisson, Ph.D. 


Pedro J. del Nido, M.D. 


Elizabeth DeLong, Ph.D. 

Duke Clinical Research Institute 

Dawn DeMeo, M.D., M.P.H. 


David DeMets, Ph.D. 

University of Wisconsin 

Edward C. Dempsey, M.D. 


Health Sciences Center 

Loren C. Denlinger, M.D., Ph.D. 


Richard Devereux, M.D. 


Gregory Diette, M.D. 


Ana V. Diez-Roux, M.D., Ph.D. 


John P. DiMarco, M.D. 

University of Virginia 


Stephanie Dimmeler, Ph.D. 

Johann Wolfgang Goethe 

University Frankfurt 

Robert S. Dittus, M.D. 


Roger Dodd, Ph.D. 

Jerome H. Holland Laboratory 

Claire M. Doerschuck, M.D. 


Gerald Dorn II, M.D. 

University of Cincinnati 

Ivor Douglas, M.D., M.R.C.P. 



Pamela S. Douglas, M.D. 

Duke University Medical Center 

George J. Dover, M.D. 


Wonder Drake, M.D. 


Jeffrey M. Drazen, M.D. 

New England Journal of Medicine 

Dennis Drotar, Ph.D. 


Victor J. Dzau, M.D. 


Walter Dzik, M.D. 

Massachusetts General Hospital 

James Eckman, M.D. 

Emory University 

Kim A. Eagle, M.D. 


Jack A. Elias, M.D. 

Yale University 

Susan Ellenberg, Ph.D. 


Mark C. Ellisman, M.D. 

University of California at San Diego 

John Engelhardt, Ph.D. 


Serpil C. Erzurum, M.D. 


Thomas Eschenhagen, Ph.D. 

University Hospital, 

Eppendorf, Germany 

Charles T. Esmon, Ph.D. 

Oklahoma Medical 

Research Foundation 

David Evans, Ph.D. 

Columbia University 

Ronald M. Evans, Ph.D. 

The Salk Institute 

John V. Fahy, M.D. 


Zahi Fayad, Ph.D. 

Mount Sinai School of Medicine 

Donald O. Fedder, Dr.P.H. 

Society for Public Health Education 

Ted Feldman, M.D. 

Evanston Northwestern Healthcare 

Keith Ferdinand, M.D. 

Association of Black Cardiologists, Inc. 

Victor Ferrari, M.D. 



Patricia Finn, M.D. 


John R. Finnegan, Jr., Ph.D. 


Adolfo Firpo, M.D. 

Uniformed Services University 

Garret FitzGerald, M.D. 


Kevin R. Flaherty, M.D., M.S. 

University of Michigan Health System 

Kathy Foell, M.S., R.D. 

Massachusetts Department of 

Public Health 

John Fontanesi, Ph.D. 


Myriam Fornage, Ph.D. 

University of Texas Health Sciences 

Center at Houston 

Charles K. Francis, M.D. 

Robert Wood Johnson Medical School 

James Frank, M.D. 


Paul S. Frenette, M.D. 


Carol Lynne Freund, Ph.D. 

Meharry Medical College 

Felix Frueh, M.D. 

Food and Drug Administration 

Sherrilynne Fuller, Ph.D. 


Barbara Furie, Ph.D. 

Beth Israel Deaconess Medical Center 

Bruce C. Furie, M.D. 


Brian F. Gage, M.D., M.Sc. 


Patrick G. Gallagher, M.D. 


Joe G. N. Garcia, M.D. 

University of Chicago 

Daniel Gardner, Ph.D. 


Thomas A. Gaziano, M.D., M.Sc. 


Adrian P. Gee, Ph.D. 


Bruce Gelb, M.D. 


James N. George, M.D. 

University of Oklahoma 

James E. Gern, M.D. 


Hertzel Gerstein, M.D. 

McMaster University 

Appendix | 33

Robert E. Gerszten, M.D. 


Saghi Ghaffari, M.D., Ph.D. 


Patricia J. Giardina, M.D. 


Gary H. Gibbons, M.D. 

Morehouse School of Medicine 

Richard Gibbs, Ph.D. 


Don Giddens, Ph.D. 

Georgia Institute of Technology 

Henry N. Ginsberg, M.D. 


David Ginsburg, M.D. 

University of Michigan Medical Center 

Geoffrey Ginsburg, M.D., Ph.D. 


Christopher K. Glass, M.D., Ph.D. 


Alan Go, M.D. 

Kaiser Permanente of 

Northern California 

David Goff, M.D., Ph.D. 


Ary Goldberger, M.D. 


Lee Goldman, M.D., M.P.H. 


Pascal Goldschmidt, M.D. 

University of Miami 

Steven A. N. Goldstein, M.D., Ph.D. 


Steven Goodman, M.D., 

Ph.D., M.H.S. 


Philip B. Gorelick, M.D., M.P.H. 

University of Illinois 

Robert C. Gorman, M.D. 


Jerome Gottschall, M.D. 

Blood Center of Wisconsin 

Darryl T. Gray, M.D., Sc.D. 


and Quality 

David Green, M.D. 


Ronald M. Green, Ph.D. 

Dartmouth College 

Phyllis Greenberger 

Society for Women’s Health Research 

A. Gerson Greenburg, 

M.D., Ph.D. 

Brown University 

Sheldon Greenfield, M.D. 

University of California, Irvine 

Philip Greenland, M.D. 


Bartley Griffith, M.D. 

University of Maryland 

Theresa Guilbert, M.D. 

University of Arizona 

Gordon Guyatt, M.D. 


Neil R. Hackett, Ph.D. 


Roger Hajjar, M.D. 


Kasturi Haldar, M.D. 


John E. Hall, Ph.D. 

University of Mississippi 


Mary M. Hand, M.S.P.H., R.N. 


and Quality 

Richard Harding, Ph.D. 

Monash University, Clayton Campus 

Joshua M. Hare, M.D. 


John Harlan, M.D. 


Robert Harrington, M.D. 

Duke Clinical Research Institute 

David G. Harrison, M.D. 


Kevin Harrod, Ph.D. 

Lovelace Respiratory Research Institute 

Kathryn Hassell, M.D. 



Barbara Hatcher, Ph.D., 

M.P.H., R.N. 

American Public Health Association 

Jack J. Hawiger, M.D., Ph.D. 


Robert P. Hebbel, M.D. 



Adriana Heguy, Ph.D. 


John A. Heit, M.D. 

Mayo Clinic 

Frances Henderson, R.N., Ed.D. 

Consultant 

Katherine A. High, M.D. 


Christopher Hillyer, M.D. 

Emory University Hospital Blood Bank 

Alan T. Hirsch, M.D. 


Mark A. Hlatky, M.D. 


Helen H. Hobbs, M.D. 

University of Texas Southwestern 


Judith S. Hochman, M.D. 

New York University 

Brigid Hogan, Ph.D. 


David R. Holmes, M.D. 

Mayo Clinic 

Susan R. Hopkins, M.D., Ph.D. 


Keith Horvath, M.D. 

Suburban Hospital 

Edwin M. Horwitz, M.D., Ph.D. 

St. Jude Research Hospital 

Catherine L. Hough, M.D., M.Sc. 


Thomas Howard, M.D. 

University of Alabama Medical Center 

Judith Hsia, M.D. 

George Washington University 

Leonard D. Hudson, M.D. 


Peter J. Hunter, Ph.D., M.E. 

University of Auckland, New Zealand 

Steven Idell, M.D., Ph.D. 


David H. Ingbar, M.D. 


Silviu Itescu, M.B.B.S., M.D. 


Howard J. Jacob, Ph.D. 


Robert L. Jesse, M.D., Ph.D. 

McGuire Veterans Affairs 


Alan Jobe, M.D., Ph.D. 

Children’s Hospital 


Jennie R. Joe, Ph.D., M.P.H., M.A. 


Cage Johnson, M.D. 

University of Southern California 

Clinton H. Joiner, M.D., Ph.D. 


Hoxi J. Jones 

Texas Health and Human 

Services Commission 

Robert Jones, M.D. 

New York Blood Center 

Wanda K. Jones, Dr.P.H. 

Department of Health and 

Human Services 

Rudy Juliano, Ph.D. 

University of North Carolina 

Mark L. Kahn, M.D. 


Robert Kaplan, Ph.D. 


George Karniadakis, Ph.D. 

Brown University 

David A. Kass, M.D. 


Robert S. Kass, Ph.D. 


Kathy Kastan, L.C.S.W., M.A.Ed. 

The National Coalition for Women 

with Heart Disease 

David L. Katz, M.D., M.P.H. 


Steven Kawut, M.D., M.S. 


Armand Keating, M.D. 

Princess Margaret Hospital, Canada 

Steven H. Kelder, Ph.D., M.P.H. 


Health Science Center at Houston 

Catarina Kiefe, M.D., Ph.D. 

University of Alabama 

Carla F. Kim, Ph.D. 

Massachusetts Institute of Technology

Talmadge E. King, Jr., M.D. 

San Francisco General Hospital 

John P. Kinsella, M.D. 



Richard N. Kitsis, M.D. 

Yeshiva University 

Michael Knowles, M.D. 


Chapel Hill 

Kenneth Knox, M.D. 


Walter J. Koch, Ph.D. 

Thomas Jefferson University 

Thomas Kodadek, Ph.D. 


Southwestern Medical Center 

Isaac Kohane, M.D., Ph.D. 


Donald B. Kohn, M.D. 


Barbara Konkle, M.D. 


Greg Koski, M.D., Ph.D. 


Laura Koth, M.D. 


Daryl N. Kotton, M.D. 


Mark Krasnow, M.D., Ph.D. 


Jerry Krishnan, M.D., Ph.D. 


Harlan M. Krumholz, M.D., S.M. 


Rita Kukafka, Dr.P.H., M.A. 


Thomas Kulik, M.D. 

C.S. Mott Children’s Hospital 

Shiriki K. Kumanyika, Ph.D., M.P.H. 


Steve Kunkel, Ph.D. 


Peter Kurre, M.D. 

Oregon Health and Science University 

Rebecca Kush, Ph.D. 

Clinical Data Standards 

Interchange Consortium 

Robert Kushner, M.D. 


Frans Kuypers, Ph.D. 


Oakland Research Institute 

Darwin R. Labarthe, M.D., 

Ph.D., M.P.H. 

Centers for Disease Control 

and Prevention 

Peter Lane, M.D. 


Albert Lardo, Ph.D., F.A.H.A 

Johns Hopkins Hospital 

Eric B. Larson, M.D., M.P.H. 

Center for Health Studies 

Philippe Leboulch, M.D. 


Richard T. Lee, M.D. 


Branka Legetic, M.D., Ph.D., M.P.H. 

World Health Organization 

Susan Leibenhaut, M.D. 


Leslie Leinwand, Ph.D. 


Robert F. Lemanske, Jr., M.D. 

University of Wisconsin at Madison 

Kam W. Leong, Ph.D. 


Andrew Levey, M.D. 

Tufts University 

Sanford Levine, M.D. 


Robert Levy, M.D. 

Abramson Research Center 

Peter Libby, M.D. 


Richard P. Lifton, M.D., Ph.D. 


Stephen B. Liggett, M.D. 


Karen Lipton, J.D. 

American Association of Blood Banks 

Peter Liu, Ph.D. 

Canadian Institute of Health Research 

Donald Lloyd-Jones, M.D., Sc.M. 


Jose A. Lopez, M.D. 

Puget Sound Blood Center 

Joseph Loscalzo, M.D., Ph.D. 


Douglas W. Losordo, M.D. 

Caritas St. Elizabeth’s Medical Center 

Richard Lottenberg, M.D. 

University of Florida 

James E. Loyd, M.D. 


Naomi Luban, M.D. 

Children’s National Medical Center 

Bertram Lubin, M.D. 


Oakland Research Institute 

Russell V. Luepker, M.D. 


Nigel Mackman, Ph.D. 

Scripps Research Institute 

Richard T. Mahon, M.C., U.S.N.R. 

Naval Medical Research Center 

Marilyn J. Manco-Johnson, M.D. 


Douglas Mann, M.D. 


Kenneth Mann, Ph.D. 

University of Vermont 

Catherine Scott Manno, M.D. 


JoAnn Manson, M.D., Dr.P.H. 


Eduardo Marban, M.D., Ph.D. 


Thomas A. Marciniak, M.D. 


Victor Marder, M.D. 


Daniel B. Mark, M.D., M.P.H. 


Andrew R. Marks, M.D. 


Thomas R. Martin, M.D. 


Fernando D. Martinez, M.D. 


Donald J. Massaro, M.D. 

Georgetown University 

Barry Massie, M.D. 


Michael Matthay, M.D. 


Karen Matthews, Ph.D. 


Paul Mazmanian, Ph.D. 

Virginia Commonwealth University 

Patrick E. McBride, M.D., M.P.H. 


Andrew McCulloch, Ph.D. 


Jeffrey McCullough, M.D. 


Mary McDermott, M.D. 


Rodger McEver, M.D. 

Oklahoma Medical 


Richard McFarland, M.D. 


J. Michael McGinnis, M.D., M.P.P. 

Institute of Medicine at the 

National Academies 

James M. McKenney, Pharm.D. 

National Clinical Research 

Ann McKibbon, Ph.D., M.L.S. 


Bruce M. McManus, M.D., Ph.D., 

F.R.S.C., F.C.A.H.S. 

St. Paul’s Hospital, Canada 

Elizabeth M. McNally, M.D., Ph.D. 


Robert McNellis, M.P.H., PA-C 

American Academy of 

Physician Assistants 

Amy Melnick 

Heart Rhythm Society 

Michael E. Mendelsohn, M.D. 

New England Medical Center 

Hospitals, Inc. 

Jay Menitove, M.D. 

Community Blood Center 

Mark Mercola, Ph.D. 

The Burnham Institute 

Takashi Mikawa, Ph.D. 


Lisa A. Miller, Ph.D. 

University of California, Davis 

John Mittler, Ph.D. 


Alicia Moag-Stahlberg 

Action for Healthy Kids 

Appendix | 35

David R. Moller, M.D. 


Anne M. Moon, M.D., Ph.D. 


Jonathan D. Moreno, Ph.D. 


David Morris, M.D. 

Roche Pharmaceuticals 

Heather Morris 

National Association for Sport and 

Physical Education 

Edward E. Morrisey, Ph.D. 


Lori J. Mosca, M.D., Ph.D., M.P.H. 


Arthur J. Moss, M.D. 


Jay Moskowitz, Ph.D. 

Pennsylvania State University 

Albert George Mulley, M.D. 


William Munier, M.D. 


and Quality 

David Murray, Ph.D. 

Ohio State University 

Thomas H. Murray, Ph.D. 

The Hastings Center 

Mark A. Musen, M.D., Ph.D. 

Stanford University Medical Center 

Robert J. Myerburg, M.D. 

University of Miami 

Joseph H. Nadeau, Ph.D. 


Mohandas Narla, M.D. 

New York Blood Center 

Karen Near, M.D. 

Office of the Surgeon General 

James Neaton, Ph.D. 


Enid R. Neptune, M.D. 


Jeanne M. Nerbonne, M.D. 


Paul Ness, M.D. 

Johns Hopkins Hospital 

Ellis J. Neufeld, M.D. 


Jane W. Newburger, M.D., M.P.H. 


Ngai X. Nguyen, M.D., F.A.C.C., 

F.A.C.P. 

Private Practitioner 

Deborah A. Nickerson, Ph.D. 


Shuming Nie, Ph.D. 


Steven L. Nissen, M.D. 

Cleveland Clinic 

Paul W. Nobel, M.D. 


Garry Nolan, Ph.D. 


Jan A. Nolta, Ph.D. 


Carole Ober, Ph.D. 


Ira Ockene, M.D. 

University of Massachusetts 

Judith Ockene, Ph.D. 

University of Massachusetts 

Christopher O’Connor, M.D. 


Peter J. Oettgen, M.D. 


Kwaku Ohene-Frempong, M.D. 


Samuel C. Okoye, M.D., F.A.A.F.P. 

Community Outreach for 

Health Awareness 

Richard O’Reilly, M.D. 

Sloan-Kettering Institute of 

Cancer Research 

Stuart H. Orkin, M.D. 


Joseph P. Ornato, M.D., F.A.C.P., 

F.A.C.C., F.A.C.E.P. 



Jerome A. Osheroff, M.D., 

F.A.C.P., F.A.C.M.I. 


Health System 


Betty Pace, M.D. 

University of Texas at Dallas 

Allan I. Pack, M.B., Ch.B., Ph.D. 


Kristen Page, Ph.D. 

Children’s Hospital Medical Center 

Scott Palmer, M.D., M.H.S. 


Julie A. Panepinto, M.D., M.S.P.H. 


Leslie Parise, Ph.D. 


Chapel Hill 

Robertson Parkman, M.D. 


Russell Pate, Ph.D. 

University of South Carolina 

Cam Patterson, M.D. 


Chapel Hill 

Kevin A. Pearce, M.D., M.P.H. 

University of Kentucky 

Thomas A. Pearson, M.D., 

M.P.H., Ph.D. 


Emerson Perin, M.D., Ph.D. 

Texas Heart Institute 

Eric D. Peterson, M.D., M.P.H., 

F.A.C.C. 


Irina Petrache, M.D. 


Marc Pfeffer, M.D., Ph.D. 


Steven Piantadosi, M.D., Ph.D. 


David Pinsky, M.D. 


Bertram Pitt, M.D. 


Charles G. Plopper, Ph.D. 


Bruce Psaty, M.D., Ph.D. 


Lynn Puddington, Ph.D. 

University of Connecticut 

Marlene Rabinovitch, M.D. 


Daniel J. Rader, M.D. 


Shahin Rafii, M.D. 


Cynthia S. Rand, Ph.D. 


Scott H. Randell, Ph.D. 


Chapel Hill 

Adrienne Randolph, M.D. 


Margaret M. Redfield, M.D. 

Mayo Clinic 

Susan Redline, M.D. 


William Reed, M.D. 

University of California, 

San Francisco 

Bob Rehm, M.B.A. 

America’s Health Insurance Plans 

Mary V. Relling, Pharm.D. 

St. Jude Children’s Research Hospital 

Paul Ridker, M.D. 


John Roback, M.D., Ph.D. 


Robert C. Robbins, M.D. 


Rose Marie Robertson, M.D. 

American Heart Association 

John W. Robitscher, M.P.H. 

National Association of Chronic 

Disease Directors 

Dan M. Roden, M.D. 


Veronique L. Roger, M.D. 

Mayo Clinic 

Sheila H. Roman, M.D., M.P.H. 

Centers for Medicare and 

Medicaid Services 

Eric A. Rose, M.D. 


Hugh Rosen, M.D., Ph.D. 

Scripps Research Institute

Michael R. Rosen, M.D. 


Ellen Rothenberg, Ph.D. 

California Institute of Technology 

Sharon Rounds, M.D. 

Providence Veterans Administration 


Gordon D. Rubenfeld, M.D. 


George S. Rust, M.D., M.P.H. 

Morehouse School of Medicine 

David H. Sachs, M.D. 


Frank Sacks, M.D. 


J. Evan Sadler, M.D., Ph.D. 


James F. Sallis, Ph.D. 

San Diego State University 

Joel Saltz, M.D., Ph.D. 

Ohio State University 

Michael C. Sanguinetti, Ph.D. 


Maurice E. Sarano, M.D. 

Mayo Clinic 

Rajabrata Sarkar, M.D., Ph.D. 


David T. Scadden, M.D. 


Andrew I. Schafer, M.D. 


Robert P. Schleimer, Ph.D. 


Ann Marie Schmidt, M.D. 


Lynn M. Schnapp, M.D. 


Barbara Schneeman, Ph.D. 


Michael Schneider, M.D. 


Mark A. Schoeberl 

American Heart Association 

Daniel Schuster, M.D. 


Mark A. Schuster, M.D., Ph.D. 


Richard J. Schuster, M.D., M.M.M. 

Wright State University 

Sanford J. Schwartz, M.D. 


Lisa M. Schwiebert, Ph.D. 

University of Alabama, Birmingham 

Christine E. Seidman, M.D. 


Jonathan Seidman, Ph.D. 


Joseph Selby, M.D., M.P.H. 

Kaiser Permanente 

Robert M. Senior, M.D. 


William C. Sessa, Ph.D. 


Prediman K. Shah, M.D. 


Steven D. Shapiro, M.D. 


Sanford J. Shattil, M.D. 


Gary M. Shaw, Dr.P.H., M.P.H. 

California Birth Defects 

Monitoring Program 

Dean Sheppard, M.D. 


Richard Shiffman, M.D., M.C.I.S. 

Yale Center for Medical Informatics 

Ramesh A. Shivdasani, 

M.D., Ph.D. 


Carol Shively, Ph.D. 


Alan Shuldiner, M.D. 


Gerald J. Shulman, M.D., Ph.D. 


Stephen Sidney, M.D., M.P.H. 

Kaiser Permanente 

Don Siegel, M.D., Ph.D. 


Leslie Silberstein, M.D. 


Amy Simon, M.D. 

Tufts University 

Daniel Simon, M.D. 


M. Celeste Simon, Ph.D., M.S. 


David S. Siscovick, M.D., M.P.H. 


Donna Skerrett, M.D. 


Wally R. Smith, M.D. 


Susan Smyth, M.D., Ph.D. 

University of Kentucky 

Edward Snyder, M.D. 

Yale-New Haven Hospital 

Edward J. Sondik, Ph.D. 

National Center for Health Statistics 

Frank E. Speizer, M.D. 


Eliot R. Spindel, M.D., Ph.D. 

Oregon Health and Science University 

Kenneth W. Spitzer, Ph.D. 


Deepak Srivastava, M.D. 


George Stamatoyannopoulos, 

M.D., Dr.Sci. 


Jonathan S. Stamler, M.D. 


Theodore J. Standiford, M.D. 


Patrick S. Stayton, Ph.D. 


Chad Steele, Ph.D. 


Marcia L. Stefanick, Ph.D. 


Martin H. Steinberg, M.D. 


Kurt R. Stenmark, M.D. 


Lynne Warner Stevenson, M.D. 


Duncan J. Stewart, M.D. 

University of Toronto, 

St. Michael’s Hospital 

Gregg W. Stone, M.D. 

Columbia University Medical Center 

Neil J. Stone, M.D. 


Rainer Storb, M.D. 


Robert M. Strieter, M.D., R.R.T. 


Barry Stripp, Ph.D. 


Marie Stuart, M.D. 

Thomas Jefferson University 

Sam Stupp, Ph.D. 


Shankar Subramaniam, Ph.D. 


Bruce A. Sullenger, Ph.D. 


Mary E. Sunday, M.D., Ph.D. 


E. Rand Sutherland, M.D., M.P.H. 

National Jewish Medical and 


Megan Sykes, M.D. 


Robert Tarran, Ph.D. 


Chapel Hill 

Lynn M. Taussig, M.D. 

University of Denver 

Anne L. Taylor, M.D. 


Herman Taylor, M.D., F.A.C.C. 

University of Mississippi 


Jonathan Teich, M.D., Ph.D. 


Robert Temple, M.D. 


Robert S. Tepper, M.D., Ph.D. 


Bernard Thebaud, M.D., Ph.D. 

University of Alberta 

Appendix | 37

Theodore J. Theophilos 

RR Donnelley & Sons Company 

George Thomas, M.D. 

Bradenton Cardiology Center 

B. Taylor Thompson, M.D. 


Robert W. Thompson, M.D. 


Galen B. Toews, M.D. 


Gordon F. Tomaselli, M.D. 


Allison Topper 

Pennsylvania Advocates for Nutrition 

and Activity 

Eric J. Topol, M.D. 

Scripps Health 

Sheryl Torr-Brown, Ph.D. 

Spiral5 Consulting, LLC 

Jeffrey A. Towbin, M.D. 


Russell P. Tracy, Ph.D. 


Natalia Trayanova, Ph.D. 

Tulane University 

Marsha Treadwell, Ph.D. 

Children’s Hospital and Research 

Center at Oakland 

John Triedman, M.D. 


Darrell J. Triulzi, M.D. 


Daniel Tschumperlin, Ph.D. 


Reed Tuckson, M.D. 

United Health Foundation 

Rubin M. Tuder, M.D. 


Fred W. Turek, Ph.D. 


Steve Turner, M.D. 

Mayo Clinic 

Lynne Uhl, M.D. 


Eleftherios (Stephen) Vamvakas, 

M.D., Ph.D. 

Canadian Blood Services 

Cees Van der Poel, M.D. 

Sanguin Blood Supply Foundation, 

Netherlands 

Jennifer Van Eyk, Ph.D. 


Linda V. Van Horn, Ph.D., R.D. 


Donata M. Vercelli, M.D. 


Catherine Verfaillie, M.D. 


Richard L. Verrier, Ph.D. 


Marc Vidal, Ph.D. 


Tuan Vo-Dinh, Ph.D. 


Thiennu Vu, M.D., Ph.D. 


Gordana Vunjak-Novakovic, Ph.D. 


Denisa Wagner, Ph.D. 


Peter D. Wagner, M.D. 


Patricia W. Wahl, Ph.D. 


Albert L. Waldo, M.D. 


David Warburton, M.D., 

D.Sc., F.R.C.P. 


Robert Waterland, Ph.D. 


Hartmut Weiler, Ph.D. 

Blood Research Institute 


William S. Weintraub, 

M.D., F.A.C.C. 

Christiana Care Health System 

Daniel J. Weisdorf, M.D. 


Daniel Weiss, M.D., Ph.D. 


James N. Weiss, M.D. 


Scott T. Weiss, M.D. 


Nanette K. Wenger, M.D., 

M.A.C.P., F.A.C.C., F.A.H.A. 


Jennifer West, Ph.D. 

Rice University 

Laura F. Wexler, M.D., 

F.A.H.A., F.A.C.C. 


Alexander White, M.D. 

New England Medical Center Hospitals 

Samuel A. Wickline, M.D. 


David S. Wilkes, M.D. 


James T. Willerson, M.D. 

University of Texas Health 

Science Center 

Marlene S. Williams, M.D. 

Johns Hopkins Bayview Medical Center 

Mary C. Williams, Ph.D. 


O. Dale Williams, Ph.D. 


R. Sanders Williams, M.D. 


Redford Williams, M.D. 


Marsha Wills-Karp, Ph.D. 

Cincinnati Children’s Hospital 


Sandra R. Wilson, Ph.D. 


Rena Wing, Ph.D. 

The Miriam Hospital 

Raimond Winslow, Ph.D. 


Robert A. Wise, M.D. 

Johns Hopkins Asthma and 

Allergy Center 

Janet Wittes, Ph.D. 

Statistics Collaborative, Inc. 

Prescott G. Woodruff, M.D., M.P.H. 


Steve Woolf, M.D. 


Anne L. Wright, Ph.D. 


Jackson T. Wright, Jr., M.D., 

Ph.D., F.A.C.P. 


Jo Rae Wright, Ph.D. 


Mark M. Wurfel, M.D., Ph.D. 

Harborview Medical Center 

George Yancopoulos, M.D., Ph.D. 

Regenron Pharmaceuticals, Inc. 

Clyde Yancy, M.D. 

Baylor University Medical Center 

John Yates, III, M.D., Ph.D. 

Scripps Research Institute 

Herbert F. Young, M.D., M.A., 

F.A.A.F.P. 

American Academy of Family Physicians 

David W. Zaas, M.D. 


Guy A. Zimmerman, M.D. 


James Zimring, M.D., Ph.D. 


Douglas P. Zipes, M.D. 


Leonard I. Zon, M.D. 

Children’s Hospital Boston

NIH Participants 

David B. Abrams, Ph.D. 

Office of Behavioral and Social 

Sciences Research 

National Institutes of Health 

Bishow Adhikari, Ph.D. 

Division of Cardiovascular Diseases 

National Heart, Lung, and 

Blood Institute 

Matilde M. Alvarado, M.S., R.N. 

Division for the Application of 

Research Discoveries 



Barbara Alving, M.D. 

Office of the Director 

National Center for Research Resources 

Deborah Applebaum-Bowden, 

Ph.D. 




Larissa Aviles-Santa, M.D. 

Division of Prevention and 

Population Sciences 



Robert S. Balaban, Ph.D. 

Division of Intramural Research 



Timothy Baldwin, Ph.D. 




Susan Banks-Schlegel, Ph.D. 

Division of Lung Diseases 



Luiz H. Barbosa, D.V.M., M.P.H. 

Division of Blood Diseases 

and Resources 



Winnie Barouch, Ph.D. 




Peg Barratt, Ph.D. 

Office of Science Policy 


John A. Barrett, M.D. 




Petronella A. Barrow 


and Resources 



Leslie A. Bassett 

Office of Minority Health Affairs 



Glen C. Bennett, M.P.H. 





Mary Anne Berberich, Ph.D. 

Formerly with Division of Lung Diseases 



Diane E. Bild, M.D., M.P.H. 





Olivier Bodenreider, M.D., Ph.D. 

Lister Hill National Center for 

Biomedical Communications 

National Library of Medicine 

Robin E. Boineau, M.D. 




Ebony Bookman, Ph.D. 

Formerly with Division of 

Cardiovascular Diseases 



Douglas A. Boyd 

Formerly with Division for the 

Application of Research Discoveries 



Judith A. Burk 




Stephanie Burrows, Ph.D. 

Office of Science and Technology 



Denis B. Buxton, Ph.D. 




Richard O. Cannon, M.D. 




Henry Chang, M.D. 


and Resources 



Donald P. Christoferson 

Office of Administrative Management 



James I. Cleeman, M.D. 





Francis S. Collins, M.D., Ph.D. 


National Human Genome 

Research Institute 

Sandra Colombini-Hatch, M.D. 




Lawton S. Cooper, M.D., M.P.H. 





Judy Corbett 

Formerly with Office of Science 

and Technology 



Thomas L. Croxton, M.D., Ph.D. 




Jeffrey A. Cutler, M.D., M.P.H. 





Susan M. Czajkowski, Ph.D. 





Darla E. Danford, M.P.H., D.Sc. 





Camina L. Davis, M.S.H.P. 





Janet de Jesus, M.S., R.D. 





Elizabeth Denholm, Ph.D. 

Formerly with Division 

of Lung Diseases 



Patrice Desvigne-Nickens, M.D. 




Nancy L. DiFronzo, Ph.D. 


and Resources 



Michael J. Domanski, M.D. 




Appendix | 39

Karen A. Donato, S.M., R.D. 





Jonelle Drugan, Ph.D., M.P.H. 





Cynthia E. Dunbar, M.D. 




Sue A. Edington 

Division of Extramural Activities Support 


Paula T. Einhorn, M.D., M.S. 





Abby G. Ershow, Sc.D. 




Frank J. Evans, Ph.D. 




Gregory L. Evans, Ph.D. 


and Resources 



Richard R. Fabsitz, Ph.D. 





Kathryn P. Fain 


and Resources 



Lawrence J. Fine, M.D., 

M.P.H., Dr.P.H. 





Toren Finkel, M.D., Ph.D. 




Jerome L. Fleg, M.D. 




Vicki A. Freedenberg, R.N., M.S.N. 


National Institute of Dental and 

Craniofacial Research 

Lisa A. Freeny 




Charles P. Friedman, Ph.D. 

Formerly with the Center 

for Research Informatics 

and Information Technology 



Robinson Fulwood, Ph.D., M.S.P.H. 





Dorothy B. Gail, Ph.D. 




Pankaj Ganguly, Ph.D. 


and Resources 



Timothy J. Gardner, M.D. 




Nancy L. Geller, Ph.D. 

Office of Biostatistics Research 



Mark T. Gladwin, M.D. 




Roger I. Glass, M.D., Ph.D. 

John E. Fogarty International Center 



Simone A. Glynn, M.D. 


and Resources 



Stephen S. Goldman, Ph.D. 




David J. Gordon, M.D., Ph.D. 




Jeanette Guyton-Krishnan, 

Ph.D., M.S. 





Patricia Ann Haggerty, Ph.D. 

Division of Extramural 

Research Activities 



Andrea L. Harabin, Ph.D. 




Jane L. Harman, D.V.M., Ph.D. 





Liana Harvath, Ph.D. 

Formerly with Division of Blood 

Diseases and Resources 



Ahmed AK Hasan, M.D., Ph.D. 




Keith L. Hewitt 





Carla Hines, PA-C 


and Resources 



Van S. Hubbard, M.D., Ph.D., CAPT 

Division of Nutrition Research 

National Institute of Diabetes and 

Digestive and Kidney Diseases 

Carl E. Hunt, M.D. 

Formerly with Office of the Director 



Della E. Jackson 

Division of Extramural Activities Support 


Cashell E. Jaquish, Ph.D. 





Mary M. Joyce, R.N. 




Peter G. Kaufmann, Ph.D. 





Rae-Ellen W. Kavey, M.D., M.P.H. 





James P. Kiley, Ph.D. 




Harvey G. Klein, M.D. 

Clinical Center 


Chitra Krishnamurti, Ph.D. 




Jennie E. Larkin, Ph.D. 




David A. Lathrop, Ph.D. 



Blood Institute

Vicki Nghi Le 




Caron J. Lee 




Warren J. Leonard, M.D. 




Daniel Levy, M.D. 

Center for Population Studies 



Isabella Y. Liang, Ph.D. 




Michael Lin, Ph.D. 





Rebecca P. Link, Ph.D. 


and Resources 



Barbara M. Liu, S.M. 




Stacey A. Long 




Theresa C. Long 





Catherine Loria, Ph.D. 





Harvey S. Luksenburg, M.D. 


and Resources 



Martha S. Lundberg, Ph.D. 




Nicole M. Mahoney, Ph.D. 





Alice Mascette, M.D. 




Judith G. Massicot-Fisher, Ph.D. 




Clement J. McDonald, M.D. 



Alan M. Michelson, M.D., Ph.D. 




Marissa A. Miller, D.V.M., M.P.H. 




Helena O. Mishoe, Ph.D., M.P.H. 




Phyllis I. Mitchell, M.S. 


and Resources 



Stephen C. Mockrin, Ph.D. 





Traci H. Mondoro, Ph.D. 


and Resources 



R. Blaine Moore, Ph.D. 


and Resources 



Gregory J. Morosco, Ph.D., M.P.H. 





Joel Moss, M.D., Ph.D. 








Aaron B. Navarro, Ph.D. 




Cheryl R. Nelson, M.S.P.H. 





George J. Nemo, Ph.D. 


and Resources 



Emily Newcomer 




Cuong T. Nguyen 




Hanyu Ni, Ph.D. 





Patricia J. Noel, Ph.D. 




Christopher J. O’Donnell, 

M.D., M.P.H. 




Christopher E. Olaes 

Center for Research Informatics 




Victor R. Olano, M.P.H. 





Susan E. Old, Ph.D. 




Jean L. Olson, M.D., M.P.H. 





Gloria A. Ortiz 





Dina N. Paltoo, Ph.D. 




Sunil P. Pandit, Ph.D. 




Gail D. Pearson, M.D., Sc.D. 




Hannah H. Peavy, M.D. 




Charles M. Peterson, M.D., M.B.A. 


and Resources 



Appendix | 41

Sheila Pohl, M.A. 




Nancy J. Poole, M.B.A. 





Charlotte A. Pratt, Ph.D. 





Valerie L. Prenger, Ph.D. 





Dennis A. Przywara, Ph.D. 




Susan E. Pucie 


and Resources 



Frank Pucino, Pharm.D., B.C.P.S., 

F.A.S.H.P., F.D.P.G.E.C. 

Pharmacy Department 



Pankaj Qasba, Ph.D. 


and Resources 



Christina Rabadan-Diehl, Ph.D. 




Matt Raschka 





Herbert Y. Reynolds, M.D. 




Thomas C. Rindflesch, Ph.D. 




Nora I. Rivera 





Edward J. Roccella, Ph.D., M.P.H. 





Yves D. Rosenberg, M.D. 




Jacques E. Rossouw, M.D. 





Carl A. Roth, Ph.D., LL.M. 




Ann E. Rothgeb 




Ayana K. Rowley, Pharm.D. 

Pharmacy Department 



Rita Sarkar, Ph.D. 


and Resources 




Peter J. Savage, M.D. 





Charlene A. Schramm, Ph.D. 




Eleanor B. Schron, M.S., 

R.N., F.A.A.N. 




David A. Schwartz, M.D. 


National Institute of Environmental 

Health Sciences 

Susan K. Scolnik 




Jane D. Scott, Sc.D. 




Amy W. Sheetz 




Susan T. Shero, M.S. 





Phyliss D. Sholinsky, M.S.P.H. 





Susan B. Shurin, M.D. 




Denise Simons-Morton, 

M.D., Ph.D. 





Sonia I. Skarlatos, Ph.D. 




Robert A. Smith, Ph.D. 




Ellen K. Sommer, M.B.A. 





George Sopko, M.D. 




Paul D. Sorlie, Ph.D. 





Miriam C. Spiessbach 




Pothur R. Srinivas, Ph.D. 




Maria R. Stagnitto, R.N., M.S.N. 

Office of Clinical Research 



Dennis V. Stanley 



Blood Institute

Louis M. Staudt, M.D., Ph.D. 

Center for Cancer Research 

National Cancer Institute 

Virginia S. Taggart, M.P.H. 




Ann M. Taubenheim, Ph.D., M.S.N. 





Thomas J. Thom 





John W. Thomas, Ph.D. 


and Resources 



Xin Tian, Ph.D. 





Nico Tjandra, Ph.D. 




Eser Tolunay, Ph.D. 




Rachael L. Tracy, M.P.H. 





Michael J. Twery, Ph.D. 




Karen L. Ulisney, R.N., M.S.N. 




Ralph Van Wey, M.S. 





Jamie Varghese, Ph.D. 





Paul A. Velletri, Ph.D. 





Carol E. Vreim, Ph.D. 




Elizabeth L. Wagner, M.P.H. 


and Resources 



Evelyn R. Walker, Ph.D. 





Madeleine F. Wallace, Ph.D. 





Lan-Hsiang Wang, Ph.D. 




Wanda R. Ware 


Activities Support 


Lynford Warner 

Formerly with Center for 

Research Informatics and 

Information Technology 



Momtaz Wassef, Ph.D. 

Division of Cardiovascular 

Diseases National Heart, Lung, 

and Blood Institute 

Norbert D. Weber, Ph.D. 




Gina S. Wei, M.D., M.P.H. 





Gail G. Weinmann, M.D. 




Barbara L. Wells, M.D. 





Connie G. Wells 




Ellen M. Werner, Ph.D. 


and Resources 



Roy L. White, Ph.D. 





Violet R. Woo, M.S., M.P.H. 





Daniel G. Wright, M.D. 

Division of Kidney, Urologic, and 

Hematologic Diseases 

National Institute of Diabetes and 

Digestive and Kidney Diseases 

Song Yang, Ph.D. 

Office of Biostatistics Research 



Jane X. Ye, Ph.D. 




Neal S. Young, M.D. 




Zhi-Jie Zheng, M.D., Ph.D. 





Appendix | 43

Information and Resources 

NHLBI Resources 

NHLBI Home Page 

http://www.nhlbi.nih.gov 

NHLBI Strategic Plan 

http://apps.nhlbi.nih.gov/strategicplan/ 

NHLBI Information for Researchers 

http://www.nhlbi.nih.gov/resources/index.htm 

NHLBI Information for Health Professionals 

http://www.nhlbi.nih.gov/health/indexpro.htm 

NHLBI Information for Patients and the Public 

http://www.nhlbi.nih.gov/health/index.htm 

NHLBI Clinical Trial Database 

http://apps.nhlbi.nih.gov/clinicaltrials/ 

NHLBI Funding Training and Policies 

http://www.nhlbi.nih.gov/funding/index.htm 

NHLBI Training and Career Development Web Site 

http://www.nhlbi.nih.gov/funding/training/ 

NHLBI Research and Policy Update Listserv 

http://www.nhlbi.nih.gov/resources/listserv/index.htm 

NHLBI Fact Book 

http://www.nhlbi.nih.gov/about/factpdf.htm 


NIH Resources 

NIH Home Page 

http://www.nih.gov 

NIH Center for Scientific Review 

http://cms.csr.nih.gov/ 

NIH Forms and Applications 

http://grants.nih.gov/grants/forms.htm 

NIH Grants and Funding Opportunities 

http://grants1.nih.gov/grants/index.cfm 

NIH Public Involvement 

http://www.nih.gov/about/publicinvolvement.htm 


The National Heart, Lung, and Blood Institute (NHLBI) Health Information 

Center is a service of the NHLBI of the National Institutes of Health. 

The NHLBI Health Information Center provides information to health 

professionals, patients, and the public about the treatment, diagnosis, and 

prevention of heart, lung, and blood diseases and sleep disorders. For more 

information, contact: 

NHLBI Health Information Center 

P.O. Box 30105 


Phone: 301-592-8573 

TTY: 240-629-3255 

Fax: 301-592-8563 

Web site: http://www.nhlbi.nih.gov

Discrimination Prohibited 

Under provisions of applicable public laws enacted by Congress since 

1964, no person in the United States shall, on the grounds of race, color, 

national origin, handicap, or age, be excluded from participation in, 

be denied the benefits of, or be subjected to discrimination under any 

program or activity (or, on the basis of sex, with respect to any education 

program and activity) receiving Federal financial assistance. In addition, 

Executive Order 11141 prohibits discrimination on the basis of age by 

contractors and subcontractors in the performance of Federal contacts, 

and Executive Order 11246 states that no federally funded contractor may 

discriminate against any employee or applicant for employment because 

of race, color, religion, sex, or national origin. Therefore, the National 

Heart, Lung, and Blood Institute must be operated in compliance with 

these laws and Executive Orders.


September 2007

U. S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 


National Institute of Allergy and Infectious Diseases 

NIAID 

BIODEFENSE 

Preparing Through Research 

NIAID Strategic Plan for 

Biodefense Research 

2007 Update

NIAID Strategic Plan for 

Biodefense Research 

2007 Update 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 



September 2007 

www.niaid.nih.gov


Strategic Plan for Biodefense Research – 2007 Update 

Introduction 

Biological weapons in the possession of hostile states or terrorists, as well as naturally occurring 

emerging and reemerging infectious diseases, are among the greatest security challenges to the 

United States. Consequently, developing effective medical countermeasures to mitigate illness, 

suffering, and death resulting from emerging/reemerging diseases or the deployment of biological 

weapons is central to the United States government’s mission to protect and ensure the welfare of 

its citizens. The National Institute of Allergy and Infectious Diseases (NIAID), NIH, DHHS, has 

a significant responsibility to support this mission. 

The NIAID Strategic Plan for Biodefense Research was published in 2002 and was followed by 

two research agendas, one for Category A agents and another for Category B and C priority 

pathogens. This early plan focused on the importance of basic research, as well as applying that 

basic research to developing products such as diagnostics, therapeutics and vaccines. It also 

highlighted specific scientific gaps associated with priority pathogens. The plan and agendas 

acknowledged the importance of working with partners in the private and public sectors and 

collaborating with other agencies and organizations to ensure that the fruits of basic research 

would be rapidly translated into products. The principles on which these documents were based 

continue to hold true. 

NIAID also recognized that developing new medical countermeasures for biodefense and 

emerging infectious diseases is associated with specific challenges. For example, the basic biology 

and pathogenesis of threat agents are often not well understood. Many target pathogens must be 

handled under high level biosafety conditions that require specialized facilities and training. The 

regulatory path to licensure for biomedical countermeasures often requires demonstrating efficacy 

in appropriate animal models, many of which have yet to be developed. Finally, many of the target 

pathogens do not pose public health risks outside of their use as weapons, especially within the 

United States, thus, to date, there has not been a significant commercial market for products 

developed to treat diseases caused by these microbes. 

This updated Strategic Plan for Biodefense Research builds upon the successes and investments of 

the first plan and accompanying research agendas; it is consistent with the HHS Public Health 

Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy for Chemical, Biological, 

Radiological and Nuclear Threats, the HHS PHEMCE Implementation Plan, and the Homeland 

Security Presidential Directive (HSPD)-18, which outline strategies for identifying medical 

countermeasure requirements and establishing priorities for their research, development, and 

acquisition. These successes and investments include advances in understanding the biology of 

specific pathogens and the host’s immune response; construction of new biocontainment 

laboratory facilities; professional training in biosafety and biocontainment; and establishment of 

critical research resources and infrastructure that support applied science and advanced product 

development. Although the focus of this updated Strategic Plan continues to be on basic research 

and its application to product development, there is a shift from the current “one bug-one drug” 

approach toward a more flexible, broad spectrum approach. This approach involves developing 

medical countermeasures that are effective against a variety of pathogens and toxins, developing 

technologies that can be widely applied to improve classes of products, and establishing platforms 

that can reduce the time and cost of creating new products. The broad spectrum strategy 

__________________________________________________ 

NIAID Strategic Plan for Biodefense Research – 2007 Update 

1

ecognizes both the expanding range of biological threats and the limited resources available to 

address each individual threat. 

NIAID as a Partner in National Biodefense Efforts 

NIAID’s role in developing medical products to counter bioterrorism and emerging and 

reemerging infectious diseases is part of a larger national strategy, involving many agencies. The 

Department of Homeland Security (DHS) is responsible for determining which biological agents 

pose the highest threat to U.S. national security. The Department of Health and Human Services 

(HHS) then assesses the potential public health impact of each of the highest priority threats and 

establishes medical countermeasure requirements for each agent. Overall responsibility for 

coordinating research, development, acquisition, storage, maintenance, deployment, and guidance 

for using biodefense products also rests with HHS. The recently established Biomedical Advanced 

Research and Development Authority (BARDA), operating within HHS, has specific 

responsibility to facilitate collaboration between U.S. government agencies, relevant 

biopharmaceutical companies, and academic researchers; support advanced research and 

development of medical countermeasures; and promote innovation to reduce the time and cost of 

countermeasure development. The final acquisition of countermeasures for the Strategic National 

Stockpile is then provided for by Project BioShield. 

NIAID’s Strategic Plan for Biodefense Research supports the national biodefense strategy. As 

such, the Institute will continue to support basic and applied research, product development, and 

technology development for biological threats based on national priorities for medical 

countermeasures. Furthermore, NIAID will continue its direct collaborative efforts with other 

Federal agencies, academia and industry as part of the larger HHS strategy. For example, NIAID 

coordinates all NIH-supported activities aimed at the development of medical countermeasures for 

biological, chemical, radiological, and nuclear threats. 

Characterizing Biological Threats 

Homeland Security Presidential Directive (HSPD)-18, released in early 2007, outlines strategies 

for medical countermeasure research, development, and acquisition, and frames the spectrum of 

biological threats in four distinct categories: 

• Traditional Agents -- naturally occurring microorganisms or toxin products with the 

potential to be disseminated to cause mass casualties. Examples: Bacillus anthracis 

(anthrax) and Yersinia pestis (plague). 

• Enhanced Agents -- traditional agents that have been modified or selected to enhance 

their ability to harm human populations or circumvent available countermeasures. 

Example: Drug-resistant pathogens such as extensively drug-resistant (XDR) TB or 

multidrug-resistant (MDR) plague. 

• Emerging Agents -- previously unrecognized pathogens that might be naturally occurring 

and present a serious risk to human populations. Tools to detect and treat these agents 

might not exist or be widely available. Example: Severe Acute Respiratory Syndrome 

(SARS) or avian influenza. 

• Advanced Agents -- novel pathogens or other biological materials that have been 

artificially engineered in the laboratory to bypass traditional countermeasures or produce a 

__________________________________________________ 


2

more severe or otherwise enhanced spectrum of disease. Example: Multidrug-resistant 

anthrax. 

These designations expand on the traditional classifications of Category A, B, and C agents 

because they address the fact that future threats are likely to be unanticipated and ill-defined. 

While appropriate and effective for the highest priority traditional threats, such as smallpox and 

anthrax, developing medical countermeasures using a conventional “one bug-one drug” approach 

will rapidly prove unsustainable as the list of threats increases to include enhanced, emerging, and 

advanced agents. Responding to traditional and new types of threats will require the capability to 

rapidly identify unknown or poorly defined agents, quickly evaluate the efficacy of available 

interventions, and develop and deploy novel treatments to prevent or mitigate medical 

consequences and the subsequent impact on society. This Strategic Plan update will address how 

NIAID will focus future efforts to prevent and respond to traditional and novel threats. 

Research Achievements: Priming the Biodefense Product Pipeline 

Developing products that can protect against potential biological threats is an integrated process 

that includes basic and applied research, and advanced product development. Basic research is 

critical to efforts to develop interventions against bioterrorism. It lays the groundwork by 

generating new and innovative concepts based on studies of pathogen biology and host response. 

Applied research builds on basic research by validating concepts in model systems, and testing 

them in practical research settings. Successful candidates move into advanced product 

development, where they are manufactured and evaluated for safety and efficacy in animals and 

humans according to strict guidelines and regulations. 

In recent years, NIAID has greatly expanded its basic and applied research portfolio for Category 

A, B and C pathogens and toxins. The Institute has established a comprehensive infrastructure 

with extensive resources that support all levels of research. This has created a solid base for 

transitioning to a strategy that embraces multiple broad spectrum concepts. Examples of this 

infrastructure include the following. (For a complete list of NIAID resources, visit 

www.niaid.nih.gov/research/resources.) 

• Regional Centers of Excellence (RCEs) for Biodefense and Emerging Infectious Diseases 

– ten centers, located nationwide, provide resources and communication systems that can 

be rapidly mobilized and coordinated with regional and local systems in response to an 

urgent public health event. (www.niaid.nih.gov/research/resources/rce) 

• Cooperative Centers for Translational Research on Human Immunology and Biodefense 

further knowledge of human immune responses against infectious pathogens and elucidate 

molecular mechanisms responsible for both short-term immunity and long-term immune 

memory. The ultimate goal of these eight centers is to translate research on immunity to 

infection into clinical applications to protect against bioterrorist threats. 

• National Biocontainment Laboratories (NBLs) and Regional Biocontainment Laboratories 

(RBLs) – 2 NBLs and 13 RBLs are available or under construction for research requiring 

high levels of containment and are prepared to assist national, state and local public health 

efforts in the event of a bioterrorism or infectious disease emergency. 

(www.niaid.nih.gov/topics/BiodefenseRelated/Biodefense/research/resources/NBL_RBL) 

• Expanded Vaccine and Treatment Evaluation Units – multiple sites allow for more 

extensive clinical trials capacity and expertise. (www.niaid.nih.gov/factsheets/vteu.htm) 

__________________________________________________ 


3

• The Biodefense and Emerging Infections Research Resources Repository offers reagents 

and information essential for studying emerging infectious diseases and biological threats. 

(www.beiresources.org) 

• Genomics and proteomics centers include the Microbial Sequencing Centers, the Pathogen 

Functional Genomics Resource Center, the Bioinformatics Resource Centers, and the 

Biodefense Proteomics Research Centers. 

(www.niaid.nih.gov/research/topics/pathogen) 

• The In Vitro and Animal Models for Emerging Infectious Diseases and Biodefense 

resource provides screening of potential therapeutics and the development of in vivo 

animal efficacy models for evaluating drugs and vaccines. 

(www.niaid.nih.gov/topics/BiodefenseRelated/Biodefense/research/resources/invitro) 

• The Immune Epitope Database is a public database that provides information on all 

published antibody and T-cell epitopes for Category A, B and C pathogens and their 

toxins, and also provides state-of-the-art epitope analysis tools. 

(www.immuneepitope.org) 

• The NIH Tetramer Facility provides custom major histocompatibility complex (MHC) 

class I and class II tetramers for detection and characterization of host T cell responses to 

infectious agents. (http://research.yerkes.emory.edu/tetramer_core/index.html) 

NIAID has actively engaged academia and industry through a variety of grants and contracts in 

order to advance research and product development for biodefense. In addition, the Institute has 

supported a number of biodefense workshops and multiple training opportunities ranging from 

basic introductory courses to two-year fellowships to provide professional training in biosafety 

and biocontainment. These programs are available through the National Biosafety and 

Biocontainment Training Program (www.nbbtp.org), the RCEs, and NIAID Institutional Training 

Grants (www.niaid.nih.gov/ncn/training/default_training.htm). Close collaboration and 

communication with other government agencies (e.g. Department of Defense [DoD], HHS, 

Centers for Disease Control and Prevention [CDC], and the U.S. Food and Drug Administration 

[FDA]) have been critical components of NIAID’s biodefense activities. NIAID will continue to 

expand these activities as appropriate. 

Next-Generation Research: Filling the Pipeline 

Developing medical countermeasures against a finite number of known or anticipated agents is a 

sound approach for mitigating the most catastrophic biological threats. Responding to enhanced, 

emerging, and advanced agents, however, demands new paradigms that will allow for more rapid 

and cost-effective development of countermeasures. Now that NIAID, in collaboration with other 

agencies, has established a solid framework of research and product development resources for 

biodefense, the time is ripe for transitioning to new approaches that will provide the flexibility 

required to meet the challenges of non-traditional threats. NIAID has identified three “broad 

spectrum” strategies to underpin a more responsive biodefense capability. These strategies -- 

broad spectrum activity, broad spectrum technology and broad spectrum platforms -- are described 

below. 

Broad Spectrum Activity 

Broad Spectrum Activity is a characteristic that enables a particular product to mitigate biological 

threats across a wide range or class of agents. Multiplex diagnostics possessing broad spectrum 

activity will rapidly differentiate a variety of common and lesser-known pathogens in a single 

clinical sample, identify drug sensitivities, and determine how a sample pathogen is related to 

known pathogens. Vaccines demonstrating broad spectrum activity include cross-protective and 

__________________________________________________ 


4

multiple component vaccines. Cross protective vaccines induce an immune response against 

constant components of a microbe, and therefore are effective against pathogens that evolve or 

“drift” naturally or deliberately. A universal influenza vaccine is an example of a cross-protective 

vaccine. Multiple component vaccines include, within a single vaccine, elements that protect 

against viruses or microbes that are different, but usually closely related. An example of a multiple 

component vaccine is a hemorrhagic fever vaccine that contains elements of Ebola, Marburg, and 

Lassa viruses. 

There are a number of traditional threats for which safe and effective treatments are either nonexistent, 

of limited usefulness, or susceptible to emerging antimicrobial resistance and genetically 

engineered threats. A limited number of anti-infectives with broad spectrum activity directed at 

common, invariable, and essential components of different classes of microbes could potentially 

be effective against both traditional and non-traditional threats. This approach would allow a small 

number of drugs to replace dozens of pathogen-specific drugs. Additionally, strategies to 

overcome antibacterial resistance could extend the clinical utility of existing broad spectrum antiinfectives 

and have immediate benefits. Treatments that target host immune responses have the 

potential to be effective against multiple diseases. These immunomodulators reduce morbidity and 

mortality by controlling responses that contribute to disease (e.g. cytokine storms) or nonspecifically 

activating the host’s natural immune defenses to induce a faster, more potent 

protective response. 

Broad Spectrum Technology 

Broad Spectrum Technology refers to capabilities -- such as temperature stabilization or delivery 

method -- that can be engineered into a wide array of existing and candidate products. Developing 

countermeasures that will be useful in responding to future threats represents a major challenge, 

given the capabilities that these products must possess. They should be safe and effective against 

multiple pathogens in people of any age and health status. To be appropriate for storing in the 

Strategic National Stockpile, the products should be suitable for long-term storage at room 

temperature, have simple compact packaging, be easily delivered in a mass casualty setting, confer 

protection with limited dosing, and have single dose delivery devices that can be selfadministered. 

Added to these factors is the potential need to produce additional quantities with 

little notice, requiring manufacturers to take the costly step of keeping production facilities on 

standby. 

Broad Spectrum Platforms 

Broad Spectrum Platforms are standardized methods that can be used to significantly reduce the 

time and cost required to bring medical countermeasures to market. For example, a proven 

monoclonal antibody fermentation and purification method can be applied to rapidly develop any 

therapeutic monoclonal antibody, avoiding lengthy development work. Other examples of 

platform technologies include screening systems, in vitro safety testing, expression modules, 

manufacturing technologies, and chemical synthesis designs. The potential to rapidly apply such 

platform methods to developing new countermeasures will considerably shorten and streamline 

the process. 

Future Directions 

NIAID will implement a Research Agenda that supports these three broad spectrum approaches 

for developing new drugs, vaccines, devices, and diagnostics for emerging infectious diseases and 

biodefense. As such, basic and applied research and product development will focus on the 

following strategies. 

__________________________________________________ 


5

Basic Research 

• Expand basic microbiology and immunology research to support the broad spectrum activity 

approach. 

• Use genomics and bioinformatics tools to model complex molecular pathways that can predict 

common pathogen and host targets. Move toward a systems biology approach in which 

discrete knowledge about pathogens and hosts is integrated into a comprehensive picture of 

the full host-pathogen interface. 

• Promote discovery and development of natural anti-microbial proteins, such as defensins. 

• Expand research on anti-infective resistance mechanisms and develop approaches to overcome 

them. 

• Advance understanding of the innate and adaptive immune systems to target design and 

development of next generation adjuvants for vaccines or new therapeutics. 

• Improve understanding of cellular and molecular pathways to identify new targets for vaccines 

and therapeutics. 

Applied Research and Product Development 

• Encourage development of multiplex diagnostics and broad spectrum vaccines and drugs. 

• Expand in vitro and in vivo screening resources for drugs and vaccines against high priority 

pathogens. 

• Develop animal models to support drug and vaccine efficacy studies. 

• Offer a broad array of preclinical services, including pharmacology and toxicology to 

characterize and evaluate candidate products. 

• Devise novel delivery systems and temperature stabilization technologies for vaccines and 

drugs. 

• Evaluate immunomodulators as adjunct treatment along with traditional anti-infective therapy. 

• Evaluate novel adjuvants to increase potency of vaccines and reduce number of doses required 

for maximum protection. 

• Create formulations that improve bioavailability and allow for multivalent drugs and vaccines 

• Develop universal expression frameworks for drugs (e.g. RNAi; monoclonal antibody 

frameworks). 

• Establish manufacturing platforms (e.g. microwave technology for chemical synthesis) for 

rapid and cost-effective production of therapeutics and vaccines for human use. 

• Expand clinical trial capabilities for evaluation of new drugs. 

• Design adaptive diagnostic systems that allow for simple and rapid incorporation of additional 

targets. 

• Develop new classes of antibiotics. 

As NIAID focuses on these key biodefense research and development activities, the Institute will 

continue to support training in biosafety and biocontainment as needed to ensure that research staff 

have the necessary tools and training to safely conduct biocontainment research. 

Implications of Biodefense Research for Other Diseases 

The large investment in biodefense research and product development will significantly benefit 

other areas of medicine. Many of the organisms under study and a host of other emerging 

infectious diseases and drug-resistant microbes are significant public health threats, both within 

the United States and in other parts of the world. Research on microbial biology and pathogenesis 

will enhance understanding of these and other naturally occurring infectious diseases. Advances in 

developing diagnostics, vaccines, and therapeutics with broad spectrum activity will have direct 

__________________________________________________ 


6

elevance to many naturally occurring diseases, as well as spin-off benefits for developing other 

broad spectrum products. Broad spectrum technologies that improve product stability, potency, 

and ease of use will benefit many classes of new diagnostics, vaccines, and therapeutics, 

regardless of the disease target. The most obvious gain will be for interventions to prevent, 

diagnose, and treat major killers such as malaria, tuberculosis, HIV/AIDS, and a spectrum of 

emerging and reemerging diseases. This is especially important in countries where public health 

infrastructure cannot support delivery of products that require a cold chain, multiple doses of a 

vaccine, or advanced diagnostic equipment. Broad spectrum platforms have the potential to reduce 

time and cost of developing new products for many medical conditions. Basic research on host 

defenses will greatly enhance our understanding of the molecular and cellular mechanisms of the 

innate immune system and its relationship to the adaptive immune system, and lead to 

improvements in treatment and prevention of immune-mediated diseases, such as systemic lupus 

erythematosus, rheumatoid arthritis, and other autoimmune diseases. Finally, improved 

understanding of mechanisms of regulation of the human immune system will have positive spinoffs 

for diseases such as cancer, immune-mediated neurological diseases, and allergic and 

hypersensitivity diseases, as well as for preventing rejection of transplanted organs. 

Conclusion 

The nation must be ready to protect its citizens with safe and effective treatments against potential 

biological threats. NIAID, in collaboration with other government agencies, will continue to play a 

significant role in this mission. Through NIAID’s support of basic and applied research, advanced 

product development, and research resources, much progress has been made in developing 

countermeasures for some of the highest threat pathogens. It is clear, however, that time and 

resources cannot sustain a “one bug-one drug” approach for the long term. The new broad 

spectrum strategy and supporting Research Agenda will focus on developing countermeasures that 

act against multiple agents, as well as technologies and platforms that can improve the quality of 

products and shorten the time and cost of development. NIAID’s product development 

infrastructure, biocontainment facilities, and research resources will be used to evaluate the most 

promising products, technologies and platforms through preclinical and clinical development. 

This approach will most effectively utilize the strengths of NIAID and its stakeholders in the 

national biodefense preparedness effort. It will also provide enormous benefits to many other areas 

of biomedical research and development and truly usher in 21 st century medicine for future 

generations. 

__________________________________________________ 


7


HHS Public Health Emergency Medical Countermeasures Enterprise Strategy for Chemical, 

Biological, Radiological and Nuclear Threats, Federal Register/Vol. 72, No. 53/ Tuesday, 

March 20, 2007/Notices 

(www.hhs.gov/aspr/barda/documents/federalreg_vol72no53_032007notices.pdf) 

HHS Public Health Emergency Medical Countermeasures Enterprise Implementation Plan 

for Chemical, Biological, Radiological and Nuclear Threats, Federal Register/Vol. 72, No. 77/ 

Monday, April 23, 2007/Notices 

(http://a257.g.akamaitech.net/7/257/2422/01jan20071800/edocket.access.gpo.gov/2007/pdf/E7- 

7682.pdf) 

Homeland Security Presidential Directive – 18 

(www.whitehouse.gov/news/releases/2007/02/print/20070207-2.html) 

NIH Strategic Plan and Research Agenda for Medical Countermeasures Against 

Radiological and Nuclear Threats 

(www.niaid.nih.gov/about/overview/planningPriorities/RadNuc_StrategicPlan.pdf) 

NIAID Biodefense Research 

(www.niaid.nih.gov/topics/BiodefenseRelated/Biodefense) 

NIAID Category A, B, and C Priority Pathogens 

(www.niaid.nih.gov/topics/BiodefenseRelated/Biodefense/PDF/Cat.htm) 

NIAID Biodefense Research Agenda for CDC Category A Agents 

(www.niaid.nih.gov/topics/BiodefenseRelated/Biodefense/PDF/biotresearchagenda.pdf) 

NIAID Biodefense Research Agenda for CDC Category A Agents, 2006 Progress Report 

(www.niaid.nih.gov/topics/BiodefenseRelated/Biodefense/PDF/CatA_2006.pdf) 

NIAID Biodefense Awards, FY 2006 

(www.niaid.nih.gov/topics/BiodefenseRelated/Biodefense/research/funding/FY2006+Awards/2006. 

htm) 

NIAID Current Funding Opportunities in Biodefense 

(www.niaid.nih.gov/topics/BiodefenseRelated/Biodefense/research/funding) 

__________________________________________________ 


8

U.S. DEPARTMENT OF 

HEALTH AND HUMAN SERVICES 


National Institute of General Medical Sciences 

INVESTING IN DISCOVERY 

NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES 

STRATEGIC PLAN 2008 –2012

COVER 

Top row (left to right) 

Neural tube formation in a developing zebrafish, an organism commonly used 

for genetic research. Courtesy of Alexander Schier, Harvard University. 

Alejandro Sánchez Alvarado studies tissue regeneration in aquatic flatworms. 

Photo at the University of Utah by William K. Geiger. 

Image created using computational biology to show differences between two 

human brains. Courtesy of Arthur Toga, University of California, Los Angeles. 

Fluorescent dyes highlight chromosomes and microtubules during cell division. 

Courtesy of Edward Salmon, University of North Carolina at Chapel Hill. 

Second row (left to right) 

Structure of a ribosome, the site of protein production. Image by Catherine 

Lawson, Rutgers University and the Protein Data Bank. 

White dots mark telomeres, which protect the tips of chromosomes. Courtesy 

of Hesed Padilla-Nash and Thomas Ried, National Institutes of Health. 

NMR expert Michael Summers studies HIV structure and leads an initiative 

to maximize student diversity at the University of Maryland, Baltimore County. 

Courtesy of Michael Summers. 

Third row 

Structural biologist Mavis Agbandje-McKenna examines how influenza infects 

cells. Photo at the University of Florida in Gainesville by David Blankenship. 

Fourth row (left to right) 

Image taken using a new technique called multicolor STORM, which shows individual 

molecules within cells in unprecedented detail. Courtesy of Xiaowei Zhuang, 

Harvard University. 

Gene Robinson studies the molecular basis of honeybee behavior, which is controlled 

by some of the same genes that regulate daily rhythms in humans. Photo 

at the University of Illinois at Urbana-Champaign by L. Brian Stauffer. 

TABLE OF CONTENTS 

Top row (left to right) 

A DNA-repair enzyme encircling a strand of DNA. Courtesy of Tom Ellenberger, 

Washington University in St. Louis School of Medicine. 

Lung damage like that shown here is a focus of teams of critical care specialists 

and genomic researchers. Courtesy of Hamid Rabb, Johns Hopkins Medicine. 

A budding yeast cell frozen in time in an X-ray microscopy image. Courtesy 

of Carolyn Larabell, University of California, San Francisco, and the Lawrence 

Berkeley National Laboratory. 

Crystal of the fungal lipase enzyme. Courtesy of Alexander McPherson, 

University of California, Irvine. 

Second row (left to right) 

Abnormal protein deposits look like balls of steel wool in a micrograph of brain 

tissue from a person with Alzheimer’s disease. Courtesy of Neil Kowall, Boston 

University School of Medicine. 

Three-dimensional view of a cell’s Golgi apparatus. Courtesy of Kathryn Howell, 

University of Colorado Health Sciences Center. 

Organic chemist Amir Hoveyda develops catalysts for chemical reactions that 

produce biologically active compounds. Courtesy of the Office of Public Affairs, 

Boston College. 

Third row 

Biophysicist Margaret Gardel studies how the cystoskeleton helps the cell move 

and change shape. Photo at the University of Chicago by Lloyd DeGrane. 

Fourth row (left to right) 

Scanning electron micrograph showing two types of bacteria. Courtesy of Tina 

Carvalho, University of Hawaii at Manoa. 

Bioinformatician Atul Butte analyzes the genomic relationships between diseases 

and investigates new uses for existing medicines. Courtesy of Atul Butte, 

Stanford University.

TABLE OF CONTENTS 

2 INVESTING IN DISCOVERY 

4 WHY BASIC RESEARCH? 

6 INSTITUTE PROFILE 

8 STRATEGIC GOALS 

18 INSIDE NIGMS 

19 STRATEGIC PLANNING PROCESS

NIGMS Core Principles 

Sponsor and promote basic research 

as an essential aspect of science 

to improve human health. 

■ ■ ■ 

Foster innovation and discovery 

to unveil new knowledge 

that will lead to future 

transformations in medicine. 

■ ■ ■ 

Employ integrative 

and interdisciplinary approaches 

in the pursuit and dissemination 

of scientific knowledge. 

■ ■ ■ 

Develop a biomedical research 

workforce representative of American 

society at large and actively support 

training of the next generation 

of scientists. 

■ ■ ■ 

Ensure stability and rigor 

in the nation’s basic biomedical research 

enterprise and infrastructure. 

■ ■ ■ 

Communicate openly with 

the scientific community and the public 

2 

about the needs, value, and impact 

of the biomedical research enterprise. 

National Institute of General Medical Sciences | Strategic Plan 2008 – 2012 

INVESTING IN DISCOVERY 

The investments of the National Institute of General 

Medical Sciences (NIGMS) in broad and diverse 

areas of basic research have built a strong 

foundation of knowledge for biomedicine. Because 

science is an activity driven by human insight, the 

Institute has always believed that providing career 

stability and workforce diversity are key strategies 

for maintaining a healthy research enterprise. 

I, personally, have been fortunate to experience the benefits of 

these investments throughout my scientific career. As an undergraduate, 

graduate student, and postdoctoral fellow, my training and research were 

supported through research grants to my advisors. When I started my 

independent career, my research projects were funded through a thennew 

program directed to beginning faculty members. 

As with most basic scientists, my research followed a winding path 

of discovery. Early in my career, I was fortunate to get to work on grantsupported 

projects to explore a diversity of scientific topics. These ranged 

from the development of new physical methods to analyses of the fundamental 

chemical basis of enzyme action, the study of metalloprotein 

structures, and biological approaches to understanding gene regulation. 

Much of this research was greatly enhanced by the molecular biology 

revolution, which itself had been driven substantially by earlier NIGMSfunded 

studies. 

As a faculty member, I saw first-hand the tremendous impact of 

NIGMS-supported training grants at my academic institution, as well 

as the influence of these and other programs on the recruitment of a 

diverse group of students into research. Later in my career, I witnessed 

how NIGMS-directed programs could bring together larger groups of 

scientists to tackle important problems using emerging concepts and 

technologies. 

As Director of NIGMS, my job now is to look ahead. I have been 

entrusted to assure that NIGMS makes its financial investments with 

a careful eye toward their long-term impact on the research enterprise 

and the scientists who do the research. 

What lies ahead? The incredible complexity of biology is something 

that tantalizes and challenges us. We recognize that most biological 

processes involve large numbers of components, interacting directly 

and indirectly. But we do not yet have all the tools, both technical and 

intellectual, to understand such systems in a predictive sense. Biological 

complexity, nuances of our genomic lexicon, and many other mysteries of 

biomedicine are waiting to be solved to improve health and fight disease.

Furthermore, we know that fundamental discoveries are yet to be 

made. While no one can predict which basic findings will be the ones 

that shift paradigms or create the medical breakthroughs of tomorrow, 

I am confident that such discoveries will be made over the period of 

time covered by this plan. 

All of us see science evolving at an ever-increasing rate as new 

advances build on those from the past, and it is critical that the support 

of science adapts to this rapidly 

changing landscape. We must take 

stock of the overall system of bio- 

What lies ahead? 

medical research funding and 

The incredible examine how precious taxpayer 

complexity of biology 

be used to support the scientific 

is something that enterprise—today and into the 

resources allocated to NIGMS can 

future, harnessing the creativity 

tantalizes and 

of a broad group of scientists. 

challenges us. 

We developed the NIGMS 

Strategic Plan 2008–2012 through 

a comprehensive consultation 

process that gathered perspectives and opinions from scientists, policymakers, 

scientific and professional societies, the general public, and 

Institute staff. The plan articulates the Institute’s core principles and shows 

how it will make its strategic investments to ensure that a stable basic 

research environment will endure to provide the knowledge needed to 

prevent disease and improve health. 

Importantly, this plan is not a call for change for change’s sake. In 

developing it, we saw an opportunity to examine critically our own values 

and progress, and we intend the plan to serve as a tool for helping us map 

a course toward solving the great challenges facing biomedicine. Through 

existing programs and new initiatives, NIGMS aims to maximize the benefit 

of the public’s basic research investments in human health. 

Jeremy M. Berg, Ph.D. 

Director, NIGMS 

November 2007 

Opposite: NIGMS Director Jeremy M. 

Berg. Courtesy of Ernie Branson, 

National Institutes of Health. 

The structure of a gene-regulating 

zinc finger protein bound to DNA. 

Courtesy of Jeremy M. Berg. 

http://www.nigms.nih.gov 3

NIGMS Mission 

The NIGMS mission is to support 

research that increases understanding 

of life processes and lays the foundation 

for advances in disease diagnosis, treat 

ment, and prevention. NIGMS-funded 

researchers seek to answer important 

scientific questions in fields such 

as cell biology, biophysics, genetics, 

developmental biology, pharmacology, 

physiology, biochemistry, chemistry, 

bioinformatics, computational biology, 

and selected cross-cutting clinical areas 

that affect multiple organ systems. 

NIGMS also provides leadership in 

training the next generation of scientists 

to assure the vitality and continued 

productivity of the research enterprise. 

4 

79 percent of Americans agree that basic 

science research should be supported by 

the Federal Government, “even if it 

brings no immediate benefits.” 3 

WHY BASIC RESEARCH? 


The National Institute of General Medical Sciences is committed 

to encouraging and supporting basic biomedical and behavioral 

research in which scientists explore the unknown. Important 

medical advances have grown from the pursuit of curiosity about 

fundamental questions in biology, physics, and chemistry. 1 For example: 

■ A scientist studying marine snails found a powerful 

new drug for chronic pain. 

■ Studying how electricity affects microbes led to a 

widely used cancer medicine. 

■ A total surprise in a roundworm experiment yielded 

RNA interference, a gene-silencing method that has 

revolutionized medical research. 

■ Basic research on how bacterial “scissors” chop 

up DNA from invading viruses spawned the 

biotechnology industry. 

At the outset, none of these discoveries related directly to a specific 

medical or practical problem— and some of them took decades to come 

to fruition. While basic research sometimes leads directly to health 

applications, the usual outcome of basic research is knowledge, rather 

than a product. That knowledge is common currency for all biomedical 

scientists— those researchers working on specific diseases, as well as 

biomedical explorers who strive to understand basic principles of the 

human body and mind. 

Scientists conducting basic biomedical research often use model 

organisms to answer questions. Many processes that are fundamental 

to health and disease are very similar in humans, animals, and even 

single-celled organisms such as bacteria and yeast. Studies directed at 

addressing simple questions in these model organisms can often provide 

insights that have considerable relevance to human health. 

The power of this remarkable unity of biology — a consequence of the 

fact that all organisms on Earth are descendants of a common ancestor — 

has been greatly enhanced by the success of the Human Genome Project 

and other genome-sequencing projects that were enabled by many years 

of NIGMS funding. Through the common language of DNA, results from 

model organisms can be more readily, and rapidly, related to human health 

than ever before. 

Of the above examples, one in particular— the $40 billion biotechnology 

industry 2 — has produced tangible economic benefit to the nation 

through increased productivity and job creation. Biotechnology has proven 

to be a major force in modern medicine, having enabled drug manufacturers 

to create novel and effective treatments, such as therapeutic antibodies, 

that have few side effects and that have revolutionized the way physicians 

treat some types of lymphoma and breast cancer.

Through these and other dividends of the Federal research investment, 

scientists have made great strides in helping Americans live longer and 

healthier lives. Yet our work is far from done. To attack complex diseases 

of today such as cancer, heart disease, arthritis, depression, Alzheimer’s 

disease, diabetes, and many other chronic conditions, we need more 

knowledge. We need basic 

research to understand the 

No matter how counter- 

full complexity of disease 

processes, including what 

intuitive it may seem, 

happens in the body years 

before symptoms show up. 

basic research has proven 

Many of today’s therapies 

over and over to be the 

have significant limitations. 

Treatments that are applied 

lifeline of practical advances 

after the onset of serious 

disease — kidney transplants James Thomson derived the first human embryonic 

and dialysis, bypass surgery 

stem cell line and recently reprogrammed skin cells 

in medicine. to act like embryonic stem cells. Photo by Jeff Miller, 

for coronary artery disease, 

University of Wisconsin-Madison. 

— NOBEL LAUREATE ARTHUR KORNBERG 

surgical removal of tumors — 

though often lifesaving, are 

Fluorescently labeled cells confirm computational 

not optimal. Treating disease predictions about where various medicines and 

before such interventions are chemicals accumulate inside cells. Courtesy of 

needed would likely improve both outcomes and quality of life. Basic bio- Gus Rosania, University of Michigan. 

medical research has the power to move treatments in this direction, and 

in the coming years, emerging biotechnology and nanotechnology tools 

will give researchers unprecedented precision to detect and derail disease 

at its earliest stages. 

As an example of how basic research helps to fuel rapid progress 

in developing new and safer treatments and prevention strategies, one 

recent analysis 4 suggested that a $1 increase in public basic research 

stimulated approximately $8 of pharmaceutical research and development 

investment in less than a decade. 

In 2006, the National Institutes of Health (NIH) budget allocation 

totaled $28 billion, roughly half of the pharmaceutical industry’s $55 billion 

research and development spending in the same period. 5 Since the private 

sector spends the vast majority of its research dollars on translational and 

clinical research, NIH spending on basic research — roughly two-thirds of 

the NIH budget — is a critical balancing factor for the health of the overall 

national research enterprise. 

http://www.nigms.nih.gov 

5

NIGMS Authorizing Language 

“The Surgeon General is authorized, 

with the approval of the Secretary, to 

establish in the Public Health Service 

an institute for the conduct and 

support of research and research 

training in the general or basic medical 

sciences and related natural or behav 

ioral sciences which have significance 

for two or more other institutes, 

or are outside the general area of 

responsibility of any other institute, 

established under or by this Act.” 

— PUBLIC LAW 87- 838, OCTOBER 17, 1962 

Research Project 

Grants 

Research 

Training 

Centers 

Other Research 

Research Management 

and Support 

R&D Contracts 

Intramural Research 

6 

INSTITUTE PROFILE 


The Institute was established in 1962 to support basic biomedical 

research and training. NIGMS-sponsored discoveries build a fundamental 

body of knowledge that underpins much of the research 

conducted at other NIH institutes and centers. Most NIGMS research 

grants fund investigator-initiated projects. NIGMS also provides broadbased, 

multidisciplinary research training for thousands of scientists 

nationwide via institutional training grants and individual fellowships, as 

well as in the context of individual research project grants. 

Currently, NIGMS-funded research and training spans a broad 

spectrum of science, handled administratively by five components: 

DIVISION OF CELL BIOLOGY AND BIOPHYSICS fosters the study of 

molecular and cellular structure and function. Significant physics- and 

chemistry-based technological advances have fueled progress in understanding 

life at the level of molecules and atoms. Fundamental research 

in structural biology is the basis for the development of precise, targeted 

therapies for a range of diseases. 

DIVISION OF GENETICS AND DEVELOPMENTAL BIOLOGY promotes basic 

research that aims to understand mechanisms of inheritance and development. 

This research underlies more targeted projects funded by other NIH 

institutes and centers. A substantial number of these studies are performed 

in model organisms, an approach that continues to increase understanding 

of common diseases and diverse behaviors. 

Distribution of NIGMS Spending (Fiscal Year 2007) 

As has been the case for many years, more than 70 percent of the NIGMS 

6 

budget is devoted to research project grants (RPGs). Within the RPG pool, 

approximately 86 percent of the budget goes to R01 and R37 grants, 

1 percent to R21 grants, 1 percent to R15 grants, 4 percent to P01 grants, 

3 percent to R41/R42/R43/R44 grants, and 2 percent to U01 grants, including 

the Pharmacogenetics Research Network and the Models of Infectious Disease 

Agent Study. 

About 10 percent of the budget is devoted to research training in the form 

of institutional training grants and individual fellowships. Within this category, 

86 percent of the funds go to institutional training grants while 14 percent 

go to individual fellowships. Like all NIH institutes and centers, NIGMS also 

supports a substantial number of students and postdoctoral fellows as part of 

research project grants.

DIVISION OF PHARMACOLOGY,PHYSIOLOGY, AND BIOLOGICAL CHEMISTRY 

supports fundamental biology, chemistry, and biochemistry studies that 

deepen understanding of biomedicine and generate knowledge to improve 

the detection and treatment of disease. This research addresses several 

clinically relevant areas, including burns, wound healing, the effects of 

drugs and anesthesia on the body, and the total body response to injury. 

Investigations range from the molecular to the organismal level and can 

include clinical studies. 

DIVISION OF MINORITY OPPORTUNITIES IN RESEARCH sponsors a range 

of programs to increase the number of individuals from underrepresented 

groups engaged in biomedical and behavioral research. This investment 

aims to enhance the development of biomedical and behavioral researchers 

and help make the scientific workforce representative of the diverse 

U.S. population. 

CENTER FOR BIOINFORMATICS AND COMPUTATIONAL BIOLOGY funds 

research in areas that join biology with computer science, engineering, 

mathematics, physics, and statistics. Major emphasis is placed on the 

development of computational tools, including methods for extracting 

knowledge from very large data sets routinely amassed by modern 

biomedical research laboratories. 

Centers make up 9 percent of the budget. Most of these centers are 

associated with initiatives such as the Protein Structure Initiative, the Large- 

Scale Collaborative Award program, the National Centers for Systems Biology 

program, the Chemical Methodologies and Library Development program, 

and centers devoted to specific studies of trauma, burn, perioperative injury, 

and wound healing. 

Other research makes up 7 percent of the budget. The Minority Biomedical 

Research Support program accounts for 74 percent of this category. Research 

career awards represent another significant component. 

The remaining categories include research management and support, which 

contributes to administrative costs, such as NIGMS staff salaries and scientific 

review expenses (2.5 percent of the budget); research and development contracts 

(1 percent), which fund activities such as the NIGMS Human Genetic Cell 

Repository; and intramural research (less than 0.2 percent). 

Angelika Amon deciphers how chromosomes are 

distributed to daughter cells during cell division. 

Photo by Donna Coveney, Massachusetts Institute 

of Technology. 

Illustration of nerve signaling in the brain showing the 

interaction of nerve cells, blood vessels, and molecules 

like glucose and oxygen. Courtesy of Neal Prakash and 

Kim Hager, University of California, Los Angeles. 


7

Investigator-initiated 

research project grants — 

mostly R01s —will continue 

to remain the main focus 

of the overall NIGMS 

research portfolio. 

8 

STRATEGIC GOALS 


As history has proven time and again, basic research is an engine of 

progress. The knowledge that grows from fundamental exploration 

is essential. The future of America’s health depends on it, as does 

the nation’s global economic competitiveness. NIGMS strongly commits 

to continuing to invest in discovery by using a variety of vehicles to support 

basic research. 

GOAL I: ENHANCE THE BASIC BIOMEDICAL RESEARCH 

ENTERPRISE THROUGH GRANT SUPPORT FOR COMPETITIVE, 

INVESTIGATOR- INITIATED RESEARCH. 

NIGMS recognizes the need to provide scientists sufficient latitude to 

explore biomedicine in order to improve health. Although many important 

advances have occurred in a manner that could not have been anticipated, 

most scientific advances are more deliberate and require years of persistent 

work. While good research depends on a balance of ingredients, 

among the most important are adequate financial support and access 

to state-of-the-art resources and equipment. 

NIGMS will pursue this strategic goal through the following objectives: 

■ Maintain a balanced research portfolio that reflects scientific excellence 

and variety. By funding a wide spectrum of scientific topics, the 

Institute will encourage flexibility to allow emerging areas to be pursued 

promptly. Investigator-initiated research project grants—mostly R01s—will 

continue to remain the main focus of the overall NIGMS research portfolio. 

However, coordinated research programs will also provide an important 

and responsive avenue for addressing biomedical problems and creating 

resources for use by the scientific community at large. 

Cynthia Otto is both a critical care veterinarian and a researcher who examines the body’s 

response to traumatic injury. Photo at the University of Pennsylvania School of Veterinary 

Medicine by Alisa Zapp Machalek, NIGMS. 

Opposite: A microarray (top) reveals the activity of thousands of genes simultaneously. 

Courtesy of Brian Oliver, National Institutes of Health. 

This “lab on a chip” (middle) allows scientists to conduct several liquid-based experiments 

simultaneously in a space about the size of a postcard. Courtesy of Maggie Bartlett, National 

Institutes of Health. 

Carol Greider (bottom) studies how chromosome caps called telomeres and the enzyme that 

adds them, telomerase, maintain stable chromosomes. Courtesy of Johns Hopkins Medicine.

■ Facilitate career stability in the biomedical workforce. NIGMS recognizes 

that scientific investigation, as a human endeavor, requires career 

stability enabled through steady research funding. The Institute will 

protect the talent pipeline, especially by addressing the vulnerability of career 

transition times, as a way to encourage continuity in the research enterprise. 

While the Institute recognizes that obtaining NIH funding will always be a 

highly competitive process, NIGMS considers it very important that all 

investigators have a reasonable chance of success. In particular, NIGMS will 

make a deliberate effort to fund new investigators. These actions are especially 

relevant in limited funding climates that can disadvantage applicants 

who are new to the NIH system. NIGMS will also continue to provide 

bridge funding for highly meritorious investigators who are especially 

at risk during constrained budget periods. 

■ Provide support for innovative, high-risk biomedical research 

initiatives with the potential for achieving significant health impact. 

NIGMS will continue to encourage scientists to pursue innovation and risk 

in biomedical research. For science to move forward in leaps rather than 

in incremental steps, scientists need opportunities to test unconventional 

ideas and to try novel methods for solving difficult technical and conceptual 

problems that stall a field’s progress. One current effort initiated by NIGMS 

is the EUREKA (Exceptional, Unconventional Research Enabling Knowledge 

Acceleration) award program, in which review criteria focus on potential 

impact and exceptional innovation in research and/or technology. 

Through EUREKA and other programs, NIGMS will identify 

research proposals with the potential to have a significant 

impact on scientific knowledge and on human health. 


10 National Institute 

of General Medical Sciences | Strategic Plan 2008 – 2012 

■ At the Institute level, initiate enhancements to the peer review 

process. In addition to supporting NIH-wide enhancements to the peer 

review system, 7 NIGMS will continue to develop alternative in-house review 

practices and criteria that address review challenges, especially those that 

affect interdisciplinary research, quantitative 

biology, new scientific fields, 

and the entrance of new players into 

The Institute 

the biomedical research community. 

As part of the NIH Roadmap for 

recognizes that 

Medical Research, NIGMS administers 

the NIH Director’s Pioneer Award 

multiple approaches 

and the NIH Director’s New Innovator 

Award programs. Each of these pro- are needed to 

grams employs a novel, individualized 

peer review approach. NIGMS will solve complex 

pilot approaches that streamline 

administrative requirements for research problems. 

research project grants, always striving 

to ensure quality and consistency 

in the review of applications. 

■ Support research that analyzes fundamental mechanisms that 

traverse multiple organ systems. NIGMS will continue to fund research 

on clinically related problems, addressing several selected areas, including 

burns, wound healing, the effects of drugs and anesthesia on the 

body, and the total body response to injury. These areas of inquiry will 

remain an important element of the Institute’s research portfolio since 

they focus on biological phenomena on a systems-wide, organismal level 

and they are not funded in a comprehensive way by other NIH institutes 

and centers. Some of these NIGMS-funded research efforts will involve 

clinical studies, but the Institute will not fund purely outcomes-based 

research, nor will it systematically examine issues related to health care 

access and delivery. 

NIGMS supports research in selected clinical areas, including trauma, burn, and 

perioperative injury; sepsis; wound healing; and anesthesiology. 

Opposite: As part of the Models of Infectious Disease Agent Study, biostatisticians 

M. Elizabeth Halloran (top) and Ira Longini (bottom left) develop computational 

models to study disease transmission and intervention strategies. Courtesy of the 

Fred Hutchinson Cancer Research Center. 

Cell movement, revealed here using fluorescent dyes (corner), is the focus of one of 

the glue grants. Courtesy of K. Donais and Donna Webb, University of Virginia 

School of Medicine.

GOAL II: ADDRESS SELECTED SCIENTIFIC NEEDS AND 

OPPORTUNITIES THROUGH COORDINATED RESEARCH PROGRAMS. 

The Institute recognizes that multiple approaches are needed to solve 

complex research problems. Modern biomedical research is a collaborative 

enterprise that may involve one or a few laboratories or a large group 

of researchers. 


■ Facilitate team science along a continuum of scales to advance multidisciplinary 

and interdisciplinary inquiry. NIGMS endorses the scientific 

community’s recognition of the value of team science for some challenges 

in modern biomedical research. Novel combinations of researchers often 

self-assemble to broaden the canvas of biomedical inquiry and encourage 

diversity in thinking. NIGMS will continue to fund cross-cutting research 

in the basic biomedical, behavioral, and clinical sciences through collaborative 

programs among researchers from a wide range of disciplines, 

including the clinical, social, and quantitative sciences. One example is 

the Models of Infectious Disease Agent Study (MIDAS), which is using 

computational tools to simulate how infectious diseases emerge and 

spread through communities, countries, and even continents. NIGMS will 

encourage use of the recently established NIH multiple-principal investigator 

mechanism as a method to extend the scope of the Institute’s funded 

research. A key NIGMS strategy will be to accommodate the evolution 

of new fields that emerge at the interfaces of existing disciplines. The 

Institute will nurture the talent pipeline in emerging fields through its 

support of cutting-edge, rigorous training environments that accompany 

basic research pursuits. 


Large Grants Working Group 

The Large Grants Working Group, 

a subgroup of the National Advisory 

General Medical Sciences Council, and 

the NIGMS Office of Program Analysis 

and Evaluation lead evaluation teams 

to monitor the progress of NIGMS 

large grant programs. 8 

$1,121 

MILLION 

$189 

MILLION 

Budget for 

Budget for All NIGMS 

NIGMS R01s Large-Grant Programs 

Fiscal Year 2007 Fiscal Year 2007 

12 


■ Identify and develop large-scale research programs that offer value, 

insight, and the broadest applicability to the scientific community. 

The NIGMS portfolio currently includes the Large-Scale Collaborative Award 

program, the National Centers for Systems Biology, the Pharmacogenetics 

Research Network, the Protein Structure Initiative, and MIDAS. These 

endeavors conjoin the efforts of multiple institutions working in a common 

area of major biomedical significance. Advantages of large-scale science 

initiatives include their economies of scale and synergy, as well as the 

capacity to build new communities. NIGMS will continue to fund these 

efforts while assuring the proper evaluation of their outcomes. For Institutedirected 

large-scale efforts, NIGMS will determine whether project goals 

have been met in a timely fashion and assess the projects’ impact on the 

broader scientific community. The Institute will strive to ensure that instrumentation, 

data, and resources developed at NIGMS-funded large-scale 

science facilities are made broadly available to all scientists. 

■ Create programmatic linkages in support of NIH-wide translational 

initiatives. The NIH Roadmap has begun to address translational gaps 

through the Clinical and Translational Sciences Award (CTSA) program. 

NIGMS will consider possible linkages to CTSA institutions through 

NIGMS efforts such as the Medical Scientist Training Program. In concert 

with other NIH institutes and centers, NIGMS will also seek opportunities 

for enhancing workforce diversity through the nationwide CTSA network 

of clinical and translational investigators. 

■ Seek collaborative and shared research opportunities with other 

agencies and NIH institutes and centers in areas that show particular 

promise. NIGMS will continue to communicate regularly, and to 

partner when appropriate, with other Federal components that fund 

basic research, such as the National Science Foundation and the 

Department of Energy Office of Science. NIGMS will also join with 

the NIH community in several ways to achieve its mission of funding 

outstanding basic biomedical research. A key partnership includes the 

NIH Roadmap. NIGMS grantees already benefit significantly from this 

shared, trans-NIH investment. Current NIH Roadmap initiatives that fund 

a substantial number of NIGMS grantees include chemistry, computational 

biology/bioinformatics, imaging, nanomedicine, proteomics, and 

structural biology. In addition, several new NIH Roadmap initiatives will 

benefit the Institute’s grantee pool, providing funding and collaborative 

opportunities in epigenetics, microbial ecology, and other areas of 

science relevant to the NIGMS mission.

■ Expand support for resources and database development to facilitate 

biomedical research advances. Advances in genomics and computer 

science have created incredible opportunities to systematically explore 

biomedical problems related to human health. NIGMS will continue to play 

a key role in supporting the creation of research resources including sample 

repositories, databases, and interoperable software and hardware tools 

that enhance data exchange among 

diverse groups of researchers. As 

part of this involvement, NIGMS 

The Institute will strive to 

will develop 

policies to ensure the 

ensure that instrumentation, broad availability and interoperabil 

ity of publicly 

developed resources. 

data, and resources 

The Institute 

will continue to play 

a leadership 

role through oversight 

developed at NIGMS- of the Biomedical Information 

Science 

and Technology Initiative 

funded large-scale science Consortium, 

which consists of 

senior- level representatives from 

facilities are made broadly each of 

the NIH institutes and 

centers 

plus representatives of 

available to all scientists. 

other Federal 

agencies concerned 

with biocomputing. 

Andrzej Joachimiak (above) leads a structural genomics center supported by the Protein 

Structure Initiative, which aims to make the detailed structures of most proteins obtainable 

from their DNA sequence. Courtesy of Argonne National Laboratory. 

Mary Relling (top) is a member of the NIH Pharmacogenetics Research Network and 

seeks to understand how a person’s genetic make-up influences his or her response to 

anticancer medications. Courtesy of St. Jude Children’s Research Hospital. 

This network diagram (corner) shows all of a yeast cell’s protein-protein interactions, 

which mirror many of those in humans. Courtesy of Albert-László Barabási, University of 

Notre Dame, and Hawoong Jeong, Korea Advanced Institute of Science and Technology. 


13

Fostering diversity cannot be 

separated from the broader 

challenges of future 

workforce development. 

14 National Institute of General Medical Sciences | Strategic Plan 2008 – 2012 

GOAL III: IDENTIFY INNOVATIVE APPROACHES AMONG 

INDIVIDUALS AND INSTITUTIONS TO FOSTER TRAINING 

AND THE DEVELOPMENT OF AN INCLUSIVE AND EFFECTIVE 

SCIENTIFIC WORKFORCE. 

A key aspect of the NIGMS mission is nurturing the biomedical research 

workforce, and achieving a workforce that accurately reflects the U.S. 

population remains an Institute priority. The NIGMS training investment 

will continue to set a high standard for students’ acquisition of both 

research skills and important career-related knowledge beyond specific 

research training. The positive effects of NIGMS-funded training grants 

and fellowships are extended through collaborative interactions with 

students and faculty within and across academic departments. 


■ Support a broad range of high-quality institutional training programs 

across the biomedical sciences. The Institute views a rigorous, yet 

nurturing, training environment as a key element of a healthy research 

enterprise. NIGMS recognizes the broader effects of its institutional 

training grants in that these programs impact many students and faculty 

beyond those supported by the grants. NIGMS will leverage its training 

investment by encouraging institutional training grant recipients to 

continually improve their existing practices while also welcoming new 

approaches. NIGMS is keenly aware of the need for more personnel in 

quantitative disciplines as well as the integrative sciences like physiology, 

pharmacology, and the clinical sciences. The Institute will consider 

approaches that provide institutional incentives that encourage students 

to interact with investigators in more than one discipline. 

■ Provide funding for graduate students and postdoctoral fellows 

through investigator-initiated research project grants. The NIGMS 

research training investment is multifaceted and tightly linked to the 

Institute’s workforce development efforts. Independent of its institutional 

training grant activities, the Institute will continue to support the training 

of students and fellows working in individual-investigator (mostly R01 

grant-funded) laboratories. NIGMS considers this an important avenue 

for research training. The Institute also acknowledges the reality that 

one size does not fit all, and it will remain open to both distinct training 

mechanisms and alternative career outcomes that depend on “marketplace” 

influences.

■ Expand and extend the NIGMS commitment to facilitating the 

development of a diverse and inclusive biomedical research workforce. 

Fostering diversity cannot be separated from the broader challenges of 

future workforce development. Dimensions of diversity include ethnicity, 

gender, disability, socioeconomic status, and national origin. The Institute 

is also aware of the low representation of women in leadership positions 

in the basic sciences and aims to close these gaps. NIGMS acknowledges 

the special circumstances faced by various segments of society in accessing 

career opportunities. The Institute will examine the purpose, intent, 

and desired outcomes of NIGMS-sponsored training programs as they 

relate to workforce diversity. 

■ Address diversity and workforce development in all programs administered 

by NIGMS as a matter of both policy and practice. NIGMS is 

committed to the regular and rigorous review of all of its training efforts, 

including special diversity and career development programs, as well as 

to achieving closer coordination among the Institute’s various programs. 

NIGMS will continue to evaluate its efforts to promote biomedical research 

workforce diversity, seeking the most productive ways to distribute funding, 

and will continue to integrate diversity efforts across its programs. The 

Institute will consider implementing a “broader aims” component of 

research project grant applications that explicitly evaluates an investigator’s 

training, mentoring, and diversity activities. 

■ Adopt a comprehensive, systems-based approach to address future 

workforce development issues. The challenge of scientific workforce 

diversity is fundamentally a systems problem, and NIGMS will approach 

it in this fashion. The Institute will investigate the issue of workforce diversity 

in a data-driven, scientifically rigorous manner. Developing effective 

approaches will require that NIGMS continually acquire evidentiary data, 

even if those data do not lead to concrete solutions in the near term. 

NIGMS will expand its investment in research to understand the efficacy 

of interventions designed to increase diversity. The Institute will assess the 

feasibility of developing computer models that reflect key trends in workforce 

development and related career path issues, incorporating pivotal 

demographic, societal, and behavioral variables. NIGMS will also continue 

to identify and use early predictors of longer-term outcomes for enhancing 

workforce diversity at research institutions. 

Opposite: Carlos Gutierrez studies how bacteria acquire and transport iron and leads the 

Minority Access to Research Careers and Minority Biomedical Research Support programs 

at his institution. Courtesy of Public Affairs, California State University, Los Angeles. 

NMR spectrum (top) shows how an enzyme changes shape, which is vital to its function. 

Courtesy of Dorothee Kern, Brandeis University. 

Susan Wente and student Kristen Noble (bottom) investigate how molecules travel between the 

nucleus and cytoplasm of the cell. Photo by Dana Thomas for Vanderbilt Medical Art Group. 


Nobel Prize-Winning Research 

In its 45-year history, NIGMS has funded 

the Nobel Prize-winning work of 64 

scientists (see http://www.nigms.nih.gov/ 

GMNobelists.htm). Recent Nobelists 

supported by NIGMS include: 

■ Mario R. Capecchi & Oliver Smithies 

Physiology or Medicine 2007 

■ Roger D. Kornberg 

Chemistry 2006 

■ Andrew Z. Fire & Craig C. Mello 


■ Robert H. Grubbs & Richard R. Schrock 


■ Avram Hershko & Irwin Rose 


■ Paul C. Lauterbur 


■ Roderick MacKinnon 


16 


GOAL IV: ADVANCE AWARENESS AND UNDERSTANDING OF 

THE BASIC BIOMEDICAL RESEARCH ENTERPRISE, INCLUDING 

ITS VALUE, REQUIREMENTS, AND POTENTIAL IMPACT. 

NIGMS values transparency and positive relations with the scientific community 

and the public as critical to carrying out its mission. The Institute 

also believes that it is important to contribute to improvements in science 

education at the K-12 and other levels as a distinct diversity and workforce 

development strategy. 


■ Continue to foster an open dialogue with the scientific community 

about evolving scientific trends, gaps, and opportunities. NIGMS will 

communicate with its grantees and other members of the scientific 

community directly and through partnerships with universities, research 

institutes, scientific and professional societies, and organizations. The 

Institute will continue to issue regular programmatic updates to these 

constituents and seek input and feedback from them. NIGMS will also 

enhance efforts to empower its approximately 4,000 grantees and its 

advisory council members to serve as a highly visible group of ambassadors 

who can effectively and broadly communicate Institute programs 

and policies to multiple audiences. Additionally, the Institute will explore 

ways to increase communication among scientists working in diverse 

fields, potentially leading to new interactions and discoveries. 

Surgeon J. Perren Cobb (left) leads a multidisciplinary group of scientists who 

seek to identify gene activity patterns that signal sepsis, a dangerous response 

to severe injury. Courtesy of J. Perren Cobb, Washington University in St. Louis 

School of Medicine. 

Sea urchin embryos (right) in different stages of cell division. Courtesy of George 

von Dassow, University of Washington. 

Opposite: Haouamine A (top), a promising anticancer candidate, is one of many 

organic molecules synthesized in the laboratory of Phil Baran. Courtesy of Paul 

Krawczuk, Scripps Research Institute. 

Molecular biologist Marion Sewer and student Houman Khalili (corner) investigate 

the regulation of steroid hormone biosynthesis. Photo at the Georgia Institute of 

Technology by Gary Meek.

■ Raise public awareness and understanding about the value and 

impact of basic biomedical research. NIGMS will continue its efforts 

to communicate with the public about its goals and research results, 

as well as about NIH and its contributions to the nation's health. In our 

increasingly technology-driven society, knowledge of science—as well 

as how science is done—is important for making personal health and 

community decisions as 

well as for succeeding in 

NIGMS values transparency a wide variety of careers. 

Toward this end, NIGMS 

and positive relations with the will team with NIH institutes 

and centers and/or 

scientific community and the other organizations to 

increase scientific literacy. 

public as critical to carrying out 

The Institute will also work 

to diminish misperceptions 

its mission. 

about biomedical science 

and scientists that stem 

from outdated stereotypes 

and lack of information. NIGMS will continue to 

provide students, teach 

ers, and the general public with educational materials that illustrate the 

value of basic research and encourage the 

pursuit of scientific careers. In support of 

its efforts to foster workforce diversity, the 

Institute will partner with organizations 

and institutions to target the distribution 

of NIGMS educational and career-focused 

resources to students who belong to 

groups that are underrepresented in the 

biomedical research workforce. 


In addition to periodic 

discussions with the scientific 

community to identify broad 

research themes, NIGMS 

routinely sponsors scientific 

workshops to focus on 

particular areas of 

opportunity and develop 

plans for specific initiatives. 

18 

INSIDE NIGMS 


Strategic planning at NIGMS has always focused on identifying broad 

research themes and opportunities in the biomedical sciences that 

are either currently available or are likely to emerge in the coming 

years. In addition to periodic discussions with the scientific community to 

identify broad research themes, NIGMS routinely sponsors scientific workshops 

to focus on particular areas of opportunity and develop plans for 

specific initiatives. The results of these workshops are documented in 

reports presented to the National Advisory General Medical Sciences 

Council, which must give approval for Institute-proposed initiatives. 

Proposed new NIGMS research and training programs are made public 

at the open session of advisory council meetings. Council approval of new 

initiatives (and major changes to existing initiatives) is called “concept 

clearance.” Concept clearance authorizes NIGMS staff to develop plans, 

publish funding opportunity announcements in the NIH Guide for Grants 

and Contracts, and award grants. During the initiative planning stages that 

follow concept clearance, NIGMS welcomes comments and suggestions 

from the community. 

The research priorities identified by scientific experts in planning meetings 

such as those convened by NIGMS influence future research activities 

in several ways. The reports of these meetings are widely disseminated 

among the community of biomedical scientists who are keenly aware of 

and attentive to emerging opportunities and the stated priorities of funding 

agencies. The mere communication of these research opportunities can 

be a major influence on the direction of investigator-initiated research, as 

scientists seek to develop successful proposals for research funding. 

These stated priorities also influence the Institute’s grant funding 

decisions. While the results of peer review are always a major consideration 

in the funding of research proposals, the peer review score is not the 

only factor considered when Institute staff and advisory council members 

recommend specific grant applications for funding. Among the other factors 

taken into account is scientific program need. Meritorious proposals, 

but with somewhat poorer peer review scores, may still be funded if they 

are designated as being of high program priority. Investigators who have 

not received prior NIH funding are also given special consideration. 

Discussion among scientific experts can also identify areas of research 

in which a more active role of the Institute is required to stimulate the 

submission of research proposals. In some cases, NIGMS issues a program 

announcement or request for applications when needed to extend or 

enhance the Institute’s research portfolio.

STRATEGIC PLANNING PROCESS 

The NIGMS Strategic Plan 2008 –2012 is the result of a comprehensive 

consultation process that began in the fall of 2006 and solicited 

perspectives, opinions, and other input from scientists, policymakers, 

scientific and professional societies, the general public, and Institute staff. 

NIGMS Director Jeremy M. Berg appointed a strategic planning committee, 

composed of NIGMS staff and broadly representing the Institute, to develop 

the procedures, format, and timetable for the overall strategic planning 

process and to define some of the key issues. Following an announcement 

in the Federal Register, NIGMS posted questions on its Web site between 

February 20 and March 20, 2007. These included: 

■ What factors should NIGMS consider in deciding how to set its 

priorities with respect to new and existing areas of support? 

■ What factors should NIGMS consider in deciding how to 

set its priorities with respect to research training? 

■ What new and emerging areas, approaches, or technologies 

in basic biomedical research should NIGMS pursue? 

■ As part of its efforts to maintain a balanced research 

portfolio, how can NIGMS best encourage and support 

research that is highly innovative and/or risky? 

■ Are there areas of current NIGMS research activity that 

should receive less emphasis? 

■ How can NIGMS enhance its communications with the 

scientific community and the public? 

■ How can NIGMS more effectively promote and encourage 

greater diversity in the biomedical research workforce? 

Following the Internet comment period, NIGMS convened a 2-day conference 

in April 2007. About 50 participants were invited to represent all the 

dimensions of the NIGMS extramural scientific community. The participants 

met in both breakout and plenary sessions to discuss Institute plans and 

priorities. Discussion was framed around the same set of questions and 

issues presented in the Internet comment period. 

NIGMS staff worked at length to distill input from both the posted 

questions and the conference, and this information was used to formulate 

a draft plan, which was posted on the NIGMS Web site for public comment 

in September 2007. 

NIGMS staff work in the Natcher 

Building on the NIH campus in 

Bethesda, Maryland. Courtesy of 

Alisa Zapp Machalek, NIGMS. 


NIGMS staff and contractors, October 2006. 

Courtesy of Bill Branson, National Institutes 

of Health. 

REFERENCES 

20 National Institute of General Medical Sciences | Strategic Plan 2008 – 

2012 

1 Koshland DE Jr. Philosophy of Science. The Cha-Cha-Cha Theory 

of Scientific Discovery. Science 2007 317:761-2. 

2 Hildreth M. Resilience: America’s Biotechnology Report 2003. San Diego, CA: 

Ernst & Young; 2003. 

3 America Speaks: Poll Data Summary Vol 6. Alexandria, VA: 

Research!America; 2005. Available from: http://researchamerica.org/ 

uploads/AmericaSpeaksV6.pdf. 

4 Toole AA. Does Public Scientific Research Complement Private 

Investment in Research and Development in the Pharmaceutical 

Industry? J Law Econ 2007 50:81-104. 

5 Pharmaceutical Research and Manufacturers of America, 

Pharmaceutical Industry Profile 2007. Washington, DC: PhRMA; 2007. 

6 R01: NIH Research Project Grant; R37: Method to Extend Research 

in Time (MERIT) Award; R21: Exploratory/Developmental Grant (currently 

being phased out at NIGMS); R15: Academic Research Enhancement 

Award (AREA); P01: Research Program Project; R41-44: Small Business 

Innovation Research (SBIR) and Small Business Technology Transfer 

(STTR) Grants; U01: Research Project - Cooperative Agreement. 

7 http://enhancing-peer-review.nih.gov 

8 Large-Scale Collaborative Award program, National Centers for 

Systems Biology, Pharmacogenetics Research Network, Protein 

Structure Initiative, and Models of Infectious Disease Agent Study.

DISCRIMINATION PROHIBITED 

Under provisions of applicable public laws enacted by Congress since 1964, no person 

in the United States shall, on the grounds of race, color, national origin, handicap, or age, 

be excluded from participation in, be denied the benefits of, or be subjected to discrimina - 

tion under any program or activity (or, on the basis of sex, with respect to any education 

program or activity) receiving Federal financial assistance. In addition, Executive Order 

11141 prohibits discrimination on the basis of age by contractors and subcontractors in 

the performance of Federal contracts, and Executive Order 11246 states that no federally 

funded contractor may discriminate against any employee or applicant for employment 

because of race, color, religion, sex, or national origin. Therefore, the programs of the 

National Institute of General Medical Sciences must be operated in compliance with these 

laws and Executive Orders. 

ACCESSIBILITY 

This publication can be made available in formats that are more accessible to people 

with disabilities. To request this material in a different format, contact the NIGMS 

Office of Communications and Public Liaison at 301 - 496-7301, TDD 301 -402-6327; 

send e-mail to info@nigms.nih.gov; or write to the office at the following address: 

45 Center Drive MSC 6200, Bethesda, MD 20892-6200. This publication is available 

online at http://www.nigms.nih.gov/StrategicPlan/.

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1 of 1 1/2/2012 11:50 AM

NIEHS 2006–2011 Strategic Plan 

New Frontiers in 

Environmental Sciences 

and Human Health

C O N T E N T S 

2006–2011 Strategic Plan 

New Frontiers in 

Environmental Sciences 

and Human Health 

2 A New Vision 

4 New Frontiers 

6 Critical Challenges 

8 NIEHS Goals: Today and Beyond 

22 Appendix: Participants at the 

NIEHS Strategic Planning Meeting 

24 Notes 

Published by Environmental Health Perspectives (ISSN 0091-6765), 

a publication of the Public Health Service, U.S. Department of Printed on 30% post-consumer 

waste recycled paper. 

Health and Human Services. [NIH Publication 2006-218]

2 

A New Vision 

NIEHS 2006–2011 STRATEGIC PLAN | http://www.niehs.nih.gov/external/plan2006 

The environment represents a key contributor 

to human health and disease. Exposures to many 

substances, such as pollutants, chemicals, allergens, 

and natural toxins, all originate from the environment 

and can have a detrimental effect on health. 

Diet and lifestyle can interact with these environmental 

factors and increase or decrease their effects 

on health. Some of these environmental factors are 

under our own individual control, while others 

need to be controlled at the source through formal 

public health decisions. 

At the National Institute of Environmental 

Health Sciences (NIEHS), our work is driven by a 

desire to understand how the environment influences 

the development and progression of disease. 

As we move forward, we will focus our research on 

scientific questions that form the basis for identification 

and prevention of hazardous exposures and 

that lead to improvements in health. 

The NIEHS vision is to prevent disease and 

improve human health by using environmental sciences 

to understand human biology and human 

disease. This new vision will require a change in 

the way we conduct basic science. Traditionally, 

this research was carried out by single investigators 

working on narrowly defined hypotheses. Our new 

strategy adds integrated science teams conducting 

disease-focused research on complex hypotheses

The NIEHS vision is to prevent disease and improve human health by using 

environmental sciences to understand human biology and human disease. 

regarding the interplay of environmental agents 

and other risk factors, such as genetics, age, diet, 

and activity levels. Recent advances in technology 

make this multifaceted research possible. 

The scientists and staff of the NIEHS are committed 

to identifying and pursuing new frontiers in 

biomedical research that are likely to have the greatest 

impact on human health. Through a comprehensive 

strategic planning process, the NIEHS has 

developed a new set of goals for 2006–2011, which 

we believe will allow us to fulfill this vision. 

I was personally involved in the strategic planning 

process and am fully committed to the goals 

outlined in this document. I want to personally recognize 

and thank the dedicated individuals, both 

within the NIEHS and in our extended community 

of investigators, clinicians, and interested public, 

who participated in this planning process. Without 

their dedicated efforts on our behalf, the development 

and refinement of these strategic initiatives for 

the NIEHS would not have been possible. Among 

many, the members of the National Advisory 

Environmental Health Sciences Council deserve 

special recognition for their continued leadership 

and critical and objective guidance to our institute. 

These strategic initiatives form a blueprint from 

which we will move forward to apply environmental 

sciences to human health. There is much we plan to 

achieve, and I am excited about the opportunities 

before us. However, this plan is only our starting 

point. If we are to succeed, we’ll need to be persistent, 

but also remain nimble and responsive to 

opportunities and challenges that are currently 

unforeseen. This is part of the excitement of beginning 

this endeavor, because encountering these 

unknowns will help us tweak the path for achieving 

our vision. 

We find ourselves at an exciting time when new 

technology and testing methods are creating 

unique opportunities for scientific discovery. The 

time is right for increasing our knowledge of the 

cellular and molecular effects of environmental 

exposures. When we succeed, you will be able to 

better understand the health risks associated with 

environmental factors in order to protect your own 

health. And, state and federal authorities will possess 

the scientific knowledge needed to make the 

most appropriate public health decisions. 

Sincerely, 

David A. Schwartz, MD 

Director, National Institute of Environmental Health Sciences 

and National Toxicology Program 

New Frontiers in Environmental Health Sciences and Human Health 3

4 

New Frontiers 

We have mounting evidence that environ 

mental factors contribute substantially to most 

diseases of major public health significance. Most 

of the principal causes of death in the United 

States (cancer, chronic lung disease, diabetes, 

metabolic disorders, and neurodegenerative conditions) 

are known to have significant environmental 

causes. In addition, environmental effects on 

chronic, nonfatal conditions (birth defects, 

asthma, neurodevelopmental dysfunctions, and 

reproductive problems) are also well-documented. 

Results from studies of twins reveal that development 

of chronic human disease owes as much, 

or more, to environmental components as it does 

to genes. 

The ways in which our environment affects 

diseases and health conditions can differ from 

individual to individual depending on temporal 

factors (age and developmental stage), spatial 

factors (geographic location), and unique circumstances 

(comorbid disease, nutritional status, 

socioeconomic status, and genetics). 

This strategic plan describes the three critical 

challenges facing environmental health sciences 

and goes on to set major goals for the NIEHS to 

achieve. 


What do we mean by “environment”? In the 

broadest sense, the environment is what is all 

around you; it consists of the chemicals, foods, 

drugs, and natural products that you touch, eat, 

and breathe in everyday life. In practice, the 

NIEHS focuses its resources on studies of the 

effects of environmental agents that fall into three 

main categories: pollutants and chemicals such as 

lead, mercury, and ozone; useful commercial products 

that enter our environment and may have 

health implications, such as pesticides and herbicides; 

and natural toxins that are part of our everyday 

life, such as toxins produced by molds and 

dust mites. However, many other factors known to 

be important for health status, such as diet and 

exercise, can work separately or in combination 

with environmental agents (and with host factors 

such as genetic makeup) to influence human 

health and disease. The “environment” studies 

conducted by the NIEHS will continue to focus 

on understanding the fundamental changes in 

basic biology caused by exposure to environmental 

agents. However, this work will not be in isolation, 

and the integration of our environmental 

health science mission with understanding the 

health implications of these other health-determining 

factors is one key to improving our health 

by improving our environment.

And what do we mean by “environmental disease”? 

All diseases generally have complex etiologies that 

allow for multiple causal and pathogenic factors 

including exposure to environmental agents. 

Experience tells us that virtually all human 

diseases can be caused, modified, or altered by 

environmental agents. Hence, it is not possible 

to develop a definitive list identifying the diseases 

that are clearly caused by environmental factors. 

Instead, as is the case for environmental agents, one 

key to improving human health is identifying and 

understanding the basic biological processes that are 

altered by environmental factors, and that stimulate 

disease processes to begin or the course of the disease 

to be substantially altered. 

The NIEHS vision is to prevent disease and 

improve human health by using environmental 

sciences to understand human biology and 

human disease. 

The fundamental mission for achieving the NIEHS 

vision lies in understanding the complex relationship 

between environmental risk factors and human biology 

within affected individuals and populations, and in 

using this knowledge to prevent illness, reduce disease, 

and promote health. To accomplish this, the NIEHS 

will support research and professional development in 

the environmental health sciences, environmental 

clinical research, and environmental public health. 


6 

Critical Challenges g 

To succeed, the the NIEHS NIEHS must must address address three three critical challenges: 

critical challenges: 

The First Challenge—Programmatic Scope: 

What diseases and what exposures will be the focus of 

the NIEHS research portfolio? 

In general, the NIEHS will set research priorities 

to focus on diseases for which there is a strong 

indication of an environmental component and for 

which there is high or increasing prevalence in the 

U.S. population. In addition, the NIEHS will 

focus on exposures that carry the highest risk to the 

largest population or hold the most promising 

hope of clarifying an important disease process. In 

this way, the NIEHS can optimize the future utility 

of the scientific research we support today and 

have the largest impact on human health in the 

near future. However, the NIEHS will continue to 

fund higher-risk research efforts aimed at identifying 

more diseases that are impacted by environmental 

exposures as well as classical research aimed 

at evaluating the potential for health implications 

of emerging environmental exposures. 


The Second Challenge—Integrative Science: 

Given the explosion in new science that has occurred in 

the last decade, how will we focus our research efforts 

on the most appropriate science for a given disease and 

the related environmental exposures? 

The NIEHS will take a leadership role in improving 

human health by using environmental exposures to 

understand human biology and human disease. 

This vision is a complex one, requiring a change 

in approach to basic research, moving from our 

traditional science base of single investigators with a 

clear hypothesis to integrated research teams 

addressing the complex hypotheses associated with 

the interplay of environmental factors with many 

other factors (e.g., genetics, lifestyle, age, sex) on 

disease incidence and prognosis. The NIEHS is in a 

unique position to focus on the interplay between 

environmental exposures, vulnerable populations, 

human biology, genetics, and the common diseases 

that limit our longevity and quality of life. As we 

increase our understanding of how the human 

genome functions, the classical approach to environmental 

health research that focuses on identifying 

health hazards will be expanded to develop and 

use better tools, both to understand disease etiology 

as well as to fill data gaps regarding environmental 

health hazards. This knowledge, in turn, will 

improve our ability to identify important environmental 

toxicants, determine how past and present 

exposures contribute to an individual’s disease 

status, and improve the clinical outcome of 

environmentally caused and mediated disease.

The Third Challenge—Public Health Impact: 

How will we develop the scientific knowledge that 

empowers people to improve their environmental 

choices, allows society to make appropriate public 

health decisions, and results in our living healthier lives? 

The NIEHS will develop initiatives aimed at identifying 

the complex factors in our environment 

than can increase one’s risk of disease. The research 

supported and conducted by the NIEHS already 

forms the basis through which most public health 

agencies identify and manage harmful environmental 

exposures. We know that with the right 

information, it is possible to improve our lives by 

taking steps to avoid harmful environmental exposures 

and lifestyles. Having that knowledge available, 

either directly or through our medical 

providers or community organizations, is key to 

making this happen. Everyone’s environment is 

important to his or her health, but different groups 

of people are exposed to different agents by virtue 

of where they live, work, and play. And two people 

exposed to the same environmental agent could 

respond differently due to other factors such as 

genetics and age. The ways in which environmental 

agents increase disease risks for an individual are 

still poorly understood. As the NIEHS moves forward, 

we are committed to supporting the basic 

research that drives the scientific basis for health 

decisions, as well as the applied research that fills 

gaps in our understanding of environmental health 

risks. 

Our Commitment: To move our vision 

forward, the NIEHS will identify and fund the best science 

possible to address the diseases and exposures that are likely 

to have the greatest impact on human health. 


8 

NIEHS NIEHS Goals: Goals: 

y y 

Toda Today and Beyond Be ond 

The following seven goals represent strategic 

investments that ensure all three major research 

components of the NIEHS (intramural, extramural, 

and the National Toxicology Program[NTP]) 

continue to have the greatest impact on 

preventing disease and improving human health. 

These seven goals form the core of the NIEHS 

Strategic Plan and outline enhancements to the 

current NIEHS research portfolio that will 

expand our basic and applied science efforts in 

both exposure-oriented and disease-oriented 

research, improve the scientific utility of 

community-based research by embracing a wider 

geographic approach to identify more diverse 

environmental and genetic factors, and provide 

needed support for recruiting and training 

tomorrow’s scientists. These seven goals span all 

three critical challenges. Our commitment to 

these goals through existing programs and new 

initiatives will allow the NIEHS to maximize the 

benefits of our research investments for the 

nation’s health. 


GOAL I: 

Expand the role of clinical research in 

environmental health sciences. 

The NIEHS will encourage research that emphasizes 

the study of environmental exposures to 

inform clinical research. Traditionally, environmental 

impacts on disease have been studied from 

either the perspective of the exposure or the perspective 

of the disease. Advances in biology over 

the last few years have been remarkable in creating 

the opportunity to address environmental disease 

from a more integrated perspective. One important 

area where this integration could take place is 

within an expanded clinical research program. This 

approach will use environmental exposures to provide 

a greater understanding of human disease by 

strengthening the evidence that a given exposure is 

toxic, determining how specific environmental 

exposures affect disease etiology and progression, 

and using environmental exposures to identify 

molecular targets to determine susceptibility and 

intervention. Diseases for which environmental 

health sciences can provide important clinical 

insight include (but are not limited to) such common 

disorders as immune-mediated diseases, neurodevelopmental 

disorders, neurodegenerative 

diseases such as late-onset Parkinson’s disease, cardiovascular 

diseases, reproductive disorders, and 

lung diseases, especially asthma. There are three 

major steps that must be accomplished for this 

effort to be successful. 

Encourage clinical research that emphasizes the use of 

environmental exposures to understand and better characterize 

common, complex diseases. This approach 

assumes that common, complex diseases are syndromes 

that represent many pathological entities,

and that environmental agents can be used to narrow 

the pathophysiological phenotype so that an 

exposure–response relationship can be investigated. 

For example, in complex diseases such as asthma, 

individual responses to different environmental 

agents can help aggregate patients into discrete subtypes 

that can more effectively be evaluated for the 

specific pathogenic mechanisms that are causing 

symptoms. In this way, environmental agents can 

provide the key to differentiating among the 

numerous phenotypes for such complex diseases. 

Assuming the different phenotypes are linked to 

different mechanisms, this will generate the following 

immediate public health benefits: improved 

understanding of host susceptibility, stronger linkages 

between exposure and disease, improved disease 

prevention, and the development of clinically 

relevant biomarkers that can be used to identify 

additional environmental agents of concern. 

Develop improved research models for human disease 

using our knowledge of environmental sciences and 

human biology. Knowledge of comparative genomics 

linked with an added emphasis on research findings 

from humans now offers new opportunities for 

developing models of human disease and disease 

pathogenesis that enhance understanding of the 

linkage between genes, exposures, biology, and disease. 

With more creative application and development 

of these models, the NIEHS hopes to identify 

critical pathways that improve our ability to extrapolate 

and translate laboratory findings to humans. 

In addition, improved in vivo models could be used 

to uncover new mechanisms associated with disease. 

One important area with high priority will be 

epigenetics, where environmental influences might 

have a particularly strong impact. Finally, a wide 

array of genetically modified animals can provide 

researchers new resources for conducting experiments 

in comparative biology, identifying conserved 

biological responses that uncover new 

biological mechanisms, and testing the importance 

of genes in exposure–response relationships. 

Enhance the role of the clinical investigator in environmental 

health sciences. A clinical research program 

requires physicians and Ph.D.s who are trained to 

conduct and/or support clinical research in environmental 

health sciences. Medically trained scientists 

are familiar with the varied manifestations of 

human disease and can focus their own research on 

scientific questions that are clinically relevant. In 

addition, the integrative possibilities for using 

clinical research to address exposure-specific or 

disease-specific environmental questions necessitate 

physician-scientists providing support to basic or 

public health investigators who wish to focus their 

interests on clinically relevant areas of human disease. 

Another possibility for strengthening the 

focus on clinical research includes enhancing the 

biomedically related dimensions of doctoral 

training programs. 


GOAL II: 

Use environmental toxicants to understand 

basic mechanisms in human biology. 

Studying environmental exposures can provide a 

controlled method for targeting and manipulating 

cellular machinery in ways that provide insight 

into both basic biology and the mechanistic events 

leading to clinical disease. Because environmental 

agents can operate early in the disease process, they 

indicate useful techniques for uncovering very early 

events in disease pathogenesis. These techniques 

can be used to identify methods to diagnose diseases 

before they are clinically evident, to develop 

early interventions that prevent progression to endstage 

disease, and to identify targets for screening 

additional environmental agents. In this way, environmental 

agents have tremendous potential for 

use as probes in understanding the processes of 

common chronic diseases, as well as identifying 

possible routes for intervention. Through this goal, 

the NIEHS will expand the “toolbox” developed 

under the National Institutes of Health (NIH) 

Roadmap initiative titled “New Pathways to 

Discovery.” This expanded “toolbox” will enhance 

technologies for environmental research over the 

next decade. The initial efforts under this initiative 

will concentrate on three fundamental biological 

processes, elucidated below, having immediate 

implications for environmental health sciences. 

10 NIEHS 2006–2011 STRATEGIC PLAN | http://www.niehs.nih.gov/external/plan2006 

Support research that improves our understanding 

of signal transduction pathways and their influence on 

disease. Cells respond to environmental signals, 

toxicants, and stressors through multiple mechanisms, 

many involving communication pathways 

such as signal transduction. The identification, 

quantification, and interpretation of the signal 

transduction pathways affected by the environment 

that play critical roles in human diseases are likely 

to present new avenues for therapeutic intervention 

and prevention of environmental disease. Of immediate 

importance is increasing our knowledge of the 

pathways involved in oxidative stress, inflammation, 

and apoptosis, as well as the impact of these 

processes on common diseases. These processes are 

increasingly recognized as important pathways that 

underlie many environmentally induced diseases. 

These pathways and their responses to environmental 

insults will help to uncover causes and treatments 

for a variety of human diseases. 

Expand our understanding of environmental influences 

on genome maintenance/stability and its impact on 

human health. Human cells are astonishingly good 

at defending the integrity of their genome using 

DNA repair and other damage-tolerance systems 

to limit the impact of assaults on their integrity. 

Environmental exposures have been shown to create 

DNA damage, but can also affect the ability of 

a cell to repair DNA once damage has occurred. 

The failure to repair DNA damage can initiate a 

large number of human diseases, and more effort is 

needed to evaluate the role of the environment in 

altering genome maintenance and stability. Thus, 

the study of environmental factors that modify 

DNA damage, repair, and maintenance is an 

important area of investigation, particularly with 

regard to aging, cancer, and cell death.

Lead a concerted effort to improve our understanding of 

epigenetic influences on health. A dynamic interplay 

exists between the input received from the extracellular 

environment and the expression of genes 

within a cell. Integration of the key cellular signals 

to produce very specific genomic responses is 

essential to proper cellular function and disease 

avoidance. Environmental signals can alter the 

functioning of genes in many ways, both directly 

and indirectly. Epigenetics refers to a group of 

mechanisms that regulate patterns of inheritance 

and gene expression without changing DNA 

sequences and that are potentially crucial in the 

interface between genes, environment, and disease. 

These mechanisms include, but are not limited to, 

DNA methylation, imprinting, and histone acetylation 

and post-translational modifications. The 

overall impact of environmental changes on these 

mechanisms remains poorly understood, yet the 

consequences of modifying them can result in an 

increased risk of developing cancer, immunologic 

diseases, and other complex diseases. 

NIH Roadmap: The NIEHS participates in, and 

benefits from, a number of Roadmap initiatives. For example, since 

August 2005, the NIEHS, through the NTP, has formally partici 

pated in the NIH Roadmap Molecular Libraries Initiative (MLI). This 

collaborative effort is aimed at assisting the MLI project leaders 

with development of their screening program by adding a toxicity 

testing capability to the MLI effort. In addition, this collaboration is 

allowing rapid implementation of the NTP’s High Throughput 

Screening Assays program by providing the NTP access to estab 

lished testing laboratories through interinstitute cooperation. 

Specifically, the NTP, through its association with the MLI, has the 

opportunity to generate information that links data on the biologi 

cal activity of environmental substances generated from high- 

throughput screening assays with toxicity end points identified in 

the NTP’s toxicology testing program. 

The NIEHS is one of 27 research institutes and centers that comprise the 

National Institutes of Health (NIH). 


GOAL III: 

Build integrated environmental health 

research programs to address the crosscutting 

problems in human biology and 


Interactive, team-based scientific research will be 

needed to optimize our ability to integrate research 

from all levels of investigation in order to contribute 

to overall health and reduce the burden of 

complex, multifaceted diseases. The study of how 

an environmental agent affects molecular targets, 

cellular function, tissue function and organism survival 

will need to be related up and down a continuum 

of biological complexity that ultimately 

informs us about the etiology, pathogenesis, and 

distribution of disease. Scientific contributions 

from epidemiology, toxicology, molecular and cellular 

biology, bioinformatics, clinical medicine, 

and many other fields will need to be coordinated 

and integrated. This collaborative approach will 

enable us to fully understand complex diseases and 

identify the most likely environmental links, and 

more effectively reduce health risks and disease 

burdens in human populations. 

Promote interdisciplinary, integrative research 

approaches. The NIEHS should design and implement 

models for research that integrate clinical, 

epidemiological, and toxicological research with 

basic mechanistic studies to address disease etiology, 

pathogenesis, susceptibility, and progression. 

By fostering such broad-based, collaborative 

research, the NIEHS will increase the relevance of 

basic scientific discoveries in environmental health 

sciences to human disease and rapidly and more 

effectively move this knowledge into clinical and 

public health application, ultimately improving 

human health. As a first step, the NIEHS research 


programs will be reoriented to foster collaborations 

across teams of scientists with complementary skills 

and areas of expertise. These collaborations will 

enable the NIEHS to better address important 

research needs and enable the institute to better align 

with cross-NIH efforts such as the NIH Roadmap 

for Medical Research (http://nihroadmap.nih.gov). 

Identify and remove barriers to integrative research. 

Integrative research requires teams of investigators 

who are willing to cross the boundaries of their 

own disciplines to develop research that they simply 

can’t do on their own. The NIEHS will examine 

how the current structure of incentives and 

grants (e.g., peer review, training, and funding 

mechanisms) can be changed and use this information 

to encourage the creation of the integrated 

research teams that will be needed to perform 

future environmental health research. 

Improve and expand access of researchers to advanced 

technology and scientific infrastructure. The face of 

modern environmental health research is constantly 

changing, and new technologies have 

played an important role in driving these changes 

and leading to new discoveries. Cutting-edge environmental 

health research utilizes these newer, 

resource-intensive technologies in many ways, such 

as the use of mass spectrometry and NMR in 

metabonomics and proteomics research. These 

technologies are expensive and require expertise 

that is not always available at every institution or in 

every research group. For this reason, the NIEHS 

will foster efforts to coordinate and collaborate in 

the use of technologically advanced instruments 

and to provide access to conceptually demanding 

scientific infrastructure, ultimately accelerating 

discoveries in environmental health sciences.

GOAL IV: 

Improve and expand community-linked 

research. 

The NIEHS has a noted tradition of supporting 

research relevant to understanding health disparities 

and concerns of disadvantaged communities. 

Different groups of people are exposed to potentially 

toxic agents depending on where they live, 

work, and play. Differences in the environment are 

thought to contribute substantially to the excess burden 

of disease found in minority populations or 

impoverished communities. Examples of health indicators 

for which these disparities exist include shorter 

life expectancy, higher cancer rates, more birth 

defects, greater infant mortality, and higher incidence 

of asthma, diabetes, and cardiovascular disease. 

The ways in which poverty and other factors 

create these health disparities are still poorly understood. 

However, there is increasing evidence that 

poor and minority groups are burdened with a disproportionate 

share of residential and occupational 

exposure to hazardous substances such as metals, 

pesticides, wood dusts, and air pollutants. In addition, 

the increasing mobility of our population 

raises the likelihood that exposures occurring 

remotely must be accounted for in assessing environmental 

exposure history as a contributor to disease 

burden. Thus, environmental exposures 

represent an important area of investigation for 

understanding and ameliorating the health disparities 

suffered by the disadvantaged of this nation 

and around the world. 

The NIEHS is the primary federal agency 

responsible for supporting research, prevention, 

and training efforts to reduce the adverse health 

impact of environmentally related diseases. 

DISCOVER: The NIEHS is developing a new 

research grant program called DISCOVER (Disease Investigation 

for Specialized Clinically Oriented Ventures in Environmental 

Research). DISCOVER will bring together basic, clinical, and pop- 

ulation-based scientists to conduct integrative research pro 

grams on (1) understanding the etiology and pathogenesis of 

human diseases influenced by environmental factors, (2) using 

exposure to understand the interplay between genetic and envi 

ronmental factors, and (3) applying available state-of-the-art 

technologies and methods to improve human health. 


Therefore, the NIEHS has taken a lead role both 

in investigating the environmental influences on 

these conditions in minority and socioeconomically 

disadvantaged populations and in developing 

tools and strategies that will prove effective for 

reducing health disparities. We will continue to 

support research, both domestically and globally, 

that can offer important insights into how to 

reduce exposures and disease incidence in these 

community settings. 

Focus on populations that are exposed to high concentrations 

of environmental agents that are thought to 

cause human disease. NIEHS-supported scientists 

have long recognized that exposures to environmental 

pollutants vary by locality around the 

world and can offer fruitful avenues for defining 

the impact of the environment on human health. 

The likelihood of exposure to environmental toxicants 

increases in most economically disadvantaged 

communities and is associated with an excess disease 

burden in these communities. Studies on the 

higher levels of environmental exposure in defined 

communities can lead to insight into potential 

health effects and can also offer unique opportunities 

for teasing apart different cellular pathways that 

contribute to the development of complex diseases. 

Use of newly developed technologies in exposure 

assessment and exposure biology will also facilitate 

this research, leading to a greater understanding of 

disease risk, pathogenesis, and prevention. 

Focus on diseases that are unevenly distributed and 

have a high impact on morbidity and mortality. 

Variations in the incidence of diseases offer clues 

that may suggest where environmental agents are 

contributing to disease pathogenesis. The NIEHS 

will aggressively pursue research that follows up on 

these clues to target the most prevalent and severe 


diseases. Targeting these diseases, which have 

great variation across communities, maximizes the 

probability that this research will have the greatest 

possible impact on major problems in public health. 

Develop a program in global environmental health. In 

the modern global economy, very few environmental 

concerns can be truly described as affecting only 

a single country or geographic region. As the 

nation’s premier environmental health research 

institute, the NIEHS has an obligation to address 

environmental health issues both nationally and 

globally. By expanding the definition of community 

to include a broader global perspective, the 

NIEHS is able to create the partnerships necessary 

for an effective global research strategy. The 

NIEHS is in the process of cultivating partnerships 

to better leverage resources in pursuit of new and 

emerging opportunities in global environmental 

research. 

Build capacity to pursue research in global environmental 

health. One of the major deterrents to bringing 

cutting-edge mechanism-driven environmental 

health research to bear on global health problems is 

a lack of proper research training and access to a 

research infrastructure in many countries. The 

NIEHS will pursue three avenues for increasing the 

current capacity of trained personnel and research 

infrastructure: (1) develop training opportunities for 

young investigators from other countries; (2) work 

with universities to develop regional environmental 

health centers designed to work in collaboration 

with U.S. agencies operating overseas, nongovernmental 

organizations, and host governments; and 

(3) encourage all three major components of the 

NIEHS (intramural, extramural, and NTP) to 

have international partners.

GOAL V: 

Develop sensitive markers of environmental 

exposure, early (preclinical) biological 

response, and genetic susceptibility. 

Without accurate, personalized measures of exposure, 

we simply will not be able to assess the 

importance of the environment on human health. 

Thus, improvement in exposure assessment has to 

be one of the top priorities for research in environmental 

health science. Identifying and characterizing 

past environmental exposures is currently very 

difficult, if not impossible, for many agents of concern. 

The methodologies for detection and measurement 

of the actual exposure sustained by a 

human or other organism is most often weak and 

imprecise. This is in striking contrast to the robust 

tools we employ in the fields of genetics and 

genomics. In order to advance the field of environmental 

health sciences, we need personalized measures 

of environmental exposure that rival the 

ability to measure genetic variability between individuals. 

The increasing sophistication of our 

understanding of the biological pathways involved 

in host response to a given exposure points the way 

toward the use of that knowledge in the development 

of improved methods for detecting and measuring 

environmental exposures. 

Develop validated biomarkers of exposure, susceptibility, 

and effect. The NIEHS, through the Genes and 

Environment Initiative, plans to support the development 

of biomarkers that would be accurate for 

the relevant timeframes (such as previous or historical 

exposures), be mechanistically linked to diseases 

of interest, and serve to link environmental 

exposures with biological effects. The ultimate 

goal is integration across biomarkers, allowing 

researchers to study disparate biological responses 

to exposures. Modern molecular biology has provided 

biomedical research with an array of technologies 

that allow us to look at large numbers of 

genes, proteins, and other cellular components 

using small biological samples. It is possible that 

these same technologies may hold some promise 

for registering changes in cellular components following 

environmental exposures that remain in the 

body for a sufficiently long period of time to serve 

as biomarkers of past exposure. It would be particularly 

valuable to focus on a specific exposure– 

disease relationship and address it using multiple 

exposure assessment tools. Research areas with a 

critical need for specific biomarkers include common 

biological responses (inflammation, oxidative 

stress, apoptosis, and DNA damage), markers of 

gene and protein expression, and markers of organ 

dysfunction. 

Develop new exposure technologies. Measurement of 

exposures in the general environment may also be 

improved through the use of newer technologies. 

These technologies need to be cheaper, faster, and 

better than those currently available. Practical 

needs, such as real-time measurement of exposures, 

detection of low doses, quick turnaround, and high 

throughput, are minimal requirements of this 

objective. The NIEHS will also capitalize on continued 

improvements in portability and sophistication 

of personal monitoring devices, field 

monitoring devices, and surveillance kits. Of particular 

interest is the use of nanotechnology for 

low-cost, micro-scale characterization of environmental 

and biological samples and in imaging technologies 

to evaluate environmental exposures. 

Imaging technologies are a potentially rich area for 

innovation in environmental health research and can 

be used to identify functional changes in exposure 


and effects (e.g., MRI to quantify manganese and 

iron in the brain). Accelerator mass spectrometry 

may be another ultrasensitive tool for detecting 

exposures, and molecular imaging may be useful for 

investigating protein–protein interactions. 

Address institutional barriers to effective exposure 

assessment and toxicity assessment in humans. 

In many evaluations of health risks, among the 

biggest hurdles to overcome are the historical 

approaches and means by which previous evaluations 

were conducted. The changing face of biomedical 

research, however, requires a fresh 

evaluation of how we evaluate exposures and risks. 

Acceptance of new methods and techniques 

requires a number of scientific tasks that the 

NIEHS can lead. Examples include standardization 

and validation in sampling methodologies, 

development of exposure assessment strategies and 

tools, and illustration of the use of novel biomarkers 

and predictive models. Improved bioinformatics 

will also be needed to analyze and link the large 

data sets currently being generated. Additionally, 

the NIEHS will work to develop protocols and 

controls that ensure appropriate use of biomonitoring 

and biomarker data in human studies, including 

attention to ethical concerns. 


GOAL VI: 

Recruit and train the next generation of 

environmental health scientists. 

The NIEHS is committed to cross-disciplinary 

training to attract the next generation of environmental 

health scientists and train them for the interdisciplinary 

research of the future. Environmental 

health scientists will need to be conversant in more 

than one discipline so that their research will have 

the greatest impact on understanding human 

health and disease. Along with developing interdisciplinary 

teams of scientists to work together on 

important environmental health issues, the NIEHS 

will extend its current commitment for training in 

the disciplines of epidemiology, exposure assessment, 

toxicology, cell and molecular biology, 

genetics, and bioinformatics, and will add crossdisciplinary 

training. In addition, the NIEHS must 

find a way to attract the brightest young students 

and scientists into our field in order to ensure that 

the full promise of environmental health research is 

met. This is especially true for scientists in fields 

that have not traditionally focused on environmental 

health, such as medicine, computer science, 

bioengineering, and biophysics. 

Increase recruitment of talented students into environmental 

health sciences. A variety of strategies will be 

pursued to increase the visibility of the field of 

environmental health sciences and to create incentives 

for recruitment. Providing field experiences 

for interested students, increasing the likelihood of 

funding for future researchers, aggressively recruiting 

students at health fairs and scientific meetings, 

and creating customized approaches for attracting 

students at various points in the educational 

pipeline (high school, college, and graduate

school) will increase awareness and interest. 

The NIEHS will enhance opportunities for young, 

motivated high-school and undergraduate students 

to participate actively in research. 

Engage the broader biomedical community in environmental 

health research. Schools of medicine, schools 

of public health, and traditional graduate science 

programs have an important role to play in the 

overall effort to provide a more robust focus in 

environmental health sciences. The success of the 

clinical research program is linked to our ability to 

integrate environmental health science more effectively 

into medical school curricula and research so 

that future physicians are better equipped to consider 

and understand the interaction of environment 

with human health. In addition, public 

health scientists are traditionally trained in multiple 

fields and are an excellent resource for helping 

the NIEHS develop the research teams of the 

future. However, the underpinning of all of our 

research efforts is based in fundamental research 

and will require continued support of trainees in 

basic disciplines in the biomedical sciences. 

ONES: The Outstanding New Environmental Scientist 

(ONES) Award is a first independent research grant designed to 

attract the most talented younger researchers into the field of 

environmental health sciences. The NIEHS aims to identify a 

cadre of outstanding scientists in the early, formative stages of 

their careers who are interested in developing a career in 

environmental health sciences research, and to provide a strong 

start for these individuals. These grants will assist young 

scientists in launching innovative research programs focusing on 

problems of environmental exposures and human biology, human 

pathophysiology, and human disease. 


GOAL VII: 

Foster the development of partnerships 

between the NIEHS and other NIH institutes, 

national and international research agencies, 

academia, industry, and community organizations 

to improve human health. 

The NIEHS depends on strong partnerships with a 

wide variety of organizations and agencies to 

achieve its mission. Community groups are key 

partners in identifying environmental issues and 

diseases of concern, as are regulatory agencies, 

academia, and industry. Studies can be initiated 

more successfully and results will be more useful if 

the perspectives of all stakeholders are represented 

in the planning process. 

Engage partners across disciplines in government, 

academia, and industry to expand the reach and relevance 

of environmental health sciences. Unlike many 

other fields of research, environmental health science 

research is not limited by an organ system, a 

methodological approach, a single disease, or a 

population. Its multidisciplinary nature offers great 

promise, but also presents challenges. Since research 

activities are usually organized around disciplines 

and institutions, there are barriers to collaborations 

across disciplines and missions. Public investments 

will be optimized by developing ways to integrate 

across multiple disciplines and research groups. 

Provide leadership in developing partnerships to facilitate 

critical studies. Many organizations and agencies 

have access to long-standing study populations 

that are relevant to issues other than those they 

were originally assembled to address. In many 

cases, other organizations or agencies will have 

questions or concerns in environmental health 

sciences that might be answered most effectively by 


using an existing study population. The NIEHS 

intends to provide leadership in developing means 

for scientists from multiple organizations and 

agencies to share access to study populations 

and/or their data. This leadership will include 

enhancing the stability/accessibility of databases, 

repositories, and registries through partnerships 

with other organizations. These types of partnerships 

will also be brokered to provide more opportunities 

to study unique populations through twin 

registries, occupational cohorts, and large cohorts 

that cannot be assembled by a single agency. 

Through these partnerships, the NIEHS will also 

investigate identification of high- and low-exposed 

populations that could be used in comparative 

studies. Partnerships could also help develop tools 

to better assess social and economic inequities that 

are becoming increasingly important in understanding 

relative disease risks within a population. 

Work with agency, industry, and community partners to 

enhance communication and translation of research 

results into effective means to protect public health. 

The NIEHS needs to reach out and engage its key 

partners, both to ensure we are funding the best 

and most relevant science and to ensure that we are 

making the greatest possible impact on the nation’s 

health. We will continue to improve our ties to our 

partners, to ensure that the best science is brought 

to the processes of health care, community intervention, 

and regulatory decision-making.

SUMMARY 

The scientific challenge posed by environmental 

health science research is to support the best science 

possible to develop the tools and information 

needed to improve the health of humans worldwide. 

This challenge will require a very broad 

scientific view with the ability to focus on the 

questions that are relevant to the practical needs of 

the public while providing flexibility to address the 

needs of the future. The researchers and staff supported 

by the NIEHS are dedicated to using what 

we know regarding the interaction of humans and 

other organisms with their environment to understand 

human disease and improve human health. 

The strategic goals outlined in this document focus 

on the future and describe the directions for environmental 

health sciences to support the best science 

possible into the 21 st century. With the hard 

work and dedication of us all, the NIEHS can 

move into this new era of exciting challenges that 

hold the promise of better environmental health. 

Genes and Environment 

Initiative: In an effort to accelerate our under 

standing of how genetic and environmental risk factors influence 

health and disease, the NIH has launched the Genes and 

Environment Initiative (GEI). 

The GEI has two main components: a system for analyzing genetic 

variation in groups of patients with specific illnesses, and an envi 

ronmental technology development program to produce and vali 

date new methods for monitoring environmental exposures that 

interact with a genetic variation to result in human diseases. The 

NIEHS is taking a lead role in the environmental technology devel 

opment program, and the GEI Working Group is co-chaired by 

NIEHS director David Schwartz and Francis Collins, director of the 

National Human Genome Research Institute. 

This initiative is seen as so important to the advancement of bio 

medical research that companies including Pfizer, Inc., of New 

York, NY, and Affymetrix, Inc., of Santa Clara, CA, announced they 

will jump-start the GEI by contributing over $20 million dollars to 

the project through a public–private partnership known as the 

Genetic Association Information Network (GAIN). 


The Process 

The development of the NIEHS Strategic Plan 

followed a detailed and accelerated timetable 

beginning in the spring of 2005, and engaged a 

broad spectrum of individuals—investigators, 

clinicians, other scientists, engineers, policy advocates, 

and interested citizens—in providing their 

perspectives and opinions to the institute. The 

initial step in the process was an invitation to 

NIEHS stakeholders to help identify promising 

areas of need and opportunity in the environmental 

health sciences, as well as to suggest 

new potential directions for the NIEHS and its 

research programs. Key milestones in the planning 

sequence included the following initiatives 

and events: 


NIEHS staff, with additional input from area 

investigators in Research Triangle Park, formed a 

strategic planning working group to develop the 

procedures, format, and timetable for the overall 

strategic planning process and to define some of 

the key issues. 

Following an announcement in the Federal 

Register, a six-question web survey was posted on 

the NIEHS website between June 22 and August 

5, 2005. The questions posed were: 

1. What are the disease processes and public 

health concerns that are relevant to environmental 

health sciences? 

2. How can environmental health sciences be 

used to understand how biological systems 

work, why some individuals are more 

susceptible to disease, or why individuals 

with the same disease may have very different 

clinical outcomes? 

3. What are the major opportunities and 

challenges in global environmental health? 

4. What are the environmental exposures that 

need further consideration? 

5. What are the critical needs for training 

the next generation of scientists in environmental 

health? 

6. What technology and infrastructure are 

needed to fundamentally advance 

environmental health science? 

Over 400 responses were received from scientists 

and clinicians in universities, other research 

institutions, and government, as well as from 

advocacy groups and individual citizens. NIEHS 

staff worked at length to distill all the input into a 

single summary document.

Over 400 responses were received from scientists and clinicians in universities, other 

research institutions,and government, as well as from advocacy groups and individual citizens. 

Using the input from the web survey, six 

broadly defined discussion topics were identified as 

being central to strategic decision-making on the 

future direction, emphasis, and priorities of NIEHS 

programs. 

In September, senior NIEHS staff made a 

detailed presentation on the strategic planning 

process at the scheduled meeting of the NIEHS 

National Advisory Environmental Health Sciences 

Council. Questions and discussions at the meeting 

explored options for analysis and decision-making 

in key areas. 

To continue the strategic dialogue, a “Strategic 

Planning Forum” was hosted by the NIEHS on 

October 17 and 18, 2005, in Chapel Hill, North 

Carolina. The forum was co-chaired by Dr. 

Frederica Perera, professor of environmental health 

sciences and director of the Columbia Center for 

Children’s Environmental Health at Columbia 

University’s Mailman School of Public Health, and 

Dr. Gerald Wogan, Underwood-Prescott Professor 

of Toxicology Emeritus and professor of chemistry 

emeritus at the Massachusetts Institute of 

Technology. Over 90 invited scientists, clinicians, 

and persons representing support and advocacy 

organizations participated in a highly interactive 

program involving intense, small-group discussion 

on six core topics related to future NIEHS priorities. 

Each discussion group was given specific issues 

and questions to consider in their respective topic 

area; was asked to reach a general consensus on 

their conclusions; and reported their outcomes at a 

plenary session that followed. The procedure was 

followed through three successive cycles to cover all 

six topics. Additionally, following the plenary 

presentations, all participants were asked to list the 

proposed priorities they felt were most important in 

each topic area. Questions were also posed at the 

conclusion of the meeting for the attendees’ consideration 

and response. 

The substantial input from the Strategic 

Planning Forum was gathered and analyzed by 

NIEHS staff and advisors. Recommendations and 

subject area priorities were weighed, as were the 

detailed transcripts from every discussion group. 

Summaries from the discussion sessions were combined 

into a formal “proceedings” of the forum. 

Additional discussions were held in November 

2005 with members of the NIEHS Public Interest 

Liaison Group, representing nongovernmental medical, 

environmental, and policy organizations with 

interests in the institute and the future direction of 

environmental health research, research applications, 

and policy. Emerging NIEHS scientific priorities 

were the central topic of the discussions. 

The draft NIEHS Strategic Plan was posted on 

the NIEHS website for public comment in 

December 2005. Feedback from the website was 

gathered for consideration as the document continued 

to be revised. 

Key components of the NIEHS Strategic Plan 

were shared with staff at an all-hands meeting in 

January 2006 hosted by the institute director. 

Following advanced distribution, the proposed 

NIEHS Strategic Plan was presented to and discussed 

at the NIEHS National Advisory Environmental 

Health Sciences Council meeting in February 2006. 

In response to the council discussion, the plan was 

further revised and finalized. 


Appendix pp 

Participants at the NIEHS Strategic Planning Forum 

Vas Aposhian, PhD 

Professor 


Trevor Archer, PhD 

Chief, Laboratory of Molecular Carcinogenesis 



Dan Baden, PhD 

Professor and Center Director 

University of North Carolina Wilmington 

Marianne Berwick, PhD, MPH 

Chief, Epidemiology 

University of New Mexico School of Medicine 

Christopher Bradfield, PhD 


University of Wisconsin—Madison 

Deborah Brooks 

President and CEO 

The Michael J. Fox Foundation for 

Parkinson’s Research 

Jim Bus, PhD, DABT 

Science Policy Leader 

Dow Chemical 

Gwen Collman, PhD 

Chief, Susceptibility and Population Health Branch 



Deborah Cory-Slechta, PhD 

Director, EOHSI 

University of Medicine and Dentistry 

of New Jersey—Robert Wood Johnson 

Medical School 

George P. Daston, PhD 

Procter & Gamble 

Kathleen Dixon, PhD 

Department Head, Molecular and Cellular Biology 


David Eaton, PhD 

Center Director 


Peyton Eggleston, MD 


Johns Hopkins Bloomberg School of Public Health 

John Essigmann, PhD 


Massachusetts Institute of Technology 

Bill Farland, PhD 

Acting Deputy Assistant Administrator for Science 

Environmental Protection Agency 

Elaine Faustman, PhD, DABT 



Robert Floyd, PhD 

Member and Program Head 

Oklahoma Medical Research Foundation 

Ruth Frischer, PhD 

Frischer-Dambra Consulting Corporation 

Mike Gallo, PhD 





Marilie Gammon 


University of North Carolina at Chapel Hill 

Joseph Graziano, PhD 

Professor and Associate Dean for Research 


Lisa Greenhill, MPA 

Associate Executive Director 

Association of American Veterinary 

Medical Colleges 

John Groopman, PhD 

Professor and Chair, Department of 

Environmental Health Sciences 


Traci Hall, PhD 

Senior Investigator 



Bruce Hammock, PhD 



Carol Henry, PhD DABT 

DABT Vice President 

American Chemistry Council 

Irva Hertz-Picciotto, PhD, MPH 



John Hildebrandt, PhD 


Medical University of South Carolina 


Michael Holsapple, PhD 

Executive Director 

International Life Sciences Institute 

Michelle Hooth, PhD 

Toxicologist 



Howard Hu, MD, ScD 


Harvard School of Public Health 

Barbara Hulka, MD 

Kenan Professor Emerita 


Phil Iannaccone, MD, DPhil 



Randy Jirtle, PhD 



Jerry Keusch, MD 

Associate Dean for Global Health 

Boston University School of Public Health 

Cathy Koshland, PhD 


University of California, Berkeley 

Jim Krieger, MD 

Chief, Epidemiology, Planning & Evaluation 

Public Health—Seattle & King County 

Thomas Kunkel, PhD 

Chief, Laboratory of Structural Biology 



Bruce Lanphear, MD, MPH 

Center Director 

Cincinnati Children’s Hospital Medical Center 

Paul Lioy, PhD 





Stephanie London, PhD 




Fernando Martinez, MD 


University of Arizona

Cynthia McMurray, PhD 


Mayo Clinic 

Elise Miller, MEd 


Institute for Children’s Environmental Health 

Fred Miller, MD, PhD 

Director, Environmental Autoimmunity Group 



Lee Newman, MD 


University of Colorado Health Sciences Center 

David Ozonoff, MD, MPH 


Johns Hopkins University/Boston University 

School of Public Health 

Dhavalkumar Patel, MD, PhD 



David Peden, MD 



Frederica Perera, DrPH 



John Peters, MD 

Hastings Professor 


Jim Popp, DVM, PhD 

Vice President Elect, Society of Toxicology 

Stratoxon, LLC 

Ken Ramos, PhD 

Professor and Chairman, Biochemistry and 

Molecular Biology 

University of Louisville 

Carrie Redlich, MD, MPH 



Isabelle Romieu, MD, MPH, DSc 

Instituto Nacional de Salud Publica 

Marschall Runge, PhD 

Professor and Chair, Department of Medicine 


Ivan Rusyn, MD, PhD 

Assistant Professor 


Stephen Safe, DPhil 


Texas A&M University 

Regina Santella, PhD 



David Savitz, PhD 

Professor and Chairman, Department of 

Epidemiology 


Ellen Silbergeld, PhD 



Martyn Smith, PhD 


University of California, Berkeley 

Peter Spencer, PhD 

Senior Scientist and Center Director 

Oregon Health Sciences University 

Bill Suk, PhD 

Director, Center for Risk and 

Integrated Sciences 



Jim Swenberg, DVM, PhD 



Jack Taylor, MD, PhD 




Palmer Taylor, PhD 

Associate Vice Chancellor for Health Sciences 


Sholom Wacholder, PhD 



Cheryl Lyn Walker, PhD 


University of Texas MD Anderson Cancer Center 

Clarice Weinberg, PhD 

Chief, Biostatistics Branch 



Bruce Weir, PhD 

Director, Bioinformatics Research Center 

North Carolina State University 

Brenda Weis, MSPH, PhD 

Special Assistant to the Director 



David Wheeler, PhD 

Associate Professor 


Allen Wilcox, MD, PhD 




Marsha Wills-Karp, PhD 


Cincinnati Children’s Hospital Medical Center 

Nsedu Obot Witherspoon, MPH 


Children’s Environmental Health Network 

Jerry Wogan, PhD 

Professor Emeritus 

Massachusetts Institute of Technology 

Shelia Zahm, PhD, ScD 

Deputy Director, Division of Cancer Epidemiology 

and Genetics 


Darryl Zeldin, MD 




Harold Zenick, PhD 

Acting Director, National Health and 

Environmental Effects Research Laboratory 

Environmental Protection Agency 


The NIEHS, located in Research Triangle Park, North Carolina, is 

one of 27 research institutes and centers that comprise the 

National Institutes of Health (NIH), U.S. Department of Health and 

Human Services (DHHS). The mission of the NIEHS is to reduce the 

burden of human illness and disability by understanding how the 

environment influences the development and progression of 



NOTES:

P.O. Box 12233 

Research Triangle Park, North Carolina 27709-2233 

Published by Environmental Health Perspectives (ISSN 0091-6765), 

a publication of the Public Health Service, 

U.S. Department of Health and Human Services. 

[NIH Publication 2006-218] 

U.S. Department of Health and Human Services 


National Institute of Environmental Health Sciences


CANCER CHANGING THE CONVERSATION 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 


The Nation’s Investment in 

Cancer Research 

AN ANNUAL PLAN AND BUDGET 

PROPOSAL FOR FISCAL YEAR 2012

CONTENTS 

1 Foreword: Changing the Conversation 

3 Cancer Biology 

10 Prevention and Screening 

18 Care and Treatment 

24 The NCI Portfolio 

28 Partnering for Progress 

32 Preparing a New Generation for Cancer Research 

33 Provocative Questions 

34 Profles of Six Cancers: Introduction 

34 • Melanoma 

38 • Glioblastoma 

41 • Acute Myeloid Leukemia 

44 • Neuroblastoma 

46 • Lung Cancer 

48 • Ovarian Cancer 

52 Revitalizing the Nation’s Cancer Clinical Trials System 

54 Director’s Afterword 

56 Budget

FOREWORD: Changing the Conversation 

Advances accrued over the past decade of cancer research have fundamentally 

changed the conversations that Americans can have about 

cancer. Although many still think of a single disease affecting different 

parts of the body, research tells us—through new tools and technologies, 

massive computing power, and new insights from other felds—that cancer is, 

in fact, a collection of many diseases whose ultimate number, causes, and 

treatment represent a challenging biomedical puzzle. Yet cancer’s complexity 

also provides a range of opportunities to confront its many incarnations. 

We now know that cancer is a disease caused by changes in a cell’s genetic 

makeup and its programmed behavior. Sometimes these changes are spontaneous, 

and sometimes they arise from environmental or behavioral triggers, such 

as ultraviolet radiation from sunlight or chemicals in tobacco smoke. We have 

at hand the methods to identify essentially all of the genomic changes in a cell 

and to use that knowledge to rework the landscape of cancer research, from 

basic science to prevention, diagnosis, and treatment. 

This knowledge brings us—and our national conversation—to a crucial opportunity 

for acceleration in the study of cancer and its treatment. The emerging 

scientifc landscape offers the promise of signifcant advances for current and 

future cancer patients, just as it offers scientists at the National Cancer Institute—and 

in the thousands of laboratories across the United States that receive 

NCI support—the opportunity to dramatically increase the pace of lifesaving 

discoveries where progress has long been steady but mostly incremental. Some 

of the important scientifc discoveries and their potential implications are recounted 

in the pages that follow. 

The scientifc puzzles we work to solve are illustrated in this document through 

profles of six cancers in which the arc from basic research to clinical utility to 

patient outcomes is especially evident. We could have picked other cancers, 

and in future reports we undoubtedly will, but each of these profles highlights 

the unique contribution that federal investment through NCI has made and 

can make. 

N A T I O N A L C A N C E R I N S T I T U T E | 1

2 

In this report we also hope to spark a broader conversation about the value of 

the nation’s portfolio of investments in efforts to control cancer—from basic 

research, to prevention and diagnosis, to education about cancer causes and 

cancer care and treatment, to the support of cancer survivors. Indeed, we have 

a lot to talk about. 

While those perspectives are only beginning to inform the American public’s 

perception about cancer and its treatment, the trajectory of cancer deaths 

refects real and sustained reductions over the past decade or so for 

numerous cancers, including the four most common: breast, colorectal, lung, 

and prostate. We have identifed proteins and pathways that different cancers 

may have in common and represent targets for new drugs for these and many 

other cancers—since so often research in one cancer creates potential benefts 

across others. And we have made great strides in strategies to prevent cancer 

(such as quitting smoking and limiting hormone replacement therapy), 

and to detect cancer earlier, when treatment is more effective and outcomes 

more favorable. 

We reap the rewards of investments in cancer made over the past 40 years or 

more, even as we stake out a bold investment strategy to realize the potential 

we see so clearly. No matter what the fscal climate, NCI will strive to commit 

the resources necessary to bring about a new era of cancer research, diagnosis, 

prevention, and treatment. 

A fair share of those resources will be committed to the technical work 

required to understand the full dimensions of the molecular basis of cancer, 

coupled with the intricate analyses that translate that understanding into 

actionable strategies to reduce the burden of cancer. And we are continually 

reminded that cancer research, perhaps more than the study of any malady, 

involves the deepest knowledge of human biology. 

| N A T I O N A L C A N C E R I N S T I T U T E

Scanning electron micrograph 

of breast cancer cells clumped 

together to form a tumor. 

Cancer Biology 

Cancer is a disease of cells gone awry, of uncontrolled proliferation, of 

the loss of normal patterns of cell behavior. Cancer arises from a series 

of genetic and epigenetic changes (usually DNA-associated proteins 

that infuence gene expression) that endow the cancer cell with its malignant 

behavior. During their transformation from normal to cancer, tumor cells 

undergo a large number of key changes. At the simplest level, cancer cells divide 

at inappropriate times. They don’t respond to the stop and go signals that normal 

cells do. In their development into tumors, they acquire a range of characteristics 

that help them survive, proliferate, invade, and grow. These changes include 

the production of new blood vessels (angiogenesis) to bring needed nutrients for 

continued tumor growth, and also include physiological actions that block the 

body’s attempts to get rid of cancerous cells through immunological responses. 

The tumor develops into what researchers now realize is essentially a new tissue— 

perhaps even analogous to a new organ—becoming a complex mixture of tumor 

and normal cells in the tumor microenvironment that help support the existence 

and continued proliferation of the embedded cancer cells. And, most devastatingly, 

cancer cells learn to move from their initial home to new, sometimes 

distant, sites in the body. 

Despite these complexities and challenges, scientists now have a rapidly growing 

knowledge of the biology of a vast array of cancers, across a wide range of sites, 

both in solid tissue and blood. Some cancers exhibit characteristic changes, while 

changes in other cancers may be more heterogeneous. What are the changes? 

What causes each change? Where in its unnatural life cycle is a cancer cell most 

vulnerable? It is a hugely complicated set of questions. But it is also a list against 

which we have made huge strides. 


4 

The study of cancer biology must be as diverse as the stages of tumor development 

and the panoply of diseases being studied. Understanding the biology of 

cancer requires intensive work at the laboratory bench, in the cold room, at the 

computer, and at the blackboard. It utilizes such diverse tools as cells grown in 

culture, frozen human tissues, and organisms as simple as fruit fies or yeast. 

It involves dialogues and conversations, in person and in the scientifc literature. 

NCI’s cancer biology research—initiated largely by investigators in hundreds of 

NCI-funded laboratories across the U.S.—helps build the basic knowledge of 

normal and cancerous cells, developing an ever-deeper understanding of 

biological mechanisms that may provide the basis for clinical applications to 

follow. We support and coordinate research projects at NCI and at universities, 

hospitals, research foundations, and businesses across the U.S. and abroad. This 

lofty mission starts with the simplest of questions: What is—and isn’t—normal? 

From such deceptively simple questions, the study of cancer biology builds the 

foundation for progress in cancer prevention, screening, diagnosis and treatment. 

Cancer research today, especially on the frontiers America’s cancer researchers 

are renowned for spearheading, requires investment at a scale unimaginable 

40 years ago. 

The study of cancer biology touches on a number of important threads. Researchers 

study cancer-related mechanisms of DNA damage and repair, and investigate 

tumor immunology, as well as other responses of the body to cancer, and the 

biology of malignancies of the immune system. They identify interactions of 

cancer cells with the host microenvironment, and seek to better understand the 

molecular mechanisms of tumor growth and progression to more aggressive 

behaviors, such as angiogenesis, invasion, and metastasis. They develop 

genetically engineered mouse models of cancer to understand the progression 

of cancers and test interventions in intact organisms, and they analyze cancers 

as complex systems via computational models. 

The discoveries of basic biology in cancer are usually more than a simple step 

away from clinical application. These are the scientifc advances, however, that 

drive further research into new drugs and treatments—the backbone, if you will, 

of progress for patients in the future. 

To help illustrate the power of this dynamic research engine, we present two 

stories to show the dynamic nature of this feld and the way that cancer research 

gets done. 

| N A T I O N A L C A N C E R I N S T I T U T E 

Conceptual illustration of DNA.

A CONTROL GOES WRONG: IDH GENE MUTATIONS 

How do tumor cells acquire their new characteristics? 

One way is through the acquisition of mutations in their 

genes that, in turn, lead to production of abnormal 

proteins. In this way, cancer cells can co-opt, or highjack, 

a normal physiological process and generate new 

characteristics that help them survive or proliferate. 

Cancer biologists continue to identify and characterize 

these types of mutations. 

IDH, an enzyme (a protein that speeds up, or catalyzes, 

chemical reactions in the body) plays an essential role in 

converting simple carbohydrates into the molecule that 

the cell uses as a key energy source. About two years 

ago, mutations in the IDH gene were identifed in glioma, 

a type of brain cancer. Prior to that time, scientists were 

not aware that IDH and the pathway in which it works 

played an essential role in the development of any 

cancer. Since then, however, more than 70 percent of 

low-grade gliomas and secondary glioblastomas (more 

aggressive tumors that arise from low-grade gliomas) 

have been found to have mutations in the IDH gene. 

Research has also confrmed that some cases of 

two other very different tumor types, acute myeloid 

leukemia, a cancer of the blood and bone 

marrow, and lung cancer, carry mutations 

in these genes. 

The enzyme activities of the proteins 

produced by mutant forms of the IDH 

gene are different from those of normal 

proteins. IDH normally changes 

the simple carbohydrate isocitrate into 

a new compound, ketoglutarate. The 

mutations make this enzyme dysfunctional. 

Instead of making ketoglutarate, 

IDH now consumes ketoglutarate and 

makes a third compound, hydroxyglutarate. 

One consequence of this difference 

is that the tumor cells with IDH gene 

mutations produce much more hydroxyglutarate 

and much less ketoglutarate, 

metabolic changes common to cancer 

cells. These two compounds regulate a 

wide range of biological processes, such 

as how the cells use sugars or iron and how 

they respond to oxygen levels. In essence, 

these changes force cells to take on the energy 

metabolism of cancer cells. 

Even more importantly, if the mutant IDH proteins are 

eliminated from cells, the cells revert to their normal 

behavior. To gain more insight into how IDH gene mutations 

affect the growth and survival of cancer cells, and 

building on other NCI-funded basic research, the Broad 

Institute of MIT and Harvard is participating in NCI’s 

Cancer Target Discovery and Development Network 

(http://ocg.cancer.gov/programs/ctdd.asp), to identify 

small molecules that block the production of hydroxyglutarate 

by mutant IDH proteins. 

Computed tomography (CT) 

scan in axial section through 

the head of a 30-year old 

man with a malignant, 

rapidly growing glioma 

(yellow, lower right). 


6 


HARNESSING THE IMMUNE SYSTEM FOR THERAPEUTIC 

INTERVENTION IN CANCER 

Another area of intense research in cancer cell biology 

is aimed at understanding how tumors evade the body’s 

immune system, its natural defense against infections 

and other diseases, including cancer. 

The immune system is comprised of white blood cells, 

including B-cells and T-cells, natural killer cells, macrophages, 

and dendritic cells, as well as other components; 

it can usually control or destroy invading bacteria 

and viruses. But cancer cells often evade that fate, 

because they resemble normal, healthy cells in enough 

ways to impede immune responses from being directed 

against them. In addition, even as tumors grow and their 

cells develop more and more genetic mutations, in effect 

becoming more “foreign” to the body, they can suppress 

the function of normal cells in their microenvironment to 

further thwart the immune system’s ability to attack and 

destroy cancer cells. Over the past decade, NCI funding 

has supported a number of researchers studying 

ways to strengthen the body’s immune response against 

tumors or harness the power of the immune system. 

This therapeutic strategy, called immunotherapy, often 

involves the use of laboratory-made antibodies, socalled 

monoclonal antibodies, that hone in on specifc 

proteins or antigens located on the surface of cancer 

cells. When the antibodies bind to their corresponding 

antigens on cancer cells, they can alert the immune 

system that the cancer cells are foreign invaders that 

must be eradicated. Binding 

of these antibodies to cancer 

cells may also disrupt communications 

systems inside 

the cells, causing the cells 

to self-destruct. Although 

some antigens targeted in this 

manner are also found on the 

surface of normal cells, they 

are often much more abundant 

on cancer cells, making 

them excellent targets for 

immunotherapy. 

The monoclonal antibody 

trastuzumab was developed 

in part through NCI-supported 

research. 

One particularly well known monoclonal antibody, 

trastuzumab (Herceptin), developed in the 1990s, can 

exert its anti-cancer effects by several mechanisms, 

including targeting a cell-surface protein called HER2. 

This protein was frst identifed over a decade earlier 

when researchers studying cancer in rodents discovered 

that the rodent version of HER2 contributed to the 

development of tumors, which led to the subsequent 

recognition in humans that approximately one-quarter 

of women who develop breast cancer have tumors that 

produce much more HER2 than normal (referred to as 

HER2-positive). These cancers are particularly aggressive, 

but trastuzumab treatment greatly improves the 

overall survival of many women with HER2-positive 

disease and is usually administered in combination with, 

or after treatment with, conventional chemotherapy and 

possibly radiation. 

As with much of the research NCI funds, fndings about 

one kind of cancer can translate into advances against 

others. In 2010, the Food and Drug Administration 

approved the use of trastuzumab to treat HER2-positive 

stomach cancer after a clinical trial showed patients 

treated with this antibody had improved survival. Stomach 

cancer is a notoriously diffcult to treat cancer, and 

trastuzumab is the frst promising new therapy approved 

for this disease in two decades.

COMPUTATIONAL MODELS 

Cancer systems biology applies computational and 

mathematical modeling to better understand the complexities 

of cancer. Its growth has been spurred over the 

past few years by signifcant technological advances in 

high-throughput techniques, such as microarrays, next 

generation genome sequencing, and techniques used to 

analyze protein interactions with DNA. 

Traditional engineering sciences use computational modeling 

to predict what effects a broken wire will have on an 

electronic circuit. In the same fashion, cancer systems 

biology modeling can predict what effects various anticancer 

drugs will have on a cell or a patient. Traditional 

approaches to drug design rely primarily on linear logic 

or one-gene models, but blocking one target molecule is 

not always suffcient, because cells often fnd alternative 

routes to escape the blockage. This is one reason why 

many current drug design strategies fail. The systems 

biology approach is well suited for analyzing diseases 

such as cancer, which involve a large number of genes 

and pathways interacting via complex networks. Many 

researchers believe that a systems biology approach has 

the potential to overcome the limitations of linear models 

and identify new options for cancer treatment. 

Computational modeling works by investigating the 

relationships between the pathways that control the cell’s 

response to infammation, growth factors, DNA damage, 

and other events. The goal is to create a dynamic model 

of the biological processes related to cancer initiation, 

progression, and metastasis. The resulting data are then 

applied to sophisticated mathematical, statistical, and 

computational methods, and the results are used to predict 

patients’ responses to new drugs. “With computational 

models, you might be able to intelligently guess what 

will and won’t work for a patient before you try it,” said 

Paul Spellman, Ph.D., a researcher at Lawrence Berkeley 

National Laboratory, supported in part by the NCI Integrative 

Cancer Biology Program, or ICBP. “It offers the 

chance to learn about biological phenomena that might 

take thousands of hours in the laboratory to discover.” 

These types of advances are critically dependent on NCIfunded 

research, such as the ICBP, which currently funds 

nine Centers for Cancer Systems Biology. 

A transcriptional network of proteins 

related to brain tumors. Arrows 

indicate possible protein relationships 

derived from computational modeling, 

overlayed on immunofuorescent 

stains of tumor cells. 


8 


THE CANCER GENOME ATLAS 

Near the end of 2005, NCI and the National Human 

Genome Research Institute announced plans for an 

intriguing new initiative. Each committed $50 million 

over several years to what would be a pilot project, 

designed to determine whether large-scale sequencing, 

followed by intricate analysis and characterization, could 

accelerate understanding of the molecular basis of cancer. 

It was an ambitious undertaking, conducted through 

a network of more than 150 researchers at dozens of 

institutions across the nation, including a biospecimen 

resource to collect, process, and distribute tissue samples; 

genome sequencing centers; and genome characterization 

centers, which are identifying larger-scale 

genomic changes, such as gene copy number changes 

(increases and decreases), gene expression, DNA modifcation, 

and chromosomal translocations that can lead 

to cancer’s development and progression. The frst types 

selected for study were brain, ovarian, and lung cancers. 

Fewer than three years after its announcement, 

The Cancer Genome Atlas (TCGA, as it was nicknamed) 

delivered its frst results. In glioblastoma multiforme, 

the most common—and deadly—form of brain cancer, 

TCGA researchers identifed three previously unrecognized 

mutations that occur in the disease with signifcant 

frequency, along with core pathways that are disrupted 

Sequencing of 

DNA involves many 

complex procedures, 

including those 

depicted here: Loading 

beads, comprised 

of long pieces of DNA, 

into wells on plates 

(middle), which are 

then placed into a 

DNA sequencer 

(at left) and read 

as scatter plots 

(at right) or “satay 

plots,” whereby 

each colored dot 

on the plot is one 

base pair in a DNA 

sequence. 

in glioblastoma. The results, based on the genomes 

of 206 patients, also pointed to a potential mechanism 

of resistance to a chemotherapy drug commonly used 

in glioblastoma. A follow-up fnding from this study, 

announced in 2010, showed that glioblastoma is not a 

single disease, but appears to be four distinct molecular 

subtypes, each susceptible to different treatments. This 

knowledge has potential, over time, to lead to therapies 

better tailored to each subtype. 

TCGA’s science is providing the catalyst for further 

research that holds promise to affect the treatment of 

many forms of cancer—beginning with the knowledge 

of its genes and how they go wrong. 

TCGA’s plan for the next few years is as ambitious 

in today’s environment as it was at the beginning: 

sequence, characterize, and understand the genomic 

changes of 20 or more additional tumor types. 

In addition to looking at genetic changes, TCGA will also 

be exploring epigenetic changes, which involve the addition 

or removal of chemical tags and DNA-associated 

proteins to the DNA itself. These epigenetic changes 

can lead to the development and spread of cancer and 

are vital to the understanding of the cancer process.

JAVED KHAN, NCI MOLECULAR BIOLOGIST 

“During my 

training as 

a pediatric 

oncologist at 

Cambridge 

University in 

the early 1990s, 

I was struck by 

how limited our 

knowledge was 

about the biology 

of childhood 

cancers.” 

That stark 

assessment, 

particularly 

the inability 

to know why 

some patients 

with a given 

type of cancer 

respond 

to treatment, 

while others do 

not, led Javed 

Khan, M.D., 

to the study of 

molecular biology—and ultimately to join the Pediatric 

Oncology Branch in NCI’s Center for Cancer Research. 

“I came to NCI to do a combination of clinical practice 

and cutting-edge science—what is now called translational 

medicine,” said Khan. That led him to genomics 

and recently to a sweeping effort in children’s cancers. 

Launched in 2010, the NCI-sponsored Pediatric Cancer 

Genome Project is sequencing the genomes of tumors 

from hundreds of children with cancer to discover 

genetic changes causing or driving the disease. 

The goal, Khan said, is to “identify the Achilles’ heel 

of these cancers.” 

Researchers involved in this project are at St. Jude 

Children’s Research Hospital and the Washington 

University School of Medicine in St. Louis. St. Jude 

has a repository of biological samples and clinical 

information from children who have been treated there 

since the 1970s. The collection represents a treasure 

trove of information about cancer, and it can now be 

scrutinized using the latest genomic technologies. 

Importantly, sequencing genomes of patients 

and tumors is a starting point. Once an alteration 

in a gene has been discovered, said Khan, 

further research needs to be done in order to 

determine whether that changed gene affects 

behavior in a cell. “The easiest mutations to 

understand are those that affect the proteincoding 

regions of DNA, which comprise 2 percent 

of the genome. That’s important because 

proteins can be good drug targets.” 

“You have to sequence many hundreds of genomes 

to look for what’s commonly changed in 

that 2 percent,” added Khan. “And if it’s commonly 

changed, then you would hypothesize 

that’s actually an important area; this may be 

a gene that’s important for driving that tumor.” 

This type of change is known as a driver mutation. 

“It is most likely,” said Khan, “that most 

of the changes that we see are not going to be 

driver mutations; the majority of the changes 

are not going to be functionally signifcant. Perhaps 

fve or 10 genetic alterations will be the 

drivers that become targets for future therapies 

in pediatric cancer.” 

Initially, genomic characterization will assist 

clinicians in prescribing appropriate treatments. By 

genomic profling of patients, Khan said, “we fnd that 

we can separate the tumors out into the good and poor 

players. The good players we know respond to therapy.” 

Because they are childhood cancers, added Khan, “at 

the genetic level, they’re not as complicated as, say, 

breast cancers, which have accumulated multiple mutations 

over many years.” Yet, these single mutations or 

changes identifed in rarer childhood cancers may be 

important drivers in many other cancers. 

Winnowing down a list of potential therapeutic targets 

will be one of NCI’s key contributions in the years ahead, 

posited Khan. The pharmaceutical industry, he said, will 

not follow every discovery of a single mutated gene. NCI 

and academia will primarily be the players responsible 

for validating the importance of gene mutations and 

alterations in cancer biology and resolving which are the 

ones best suited for drug development. It is, said Khan, 

all about a “translatable type of research.” 


10 

Prevention and Screening 

Prevention and screening represent the twin pillars of our pre-emptive 

defenses against cancer. Cancer prevention includes efforts to forestall 

the process that leads to cancer, along with the detection and treatment 

of precancerous conditions at their earliest, most treatable stages, and the 

prevention of new, or second primary, cancers in survivors. Cancer screening 

identifes either precancers or early cancers that are still highly amenable to 

treatment while the number of malignant cells is very small. 

Research on cancer prevention and screening focuses on three main areas: 

developing early detection and screening strategies that result in the identifcation 

and removal of precancerous lesions and early-stage cancers; developing 

medical interventions, such as drugs or vaccines, to prevent or disrupt the 

carcinogenic process; and risk assessment, including understanding and 

modifying lifestyle factors which increase cancer risk. To illustrate our progress 

in this area, we present three examples—colorectal cancer screening, cervical 

cancer vaccines, and ending tobacco use—of different approaches to cancer 

prevention and screening that can dramatically reduce cancer burden. 

| 

N A T I O N A L C A N C E R I N S T I T U T E 

Virtual colonoscopy uses CT scans 

to create an image of the colon 

and detect precancerous polyps.

Screening for Colorectal Cancer 

Colorectal Incidence and Mortality 1975-2007 

Rates per 100,000 people 

70 

60 

50 

40 

30 

20 

10 

0 

1975 

1977 

1979 

1981 

A prime example of the power of prevention research is the substantial progress 

we have made in reducing colorectal cancer incidence and death, with new 

insights illuminating the way toward even greater reductions in the near future. 

Colorectal cancer, currently the second leading cause of cancer death in this 

country, is frequently preventable and highly treatable if detected early. From 

1975 through 2007, mortality from this disease declined by 40 percent in the U.S., 

due to changes in risk factors, increased screening, and advances in treatment. 

The Cancer Intervention and Surveillance Modeling Network (CISNET), sponsored 

by NCI’s Division of Cancer Control and Population Sciences, estimates that more 

than 50 percent of this decline can be attributed to screening tests, including 

fecal occult blood tests (FOBT), fexible sigmoidoscopy, and colonoscopy. These 

screening tests help reduce colorectal cancer mortality by identifying early-stage 

cancers and adenomatous polyps, which can be precursors to colorectal cancer, 

for removal. 

Besides improvements in risk factor modifcation and treatment, there are substantial 

opportunities for improvements in colorectal cancer screening, through 

better adherence to screening recommendations and increased accuracy of 

screening tests. According to a 2008 survey conducted by the Centers for Disease 

Control and Prevention, only 64 percent of respondents age 50 or older reported 

having an FOBT within the preceding year or a sigmoidoscopy or colonoscopy 

within the previous 10 years. Factors that likely contribute to this lack of full 

compliance include limited access to affordable health care, resistance to dietary 

limitations imposed prior to screening, and aversion to bowel cleansing techniques 

and invasive procedures associated with colonoscopy and sigmoidoscopy. 

1983 

1985 

1987 

1989 

1991 

1993 

1995 

1997 

1999 

INCIDENCE 

MORTALITY 

2001 

2003 

2005 

2007 


12 


Because no cancer screening test is 100 percent accurate, scientists continue 

to develop new screening tests and improve existing tests. In one cutting-edge 

area of research, scientists supported by the NCI Alliance for Nanotechnology 

in Cancer are trying to improve the accuracy of colonoscopy using gold-coated 

nanoparticles to target cancerous or precancerous cells in the colon wall 

before a visible growth has formed. Light emitted from the colonoscope would 

be refected by the nanoparticles, allowing the abnormal cells to stand out 

better from the surrounding normal cells. The use of nanoparticles to deliver 

toxic agents to cancerous cells in the colon is also being investigated. 

Another line of research focuses on the use of drugs or other agents to prevent 

colorectal cancer, especially among individuals at increased risk of this disease. 

Clinical trials sponsored by NCI’s Division of Cancer Prevention, Division of 

Cancer Epidemiology and Genetics, and Division of Cancer Treatment and 

Diagnosis, have already shown that nonsteroidal anti-infammatory drugs 

(NSAIDs)—aspirin, celecoxib, and sulindac (plus difuoromethylornithine)—can 

reduce the incidence of new adenomatous polyps in people who have had one 

or more polyps removed previously. Moreover, a recent analysis of data from 

four clinical trials showed that aspirin taken for several years at a dose of at 

least 75 milligrams per day reduced colorectal cancer incidence and mortality. 

Because NSAIDs have been associated with a number of adverse effects, 

fnding even safer, more-effective preventive agents than those already identifed 

is an important emphasis of further research. 

A Vaccine to Prevent Cervical Cancer 

As recently as the 1940s, cervical cancer was a major cause of death among 

women of childbearing age in the U.S. Widespread introduction of the Papanicolaou 

test (better known today as the Pap test) in the 1950s, which allows 

early detection of abnormal and cancerous cells in the uterine cervix, helped 

reduce cervical cancer incidence and mortality in this country by more than 

70 percent. Cervical cancer now ranks 14th as a cause of cancer death among 

American women. 

Nevertheless, in certain populations and geographic regions of the U.S., cervical 

cancer incidence and death rates are still high, due in large part to limited access 

to cervical cancer screening and follow-up care. Cervical cancer incidence and 

death rates also remain high in developing countries, where more than 80 percent 

of cervical cancer cases occur. Worldwide, cervical cancer is the third most 

common cancer among women and the second most frequent cause of cancerrelated 

death, accounting for nearly 300,000 deaths annually. As in this country, 

limited access to cervical cancer screening and follow-up care are signifcant 

factors contributing to the burden of cervical cancer.

Human papillomavirus particle 

visualized using a transmission 

electron micrograph. 

In recent decades, increased understanding of how cervical cancer develops 

has led to major advances in the early detection and prevention of this disease. 

We now know that persistent infections with certain types of the human 

papillomavirus (HPV) are the cause of the vast majority of cases of cervical 

cancer. Scientists in NCI’s Division of Cancer Epidemiology and Genetics made 

crucial discoveries that led to this awareness, and scientists in NCI’s Center 

for Cancer Research pioneered techniques that enabled the development of 

two FDA-approved vaccines to prevent cervical cancer. These vaccines target 

two types of HPV that cause approximately 70 percent of cervical cancer cases 

worldwide, and one of the vaccines additionally targets two types of HPV that 

cause about 90 percent of cases of genital warts. 

Scientists at NCI have made crucial discoveries that led to the awareness of how 

cervical cancer develops and pioneered techniques that enabled the development 

of vaccines to prevent the disease. 

HPV infection causes several types of cancer—anal, vulvar, vaginal, and 

oropharyngeal—in addition to cervical cancer. There is potential for vaccines 

to prevent these other HPV-associated cancers. 

Despite this success, much more needs to be done. At least 13 other types of 

HPV are classifed as oncogenic, or high-risk for cancer. The approved HPV 

vaccines offer modest cross-protection against some, but not all of these 

additional high-risk virus types. 

Developing new vaccines that provide broader 

and more effective cross-protection— 

ideally, against all oncogenic types of 

HPV—is a priority. The availability of 

vaccine formulations that are less 

costly to produce and might not 

require refrigeration would also 

encourage the implementation 

of vaccination programs more 

widely, especially in less 

developed countries. 


14 

THE NATIONAL LUNG SCREENING TRIAL 

Recent initial 

results from the 

National Lung 

Screening Trial 

(NLST), a randomizednational 

study involving 

more than 

53,000 current 

and former 

heavy smokers 

ages 55 to 74, 

demonstrated 

that screening 

with low-dose 

helical computed 

tomography (CT), compared to standard chest X-ray, 

resulted in 20 percent fewer lung cancer deaths among 

trial participants screened with low-dose helical CT. 

These results of the NLST, sponsored by NCI at a cost of 

over $250 million over a period of eight years, provide a 

method to prevent death from lung cancer by screening 

people at especially high risk. In particular, those who 

have been heavy smokers may beneft the most from 

a helical CT, which can fnd small, potentially lethal 

lesions at early, treatable stages of the disease. 

“This is the frst time that we have seen clear evidence 

of a signifcant reduction in lung cancer mortality with a 

screening test in a randomized controlled trial. The fact 

that low-dose helical CT provides a decided beneft is a 

result that will have implications for the screening and 

management of lung cancer for many years to come,” 

said Christine Berg, M.D., NLST project offcer at NCI. 

The NLST was an extremely complicated study to 

coordinate. To ensure and enhance the representativeness 

of the results, NLST was conducted at 33 centers 

throughout the country. The expertise of designing and 

managing very large-scale clinical trials with very clear, 

closely monitored communication was something that 

demonstrated, yet again, the importance of a federal 

role in coordinating and managing a trial with tens of 

thousands of subjects. 

A large number of detailed analyses of NLST data due 

out in 2011 should provide scientists with a deeper 

understanding of this disease, its causes, and other 

potential ways to reduce its burden. The NLST clearly 


Scans of a normal lung 

using computed tomography, 

or CT. 

offers a tool for the 

screening of highrisk 

people, along 

with a prescient 

reminder that the 

best way to avoid 

being at high risk 

is to avoid smoking. 

As with all cancer 

clinical trials, the 

NLST provided answers 

to a set of specifc questions related to a specifc 

population. Whether those answers can be used to provide 

general recommendations for the entire population 

will be the subject of future analysis and study. The vast 

amount of data generated by NLST, which are still being 

collated and studied, will greatly inform the development 

of clinical guidelines and policy recommendations. 

Those, however, are decisions that ultimately will be 

made by other organizations. 

According to Richard Fagerstrom, Ph.D., co-chief 

statistician for the NLST, “There are many other things 

that we will learn from this study, other than just 

whether screening with helical CT decreases lung 

cancer mortality. We will also get considerable information 

about the cost-effectiveness of the technique. This 

will be important input for third-party payers for the 

procedure, such as Medicare, to see whether this will 

actually be economical. This could have a major positive 

impact on the health care system as far as costs go.” 

Fagerstrom also noted that there is a sizable amount 

of information to be parsed with respect to different 

kinds of specimens, including sputum, blood, and even 

urine. And the database is open to investigators at other 

institutions, not just those affliated with the trial. 

Important as these fndings are, they will not curtail 

NCI’s efforts to reduce or eliminate the use of tobacco. 

Smoking cessation is still the best way to prevent death 

from lung cancer.

Curbing the Use of Tobacco 

The area of cancer prevention that has the potential to yield the largest public 

health beneft in the U.S. and worldwide is accelerating efforts aimed at prevention 

and hastening cessation of tobacco use. Tobacco use, in particular cigarette 

smoking, is the nation’s leading cause of preventable death, not only from cancer 

but also from heart disease and several other conditions. Besides causing most 

cases of lung cancer, tobacco has been linked to cancers of the throat, mouth, 

nasal cavity, esophagus, stomach, pancreas, kidney, bladder, and cervix, among 

others. Tobacco use accounts for approximately 30 percent of all U.S. cancer deaths. 

The prevalence of cigarette smoking in the U.S. remains unacceptably high, and 

the decline in tobacco use observed since the early 1970s has stalled in recent 

years. Current estimates of smoking prevalence for U.S. adults indicate that one 

in fve smokes cigarettes. 

Overall smoking prevalence fgures mask vast disparities in tobacco use and 

lung cancer mortality when education level, race, ethnicity, and other factors 

are taken into account. For example, among all population groups in the 

U.S., black men have the highest death rate from lung cancer. Smoking rates 

in the U.S. are inversely associated with education: the higher one’s level of 

education, the less likely he or she is to smoke. For example, 41 percent of 

adults with the end-product of a high school education smoke, whereas only 

6 percent of adults with a graduate degree smoke. Among military personnel, 

42 percent of men between the ages 18 and 25 are smokers, while 22 percent of 

white servicemen between the ages of 18 and 24 use smokeless tobacco. These 

fgures emphasize the need for new strategies and interventions to reduce 

tobacco use among population groups that have been only marginally infuenced 

by existing strategies and interventions. 

To address signifcant gaps in research on understudied and underserved 

populations relating to tobacco-related health disparities, NCI, in partnership 

with the American Legacy Foundation, created a network of researchers, the 

Tobacco Research Network on Disparities or TReND (http://www.tobaccodisparities.org). 

One of TReND’s frst research projects sought to develop an index 

to measure how various racial, ethnic, and socioeconomic groups are exposed 

to, and perceive, tobacco-related messages. 

NCI supports a large portfolio of smoking cessation research and the 

National Network of Tobacco Cessation Quitlines (1-800-QUIT-NOW) and 

Smokefree.gov (http://www.smokefree.gov). In 2009, NCI launched Smokefree 

Women (http://women.smokefree.gov) to provide evidence-based cessation 

guidance tailored to the needs of female smokers and to develop an online 

support community, utilizing websites for women who want to quit. NCI 

researchers are also working to help NCI-designated Cancer Centers improve 

delivery of cessation services to patients who smoke. Continued smoking in 

patients with cancer can reduce the effectiveness of cancer treatments, slow 

healing times, and increase the risk of second primary cancers. 


16 


NCI CENTER TO REDUCE CANCER HEALTH DISPARITIES 

Cancer’s burden is not equally distributed. There are 

differences in the incidence, prevalence, and mortality 

of cancer among specifc population groups in the 

United States. The Center to Reduce Cancer Health 

Disparities (CRCHD) is the component of NCI 

dedicated to confronting those inequities, particularly 

in understanding how biological, environmental, 

social, and cultural factors contribute to differences 

in cancer prevention, care, and treatment. 

One of CRCHD’s fagship programs, the Community 

Networks Program (CNP), features innovative 

partnerships among academic institutions, 

community organizations, and community-serving 

healthcare providers. For example, a program called 

CNP-Redes en Acción [Networks in Action] increased 

enrollment of children in clinical trials by 48 percent, 

and CNP-Hawaii demonstrated an increase in 

mammography screening rates from 35 percent 

to 62 percent among Filipino women through the 

use of educational billboards on buses. 

Another CRCHD program of note is the Patient Navigation 

Research Program. A patient navigator, who could 

be a registered nurse, a social worker, or even a patient 

who has been treated for cancer at that center, acts 

as a guide through the often daunting treatment of cancer. 

Navigators work with patients, survivors, families, 

and caregivers to help them access and chart a course 

through the healthcare system, overcoming barriers to 

quality care.

GLOBAL HEALTH AND A GLOBAL PERSPECTIVE 

No nation exists 

in a vacuum, and 

cancer is clearly 

a disease that 

defes borders. 

American researchers 

beneft 

from a broader 

perspective by 

engaging in 

research outside 

U.S. territories, 

just as international 

researchers 

make signifcant contributions to NCI’s overall mission 

while acquiring knowledge, skills, and abilities to enhance 

the research environment in their home countries. 

The global burden of cancer is large and growing larger. 

Each year, more than 11 million people are diagnosed 

with cancer worldwide. By the year 2020, this number is 

expected to increase to 16 million. Cancer causes more 

than eight million deaths each year, or approximately 13 

percent of all deaths worldwide. Within developing countries, 

cancer is projected to increase rapidly over the next 

few decades. Unless current trends change, cancer in 

developing countries is expected to represent 70 percent 

of the global cancer burden by the year 2030, a statistic 

driven by demographic shifts toward more elderly populations 

and the movement toward more Western lifestyles, 

most notably increased per capita tobacco consumption 

and higher-fat, lower-fber diets. 

A global cancer research perspective offers myriad opportunities 

that a U.S.-only research focus would not 

afford. For example, international studies enable us to 

investigate rare cancers—such as certain inherited, 

familial types of kidney cancer, melanoma, and other 

cancers—by providing access to much larger populations 

of patients than can be found within the confnes of our 

national borders. A global perspective also expands the 

diversity of environments occupied by humans, providing 

unique opportunities to explore relationships between 

genes and specifc environmental exposures, including 

infectious agents that may be associated with cancer. 

We are often reminded today that the world is interconnected, 

politically and economically. Nations have 

obligations to each other, and biomedical research 

is no exception. NCI can help other nations confront 

and study their unique cancer burdens. In that vein, 

NCI will soon be strengthening its commitment, with 

the establishment of a center for global health. 

The new center will have much to do, from addressing 

cancer burdens of nations with populations numbering 

many hundreds of millions, to overcoming the seemingly 

simple barrier of delivering vaccines to places that 

lack even the infrastructure for refrigeration of such 

medications. 

Consider, for example, that sub-Saharan African countries 

are least prepared to address a growing cancer 

burden, yet 20 percent of cancers in Africa may be 

preventable, because they are linked to infectious agents 

such as viruses, bacteria, and parasites. Two overwhelmingly 

preventable cancers, liver and cervical, account for 

approximately 60 percent of the cancer-related deaths in 

eastern and western regions of Africa. In many areas of 

Africa, liver cancer is the top cancer for males and cervical 

cancer is the leading cancer for females. This kind of 

prevention will not be a simple matter, however. The lead 

time for the development of vaccines against cancercausing 

agents is measured in decades. In the case of 

hepatocellular cancer caused by hepatitis B virus, to take 

just one example, there is a vaccine available; for hepatocellular 

cancer caused by hepatitis C, none yet exists. 

There are other parts of the world where cancer risks 

are high, some even higher than in Africa; as an 

example, nasopharyngeal carcinoma is common in parts 

of Asia. By evaluating high-risk areas around the world, 

we have gained a better understanding of previously unknown 

risk factors and the underlying causes of cancer. 

Several such international studies are examining possible 

environmental and genetic risk factors in different 

populations, including exposures from polycyclic aromatic 

hydrocarbons, environmental pollutants that may contribute 

to increased incidence rates of a variety of cancers. 

Looking at variations in cancer risk in children globally 

can also have striking implications. NCI-supported 

scientists, including Cheryl Willman, M.D., pathology 

professor at the University of New Mexico, have studied 

leukemia in Hispanic children. Some of these children 

have a signifcantly increased risk of relapse for acute 

lymphoblastic leukemia (ALL), which is independent of 

other prognostic factors. Findings from studies in this 

high-risk population characterized unique clusters of 

genes associated with the children who also have a high 

percentage of Native American ancestry. These studies 

also reveal the striking clinical and genetic heterogeneity 

in high-risk ALL and point to novel genes which may 

serve as new targets for diagnosis, risk classifcation, 

and therapy. 


18 

Care and Treatment 

The development of more effcient and effective cancer treatments—treatments 

that destroy cancer cells while leaving surrounding healthy tissue 

unharmed—is a critical element of NCI’s research agenda, particularly the 

development of therapies tailored to the cancers of individual patients. While the 

immediate goal is cancer treatment, targeted interventions may ultimately have 

an important role in cancer prevention, as well. 

Our understanding of the molecular changes in cancer is leading to the dawn of 

an age of genetically informed cancer medicine. We are now designing precise 

therapies to hone in on specifc targets that drive tumor cell proliferation and 

survival, including not only targets in cancer cells, but also targets in surrounding 

cells, the so-called tumor microenvironment. 

We are also learning that the complexity of molecular interactions within and 

among cancer cells, and between cancer cells and normal cells, will require 

refnement of multi-agent treatment approaches against cancer. As a result, 

development of future treatments will require innovative strategies and partnerships—among 

academics, the public sector, and industry. Fashioning this new 

approach will require NCI’s involvement and leadership at every step, particularly 

when it comes to combinations of experimental drugs produced by more than 

one company. 


Woman being positioned in front 

of radiation gantry device (tilted 

at 45 degree angle) for breast 

cancer treatment.

MATCHING DIAGNOSIS WITH TREATMENT 

We are still in the 

early days of genetically 

informed 

cancer medicine. 

Much of the focus 

has been on the 

development 

of molecularly 

targeted therapies, 

such as 

imatinib (Gleevec) 

and trastuzumab 

(Herceptin). But 

cancer researchers 

and pharmaceutical 

and 

biotechnology 

companies are 

beginning to 

devote greater attention 

to another 

part of the therapeutic 

equation: the tests—or molecular diagnostics, as 

they are often called—that are needed to determine not 

only whether a patient’s tumor expresses the molecule 

being targeted, or whether it is mutated, but also whether 

the cancer cell’s overall mutational gene expression 

profles predict a good response to the treatment. 

It’s all part of the move away from nonselective therapeutics, 

explained Paul Mischel, M.D., a researcher at 

UCLA’s Jonsson Comprehensive Cancer Center. “If we’re 

dealing with therapies that target specifc enzymes, the 

alterations in those enzymes and the pathways that they 

regulate are often different in patients with the same 

types of cancers, so having molecular diagnostics is 

essential to selecting optimal therapies,” he said. 

In 2002, for example, an international research team 

that included scientists from NCI and the Sanger Institute 

in Britain, as well as other international partners, 

identifed a specifc mutation in a gene called BRAF that 

is present in about 60 percent of tumor samples from 

patients with metastatic melanoma, a disease with a 

poor prognosis and for which treatment advances have 

been rare. Additional laboratory studies showed that 

the mutated BRAF gene alone could transform normal 

cells into cancerous cells. These fndings led researchers 

to develop several drugs that target the mutated 

BRAF gene. One of these 

drugs, PLX4032, has already 

moved into a phase 

III clinical trial, enrolling 

only patients whose tumor 

cells have mutations in the 

BRAF gene, based on the 

results of a diagnostic test. 

Earlier trials of PLX4032 

had demonstrated promising 

results, with the majority 

of patients experiencing 

tumor shrinkage, including 

some patients in whom 

tumors were eradicated. 

A drug called crizotinib has 

followed a similar path to 

PLX4032. Initially developed 

to treat tumors with mutations 

in a gene called MET, 

crizotinib also inhibits a 

protein called ALK that has been associated with the 

development of some cancers, including lung cancer. 

In 2007, in lab and mouse model studies, researchers 

showed that a genetic alteration in ALK—a fusion 

with another gene, EML4—could lead to inappropriate 

expression of ALK and to tumor development. They also 

found the EML4-ALK gene fusion in a small percentage 

of tumor samples from patients with one type of lung 

cancer. Based on the discovery, an early clinical trial 

testing crizotinib that was already enrolling patients was 

altered to enroll more patients with advanced lung cancer 

whose tumors had the ALK gene alteration. Based 

on the excellent response of these patients to crizotinib 

in this early trial, the drug is now being tested in a phase 

III clinical trial of patients with ALK-positive lung cancer. 

The technological and logistical aspects of molecular 

diagnostics are not the only diffculty. There are 

numerous interconnected pathways in a cancer cell,” 

said Sheila Taube, Ph.D., of NCI’s Program for the 

Assessment of Clinical Cancer Tests. “If you cut off one 

pathway, there may be another pathway the cell uses 

to accomplish the same end,” said Taube. “So if you 

measure only one piece of a pathway that may be 

involved, that may not be suffcient to know whether 

the patient will respond to the drug.” 


20 

NCI and its partners are taking steps to enhance the process of drug development—from 

target identifcation and validation, to high-throughput screening 

and chemical design optimization, to testing in animal models, to the design of 

mechanisms for monitoring in vivo activity. At the end of the process is translation 

of discoveries into human clinical trials and treatments. The challenge now 

is to prioritize which targets to pursue and then to move them into an effcient 

platform for development. NCI’s mission is not to compete with the private sector. 

Rather, we work to develop therapies for both common and rare cancers that 

are not being vigorously pursued by industry. NCI’s resources, from chemistry to 

toxicology, are also of great utility for many academic researchers. 

For the majority of cancer patients, surgery—often followed by radiation or 

chemotherapy—remains a key component of treatment and one that NCI is 

continually working to improve. One outcome of a major surgical study supported 

by NCI and its sponsored cooperative groups gained attention recently when it 

was shown that, for 20 percent of breast cancer diagnoses, extensive removal of 

cancerous lymph nodes from the axilla had no advantage. The surgery did not 

change treatment outcome, improve survival, or make the cancer less likely to 

recur, while it did increase recovery time and result in complications such as 

lymphedema and infection. Extensive lymph node removal proved unnecessary 

because the women in the study had chemotherapy and radiation, which probably 

eliminated any disease in the nodes. 

Many chemotherapy drugs used in breast and other cancers over the decades 

have their foundations in NCI research. Today, NCI’s Chemical Biology 

Consortium, a network of institutions that have formally agreed to collaborate, 

is working in the early phases of the drug discovery process in high-throughput 

screening studies to identify small molecules that have anticancer activity. 

This integrated research consortium stands at the interface of chemical biology 

and molecular oncology. 

As potential treatments—drug-like small molecules, large biologic molecules, 

and those that target immunologic function—emerge, researchers will need to 

develop new ways to assess their effcacy and establish the proper treatment 

regimens. Likewise, NCI is aggressively seeking to enhance the clinical trials 

system to better accommodate targeted therapies and accurately assess 

genomic changes in patients. 

We can expect that over time, tailored treatment that depends on the molecular 

profle of the tumor will become the norm for most malignancies. The challenge 

is fnding the best match between the tumor and therapeutic regimen for each 

patient. The feld is taking steps now to ensure that in the years ahead, targeted 

therapies are available for many types of cancer. 

| 

N A T I O N A L C A N C E R I N S T I T U T E

POPULATION SCIENCE AND CO-MORBIDITY 

The diagnosis and treatment 

of cancer, already complex 

in nature, are made all the 

more diffcult by the fact that 

many patients also have other 

diseases. According to recent 

research, much of which was 

funded by NCI grants, these 

co-morbidities—particularly 

diabetes, hypertension, and 

obesity—are common in breast, 

prostate, colorectal, and lung 

cancer patients, especially in 

those who are older and of lower 

socioeconomic levels. Studies 

also show an increased risk 

of death in patients with comorbidities, 

as these patients 

often have poorer prognoses 

and fewer treatment options. 

Patients with multiple diseases are typically disqualifed 

from clinical trials, thereby restricting researchers who 

study co-morbidities to the use of observational data. 

Early on, NCI recognized an opportunity to work within 

this limitation. NCI researchers have refned alreadyexisting 

indices of co-morbidity and enhanced older 

analyses, resulting in an easy-to-implement measurement 

algorithm for co-morbidity. This new tool permits 

investigators using databases such as NCI’s SEER- 

Medicare data registry to study the four most common 

cancers tied to co-morbidity in a more in-depth and 

effcient manner. 

Consider another example of a co-morbid cancer 

condition about which we’re gaining greater knowledge. 

Chronic obstructive pulmonary disease (COPD) is a 

well-established risk factor for lung cancer, and both 

diseases are strongly linked to smoking. Recent genome-wide 

association studies (which search across 

the genome for common, small variations in inherited 

genes) have identifed a genetic region on chromosome 

number 15 that is associated with smoking behavior, 

lung cancer, and probably COPD. NCI-supported 

research is underway to better understand whether 

this region helps to regulate smoking behavior, which 

can modify the risk for both lung cancer and COPD. 

Genome-wide association studies are also uncovering 

genetic loci that are linked to diseases not previously 

thought to be related to one another. Variants of genes 

CDKN2A and CDKN2B are now associated with contributing 

to the risk of melanoma and type 2 diabetes. 

A variant of another gene, CDKAL1, is linked to type 2 

diabetes and prostate cancer, and the gene JAZF1 to 

type 2 diabetes and prostate cancer. While these studies 

are still mostly in their early stages, linking different 

diseases to the same common genes or gene variants 

could point toward common treatments in the future. 

Much research remains to be conducted before scientists 

can develop treatments to help patients struggling 

with co-morbidities and individuals with multiple chronic 

conditions. 

“There is a compelling need to better understand the 

prevalence and consequences of cancer co-morbidities, 

especially given the rising rates of other chronic conditions 

such as obesity and diabetes,” said Robert Croyle, 

Ph.D., director of NCI’s Division of Cancer Control and 

Population Sciences. “Clinicians need evidence-based 

guidance concerning complex patients who don’t match 

the characteristics of patients enrolled on clinical trials. 

Multidisciplinary coordinated care shows promise for 

patient management, but we’ll have to expand trials 

and observational data collection to answer the many 

questions we have about co-morbidities.” 


22 

| 

AN IMAGING AGENT REBORN 

Since 2009, the halt in operations of several nuclear reactors 

caused a global shortage of isotopes commonly 

used in medical imaging and diagnostic procedures, 

particularly in cancer. In the rush for a solution to the 

shortage, NCI played a new and vital role. 

Many diagnostic imaging tests, including bone scans 

that utilize Single Photon Emission Computed Tomography 

(SPECT), require the use of tracers. Bone scans are 

essential tools in the diagnosis of bone metastases in 

cancer patients, especially those with cancers (such as 

breast and prostate) that tend to metastasize to bone. 

In January 2011, FDA approved a New Drug Application 

(NDA) from NCI for a previously approved drug, Sodium 

Fluoride F18, to be used in bone scans. The NDA is the 

vehicle through which drug sponsors formally propose 

that the FDA approve a pharmaceutical for sale and 

marketing in the U.S. and was required at this time, 

because this would be a new use for this substance. 

In contrast to the only previously approved radioactive 

tracer for bone scans, Sodium Fluoride F18 is not 

subject to the supply problems that led to the 

recent nationwide shortages of the more commonly 

used tracer, Tc-99m. 


Sodium Fluoride F18 is more expensive than the other 

tracer, but it can be produced in medical cyclotrons, 

which are available at many research universities and 

commercial suppliers in the United States. This drug 

also provides better images because it uses Position 

Emission Tomography (PET) instead of SPECT imaging, 

allowing for improved, earlier detection of abnormalities. 

In bringing this imaging agent to FDA for approval, 

NCI made an agent available that, because of its high 

development costs coupled with its limited market, no 

commercial entity had an interest in developing. NCI 

moved forward with this drug approval for public health 

reasons and to facilitate treatment of rare diseases. 

New Drug Applications are expensive for a variety of 

reasons, including the cost of clinical trials to demonstrate 

safety and effcacy of the new substance, fling 

fees, and manufacturing and distribution costs, all of 

which could easily amount to many millions of dollars. 

Medical cyclotron for production 

of radioactive tracers

Fast Facts for Advances in Cancer Treatment 

New drugs and clinical trials 

• 12 new drugs or drug uses were approved for oncology by the FDA in 2010. 

0 

• 348 phase III oncology trials are ongoing in the U.S. 

• 861 cancer medicines from industry are in some step of the trial process 

(2009 data). 

• 2,000-plus clinical trials accepting children and young adults are in progress. 

• 200-plus prevention trials are open. 

• 100-plus screening trials are open. 

Selected 2010 highlights and trends in drug development. 

• The frst-ever therapeutic cancer vaccine was approved. 

• Drug inhibitors for specifc targets, such as BRAF and ALK genes, are 

being developed. 

• There are a vast number of new targeted therapies entering trials. 

• Advances in understanding drug resistance are being turned into 

new therapies. 

Major Stages of Clinical Trials: 

How New Agents are Tested 

1 

Phase 0 

Does agent hit 

intended target? 

Phase I 

Safe? 

2 

Phase II 

Effective? 

3 

Phase III 

Better than 

current? 

Approved 

drugs 


24 

The NCI Portfolio 

Extramural Research: Funding and conducting innovative research are 

the highest priorities at NCI. The NCI Extramural Research Program 

reaches nearly 650 universities, hospitals, Cancer Centers, and other sites 

throughout the U.S. and more than 20 other countries. Over 80 percent of NCI’s 

current budget funds extramural research activities. NCI has six divisions and 

several key centers. 

| 

Five of the divisions oversee and coordinate extramural activities: 

• The Division of Cancer Biology provides funding for research that investigates 

the basic biology behind all aspects, including the causes, of cancer. 

• The Division of Cancer Control and Population Sciences supports a 

comprehensive program of genetic, epidemiologic, behavioral, social, and 

surveillance cancer research. 

• The Division of Cancer Prevention supports research to determine and reduce 

a person’s risk of developing cancer, as well as research to develop and 

evaluate cancer screening procedures. 

• The Division of Cancer Treatment and Diagnosis works to identify and 

translate promising research areas into improved diagnostic and therapeutic 

interventions for cancer patients. 

• The Division of Extramural Activities coordinates the scientifc review 

of extramural research funding applications and provides systematic 

surveillance of that research after awards are made. 

Intramural Research: A portion of NCI’s research dollars supports the work of 

scientists in the two intramural sections: 

• The Center for Cancer Research is home to more than 250 scientists and 

clinicians, organized into more than 50 branches and laboratories, conducting 

basic, clinical, and translational science to advance knowledge of cancer and 

AIDS. The Center’s researchers translate their discoveries into clinical applications 

by utilizing the infrastructure provided by the NIH Clinical Center, 

the largest clinical research hospital in the world. 

• The Division of Cancer Epidemiology and Genetics conducts population 

and multidisciplinary research to discover the genetic and environmental 

determinants of cancer and new approaches to cancer prevention. 

In addition to the six divisions and the Center for Cancer Research, NCI’s Offce of 

the Director contains a number of offces that perform important functions and 

provide services across the institute, including bioinformatics, training, health 

disparities, and HIV/AIDS, among others, and supports research in several 

high-technology areas through the Center for Strategic Scientifc Initiatives. 


Career 

Programs 

1.5% 

NRSA 

Fellowships 

1.3% 

Funding Categories for Fiscal Year 2010 

Research & 

Development 

Contracts 

12.0% 

Centers 

12.0% 

Other 

Research 

7.2% 

Intramural 

Research 15.8% 

Research Project 

Grants 42.5% 

Research Management 

and Support 7.5% 

Buildings and Facilities 

0.2% 

Funding Category Funding % of Total 

[in thousands] 

Research Project Grants $2,168,058 42.5% 

Intramural Research $805,332 15.8 % 

Other Research $367,699 7.2% 

National Research Service Award Fellowships $67,564 1.3 % 

Career Programs $74,914 1.5 % 

Centers $611,133 12.0 % 

Research & Development Contracts $613,762 12.0 % 

Research Management and Support $381,765 7.5 % 

Buildings and Facilities $7,920 0.2 % 

Total FY2010 Budget $5,098,147 

Figures for FY2010 exclude American Recovery & Reinvestment Act (ARRA) funding. 


26 

| 


THE AMERICAN RECOVERY AND REINVESTMENT ACT (ARRA) 

In February 2009, after President Obama 

signed into law the American Recovery and 

Reinvestment Act, NCI began to face the kind 

of problem most of us would love to have: 

spending an unexpectedly large amount of 

money. The recovery act—or ARRA, as it 

became known—provided NCI with approximately 

$1.3 billion in additional funding over 

its annual appropriation, to be allocated over 

a two-year period. This special allocation was 

a welcome infusion, but one that also altered 

funding expectations for the years to follow. 

ARRA spending carried with it some particular 

concerns, not the least of which was separately 

managing two-year economic stimulus 

funds alongside NCI’s annually appropriated 

budget. ARRA was, frst and foremost, about 

jobs and hiring, about sustaining and building 

the American workforce. NCI committed 

approximately $747 million, or 60 percent of 

ARRA funds, to the support of 573 research 

grants, through supplements to existing, 

longer-term grants and to new, competing 

research proposals, many funded for two 

years. Mindful of our responsibility to increase 

the scientifc workforce, NCI also invested in 

new faculty awards to NCI-designated Cancer 

Centers and to minority institution/NCI Cancer 

Center partnerships. 

In scientifc terms, however, two years is a 

very short time. This is, after all, a feld that 

generally makes incremental progress, building 

experiment on experiment, publication on 

publication, with most projects carried out 

over a multiyear period. In planning for ARRA 

spending, NCI’s leaders were well aware that 

many two-year grantees would apply for extensions 

or follow-on research in years ahead. 

Likewise, there was a clear expectation that 

many unsuccessful, but meritorious, ARRA 

applications would be revised and resubmitted 

for conventional research support. In short, we 

continually asked ourselves: How much appropriated 

money will we have in the years ahead 

to support work begun under ARRA? 

That’s still a somewhat open question, as we 

wait to see what appropriations and application 

pools look like in the near future. In a 

continued time of economic diffculty, however, 

careful scrutiny will be key, even in the most 

optimistic of scenarios. 

NCI’s planning for ARRA was not built solely 

around grants; the institute funded a number 

of new initiatives and, importantly, added to 

some ongoing grants so that a certain amount 

of risk in the years beyond those for which 

funding was designated was lessened. 

In particular, The Cancer Genome Atlas, 

already a prominent program, received ARRA 

funding from NCI and its sister institute, the 

National Human Genome Research Institute, 

to begin to identify all of the relevant genomic 

alterations in 20 or more tumor types. Refecting 

its signifcance, the National Institutes of 

Health named TCGA as one of its seven signature 

ARRA projects and Vice President Biden 

named it as the No. 2 ARRA project for the 

nation. Other NCI ARRA investments included 

the funding of nearly 40 early-phase clinical 

trials of new, molecularly targeted treatments; 

enhancement of the NCI Community Cancer 

Centers Program; development of methods 

of banking biological samples and for creating 

bioinformatics platforms; efforts to bring 

scientists from other disciplines to the study 

of cancer; and supplemental funding for 

NCI-designated Cancer Centers.

Clinical Community Oncology Program 

Minority-based Community 

Oncology Program 

NCI Community Cancer Centers Program 

NCI-designated Cancer Centers 

NCI’S NATIONWIDE REACH 

Promising laboratory discoveries, the foundation of biomedical science, begin a lengthy 

process to translate scientifc knowledge into new treatments for cancer patients. 

Along that path, from the laboratory to the clinic, NCI supports a number of important 

initiatives across the United States. 

NCI’s Cancer Centers, which currently number 66 facilities nationwide, are largely 

based in research universities that are home to many of the hundreds of NCI-supported 

scientists who conduct a wide range of intense, laboratory research into cancer’s origins 

and development. Their work is echoed throughout this document. 

The Cancer Centers Program focuses on trans-disciplinary research, including population 

science and clinical research. Those centers with a comprehensive designation, of 

which there are currently 40, must have a robust portfolio of research in basic, population, 

and clinical research, and must additionally demonstrate professional public 

education activities in the communities they serve. 

Many of the Centers are also treatment facilities that deliver the latest medical advances 

to patients, including the support of cancer survivors and outreach out to underserved 

populations. Cancer Centers, like all NCI programs, are subject to peer review each 

time they apply for renewal of their support grants. 

The NCI Community Cancer Centers Program came into existence to test the concept 

of a national network of community cancer centers to expand and deliver advanced 

care in local communities. 

NCI’s Clinical Community Oncology Program (CCOP) connects more than 3,000 

community-based physicians at nearly 400 hospitals in 34 states and Puerto Rico with 

academic investigators, to accelerate implementation of NCI-sponsored cancer treatment, 

prevention, and control clinical trials. By providing community level access to 

clinical trials CCOPs boost the participation of underserved populations. 

NCI’s Minority-based Community Oncology Program, a companion program to the 

CCOP, is focused in areas where physicians serve sizable minority populations. 


28 

Partnering for Progress 

Progress in cancer research depends upon partnerships—in the use of new technologies; 

in collaborations to advance experimental techniques; in innovative 

methods of helping fund the earliest stages of development of small companies 

working in the cancer feld; and in the testing of new molecular agents in cancer patients. 

Supporting partnerships touches NCI programs too numerous to mention encyclopedically, 

but certainly includes programs such as those detailed on the next few pages. 

NCI’s Experimental Therapeutics Program (NExT) makes available to outside researchers— 

from academia and industry—research resources not readily available at most medical 

centers. These resources can shave years from the 10-year to 12-year development cycle 

of a new drug, as well as help bring down the nearly billion-dollar development cost 

of many cancer drugs. NExT is also facilitating the earliest phase of clinical testing in 

humans, known as phase 0, which tests new, molecular agents in sub-therapeutic doses, 

in small numbers of patients, to see whether potential new anticancer agents hit their 

intended targets. 

As a model of working with industry to promote and develop new drugs, the frst substance 

tested as part of a phase 0 trial was the drug ABT-888, a drug candidate that 

inhibits a cancer protein called PARP, which was provided by Abbott Laboratories. 

“The successful and expeditious conduct of this trial, and the impact it has had on the 

development timeline of ABT-888 at Abbott, provide an initial example of improved 

therapeutics development in oncology,” said James H. Doroshow, M.D., director of 

NCI’s Division of Cancer Treatment and Diagnosis, who spearheads the NExT program. 

NCI is also utilizing the phase 0 trial to test new imaging agents. 

| 


Scientist examining wells 

containing cell cultures. 

Molecular Technologies 

As an example of another partnership, in 1998, NCI established the groundwork 

for a program focused on technology development to meet the needs of cancer 

researchers and clinicians. 

Taking risks on early-stage, potentially transformative technologies, the 

Innovative Molecular Analysis Technologies (IMAT) program has contributed to 

many technologies that are now on the market and in frequent application across 

cancer research and clinical communities. As with other NCI programs, IMAT 

subjects all applications to competitive peer review. 

Commercial products now in widespread use, such as RNALater, Affymetrix gene 

chips, Illumina bead platforms, and Quantum dot labeling to monitor complex interactions 

within living cells, were considered high-risk ideas when initially funded 

through the IMAT program. Yet, their current availability and applicability to multiple 

clinical and basic sciences research settings are a testament to the pay-off that 

such transformative technologies have provided to the feld of cancer research. 

To take just one example of the program’s success, James Landers, Ph.D., 

professor of chemistry at the University of Virginia, used IMAT funding to help 

develop a technology for T-cell lymphoma diagnosis he calls a “lab on a chip.” 

This highly integrated system is capable of detecting infectious agents present 

in complex biofuids in less than 30 minutes, and the diagnosis of certain blood 

cancers in under an hour. 


30 

Small Business Innovation 

Funding is a vital component of any partnership, and NCI has become one of the 

largest sources of early-stage cancer research technology fnancing in the U.S. 

Its Small Business Innovation Research (SBIR) program, along with the closely 

allied Small Business Technology Transfer Program, are NCI’s engines for 

developing and commercializing novel technologies to prevent, diagnose, and 

treat cancer. 

The two programs seek to increase small business participation and private 

sector commercialization of technology developed through federal research and 

development. The SBIR program has made great strides in confronting one key 

funding gap between the end of an award and the subsequent round of private 

fnancing needed to advance a product or service toward commercialization. 

To cover this gap, NCI’s unique Bridge Award is specifcally designed to incentivize 

partnerships between second phase SBIR awardees and third-party investors 

and strategic partners. The Bridge Award more than triples the amount of 

funding available to SBIR applicants, and has often proved an entrée into private 

funding. 

One of the frst companies to receive NCI Bridge funding was Florida-based Altor 

BioScience Corp., which is advancing the discovery and development of targeted 

immunotherapeutic agents for the treatment of cancers, viral infections, and 

infammatory diseases. Altor used funding from a $3 million SBIR Bridge grant to 

support clinical development of ALT-801, an immunotherapeutic agent. 

In January 2011, Altor announced it had raised more than $10 million in private 

fnancing to complete multiple phase II clinical trials of the new agent. In looking 

for such investments, companies “have their own due diligence,” said Altor chief 

executive Hing C. Wong, Ph.D., “but they always love to see what NIH thinks about 

the product and the technology. They really like that kind of validation.” 

| 

NCI has become one of the largest sources of early-stage cancer research 

technology financing in the U.S. 


ImaginAb 

To the casual observer, biomedical imaging still means 

devices such as a CT scan or X-ray: technology that 

looks inside the body to visualize everything from broken 

bones to masses inside organs. For Anna Wu, Ph.D., 

of the Crump Institute for Molecular Imaging at UCLA, 

today’s most advanced molecular imaging technologies 

are “tools to look at very specifc biological questions in 

living people.” 

Image of a prostate 

cancer grafted onto a 

mouse (lit up in yellow at 

hip) and detected using 

a tracer developed by 

ImaginAb 

Wu is the founder of, and chief scientifc advisor to, a 

small California-based biotechnology and nanotechnology 

company called ImaginAb, Inc., which is focused 

on developing a new class of highly targeted proteins 

for imaging and therapy, based on engineered antibody 

fragments. 

Antibodies, which detect and help destroy invaders, are 

substances that can also be engineered to bind to the 

molecules on the surface of cells that display specifc 

proteins. The antibodies may be used therapeutically to 

prevent tumor growth by blocking specifc cell receptors 

or by delivering chemical doses to a specifc target. 

What ImaginAb has done is to reformat antibodies into 

smaller fragments suitable for diagnostic imaging in 

order to target a given cancer. These small antibody 

fragments are tied to a positron emitting isotope that 

allows for molecular imaging of cancer cells using 

PET (Positron Emission Tomography). 

NCI’s SBIR program, through its competitive peer 

review process, made ImaginAb one of its SBIR funding 

awardees. That infusion, says Wu, “has been invaluable 

to the company’s survival and growth. The NCI funding 

helped us move forward at a very tough time when 

investment capital was simply not available.” Today, 

ImaginAb has major global companies as clients 

and has re-engineered over a dozen therapeutic 

antibodies into fragments for imaging and possibly for 

novel therapies. 


32 

Preparing a New Generation for Cancer Research 

Together, NCI’s training programs span basic research, investigational 

therapeutics, and population-based studies. The NIH is, in many ways, 

analogous to a large research university. Its investigators are often referred 

to as faculty, and many of its scientists are able to qualify for tenure in the intramural 

programs of their institutes. 

The largest program is run by the Center for Cancer Research, which, as part of 

the NCI intramural research program, offers fellowships for training in the basic 

and translational sciences, as well as in the clinic on the NIH campus. About 

1,300 fellows are enrolled in the program each year. For clinical fellows, the NIH 

Clinical Center brings together, under one roof, the treatment of patients with 

laboratory science—a unique arrangement for researchers who typically don’t 

get to do both clinical and basic research on the same research project. 

In addition to providing intramural training, the NCI Center for Cancer Training 

(CCT) is dedicated to building cancer research capacity at institutions across the 

nation and fostering the next generation of the cancer research workforce—a 

diverse, multidisciplinary workforce. NCI supports a range of fellowships, Career 

Development Awards, Institutional Training Awards, and Institutional Education 

Awards to help early-stage scientists and clinicians become independent investigators 

and to encourage senior scientists to become mentors for their younger 

colleagues. 

NCI also has a long history of bringing students into the labs on the NIH campus 

in Bethesda, Md. Each summer, the campus is infused with new faces of 

undergraduates and graduate students who spread out in labs and clinics. 

Several years ago, these opportunities were expanded to include gifted high 

school students. 

Training also takes place beyond the NIH campus in Bethesda. NCI’s campus in 

Frederick, Md., runs student internship programs that enroll local high school 

students over the summer and during the school year. 

| 


Provocative Questions 

This has been a challenging and hopeful time for NCI to lead the nation’s 

cancer research program. Over the past two decades researchers have 

unraveled some of the mysteries that happen to the genome of a cancer 

cell and how a cancer cell behaves in its local environment. With better understanding 

and recent technological advances in many felds, such as genomics, 

molecular biology, biochemistry, and computational sciences, progress has 

been made on many fronts, and a portrait has been made of many cancers. 

With sustained and accelerated funding, NCI can build upon today’s cancer 

advances with provocative thinking by asking research questions that build 

on recent discoveries. 

NCI is reaching out to researchers in various disciplines to pose and articulate 

“provocative questions” that can help guide the nation’s investment in cancer. 

Provocative questions may be built on older, neglected observations that have 

never been adequately explored, or on recent fndings that are perplexing, or 

on problems that were traditionally thought to be intractable but now might be 

vulnerable to attack with new methods. 

Through face-to-face meetings and a public website, the Provocative Questions 

initiative is intended to engage NCI’s scientifc community in serious debate and 

energize NCI’s many constituencies. Here are some of the questions that have 

been discussed at workshops and online: 

• What molecular mechanism(s) are responsible for the well-documented 

association of obesity with certain types of cancer? 

• Why are some disseminated cancers cured by chemotherapy alone? 

• Why do many cancer cells die when suddenly deprived of a protein encoded 

by an oncogene? 

You can read, submit, and comment on questions at: http://provocativequestions. 

nci.nih.gov. 


34 

Cancer Profles: 

Introduction 

The progress achieved against the six 

cancers that are profled in this section 

exemplify NCI’s investment in scientifc 

research, from basic and population 

science to applications in prevention 

and cancer care. The stories of these 

cancers illustrate how molecular and 

genomic data have enhanced identifcation 

of cancer subtypes and provided 

insight into potential therapeutic 

targets, yielding tangible benefts for 

patients, sometimes in less than 10 

years from the time of genetic discovery 

to initial clinical trials. Every cancer 

has a different part of the story to tell— 

whether it is simply the ability to distinguish 

which patients would beneft from 

more aggressive therapy, as with acute 

myeloid leukemia, or a new drug with 

potential therapeutic benefts for two 

different cancers, as with neuroblastoma 

and lung cancer. The element tying 

these stories together is the role of NCI. 

While we made great progress in some 

of the cancers highlighted in this section, 

there are others that continue to be 

more formidable. It is for these cancers 

that NCI’s continued support cannot be 

underestimated. We are just beginning 

to untangle the mysteries underlying 

these diseases, and we must maintain 

that momentum to make progress that 

could lead to new screening, diagnosis, 

or treatment techniques. Such progress 

is achievable, but not inevitable. 

Each passing year brings real progress, 

but also deeper understanding of how 

diffcult these diseases are to conquer. 

Continued progress will require heightened 

dedication to using science to 

better understand and counteract the 

collection of diseases we call cancer. 

| 


M E L A N O M A 

The majority of skin cancers are 

basal or squamous cell carcinomas, 

which together are also designated 

as non-melanoma skin cancers. 

Most forms of non-melanoma skin 

cancer are highly curable and can be 

prevented by reducing sun exposure. 

Sun exposure can also increase the risk 

of melanoma, a form of skin cancer 

that begins in melanocytes, the cells 

that produce melanin. Although 

melanoma accounted for fewer than 

70,000 of more than two million cases 

of skin cancer in 2010, it caused more 

deaths than any other type, with an 

estimated 8,700 deaths in 2010. Over 

the past 30 years, the incidence of melanoma 

in the U.S. has nearly tripled. 

The majority of melanoma patients 

are diagnosed with localized disease, 

and surgery is curative in most localized 

cases. The signifcance of early detection 

of melanoma, when it is still at a 

localized stage and treatable, cannot 

be minimized. However, melanoma patients 

with advanced metastatic disease 

rarely survive more than a year after 

diagnosis, with a fve-year survival rate 

of 15 percent. 

Outcomes for advanced-stage 

melanoma have not improved substantially 

for decades, but results of recent 

clinical trials suggest that new therapeutic 

strategies may change this trend. 

In August 2010, Plexxikon, a small 

drug development company, announced 

that one of its drugs—PLX4032—had 

elicited a response in more than 80 

percent of melanoma patients in an 

early-phase clinical trial. PLX4032 

caused the tumors in 24 of the 30 trial 

participants to shrink by at least 

30 percent, while the tumors of two 

patients disappeared.

Micrographic image of a 

melanoma cell. 

Just a few months later, evidence of 

the drug’s effectiveness grew even stronger: 

a clinical trial involving hundreds 

of participants across many institutions 

showed that metastatic melanoma 

patients treated with PLX4032 lived 

longer than those who had been given 

the chemotherapy drug dacarbazine, 

which is the current standard of care. 

Taking a closer look at the research 

that made this promising drug possible 

provides a powerful example of how 

basic cancer research is translated into 

therapeutic potential. PLX4032 is a 

molecularly targeted therapy, a drug 

that is intended to be used to change 

the activity of a specifc molecule or 

group of molecules. This drug was 

designed to inhibit the activity of a 

mutant form of a protein called BRAF. 

BRAF is the most commonly mutated 

gene in melanoma (mutated in over half 

of all melanomas) and is also mutated 

to a lesser degree in at least a few other 

cancer types, including lung cancer. 

Knowledge of the BRAF protein 

as a pro-growth signaling molecule 

emerged initially from years of basic 

laboratory research. Subsequently, 

BRAF gene mutations in melanoma 

were discovered by scientists in the 

United Kingdom in 2002, and these 

mutations were shown to render 

the BRAF gene oncogenic. The high 

prevalence of BRAF gene mutations in 

melanoma made it a candidate therapeutic 

target and, according to Harvard 

Medical School professor and NCIfunded 

investigator Lynda Chin, M.D., 

was a transformative event that helped 

spur enthusiasm for cancer genome 

sequencing. This newfound enthusiasm 

eventually grew into large-scale efforts 

such as The Cancer Genome Atlas. 

Early attempts to target BRAF in 

melanoma were unsuccessful in the 

clinic, in part because the drugs used 

interfered with BRAF function in both 

cancer and normal cells. To address 

this issue, a team that included NCIsupported 

investigators used highthroughput 

screening, in combination 

with structural biology, to identify 

compounds that inhibit the activity 

of the mutant form of the BRAF gene 

found in most melanomas, but have 

little effect on the BRAF gene found in 

normal cells. This research demonstrated 

that it is possible to selectively target 

the mutant form of the BRAF gene 

with PLX4032. The results from the 

phase I clinical trials testing the effcacy 

of PLX4032 were published just eight 

years after the discovery of the BRAF 

gene mutation. 

Clinical researchers will continue to 

evaluate PLX4032 in patients, and 

additional laboratory research will be 

conducted in parallel to gain insight 

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into how melanoma cells respond to 

BRAF inhibition. There already is 

evidence that many tumors initially 

responsive to PLX4032 eventually 

become resistant to the drug, a phenomenon 

that occurs with many molecularly 

targeted drugs, as cancer cells evolve to 

bypass the blocked signaling pathway. 

In many cases, the bypass mechanisms 

that allow tumors to become resistant 

to the drug are understood. Next-generation 

strategies based on the knowledge 

of these bypass mechanisms will 

allow researchers to use combinations 

of drugs to target multiple pathways 

simultaneously and hopefully prevent 

or reduce resistance. Researchers also 

are seeking clues about why some 

melanoma patients with the mutant 

BRAF gene do not respond as well to 

PLX4032 as others do. This information 

will ensure that PLX4032 can be 

used in patients most likely to beneft 

from the drug and may drive development 

of new or combination strategies 

to treat other patients. Furthermore, 40 

percent of melanomas lack a mutation 

in the BRAF gene; for these patients, 

identifcation of new pathways is even 

more critical. 

MELANOMA RISK ASSESSMENT TOOL 


Research continues to contribute 

to the body of knowledge on the 

mechanisms that drive malignant cell 

behavior. Understanding these mechanisms 

may lead to targets other than 

the BRAF gene. For example, germline 

mutations in the p16 gene have been 

identifed in about half the patients with 

familial melanoma. A recent genomewide 

association study identifed three 

additional genes associated with risk of 

melanoma. As illustrated with the example 

of PLX4032, NCI plays a pivotal 

role in rapidly moving drugs through 

the full arc of research from the laboratory 

to the clinic. NCI support is critical 

to continued efforts to build on the 

successes of drugs such as PLX4032 so 

that clinical results can fuel the cycle for 

the next generation of promising new 

drugs for melanoma. 

An online Melanoma Risk Assessment Tool is now available to help physicians assess a person’s risk of developing the 

disease. Developed by a group of researchers from NCI, the University of Pennsylvania School of Medicine, Memorial 

Sloan-Kettering Cancer Center, and the University of California, San Francisco, the tool uses easily obtainable information 

to estimate a person’s risk of developing skin cancer within the next fve years. Te research team identifed 

several factors that can predict skin cancer risk, including geographic area, hair color, complexion, sunburn type, tan 

type, age, and moles and freckling. 

Te program (available on the NCI website at http://www.cancer.gov/melanomarisktool), uses a complex mathematical 

formula to calculate risk, and allows doctors to quickly and easily identify patients at increased risk for developing 

melanoma (and indirectly for other skin cancers), who could then undergo interventions, such as a complete skin 

exam, special counseling to avoid sun exposure, regular self and professional surveillance of moles, or participation 

in clinical trials for skin cancer prevention.

IMMUNOTHERAPIES FOR MELANOMA 

In a simple sentence, the New York Times on March 25 

reported a significant step against a feared cancer: 

“The first drug shown to prolong the lives of people with 

the skin cancer melanoma won approval from the Food 

and Drug Administration on Friday.” 

The new drug, Yervoy (ipilimumab), was developed by 

James Allison, Ph.D., who is today head of the immunology 

program at the Memorial Sloan-Kettering Cancer Center in 

New York. The new medication stands out in its mechanism 

of action, as well. “The treatment,” Allison told the New 

York Times, “is of the immune system, it’s not of the tumor.” 

For more than two decades, Allison has studied the 

mechanisms that regulate the immunologic responses of 

T lymphocytes, which are commonly referred to as T-cells; 

he works to manipulate T-cell response, in order to develop 

novel tumor immunotherapy approaches. 

“The success of ipilimumab underscores the importance 

of basic research to clinical achievement,” Allison said in 

a statement. “The concept came directly out of our studies 

on fundamental mechanisms of regulation of T-cell 

responses.” 

According to the FDA, “Yervoy’s safety and effectiveness 

were established in an international study of 676 patients 

with melanoma.” Patients were randomly assigned to 

receive one of three treatment regimens: Yervoy plus an 

experimental tumor vaccine called gp100, Yervoy alone, or 

the vaccine alone. Those who received the combination of 

Yervoy plus the vaccine or Yervoy alone lived an average 

of about 10 months, while those who received only the 

experimental vaccine lived an average of 6.5 months. 

Prior to the recent approval, treatments for melanoma 

were more limited, given that many melanomas are 

relatively resistant to standard chemotherapeutic agents. 

Two FDA-approved drugs, interleukin-2 (IL-2) and 

dacarbazine, produced a response in only 10 percent 

to 20 percent of patients. 

Other approaches to stimulate immunity against tumors 

use a technology called adoptive T-cell therapy. During this 

therapy, specific T-cells from the immune system of the 

patient, or a matching donor, are harvested from the blood. 

The T-cells are then activated outside the body in the 

laboratory to recognize tumor cells and destroy them. 

The modified T-cells are then infused back into the patient 

and are “adopted” by the body to enhance its natural 

immune system. This treatment approach is being tested 

in various early-stage and late-stage clinical trials. NCI 

trials, led by Steven Rosenberg, M.D., Ph.D., chief of surgery 

at NCI, tested adoptive transfer therapy in melanoma by 

transfusing patients with tumor-specific T-cells called 

tumor infiltrating lymphocytes. 

Rosenberg believes adoptive T-cell therapy may prove a 

useful tool in cancers beyond melanoma. “We have 

demonstrated that gene-modified T-cells can recognize 

and kill melanoma cells over-expressing a specific antigen, 

leading to a clinical 

response in 

some patients,” 

said Rosenberg. 

“With these 

trials, we hope to 

extend this type 

of immunotherapy 

to patients 

with more common 

cancers, 

such as breast 

and colon.” 

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G L I O B L A S T O M A 

Cancers of the brain are 

relatively rare but often 

devastating diseases; just 

1.5 percent of malignant primary 

cancers originate in the brain. Glioblastoma 

multiforme (GBM) is the 

most common form of primary 

brain cancer and is one of several 

types of glioma, a tumor type that 

arises in cells of the brain and spine 

called glial cells. In the U.S., roughly 

11,000 people are diagnosed with 

primary GBM every year. Though 

GBM rarely metastasizes to other 

organs, it spreads aggressively within 

the brain and is more deadly than 

most other brain malignancies. 

Patients with newly diagnosed 

GBM generally respond poorly to 

conventional treatments and have a 

median survival of approximately 

one year following diagnosis. 

Recently, research has proceeded 

from small, incremental improvements 

to greater progress in our understanding 

and treatment of GBM. 

Through the coordinated efforts 

of NCI-funded initiatives—including 

The Cancer Genome Atlas, the 

Glioma Molecular Diagnostic Initiative 

(GMDI) and the Repository 

of Molecular Brain Neoplasia Data 

(REMBRANDT)—scientists have 

collected and molecularly characterized 

an unprecedented number of 

these rare tumors. Analysis of TCGA 

sequencing data revealed that GBM 

is not a single disease but has at least 

four molecular subtypes: proneural, 

neural, classical, and mesenchymal. 

Because different cellular pathways 

are affected in these subtypes, differences 

in treatment responses are 

observed. This fnding is paving the 


way for more informed selection of 

therapies for GBM patients, who 

have traditionally all been treated the 

same way because their tumors look 

alike under a microscope. 

TCGA has also identifed connections 

between features such as 

the age of the patient and molecular 

subtype. The proneural subtype is 

associated with younger patients, 

mutations in the IDH1 and TP53 

genes, and resistance to chemotherapy 

and radiation. 

Alternatively, the classical subtype 

with abnormalities in the EGFR 

gene has shown the best response 

to therapy. The next step is to 

Glioblastoma cells seen 

using fuorescent dyes 

to highlight cellular 

structures and proteins.

determine how to leverage advanced 

diagnostic procedures, such as 

molecular profling, and to identify 

various GBM subtypes and match 

them with more appropriate patient 

therapies. Drugs that affect some of 

these pathways are available and, 

though promising in theory, have 

had mixed results in clinical trials. 

The diffculty of translating 

information about genetic abnormalities 

into successful treatments 

underscores the need for a viable 

laboratory model of GBM. It has 

been diffcult to culture these cells in 

a manner that retains their unique 

characteristics and molecular profles. 

Recently, researchers from the 

NCI intramural program and other 

institutions isolated rare cells from 

glioma tissues that resemble normal 

neural stem cells but have all the 

genetic abnormalities of the tumor. 

These “cancer stem cells” likely will 

be a better model for studying GBM 

and screening hundreds of drugs 

or combinations of drugs than the 

traditional cancer cell lines used until 

now. The hope is that improved cancer 

models will speed the availability 

of treatments to patients. 

Angiogenesis, the formation of 

new blood vessels, is a critical process 

during the development of nearly 

all tumors, including GBM. As a 

tumor continues to grow, it needs a 

suffcient supply of nutrients that can 

only be provided by the development 

of new blood vessels to the tumor. 

By understanding the mechanisms of 

angiogenesis, potential therapeutic 

targets can be identifed. Bevacizumab 

(Avastin) became the frst 

FDA-approved agent that was 

specifcally developed as an angiogenesis 

inhibitor. NCI played a key 

role in promoting the use of bevacizumab 

for the treatment of GBM— 

the frst new FDA-approved treatment 

for recurrent GBM in nearly 

30 years. 

In the future, tumors like GBM 

will no longer be defned solely under 

the microscope, but also on the basis 

of their molecular characteristics. 

As we expand molecular diagnostics 

to the full GBM genome, NCI will 

continue to play a pivotal role in 

providing resources and expanding 

the scientifc infrastructure to apply 

fndings to inform the next steps of 

discovery. 

MRI of an adult brain with 

invasive glioblastoma in left 

frontal lobe, colored red. 

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40 

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MO L ECU L AR PROFILIN G 

Microarray of diffuse large B-cell lymphoma. 

Over the past 20 years, scientists have developed and 

refned a great wealth of laboratory techniques, such as 

PCR (a process that amplifes DNA or RNA) and protein 

and DNA microarrays comprised of small chips dotted with 

thousands of microscopic pieces of DNA, thus spurring the 

next generation of technological tools—molecular profling. 

Molecular profling uses an amalgamation of these 

techniques and others, to provide a more comprehensive 

picture of an individual tumor’s characteristics. Some of 

these characteristics include mutations or other changes 

in the DNA sequence, epigenetic changes, and unique 

patterns in the expression of thousands of genes and 

proteins. By providing a molecular map of an individual 

cancer, molecular profling may allow clinicians to determine 

the origin of a cancer, its potential for metastasis, its 

drug responsiveness, and the probability of its recurrence, 

resulting in treatment strategies tailored specifcally to 

individual patients. 


NCI-supported researchers were among the frst to demonstrate 

that molecular profling could help classify similar 

types of cancers. Tey used two different types of leukemia 

—acute myeloid leukemia (AML) and acute lymphoblastic 

leukemia (ALL)—as test cases to demonstrate the utility 

of this approach. Distinguishing AML from ALL is critical 

for successful treatment, and although the distinction 

between AML and ALL has been well established, there is 

no single test that is suffcient to establish the diagnosis 

and identify the tumor type. Current clinical practice involves 

interpretation of the tumor’s morphology and other 

physical characteristics, which are determined by several 

specialized tests. Although usually accurate, errors occur, 

and leukemia classifcation remains imperfect. By using a 

more systematic approach to classify cancer—molecular 

profling—researchers were able to not only distinguish 

between the two types of leukemia, but also to predict 

their responsiveness to chemotherapy. Molecular profling 

has the potential to offer signifcant improvements in the 

molecular diagnosis and targeted treatment of the disease, 

providing a useful supplement to existing diagnostics. 

Numerous other NCI studies have used molecular profling 

techniques to further classify two types of diffuse large 

B-cell lymphoma (DLBCL)—the most common type of non- 

Hodgkin lymphoma. Tese cancer types are indistinguishable 

when frst diagnosed, but are clinically very different 

as the disease progresses: 40 percent of patients respond 

well and exhibit prolonged survival while 60 percent 

do not. Led by Louis Staudt, M.D., Ph.D., head of NCI’s 

Molecular Biology of Lymphoid Malignancies Section, a 

team of researchers from several institutions used molecular 

profling to show that there is signifcant diversity 

among the tumors of DLBCL patients. Tey identifed two 

molecularly distinct forms of DLBCL and associated each 

form with a clinical outcome. Tese profles were then 

used to develop mathematical predictors, which accurately 

divided patients into two categories—those with good and 

those with poor prognoses—and proved to be a more powerful 

tool than the standard methods for the identifcation 

of high-risk patients. 

Te potential of molecular profling is not limited to leukemia 

and lymphoma; progress is being made with molecular 

profling of many solid tumors as well. However, much 

research still needs to be done before this tool can be used 

routinely in the clinic.

Light micrograph of large 

numbers of white blood cells in 

a patient with AML. 

A C U T E M Y E L O I D L E U K E M I A 

M 

ore than 12,000 Americans 

were diagnosed with AML 

in 2010, and nearly 9,000 

died from the disease. Following 

diagnosis, patients with AML have 

an overall fve-year survival rate of 

23 percent. 

AML is a cancer of the bone 

marrow that develops when a type of 

precursor cell, the myeloblast, proliferates 

unchecked and fails to differentiate, 

resulting in accumulation 

of myeloblasts in the bone marrow 

and blood. AML is characterized 

by a high degree of genetic alterations—about 

half of patients with 

AML have chromosomal changes or 

rearrangements that can be seen by 

special staining procedures and visualized 

under the microscope (karyotyping). 

AML illustrates the key 

role of NCI support in untangling 

the myriad mutations that underlie 

cancer. Discovering these mutations 

is the frst step in the development of 

new treatments. 

Recent advances in understanding 

the genetics of AML have moved 

diagnosis beyond karyotyping to 

molecular profling (see molecular 

profling box), resulting in improved 

classifcation and stratifcation of 

cancer subtypes. Molecular profling 

refers to a series of high-throughput 

techniques that scientists use to measure 

many characteristics of the cell, 

essentially giving a snapshot of the 

cell at the moment of the test, which 

includes extensive characterization 

of DNA through sequence analysis, 

determination of whether there are 

extra copies of some genes, and assessment 

of other changes to DNA or 

DNA-associated proteins that may 

infuence gene expression (sometimes 

called epigenetic changes). In addition, 

it is possible to gain insight 

into pathways that are active in a 

cell by measuring levels of proteins 

and messenger RNA (the templates 

from which proteins are formed), as 

well as looking at patterns of expression 

of microRNAs, which are small 

RNA molecules capable of regulating 

gene expression. Piecing together the 

information provided by molecular 

profling will provide the map that 

eventually may guide us to new 

therapies for AML. 

In 2003, Timothy Ley, M.D., 

professor of genetics at Washington 

University in St. Louis, and his 

colleagues applied for an NCI grant 

to sequence all of the genes in the 

normal and leukemic cells of patients 

with AML. At the time, sequencing 

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the entire genome of cancer patients 

was an extremely expensive and ambitious 

concept. Despite debate as to 

what might be learned, NCI supported 

the proposed research. Ultimately, 

Ley’s team identifed a mutation in 

the gene for DNA methyltransferase 

3A (the DNMT3A gene) in the 

tumor cells of AML patients who did 

not exhibit any large-scale chromosomal 

changes. DNA methyltransferases 

add molecules called methyl 

groups to DNA, which can infuence 

DNA structure and activity. High 

levels of methylation in regions of 

DNA that control expression of specifc 

genes often result in lower levels 

of expression of those genes. 

This particular DNMT3A gene 

mutation is associated with poor 

outcomes for AML and can be used 

to make treatment decisions: for 

patients with a DNMT3A gene mutation, 

chemotherapy is not the best 

treatment option. These data suggest 

that molecularly informed therapies 

will be selected for a patient’s individual 

cancer, resulting in a therapy 

that would likely have the highest 

effcacy. 

Subsequently, in 2009, Ley’s 

team linked mutations in isocitrate 

dehydrogenase 1 and 2 (IDH1/2 

genes), which had previously been 

found in glioblastoma, to AML. 

Within a year of the IDH1/2 gene 

mutation discovery in AML, studies 

conducted by a group partly 

funded by an NCI specialized cooperative 

center grant designed to 

bring together physical scientists, 

engineers, cancer biologists, and 

oncologists in collaboration with a 

pharmaceutical company, revealed 


that these mutations resulted in the 

excess production of the cellular 

metabolite, 2-hydroxyglutarate 

(2HG). Studies suggest that IDH1/2 

gene mutations may not be the frst 

step in development of either AML 

or glioblastoma but are potential 

drivers for tumor progression. As 

this profle illustrates, understanding 

the molecular changes underlying 

cancer can provide the foundation 

for ultimately improving the way we 

deliver therapy and identifying new 

targets for therapy. 

“It’s an amazing time 

in cancer research. 

I’m convinced that 

some of the fndings 

are so clear and 

so informative and 

have such a tremendous 

potential to 

change things that 

I think it’s possible 

only to be optimistic 

about the future.” 

— Tim Ley, M.D., Professor of 

Genetics, Washington 

University in St. Louis

EPIGENETICS 

Looking back on discoveries made in just the last decade 

or two, it’s easy to see the hope—and promise—that the 

future holds. For example, we know much more about 

both genetic alterations (changes to the DNA sequence, 

changes in gene copy number, and rearrangements of 

chromosomal DNA) and epigenetic changes (persistent 

changes in gene activity that result from the addition or 

removal of chemical tags and DNA-associated proteins to 

DNA that affect how and when genes are turned on or off) 

and how these changes lead to initiating development 

and spread of cancer. 

Te initiation and progression of cancer are controlled by 

both genetic and epigenetic changes; however, unlike 

genetic alterations, epigenetic changes are potentially 

reversible. Following the approval of several drugs that 

target specifc molecules involved in the epigenetic regulation 

of gene expression, the use of epigenetic targets is 

emerging as a valuable approach to chemotherapy as 

well as chemoprevention of cancer. 

Normal epigenetic modifcations encompass two major 

types of changes: DNA methylation and modifcations to 

the components that make chromosomes, or chromatin, 

each of which is altered in many cancer cells. As a result, 

cells cannot appropriately control gene expression (genes 

are repressed when they should be activated or activated 

when they should be silent) and thus cell proliferation 

can occur at inappropriate times, augmenting cancer 

development. 

No methylation 

Active gene 

Te potential reversibility of epigenetic modifcations 

suggests that they are viable targets for the treatment of 

cancer, and a small number of drugs that target epigenetic 

changes have been developed over the years. An NCI 

developmental research grant supported the development 

of vorinostat (Zolinza), which targets histone modifcations 

and it, along with a second inhibitor for histone modifcations, 

romidepsin (Istodax), has been FDA approved for the 

treatment of T-cell lymphoma. A recent study suggested 

that vorinostat also possesses some activity against recurrent 

glioblastoma multiforme, resulting in an improved 

median overall survival of 5.7 months. Decitabine (Dacogen) 

and azacitidine (Vidaza), which target DNA methylation, 

have been approved for the treatment of myelodysplastic 

syndrome—a pre-cancerous state that frequently 

leads to deadly cancer of the bone marrow. A few years ago, 

the latter diagnosis was a death sentence. Today, patients 

have a good chance of remission with fewer side effects 

than offered by conventional chemotherapy. Tese drugs 

offer the potential for chemoprevention, by reversing 

epigenetic changes before they lead to full-blown cancer. 

Conceptual DNA helix showing 

regions silenced due to 

addition of a methyl group 

or active due to absence of 

a methyl group. 

Methyl group 

Methylation 

Silenced gene 

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N E U R O B L A S T O M A 

Each year about 700 children 

in the U.S. are diagnosed 

with neuroblastoma (which 

comprises about 7 percent of pediatric 

cancers), and approximately 

200 children die of the disease. Little 

is known about risk factors for 

neuroblastoma, though 1 percent to 

2 percent of patients have a family 

history of neuroblastoma. The rarity 

of the disease makes NCI’s involvement 

in funding research and developing 

new therapies particularly 

critical, as pharmaceutical companies 

are unlikely to invest in diseases 

for which there is a small potential 

market. 

As we have been learning for 

many cancers, neuroblastoma is not 

a single disease. Researchers have 

identifed three biologically distinct 

types of neuroblastoma. The three 

risk categories for neuroblastoma— 

low, intermediate, and high—which 

indicate patient prognosis, are based 

in part on these biological types. 

High-risk neuroblastoma accounts 

for about half of all cases and is the 

most challenging to treat. Most cases 

of high-risk neuroblastoma occur in 

children one year of age and older. 

Five-year survival rates in children 

one year of age or older have improved, 

increasing from 35 percent in 

the period from 1975 to 1978 to 65 

percent from 1999 to 2002. Despite 

improvements in survival, current 

therapy is not adequate for about half 

of children with high-risk disease. 

Developing new therapies for 

high-risk neuroblastoma has posed a 

signifcant challenge; until recently, 

these children had few treatment 

options other than escalating doses 


of chemotherapy and radiation 

therapy. Other cancers are informing 

potential therapies for neuroblastoma, 

as some mutations are shared 

across disease types. 

Just this past year, results from 

an NCI-funded Children’s Oncology 

Group (COG) clinical trial demonstrated 

that ch14.18, an antibody that 

binds to a cell surface protein called 

GD2, is effective for children with 

high-risk neuroblastoma when given 

in conjunction with other immuneboosting 

drugs. An approximately 10 

percent increase in two-year survival 

(which went from 75 percent to 86 

percent) was observed among patients 

who had been treated with the 

antibody and immune-boosting drugs 

compared with those who had been 

treated with standard therapy. The 

initial discovery that most neuroblastoma 

cells express GD2 on their 

surfaces was made in the 1980s, 

but translation of this fnding into a 

successful therapy took nearly two 

decades. Because GD2 is not found in 

more common cancer types, pharmaceutical 

companies exhibited little 

interest in making the ch14.18 antibody. 

Instead, NCI manufactured and 

provided the antibody for the phase 

III trial that demonstrated effcacy 

and continues to manufacture the 

A neuroblastoma cell 

viewed with a scanning 

electron micrograph; the 

cell has a rough surface 

with many fnger-like 

cytoplasmic projections.

“NCI’s role in the 

success of this trial 

went far beyond 

funding. The COG 

team that led the 

clinical trial had 

access to a unique 

and outstanding 

resource: NCI’s 

drug production 

facility, where NCI 

scientists manufactured 

the antibody 

because no privatesector 

company was 

willing to do so. ” 

— John Maris, M.D., Director, 

Center for Childhood Cancer 

Research, Abramson Family 

Cancer Research Institute 

Wells of neuroblastoma 

cells in culture, used to 

test the effects of potential 

therapeutic agents on 

the cells. 

antibody for ongoing COG trials. 

The translation of ch14.18 from 

discovery to the clinic took 20 to 

25 years; however, under the right 

circumstances, development of new 

therapies can occur more rapidly. 

In 2008, an NCI-funded laboratory 

discovered that mutations in the 

anaplastic lymphoma kinase (ALK) 

gene cause the majority of hereditary 

neuroblastoma cases. In addition, the 

ALK gene is mutated or amplifed in 

approximately 7 percent of sporadic 

neuroblastoma cases. While many 

genetic discoveries are heralded as 

promising targets for screening or 

therapy, the ALK’s gene potential 

as a therapeutic target was quickly 

exploited. The ALK gene is also mutated, 

through a different mechanism 

(fusion with another gene by chromosomal 

rearrangement), in about 

3 percent to 5 percent of non-small 

cell (NSCLC) lung cancers (see lung 

cancer profle). The potential of the 

ALK gene as a target for NSCLC in 

addition to neuroblastoma resulted 

in increased interest in developing 

drugs against the ALK gene and 

quickly led to the launch of a COG 

phase I clinical trial of crizotinib, an 

ALK inhibitor that had demonstrated 

success in a lung cancer phase I 

trial—just one and a half years after 

the initial genetic discovery in neuroblastoma. 

Much attention has been focused 

on genetic discoveries such as the 

ALK gene fndings, but understanding 

basic biology can also lead to new 

interventions. Researchers in NCI’s 

intramural program observed that 

retinoids (derivatives of vitamin A) 

imposed growth control and induced 

differentiation in neuroblastoma cells 

grown in the laboratory. By investigating 

the mechanisms leading to differentiation, 

scientists discovered that 

retinoic acid was inducing chemoresistance 

through a cellular survival 

signaling pathway involving the AKT 

family of protein kinases. Inhibition 

of AKT with a small molecule called 

perifosine slowed cell growth and 

sensitized tumors to chemotherapy. 

Identifcation of leads for testing 

in future clinical trials likely 

will stem from continued efforts to 

understand the basic biology that 

drives tumor formation. One aspect 

of neuroblastoma that intrigues 

researchers is the fact that many lowrisk 

tumors resolve spontaneously, 

suggesting that the body is capable 

of eliminating at least some cells that 

go awry. Uncovering the mystery of 

spontaneous regression might have 

implications for the prevention and 

treatment of neuroblastoma and 

other cancers in the future. 

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L U N G C A N C E R 

An estimated 220,000 individuals 

were diagnosed with some 

form of lung cancer in 2010. It 

is the leading cause of cancer-related 

death, with more than 157,000 

predicted deaths in 2010. Smoking is 

far and away the most important risk 

factor for lung cancer. It is evident 

that risk increases with the number 

of cigarettes smoked per day and the 

duration of smoking. Deaths from 

lung cancer have been decreasing in 

men since 1990, but have been stable 

in women since 2003 after continuously 

rising for several decades. 

These trends refect historical differences 

in smoking between men and 

women, and the decrease in smoking 

rates over the past 40 years. 

The cancer community is poised 

to take advantage of the convergence 

of genetic information, appropriate 

screening techniques (see section on 

NLST on page 14), and new targeted 

therapies for lung cancer. For the 

enormous number of individuals 

who will face a diagnosis of lung 

cancer this year, any brighter outlook 

is most welcome. 

When we say lung cancer, we 

are actually referring to four different 

subtypes. Three subtypes are 

non-small cell lung carcinomas, or 

NSCLC: adenocarcinoma, squamous 

cell carcinoma, and large cell carcinoma; 

the fourth subtype is small cell 

carcinoma. This frst-level classifcation 

is likely to be the start of solving 

a complicated challenge of linking 

diagnostic characteristics to the most 

effective treatments. NCI-supported 

researchers are beginning to uncover 

genetic drivers of these four subtypes 

and applying this molecular knowl- 


edge for clinical beneft. However, 

it is clear that the best in diagnostic 

technologies and therapeutic advances 

will be needed to make signifcant 

progress in treating this very complex 

collection of diseases. Ideally, 

this will be complemented by downward 

trends in smoking rates, which 

is the most effective way to reduce 

the burden of lung cancer. 

There are currently several mutations 

that are known to exist in lung 

cancer, including EGFR and RAS 

gene mutations in non-small cell lung 

Scanning electron micrograph 

image of a small 

cancerous tumor inside 

an alveolus, or air sac, 

in a lung.

cancer. As with melanoma and some 

other cancers, BRAF gene mutations 

have also been found in lung cancers. 

Last year, researchers identifed 

a genetic target known as a gene 

translocation, or movement of a gene 

fragment from one chromosomal 

location to another. The translocated 

gene, EML4-ALK—found in 5 percent 

of NSCLC patients—can be acted 

on by crizotinib, a promising new 

drug with minimal side effects. Crizotinib 

acts by blocking the ALK kinase, 

believed to promote tumor growth. 

Results from this phase I trial showed 

that more than half of treated patients 

experienced tumor shrinkage while 33 

percent had their tumors stabilize. The 

development of crizotinib was made 

possible through molecular tumor 

characterization that was conducted at 

NCI-designated Cancer Centers. The 

drug was frst tested against anaplastic 

large-cell lymphoma as well as on neuroblastoma 

and NSCLC cells grown 

in the laboratory. Preliminary results 

of the phase I trial were so promising 

that a trial testing crizotinib in children 

with neuroblastoma was launched less 

than six months after the release of the 

results (see neuroblastoma profle). 

While efforts to further decrease 

smoking rates are critical, there is 

also great opportunity to utilize 

molecular and genetic information to 

signifcantly improve the treatment 

options available to patients diagnosed 

with lung cancer. This will require 

continued investigation into the 

biology of the various types of lung 

cancer and coordination between 

laboratory and clinical researchers to 

optimize existing treatment strategies 

and develop new ones. 

“I think it’s an exciting 

time now, because 

if we can infuence 

early diagnosis and 

prevention of lung 

cancer, and care of 

discovered lung cancer, 

we could actually 

make a major change 

to total cancer mortality 

in the United 

States. [Already] the 

total cancer mortality 

has gone down over 

the past fve to ten 

years mainly due to 

decreases in cigarette 

smoking.” 

— John Minna M.D., 

director of the Harmon Center 

for Therapeutic Oncology 

Research at the University 

of Texas Southwestern 


C A N C E R P R O F I L E S : L U N G C A N C E R 


48 

| 

O V A R I A N C A N C E R 

In 2010, ovarian cancer was the 

ffth most common cause of 

cancer death in U.S. women. Each 

year more than 21,000 American 

women are diagnosed with ovarian 

cancer, and about 14,000 die from 

the disease, making ovarian cancer 

the most deadly cancer of the female 

reproductive tract. Though this 

cancer is diagnosed in adult women 

of all ages, the fve-year survival rate 

of 57 percent for women under 65 

years of age is nearly twice that of 

women over 65. Ovarian cancer is 

particularly devastating because the 

disease frequently is not recognized 

until relatively late in its progression, 

due to the lack of early symptoms 

and effective screening tests. 

Currently, fewer than 20 percent of 

ovarian cancers are diagnosed early, 

when treatment is most effective. 

Prognosis is particularly discouraging 

for patients with advanced-stage 

disease—only about one-third live 

fve years past their diagnosis. 

Although ovarian cancer continues 

to be a major problem, cancer 

researchers are making headway 

in improving diagnosis and treatment 

as well as advancing our basic 

understanding of this disease, and 

NCI is mounting several major 

efforts to push progress in these 

areas. For example, the most aggressive 

type of ovarian cancer was one 

of the three cancer types analyzed 

during the pilot phase of The Cancer 

Genome Atlas. In early studies, 

signifcant heterogeneity was observed 

among the nearly 500 ovarian 

tumors that underwent molecular 

characterization. While virtually all 

of the tumors had mutations in the 


well-characterized tumor suppressor 

gene p53, there were other mutations 

present in smaller subsets of tumors, 

including mutations in BRCA1 and 

BRCA2 (genes also associated with 

hereditary breast cancer). 

Another fnding from the ovarian 

cancer characterization has exciting 

therapeutic potential. There are 

many DNA copy number changes— 

large regions of DNA whose number 

of copies are increased or decreased, 

Ovarian cancer cells 

viewed with a scanning 

electron micrograph; 

these are pleomorphic 

epithelial cells covered in 

microvilli.

compared with normal DNA— 

consistent with a high level of genomic 

instability. There are some 

indications from studies on ovarian 

and other types of cancer that it 

may be possible to exploit genomic 

instability therapeutically. In addition, 

there may be recurring patterns 

to some regions of DNA whose copy 

number is increased or decreased. 

Areas of increased copy number 

found in a high proportion of ovarian 

cancers are likely to contain one 

or more oncogenes that contribute 

to the malignant properties of the 

cancer. Cancer biologists can analyze 

the candidate genes that lie within 

these regions to determine which 

are the most important for ovarian 

cancer. This type of analysis may 

identify new therapeutic targets with 

relevance to a high proportion of 

ovarian cancers. 

As with all TCGA data, the 

genomic information is being made 

freely available to the scientifc community, 

providing opportunity for researchers 

from different backgrounds 

and with different perspectives to 

gain insight into the disease. In one 

example, the comprehensive molecular 

analysis carried out by TCGA is 

being used by systems biologists to 

develop computational models that 

aim to predict patient response to 

various therapeutic interventions 

based on a tumor’s molecular profle. 

These and other efforts eventually 

should help match patients with molecularly 

diverse ovarian tumors to 

the most appropriate treatments. 

Despite the challenges to treatment 

of advanced ovarian cancer, 

some progress is already being made. 

For example, bevacizumab (see 

glioblastoma profle) has demonstrated 

activity in women with recurrent 

ovarian cancer. In 2010, results 

from a phase III clinical trial studying 

the effect of adding bevacizumab 

to standard chemotherapy treatment 

in women with newly diagnosed, 

advanced ovarian cancer, found that 

addition of the drug extended survival 

by several months compared to 

standard chemotherapy alone. 

Technological advances in the 

areas of molecular diagnostics and 

imaging have potential to facilitate 

the development of effective and 

minimally invasive early-detection 

tests. Through its Early Detection 

Research Network and other mechanisms, 

NCI supports translational 

researchers at institutions across the 

country who are using varied approaches 

to identify potential screening 

biomarkers and conducting the 

necessary clinical and epidemiological 

research to confrm promising 

leads. Much of the work is focused 

on developing panels of biomarkers 

that can more accurately detect cancer 

at an early stage. Some progress 

is being made in this area, but it is 

clear that more work is needed to 

develop tests suffciently sensitive 

to detect cancer early enough to 

improve patient outcomes. 

C a N C e r p r o f i l e s : o v a r i a N C a N C e r 


50 

| 

IMMUNOTHERAPY ADVANCES 

Te pace of progress in immunotherapy has quickened 

in recent years, with some early-stage clinical trials of 

different therapies showing positive results for several 

different cancer types. In a recent large clinical trial, a 

monoclonal antibody called ipilimumab (also known as 

MDX-010), which treats cancer by binding to cells of the 

immune system and inhibiting their activity, became the 

frst immunotherapeutic agent to show an increase in 

the survival of patients with advanced melanoma whose 

disease was no longer responding to other treatments. 

Given the paucity of effective treatments for patients 

with advanced melanoma, this fnding represents a 

signifcant therapeutic advance. In late March, the FDA 

approved that drug, which will be marketed under the 

name Yervoy, to treat late-stage melanoma. 

As of early 2011, there were nine such immunotherapeutic 

agents that are FDA-approved, including 

trastuzumab. Many other such agents, for many types 

of cancers, are being tested in clinical trials. 

Immunotherapy using a syringe 

to remove purifed lymphocytes 

from a blood bag, prior to 

addition of Interleukin-2 (IL- 2). 


Other forms of immunotherapy also hold promise. Last 

year FDA approved the frst therapeutic cancer vaccine. 

Sipuleucel-T (Provenge) is designed for men with 

advanced prostate cancer. A different therapeutic vaccine 

developed by NCI investigators to treat advanced 

prostate cancer is moving into a phase III, or advanced, 

clinical trial. 

Other potentially promising immunotherapy approaches 

include inducing the immune system to target so-called 

tumor stem cells—or tumor-initiating cells, which are 

thought to be a chief cause of cancer recurrences—or to 

attack normal cells in the tumor microenvironment that 

cooperate with tumor cells to help them survive and 

spread to other parts of the body. 

Despite the progress we have made, more therapies to 

effectively stimulate the immune system to destroy cancer 

cells and promote destruction of tumors are urgently 

needed. Te development of reliable animal models of 

cancer that more closely mimic how the human immune 

system responds to tumors will provide invaluable tools 

for developing future immunotherapy agents and vaccines 

for cancer.

SYNTHETIC LETHALITY 

Finding drugs that kill cancer cells while leaving normal 

cells unscathed has been a major challenge in cancer 

treatment. However, there have been considerable advances 

in genomics in the last decade that have revealed 

a novel and promising approach: synthetic lethality. Te 

concept is simple—a compound targeting a particular 

gene or pathway is selectively lethal to cells that harbor 

a cancer-causing mutation in a complementary pathway. 

Healthy, noncancerous cells are spared. In this method, 

two genes are said to be in a synthetic lethal relationship 

if disruption of either gene alone is not lethal, but changes 

in both genes—either by mutation or chemical inhibition— 

causes cell death. 

Te approach tailored for cancer biology is based on the 

premise that oncogenic mutations often cause cancer 

cells to develop secondary dependencies on other genes 

that are not inherently oncogenic. Chemical inhibitors that 

disrupt these latter genes result in an oncogene-specifc 

synthetic lethal interaction, and thus cell death. Healthy, 

noncancerous cells are spared. 

As an example, an exciting new class of drugs, called PARP 

(poly adenosine-disposphate-ribose polymerase) inhibitors, 

is being tested in a number of clinical trials in cancer 

patients with BRCA gene mutations. Te BRCA and PARP 

genes, which have a synthetic lethal relationship, play 

different, but complementary, roles in DNA repair. Loss of 

either of these genes allows the cell to survive; but when 

PARP activity is blocked in cells with BRCA gene mutations, 

the cells lose their ability to repair themselves, 

resulting in cell death. Equally important, PARP inhibition, 

which kills cancer cells, spares cells that have at least one 

normal copy of the BRCA gene. 

Results from a recent phase I study using olaparib, a PARP 

inhibitor, showed that nearly 60 percent of patients who 

were BRCA gene mutation carriers and had ovarian 

cancer, breast, or prostate cancer, had some measure 

of clinical beneft. More than one-third of patients had 

tumor shrinkage in phase II studies of olaparib (AZD- 

2281) conducted in women with BRCA1 or BRCA2 gene 

mutations and advanced chemotherapy-refractory breast 

or ovarian cancer. A second PARP inhibitor, iniparib (BSI- 

201), appears to be even more promising. In combination 

with conventional chemotherapy, iniparib improved the 

duration of overall and progression-free survival in women 

with metastatic triple-negative breast cancer nearly 

40 percent compared to those who received chemotherapy 

alone. Iniparib did not cause additional toxicities. 

Cancer patients with BRCA1 and BRCA2 gene mutations 

are not the only candidates for PARP inhibition therapy. 

Te Cancer Genome Atlas has revealed numerous other 

tumors with defects in DNA repair, creating opportunities 

for more types of synthetic lethality-based therapies. 

Researchers are also using the concept of synthetic lethality 

in genome-wide and chemical searches to identify 

cancer-killing drug combinations and new gene-targets to 

kill lung cancer cells. An NCI-sponsored study identifed 80 

new genes that were synthetically lethal in combination 

with taxol treatment of cancer cells. Inactivation of these 

genes killed lung cancer cells but not normal cells, and only 

in the presence of a very low dose of taxol. Tis type of synthetic 

lethal approach has enormous potential not only for 

the treatment of lung cancer but numerous other cancers 

as well. Trough combining novel, synthetic lethal inhibitors 

with traditional chemotherapeutic drugs, unlimited 

numbers of genetically diverse cancers could potentially 

be treated with fewer side effects. Tese fndings seem to 

have great potential, but they were made in cultured cells, 

and it has not yet been determined 

that they accurately 

predict therapeutic response 

in people with cancer. 

Depiction of a signaling pathway 

that could be affected by 

synthetic lethality. Shown are 

two types of transmembrane 

protein receptors, smoothened 

(red) and patched 

(blue) that could be targeted. 

C a N C e r p r o f i l e s : o v a r i a N C a N C e r 


52 

Revitalizing the Nation’s Cancer Clinical Trials System 

If today’s new understandings of cancer biology are to beneft cancer patients 

on a broad scale, they must be coupled with a modernized system for conducting 

cancer clinical trials. This system must enable clinical researchers across 

the nation to acquire tumor specimens and conduct genetic tests on each patient, 

to effciently sequence the DNA from those samples, to manage and secure vast 

quantities of genetic and clinical data, and to identify subsets of patients with 

tumors that demonstrate changes in specifc molecular pathways—pathways that 

can be targeted by a new generation of cancer therapies. And all of this must be 

done one patient at a time. 

As part of its effort to transform the cancer clinical trials system, NCI asked the 

Institute of Medicine (IOM) in 2009 to review the Clinical Trials Cooperative Group 

Program. This program involves a national network of 14,000 investigators 

currently organized into nine adult Cooperative Groups and one pediatric 

cooperative group that conduct large-scale cancer clinical trials at 3,100 sites 

across the U.S. The IOM report, issued in April 2010, noted that the current trials 

system—established a half-century ago—is ineffcient, cumbersome, underfunded, 

and overly complex. Among a series of recommendations, the report 

urged that the existing adult cooperative groups be consolidated into a smaller 

number of groups, each with greater capabilities and the ability to function with 

the others in a more integrated manner. 

| 


In December 2010, NCI announced its intent to begin consolidating the current 

nine adult cooperative groups into up to four state-of-the-art entities that will 

design and perform improved trials of cancer treatments, as well as explore 

methods of cancer prevention and early detection and study quality-of-life issues 

and rehabilitation during and after treatment. The sole pediatric cooperative 

group was created by consolidating four pediatric cooperative groups a number of 

years ago, and that group will not be affected by the current consolidation effort. 

NCI also intends to consolidate nine existing tumor banks into three to give 

researchers improved access to a nationally integrated tissue resource. 

Currently, optimal use of tissue specimens from NCI-supported prospective 

trials is impeded by the lack of a national IT system for locating tissue, the lack 

of standard operating procedures, and the lack of a transparent process to 

prioritize the distribution of specimens on a national scale. 

Revitalizing a cancer clinical trials system must enable researchers across the nation 

to acquire tumor specimens and conduct genetic tests on each patient, efficiently 

sequence DNA, and identify subsets of patients with tumors that demonstrate changes 

in specific molecular pathways. 

The consolidation of the cooperative groups is also intended to improve the effciencies 

of operations centers and data management centers, and to facilitate the 

training of investigators in applying molecularly based approaches to large-scale 

clinical trials. In addition, NCI envisions using the Cooperative Group Program as 

a means for preparing the oncology community, including community physicians, 

for the widespread introduction of molecularly-based therapies. 

The consolidation of the Cooperative Group Program is the most recent in a 

series of changes initiated by NCI, through its Division of Cancer Treatment and 

Diagnosis and the Coordinating Center for Clinical Trials, to revitalize the nation’s 

cancer clinical trials system. Other transformative changes introduced in recent 

years include those outlined in a working group report which can be found at 

http://ccct.cancer.gov/fles/OEWG-Report.pdf: 

• Reduce by half the time to initiate new clinical studies and terminate studies 

not begun within 18 to 24 months of concept approval. 

• Revamp the prioritization process for large phase II and phase III treatment 

trials by creating disease-specifc and modality-specifc steering committees. 

• Improve the use and effciency of the NCI Central Institutional Review Board, 

which reduced the average time for fnal sign-off on protocols for national 

trials from 150 days in 2007 to 42 days in 2010. 

• Increase reimbursement to clinical trials sites. 


54 

| 


Director’s Afterword 

Iwas 

sworn in as the new Director of the National Cancer Institute just nine 

months ago, so this is the frst time that I have been privileged to voice my 

pride in NCI’s past accomplishments and the promise of future achievements 

in its annual report on budget needs and priorities. 

Although I am new to this position, I am not new to cancer research or to the 

NCI. I received my scientifc training here more than 40 years ago, started to 

work on cancer-causing viruses shortly thereafter, and have been supported by 

NCI funds throughout my career. In these intervening years, I have witnessed 

profound changes in our knowledge about the biology of cancer. When I began to 

study animal models of cancer in the early 1970s, the collective understanding of 

the origins and progression of cancer was negligible; now we are able to describe 

such events in minute detail at the molecular level. This transformation has been 

accompanied by gradual—and occasionally dramatic—improvements in the 

control of human cancer. In an increasing number of cancers, new concepts about 

the biology of cancer are now driving benefcial changes in the ways we prevent, 

diagnose, and treat disease. 

The importance of the NCI throughout this rich history can best be appreciated 

by considering the amazing diversity of the approaches it has undertaken to 

control cancer—through basic research on normal cells, genes, and proteins; 

through studies of the pathogenesis of various forms of cancer; and through 

efforts to improve the prevention, diagnosis, and treatment of cancers. 

In the frst half of this report, we have tried to convey the depth of these enterprises, 

while emphasizing at least three big ideas. First, cancer constitutes a complex 

set of diseases. It is not simply one disease that happens to affict many organs 

of the body; it is, instead, many different disorders that display some common 

themes, including mutations in many important genes, alterations in essential cell 

functions, and novel interactions with the cellular environment in which tumors 

grow. Second, cancers can be controlled in many different ways. As refected in 

their biological complexity, cancers invite several strategies to improve control. 

These include a number of approaches to prevention, multiple methods to 

screen for early stages of carcinogenesis, more precise diagnostic tests, and better

therapies. The improved treatments are based on knowledge of specifc genetic 

changes in cancer cells, the functions of the immune system, the susceptibilities 

of cancer cells to various drugs and radiotherapy, and an understanding of the 

symptoms and complications of these diseases. 

Third, advances against cancer that beneft people depend on science of many 

kinds. Progress in the control of cancer has required new knowledge from the 

many felds of research that the NCI supports—from molecular and cell biology, 

genetics, virology, immunology, and chemistry; from animal models of cancer; 

from the behavior and biology of human beings; and from many other directions. 

In brief, cancer represents one of the greatest challenges to the strength of modern 

medical science. 

My colleagues and I have chosen to illustrate these ideas, and the complexity they 

embody, by describing recent progress made against six kinds of cancer, chosen 

somewhat arbitrarily from a much larger repertoire of successes. We acknowledge 

that none of these six stories is over; in all situations, we have much more to do. 

But each narrative reveals a promising path to further progress. 

The men and women who have achieved these successes and who are poised 

to extend them represent our greatest resource. With the additional funds 

requested here, their ambitions and talents can be unleashed, ensuring that the 

NCI can take the greatest possible advantage of the opportunities created by its 

remarkable history. 

Harold Varmus, M.D. 

Director, National Cancer Institute 


56 

| 

This budget request consists of 

two components: the increase 

required to maintain our present 

level of operations (current services) 

and the increase required to 

initiate new initiatives and expand 

existing ones. 

It should be noted that we have 

carefully reviewed our current 

expenditures and have found 

important effciencies and savings. 

The current services increase is 

the amount that will be required to 

sustain NCI programs, restore some 

of the funding cuts that have been 

implemented over the past several 

fscal years, and provide for some 

minimal growth. Noncompeting Research 

Project Grants (RPGs) would 

be funded at committed levels, the 

number of competing RPGs would 

be maintained at the FY 2010 level, 

and most other mechanisms would 

receive suffcient increases to cover 

cost of living adjustments based 

on the Biomedical Research and 

Development Price Index (BRDPI). 

This budget level also includes 

funds to make critically needed 

capital repairs and improvements at 

the NCI-Frederick Federally Funded 

Research and Development Center. 

The additional funds requested 

refect the Institute’s assessment 

of where more funding will make 

the greatest difference in reducing 

cancer incidence and mortality. 

Together, with growing the research 

grants portfolio, these new or expanded 

initiatives—cancer genomics, 

transformation of the clinical 

trials system, and more effective 

translation of research results to 

clinical utility—offer the greatest 

current hope of advances against 

cancer. 


Te 2012 Budget Request 


At a Glance (dollars in thousands) 

Fiscal Year 2011 Estimate $5,103,388 

Current Services Increase 207,869 

Subtotal 5,311,257 

Fiscal Year 2012 Additional Resources 

Support Individual Investigators 173,000 

Genomics 145,600 

Clinical Trials 125,000 

Translational Sciences 

Subtotal 

Total NCI 

115,000 

558,600 

$5,869,857 

Conceptual computerized 

image of DNA.


Printed March 2011

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