YSM Issue 85.4

Yale Scientific

Established in 1894

THE NATION’S OLDEST COLLEGE SCIENCE PUBLICATION

October 2012

Vol. 85 No. 4

COMPETING

VISIONS

Will science sway your vote?

PAGES 20-22

The link between protein

expression and alcoholism

propensity in Mus musculus

Sizing Up Autism

The correlation between

autism spectrum disorders

and abnormal head growth

Pluripotent Politics

How the challenges of

federally-sponsored stem cell

research impact scientists

PAGE 6 PAGES 16-17 PAGES 20-22

everyday Q&A

Q&A

What is the Higgs Boson?

The science behind the “God particle.”

On July 4, 2012, scientists at

the European Organization for

Nuclear Research — the world’s

largest particle physics laboratory,

also known by its French

acronym CERN — announced

the discovery of a particle likely

to be the long-sought-after Higgs

boson. Putting aside the public

hype of the Higgs as a “God

particle,” what exactly does this

discovery mean?

The Higgs is the last expected

piece of a theory called the Standard

Model, which essentially

describes how the universe works

on a subatomic scale. It is by the

Standard Model, for example,

that we can manipulate electrons

precisely enough to see individual atoms through microscopes.

In spite of all it can explain, however, the Standard Model has

a missing piece.

The model predicts that electromagnetism and the weak

force, which causes nuclei to decay, are really two sides of the

same coin and that these forces are composed of counterpart

particles: photons, and W and Z bosons. Because of the

analogous, correspondent nature of the two forces, scientists

Q&A

BY ANDREW DEVEAU

Have you ever thought about what space could smell like?

Describing the stench of space as “sulfurous” and “metallic,”

astronauts have reported scents similar to seared steak, hot metal,

and gunpowder. There is no firm consensus, but these accounts

can agree on one thing: space stinks.

According to astronauts, the smell is not apparent when wearing

a spacesuit: an odor only emerges after removing their suits in the

safety of the space shuttle. Scientists think that this alien aroma

may arise because particles outside in space continue to cling to

spacesuits inside the space shuttle. These particles, likely polycyclic

aromatic hydrocarbons that form in space during combustion

after a star’s death, mix with air in the space shuttle to create a

distinctive smell.

The odor has become so notorious that NASA is trying to

recreate the smell of space back on Earth for astronaut-training

purposes. With the help of a scent chemist who recreated the

scent of the Mir space station for an art exhibition, NASA hopes

the scent of space itself will be recreated just as successfully. Until

then, the smell remains just another elusive mystery of outer space.

An artist’s approximation of a collision of two protons

that produce a Higgs. Courtesy of CERN National

Geographic.

What Does Space Smell Like?

A whiff of the final frontier.

BY AHMED ANSARI

expected the W and Z bosons to

be massless like the photon, but

these particles were surprisingly

found to have significant mass,

leaving researchers puzzled by

inconsistency.

The addition of the Higgs to

the Standard Model accounts

for the seemingly inexplicable

mass of W and Z bosons: Higgs

particles create a field or “fluid”

(known as Higgs Condensate)

through which all particles in

existence continually travel. This

field acts as a barrier to movement

and thus varying degrees

of resistance, depending on

the properties of the particle in

question, contribute to perceived

mass. Some particles, like W and Z bosons, slow down in the

Higgs field, while other particles, like photons, zip through it

unaffected, massless and minute.

Although this model serves as a strong theory, the existence

of the Higgs has been difficult to prove — until this summer’s

discovery. While CERN researchers have yet to confirm the

discovered particle’s identity indefinitely, it is very likely the

missing piece in our physical understanding of the universe.

Particles in space may mix with air in the space shuttle to

create a distinct “space” smell. Courtesy of Acclaim Images.

2 Yale Scientific Magazine | October 2012 www.yalescientific.org

NEWS

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6

6

7

7

8

9

10

11

Letter from the Editor

New Grant For Cancer Research

Alcoholism in Mice

Professor Joan Steitz Honored as Role

Model for Women in Science

Professor Horwich Receives Shaw Prize

Yale Professor Fact Checks Nature

Natural Birth Induces Protein Linked

to Brain Development

On The Road to Attenuating

Neuropathic Pain

Stress and Ecosystems

FEATURES

26

28

30

Bioethics

Pluripotent Politics

Micobiology

Exploring the Microbiome

Politics

The Politics of FDA Approval

contents

October 2012 / Vol. 85 / Issue No. 4

12

20

The Latest Superstar

Couple: Closing in on

Kepler-36

Meet the galaxy's hottest new superstar

couple, Kepler 36b and Kepler 36c. Professor

Sarbani Basu of Yale's Astronomy

Department is part of a team that just

discovered Kepler 36, the first planetary

group comprised of planets of strikingly

different densities and compositions so

close in proximity to each other.

ON THE COVER

Competing Visions: Will Science Swing Your Vote?

With the election one week away, which issues do you care about?

This article covers the underlying science, current facts, and each

candidate’s stance towards the two science issues Yale undergraduates

found most important: alternative energy and climate change.

31

32

33

34

Technology

3D Organ Printing

Health

MythBusters: Taste Mapping

Astronomy

NASA Rover Curiosity Cruises Onto

Mars

Education

The Story of Science at Yale, Part III:

Science at Yale on the Horizon

14

Curing the "Bubble

Boy"

Yale researchers on a multi-institutional

team have demonstrated that gene therapy

is a viable option for treatment of adenosine

deaminase severe combined immunodeficiency

(ADA-SCID). Professor Meffre

of the Department of Immunobiology

explains this disease and the options for its

treatment.

is History: Microprobe

analyses decipher the identity of

18This

metallurgical artifacts

35

36

37

39

Book Review

The Vision Revolution

Zoology

Laughter Across the Animal Kingdom,

From Rats to Humans

Alumni Profile

Jennifer Staple-Clark '03

Cartoon

A Different Political Campaign

16

Sizing Up Autism

Several studies over the past decade

have linked head overgrowth to autism,

and a recent study by Dr. Katarzyna

Chawarska at the Yale Child Study Center

shows the correlation between autism and

overgrowth in general. This research aims

to further understand the biological underpinnings

of autism and ultimately advance

to the development of treatment or a cure

for the disorder.

23

Carfilzomib: The Latest

Triumph of Targeted

Therapies Development

www.yalescientific.org

October 2012 | Yale Scientific Magazine 3

THEME

“

Only by ensuring that scientific data is never distorted

or concealed to serve a political agenda, making

scientific decisions based on facts, not ideology, and

including the public in our decision making process

will we harness the power of science to achieve our

goals – to preserve our environment and protect our

national security; to create the jobs of the future,

and live longer, healthier lives.”

“

The federal government has a vital role to play

in conducting sound science and making the

resulting data available.”

I will ensure that the best available scientific

and technical information guides decisionmaking

in my Administration, and avoid the

manipulation of science for political gain.”

“Climate change is the one of the biggest issues of

this generation, and we have to meet this challenge

by driving smart policies that lead to greater growth

in clean energy generation and result in a range of

economic and social benefits.

“A crucial component of my plan for a stronger

middle class is to dramatically increase domestic

energy production and partner closely with

Canada and Mexico to achieve North American

energy independence by 2020.”

— Barack Obama — Mitt Romney

Though they declined a science debate,

both Barack Obama and Mitt Romney

answered 14 questions from Scientific

American and ScienceDebate.org

“regarding some of the biggest

scientific and technological

challenges facing the nation.”

Above are some quotes from their

respective answers. To read

their full responses

and more about

each candidate’s

stance on science

issues, visit www.

sciencedebate.org.

october 2012

neuroscience medicine bioethics

Sizing Up AUtiSm

Vol. 85 No. 4

plUripotent politicS

A history of the challenges of

federally sponsored stem cell

research and what it means for

scientists

October 2012 Volume 85 No. 4

Editor-in-Chief

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F R O M T H E E D I T O R

SCIENCE & POLITICS

Scientists and politicians have always had their disagreements. From the post-World War II atomic

weapon disputes to the current storm over stem cells, the views of researchers and policy makers have

clashed throughout the course of modern history. But perhaps the situation now is more urgent than ever.

As politics continues to polarize, citizens have only become further entrenched in their values, often

losing sight of the hard facts supported by quantitative data and evidence. Surgeon Generals have been

victim to a trend of diminishing jurisdiction over public health measures, while politicians cave to expectations

of preventing science from “interfering” with their values — a stark contrast from the past

with presidents, such as John F. Kennedy, who needed to assure that religion and other biases would not

cloud their role as leaders.

And this is not solely an issue of political preference: both Democrats and Republicans are guilty of

these acts, “massaging” statistics and vacillating until scientific facts are distorted, twisted, and politicized.

While it may be easy to peg a certain party as pro- or anti-science, many politicians will highlight evidence

that favors their point and downplay dissenting data depending on the issue. Whether it is a blatant dismissal

or a lack of understanding, science clearly warrants serious attention in political decisions. Some

hold steadfast to the notion that science should solely inform and not create policy, but it is clear that

such a belief has introduced gaping issues with interpretation — and scientists are the experts that can

bridge the gap between misguided politics and the scientific truth.

Today, several major challenges of our nation grapple with science: global warming, abortion, stem cell

research, resource usage, and energy independence, among many others. And as scientific advancements

naturally make science increasingly pervasive and relevant to everyday life, voters need to keep politicians

accountable for sound science policy. In light of the upcoming election, the Yale Scientific explores the

intersection of science and politics. While a considerable amount of current research is directed toward

developing medication and innovating therapeutics, the novel scientific applications cannot reach patients

without the necessary approval by the FDA. Dr. Joseph Ross, Assistant Professor of General Internal

Medicine at the Yale School of Medicine, is an expert on federal medical policy and has studied the efficiency

of the FDA compared it its international counterparts. Testament to the high-quality screen of

this regulatory process is the reported success and acclaim of the recently-approved, groundbreaking

targeted therapy for multiple myeloma developed in the laboratory of Craig Crews, the Lewis B. Cullman

Professor of Molecular, Cellular, and Developmental Biology at Yale. In addition, this issue features

science policy that Yale undergraduates ranked most relevant to them and covers the underlying science,

current facts, and each presidential candidate’s stance on these issues.

As election day fast approaches, it may be interesting to recognize that democratic elections essentially

boil down to a scientific experiment as we come together to decide which variables to tweak based from

past observations to produce desired results. In fact, as several scholars have noted, the founding fathers

of our country often referred to our nascent nation as an experiment as they crafted the untested system

with a healthy splash of equality, liberty, and order. And although few believed that our nation would

persist, the results — like those of science experiments — were unexpected, as democracy emerged as

arguably the most stable and sustainable form of government to date. By casting our votes with science

in mind, we are not only emphasizing the importance of science in politics but perhaps also ultimately

honoring the very foundation our nation was founded on.

William Zhang

Editor-in-Chief

About the Art

The Yale Scientific Magazine (YSM) is published four times a year by

Yale Scientific Publications, Inc. Third class postage paid in New

Haven, CT 06520. Non-profit postage permit number 01106 paid

for May 19, 1927 under the act of August 1912. ISN:0091-287.

We reserve the right to edit any submissions, solicited or unsolicited,

for publication. This magazine is published by Yale College

students, and Yale University is not responsible for its contents.

Perspectives expressed by authors do not necessarily reflect the

opinions of YSM. We retain the right to reprint contributions,

both text and graphics, in future issues as well as a non-exclusive

right to reproduce these in electronic form. The YSM welcomes

comments and feedback. Letters to the editor should be under

200 words and should include the author’s name and contact

information. We reserve the right to edit letters before publication.

Please send questions and comments to ysm@yale.edu.

The QuesT for speech

Exploring treatment for children with autism

page 17

Yale Scientific

Established in 1894

The NaTioN’s oldesT College sCieNCe PubliCaTioN

Smirnoff “mice”

Protein Expression Linked

to Alcoholism Propensity in

Mus musculus

Competing

Visions

The Correlation Between

Autism and Abnormal

Growth

Will science sway your vote?

PAGES 20-22

PAGE 6 PAGES 16-17 PAGES 20-22

The cover, designed by guest artist David Yu, puts the 2012 presidential

candidates into the shoes of scientists as they plan their campaigns. Votes,

like experimental data, are the results of many complex processes and

factors. It does not take a research scientist to realize the importance of

scientific topics, not only in this campaign but for the future of our country.

In the April 2012 issue of the Yale Scientific, we inadvertently ran an image of the

ESET Android without giving proper attribution. ESET is a global provider of antivirus

software with 100 million users and offices around the world. While our arts team took

some creative liberties with the android image, we would like to give ESET full credit for

its artwork. ESET is an ardent supporter of education and academic research, and we

would like to express our appreciation to ESET for allowing us to correct the record.

CHEMISTRY

New Grant to Investigate Novel

Approaches in Cancer Research

BY JAYANTH KRISHNAN

The National Cancer Institute (NCI) recently awarded

two Yale Professors of Chemistry, Alanna Schepartz and

Andy Phillips, a $2.5 million research grant to investigate

unique ways to inhibit protein targets that are currently

considered “undruggable” and

are responsible for the malignancy

of certain cancers. Such

protein targets could include transcription

factors, protein-protein

interactions and kinases. This

highly competitive grant was won

through the NCI’s Provocative

Questions program, which challenges

scientists to work on crucial

problems that are often neglected.

Schepartz and Phillips, along

with chemist Dylan Taatjes of

the University of Colorado, have

selected a project that attempts

to correct dysfunctional regulation of the crucial tumor

suppressor p53. Commonly called the guardian of the

NEUROSCIENCE

Smirnoff “Mice”: Protein Expression Linked to

Alcoholism Propensity in Mus musculus

BY JASON YOUNG

Andy Phillips (left) and Alanna Schepartz

(right) have been awarded $2.5 million from

the National Cancer Institute. Courtesy of

Dr. Phillips and Dr. Schepartz.

Yale Professor of Psychiatry Jane Taylor and her graduate

student Jacqueline Barker have identified some of

the first innate biochemical differences

underlying alcoholismrelated

behavior in the brains

of mice.

Because researchers have found

it difficult to distinguish between

the innate biological or neurological

factors for alcohol abuse

propensity and the changes in

the brain caused by heavy alcohol

consumption, the underlying neurological

causes for alcoholismrelated

behavior remain largely

unknown. However, recent studies

have linked addictive behavior

and alcohol consumption to changes in neural plasticity,

the adaptability of the brain to respond to neuronal

activity.

Barker performed a series of tests to first identify and

isolate mice that demonstrated vulnerability to addictive

behaviors before exposure to alcohol. She and Professor

Differences in the brains of mice have

been linked to alcoholism vulnerability.

Courtesy of Wikicommons.

genome, p53 is the transcription factor that prevents cells

from becoming oncogenic. Schepartz and Phillips want

to apply new techniques in chemical biology to develop

novel molecules that can gain entry to the cell and properly

regulate the expression of genes

affiliated with p53 to prevent cells

from becoming malignant, which

has been and continues to be a

major goal of this field.

Many scientists regard modern

cancer research as highly empirical,

yet dependent on trial and error.

Scientists often combine various

drugs and chemotherapeutic agents

at several different molar concentrations

to test if their concoction

induces apoptosis, or programmed

cell death, to malignant cells. The

research Schepartz and Phillips

plan to carry out is a hypothesis-driven approach based

on the belief that the best cure for cancer is prevention.

Taylor hypothesized that differences in the prevalence

of molecules relating to neural plasticity in a part of the

brain known as the ventromedial

prefrontal cortex (vmPFC) would

cause differences in vulnerability to

alcohol-addiction-related behavior.

The study found that the modified

neural protein PSA-NCAM, which

is involved in learning and memory,

is causally linked to the extinction of

alcohol-seeking behavior. This protein

was expressed at lower levels

in the vmPFCs of mice at risk for

alcoholism-related behavior than in

mice that were not.

Further studies examining sex differences

and targets regulating gene

expression are currently underway. Taylor hopes that in

the future, the findings can be applied to humans to help

identify alcohol addiction and related disorders. “This

work will allow us to find genes and molecules that might

put people at risk,” Taylor says.

This research was supported by the NIAAA.


Professor Joan Steitz Honored As

Role Model For Women Scientists

Professor Joan Steitz, Sterling Professor of Molecular

Biophysics and Biochemistry, recently received two major

awards for her achievements as a woman scientist.

Steitz received the Pearl Meister Greengard Prize, an

award given by Rockefeller University

that recognizes outstanding achievements

in science and aims to combat

discrimination against women in the

field. She also received the 2012 Vanderbilt

Prize in Biomedical Science for her

“stellar record of research accomplishments”

and pioneering work that has

helped develop the current understanding

of RNA and its role in health and

disease. As part of the award, Steitz will

visit the Vanderbilt University School of

Medicine to deliver a talk as a part of

the Flexner Discovery Lecture Series,

which features guest lectures from “the world’s most

eminent scientists.”

Despite these recent accolades, among many others,

BY ANNY DOW

Professor Horwich Receives Prestigious Shaw

Prize

Dr. Arthur L Horwich, Professor of Genetics and Pediatrics

at the Yale School of Medicine, was recently awarded

the Shaw Prize for elucidating

the role of chaperonins in

protein folding. This prize was

shared with collaborator Ulrich

Hartl from Max Planck Institute,

Martinsreid, Germany.

The one million-dollar Shaw

Prize, awarded in Hong Kong,

distinguishes scientific breakthroughs

throughout the world

that enhance societal progress.

Three prizes are given annually,

one each in the categories of

Astronomy, Life Science and

Medicine, and Mathematical Sciences. The Life Science and

Medicine award was presented to Horwich in September

for his research revealing important mechanisms of protein

folding. His research found that the protective environment

created for proteins by chaperonins allows for efficient and

undisturbed formation.

After first publishing this research in 1989, Hor-

Professor Joan Steitz’ lecture.

Courtesy of Professor Steitz.

BY SMITA SHUKLA

Horwich receiving Shaw Prize from Hong

Kong’s Chief Executive C.Y. Leung.

Courtesy of Dr. Horwich.

WOMEN IN SCIENCE

Steitz was not always certain about her career path. When

she was a college student in the 1960s, there were very

few women in science. Inspired by the work she did under

cell biologist Joseph Gall, she pursued studies at Harvard

University and worked with influential

scientists, such as Nobel Prize winner

James D. Watson, against the odds. During

her career, she has conducted research on

how RNA operates in both bacteria and

vertebrate cells and is now considered one

of the leading scientists in her field.

“The most rewarding part of [being a

scientist] is working in the lab,” Steitz said.

“You discover and figure out things that

nobody ever knew because of the experiments

that you’ve done. I think that’s the

biggest thrill for all scientists.”

Steitz is passionate about her work

and is currently researching different types of noncoding

RNA-protein complexes, providing critical insights into

viruses and disease states.

BIOLOGY

wich became a Howard Hughes Medical Institute Investigator.

Over the past twenty years, Horwich has worked

with biochemical reconstitution,

X-ray crystallography, and

genetic manipulation techniques

to build upon his initial findings.

This early discovery holds great

importance for research today

on complications associated with

protein malformation.

Currently, Horwich’s lab is

studying neurodegenerative diseases

that are associated with

protein malformation. Indeed,

Horwich posed a question that

demonstrates the new goal of

his laboratory: “If molecular chaperones [are] so good at

helping our proteins fold, then why do we have neurodegenerative

diseases?” Horwich hopes that studying protein

folding in neurons will help develop the understanding of

medical issues such as amyotrophic lateral sclerosis, a disease

of the malformation in neurons which control voluntary

muscle movement.

www.yalescientific.org October 2012 | Yale Scientific Magazine 7

DATA ANALYSIS

Yale Professor Clears Olympic Swimming Controversy

Almost immediately after Nature released its controversial piece

on Chinese Olympic swimmer Ye Shiwen, titled “Why great

Olympic feats raise suspicions,” the response letters began to

flood in, including one written by Yale Associate Professor of

Molecular, Cellular, and Developmental Biology, Weimin Zhong.

In the Nature article, Ewen Callaway contributed to the ongoing

debate about the integrity of Ye’s world-record-breaking

performance in the 2012 London Olympics by arguing that the

16-year-old’s “anomalous” race, while not proof of foul play,

certainly raised concerns. He claimed that not only did Ye beat

her personal best in the 400 IM by more than seven seconds, but

she also out-swam American gold-medalist Ryan Lochte in the

last 50 meters of their respective 400 IM races. Within three days

of publication, Callaway’s article had drawn what Nature editors

called an “extraordinary level of outraged response.”

In China, scientists and other readers of Nature, angered by

the piece, contacted the Chinese Biological Investigators Society

(CBIS), a group of scientists who collaborate on scientific

research, projects, and other miscellaneous issues.

Zhong, Vice-President of the CBIS, was aware of the controversy

surrounding Ye’s swim but had not given it much attention

until the group was contacted by Chinese scientists. “This is

the first case in which we got involved in something that’s not

scientific,” Zhong said, “but analyzing data is scientific, and the

problem is that they selectively took out data. That’s a no-no in

science.”

Zhong worked with his colleagues Hao Wu and Linheng Li, professors

from Harvard and Stowers Institute for Medical Research,

Ye Shiwen celebrates after winning the women’s 400 IM at the London 2012

Olympics. Courtesy of The Guardian.

BY BRENDAN SHI

Courtesy of Nature.

respectively, to expose this scientific fallacy. In their response letter,

which Nature would later publish as “Some facts about Ye Shiwen’s

swim,” they demonstrated that Ye’s previous personal best was actually

only five seconds slower than her world record time, compared

to the seven-second difference that Nature reported.

These researchers then compared Ye’s improvement

with the improvements of other young swimmers,

finding that, historically, many other prominent teenage

swimmers had improved their times by five or more

seconds, including Ian Thorpe, Adrian Moorhouse,

and Elizabeth Beisel.

Finally, they challenged Callaway’s comparison of

Ye and Lochte’s times in the last 50 meters of their

respective races, questioning Callaway’s decision to

omit the fact that Lochte finished his 400 IM an entire

23 seconds faster than Ye Shiwen or that Lochte was

not even close to being the fastest man in the last 50

meters. Zhong recognized that it would be easy to label

Nature’s article as biased. “Oftentimes, it’s not very easy

to tell the difference between incompetence and bias.

I don’t think there’s any ill-will — it looks to me like

the Nature reporter was just lazy,” he said.

It was that laziness and Nature’s failure to adhere to

higher standards of factual reporting that drew him

into the controversy in the first place. “If we aren’t

sure about things, we tend not to write anything about

it,” he said, “but in this case, the facts are very easy to

find, and once you look at the facts there’s absolutely

no basis for the accusation.”


NEUROBIOLOGY

Natural Birth Induces Protein Linked to Brain

Development

BY ALYSSA PICARD

A team of researchers led by Tamas Horvath, Professor of Comparative

Medicine, Neurobiology, and Obstetrics and Gynecology at

the Yale School of Medicine, has found that natural birth, not delivery

by Caesarian section (C-section), stimulates production of a protein

important for brain development.

The discovery was a chance finding for the researchers, who were

initially investigating the role that mitochondrial uncoupling protein

2 — or UCP2 — plays in the brain. It is believed that the main role

of the protein is to enable cells to metabolize fat, a key process for

the adaptability of cells. The researchers were studying this protein

in post-natal mice and looked for differences in expression between

in utero and ex utero as a control. “What we noticed was that if the

animal was naturally born, the expression of the UCP2 was significantly

higher than if the pup was taken from C-section,” Horvath explains,

“and that’s when the whole thing started to be interesting for us.”

Method of birth may play a role in how one’s brain develops

into adulthood. Courtesy of CNN.

of the procedure. “If there is a biological process that makes a difference

between C-sections and natural birth, it will at least be good

to know and see how [one] can take that into consideration,” he says.

Horvath also points to the possibility that future studies could reveal

the threshold of medical need for women to have a C-section.

In future studies, Horvath plans to investigate the triggers of UCP2

induction to determine why it occurs with natural birth, which could

lead to the development of methods to mimic it through surgical

means. He also plans to expand on the original finding with additional

studies on surgically and naturally born mice and eventually dogs. This

may include following their development and behavior throughout

their life, but the long-term goal remains to conduct studies in the

human population.

Lower levels of UCP2 lowered connectivity between hippocampal

neurons (mouse hippocampal neurons seen here). Courtesy

of Institute for Neurological Discoveries, Kansas University.

Once the team established the connection between higher levels of

UCP2 and natural birth, they turned their attention to the role that

UCP2 has on brain development. By inferring the UCP2 expression

using chemical methods and genetic suppression, the team discovered

that lower UCP2 expression resulted in less connectivity between the

neurons in the hippocampus — the part of the brain responsible for

developing memory and aiding the learning processes. Additionally,

mice with lower levels of UCP2 performed differently in simple tasks

associated with the hippocampus region. They exhibited less spatial

awareness, moved more slowly, and showed greater anxiety about

moving into open areas than did the mice with normal levels of UCP2.

The discovery comes at a time when many women, especially those

in the United States, are electing to have C-sections out of convenience

rather than medical necessity. Though the World Health Organization

recommends that the C-section rate be less than 10 percent to 15

percent, the rate in the U.S. has climbed from 4.5 percent in 1965 to

32 percent in 2007. While Horvath does not think this discovery will

halt the trend, he is hopeful that it will lead to a greater understanding

C-section rates have been climbing in the US in recent years.

Courtesy of CDC.


NEUROSCIENCE

On The Road to Attenuating Neuropathic Pain

Neuropathic pain is a chronic

condition, often resulting from

prior conditions such as diabetes,

shingles, and traumatic injury due

to hyper excitability of certain

voltage-gated sodium channels. The

condition affects approximately

18 percent of the population, in

addition to being a considerable

cost burden to the United States

economy. And the symptoms can

be harrowing, from a shooting

and burning pain to tingling and

numbness. While treatments do

exist, they are accompanied by side

effects. For example, non-selective

sodium channel blockers are used

to treat chronic pain, but they can

affect several voltage-gated sodium

channels, thus causing severe unintentional

side effects. Omar Samad, Associate Research Scientist,

and Stephen Waxman, Professor of Neurology, Neurobiology, and

Pharmacology and Director of the Center for Neuroscience &

Regeneration Research at Yale University, have managed to attenuate

neuropathic pain caused by traumatic nerve injury in rats by

targeting the Na v

1.3 sodium channel. This novel gene knockdown

technique shows promise for finding a method for effective and

specific treatment.

Samad and colleagues chose to focus on the Na v

1.3 sodium channel

because their earlier studies indicated that its upregulation in

nerve-injured rats is coupled with neuropathic pain. To treat pain at

the source, the team utilized a peripheral Na v

1.3 gene knockdown

technique to gauge the therapeutic efficacy of targeting this channel.

Using computational algorithms, Samad searched for a molecule that

BY MAHBUBA TUSTY

Images of the dorsal root ganglion in the peripheral nervous system. (Left) Green marks the

neurons treated with the Na v

1.3 gene knockdown technique. (Middle) Red marks all of the

neurons in the image. (Right) The merged image shows the red-marked neurons that were

not affected by the gene knockdown technique, while the yellow/orange-marked neurons

shows the treated neurons. Courtesy of Dr. Omar Samad.

The graph demonstrates that Na v

1.3 gene therapy alleviates pain in rats with injured

nerves compared to no treatments on the injured rats. Courtesy of Dr. Omar Samad.

would block Na v

1.3 expression, and then experimentally identified

the two most promising “hits”. In order to simulate the conditions

that often cause neuropathic pain, the experimenters used rats that

had injured nerves. The two most promising molecules were then

delivered directly into the dorsal root ganglion of these experimental

rats, and then the rats were assessed for pain behavior.

This experimental approach showed very promising results. The

lab’s data showed that these specific molecules were successful in

attenuating the neuropathic pain caused by nerve injury in rats. This

finding served as a confirmation of the Na v

1.3 sodium channel’s

role in neuropathic pain. Importantly, the method was found to

be specific to the Na v

1.3 sodium channel, leaving other channels

unaffected and thus avoiding potential side effects.

Samad and colleagues have therefore shown that knocking down

Na v

1.3 has therapeutic benefits in their animal

model. With the results of this research, pharmaceutical

companies and research groups

can now direct their attention to working with

the Na v

1.3 sodium channel in humans. With

this approach, potential gene therapies can be

developed for treating chronic pain. By focusing

on this one sodium channel, medications

for neuropathic pain will have the potential to

be more effective and specific with fewer side

effects and greater patient usage.

This research was conducted in Dr. Stephen

Waxman’s laboratory. It was supported by the

Department of Veteran Affairs and the Nancy

Taylor Foundation for Chronic Diseases.

Other authors involved in the study were

Andrew M. Tan, Xiaoyang Cheng, Edmund

Foster, and Sulayman D. Dib-Hajj.


BY KRISTEN DOWLING

ECOLOGY

Stress and Ecosystems:

Role of Predation Reconsidered in the Hunt for Stable Ecology

Ecosystems are losing predators faster than organisms in any

other trophic level, and this may be of even more concern for the

stability of nutrient cycles than previously thought. Recent research

at the Yale School of Forestry and Environmental Studies from

former postdoctoral associate Dr. Dror Hawlena and his colleagues

demonstrates how predators considerably influence belowground

community functions by instilling fear in their prey.

Stressed grasshoppers reared in the presence of spider predators

show elevated metabolisms and consequently have diets high in

energy-rich carbohydrates. In addition, stress hormones increase the

conversion of proteins to glucose, a process that excretes nitrogen.

These two reactions to stress increase the carbon –to-nitrogen ratio

in grasshoppers’ bodies.

Hawlena’s experiments tested the effects of this body chemistry

variation on the decomposition of plant litter. He reared grasshoppers

in the field with and without the risk of spider predation. “You

can manipulate the risk of predation without actually killing the

prey by gluing the mouthparts of spiders,” Hawlena explained. The

grasshopper carcasses were then allowed to decompose in laboratory

microcosms of their grassland habitat.

Plant litter was added to each of the microcosms, and the

researchers measured rates of carbon mineralization, the release

of carbon dioxide during microbial decomposition. Notably, the

mineralization of grass litter in soil where the stressed grasshoppers

decomposed was 62 percent lower than the soil with the

non-stressed grasshoppers. These results suggest a causative link

between the changes in prey body chemistry and altered functioning

Graphs A & B above show the cumulative carbon mineralization of the decomposition

of the grasshoppers and plant litter, respectively. Steps 1 and 2 show the

decomposition of grasshoppers and plant litter and the corresponding respiration

of carbon dioxide. Courtesy of Dr. Dror Hawlena.

The grasshopper herbivore Melanoplus femurrubrum. Courtesy

of Dr. Dror Hawlena.

of the soil microbial community. Hawlena hypothesizes that this

is due to nitrogen’s role in priming microbes to break down plant

litter. In the presence of lower levels of nitrogen, plant decomposition

decreases.

Conducted over a three-year period, variations on the experiment

included measuring decomposition rates in the field rather than in

the laboratory microcosm, and using artificial grasshopper carcasses

whose C:N ratios spanned greater variation than those observed

in nature. Collectively, the experiments’ results

suggest that predation exerts top-down, cascading

effects on plant decomposition in both

laboratory and field settings by fear-induced

changes in prey body chemistry.

Hawlena stresses the importance of these

findings. “We show that if you add a tiny

amount of animal you can change the way the

microbial community is processing resources.

Therefore even a small amount of animal detritus

can be extremely influential in regulating the

recycling rates of different nutrients.”

This research has major repercussions for

how scientists think about ecosystems. The

interconnections of every trophic level have

been underestimated, especially in terms of

top-down control and nutrient cycles. The

biological, chemical, and physical stability of

ecosystems is truly reliant on each member’s

contributions. The predators, whose role in

the ecosystem is more important than previously

expected, are disappearing at alarming

rates. Hawlena warns, “These results may be

an important hint that we need to take seriously

what we do to the predators.”


The Latest Superstar Couple:

Closing in on Kepler-36

BY LI BOYNTON

Colored pixels represent relative flux increasing from

blue to green, with each row symbolizing an individual

transit light curve. The Kepler 36 planets’ curved bands

convey fluctuating periods, a product of their gravitational

pulls on each other. Courtesy of Science.

12 Yale Scientific Magazine | 2012

Imagine looking up at the night sky and

seeing a gas giant three times the size

of our ordinary moon. This is how

Kepler-36c, a newly discovered gaseous planet,

appears from the surface of Kepler-36b, its

rocky neighbor in the Kepler-36 planetary

system. The Kepler-36 system is the first

planetary group comprised of planets of such

strikingly contrasting densities and compositions.

“Are we alone in the universe?” This question

first captured the imaginations of scientists,

theologians, and philosophers hundreds

of years ago, and fuels the current exploration

of planets outside our solar system. As

of now, a total of 838 confirmed extra-solar

planets have been discovered. But Kepler-36

mystified astrophysicists who wondered how

two vastly different worlds ended up in such

close orbit. As Dr. Sarbani Basu of the Department

of Astronomy at Yale explained, “The

pivotal moment in our project was when we

figured out that these two very

different planets are orbiting

around the same star. That’s

when we started to look at the

system as a whole, rather than

as just two more extra-solar

planets.” Extra-solar planets

are nothing new to astronomers

like Basu, but strikingly

different planets in close proximity

presented scientists with

a yet-undiscovered type of

planetary system.

“One of These Things is Not Like

the Other”

Modern astronomy hypothesizes

that large gas-giant

planets cannot form close to

their host stars because stellar

wind would blow away most of the surrounding

gas in the disc, causing the planet to lose

mass quickly. Therefore, this discovery of a

massive Jupiter-like extra-solar planet, or exoplanet,

near a main-sequence star has opened

new horizons to studying planetary formation.

When researchers studying this system first

landed on the data relayed back from NASA’s

Kepler spacecraft, they were no longer surprised

to see the gas giant Kepler-36c close to

its parent star. They were surprised, however,

to see planets as different as Earth-like Kepler-

36b and gas-giant-like Kepler-36c coexisting

within such close orbital planes. The discovery

of diverse planets separated by a mere 0.013

AU revolutionized astronomical thinking on

how planetary systems form and evolve.

In our solar system, there is a clear differentiation

between rocky and gaseous planets;

the former are confined to the inner part of

our system, and the latter found in the outer

parts. This trend is in accord with condensation

theory, which hypothesizes that interstellar

dust is an essential ingredient in the formation

of planets. Areas closer to the sun are at higher

temperatures and are home to the hotter, rocky

planets. Farther away from the sun, colder

temperatures allow gases to move slowly and

are thus more affected by gravity. As a result,

interstellar dust grains come together to form

the foundation of gas giants.

The detection of giant planets close to other


ASTRONOMY

stars proves that this pattern is not universal;

planetary orbits can indeed change significantly

after their formation. Basu’s international team

of approximately 40 scientists from five different

countries set out to uncover the intricacies

of this anomaly: the Kepler-36 system and its

two starkly contrasting planetary members.

Kepler-36b, nicknamed a “Super-Earth,” is

rocky like our home planet but is a staggering

4.5 times more massive with a radius 1.5 times

greater than that of Earth. Kepler-36c, is a gaseous

planet 8.1 times more massive than Earth

with a radius 3.7 times greater. Kepler-36b and

Kepler-36c are 20 times more closely spaced

and have a larger density difference than any

adjacent pair of planets in our solar system.

Joining Forces: From Planetary Closeness to Scientific

Collaboration

The planetary subgroup of the team,

led by Josh Carter, a Hubble fellow at the

Harvard Smithsonian Center for Astrophysics,

discovered the larger planet and its host

star during a first quick look at data from

the Kepler spacecraft, a space observatory

launched by NASA to discover Earth-like

planets orbiting other stars. They noticed the

the larger planet Kepler-36c as it transited

in front of the host star, blocking some of

its light to give a characteristic dip or transit

signal. However, while Kepler planetary data

can tell you how big a planet is relative to its

star, it cannot determine how big this planet

is with certainty until the size of the star is

determined. This is where the stellar physics

subgroup that Basu is involved with came in.

Using asteroseismology, the study of stars by

observing their natural solar-like oscillations

that occur as a result of sound wave excitation

by turbulence in the star, they determined

the properties of the system’s parent star. By

measuring various oscillations, the team was

able to calculate the size, mass, and age of

the host star to exquisite precision. Once the

group gave the stellar data to the planetary

team, Carter and his colleagues were able to

further analyze Kepler-36c to discover its size

and composition.

The Power of the Human Eye

At first, the Kepler-36 team did not realize

Kepler-36c had company, let alone close

company. The smaller Kepler-36b planet is so

small that it does not leave much of a signature

in the amount of light it blocked from

Kepler-36a. Consequently,

it was thus

rejected by the automatic

code of the

Kepler data analysis

center, which makes

the usual assumption

of periodic orbits

and cannot detect

imprecise periods

of relatively smaller

planets such as

Kepler-36b’s. However,

Kepler-36b is

so remarkably close

to its massive neighbor

that it alters the

gravitational field

felt by the smaller

planet and changes

the strict period

nature of trasits.

This is known as

transit timing variation. Because this period

was not well determined, Carter’s team had

to collect data by hand instead of using the

usual programs. They used an algorithm

known as “quasi-periodic pulse detection” to

methodically check planetary systems already

in the Kepler data, and in this way stumbled

upon Kepler-36b. Basu emphasized that this

discovery would never have happened without

persistent manual follow-up to the team’s

practiced intuitions. “The major implication in

my mind is to not believe in automated pipelines.

Nothing can substitute for the human

eye. If Josh hadn’t looked at this system by

eye, we wouldn’t have known that there was

this second rocky planet sitting there.”

The curves above represent theoretical models for planets of

a given composition, with dotted curves modeling terrestrial

bodies and dashed curves modeling Earth-like solid cores surrounded

by hydrogen or helium envelopes. Courtesy of Science.

The Future of Kepler-36

About the Author

The discovery of the close two-planet

system has shed light on extreme violations

of traditional orbit-composition patterns.

The international team studying this system

galvanized the astronomy community with

greater interest in understanding how planets

with such different compositions can fall into

such astonishingly close orbits. Kepler-36b and

Kepler-36c have managed to achieve orbital

stability at fascinatingly close range. The team

has announced its determination to continue

analyzing more Kepler data to locate similar

planetary systems in the hopes of unearthing

similar close encounters.

Li Boynton is a junior in Calhoun College double majoring in Molecular, Cellular

and Developmental Biology and East Asian Studies. She is the Production Manager

for the Yale Scientific, and works in Dr. Anjelica Gonzalez’s lab using bioengineered

transmigration models to study immunological responses to inflammatory signals.

Acknowledgements

The author would like to thank Professor Sarbani Basu for sharing her knowledge

on astronomy and the Kepler-36 system.

Further Reading

• Carter, Joshua A., et al. “Kepler-36: A Pair of Planets with Neighboring Orbits

and Dissimilar Densities.” Science 337 (2012): 556-59. AAAS. Web. 25 Sept.


Curing the “Bubble

Boy”

BY ELISA VISHER

Severe combined immunodeficiency

(SCID), also known as the “bubble boy

disease,” is a rare genetic disease that

affects people around the world. Characterized

by gross deficiencies in the immune system,

the disease is so dubbed colloquially because a

child with SCID in the 1970s and 80s famously

lived in a plastic bubble to protect himself from

opportunistic infections. He was the longestliving

child with SCID at the time, when the

plastic bubble was the only treatment option

available. While SCID used to be a fatal disease

with no real treatments, it can now be managed

by enzyme replacement and bone marrow

transplants. Promising research has recently

shown that gene therapy may soon replace

these traditional therapies.

The Immune System

David Vetter, the “Bubble Boy.” Courtesy

of Boston GRIO.

SCID generally affects the patient’s B and T

cells. B and T cells are the main components

of the adaptive immune system that works in

conjunction with the innate immune system to

protect the body from foreign pathogens. The

innate immune system recognizes and attacks

invading cells, which may destroy invading

pathogens but may not completely fight off

the infection alone. The adaptive system then

helps the innate by recognizing pathogens and

responding specifically to each one. In addition,

the adaptive immune system remembers each

pathogen it has encountered and can launch a

faster, more effective response against the same

pathogen in the future.

What is ADA-SCID?

One of the more common forms of SCID

is ADA-SCID, so named because the mutation

affects the formation of the enzyme adenosine

deaminase (ADA). Adenosine deaminase

breaks down byproducts of DNA formation

in the cell. When the enzyme is not working, as

in ADA-SCID patients, these byproducts accumulate

in the cell. This accumulation creates a

toxic environment that kills emerging immune

system cells before they can mature. With

almost no B or T cells, people with ADA-SCID

essentially have no adaptive immune system.

Treating ADA-SCID: Traditional Methods

Traditionally, ADA-SCID has been managed

with enzyme replacement therapy. Doctors

inject the ADA-SCID patients with the missing

adenosine deaminase, but this treatment can be

problematic. As Associate Professor of Immunobiology

Eric Meffre says, “You can detoxify

the cell serum, but it is not as efficient as healthy

systems because the enzyme that you give intravenously

does not get into the cells themselves.

Although it improves the patients’ conditions, it

still does not reconstitute the immune system.”

This treatment is not considered a cure, and

other options are usually explored as long-term

options for ADA-SCID patients.

One accepted cure for ADA-SCID is a bone

marrow transplant. If the transplant is accepted

by the patient’s immune system, no other treatments

are needed. However, donors must be

biological matches with recipients, which are

usually limited to family members, so marrow

transplants are often unavailable.

Treating ADA-SCID: New Options

Recent research has shown that gene therapy

may be a viable alternative to the traditional

transplant. Currently, it is available at a select

number of institutions including the National

Institutes of Health (NIH). So far, 20-30

individuals have been treated and all have

survived. A multi-institutional research team

led by Meffre is working to better understand

the implications of this treatment. To perform

gene therapy for ADA-SCID, doctors

first isolate stem cells from the patients. They

then transform these cells into functional

bone marrow cells by infecting the stem cells

14 Yale Scientific Magazine | October 2012


GENETICS

A

dsDNA

Insulin

LPS

ADA1

postGT- new emigrant B cells

ADA2

with D a retrovirus whose genome contains a

functional version of ADA. These cells then

have normal metabolic function and can be

re-injected into the patient, who will then

express normal ADA function and no longer

be immunodeficient. So far, ADA gene therapy

has been the only successful gene therapy trial.

Some patients have been followed for more

Figure 6

than ten years, and no significantly problematic

side effects have been observed. As Meffre

says, “The patients are alive and have normal

lives. The kids go to school.” Though not

life-threatening, autoimmune reactions have

sometimes been observed as a side effect from

ADA gene therapy.

ADA1- 35 ADA1- 17 ADA2- 231 ADA2- 245

Understanding the Side Effects

ADA3

Nonpolyreactive (%) Polyreactive (%)

Because the autoimmune side effects are not

fully understood, Meffre and his team examined

this phenomenon in greater detail. Meffre

says, “What we think is happening is that you

get a system that is just partially fixed. When

you do gene therapy, not all the stem cells in

gene therapy may be corrected. This means

that, at the end, you may still have a patient

that is a mosaic.” Meffre thinks that the toxic

accumulation of metabolites signals a receptor,

which then block receptors for autoreactive B

cells. When doctors artificially give adenosine

deaminase, B and T cells develop and proliferate,

but nearly all the B cells that exit the bone

marrow are autoreactive. This problem affects

patients treated with enzyme injections as well

as gene therapy patients.

B

Frequency of polyreactive

B cell clones (%)

Frequency of anti-nuclear

B cell clones (%)

40 *

Finding Children with SCID

ADA3- 25

SAUER et al. 2011: Figure 6

OD405

OD

4 405

4

OD 405

4 4

OD 405

3

3

3

30

2

2

2

20

1

1

1

0

0

0

10

0.01 0.1 1 0.01 0.1 1 0.01 0.1 1 µg/mL

4

4

OD 405

0

OD405

HD preGT postGT

3

3

3

(n=10) (n=3) (n=3)

2

2

2

C

n.s.

1

1

1

40 *

0

0

0

0.01 0.1 1 0.01 0.1 1 0.01 0.1 1 µg/mL

30

4

OD 405

4 OD405

4

OD 405

3

3

3

20

2

2

2

10

1

1

1

0

0

0

0

0.01 0.1 1 0.01 0.1 1 0.01 0.1 1 µg/mL

HD preGT postGT

(n=8) (n=3) (n=3)

Autoimmune 20 functions 17 of B cells in 15 three ADA SCID patients after gene therapy

25

24

34

80

83

85

versus that of a control (HD). Courtesy of Eric Meffre, Yale Department of Immunobiology.

ADA3- 40

Due to these potential side effects, gene

therapy is only considered for life-threatening

diseases that affect children early in life. Most

SCID patients are diagnosed at birth or shortly

after because of noticeable immune problems.

Some states mandate screening for SCID diseases

at birth, including Connecticut, where

Yale-New Haven Hospital serves as the center

for SCID screening. Early diagnosis also gives

doctors a longer window to look for a bone

marrow donor; there are no side effects from

bone marrow transplant if it occurs before the

child’s first birthday. Unfortunately, high costs

have prevented SCID blood screenings from

achieving universal adoption.

ADA gene therapy corrects central B-cell tolerance in ADA-SCID patients. (A) Antibodies expressed by new emigrant/transitional

(CD19 + CD10 + IgM hi CD27 - ) B cells from ADA-SCID patients were tested by ELISA for polyreactivity (tested against dsDNA,

insulin, and LPS). Dotted lines show ED38-positive control. Horizontal lines show cutoff OD405 for positive reactivity. For each

individual, the frequency of polyreactive and nonpolyreactive clones is summarized in pie charts, with the number of antibodies

tested indicated in the centers. (B) Decreased frequencies of polyreactive new emigrant/transitional B cells in ADA-SCID

patients after gene therapy although they remain significantly elevated compared to those in healthy donors; *p=0.05-0.005. (C)

ADA gene therapy completely restores the central removal of ANA-expressing developing B cells. The frequencies of antinuclear

new emigrant/transitional B cells in ADA-deficient patients after gene therapy are significantly decreased compared to

preGT and are comparable to those in healthy controls; *p=0.05-0.005; n.s.= not significant. In panels (B) and (C) each diamond

represents an individual, and the average is shown with a bar. The dashed horizontal lines corresponds to the average

frequency in HD of polyreactive and ANA-expressing B cells, respectively. (D) Antibodies expressed from ADA-deficient new

emigrant/transitional B cells show various patterns of cytoplasmic stainings and are devoid of nuclear reactivity. Two examples

for anti-cytoplasmic new emigrant B cells are shown for each patient.

*

The Future of Gene Therapy

About the Author

While ADA gene therapy has been initially

successful, Meffre says that expanding the

treatment to other diseases is not viable

until gene therapy technology improves. In

another gene therapy trial, doctors treated

four patients, and two of these patients died

from lymphoma. In this trial, overexpression

of the gene caused unrestrained proliferation

of T-cells and lymphoma. Overexpression

resulted because when the retrovirus infected

the genome with the corrected gene, it

inserted itself into a more active area of the

genome. Scientists cannot yet target the location

of this retroviral insertion and instead

use a completely random process. Technology

to target the retrovirus to infect specific

areas of the genome, preferably at the exact

place where the gene is normally located

in the human genome, must be developed

before gene therapy can be applied to other

diseases.

Despite these difficulties, gene therapy will

always be an attractive treatment possibility

for gene-related diseases because it is truly à

la carte medicine. Once technology is developed,

the treatment has the potential to cure

any genetic disease, even ones caused by rare

or de novo mutations. Of course, some diseases

will be easier to treat than others, such

as those in which the body tissue of interest

(in this case, bone marrow) is easier to isolate

and target. Clinical trials for ADA-SCID have

provided the first successful, safe use of this

exciting technology in the process of saving

lives. For those still struggling with other

genetic diseases, treatment is not yet possible,

but relief may soon come.

Elisa Visher is a junior in Trumbull College double majoring in Anthropology and

Biology. She works in the Yale Molecular Anthropology Lab and Paul Turner Lab.

Acknowledgements

The author would like to thank Professor Eric Meffre for his time, patience, and

comprehensive explanation of ADA-SCID and its treatment.

Further Reading

• Sauer, AV, H Morbach, I Brigida, A Aiuti, and E Meffre. “Defective B cell tolerance

in adenosine deaminase deficiency is corrected by gene therapy.” Journal of

Clinical Medicine 2012; 122 (6): 2141–2152.


Sizing Up Autism

The Correlation Between Autism and Abnormal Growth

BY JESSICA SCHMERLER

The most exciting day in most parents’

lives is when their child says “mommy”

or “daddy” for the very first time. But

what if one day, their seemingly happy and

healthy toddler suddenly lost the ability to communicate?

Or worse, if their child never began

to speak at all? This is the fate of the parents

of the thousands of children diagnosed with

autism each year. Currently one in a hundred

children born are diagnosed with disorders

in the autism spectrum (ASD), four boys to

every girl. The diagnosis encompasses a broad

range of symptoms, which present themselves

as any form of difficulty in pretend play, social

interaction, or verbal/non-verbal communication.

Evidence available today suggests that

the increasingly broad definition applied to

“autism” may be complicating the opportunities

for effective treatment, ultimately creating more

issues than it resolves.

As defined by the National Institute of

Health (NIH), autism is “a developmental

disorder that appears in the first 3 years of life,

and affects the brain’s normal development

of social and communication skills.” Children

can be diagnosed as having ASD if they fail

to meet any of the typical markers of normal

development, including babbling by 12 months,

gesturing by 12 months, saying single words

by 16 months, saying two-word spontaneous

phrases by 24 months, and losing any language

or social skills at any age.

The Etiology and Phenotypes of Autism

The classification ASD can be applied to

an enormous array of developmental delays,


ASD is associated with an increased

TCV. Courtesy of the Simons Foundation

Autism Research Initiative.

which in turn generates obstacles to study the

disorder. The past few decades have seen an

increased incidence of autism, often linked to

the broadening of the scope of the diagnosis.

The NIH notes that a child diagnosed with

high-functioning autism today would most

likely have been considered merely strange

30 years ago. The problem that arises with the

present characterization of autism is that one

child who loses his ability to speak and another

child who makes repetitive hand motions

would both be diagnosed with ASD. The

biological process leading to loss of speech

is most likely different than the one leading

to repetitive gestures, and yet both would be

considered causes of autism. In other words,

the major barrier posed to study and discovery

of the etiology of autism is the myriad

subsets of the designation “autism” and, in all

likelihood, multiple genetic or environmental

origins of the disorder.

Elucidating the distinctions between subsets

of autism and correspondingly developing

a more specific etiology of each would

allow for far more individualized treatment

of children diagnosed with ASD. Many studies

have attempted to investigate the variety

of ASD phenotypes, including the UC Davis

MIND Institute that piloted the Autism

Phenome Project (APP) to study the distinct

phenotypes associated with autism. The

APP is a longitudinal study that establishes

differences in medical evaluations, environmental

exposure/epidemiology, behavior/

neuropsychology, genomics, brain structure

and immune function.

One identified phenotype associated with

autism is abnormally large Total Cerebral

Volume (TCV) and, correspondingly, Head

Circumference (HC) – collectively called

macrocephaly. Researchers at Yale University’s

Child Study Center have undertaken studies

in the connectivity of growth and neural

development to assess risk and predict developmental

phenotype of young boys through

growth measurement. A group of 184 boys

aged birth to 24 months, composed of 55

typically developing controls, 64 with ASD,

34 with Pervasive Developmental Disorder

Not Otherwise Specified (PDD-NOS), 13

with global developmental delays, and 18 with

other developmental problems, was analyzed

for head circumference, height, weight, and

social, verbal and cognitive functioning.

Boys with autism were significantly taller by

4.8 months, had a larger HC by 9.5 months,

weighed more by 11.4 months, were in the

top ten percent in size in infancy (correlated

with lower adaptive functioning and social


NEUROLOGY

Neurological data is collected using brain MRIs. Courtesy of popsci.com.

deficits), and showed accelerated HC growth

in the first year of life.

Making Sense of the Research

The results of this study engender several

important questions regarding the correlation

between overgrowth and autism. First,

whether abnormal growth is a symptom

or cause of autism in young boys remains

unknown. Symptoms are usually detected

between the ages of 12 and 24 months, but

neurological changes have been detected

at as early as four months of age. Since

the growth rate diverges at four months,

whether divergence of neurological function

or overgrowth occurs first is unclear. The

genetic underpinnings of divergent growth

and symptoms of ASD are also unknown,

so establishing a correlation is difficult. If the

etiologies were better understood, researchers

could study the source of both divergent head

growth and onset of autism symptoms and

any associated clinical implications of these

genetic mutations.

Dr. Katarzyna Chawarska of the Yale Child

Study Center explains, “When overgrowth

was first described 10 years ago, the idea was

that it could be used to predict autism. That’s

not true, the phenomenon also happens,

albeit much more rarely, in typical children,

and there are some children with autism who

don’t express head overgrowth.” Based on

the results of her study, Chawarska proposes

three hypotheses regarding the correlation of

overgrowth and autism: overgrowth coincides

with, precedes, or follows development of

symptoms. To understand the correlation

between physical abnormalities and autism

would serve not only to identify warning

signs for the development of the disease but

also allow for treatments that could prevent

progression of autism or improve the quality

of life for those affected.

Two significant characteristics set the Yale

study apart from others that have addressed

the connection of autism to TCV/HC. First,

past studies have investigated only divergent

head growth; the Yale study associates

general overgrowth with autism. Chawarska

says, “This phenomenon of overgrowth is

not restricted to neural tissue. This implication

might shift the emphasis [of research]

from seeking causes of overgrowth in purely

neural mechanisms to other growth factors

(hormones) that affect growth across multiple

types of tissues.” Other tissues affected

by overgrowth include skeletal and muscular

tissues. The second important difference is

that Yale’s study did not find any significant

difference between boys with regressive and

non-regressive forms of autism. Many other

studies have implicated regression as a major

distinguishing factor in the development

of macrocephaly. According to Chawarska,

regression is a very variable, subjective qualification,

as the way regression is measured

is not standardized. Most other studies use

retrospective parental reports of regression,

rather than observing the “regression” itself.

Chawarska makes the distinction, “what is

called regression we define as a plateau; the

child stops progressing.”

While the genetic basis of this observed

overgrowth still frustrates experts, researchers

at the Yale Child Study Center recognize that

expression of autism is not solely dependent

on genetics. Rather, a significant connection

between neural development and the environment

has been established as well. For children

expressing early symptoms of autism, the

center aims to “enhance their social experience,

hoping that by enriching repertoire of

skills [they] can enrich their experience, and

this is an enormous component in neural

development.” Research continues to be

conducted to uncover the molecular etiology

of the autistic phenotypes, but until such

a discovery is made, the development of

individualized behavioral interventions may

potentially lessen the severity of ASD.

About the Author

Jessica Schmerler is a sophomore Molecular, Cellular & Developmental Biology

major in Jonathan Edwards College. She is a Layout Editor for the Yale Scientific

Magazine as well as the Layout Editor and Staff Writer for the Yale Journal of

Medicine and Law.

Acknowledgements

The author would like to thank Dr. Katarzyna Chawarska of the Yale Child Study

Center for her time and in-depth description of her research.

Further Reading

• Chawarska K, Campbell D, Chen L, Shic F, Klin A, Chang J. Early Generalized

Overgrowth in Boys With Autism. Arch Gen Psychiatry. 68:1021-1031(2011).


This is History

Microprobe Analyses Decipher Identities of Metallurgical Artifacts

BY THERESA OEI

Indiana, we are simply passing through

history. This, this is history.” Belloq’s line

referring to the Ark of the Covenant

from Raiders of the Lost Ark highlights the role

of artifacts in understanding historical truth.

Technologies such as element mapping and

microanalysis techniques enable archaeologists

to play historical detectives, deciphering

artifacts to contribute to our knowledge of the

past. According to Dr. Robert Gordon, a Yale

professor in Geology and Geophysics, “The

intellectual challenge of examining the artifacts

transmits a historical record and enlightens our

understanding of people’s interaction with

materials and the natural

world.” Artifacts stand as

silent and irrefutable witnesses

to history and the

technology of their eras.

Encountering the Artifact

The work of Gordon and

Colin Thomas, a graduate

student in Yale’s Anthropology

department, exemplifies

the archaeological

approach to discovering

historical truth. Archaeologist

Dr. Richard Hunter,

Founder and President of

Hunter Research Historical

Resource Consultants, was commissioned to

work on an excavation behind the state house

in New Jersey. There, under centuries of debris,

he found an 18 th century metallurgical site,

which he believed was a furnace for converting

iron into steel. During the excavation, the

foundations of a furnace house were revealed,

but the most interesting artifacts were what

appeared to be iron bars. These iron bars were

sent to Thomas and Gordon for identification

and confirmation.

Gordon’s work began in a “typical” way: “I

have something that looks unpromising like bits

of iron or slag, and I ask how old? What does

it tell of the technological ability or scientific

understanding of its time?” The multistep process

of extracting data from the artifact begins

with an examination of its size and shape. Then

the microstructure is examined under a light

microscope and probe. Based on knowledge of

the technology of its era of origin, the artifact

can be identified by comparing it to a reference

collection of metal artifacts, the only one of

which in the United States is housed at Yale.

Microstructure Analysis

The excavation site in Trenton, New Jersey. Courtesy of Dr. Robert Gordon.

The metal bar artifact was examined by

a microstructure analysis

technique that maps the elements

found in the microstructure

and identifies the

type of iron contained in

the artifact. For example,

sulfur, silicon, and carbon

are expected to appear

in cast iron. Mapping for

oxygen shows the amount

of oxidative corrosion that

has taken place in the iron.

In tandem with scanning

electron microscopy, energy

dispersive X-ray spectrometry

(EDS) creates elemental

maps by focusing a beam

of electrons on the artifact,



ARCHAEOLOGY

which consequently releases an x-ray spectrum.

The spectrum lines can be identified and their

intensity measured to determine the concentration

of the elements in the sample. Here, EDS

analysis determined the composition of the

external oxidation products, and wavelength

dispersive analysis (which measures the concentration

of selected elements) quantified

the metal’s constituents, enabling Gordon and

Thomas to decipher the metal’s microstructure.

After analzing both the internal metal and

the external oxidation product, the microstructure

of the metal itself proved that it was

not wrought (pure) iron as suspected. Instead,

carbon graphite flakes suggested the artifact

was cast iron. The microstructure had a consistent

iron nitride precipitate along its metal

matrix, a product formed during the cooling

of metal. This indicated that the piece of cast

iron had been subjected to repetitive heating

and cooling, which suggests that the artifact

was part of the furnace itself. Non-metallic

elements were also identified in the sample, the

most abundant being iron oxide. Iron oxide is a

product of an internal oxidation reaction that

occurs over time, replacing the graphite flakes

of cast iron.

The artifact was then compared with a reference

specimen, which came from a pair of

andirons used to hold wood fuel in a fireplace.

X-ray mapping and imaging showed that the

reference and artifact had similar structures.

While both had graphite flakes, those in the

artifact had been replaced mostly with iron

oxide. Iron oxide has a low uniform iron concentration,

and the artifact did not show any

concentration gradients in iron or oxygen at

the border between the metal and the reaction

product. In contrast, iron in the reference specimen

was diluted in the areas surrounding the

graphite flakes by the increased oxygen that was

contributing to the reaction. The comparison

showed that both the artifact and reference

were undergoing the same internal oxidation

reaction. However, this reaction was still

underway in the reference specimen whereas it

had already reached equilibrium in the artifact.

Final Identity

All these analyses identified the artifact as a

grate bar from the firebox in the furnace. The

cast iron of the furnace bars is particularly

susceptible to internal oxidation because of

oxygen solubility in the metal, elements with

oxygen affinity (silicon, manganese, and phosphorus),

and the high diffusion rate of oxygen.

The iron bar artifact received at Gordon’s lab. Courtesy of Dr. Robert Gordon.

The fire of the furnace provides oxygen, and

the high temperature increases the speed of

oxygen diffusion. Internal oxidation degraded

the grate bar, but technology recovered its

original composition and identity.

History of the Cementation Furnace

The knowledge extracted from the artifact

can be placed in a historical context, enriching

our understanding of colonial America.

The excavation site was confirmed as a steel

cementation furnace built in the 1740s used to

convert iron into steel, a complex process that

was being developed in Germany and Great

Britain at the time.

The excavation site belonged to the Trenton

Steel Works, which was built on Petty’s Run, a

tributary of the Delaware River. Between 1745

and 1750, Benjamin Yard built the cementation

furnace — one of four of its kind built

in the U.S — marking a radical move for

colonial economic independence. Great Britain

responded by passing the Iron Act in 1750,

which attempted to limit the development of

iron manufacturing in the U.S. The colonists

wanted cheap sources of steel for cheaper

production for agricultural and military purposes;

Great Britain’s effort to stifle economic

progress, including iron manufacturing, in the

colonies was a large factor leading to the Declaration

of Independence.

Through their use of scientific techniques,

Gordon and Thomas were able to enhance

our understanding of 18 th century America.

Artifacts are the doors to historical truth, and

scientists like Gordon and Thomas hold the

key to unlocking this potential.

About the Author

Theresa Oei is a sophomore Molecular Biophysics and Biochemistry major in

Pierson college. She is on the board of Synapse, Yale Scientific Magazine’s Outreach

Program, and works in Professor Steitz’s lab studying target genes of the viral miR-

NAs HSUR4 and HSUR5 for their role in tumorigenesis.

Acknowledgements

The author would like to thank Doctor Gordon for his time and inspiring dedication

to archaeological discovery and research.

Further Reading

• Gordon, Robert. “Process Deduced from Ironmaking Wastes and Artifacts.” Journal

of Archaeological Science. Vol 24 (1997): 9-18.


Competing Visions:

Will Science Swing Your Vote?

By John Urwin

One week. In one week we shall wake

up, go to school or work, and carve

out fifteen minutes to participate in

what has perhaps become the ultimate symbol

of modernity: free elections. For months now

we have been inundated with commercials,

speeches, and debates all telling us what to

do on this one day: the day we choose our

next president.

This year’s campaigns have emphasized vital

areas of interest like economic recovery, the

national debt, and healthcare. However, many

other important issues have fallen through the

cracks. Among these is science policy.

The reason why is clear. We value science,

but it just does not seem as pressing as other

issues. In a recent poll conducted by the Yale

Scientific Magazine, a majority of Yale undergraduates

deemed science policy important

(x = 3.43, on a ten-point scale) in determining

their vote for president. Yet, when asked

to rank science policy against other topics,

science policy was consistently ranked as

less important (x=6.23) than almost every

other election topic. Moreover, a majority

of Yale undergraduates replied that they

believed themselves to be either “not very well

informed” or only “somewhat well informed”

about the current science issues facing

America. This needs to change. Presented

here are the underlying science, the current

facts, and each candidate’s stance on the two

science issues that surveyed Yale students

regarded most important: alternative energy

and climate change.

Alternative Energy

At the heart of every power plant is a spinning

wheel, known as a turbine. In slightly

more technical terms, every power plant produces

electric current the same way: by rotating

a loop of wire through a magnetic field.

This technique is ubiquitous for all power

plants, including coal, natural gas, petroleum,

nuclear, hydro, wind, geothermal, and solar

plants. It is only in how they spin this turbine

that they differ.

Windmills let gusts of wind spin their massive

blades, while hydropower plants (dams)

use the force of flowing water to rotate

turbines. All other types of common power

plants — coal, natural gas, petroleum, nuclear,

solar, geothermal — use the same technique

to rotate their turbines: they boil water.

Each power plant boils water either by

generating heat via an exothermal process

(combustion for coal, petroleum, and natural

gas; nuclear fission for nuclear) or collecting

it from the environment (solar, geothermal).

The heat from these processes is used to

convert water into highly pressurized steam.

This superheated steam, which can reach temperatures

of 1,000 °F and pressures of 3,500

pounds per square foot, is then fed through

pipes to a turbine, thereby spinning it. This

flow of pressurized gas generates electric

current for routine functions.

Despite their shared mechanism, not all

power plants affect the environment equally.

Fossil-fuel-burning plants (those that combust

coal, petroleum, and natural gas) are environmentally

harmful, producing vast amounts

of carbon dioxide and significant quantities

of other pollutants. Moreover, fossil fuels


POLITICS

Schematic of a nuclear power plant’s steam generator. Courtesy of Free Info Society.

take millions of years to form and exist in

limited quantities. Nuclear plants, on the other

hand, produce only small quantities of waste

(millions of times less by weight than coal

combustion), but the radioactive waste they

produce is highly toxic and persists almost

indefinitely in waste dumps (it can take millions

of years for even half of the waste to

decay).

By greater contrast, hydro, wind, solar, and

geothermal power plants have renewable

sources and do not emit significant amounts

of pollutants. These environmental considerations

are important not only to maintain

clean air, ensure sanitary water, and preserve

nature but also to address and ideally resist the

dawning realities of global warming.

A Look At The Numbers

Last year, the U.S. consumed 97.30 quadrillion

kJ of energy. Assuming you consume

2,000 calories per day, that’s enough energy to

‘power’ you for the next 30,100,000,000,000

years.

The vast majority (82 percent) of this

energy comes from burning fossil fuels. Petroleum

(36 percent), natural gas (26 percent), and

coal (20 percent) make up nearly all of this.

In the U.S., only 16.6% of the total energy

used comes from “clean” energy sources. Of

this, 63.6% comes from nuclear power plants,

24.4% is from hydropower plants, 9.0% is

from windmills, and the rest (3.0%) is a combination

of solar and geothermal.

The U.S. lags internationally in the use of

alternative energy. In 2010, for instance, over

45% of German electricity came from either

nuclear or renewable sources.

Two Visions

Sources and consumption of energy in the United States. Courtesy

of the US EIA Annual Energy Review 2011.

While both Mitt Romney and Barack

Obama center their energy policies on achieving

energy independence

by increasing

domestic production,

they differ in how

they want to achieve

this goal.

Broadly speaking,

the Republican

platform aims to

decrease oil imports

by letting the private

sector develop the

U.S.’s own natural

reserves. There are

undeniably ample

quantities of fossil

fuel within the U.S.

(237 trillion tons of

US primary energy production based on

source from 1949-2011. Courtesy of the US

EIA Annual Energy Review 2011.

coal, 219 billion barrels of oil, and just under

2 trillion cubic feet of natural gas), although

these supplies are not unlimited. Overly

aggressive exploitation of these reserves could

cause environmental damage, and a continued

dependence on coal and natural gas power

plants would exacerbate global warming.

By comparison, the Democratic platform

is to actively encourage the development of

alternative energies while moving the emphasis

away from fossil fuels. This approach is

costly; nuclear power plants are five-to-ten

times more expensive to build than coal

plants,, though their long-term operating costs

are comparable.

For each party, more detailed plans, available

online (see Further Reading), are both more

nuanced and more convergent than is commonly

acknowledged. The most important

questions we face do not ask “which one,”

but “to what degree.”

Climate Change

By this point, we’ve all heard of climate

change. There is a lot of carbon dioxide in

the atmosphere (390 ppm). There used to be

way less before industrialization (<300ppm).

We keep producing it (4.76 metric tons per

person globally). Fossil fuels are to blame (29

additional gigatons of CO2 per year). The

earth gets hotter (0.014°F per year). Oceans

rise, polar bears drown, and Norwegians go

to the beach. These facts are understood, but

the underlying science is far more interesting

and rarely discussed.


POLITICS

the rays cannot travel directly to

the surface because they must

pass through the atmosphere

first. Atmospheric gases absorb

radiation and emit it in all directions,

so some of the radiation is

‘trapped’ within the atmosphere.

This effect simultaneously slows

the rate of cooling of the planet

and increases the amount of heat

absorbed. Both of these raise the

average temperature. This effect

is not subtle; if Earth lacked an

atmosphere, it would be around

60°F colder than it is today.

To fully understand global

warming, we must also acknowledge

that not all gases are equal;

some gases absorb the sun’s

rays readily, while others don’t.

Those gases that easily absorb

solar energy are known as greenhouse

gases. The more greenhouse

gases there are in the

atmosphere, the more heat the

earth retains and the warmer the

planet will be. This, in short, is

global warming.

Each year, the U.S. produces

5,500,000 tons of carbon dioxide.

Nearly all of this comes

from burning fossil fuels: 32

percent comes from coal plants

alone, 30 percent comes from

transportation, 17 percent comes

from heavy industry, and 7

percent comes from non-coal

combustion power plants. The

remaining 14 percent comes

from various sources.

Compared to other modern-

ized countries, the U.S. does poorly. We are

the second largest producer of carbon dioxide,

trailing only China. And while U.S. emissions

are decreasing, we remain behind the curve.

Two Visions

Let’s clarify one aspect right away: both

candidates acknowledge global warming

as real and influenced by man. They differ,

however, in the degree to which they believe

man has caused global warming and how they

wish to address it.

As previously discussed, the same principles

that applied to alternative energy also

apply to global warming. Republicans tend to

prefer a more economical, less environmental

approach, while Democrats prefer a more

environmental, less economical approach.

While Barack Obama favors an active

approach to reducing carbon emissions, Mitt

Romney views such a stance as a hindrance

to the economy and instead prefers loosening

environmental regulations.

One Week, One Click

On Tuesday, November 6, 2012, we will

elect our next president. With alternative

energy policy and the global warming just

small pieces of the increasingly complicated

and scientifically involved challenges facing

us, Thomas Jefferson’s words have never been

more true: “Democracy demands an educated

and informed electorate.” Today more than

ever, it is vital to be aware, to know the issues,

the facts, and the science behind the choices

facing our nation, and to voice your opinion

accordingly. The information is out there. In

fact it is more accessible now than ever before,

waiting just a click away.

Carbon emissions by country. Courtesy

of Stanford Kay.

The greenhouse effect underlies most of

the science behind global warming. Gases

in the atmosphere absorb the sun’s rays to

varying degrees, causing the amount of heat

retained (and therefore the temperature) to

vary based on gas concentrations.

Imagine two planets: one without an atmosphere

(like Mars) and one with an atmosphere

(like Earth). On the Mars-like planet, the sun’s

rays travel directly to the rocky surface, where

they are absorbed and then reflected directly

back into space. On the Earth-like planet,

About the Author

John Urwin is a junior Molecular Biophysics and Biochemistry major in Jonathan

Edwards College. He is a Layout Editor for Yale Scientific Magazine and has

worked in Professor Colón-Ramos’ lab studying nervous system development in C.

elegans.

Further Reading

• “Energy, Climate Change, and Our Environment,” The White House--President

Barack Obama, March 2012. http://www.whitehouse.gov/energy


On July 20, 2012, the U. S. Food

and Drug Administration granted

accelerated approval of the drug

carfilzomib, developed by Professor Craig

Crews of Yale’s department of Molecular

Cellular, and Developmental Biology. Carfilzomib,

which goes by the name of Kyprolis,

is approved for the treatment of patients with

multiple myeloma who have received at least

two prior therapies and have demonstrated

disease progression on or within 60 days of

the completion of their last therapy. The

approval of carfilzomib represents 14 years

of dedicated research and clinical trials, as

well as another triumph of targeted therapies

in the treatment of cancer.

Multiple Myeloma

Multiple myeloma is a cancer of plasma

cells. Plasma cells are a type of white blood

cell in the bone marrow that produce antibodies.

These cells originate within the bone

marrow, but differentiate into B lymphocytes

(also known as B cells) by the time they enter

the blood. From B-cells, they make their terminal

differentiation into plasma cells. Plasma

cells are an integral part of the immune

system - they contribute to the immune

response by producing antibodies that target

foreign pathogens for destruction. Multiple

myeloma accounts for 1% of all cancers, and

10% of all cancers of the bone marrow. The

American Cancer Society estimates that over

20,000 new cases of multiple myeloma will

be diagnosed in the United States each year.

The exact cause of multiple myeloma

is unknown, but it is believed to be the

combined result of genetic defects and

environmental toxins. Symptoms of multiple

myeloma include abnormal bleeding, bone or

back pain, anemia, and numbness or weakness

in the limbs. Multiple myeloma usually

affects people between 65 and 70 years of age

and the prognosis is generally very poor: multiple

myeloma is an incurable malignancy. The

median survival time post-diagnosis is 3-4

years, although this number depends on the

stage of cancer prior to diagnosis. According

to the international staging system for

Multiple Myeloma, which is based on the on

the serum b-2 macroglobulin level and albumin

level, patients at stage I have a median

survival of 62 months (~5 years), patients at

stage II have a median survival of 44 months

(~3.5 years), and patients at stage III have a

median survival of 29 months (~2.5 years).

Proteasome inhibitors as Multiple Myeloma drugs

Cancer is a disease causing uncontrolled

growth and replication of cells. Thus, cancer

treatments seek to slow the growth of or kill

these mutant cells. The problem with many

popular cancer therapy methods like chemotherapy

and radiation treatments is that they

are unable to distinguish between cancerous

and non-cancerous cells and ultimately kill

enough normal cells to make a patient very


MEDICINE

Craig Crews, the Lewis B. Cullman Professor

of Molecular, Cellular and Developmental

Biology and executive director of

the Yale Small Molecule Discovery Center.

Courtesy of Craig Crews.

sick. These methods essentially try to cure

the patient with a poison. The idea ofgtreating

patients with drugs that have lesser

side-effects is what makes newer, “targeted

therapies” so appealing to researchers and

physicians. The idea of targeted therapies

is that the drug can be prescribed in a way

more personalized to the patient’s specific

disease, and should be able to selectively kill

only cancer cells.

The nature of the plasma cells involved

in multiple myeloma offers a unique way to

target and kill these cells. One of the main

functions of plasma cells is to produce large

quantities of antibodies for the immune

response. To produce the antibodies, the cell

must synthesize the proteins the antibodies

are composed of, ensure that they are folded

properly, and then export them from the cell.

The bulk of the synthesis and folding of antibodies

occurs in the endoplasmic reticulum

(ER), one of the cell’s main organelles. When

proteins don’t fold properly and build up, the

stress level of the ER increases. If the ER

stress becomes too great, the ER will signal

the cell to undergo apoptosis (programmed

cell death). The proteasome can lower this

stress. In simple terms, the proteasome is akin

to a cellular garbage truck. It can break down

proteins, and thus is the cell’s main tool in getting

rid of unwanted or misfolded proteins.

However, if the action of the proteasome is

blocked or inhibited, it can no longer aid in

lowering ER stress, and these cells are more

likely to undergo apoptosis. Because cancerous

plasma cells have a very high protein

payload, they are much more susceptible to

proteasome inhibitors. Thus, at the proper

concentration, a proteasome inhibitor could

selectively kill cancerous cells (by only targeting

the sensitive, cancerous plasma cells).

A history of proteasome inhibitors

Epoxomicin, the linear peptide from

which carfilzomib is derived, was one of

the first identified proteasome inhibitors. It

was isolated as a natural product produced

by a fungus collected by a Japanese research

group, Hanada et al, at the Bristol Meyers

Squibb Research institute in Toyko in 1992.

It was originally identified as an antitumor

agent, but it was not until

seven years later that the

Crews lab determined that the

method of antitumor action

of epoxomicin was though the

inhibition of the proteasome.

The Crews lab also found

that within epoxomicin, it is

the α,β-epoxyketone pharmacophore

that is responsible

for the selective inhibition

of the proteasome. This

selective inhibition occurs

when expoxomicin forms an

unusual six-membered mor-

The system of targeting a protein to the proteasome for degradation. Ubiquitin is activated

by the E1 and E2 ligases, and added to the protein to be targeted for destruction

by the E3 ligase. The proteasome recognizes a chain of ubiquitin molecules attached to

a protein, and then will proceed to degrade that protein. Courtesy of Thomas Pollard.


Multiple myeloma cells (in purple), in

a bone marrow smear from a patient

with multiple myeloma, proliferate more

quickly than normal cells. Courtesy of

Craig Crews.

pholino ring with the amino terminal catalytic

Thr-1 of the 20S proteasome. However, for

such a compound to become a pharmaceutical,

it would have to be even more specific

in its binding selectivity, and would have to

have a lower toxicity.

One of the most common drugs used currently

for the treatment of multiple myeloma

is a protease-specific inhibitor called bortezomib

(known as Velcade). However, the

drug has several undesirable side effects. One

serious problem associated with bortezomib

was the side effect of peripheral neuropathy,

a condition in which damage to the peripheral

nerves causes pain, numbness, and muscle

problems. Another problem with bortezomib

is that patients typically acquire resistance.

These flaws led to the need for a secondgeneration

proteasome inhibitor.

Drug development

For Crews, there was a great incentive to

using natural products. Said Crews, “Evolution

has selected for exquisitely potent and

selective inhibitors. These are the ideal probes

already, so the mystery was figuring out how

they work. I’m interested in the mode of

action.” Epoxomicin in particular interested

Crews. The group at Bristol Meyers Squibb

dropped the epoxomicin project because

they did not know the mechanism of its

antitumor activity. Crews, who was very

much interested in mechanism-of-action

studies, decided to pick up the study of this


MEDICINE

promising compound. As

Crews explained, “Epoxomicin

had already displayed

potent antitumor

activity. The fact that they

were interested in it, but

just didn’t know how it

worked. Well, the challenge

appealed to me.” He

devised a total synthesis

of the natural product,

then, through biotin tagging

experiments, the lab

was able to determine that

epoxomicin acts by binding

the 20S subunit of the

proteasome, effectively

blocking it.

The lab then proceeded

to alter the compound to

try to get a more potent

and specific binding and

inhibition..According to

Crews, “There are three

catalytic activities in the proteasome that

have different specificities. The natural

product [epoxomicin] could target two of the

three. The goal of our project was to develop

an analog of this natural product that could

be specific for just one.”

One of these derivatives, named YU101,

had potent antitumor activity, and was able

to inhibit the proteasome better and more

specifically than epoxomicin. Indeed, it was

able to inhibit the proteasome better than

bortezomib, which at the time had just been

approved for the treatment of multiple

myeloma. Furthermore, Crews speculated

that the peripheral neuropathy side effect of

bortezomib was due to ths boronateygroup

in the compound (a boron bonded to two

hydroxyl groups and a hydrocarbon), as

boronate is an unusual pharmacore. YU101

did not have a boronate moiety, and thus was

not likely to cause peripheral neuropathy.

It appeared that Crews might have a viable

drug.

Various depictions of the proteasome. (A) An electron micrograph of the proteasome.

(B-C)Computer generated space filling models of the proteasome..

Courtesy of Thomas Pollard.

change was adding a morpholine ring to the

end of compound opposite the epoxy ketone

to boost its solubility. This compound is now

known as carfilzomib.

With the support of investors, Proteolix

was able to file a New Drug Application to

start clinical trials. Carfilzomib defied the

odds, successfully making its way through

Phase I and II clinical trials. As predicted,

carfilzomib did not produce the side effect

of peripheral neuropathy. This lower toxicity

is crucial. Crews explains that “the problem

with Velcade is that the dose limiting toxicity

prevents physicians from

being able to achieve more

than about 60% of proteasome

inhibition. With

Carfilzomib, because of

the better side effect profile,

physicians can dose

to about 75% proteasome

inhibition.”

After achieving this success

in Phase I and II trials,

in 2009, Onyx Pharmaceuticals

acquired Proteolix

and advanced the compound

through a Phase IIb

trial that led to the drug’s

accelerated approval in

July. Carfilzomib is also

going through a Phase III

trial to explore its efficacy

in solid tumors.

The FDA approved

Carfilzomib after 14 years

of dedicated research and

clinical trials. It is one of the triumphs of

targeted therapies in the treatment of cancer.

More than this though, carfilzomib is a

triumph for academic labs. Pharmaceutical

companies develop the vast majority of drugs,

yet it was an academic lab that developed this

drub. When the Crews lab picked up epoxomicin

as a project, the goal was to understand its

mechanism of action, rather than to develop

a drug. However, using solid scientific methods

and elegant experiments, they were able

to capitalize on this academic endeavor and

advance the field of cancer therapy.

About the Author

Kaitlin McLean is a senior Molecular, Cellular and Developmental Biology

major from Madison, Wisconsin. She has been working in the Crews Lab since her

freshman year and will be conducting her intensive B.S. research project under the

supervision of Professor Craig Crews.

Clinical trials and FDA approval

To start the long journey towards FDA

approval, Crews started South San Franciscobased

company, Proteolix, along with Caltech

professor Raymond J. Deshaies. The company,

despite trying many different variations of

epoximicin, finally settled on YU101 as the

best option, with one slight change. The final


Acknowledgements

I would like to profoundly thank Professor Crews for his time, effort, and passion.

Further Reading

• Pingali, S. R., Haddad, R. Y., & Saad, A. (2012). Current concepts of clinical management

of multiple myeloma


FEATURE

BIOETHICS

Pluripotent Politics:

The Uphill Struggle for Federally Funded Stem Cell Research

By Daniel Arias

The field of stem cell research is rife with both opportunity

and controversy. Scientists, politicians, and everyday civilians have

significant stakes in these two areas. Although stem cell research

holds promises of great advancement in therapeutic medicines, it

presents challenging questions about the morality of embryonic

research. These areas of contention are evidenced, however, not

in the discussion of U.S. stem cell research itself but in discussions

of funding: should the government support grants for stem cell

research?

“We are in a strange situation in the United States [where] our

only public issue has been about funding,” says Professor Stephen

Latham, Director of the Yale Interdisciplinary Center for Bioethics.

“In contrast with other places, stem cell research has always been

legal in the U.S. The only question has been ‘Has tax money been

used to pay for it?’”

A Field is Born

Human embryonic stem cell research can largely trace its roots

to 1998. In November of that year, a professor at the University

of Wisconsin by the name of James Thomson published an article

in the journal Science that announced the creation of the first line

of human embryonic

stem cells (hESCs).

Back in 1995, Thomson

had already perfected

the techniques

to grow stem cells from

a primate in the laboratory,

a process that had

taken four years of trial

and error. Using these

same techniques, he

then tried to create the

first hESC line, using

leftover embryos from

a local in vitro fertilization

clinic. His first try was a success, leading to the creation of the

first human stem cell line ever.

Thomson’s stem cell breakthrough held much promise for medicine

because of the very nature of stem cells themselves. A stem

cell is an undifferentiated cell, capable of becoming, with limited

exception, any fetal or adult cell type in the body (a trait known

as “pluripotency”). A stem cell can become part of the skin, the

The ECS is responsible for appetite and award-seeking behavior. Courtesy of BBC Science Features

nervous system, the lungs, or any other part of the body. Naturally,

this makes stem cell researchers eager to translate the properties of

stem cells to tissue and organ transplantation, where one’s own stem

cells could be used to regrow one’s own damaged tissue.

What makes Thomson’s research all the more interesting is that it

was accomplished with private funds, free from government expense.

But Thomson had no choice but to use private dollars. In 1974,

Congress banned government funding to embryonic research. In

the aftermath of the 1973 Supreme Court decision in Roe v. Wade,

some groups felt deeply concerned about embryonic research, insisting

that Roe v. Wade would lead to unregulated use of fetal tissue

leftover from abortions. Congress acted swiftly and banned federal

funding for embryonic research altogether, allowing the ban to be

lifted only with the establishment of guidelines to regulate research.

Restriction and Resistance

“ ”

In contrast with other places, stem

cell research has always been legal

in the U.S. The only question has

been ‘Has tax money been used to

pay for it?’

Shortly after Congress enacted the ban, the scientific community

pressured the Department of Health and Human Services (HHS)

and its primary research organization, the National Institutes of

Health (NIH), to lift the Congressional ban. The wording of the ban

gave the HHS Secretary discretion to lift the ban, with the NIH pressuring

HHS in 1979 and 1986

to do so; both these efforts

failed. In fact, HHS decided

in 1987 to end the debate and

issued an outright ban of all

fetal tissue research, regardless

of the source of funding.

While researchers in the

United States received no

federal financial support for

fetal cell research, researchers

in other parts of the world

were advancing the field in

their steed. As advances in

fetal cell research progressed

internationally (as in the case of Anders Björklund’s Parkinson cell

therapy studies in Sweden), the NIH strengthened its advocacy for

embryonic research. Nevertheless, the 1988 NIH recommendation

to fund embryonic and fetal research was shot down by then

HHS Secretary, Louis Sullivan, and the moratorium persisted. The

United States would continue to lag behind the world in the fields

of embryonic and fetal research.

— Professor Stephen Latham

Director of the Yale Interdisciplinary Center for Bioethics


BIOETHICS

FEATURE

At this point, Congress was prompted by

patient advocacy groups and attempted to act

to overturn the ban on embryonic research.

In 1990, a bill overturning the ban on human

embryonic research passed the House and

Senate but was vetoed by President George H.

W. Bush. Following the 1992 election, President

Clinton issued an executive order commanding

the HHS Secretary to lift the ban; after his order

drew heavy criticism from the pro-life movement,

Clinton reversed his position and allowed

the ban to stay in place. It would not be until the

end of his second term in office that the issue

of the ban would be revived.

The New Millennium and the Stem Cell

Détente

The first significant event towards loosened

funding restrictions occurred in 2000, when the

Clinton administration announced that the NIH

would accept applications for federally funded

embryonic stem cell research provided that the

embryos used for research were obtained from fertility clinics who

would otherwise discard them. Though the order prohibited funding

that would facilitate the destruction of an embryo, researchers could

apply for grants to work on new cell lines if the establishment of

the cell line was conducted using private funds.

Though this represented a significant milestone in the uphill

struggle for federally funded hESC research, the implementation

of this order was cut short by the 2000 presidential election. The

election of President George W. Bush created a de facto freeze on the

issue, for Bush had announced during his campaign that, if elected,

he would reverse Clinton’s policy on hESC funding. As the debates

over hESC research were reignited, Bush directed HHS to conduct a

second study on the issue while the President formulated a decision.

On August 9, 2001, President Bush announced his decision: the

Administration would be the first in U.S. history to provide federal

funds for hESC research. Rather than reverse Clinton’s policy, Bush

tailored it by attaching a caveat: federal funds could only be obtained

for research using pre-existing cell lines (pre-existing being defined

as existing before his address) which were obtained as discarded

material from fertility clinics by the informed consent of the donors.

A total of 21 cell lines would be now available for federal funding

in the United States.

With the election of President Obama (who, during his inaugural

address, pledged to “restore science to its rightful place”) came a

renewed push for expanded hESC funding. On March 9, 2009,

President Obama removed the federal funding restrictions for novel

stem cell lines, provided that the development of these stem cell

lines did not involve public funds.

While this history suggests a long and arduous path to victory for

embryonic stem cell research, it is important to consider that the

U.S. spends a relatively minor amount of funding towards human

embryonic stem cell studies. In 2011, the NIH directed $123 million

to hESC research; non-embryonic non-human stem cell research,

in the same year, received over five times that amount. As a portion

of the total 2011 NIH budget, hESC research received 0.39% of

Human embryonic stem cells. Image courtesy of Diane Krause from ESCRO

(Embryonic Stem Cell Research Oversight at Yale).

NIH funding.

To address this gap, states have established their own funds for

stem cell research. Latham explains that, during the Bush years, there

were researchers at Yale and the University of Connecticut who

took advantage of the Connecticut funding program, most receiving

small seed grants that got their research started. Yale received

about half of the Connecticut funding and continues to do so; the

state of Connecticut has spent $59 million in the last five years on

grants-in-aid for stem cell researchers.

A Course for the Future

As states attempt to supplement federal funding, the research

focus in the field of stem cells has been shifting. “We see people

shifting their interests towards induced pluripotent cells,” says

Latham. “Induced pluripotent cells are specialized cells, such as skin

cells and red blood cells, which undergo forced de-specialization.

You can generate tissue using induced pluripotent cells that come

from the person who will be receiving the tissue, so genetic matching

isn’t an issue,” explains Latham. “Furthermore, there aren’t the

ethical problems of human embryonic stem cells, since you don’t

need an embryo to make these cells.”

The shift to induced pluripotent cell research, however, does

not mean a death knell for embryonic stem cell research. “We can’t

shift completely,” says Latham. “The gold standard for pluripotency

[remains] the embryonic cell... We can’t completely stop, but there

has been a shift.”

As science and politics develop around the shifting focus of

stem cell research, undoubtedly the issue of funding will continue

to constitute a significant factor in the direction of research. Each

presidential administration in the last quarter of the century has

refocused the course of stem cell research through the power of

the purse. As November looms nearer and nearer, researchers and

patients around the world will be holding their breaths to see how

the upcoming election will attempt to answer the perpetual question:

Who pays?


FEATURE

MICROBIOLOGY

Exploring the

Microbiome

BY TESHIKA JAYEWICKREME

On every part of the human body, from our nose to our gut, live

ten to a hundred trillion microbes. They outnumber our own cells

10 to 1, our genome 100 to 1. Indeed, these tiny living organisms,

many of which are bacteria, line every surface of the human body,

both inside and out. Yet most bacteria are far from foreign invaders,

as they have been passed down from our mothers during birth and

with us our entire lives, while we picked up other bacteria along the

way. With each diaper change, these bacteria grew and multiplied,

frantically racing to cover us with a protective blanket of good

bacteria before any of their harmful cousins took residence. From

our first cut, to our last breath, microbes live alongside our own

cells in harmony. Together, the genes these microorganisms encode

what scientists call the human microbiome.

What is the Microbiome?

The term microbiome may seem contradictory at first. When

ecologists talk about biomes, they are usually referring to expansive

regions on Earth like the tropical rainforests of South America or

the great Savannahs of Africa. In reference to size, the microbiome

is different; its organisms are microscopic. If all the microbes inside

a single human were weighed, it may amount to less than a single

rabbit. Yet what the microbiome lacks in mass, it more than makes

up for in diversity.

“What is great about the gut is that the density of bacteria is

incredibly high…higher than any other ecological location that we

know of,” explains Dr. Andrew Goodman, an associate professor

in microbial pathogenesis at Yale University. A single human gut

houses more species of microbes than species of animals in an

entire forest.

Biomes are more than just the species within them. When ecologists

venture through the frigid Arctic tundra, they are not solely

in search of samples to classify. What scientists care most about

biomes is how the organisms inside interact and adapt. Scientists

want to know why one species of fox survives better than another.

It is this competition among species that interests scientists most.

Similarly, with the microbiome, scientists are comparing variations

on the micro scale. How do these variations lead to differences

between people? “This variation matters,” says Goodman, “ and it

has consequences on health.”

Numerous modern diseases may potentially have roots in the

microbiome. For example, scientists find that the guts of obese

individuals contained more firmicutes, a common type of bacteria,

than their healthier counterparts. Using zebrafish specially raised

with and without firmicutes in their guts, researchers found that

these bacteria help increase fat absorption in the gut. What may have

initially been an adaptation to help our ancestors survive famine

may now contribute to the obesity epidemic.

The Microbiome as a Genome

Even amongst the most passionate scientists, few would ever opt

for a safari through the gut over the savannah. Diversity among

bacteria does not entail brightly colored feathers or exotic mating

rituals. All of this diversity exists instead as differences in bacterial

genomes in the A’s, T’s, G’s, and C’s found within their DNA.


MICROBIOLOGY

FEATURE

Broadly put, the genome contains all the instructions necessary

for a cell to survive and grow. Imagine a genome as a recipe book,

with each recipe producing a new protein. While there are slight

differences in flavor between different human genomes, often dictating

differences in physical features, each bacterial genome has

entire recipes not found in the human genome. The microbiome has

trillions of bacteria and adds volumes of new recipes to the human

genome — 8 million new ones to our existing 22,000 — forming

a library of recipe books scientist call the Metagenome. What scientists

see is that the human body does not rely solely on human

genes. These extra bacterial genes help make new proteins to break

down toxins and perform other functions that would otherwise not

be possible within the human body.

Understanding the Metagenome Through the Human Microbiome

Project

Goodman describes the metagenome as a “description of the

capacity of a [bacterial] community to carry out a function.” The

metagenome is a collection of all the possible recipes, or genes, that

bacteria add to humans. While many of these genes only perform

functions for the bacteria, some provide vital functions to their

human hosts. Scientists have known about this enormous cache of

genes for quite some time, yet it was not until recently that they were

actually able to determine the sequence of a human metagenome.

In 2008, the National Institute of Health launched the Human

Microbiome Project as an attempt to sequence the microbiomes

Over 90 percent of the cells on the human body are actually

microbes. Courtesy of Dr. Andrew Goodman.

of 242 healthy adult volunteers. Ultimately, scientists wanted to

understand the variations among different humans. Do humans

host the same types of microbes or are these microbes unique to

each individual?

“It hasn’t been the case that we mostly have the same species, at

least in our guts. It’s almost the opposite. We mostly have our own

in our guts,” says Goodman. Indeed, the project leaders found that

the human microbiome was more dynamic than constant. Each individual

has his or her own set of microbes, but the surprising thing

Agar plates and tubes are used to study bacteria outside of the

gut. Courtesy of Jane Long, Yale Student.

was that despite this variation, parts of the metagenome remained

relatively the same. As one bacterial species died, another arose to

take its place, ensuring that some of the most crucial recipes are

never completely lost.

Next Steps

Sequencing the metagenome is only the first step in understanding

how humans vary. Projects like the Human Microbiome Project

provide a stepping stone for future research into the consequences

of such variation.

“It is becoming very clear that sick people have a different microbiome

than healthy people,” explains Goodman. Despite this, he

finds that one of the major obstacles of microbiome research is

the fact that the microbiome is so susceptible to other factors. “It’s

shaped by what foods you eat, it’s shaped by your own genome,

what your parents or outside forces gave you,” says Goodman.

Often, it proves too difficult to separate out the environment from

the disease.

One solution Dr. Goodman proposes is through the use of

germ-free mice. “If you can take the microbiome of a person and

transplant it to a germ-free mouse…you’ve controlled for a lot of

these questions about background variation.”

The concept of germ-free mice is relatively new in the research

community and requires specialized facilities. In Goodman’s lab,

mice are raised in a truly alien environment, one completely devoid

of any form of bacterial life. Everything they come in contact with,

from air, water, and food, is purified. All these added precautions

ensure that these mice live completely without a microbiome, and it

shows. “They are by no means healthy,” says Goodman. “While they

survive in the lab, it is unlikely that they would survive in the wild.”

However, Goodman believes that germ-free mice provide a “clean

slate” for researchers. By transferring what amounts to human fecal

matter into the mice gut, researchers are able create almost exact

replicas of diseased microbiomes. This allows researchers to study

disease on much larger scales. Instead of observing the microbiome

of a single obese human, researchers can instead observe the same

microbiome cultivated in hundreds of mice. Ultimately researchers

like Goodman hope that the added similarities these mice have to

their humans will help revolutionize biomedical research.


FEATURE

HEALTH

The Politics of FDA Approval

BY JARED MILFRED

In October of 2010, the United States Food and Drug Administration

made a stunning admission of wrongdoing. Two years prior, the

FDA succumbed to outside pressure and cleared a knee implant that

never should have been approved. The “Menaflex” had already twice

been rejected by the FDA on grounds of causing increased risk of

injury and little to no benefit to patients. But despite vocal opposition

by medical experts, four congressmen from New Jersey convinced the

commissioner of the FDA to overrule his own agency’s scientists and

approve the Menaflex on its third approval attempt. The scientists insisted

the device should at least be tested for safety, but

the congressmen asserted safety trials were not

even necessary. Public campaign finance records

revealed that each of the New Jersey congressmen

received substantial campaign donations from

ReGen Biologics, the maker of the device. All

four claimed that their pressure on the FDA was

not influenced by the money ReGen gave them,

but this connection is difficult to deny.

Perfect objectivity may be an impossible goal;

even the commissioner of the FDA is not immune

to external pressure. But the Menaflex could never

have been wrongfully approved were it not for

one particular FDA program that allowed a single,

influenceable person to overrule the collective scientific

opinion of a federal agency and circumvent

essential safety review. This was allowed because of

the FDA’s perpetual pursuit of efficiency.

The Menaflex was green-lit through an FDA program called 510(k)

or Premarket Notification. Designed to increase the efficiency of the

approval process, 510(k) allows a medical device to forgo rigorous clinical

safety trials if it is deemed similar enough to an already-approved device.

In many cases, the 510(k) program has proven to be a substantial cost

saver. It has allowed thousands of rough equivalents to bypass expensive

safety trials. But to the 210 patients who received the erroneously

approved knee implant, the 510(k) program represents the FDA at its

worst: failing to protect American citizens under the guise of increased

efficiency.

Admittedly, for the Menaflex, unethical congressional pressure could

arguably share blame with the FDA’s quest for efficiency. But a 2011

study by Dr. Diana Zuckerman, a former Yale professor and the current

president of the National Research Center for Women & Families,

showed that wrongful approvals stemming from 510(k) may be more the

rule than the exception. Zuckerman found that of all medical devices

ever recalled by the FDA because they could seriously harm patients or

result in death, more than two-thirds had been approved through the

510(k) program.

Though Congress is currently reevaluating the merits of 510(k), the

Menaflex controversy raises important questions about the cost of

efficiency itself. Does a more efficient Food and Drug Administration

actually yield better results for consumers? Many say yes. If products are

approved more quickly, they can be brought to market sooner and begin

helping patients earlier. Biomedical companies often use this argument

to justify their demand for faster approval times. Moreover, in light of

budget realities, some argue that it is prohibitively expensive to rigorously

test every new drug and medical device.

Of all medical devices ever recalled

by the FDA because they could

seriously harm patients or result in

death, more than two-thirds had

been allowed to forgo safety trials in

the name of efficiency. Courtesy of

RRY Publications.

But a loud and clear opposition disagrees. They claim that a more

efficient FDA does not yield better results for the consumer. For an

agency that regulates over 25 percent of all consumer spending in the

United States and is tasked with ensuring the safety of every person who

purchases food or uses medicine, it is reasonable to allocate more than the

eight dollars per American that Congress budgeted for the agency in 2012.

A reasonable compromise might be to charge the companies who

seek FDA approval and use that money to pay for clinical trials. This

is precisely the approach taken by the FDA since 1992 for novel drugs

whose safety have never been tested. However,

the roughly $2 billion per year the FDA currently

receives from drug companies as “user fees” raises

the potential for conflicts of interest between

sound science and financial motives. Perhaps the

only way to prevent conflicts of interest while

ensuring the highest safety standards would be

to rigorously test every drug or medical device,

regardless of similarity to previous approved

products and, furthermore, for the federal government

to be the sole source of FDA funding. On

the other hand, such an approach is the antithesis

of efficiency and cost effectiveness.

Dr. Joseph Ross, Assistant Professor of General

Medicine at the Yale School of Medicine, is an

expert on federal medical policy and its impact

on quality of medical care. He recently published

a study in The New England Journal of Medicine

comparing the average approval time of the FDA to those of its peer

agencies, the European Medicines Agency and Health Canada. Despite

a long-standing industry claim that the FDA does not approve products

quickly enough (for lack of funding or otherwise), Dr. Ross found that

the FDA’s approval time is, on average, roughly a month and a half

faster than its peers. Speaking about the 2012 renewal of the FDA’s

authorizing legislation, Dr. Ross says, “As the new bill in Congress was

being discussed, what was coming from the industry side was ‘FDA is

still not fast enough.’ When I hear that, I think, knowing that faster is

probably sloppier, is speed really such a concern?” He continues, “For

me, the principle responsibility of the FDA is to make sure that only

safe medications are out there on the market. But there are still unsafe

drugs getting approved. If Europe were moving faster, but their safety

records were the same, maybe you could argue that the FDA should go

faster. But if the FDA is moving faster, what the industry is doing is

likely to push the FDA into making sloppy decisions.”

Many aspects of the FDA’s charter are updated only once every five

years, and just last July, the 2012 legislation was passed by Congress and

signed by President Obama. As such, a serious overhaul would likely have

to wait until 2017. But in light of recent findings, Congress may want

to do two things: (1) de-emphasize the pursuit of efficiency by either

tightening or discarding programs like 510(k) that only ostensibly increase

efficiency at the cost of safety and, (2) if ever the FDA is found slower

than its peers, reinforce the FDA overall by increasing the agency’s budget

rather than cutting corners and skipping steps of regulatory review. The

FDA may not be the hottest topic in Washington, but the regulation

of food and drugs, especially when it goes wrong, should deserve the

utmost attention of American politics.



-

-

-

-

-

Tissue engineering: from stem cells to organs

Biodegradable scaffolds are used to “guide” cells into a proper shape

while they grow. Over time, the scaffold degrades and the cells take

a particular shape, in this case, a vascular graft. Courtesy of Sashka

Dimitrievska and Dr. Laura Niklason’s Lab

TECHNOLOGY

FEATURE

COPY, PASTE, PRINT... KIDNEY?

-

3D Printing: Organ supply

closets?

-

-

October 2012 | 31

FEATURE

HEALTH

ON THE ROAD TO SWEETNESS:

A CLEAR-CUT DESTINATION?

BY MARGARETTA MIDURA

-

-

-

the tastes.

-

-

The original tongue map depicting which areas of the tongue

sense the four primary tastes. The taste buds are made up

Courtesy of James Beard Foundation.

-

-

concentrations of certain taste

32 | October 2012

ASTRONOMY

FEATURE

Curious?

NASA Rover Curiosity Cruises onto Mars

BY KATIE COLFORD

Conceptualized by a 27-year-old graduate student, named by a

12-year-old middle school student, and immortalized in a vibrant

Twitter feed, Curiosity marks the most ambitious mission ever

flown to Mars. Equipped with a whole gamut of arguably the most

complex and innovative scientific and analytical instruments to date,

Curiosity has one main mission: to determine if microbial life could

ever have survived on the now dry and dusty planet.

Although Curiosity will be roaming Mars for the next year and

a half collecting and analyzing data, perhaps the most challenging

part of the mission was simply landing the rover safely. To put it

lightly, Curiosity is the largest rover ever sent to Mars: it weighs more

than 2,000 pounds, has the dimensions of a small car, and carries

an entire science laboratory inside of it. After more than half a year

hurtling through space, the massive rover needed more innovative

engineering than the usual airbags to cushion its landing on the red

planet. Although some called it far-fetched, the solution was “analyzed,

peer-reviewed, and tested the hell out of,” as Peter Theisinger,

project manager of Curiosity, described in a press teleconference.

Plummeting into the Martian atmosphere at about 21,000 kilometers

per hour, parachutes significantly slowed the vehicle in

what engineers called the final “seven minutes of terror” before a

descent stage detached from the rover, using steerable engines to

slow the rover even further. Finally, in the last few seconds before

landing, the crown jewel of the innovative landing strategy came

into play: A sky-crane system, connected to the rover by a tethered

rope, carefully lowered Curiosity onto the planet’s surface. Upon a

Artistic representation of Curiosity on Mars. Courtesy of

NASA.

successful touchdown, the descent stage cut away from the rover,

and Curiosity surfed safely and triumphantly toward Gale Crater.

Following a successful start to the mission on Mars, Curiosity’s

technology is just as impressive, boasting instruments that would

make any laboratory on Earth envious. In order to first collect

particles, Curiosity has the typical array of collection tools that

allow it to pick up rocks and scoop sand, with one exciting, distinctive

feature: a high-powered laser that vaporizes rocks. Called

the ChemCam, the laser can shoot its target from as far away as 23

feet and is equipped not only to let Curiosity collect the thin layers

of vaporized rock but also to identify the individual atoms of the

vapor. Including a gas chromatograph, a mass spectrometer, and

a turn-able laser spectrometer, all of these instruments essentially

serve to break down the little bits of rock and sand into single

molecules. Then, it will let scientists run a wide range of tests to

Artistic representation of Curiosity’s sky-crane landing

system. Courtesy of NASA.

analyze what Martian conditions were once like. Other instruments,

such as an X-ray diffraction and fluorescence instrument, enable

scientists to look at the minerals in rocks and solids and determine

the bulk makeup of these particles. Furthermore, the Mars Hand

Lens Imager can take extreme close-up images of the Martian

surface, capturing details smaller than the width of a human hair.

While the rover carries the most complex and innovative instruments

to date, the NASA mission is also pioneering an innovative

mission back on Earth: using social media to keep the public interested

and informed on Curiosity’s progress. As Curiosity journeyed

through space, its over 1 million Twitter followers and Facebook

fans were kept up-to-date on its progress. Upon landing on Mars,

almost 100,000 people re-tweeted by-the-minute accounts of the

rover’s progress, and an interplanetary broadcast of the song “Reach

for the Stars” by popular artist will.i.am stirred excitement in many

observers. Never before has NASA space technology been so accessible

to the general population.

Perhaps this is partially because NASA has never been so close to

being able to announce news of extra-terrestrial life. “If we found

life on Mars, even if it was very low forms of life…that would

certainly be very significant in terms of how we saw ourselves,”

says Professor Peter Parker, Director of Undergraduate Studies of

Physics at Yale University. “Psychologically, I think that is a very

important thing.”

As the winner of the Rover’s naming contest, 12-year-old Clara

Ma wrote, “Curiosity is an everlasting flame that burns in everyone’s

mind.” Indeed, with continued success, this mission could leave a

legacy that burns forever.


FEATURE

EDUCATION

The Story of Science at Yale, Part III:

Science at Yale on the Horizon

BY DENNIS WANG

In his inaugural address in 1993, newly minted President Richard

Levin pledged his support for the sciences at Yale and highlighted

their importance to the university.

“Today, the scientific capability of American universities is the envy of the

world. We neglect its support at our peril.”

–President Levin, October 1, 1993

Nearly two decades later, Levin boasts a long list of accomplishments

in the sciences and across the university, most notably through

updates in the scientific curriculum and investments in new facilities.

He has increased research opportunities for students through the

Perspectives on Science and Engineering Program for freshmen, and

the Science, Technology and Research Scholars (STARS) Program for

minorities and women, and made a push to improve both recruitment

and retention of top science students. Levin has also worked to hire

professors preeminent in their fields and firmly establish Yale’s place

in the scientific community.

At the turn of the new millennium, Levin announced a $500 million

investment in science and engineering facilities, and an additional $500

million investment in facilities at the medical school.

“Yale is committed to remain on everyone’s short list of the best universities

in the world. In the 21st century, you must excel in science and engineering to

maintain that position.”

–President Levin, January 19, 2000

Levin planned for five science buildings in his 20-year commitment

to science and technology. Four of these original five buildings have

been built (Class of 1954 Environmental Science Center, Malone

Engineering Center, Class of 1954 Chemistry Research Building. and

Kroon Hall) in addition to two others that were not part of his original

plan (The Anlyan Center and Smilow Cancer Hospital).

Last summer, Kline Biology Tower was renovated and equipped with

the new Center for Science and Social Science Information as well

as a new café, now a popular hangout for science students. This past

summer, lecture halls in Sloane Physics Laboratory were renovated

and the Center for Engineering Innovation and Design (CEID) was

opened on Prospect Street, making science and engineering more

visible than ever with exhibitions of student work. Sterling Chemistry

Laboratory, Gibbs Laboratory, and Osborne Memorial Laboratories

have yet to be renovated.

In 2008, the proposed $500 million Undergraduate Science Center,

a plan for the vertical expansion of Sterling Chemistry Laboratory

to include a dining hall and a gym, was canceled due to the recession.

The project was replaced by a $50 million renovation of Kline

Chemistry Laboratory. The Undergraduate Science Teaching Center

is still on Yale’s wish list.

Levin announced on August 30, 2012 that he would step down at

the end of the academic year. In his email, he acknowledged that there

remains an unfinished agenda.

“Before us lie decisions about when to proceed with such projects as constructing

the Yale Biology Building, facilities for science teaching…”

–President Levin, August 30, 2012

Construction on the $250 million Yale Biology Building, the fifth

building, has been suspended. The “Giving to Yale” page is currently

soliciting a $100 million donation for the project.

Other projects have also met similar struggles. Science Park at

Yale, the old site of the Winchester Repeating Arms Company, was

supposed to become a hotspot for biotech companies and startups,

but after years of stagnation and several changes in ownership over

the last decade, has become an industrial complex featuring a garage,

apartments, and offices.

In its most recent display of long-term commitment, however, Yale

acquired 136 acres of land in 2007 for its West Campus, an area devoted

exclusively to science. The new property, formerly owned by Bayer

HealthCare Pharmaceuticals, gives science at Yale the room it needs to

grow. West Campus is, however, located 7 miles away from downtown

New Haven, raising concerns about how the space can be integrated

with the rest of campus and be made useful to undergraduates. West

Campus includes more than half a million square feet of ready-made

laboratory space and only cost $100 million. The Yale Biology Building,

in comparison, will cost $250 million for just 286,000 square

feet of laboratory space. Already, many interdisciplinary institutes

including the Yale Center for Molecular Discovery, the Yale Center

for Genomic Analysis, the High Performance Computing Center, and

the West Campus Analytical Core, are located at West Campus. It is

perhaps the best example of Yale’s emphasis on value for its money,

and much it of its potential remains untapped.

Yale University is a world leader in science education, but there is

always room for improvement. Thanks to the leadership and dedication

of President Levin and others like him, science at Yale is well on

its way to a brighter future.

“In the twenty-first century, no education will be complete without

a significant infusion of science and quantitative reasoning. The

curricular reforms now unfolding in Yale College were developed

expressly to meet the need for a scientifically literate citizenry,” Levin

recently noted.

In this spirit, a four-part series of 100-level biology courses was

introduced this year to provide science underclassmen with a “deeper

level of understanding,” in the words of Professor Michael Koelle.

Koelle, who teaches BIOL 101: “Biochemistry and Biophysics,”

believes that the courses will better prepare students for higher-level

classes and hopes that they will pave the way for better upper-level

electives. The supply of new offerings may have come just in time

to meet demand. The introductory biology courses were extremely

popular throughout shopping period, and more freshmen are also

declaring their interest in science majors. Koelle also added, “We are

definitely continuing to teach science courses for non-science majors!

Generating new high-quality offerings in this area is a priority at Yale

College.”

As we prepare for the transition in leadership, we can be confident

that if the next president of Yale University is anything like President

Levin, Yale will continue to improve its science programs, and will

always rise to meet the challenges of the future for Yale and for the

world.


BOOK REVIEW

FEATURE

Rating:

&&&&&

The Vision Revolution

BY GRACE CAO

The eyes are one of the most amazing parts of the human body.

Our eyes can perceive the ruby tones of a pomegranate, gaze up

to the peak of Mount Everest, and follow speeding cars quickly

enough to protect us as we cross the road. Though we do not always

fully appreciate these abilities, a

moment of thought reveals how

extraordinary they are. Dr. Mark

Changizi, Assistant Professor of

Cognitive Science at Rensselaer

Polytechnic Institute, goes a step

further than simply thinking our

eyes are remarkable. In his book.

The Vision Revolution: How

the Latest Research Overturns

Everything We Thought We Knew

About Human Vision, he compares

four different aspects of

our vision to four “superpowers,”

shifting the lens for how we normally

think about the human eye.

Changizi first discusses our

ability to understand people’s

emotions through changes in

their facial color, a superpower he

refers to as color telepathy. The

need for this skill is one reason

the author argues we have color

vision at all: to easily observe the

small changes in skin color, such

as blushing, that reflect shifts in

mood. While this claim is intriguing,

Changizi’s evidence is often

heavily anecdotal. For example, he

writes that human skin is uniquely

colorless, but explains this mainly

by citing the lack of a word to

describe the color “skin” in many

languages. A full-color insert of

figures and illustrations compensates

in part for this shortcoming,

however, and keeps the section

entertaining.

In addition to color telepathy, Changizi also asserts humans have a

form of X-ray vision ability. To see this ability in action, spread out

your fingers: hold up your hand, and try looking past your hand with

one eye closed, then the other. What you see is, obviously, much less

than when both eyes work together. According to Changizi, this is

what real X-ray vision is. Overall, this chapter is stronger than the

first, continuing to include engaging asides while also referencing

scientific studies to support the argument. Therefore, when the

author claims that the advantage of seeing through clutter was the

main driver of the evolution of our binocular vision, his argument

Mark Changizi presents his theories about why our

vision works the way it does. Courtesy of tradebit.com.

feels more substantial.

The third chapter of the book deals with future-seeing, a fascinating

explanation of why optical illusions work. True to the opening

paragraph, illustrations of optical illusions are scattered throughout

the chapter, maintaining the reader’s

interest and demonstrating an effect

of future-seeing. Changizi explains

that our brains are constantly creating

a perception of the future simply

to keep up with the present moment,

because of the time it takes to process

visual input. To tie this theory back to

the entertaining illusions, he suggests

that they occur because we think the

images are dynamic. As a result, our

brains attempt to construct a future

appearance that clashes with the static

nature of the image. This section is

perhaps the most successful in balancing

entertainment with scientific thinking,

because of the natural pairing of

the optical illusions and future-seeing.

Spirit-reading, our last superpower,

centers on an aspect of vision that is

uniquely human: the ability to read.

Many of us have struggled to perfect

our nearly illegible handwriting, but

perhaps fewer have wondered why

letters look the way they do. Changizi

suggests that letters model shapes

found in nature in a way that makes

them easy for our eyes to recognize.

He found a strong correlation between

the frequency of particular junctions

in the natural world and the frequency

of use for letters with similar-shaped

junctions. For example, corners are

easy to find, and so are Ls; on the other

hand, crosses occur rarely, and so

does the letter X. As one of the most

technical chapters, the disconnect in

this section between the scientific content and slightly artificial

superpower terminology can be jarring, but the strength of the

researched ideas makes it worth reading.

Overall, though the superpower theme can occasionally feel

gimmicky, Changizi does an excellent job of writing about vision

in an accessible way. The casual tone, frequent anecdotes, and

informative illustrations make potentially complicated ideas easy

for anyone to handle. Though the more scientific reader may be

frustrated by the basic level from which he approaches his subject,

his intriguing theories nonetheless give us a fresh perspective on

how we see the world.



FEATURE ZOOLOGY

Laughter across the Animal Kingdom,

from Rats to Humans

BY STELLA CAO

Have you ever heard a rat laugh? Jaak Panksepp has, and he finds

nothing unusual about it. Panksepp, Professor Emeritus of Psychology

at Bowling Green State University, tickles rats in his lab to elucidate

the fundamentals of laughter.

Scientists have long known that humans are not the only species

capable of laughing. In fact, most mammals, from chimpanzees to

dogs, can laugh as well. Similar to other abilities that are shared among

many species, some believe that there must be a reason the ability to

laugh at a good joke, from tickling, or some other source is shared

among so many different species. Given its prevalence and importance

in social interactions for all of these species, scientists seek to learn

more about the origins and purpose of laughter.

Panksepp is at the forefront of such research, and his work on rat

laughter has led to some interesting and unexpected observations.

First, Panksepp clarifies that rat laughter is slightly different from

that of humans. Rat laughter comes in the form of high frequency

50-kilohertz ultrasonic calls, or “chirps,” that are distinct from other

vocal emissions in rats. In other words, one cannot hear rat laughter;

they are actually high-pitched chirps that must be measured using

sensitive and specialized equipment.

Rats laugh when tickled in sensitive areas, such as the nape of

their neck. Courtesy of BBC.

In addition to differences in frequency, rats also laugh in different

situations than most humans do. While rats laugh when tickled in

sensitive areas such as the nape of their neck, young rats also laugh

when they anticipate rewards or enter new environments. Rats also

laugh when they are nervous and when trying to diffuse aggressive

situations. These observations have led Panksepp to hypothesize that

by laughing, rats display emotional health and engage in social bonding

with other fellow rats. Therefore, rats that laugh more frequently might

have a higher social standing within a group because they attract other

rat, somewhat like the class clown in elementary school.

Laughter among children during boisterous play is similar to young

rats laughing when they are tumbling together. According to Panksepp,

laughter among human children and young rats is actually quite similar.

The main difference in humans, he notes, is that humans activate

“higher order structures” like the frontal cortex when laughing at jokes,

leading to laughter in response to multiple kinds of stimuli. On the

Panskepp studies laughter by tickling rats. Courtesy of Duke

University.

other hand, adult rats do not necessarily have the cognitive mechanisms

to understand verbal jokes and sarcasm. “The use of language-based

jokes is clearly unique to humans,” says Robin Dunbar, a professor

of evolutionary psychology at the University of Oxford. Dunbar

also claims “laughter predates the appearance of language in human

evolution and was used as a mechanism to allow bonding between a

large number of individuals.”

Laughter in humans releases endorphins, which produce the feeling

of well-being in the brain. Releasing endorphins allows for bonding

among individuals in a group, which is beneficial to the hyper-social

societies humans live in. Sharing of laughter is likely to help people

bond and facilitate closer connections. Beyond this, however, behavioral

neuroscience has yet to clearly link how these tiny chemical

changes add up to cause something to seem funny to us — or rats.

Rats laugh when tickled in sensitive areas, such as the nape of

their neck. Courtesy of BBC.


ALUMNI PROFILE FEATURE

Jennifer Staple-Clark, B.A. ’03

BY PAYAL MARATHE

In September 2000, Jennifer Staple was a sophomore in Timothy

Dwight College interested in starting a new club. Twelve years later,

this project has grown into the global non-profit. Unite for Sight is an

internationally visible organization bringing eye care to communities

in India, Ghana, and Honduras.

Staple-Clark’s original inspiration for the organization came during

the summer of 2000. A biology and anthropology double major at

Yale, she experienced her first introduction to patient care while

working that summer at an optometrist’s office. She heard stories

from patients who came in with glaucoma, which if untreated, allows

pressure to build up in the eye, damaging the optic nerve and causing

irreversible blindness.

“These people had health insurance and went to other doctors but

just not eye doctors. They hadn’t noticed visual deterioration until it

was too late,” Staple-Clark says. She also noticed that a lot of New

Haven’s population did not have health insurance.

Volunteers work at local clinics, providing surgeries, preventitive

care, and education. Courtesy of Unite for Sight.

And so the first chapter for Unite for Sight was born. It started as a

group of 35 volunteers who made trips to the soup kitchen and New

Haven Public Library to spread knowledge about existing resources.

By the time of her college graduation three years later, Staple-Clark

decided to branch out to other university campuses. There are now

50 chapters of Unite for Sight in North America. The organization

expanded even further in 2004 when it launched its global health

delivery program in Ghana.

“I originally planned for it to be a student organization that would

work to eliminate patient barriers to eye care in New Haven. I did

not anticipate that it would become a worldwide health organization,”

Staple-Clark says.

Staple-Clark saw her work in college as a stepping stone for a

larger role in the realm of global eye care and health education. She

explains that about 80 percent of blindness is preventable or curable

by simple surgeries or care. Cataracts, for example, are a significant

source of blindness in developing nations, but the treatment is only a

15-minute outpatient surgery. Still, some communities cannot access

or afford this care.

“A lot of governments focus on HIV or malaria, known as killer

diseases, and don’t recognize eye care as a critical issue,” Staple-Clark

says. But she argues that the impact of blindness is often underestimated

in its impact in other measures of quality of life. In developing

countries, for instance, children often become caretakers for blind

adults, preventing them from attending school and thus contributing


Staple-Clark examines a patient in India. Since 2000, Unite for

Sight has provided eye-care services to 1.3 million people in

India, Ghana, and Honduras. Courtesy of Stanford University.

to the cycle of poverty.

With this in mind, Staple-Clark extended the global health delivery

program to India and Honduras. An annual Global Health and

Innovation Conference brings professionals from different medical

disciplines together to cross-strategize.

Additionally, Staple-Clark emphasizes the importance of research.

A core of volunteers within Unite for Sight has been studying the

“barriers to care that are impacting communities,” such as poverty

and a mother’s perception on eye care for her children. The outreach

program sends local optometrists into villages to dissipate eye care

myths such as “putting urine or breast milk in the eye” as a cure for

conditions.

She finds her work with Unite for Sight incredibly fulfilling. “I work

with remarkable local eye doctors who are collectively providing quality

care each year to more than 200,000 patients living in poverty. They

are incredibly committed and dedicated to improving health outcomes

in their countries, and I can think of nothing more rewarding than

working with them to improve lives,” she says.

Looking back, Staple-Clark reminisces how she “absolutely adored”

her time at Yale and shares some advice. “It’s so important for students

to follow their passions, not just what they are interested in but what

they could become interested in,” she says, offering her decision to

double major as an example. She only became curious about anthropology

after shopping a class on a whim. “I found the combination to be

terrific because I was able to explore cultural and medical anthropology

alongside scientific aspects of biology,” she says.

Staple-Clark’s work has not gone unnoticed on the national stage.

In 2009, she won the National Jefferson Award, regarded as the Nobel

Prize for public service. She was the 2011 recipient of the John F.

Kennedy New Frontier Award for her health advocacy and activism.

She is also a member of the President’s Council on International

Activities at Yale.

Staple-Clark plans on continuing running Unite for Sight for years

to come. She reflects, “We’ve currently reached about 1.4 million

people, but there’s a constant need in so many different locations to

bring people care. Every two years we try to add a new clinic partner,

and we’re always working to enhance our existing programs. I have

such a passion for the work we do.”


38 | October 2012

CARTOON

FEATURE

A Different Political Campaign

October 2012 | 39

Michele Dufault, Yale

College Class of 2011

(Saybrook), died in a tragic

accident on April 12, 2011.

Michele was a Physics and

Astronomy major, a strong

supporter of other women in

science, and a leader among

leaders. Michele’s senior thesis

project included the development

of novel detectors for dark

matter particles. Michele was

planning to continue work in

ocean sciences at the University

of Washington following her

graduation from Yale.

Michele was passionate about

science. Her infectious enthusiasm,

curiosity, generosity, adn

energy touched all those who

knew her. In honor of Michele’s

tremendous contributions to

Yale’s undergraduate science

commnity, we have etablished

the Michele Dugault Summer

Research Fellowship and Conference

Fund.

While it is our ultimate goal to

raise $100,000 to endow this

fund in perpetuity, in the event

we are not able to realize that

goal, we will instead create an

expendable fund that will support

activities in her name until

the funds have been expenced

(not less than 10 years).

This fund will support:

• A summer fellowship for a

Yale undergraduate woman

in the physical sciences, especially

Physics, Astronomy,

or Geology & Geophysics.

• Conferences that encourage

young women to pursue the

physical sciences, such as

the Conference on Undergraduate

Women in Physics

(held at Yale three of the

past four years).

If you wish to contribute to the

fund, please write a check payable

to Yale University, note on

the check that is is for the “Michele

Dufault Summer Fellowship

and Conference Fund” and mail

it c/o the Physics Department,

PO Box 208120, New Haven CT

06520-8120. We will transfer your

donation to the Development

Office (stewards of the fund)

promptly.

You may donate online through

Yale Development Office website

at http://giving.yale.edu. Please

select “new gift,” “other,”

when asked which area at Yale

you would like to support, and

select “Michele Dufault Fund”

when prompted.

YSM Issue 85.4

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