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2016 Scientific Report

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Published June 2016.

Cover design by Nicole Ethen.

Copyright 2016 by Van Andel Institute; all rights reserved.

Van Andel Institute, 333 Bostwick Avenue, N.E.

Grand Rapids, Michigan 49503, U.S.A.


VAN ANDEL RESEARCH INSTITUTE is proud to announce that its

Chief Scientific Officer, Peter Jones, Ph.D., D.Sc., was elected a member of the National

Academy of Sciences in May 2016. He joins VARI’s founding Director, George Vande

Woude, Ph.D., who has been a member since 1993.

Dr. Jones has been a long-standing leader in the field of epigenomics. His accomplishments include

• publication of the first study to prove how epigenetics regulates cellular differentiation

• development of DNA methylation inhibitors (DNMTi’s) as drugs

• discovery that epigenetics plays a fundamental role in aging

• elucidation of the biological processes for cellular self-control

• identification of ways to manipulate endogenous retroviruses at the root of some cancers

• co-founding the Stand Up To Cancer (SU2C) Epigenetics Dream Team and the Van Andel Research

Institute–Stand Up To Cancer Epigenetics Dream Team with Stephen Baylin, M.D.

We congratulate Peter on this well-deserved recognition.


ii Van Andel Research Institute | Scientific Report


Director's Introduction 1

Laboratory Reports

Center for Cancer and Cell Biology

Arthur S. Alberts, Ph.D. 6

Patrick J. Grohar, M.D., Ph.D. 7

Brian B. Haab, Ph.D. 9

Yuanzheng (Ajian) He, Ph.D. 11

Xiaohong Li, Ph.D. 12

Jeffrey P. MacKeigan, Ph.D. 14

Karsten Melcher, Ph.D. 16

Lorenzo F. Sempere, Ph.D. 18

Matthew Steensma, M.D. 21

George F. Vande Woude, Ph.D. 22

TABLE OF CONTENTS

Bart O. Williams, Ph.D. 24

Ning Wu, Ph.D. 26

H. Eric Xu, Ph.D. 27

Tao Yang, Ph.D. 29

Center for Epigenetics

Stephen B. Baylin, M.D. 32

Peter A. Jones, Ph.D., D.Sc. 33

Stefan Jovinge, M.D., Ph.D. 34

Peter W. Laird, Ph.D. 36

Gerd Pfeifer, Ph.D 38

Scott Rothbart, Ph.D. 40

Hui Shen, Ph.D. 43

Piroska E. Szabó, Ph.D. 44

Steven J. Triezenberg, Ph.D. 46

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Laboratory Reports continued

Center for Neurodegenerative Science

Lena Brundin, M.D., Ph.D. 50

Patrik Brundin, M.D., Ph.D. 52

Gerhard A. Coetzee, Ph.D. 54

Viviane Labrie, Ph.D. 55

Jiyan Ma, Ph.D. 57

Darren Moore, Ph.D. 58

Jeremy M. Van Raamsdonk, Ph.D. 60

Core Technologies and Services

Bryn Eagleson, B.S., RLATG

Vivarium and Transgenics Core 64

Scott D. Jewell, Ph.D.

Pathology and Biorepository Core 65

Heather Schumacher, B.S., MT(ASCP)

Flow Cytometry Core 67

Mary E. Winn, Ph.D.

Bioinformatics and Biostatistics Core 68

Confocal Microscopy and Quantitative Imaging Core 69

Small-Animal Imaging Facility 70

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Awards for Scientific Achievement

Jay Van Andel Award for Outstanding Achievement 72

in Parkinson’s Disease Research

Han-Mo Koo Memorial Award 73

Educational and Training Programs

Van Andel Institute Graduate School 75

Postdoctoral Fellowship Program 76

Internship Programs 77

VARI and Jay Van Andel Seminar Series 79

Organization

Boards 82

Office of the Chief Scientific Officer 83

Administrative Organization 84

VAI Organizational Structure 86

V


PETER A. JONES, Ph.D., D.SC.

CHIEF SCIENTIFIC OFFICER

VAN ANDEL RESEARCH INSTITUTE

Van Andel Research Institute | Scientific Report


VAN ANDEL RESEARCH INSTITUTE had strong growth and progress in the past year.

Most recently, in February 2016, Eric Xu was selected by The Protein Society for its

prestigious Hans Neurath Award, which is presented to "individuals who have made a recent

contribution of exceptional merit to basic protein research". The basis for this award was the

July 2015 article in Nature titled “Crystal structure of rhodopsin bound to arrestin determined

by femtosecond X-ray laser”. This project involved many international collaborators and an

intense effort by VARI's Xu and Melcher labs, and it produced a major advance in the field of

G protein–coupled receptors. We congratulate Eric on this well-deserved honor. We at VARI

are pleased at this recognition and proud to be his colleagues and collaborators.

Beyond that award-winning paper, our faculty had excellent publications success in 2015.

Three articles were selected as Notable Advances of 2015 by Nature Medicine: one on

heart cell regeneration coauthored by Stefan Jovinge published in Cell, and two others in

Cell on the DNA methyltransferase inhibitor 5-azacitidine, which stimulates an immune-like

inflammatory response in hindering tumor growth, coauthored by Peter Jones and by

Stephen Baylin.

Peter Laird and Hui Shen were coauthors on a series of papers published in Cell and the

New England Journal of Medicine coming out of work by the Cancer Genome Atlas Network.

Scott Jewell coauthored several papers in Science resulting from his deep involvement in

the Genotype-Tissue Expression (GTEx) project. And, Karsten Melcher and Eric Xu were

coauthors of a second Nature paper on signaling by the plant hormone jasmonate.

We look forward to continuing this strong record of publication in the best scientific journals.

FACULTY

In 2015 the Center for Epigenetics welcomed Scott

Rothbart, who will focus on understanding how histone

post-translational modifications and DNA methylation work

together to orchestrate the dynamic functions associated

with chromatin. The Center was also joined part-time

by Stephen Baylin, who is co-leader of the VARI-SU2C

Epigenetics Dream Team. He will continue his primary

appointment at Johns Hopkins and the Sidney Kimmel

Comprehensive Cancer Center.

Joining the Center for Neurodegenerative Science in 2015

was Gerhard Coetzee. Dr. Coetzee will use his expertise

with GWAS to uncover the roles of genetic risk variants in

Parkinson’s disease. Early in 2016, Dr. Jeffrey Kordower,

of Rush University Medical Center, began a part-time

appointment at VARI and will continue his collaboration

with Patrik Brundin. Also in early 2016, Viviane Labrie

arrived at VARI, and she will pursue her studies of the role of

epigenetics in Parkinson’s disease and Alzheimer’s disease.

Patrick Grohar joined the Center for Cancer and Cell

Biology in July 2015. His research and clinical work is on

Ewing sarcoma, a type of tumor that can occur in bone or

soft tissue.

1


EVENTS AND AWARDS

FUNDING

Research!America, the nation’s largest nonprofit public

education and advocacy alliance, which works to make

health research a higher national priority, named David Van

Andel and George Vande Woude its 2015 Advocacy Award

winners. The annual Research!America Advocacy Awards

program was established in 1996 to honor outstanding

advocates for medical, health, and scientific research.

Congratulations to both for a well-deserved recognition of

their years-long efforts.

Dr. Matt Steensma was one of two recipients of

the inaugural Francis S. Collins Scholars Award in

Neurofibromatosis Clinical and Translational Research.

The award was presented by Dr. Collins at VARI's NF1

Mini-Symposium in April 2015.

In May, Eric S. Lander, founding director of the Broad

Institute of MIT and Harvard University, was honored with

the Han-Mo Koo Award. He delivered both a scientific

seminar and a lay lecture in accepting the award for his

outstanding scientific achievements in genomics and the

Human Genome Project.

The Jay Van Andel Award for Outstanding Achievement

in Parkinson’s Disease Research was presented at the

September Grand Challenges in Parkinson's Disease

symposium held at VARI. The awardees were Maria Grazia

Spillantini, FMedSci, FRS, of the University of Cambridge,

and Robert Nussbaum, M.D., of the University of California,

San Francisco. In 1997, the two made related discoveries

that linked Parkinson's disease to the α-synuclein gene

and its protein, which have since been the focus of major

research efforts.

Also in 2015, VARI hosted the Michigan C. elegans

meeting (April); a joint USA/Netherlands biomedical

symposium, followed by a visit to VARI by His Majesty

King Willem-Alexander and Her Majesty Queen Máxima of

the Netherlands (June); the Origins of Cancer Symposium

"Beyond the Genome: The Role of Posttranslational

Modifications in Cancer" (July); and the International

Society for Tryptophan Research Conference (September).

Scott Jewell received a major multiyear grant from the

NIH's National Cancer Institute to support operations of

the VARI biorepository in serving as the Biospecimen Core

Resource for the NCI's Clinical Proteomic Tumor Analysis

Consortium. VARI also received part of a collaborative

NSF grant that will provide us with advanced networking

hardware to improve data storage and sharing.

Other 2015 funding awards to our researchers included

the following:

• An NCI R01 award to Jeffrey MacKeigan for

"Computational Model of Autophagy-Mediated

Survival in Chemoresistant Lung Cancer".

• An R01 award to Darren Moore for "Novel Mechanisms

of LRRK2-Dependent Neurodegeneration in

Parkinson's Disease". He also signed a new

agreement with a pharmaceutical firm.

• A Michigan Economic Development Corporation award

to Peter Jones to support two new epigenetics faculty

members and their research.

• An NCI K99/R00 grant to Scott Rothbart for

"Mechanisms Regulating DNA Methylation

Maintenance in Chromatin".

• An R21 award to Bart Williams for "Generation and

Initial Characterization of Osteocalcin-Deficient Rats".

• A Cure Parkinson's Trust award to Patrik Brundin

for "Preclinical Evaluation of Deuterium-Reinforced

Polyunsaturated Fatty Acids as a Therapeutic

Intervention for Parkinson's Disease".

We continue working in all areas toward even more success

in future years.

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CENTER FOR

CANCER AND CELL BIOLOGY

Bart O. Williams, Ph.D.

Director

The Center’s scientists study the basic

mechanisms and molecular biology of cancer and

other diseases, with the goal of developing better

diagnostics and therapies.

A depiction of arrestin binding by a phosphorylated and active rhodopsin.

The cell membrane lipids are shown as off-white, rhodopsin is blue, arrestin is red, and

phosphorus molecules are orange. The phosphorylated C-terminal tail of rhodopsin

binds to the N-domain (left) of the arrestin molecule. In the main contact region between

the two molecules (central), arrestin accommodates the ICL2 helix of rhodopsin. In this

fully activated state, the tip of arrestin’s C-domain contacts the membrane (right).

(Model by Parker de Waal of the Xu lab)

5


ARTHUR S. ALBERTS, PH.D.

Dr. Alberts earned his degrees in biochemistry and cell biology

(B.A., 1987) and in physiology and pharmacology (Ph.D., 1993)

from the University of California, San Diego. He joined VARI in

January 2000, and he was promoted to Professor in 2009.

STAFF

SARAH VANOEVEREN, B.S., B.S.

STUDENT

ANDREW HOWARD, B.A.

VISITING SCIENTIST

JULIE TURNER, PH.D.

RESEARCH INTERESTS

Our lab seeks to gain a full understanding of how cells spatially and temporally organize

the biochemical circuits that govern responses to injury, infection, and age. Our goal

is to use this information to guide the development of pharmacological agents that

block the acquisition of cancer traits. In 2015, we focused our translational research

on targeted therapies that reinforce and/or repair blood cell structure and function and

otherwise impair the ability of cancer cells to metastasize.

RECENT PUBLICATIONS

Vargas, Pablo, Paolo Maiuri, Marine Bretou, Pablo J. Sáez, Paolo Pierobon, Mathieu Maurin, Mélanie Chabaud, Danielle Lanakar,

Dorian Obino, et al. 2016. Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells.

Nature Cell Biology 18(1): 43–53.

Arden, Jessica D., Kari I. Lavik, Kaitlin A. Rubinic, Nicolas Chiaia, Sadik A. Khuder, Marthe J. Howard, Andrea L. Nestor-Kalinoski,

Arthur S. Alberts, and Kathryn M. Eisenmann. 2015. Small molecule agonists of mammalian Diaphanous-related (mDia) formins

reveal an effective glioblastoma anti-invasion strategy. Molecular Biology of the Cell 26(21): 3704–3718.

Ercan-Sencicek, A. Gulhan, Samira Jambi, Daniel Franjic, Sayoko Nishimura, Mingfeng Li, Paul El-Fishawy, Thomas M. Morgan,

Stephan J. Sanders, Kaya Bilguvar, Mohnish Suri, et al. 2015. Homozygous loss of DIAPH1 is a novel cause of microcephaly in

humans. European Journal of Human Genetics 23(2): 165–172.

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PATRICK J. GROHAR, M.D., PH.D.

Dr. Grohar earned his Ph.D. in chemistry and his M.D. from Wayne

State University. He joined VARI in 2015 as an Associate Professor,

and he has clinical and research responsibilities at Spectrum Health

and Michigan State University, respectively.

STAFF

MATT EASTON

SUSAN GOOSEN, B.S., M.B.A.

MATT HARLOW, M.S.

DIANA LEWIS, A.S.

RESEARCH INTERESTS

Our laboratory studies pediatric sarcomas, and our goal is to develop novel, molecularly

targeted therapies and to translate those therapies into the clinic. Most pediatric

sarcomas are characterized by oncogenic transcription factors formed by chromosomal

translocations. In many cases, the tumors depend on the continued expression and

activity of those transcription factors for cell survival, but few therapies that directly

target specific factors have achieved clinical efficacy. Therefore, we are developing new

approaches to target those transcription factors.

To date, we have focused on targeting the EWS-FLI1 transcription factor in Ewing

sarcoma. EWS-FLI1 is an oncogenic transcription factor formed by the t(11;22)(q24;12)

chromosomal translocation that leads to the fusion of the EWSR1 and FLI1 genes. The

result is a dysregulated transcription factor that alters the expression of over 500 genes

and drives tumorigenesis and progression. Several independent studies have shown

that silencing of EWS-FLI1 is incompatible with Ewing sarcoma cell survival. By directly

targeting EWS-FLI1, we hope to eliminate its activity as the dominant oncogene in this

tumor and thus improve patient survival.

Trabectedin (ET-743; ecteinascidin 743; Yondelis) is a natural product originally isolated

from the sea squirt, Ectenascidia turbinata. We became interested in this compound

because early clinical studies suggested that translocation-positive sarcomas were

sensitive to it. We subsequently demonstrated that trabectedin blocks EWS-FLI1 activity

at the promoter, mRNA, and protein levels of expression. In addition, we demonstrated

on a genome-wide scale that it reverses the expression of the gene signature of EWS-

FLI1. However, the compound failed in a phase II study on Ewing sarcoma.

CENTER FOR CANCER AND CELL BIOLOGY

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Subsequently, our work has focused on characterizing the

mechanism of EWS-FLI1 suppression with the goals of

understanding the failure in the phase II study, identifying

second-generation trabectedin analogs, and developing

new mechanism-based combination therapies. We have

developed a novel combination therapy of trabectedin

plus irinotecan that is synergistic. We have shown that

this combination markedly improves the suppression of

EWS-FLI1 and substantially increases the DNA damage

in Ewing sarcoma cells. We translated this therapy into

the clinic in Europe and found it was active in a patient in

Italy and in a series of patients in Germany (manuscript

in preparation). Since the drug is now approved in the

United States, we are writing a phase II protocol for this

combination therapy for the Children’s Oncology Group,

which will open nationwide for patients with relapsed

Ewing sarcoma.

Over the past year, we have characterized the mechanism

of EWS-FLI1 suppression by trabectedin, and we have

shown that mechanism is not effective at the serum

concentrations achieved in the failed phase II study,

explaining the lack of activity. More importantly, we have

identified a second-generation compound with an improved

pharmacokinetic profile that will make successful EWS-FLI1

suppression more likely, and we are working to translate

this compound to the clinic.

We have also extensively studied mithramycin, which

reverses EWS-FLI1 activity and blocks the expression of

key downstream targets. In a phase I/II trial at the National

Cancer Institute, we found that mithramycin did not achieve

serum levels high enough to block EWS-FLI1 activity. Over

the past year, our work has identified two compounds with

an improved clinical profile, one that is more potent and

another that is less toxic than the parent compound. Both

compounds reverse EWS-FLI1 activity and are extremely

active in xenograft models of Ewing sarcoma. Work

continues to understand the mechanism of EWS-FLI1

suppression for this class of compounds.

We are also taking a broader look at transcription as a

Ewing sarcoma drug target, using an siRNA screening

platform. We have identified a therapeutic vulnerability

based on alternative mRNA splicing, and we are developing

companion biomarkers that will accompany our trials and

aid in the clinical translation of our EWS-FLI1-directed

therapies. We have also identified a commonly employed

positron emission tomography (PET) radiotracer that

reflects EWS-FLI1 activity in Ewing sarcoma cells, which will

allow more precise dosing of our therapies and the direct

correlation of EWS-FLI1 activity to PET activity. Finally,

we are beginning to expand our studies to other pediatric

tumors characterized by oncogenic fusion transcription

factors.

RECENT PUBLICATIONS

Caropreso, Vittorio, Emad Darvishi, Thomas J. Turbyville, Ranjala Ratnayake, Patrick J. Grohar, James B. MacMahon, and Girma

Woldenmichael. In press. Englerin A inhibits EWS-FLI1 DNA binding in Ewing’s sarcoma cells. Journal of Biological Chemistry.

Osgood, Christy L., Nichole Maloney, Christopher G. Kidd, Susan Kitchen-Goosen, Laura Segars, Meti Gebregiorgis, Girma M.

Woldemichael, Min He, Savita Sankar, et al. In press. Identification of mithramycin analogs with improved targeting of the EWS-

FLI1 transcription factor. Clinical Cancer Research.

Kovar, Heinrich, James Amatruda, Erika Brunet, Stefan Burdach, Florencia Cidre-Aranaz, Enrique de Alava, Uta Dirksen, Wietske

van der Ent, Patrick Grohar, et al. 2016. The second European interdisciplinary Ewing sarcoma research summit — a joint effort

to deconstructing the multiple layers of a complex disease. Oncotarget 7(8): 8613–8624.

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BRIAN B. HAAB, PH.D.

Dr. Haab obtained his Ph.D. in chemistry from the University of

California at Berkeley in 1998. He joined VARI as a Special Program

Investigator in 2000, became a Scientific Investigator in 2004, and is

now a Professor.

STAFF

STEPHANIE GRANT, M.P.A.

KATIE PARTYKA, B.S.

BRYAN REATINI, B.S.

SUDHIR SINGH, PH.D.

JESSICA SINHA, M.S.

HUIYUAN TANG, PH.D.

RESEARCH INTERESTS

The promise of molecular biomarkers: improving patient outcomes through better

detection and subtyping.

Tests to detect and diagnose pancreatic cancer

STUDENTS

DANIEL BARNETT, B.A., B.S.

LELAND DUNWOODIE

ELLIOT ENSINK

PETER HSUEH, B.S.

JOEY KRETOWICZ

GARIMA VORHA, B.SC., M.B.A.

The successful treatment of pancreatic cancer critically depends on achieving an

accurate and early diagnosis, but this can be frustratingly difficult. Conventional

methods of evaluating patients—assessing scans, visual inspection of cells from a

biopsy, and weighing behavioral, health, and demographic data—do not have the detail

necessary to distinguish between benign and malignant disease or between cancers

with vastly different behaviors. Sometimes a physician can see a mass or other unusual

feature in the pancreas but is unsure what it is. Is it benign or cancerous? And if it is

cancer, what is the best course of treatment?

Our research builds on the concept that molecular-level information will provide

details about a condition that are not observable by conventional methods. Molecular

biomarkers could provide such information and enable physicians to make accurate

diagnoses and develop optimal treatment plans. We are making progress toward this

goal for pancreatic cancer. For example, in recent publications in Molecular and Cellular

Proteomics and the Journal of Proteome Research, we disclosed carbohydrate-based

biomarkers in the blood serum that improve upon the widely used blood test called

CA19-9. By using a panel of three or more independent biomarkers, we detected a

greater percentage of cancers than we could with any individual biomarker. We are

seeking to substantiate those findings and to evaluate their clinical value using serum

samples from several clinical sites.

CENTER FOR CANCER AND CELL BIOLOGY

9


Other research is aimed at further improving the biomarker

tests. The results so far suggest that each individual

biomarker arises from a distinct subpopulation of cancer

patients and from a characteristic cell type. This finding is

important because the biomarkers may reveal differences

between subgroups of tumors—a possibility we are

exploring in the research described below. For the purpose

of improving our blood tests, determining the characteristics

of the cells that produce each biomarker, as well as of the

cells that do not produce any of our biomarkers, will help to

optimize a blood test to accurately identify cancers across

the entire spectrum of patients.

The ultimate goal is to get the new tests established in

clinical laboratories in order to benefit patients. To that

end, we are working with industry partners to transfer our

biomarker assays to the clinical laboratory setting and to

begin analyzing patient samples received consecutively

from clinical sites. If we have good results, we hope to

initiate clinical trials for the diagnosis of pancreatic cancer

and, eventually, for evaluations of surveillance among

people at elevated risk for pancreatic cancer.

Better treatment through subtyping

Pancreatic cancer characteristics, such as the cell types

within the tumor, the amount of metastasis, the responses

to treatments, and overall outcomes, vary greatly among

patients. So far, identifying the underlying causes of such

differences and predicting the behavior of individual tumors

have not been possible. If we could determine what drives

the differences between the tumors or identify molecules

that help predict the behavior of each tumor, we could

establish better treatment plans for each patient or

determine the drugs that work best against each subtype.

Our research is revealing major groupings of tumors

based on the carbohydrates on the surface of, and in

the secretions from, cancer cells. The carbohydrates are

related to the CA19-9 antigen and have distinct biological

functions. In current research we want to determine the

molecular nature of the subgroups of cells and whether

the subgroups have different levels of aggressiveness or

different responses to particular drugs. We are using new

approaches for measuring carbohydrates and proteins

in tumor tissue, and we are employing powerful new

software—introduced in our recent publication in Analytical

Chemistry—to examine the cell types that produce

each carbohydrate-based biomarker. We are using that

information to evaluate whether certain types of cells

predict clinical behavior. As advances and new options

in treatments become available, this type of research is

increasingly important for guiding clinical decisions. We

are working closely with our physician collaborators to

evaluate on a case-by-case basis the value of the molecular

information and to guide our research toward improving the

tests. Ultimately, physicians could use the molecular tests

on material from biopsies, surgical resections, or blood

samples.

RECENT PUBLICATIONS

Ensink, Elliot, Jessica Sinha, Arkadeep Sinha, Huiyuan Tang, Heather M. Calderone, Galen Hostetter, Jordan Winter, David

Cherba, Randall E. Brand, et al. 2015. Segment and fit thresholding: a new method for image analysis applied to microarray and

immunofluorescence data. Analytical Chemistry 87(19): 9715–9721.

Singh, Sudhir, Kuntal Pal, Jessica Yadav, Huiyuan Tang, Katie Partyka, Doron Kletter, Peter Hsueh, Elliot Ensink, Birendra KC, et

al. 2015. Upregulation of glycans containing 3' fucose in a subset of pancreatic cancers uncovered using fusion-tagged lectins.

Journal of Proteome Research 14(6): 2594–2605.

Tang, Huiyuan, Sudhir Singh, Katie Partyka, Doron Kletter, Peter Hsueh, Jessica Yadav, Elliot Ensink, Marshall Bern, Galen

Hostetter, et al. 2015. Glycan motif profiling reveals plasma sialyl-Lewis X elevations in pancreatic cancers that are negative for

CA19-9. Molecular & Cellular Proteomics 14(5): 1323–1333.

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YUANZHENG (AJIAN) HE, PH.D.

Dr. He earned his Ph.D. from the Chinese Academy of Sciences’

Shanghai Institute of Biochemistry in 2000. In 2008, he was

recruited to Van Andel Research Institute, where he is currently

a Research Assistant Professor.

RESEARCH INTERESTS

Ligand binding is the key event that triggers intracellular signal transduction cascades,

and it is also a major focus of drug discovery. My research involves the structural basis

of ligand/receptor interactions and related drug discovery, focusing on steroid hormone

receptors, specifically, the glucocorticoid receptor and the G protein–coupled receptors

(GPCRs). My overall goal is to explore structural insights into receptor signaling and

use them to design precision drugs that specifically deliver the desired treatment effect,

but not unwanted side effects, to patients. Over the past year, we have made the

following progress.

• We have developed “dissociated glucocorticoid” molecules based on our

finding that the dissociation of transrepression from transactivation can be

achieved by interfering with the dimerization interface of the glucocorticoid

receptor.

• We have developed an exceptionally potent glucocorticoid for asthma

treatment based on our uncovering of the structural key to glucocorticoid

potency. Our primary compound outperforms the current leading drug in a

mouse asthma model and promises a better side-effects profile.

• We have determined the structure of arrestin-bound rhodopsin, which provides

a basis for understanding GPCR-mediated arrestin-biased signaling.

RECENT PUBLICATIONS

Kang, Yanyong, Xiang Gao, X. Edward Zhou, Yuanzheng He, Karsten Melcher, and H. Eric Xu. 2016. A structural snapshot of the

rhodopsin–arrestin complex. FEBS Journal 283(5): 816–821.

He, Yuanzheng, Jingjing Shi, Wei Yi, Xin Ren, Xiang Gao, Jianshuang Li, Nanyan Wu, Kevin Weaver, Qian Xie, et al. 2015.

Discovery of a highly potent glucocorticoid for asthma treatment. Cell Discovery 1: 15035.

Zhi, Xiaoyong, X. Edward Zhou, Yuanzheng He, Kelvin Searose-Xu, Chun-Li Zhang, Chih-Cheng Tasi, Karsten Melcher, and H.

Eric Xu. 2015. Structural basis for corepressor assembly by the orphan nuclear receptor TLX. Genes and Development 29(4):

440–450.

CENTER FOR CANCER AND CELL BIOLOGY

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XIAOHONG LI, PH.D.

Dr. Li received her Ph.D. from the Institute of Zoology, Chinese

Academy of Sciences, in Beijing in 2001. She joined VARI as an

Assistant Professor in September 2012.

STAFF

PAUL G. DAFT, PH.D.

SOURIK GANGULY, PH.D.

DIANA LEWIS, A.S.

NEIL (XIANGQI) MENG, PH.D.

ALEXANDRA VANDER ARK, M.S.

JIE WANG, M.D.

QI ZENG, M.D.

RESEARCH INTERESTS

Our laboratory is committed to understanding tumor dormancy and cancer bone

metastases, specifically of breast, lung, and prostate cancers. Our long-term goal is to

create a dormancy-permissive bone microenvironment so that cancer cells can be kept

dormant or be killed while they are in that state.

Project 1. Cell-specific roles of transforming growth factor (TGF)-β in bone metastases.

STUDENTS

AUSTIN M. MEADOWS

GHADA Y.T. MOHSEN

ERICA WOODFORD

Most people who die of cancer have metastases somewhere in their body, but

metastases of certain cancers, particularly of the breast, lung, or prostate, are more

likely to be found in bone. Cancer cells in bone induce either osteolytic (bone

resorption) or osteoblastic (abnormal bone formation) lesions, which can cause

fractures, spinal cord compression, hypercalcemia, and extreme bone pain. Current

treatments for bone-metastasis patients can reduce symptoms such as pain but do not

increase survival. Better understanding of the mechanism of bone metastasis is needed

in order to develop early diagnostic tests and targeted therapeutic strategies. The local

events of bone lesion development are determined by the interactions of cancer cells

with bone cells such as osteoblasts (mesenchymal lineage) and osteoclasts (myeloid

lineage), and such events are regulated by growth factors and cytokines of the bone

matrix. The cytokine TGF-β plays crucial roles in both cancerous and healthy bone, and

its effects are highly context-dependent, spatially and temporally. We aim to delineate

the cell-specific role of TGF-β in bone metastasis and identify downstream mediators

that can be targeted by new therapies.

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Our studies have produced the following results.

• Basic fibroblast growth factor (bFGF), mediated

by TGF-β signaling in cells of the myeloid lineage,

promotes breast cancer bone metastasis. By

blocking bFGF, we can reduce such bone lesion

development. In bone metastatic tissues from

breast cancer patients, TGF-β and bFGF signaling

are likely to be activated in osteoclasts and cancer

cells but inactivated in osteoblasts.

• TGF-β signaling in myeloid lineage cells promotes

bone metastasis, but in cells of the mesenchymal

lineage, the same signaling inhibits bone

metastasis. We have found that bFGF is the

functional mediator for TGF-β signaling effects only

in cells of the myeloid lineage.

Project 2. TGF-β signaling in the bone microenvironment

affects tumor dormancy.

Up to 70% of cancer patients have tumor cells in the

bone marrow at the time of initial diagnosis. It is not

known how cancer cells in bone remain dormant and later

reactivate. Understanding tumor dormancy is important

in trying to prevent the metastatic recurrences that kill

patients. Studies have shown that external cues from

the bone microenvironment can determine tumor cell

dormancy. We aim to create a dormancy-permissive bone

microenvironment and determine the mechanism by which

it supports cancer cell dormancy. We have established a

system in which loss of TGF-β signaling in myeloid lineage

cells may promote the dormancy of prostate cancer or

NSCLC in the bone marrow. We are now studying the

underlying mechanism.

• The cell-specific roles of TGF-β signaling are more

complex for bone metastasis of non-small-cell

lung cancer (NSCLC). The effects are dependent

on the types of bone lesions that are produced by

different NSCLC tumors.

RECENT PUBLICATIONS

Meng, X., A. Vander Ark, P. Lee, G. Hostetter, N.A. Bhowmick, L.M. Matrisian, B.O. Williams, C.K. Miranti, and X. Li. 2016.

Myeloid-specific TGF-β signaling in bone promotes basic-FGF and breast cancer bone metastasis. Oncogene 35(18): 2370-2378.

CENTER FOR CANCER AND CELL BIOLOGY

13


JEFFREY P. MACKEIGAN, PH.D.

Dr. MacKeigan received his Ph.D. in microbiology and immunology at

the University of North Carolina Lineberger Comprehensive Cancer

Center in 2002. Dr. MacKeigan joined VARI in 2006 as an Assistant

Professor and was promoted to Associate Professor in 2010.

STAFF

STEPHANIE CELANO, M.S.

LUCUS CHAN, PH.D.

KRISTIN DITTENHAFER-REED, PH.D.

NICOLE DOPPEL, B.S.

MATT KORTUS, M.S.

KATIE MARTIN, PH.D.

JOSH SCHIPPER, PH.D.

KELLIE SISSON, B.S.

STUDENTS

ADITI BAGCHI, M.D.

ANNALISE BOWEN

DANIELLE BURGENSKE, PH.D.

LELAND DUNWOODIE

NATE MERRILL, B.S.

NANDA KUMAR SASI, B.S.

ABIGAIL SOLITRO, B.S.

MEGAN VANBAREN

RESEARCH INTERESTS

The MacKeigan lab focuses on two hallmarks of cancer: the deregulation of cellular

energetics and resistance to cell death. These hallmarks are regulated by mTOR

signaling and contribute significantly to drug resistance in cancer. We seek a

systems-level understanding of the network that encompasses the cell metabolism and

autophagy signaling pathways. While our research focuses on human cancers, we also

apply our tumor biology expertise and pathway knowledge to study tuberous sclerosis

complex. Our laboratory uses cutting-edge tools and collaborates with multidisciplinary

experts for robust experimental design and comprehensive data analysis. All of our

research projects have one common goal: to identify novel therapeutic targets.

Autophagy and resistance to cell death

The process of autophagy functions to generate energy, clear damaged organelles,

and delay or prevent cell death during times of cellular stress. Chemotherapeutic

agents trigger autophagy, which allows cancer cells to adapt and withstand treatment.

Therefore, a better understanding of autophagy is crucial for developing new and

improved treatment strategies against cancer.

ADJUNCT FACULTY

BRIAN LANE, M.D., PH.D.

In partnership with Los Alamos National Laboratory, our lab has used predictive

computational modeling and cell-based measurements to accurately model the

autophagic process. We are pleased to report that we have received a collaborative

National Cancer Institute R01 award to validate and extend this model. The current

efforts to enhance our model will help us predict the therapeutic benefit of inhibiting

autophagy in cancer. We are also working with industry partners to determine the

effects of candidate drugs on autophagic flux, and we have identified novel genes

that are required for drug-induced autophagy. Lastly, our group conducts optimized

kinase and phosphatase assays for in vitro evaluation of compounds identified in silico.

Our research suggests that kinase inhibitors modulate autophagy and may be more

selective and effective than current lysosomotropic agents.

14 Van Andel Research Institute | Scientific Report


Cancer metabolism and dysregulated cellular

energetics

Aggressive cancers are well known for their altered

metabolic profiles and ability to withstand cytotoxic

therapies. Thus, defining the relationship between

dysregulated metabolism and evasion of apoptosis

represents a critical need in the cancer field.

Our research has shown that increased glycolysis in cancer

cells leads to significant enrichment of the mitochondrial

lipid cardiolipin, which serves many important functions in

maintaining mitochondrial health. Most intriguing is its role

in preventing the release of cytochrome c, a key event in the

initiation of apoptosis. Our results suggest that the altered

metabolic program of cancer cells may inherently support

the evasion of apoptosis through cardiolipin production.

We are investigating whether increased cardiolipin allows

cancer cells to avoid death and resist chemotherapy. We

have partnered with experts in glioblastoma multiforme and

lipid mass spectrometry to uncover the mechanisms that

may underlie cardiolipin’s ability to promote cell survival. A

more complete understanding of the synthesis of cardiolipin

and how changes in its concentration regulate cytochrome

c release will contribute toward new mitochondria-targeted

therapeutics for chemoresistant cancers.

Pathway of Hope

Tuberous sclerosis complex (TSC) is a genetic disease

resulting from mutations in the TSC1 and TSC2 genes.

These mutations inactivate the genes’ tumor-suppressive

function, driving tumor cell growth and causing

noncancerous tumors in vital organs such as the brain, skin,

eyes, lung, and heart. These tumors can cause a host of

health issues, including epilepsy and autism.

Using chemical screening techniques, we are identifying

approved, targeted compounds as possible therapies for

TSC. Our lab is also characterizing the genomic landscape

of TSC tumors using next-generation sequencing. We

have gained a comprehensive understanding of TSC tumor

biology, and we are seeking other cellular changes that

can be targeted by therapies. TSC tumors are not always

associated with second-hit somatic mutations to TSC1

or TSC2, suggesting that their pathogenesis may involve

other genetic events, which we are working to uncover. We

are also developing preclinical models of TSC for future

validation studies of our drug candidates and genomic

findings. Lastly, we have partnered with physician-scientists

expert in TSC to determine whether precision medicine

approaches can inform treatment strategies for TSC and

predict patient outcomes.

RECENT PUBLICATIONS

Solitro, Abigail R., and Jeffrey P. MacKeigan. 2016. Leaving the lysosome behind: novel developments in autophagy inhibition.

Future Medicinal Chemistry 8(1): 73–86.

MacKeigan, Jeffrey P., and Darcy A. Krueger. 2015. Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment

of tuberous sclerosis complex. Neuro-Oncology 17(12): 1550–1559.

Szymańska, Paulina, Katie R. Martin, Jeffrey P. MacKeigan, William S. Hlavacek, and Tomasz Lipniacki. 2015. Computational

analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1. PLoS One 10(3): e0116550.

Wang, Tong, Megan L. Goodall, Paul Gonzales, Mario Sepulveda, Katie R. Martin, Stephen Gately, and Jeffrey P. MacKeigan.

2015. Synthesis of improved lysomotropic autophagy inhibitors. Journal of Medicinal Chemistry 58(7): 3025–3035.

CENTER FOR CANCER AND CELL BIOLOGY 15


KARSTEN MELCHER, PH.D.

Dr. Melcher earned his Master’s degree in biology and his Ph.D. degree

in biochemistry from the Eberhard Karls Universität in Tübingen,

Germany. He was recruited to VARI in 2007, and in 2013 he was

promoted to Associate Professor.

STAFF

STEPHANIE GRANT, M.P.A.

XIN GU, M.S.

JIYUAN KE, PH.D.

AMANDA KOVACH, B.S.

EDWARD ZHOU, PH.D.

RESEARCH INTERESTS

Our laboratory studies the structure and function of proteins that have central roles

in cellular signaling. To do so, we employ X-ray crystallography in combination with

biochemical and cellular methods to identify structural mechanisms of signaling at high

resolution.

STUDENT

CHRISTIAN CAVACECE

In addition to their fundamental physiological roles, most signaling proteins are also

important targets of therapeutic drugs. Determination of the three-dimensional

structures of protein–drug complexes at atomic resolution allows a detailed

understanding of how a drug binds its target and modifies its activity. This knowledge

allows the rational design of new and better drugs against diseases such as cancer,

diabetes, and neurological disorders.

Three areas of focus in the lab are the adenosine monophosphate (AMP)–activated

protein kinase (AMPK); the receptors and key signaling proteins for a plant hormone,

abscisic acid (ABA); and the folate receptors.

AMP-activated protein kinase (AMPK)

Cells use ATP to drive cellular processes such as muscle contraction, cell growth, and

neuronal excitation. AMPK is a three-subunit protein kinase that functions as an energy

sensor and regulator of homeostasis in human cells. Its kinase activity, triggered by

energy stress (i.e., a drop in the ratio of ATP to AMP/ADP), activates ATP-generating

pathways and reduces energy-consuming metabolic pathways and cell proliferation.

To adjust energy balance, AMPK regulates

• almost all cellular metabolic processes (activation of ATP-generating pathways

such as glucose and fatty acid uptake and catabolism, and inhibition of

energy-consuming pathways such as the synthesis of glycogen, fatty acids,

cholesterol, proteins, and ribosomal RNA);

16 Van Andel Research Institute | Scientific Report


• whole-body energy balance (appetite regulation in

the hypothalamus via leptin, adiponectin, ghrelin,

and cannabinoids); and

• many nonmetabolic processes (cell growth and

proliferation, mitochondrial homeostasis, autophagy,

aging, neuronal activity, and cell polarity).

Because of its central roles in the uptake and metabolism

of glucose and fatty acids, AMPK is an important

pharmacological target for treating diabetes and obesity.

Moreover, AMPK activation restrains the growth and

metabolism of tumor cells and has thus become an exciting

new target for cancer therapy. In this project we strive to

determine the structural mechanisms of AMPK regulation

by direct binding of AMP, ADP, ATP, drugs, and glycogen,

in order to provide a structural framework for the rational

design of new therapeutic AMPK modulators.

Abscisic acid

Abscisic acid (ABA) is an ancient signaling molecule found

in plants, fungi, and metazoans ranging from sponges to

humans. In plants, ABA is an essential hormone and is

also the central regulator protecting plants against abiotic

stresses such as drought, cold, and high salinity. These

stresses—most prominently, the scarcity of fresh water—are

major limiting factors in crop production and therefore

major contributors to malnutrition. Malnutrition affects an

estimated one billion people and contributes to more than

50% of human disease worldwide, including cancer and

infectious diseases.

We have determined the structure of ABA receptors in their

free state and while bound to ABA. Using computational

receptor-docking experiments, we have identified and

verified synthetic small-molecule receptor activators as

new chemical scaffolds toward the development of new,

environmentally friendly, and affordable compounds that

will protect plants against abiotic stresses. We have

also identified the structural mechanism of the core ABA

signaling pathway, which will allow modulation of this

pathway through genetic engineering of crop plants.

Folate receptors

Folic acid and its derivatives are one-carbon donors

required for the synthesis of DNA. Rapidly dividing cells

such as cancer cells require rapid DNA synthesis and

are therefore selectively dependent on high folate levels.

This vulnerability has been therapeutically exploited since

the 1940s, when toxic folate analogs (antifolates) were

used as the first chemotherapeutic agents. However,

current antifolates have severe side effects such as

immunosuppression, nausea, and hair loss, because they

also kill nonmalignant proliferative cells.

Cells can take up folates in two main ways: by a ubiquitous,

high-capacity, low-affinity uptake system known as RFC

(reduced folate carrier) and by folate receptors. The latter

are cysteine-rich cell surface glycoproteins that allow

high-affinity uptake of folates by endocytosis but do not

take up the current antifolate drugs. While folate receptors

are expressed at very low levels in most tissues, they

are “hijacked” and expressed at high levels in numerous

cancers. This selective expression has been therapeutically

and diagnostically exploited by administering antibodies

against folate receptor α, folate-based imaging agents,

and folate-conjugated drugs and toxins. We expect that

antifolates that can be taken up by folate receptors but not

by the RFC would have greatly reduced side effects.

We have determined the structure of folate receptor α

in complex with folic acid. The structure, validated by

systematic mutations of pocket residues and quantitative

folic acid binding assays, has provided a detailed map of

the extensive interactions between folic acid and FRα. It

provides a structural framework for the design of new

antifolates that are selectively taken up by folate receptors.

Our short-term goal is to determine the structures of novel,

preclinical chemotherapeutic antifolates, bound to folate

receptors and bound to the folate-metabolizing enzymes

they inhibit, as a step toward designing antifolates that

selectively target cancer cells.

RECENT PUBLICATIONS

Kang, Yanyong, X. Edward Zhou, Xiang Gao, Yuanzheng He, Wei Liu, Andrii Ishchenko, Anton Barty, Thomas A. White, Oleksandr

Yefanov, et al. 2015. Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature 523(7562): 561–567.

Ke, Jiyuan, Honglei Ma, Xin Gu, Adam Thelen, Joseph S. Brunzelle, Jiayang Li, H. Eric Xu, and Karsten Melcher. 2015. Structural

basis for recognition of diverse transcriptional repressors by the TOPLESS family of corepressors. Science Advances 1: 21500107.

CENTER FOR CANCER AND CELL BIOLOGY 17


LORENZO F. SEMPERE, PH.D.

Dr. Sempere obtained his B.S. in biochemistry at Universidad Miguel

Hernández, Elche, Spain, and earned his Ph.D. at Dartmouth under

Victor Ambros. He joined VARI in January 2014 as an Assistant Professor.

STAFF

HEATHER CALDERONE, PH.D.

STEPHANIE GRANT, M.P.A.

JENNI WESTERHUIS, M.S.ED., M.S.

STUDENTS

SHAYNA DONOGHUE

DANIELA GOMEZ, B.S.

ALYSSA SHEPARD

RESEARCH INTERESTS

Our laboratory pursues complementary lines of translational research to explain

the etiological role of microRNAs and to unravel microRNA regulatory networks

during carcinogenesis. We mainly investigate these questions in clinical samples

and preclinical models of breast cancer and pancreatic cancer. MicroRNAs can

regulate and modulate the expression of hundreds of target genes, some of which are

components of the same signaling pathways or biological processes. Thus, functional

modulation of a single microRNA can affect multiple target mRNAs (i.e., one drug,

multiple hits), unlike therapies based on small interfering RNAs, antibodies, or smallmolecule

inhibitors.

The laboratory has active projects in the areas of cancer biology and tumor

microenvironment, with a translational focus on molecular and cellular heterogeneity

and its clinical implications for improving diagnostic applications and therapeutic

strategies. Our knowledge of microRNAs is integrated into collaborative efforts with

VARI researchers and cores, as well as into new technologies being developed for

microRNA studies. Recent work includes the following.

We use innovative multiplexed immunohistochemical/in situ hybridization assays to

implement diagnostic applications of microRNA biomarkers. Because tissue samples

are the direct connection between cancer research and cancer medicine, detailed

molecular/cellular characterization of tumors provides the opportunity to translate

scientific knowledge into useful clinical information.

• Clinically validate tumor compartment–specific expression of the microRNA

miR-21 as a prognostic marker for breast cancer. There is a focused interest

in stromal expression of miR-21 in triple-negative breast cancer, for which

prognostic markers and effective targeted therapies are lacking.

18 Van Andel Research Institute | Scientific Report


• Develop integrative diagnostics for pancreatic

cancer and precursor lesions using information

from studies of cancer-associated microRNAs

and protein glycosylation. Integrating the data

from both microRNAs and protein markers should

enhance diagnostic power and interpretation.

• Implement new technological platforms for

high-content, tissue-based marker analysis.

Our goal is a fully automated pipeline from

tissue stain to image analysis that we can use to

characterize tumor features and to study tumor

compartment–specific events, such as molecular

changes in cancer cells, paracrine signaling by

tumor-associated fibroblasts, and anti-tumor

immune cell responses.

Molecular biology and cellular biology studies help to

identify microRNA targets and regulatory networks.

• Develop methods for isolating microRNA/target

mRNA interactions in in vitro and in vivo systems.

• In preclinical models and clinical specimens,

identify tumor compartment–specific target

networks that are regulated by microRNAs.

• Evaluate tumor compartment–specific delivery

of synthetic modulators of microRNA activity in

preclinical cancer models and patient-derived

cells.

Genetic engineering of models lets us assess the role of

microRNAs within tumor microenvironment compartments.

• In animal models of breast and pancreatic

cancers, evaluate the miR-21 activity required in

cancer cell and tumor stroma compartments to

support aggressive and metastatic features.

• In preclinical models of pancreatic cancer,

replenish miR-155 immunostimulatory activity in

combination with immune checkpoint regulators to

boost anti-tumor immunity.

RECENT PUBLICATIONS

Andrew, Angeline S., Carmen J. Marsit, Alan R. Schned, John D. Seigne, Karl T. Kelsey, Jason H. Moore, Laurent Perreard,

Margaret R. Karagas, and Lorenzo F. Sempere. 2015. Expression of tumor suppressive microRNA-34a is associated with a

reduced risk of bladder cancer recurrence. International Journal of Cancer 137(5): 1158–1166.

Ensink, Elliot, Jessica Sinha, Arkadeep Sinha, Huiyuan Tang, Heather M. Calderone, Galen Hostetter, Jordan Winter, David

Cherba, Randall E. Brand, et al. 2015. Segment and fit thresholding: a new method for image analysis applied to microarray and

immunofluorescence data. Analytical Chemistry 87(19): 9715–9721.

Graveel, Carrie R., Heather M. Calderone, Jennifer J. Westerhuis, Mary E. Winn, and Lorenzo F. Sempere. 2015. Critical analysis

of the potential for microRNA biomarkers in breast cancer management. Breast Cancer: Targets and Therapy 7: 59–79.

Machiela, Emily, Anthony Popkie, and Lorenzo F. Sempere. 2015. Individual noncoding RNA variations: their role in shaping and

maintaining the epigenetic landscape. In Personalized Epigenetics, Trygve Tollefsbol, ed. Waltham, Massachusetts: Academic

Press, pp. 84–122.

CENTER FOR CANCER AND CELL BIOLOGY 19


Prostate epithelial cells expressing a Pten mutant (C124S) were differentiated for 18 days under suboptimal conditions.

Androgen receptor (red) in the luminal cells and integrin α6 (green) in the basal cells were visualized by immunostaining and

fluorescence microscopy. Image by Mclane Watson.

20 Van Andel Research Institute | Scientific Report


MATTHEW STEENSMA, M.D.

Dr. Steensma received his B.A. from Hope College and his M.D. from

Wayne State University School of Medicine in Detroit. Dr. Steensma

is a practicing surgeon in the Spectrum Health Medical Group, and

he joined VARI as an Assistant Professor in 2010.

STAFF

CURT ESSENBURG, B.S., LATG

PATRICK DISCHINGER, B.S.

DIANA LEWIS, A.S.

MARIE MOONEY, M.S.

MATT PRIDGEON, M.D.

RESEARCH INTERESTS

Our laboratory conducts research into new treatment strategies for sarcomas.

Specifically, we are interested in determining the mechanisms underlying tumor

formation in sporadic bone and soft tissue sarcomas and in neurofibromatosis type

1, a hereditary disorder caused by mutations in the neurofibromin 1 (NF1) gene.

Neurofibromin is considered a tumor suppressor that suppresses Ras activity by

promoting Ras GTP hydrolysis to GDP. People with mutations in the neurofibromin

1 gene develop benign tumors called neurofibromas and have an elevated risk of

malignancies ranging from solid tumors to leukemia, including sarcomas. The disease

affects 1 in 3000 people in the United States, of whom 8–13% will ultimately develop a

neurofibromatosis-related sarcoma in their lifetime. These aggressive tumors typically

arise from benign neurofibromas, but the process of benign-to-malignant transformation

is not well understood, and treatment options are limited, leading to poor five-year

survival rates.

Our current sarcoma-related research efforts include the development of genetically

engineered mouse models of neurofibromatosis type 1 tumor progression; the

identification of targetable patterns of intratumoral and intertumoral heterogeneity

through next-generation sequencing; genotype–phenotype correlations in

neurofibromatosis type 1 and related diseases; and mechanisms of chemotherapy

resistance in bone and soft-tissue sarcomas.

RECENT PUBLICATIONS

Foley, Jessica M., Donald J. Scholten, Noel R. Monks, David Cherba, David J. Monsma, Paula Davidson, Dawna Dylewski, Karl

Dykema, Mary E. Winn, and Matthew R. Steensma. 2015. Anoikis-resistant subpopulations of human osteosarcoma display

significant chemoresistance and are sensitive to targeted epigenetic therapies predicted by expression profiling. Journal of

Translational Medicine 13: 110.

Lane, Brian R., Jeffrey Bissonnette, Tracy Waldherr, Deborah Ritz-Holland, Dave Chesla, Sandra L. Cottingham, Sheryl Alberta,

Cong Liu, Amanda Bartenbaker Thompson, et al. 2015. Development of a center for personalized cancer care at a regional

cancer center. Journal of Molecular Diagnostics 17(6): 695–704.

Peacock, Jacqueline D., Karl J. Dykema, Helga V. Toriello, Marie R. Mooney, Donald J. Scholten II, Mary E. Winn, Andrew

Borgman, Nicholas S. Duesbery, Judith A. Hiemenga, et al. 2015. Oculoectodermal syndrome is a mosaic RASopathy

associated with KRAS alterations. American Journal of Medical Genetics A 167(7): 1429–1435.

CENTER FOR CANCER AND CELL BIOLOGY 21


GEORGE F. VANDE WOUDE, PH.D.

STAFF

CHONGFENG GAO, PH.D.

LIANG KANG, B.S.

KAY KOO

DAFNA KAUFMAN, M.S.

BEN STAAL, M.S.

Dr. Vande Woude received his M.S. and Ph.D. degrees from

Rutgers University. He joined the National Cancer Institute in 1972,

becoming the director of the ABL–Basic Research Program in 1983,

and then director of the Division of Basic Sciences in 1998. In 1999,

he became the founding Director of VARI. In 2009, he stepped

down as Director while retaining his laboratory as a Distinguished

Scientific Fellow and Professor. He is a member of the National

Academy of Sciences (1993) and a Fellow of the American

Association for the Advancement of Science (2013).

RESEARCH INTERESTS

ADJUNCT FACULTY

BRIAN CAO, M.D.

HENRY B. SKINNER, PH.D.

MET is overexpressed in many types of human cancer, and its expression correlates with

aggressive disease and poor prognosis (visit http://www.vai.org/met/). Since discovering

the MET receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF/SF), in

the mid 1980s, our lab has focused on investigating the paramount role these molecules

play in malignant progression and metastasis. As part of our ongoing effort, we focus on

the mechanisms responsible for tumor progression under the hypothesis that phenotypic

switching and chromosome instability can drive tumor progression. In addition, we

continue to develop and characterize novel research models to be used in preclinical

evaluation of new inhibitors that target MET in a variety of human cancers.

Tumor phenotypic switching: mechanism and therapeutic implications

In human carcinomas, the acquisition by cells of an invasive phenotype, a process

termed the epithelial-to-mesenchymal transition (E-MT), requires a breakdown of

intercellular junctions with neighboring cells. Upon arriving at secondary sites, a few of

the mesenchymal cells revert to an epithelial phenotype via a mesenchymal-to-epithelial

transition (M-ET). We have implicated genetic instability in cell type determination

and we have developed methods to isolate phenotypic variants from epithelial or

mesenchymal subclones of carcinoma cell lines. We have explored the signal pathway

underlying E-MT/M-ET phenotypic switching by gene expression analysis, spectral

karyotyping (SKY), and fluorescent in situ hybridization (FISH). We found that changes in

chromosome content are associated with phenotypic switching. We have further shown

that these changes dictate the expression of specific genes, which in E-MT events are

mesenchymal related and in M-ET events are epithelial related. Our results suggest that

chromosome instability can provide the diversity of gene expression needed for tumor

cells to switch phenotype.

22 Van Andel Research Institute | Scientific Report


In vivo research models: model development

and preclinical treatment evaluation

Anti-cancer therapy based on blocking the HGF–Met

signaling pathway has emerged as an important goal of

pharmaceutical research. One of the limitations of studying

the altered Met–HGF/SF signaling of human cancers grafted

in mouse models has been that the murine HGF/SF protein

has a low affinity for human MET. To overcome this, our lab

developed a transgenic human HGF-SCID mouse model

(hHGFtg-SCID), which generates a human-compatible

HGF/SF protein and thus allows for the propagation of

human tumors. This model has proven to be a valuable tool

for in vivo testing of MET-dependent cancers and is used to

evaluate treatment strategies aimed at targeting

this pathway.

RECENT PUBLICATIONS

Johnson, Jennifer, Maria Libera Ascierto, Sandeep Mittal, David Newsome, Liang Kang, Michael Briggs, Kirk Tanner, Francesco

M. Marincola, Michael E. Berens, George F. Vande Woude, et al. 2015. Genomic profiling of a hepatocyte growth factor–

dependent signature for MET-targeted therapy in glioblastoma. Journal of Translational Medicine 13: 306.

CENTER FOR CANCER AND CELL BIOLOGY 23


BART O. WILLIAMS, PH.D.

Dr. Williams received his Ph.D. in biology from Massachusetts Institute

of Technology in 1996, where he trained with Tyler Jacks. Following

his postdoctoral study with Harold Varmus, Dr. Williams joined VARI as

a Scientific Investigator in July 1999. He is now a Professor and the

Director of the Center for Cancer and Cell Biology.

STAFF

CASSIE DIEGEL, B.S.

NICOLE ETHEN, B.S.

DIANA LEWIS, A.S.

MITCH MCDONALD, B.S.

ALEX ZHONG, PH.D.

STUDENTS

CHERYL CHRISTIE, B.S.

CASEY DROSCHA, B.S.

JOHAN LEE

JON LENSING

KEVIN MAUPIN, B.A., B.S.

AGNI NAIDU, B.S.

RESEARCH INTERESTS

Our laboratory is interested in understanding how alterations in the Wnt signaling

pathway cause human disease. Wnt signaling is a process, conserved throughout

evolution, that functions in the differentiation of most tissues. Given its central role

in growth and differentiation, it is not surprising that alterations in the Wnt pathway

are among the most common events associated with human cancer. In addition,

other human diseases including osteoporosis, cardiovascular disease, and diabetes

have been linked to altered regulation of this pathway. A specific focus of our work is

characterizing the role of Wnt signaling in bone formation. Our interest is not only in

normal bone development but also in understanding whether aberrant Wnt signaling

plays a role in the metastasis of some common cancers (for example, prostate, breast,

lung, and renal tumors) to the bone. The long-term goal of this work is to provide

insights useful in developing strategies to lessen the morbidity and mortality associated

with skeletal metastasis.

Wnt signaling in normal bone development

Mutations in Lrp5, a Wnt receptor, have been causally linked to alterations in human

bone development. We have characterized a mouse strain deficient in Lrp5 and have

shown that it recapitulates the low-bone-density phenotype seen in human patients

who have that deficiency. We have further shown that mice carrying mutations in both

Lrp5 and the related Lrp6 protein have even more-severe defects in bone density. To

test whether Lrp5 deficiency causes changes in bone density due to aberrant signaling

through β-catenin, we created OC-Cre;β-catenin flox/flox mice, which carry an osteoblastspecific

deletion of β-catenin. We are addressing how other genetic alterations linked

to Wnt/β-catenin signaling affect bone development and osteoblast function. We have

generated mice with conditional alleles of Lrp6 and Lrp5 that can be inactivated via

Cre-mediated recombination and have used them to show that both Lrp5 and Lrp6

function within osteoblasts to regulate normal bone development and homeostasis. We

have also created mice lacking the ability to secrete Wnts from osteoblasts and shown

that these mice have extremely low bone mass, establishing that the mature osteoblast

is an important source of Wnts.

24 Van Andel Research Institute | Scientific Report


We are also examining the effects on normal bone

development and homeostasis of chemical inhibitors of the

enzyme porcupine, which is required for the secretion and

activity of all Wnts. Given that such inhibitors are currently

in human clinical trials for treatment of several tumor types,

their side effects related to the lowering of bone mass must

be evaluated.

Wnt signaling in mammary development

and cancer

We are addressing the relative roles of Lrp5 and Lrp6 in

Wnt1-induced mammary carcinogenesis. We have focused

our initial efforts on Lrp5-deficient mice, because they are

viable and fertile. A deficiency in Lrp5 dramatically inhibits

the development of mammary tumors, and a germline

deficiency in Lrp5 or Lrp6 results in delayed mammary

development. We are also focusing on the mechanisms that

underlie the role that Lrp6 plays in mammary development.

We are particularly interested in the pathways that may

regulate the proliferation of normal mammary progenitor

cells, as well as of tumor-initiating cells.

Wnt signaling in prostate development

and cancer

Two hallmarks of advanced prostate cancer are the

development of skeletal osteoblastic metastasis and

the ability of the tumor cells to become independent

of androgen for survival. We have created mice with a

prostate-specific deletion of the Apc gene as a disease

model. These mice develop fully penetrant prostate

hyperplasia by four months of age, and these tumors

progress to frank carcinomas by seven months. We have

found that these tumors initially regress under androgen

ablation but show signs of androgen-independent growth

some months later.

Genetically engineered mouse models

of bone disease

We have also focused on developing mouse models of

osteoarthritis and of fracture repair. In addition, we are

interested in identifying novel genes that play key roles in

skeletal development and maintenance of bone mass. For

example, current work is focused on the role of galectin-3,

a member of the lectin family, in this context.

RECENT PUBLICATIONS

Schumacher, Cassie A., Danese M. Joiner, Kennen D. Less, Melissa Oosterhouse Drewry, and Bart O. Williams. 2016.

Characterization of genetically engineered mouse models carrying Col2a1-cre-induced deletions of Lrp5 and/or Lrp6.

Bone Research 4: 15042.

Williams, Bart O. 2016. Genetically engineered mouse models to evaluate the role of Wnt secretion in bone development in

homeostasis. American Journal of Medical Genetics C 172(1): 24–26.

Valkenburg, Kenneth C., Galen Hostetter, and Bart O. Williams. 2015. Concurrent hepsin overexpression and adenomatous

polyposis coli deletion causes invasive prostate carcinoma in mice. The Prostate 75(14): 1579–1585.

Zhong, Zhendong, A., Juraj Zahatnansky, John Snider, Emily Van Wieren, Cassandra R. Diegel, and Bart O. Williams. 2015.

Wntless spatially regulates bone development through β-catenin-dependent and independent mechanisms. Developmental

Dynamics 244(10): 1347–1355.

Zhong, Zhendong A., Anderson Peck, Shihong Li, Jeff VanOss, John Snider, Casey J. Droscha, TingTung A. Chang, and Bart O.

Williams. 2015. 99m Tc-Methylene diphosphonate uptake at injury site correlates with osteoblast differentiation and mineralization

during bone healing in mice. Bone Research 3: 15013.

CENTER FOR CANCER AND CELL BIOLOGY 25


NING WU, PH.D.

Dr. Wu received her Ph.D. from the Department of Biochemistry

of the University of Toronto in 2002. She joined VARI in 2013 as

an Assistant Professor.

STAFF

HOLLY DYKSTRA, B.S.

ALTHEA WALDHART, B.S.

STUDENT

MATT HOLLOWELL

RESEARCH INTERESTS

Our laboratory studies the interface between cellular metabolism and signal

transduction. The generation of two daughter cells depends on the proper uptake

and use of nutrients that are often limited in the tumor environment. The distribution

of these nutrients is controlled not only by the intrinsic catalytic rate and allosteric

regulation of the enzymes, but also by post-translational modifications of these

enzymes by signaling molecules. At the same time, signaling molecules must respond

to cellular nutrient status and other cues such as environmental stresses and growth

factors. Our laboratory focuses on key metabolic steps in glucose and lipid catabolism

and aims to understand the mutual interactions between metabolites and signaling

during cell replication.

Fundamentally, cancer is a disease of uncontrolled cell growth. Relative to normal cells,

tumor cells have aberrant metabolic addictions that differ depending on the cell’s tissue

of origin and genetic mutations. By understanding the energy requirements and

regulatory pathways of tumor cells, more-effective treatments can be developed. Our

projects include unraveling the molecular mechanisms that regulate glucose uptake in

cancers, investigating the effect of glucose on mitochondrial activity, and exploring the

role of glucose as the link between metabolic syndrome and cancer incidence.

26 Van Andel Research Institute | Scientific Report


H. ERIC XU, PH.D.

Dr. Xu went to Duke University and the University of Texas

Southwestern Medical Center, earning his Ph.D. in molecular biology

and biochemistry. He joined VARI in July 2002 and is now a Professor.

Dr. Xu is also the Primary Investigator and Distinguished Director of

the VARI–SIMM Research Center in Shanghai, China.

STAFF

XIANG GAO, PH.D.

STEPHANIE GRANT, M.P.A.

YUANZHENG (AJIAN) HE, PH.D.

YANYONG KANG, PH.D.

KUNTAL PAL, PH.D.

KELLY POWELL, B.S.

XIAOYIN (EDWARD) ZHOU, PH.D.

STUDENTS

ERIC LI

HONGLEI MA, B.S.

PARKER DE WAAL, B.S.

TINGHAI XU, B.S.

YAN YAN, B.S.

YANTING YIN, B.S.

FENG ZHANG, B.S.

VISITING SCIENTISTS

DAVID BENSON, PH.D.

SOK KEAN KHOO, PH.D.

ROSS REYNOLDS, PH.D.

RESEARCH INTERESTS

Hormone signaling is essential to eukaryotic life. Our research focuses on the signaling

mechanisms of physiologically important hormones, striving to answer fundamental

questions that have a broad impact on human health and disease. We are studying

two families of proteins, the nuclear hormone receptors and the G protein–coupled

receptors, because these proteins have fundamental roles in biology and are important

drug targets for treating major human diseases.

Nuclear hormone receptors

The nuclear hormone receptors form a large family comprising ligand-regulated and

DNA-binding transcription factors, which include receptors for the classic steroid

hormones such as estrogen, androgens, and glucocorticoids, as well as receptors for

peroxisome proliferator activators, vitamin D, vitamin A, and thyroid hormones. These

receptors are among the most successful targets in the history of drug discovery: every

receptor has one or more synthetic ligands being used as medicines. In the last five

years, we have developed the following projects centering on the structural biology of

nuclear receptors.

Peroxisome proliferator–activated receptors

The peroxisome proliferator–activated receptors (PPARα, β, and γ) are the key regulators

of glucose and fatty acid homeostasis and, as such, are important therapeutic targets

for treating cardiovascular disease, diabetes, and cancer. Millions of patients with type

II diabetes have benefited from treatment with the novel PPARγ ligands rosiglitazone

and pioglitazone. To understand the molecular basis of ligand-mediated signaling by

PPARs, we have determined crystal structures of each PPAR’s ligand-binding domain

(LBD) bound to many diverse ligands, including fatty acids, the lipid-lowering drugs

called fibrates, and the new generation of anti-diabetic drugs, the glitazones. These

structures have provided a framework for understanding the mechanisms of agonists

CENTER FOR CANCER AND CELL BIOLOGY 27


and antagonists and the recruitment of co-activators and

co-repressors in gene activation and repression. They

also increase our understanding of the potency, selectivity,

and binding mode of ligands and provide crucial insights

for designing the next generation of PPAR medicines. We

have discovered several natural ligands of PPARγ. Our

plan is to test their physiological roles in glucose and insulin

regulation and to develop them into therapeutics

for diabetes and dislipidemia.

The human glucocorticoid receptor

The human glucocorticoid receptor (GR), the prototypical

steroid hormone receptor, affects a wide spectrum

of human physiology including immune/inflammatory

responses, metabolic homeostasis, and control of blood

pressure. GR is a well-established target for drugs, and

those drugs have an annual market of over $10 billion.

However, the clinical use of GR ligands is limited by

undesirable side effects partly resulting from receptor

cross-reactivity or low potency. The discovery of potent,

more-selective GR ligands— “dissociated glucocorticoids”

that have the potential to separate the good effects from the

bad—remains a major goal of pharmaceutical research.

We have determined a number of GR crystal structures

bound to unique ligands and have found an unexpected

regulatory mechanism: degradation by lysosomes. We also

are studying the molecular and structural mechanisms of

the dissociated glucocorticoids identified by our research.

Structural genomics of receptor LBDs

The ligand-binding domain of a nuclear receptor contains

key structural elements that mediate ligand-dependent

regulation of the receptors and, as such, it has been the

focus of intense structural studies. Crystal structures

for most of the 48 human nuclear receptors have been

determined and have illustrated the details of ligand

binding, the conformational changes induced by agonists

and antagonists, the basis of dimerization, and the

mechanism of co-activator and co-repressor binding.

The structures also have provided many surprises about

the identity of ligands and their implications for receptor

signaling pathways. There are only a few “orphan” nuclear

receptors for which the LBD structure remains unsolved.

In the past few years, we have determined the crystal

structures of the LBDs of CAR, SHP, SF-1, COUP-TFII,

and LRH-1, and our structures have helped to identify

new ligands and signaling mechanisms for these orphan

receptors.

G protein–coupled receptors (GPCRs)

The GPCRs form the largest family of receptors in the

human genome and account for over 40% of drug targets,

but their structures remain a challenge because they

are seven-transmembrane receptors. There are only

a few crystal structures for class A GPCRs, and many

important questions regarding GPCR ligand binding and

activation remain unanswered. From our standpoint,

GPCRs are similar to nuclear hormone receptors with

respect to regulation by protein-ligand and protein–protein

interactions. We focus on class B GPCRs, which includes

receptors for parathyroid hormone (PTH), corticotropinreleasing

factor (CRF), glucagon, and glucagon-like

peptide-1. We have determined crystal structures of the

ligand-binding domain of the PTH receptor and the CRF

receptor, and we are developing hormone analogs for

treating osteoporosis, depression, and diabetes. We are

developing a mammalian overexpression system and plan

to use it to express full-length GPCRs for crystallization and

structural studies.

RECENT PUBLICATIONS

He, Yuanzheng, Jingjing Shi, Wei Yi, Xin Ren, Xiang Gao, Jianshuang Li, Nanyan Wu, Kevin Weaver, Qian Xie, et al. 2015.

Discovery of a highly potent glucocorticoid for asthma treatment. Cell Discovery 1: 15035.

Kang, Yanyong, X. Edward Zhou, Xiang Gao, Yuanzheng He, Wei Liu, Andrii Ishchenko, Anton Barty, Thomas A. White, Oleksandr

Yefanov, et al. 2015. Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature 523(7562): 561–567.

28 Van Andel Research Institute | Scientific Report


TAO YANG, PH.D.

Dr. Yang received his Ph.D. in biochemistry at the Shanghai Institute

of Biochemistry and Cell Biology, Chinese Academy of Sciences, in

2001. He joined VARI as an Assistant Professor in February 2013.

STAFF

DIANA LEWIS, A.S.

JIANSHUANG LI, B.S.

JIE LI, PH.D.

HUADIE LIU, M.S.

DI LU, M.S.

KEVIN WEAVER, B.S.

RESEARCH INTERESTS

The skeletal system develops from mesenchymal cells and is the major reservoir

of mesenchymal stem cells (MSCs) in adult life. MSCs play pivotal roles in skeletal

tissue growth, homeostasis, and repair, while dysregulations in MSC renewal, linage

specification, and pool maintenance are common causes of skeletal disorders. Our

long-term interest is to investigate the signals and cellular processes orchestrating the

activities of MSCs and MSC-derived cells during skeletal development and homeostasis

and how those processes are involved in skeletal aging and disorders. Our current

projects in skeletal development and disease include a study of the sumoylation

pathway and a study of LRP1 signaling. As part of these projects, we have established

in vivo and in vitro genetic models to study the molecular mechanisms underlying

osteoarthritis and osteoporosis.

RECENT PUBLICATIONS

Chen, Shan, Monica Grover, Tarek Sibai, Jennifer Black, Nahid Rianon, Abbhirami Rajagopal, Elda Munivez, Terry Bertin,

Brian Dawson, et al. 2015. Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton.

Molecular Genetics and Metabolism 115(1): 53–60.

He, Yuanzheng, Jingjing Shi, Wei Yi, Xin Ren, Xiang Gao, Jianshuang Li, Nanyan Wu, Kevin Weaver, Qian Xie, et al. 2015.

Discovery of a highly potent glucocorticoid for asthma treatment. Cell Discovery 1: 15035.

Lu, Linchao, Karine Harutyunyan, Weidong Jin, Jianhong Wu, Tao Yang, Yuqing Chen, Kyu Sang Jeoeng, Yangjin Bae, Jianning

Tao, et al. 2015. RECQL4 regulates p53 function in vivo during skeletogenesis. Journal of Bone and Mineral Research 30(6):

1077–1089.

CENTER FOR CANCER AND CELL BIOLOGY 29


30 Van Andel Research Institute | Scientific Report


CENTER FOR

EPIGENETICS

Peter A. Jones, Ph.D., D.Sc.

Director

The Center’s researchers study epigenetics and

epigenomics in health and disease, with the ultimate

goal of developing novel therapies to treat cancer and

neurodegenerative diseases. The Center collaborates

extensively with other VARI research groups and with

external partners to maximize its efforts to develop

therapies that target epigenetic mechanisms.

Methyl (red) and acetyl (light blue) groups as epigenetic marks on nucleosomes and DNA.

Illustration by Nicole Ethen.

31


STEPHEN B. BAYLIN, M.D.

Dr. Baylin joined VARI as a Professor in the Center for Epigenetics

in January 2015 and is co-leader of the VARI-SU2C Epigenetics

Dream Team. He devotes a portion of his time to VARI. His primary

appointment is with Johns Hopkins University as the Virginia and D.K.

Ludwig Professor of Oncology and Medicine and co-head of Cancer

Biology at the Sidney Kimmel Comprehensive Cancer Center.

RESEARCH INTERESTS

The Van Andel Research Institute–Stand Up To Cancer (VARI-SU2C) Epigenetics Dream

Team is a multi-institutional effort to develop new epigenetic therapies against cancer

and to move promising therapies to clinical trials. As co-leader, Dr. Baylin oversees the

team’s research, which leverages the combined expertise of its members.

Epigenetics is the study of how the packaging and modification of DNA influences the

genes that are active or kept silent in a particular cell, and it holds untold potential for

treating cancer and other diseases. Through a detailed understanding of how normal

epigenetic processes work, scientists can identify erroneous epigenetic modifications

that may contribute to the development and progression of cancer. Epigenetic

therapies, which work by correcting these errors, have the potential to directly treat

cancer and to sensitize patients to traditional treatments such as chemotherapy and

radiation and to promising new immunotherapy approaches.

The VARI-SU2C Epigenetics Dream Team is headquartered at VARI in Grand Rapids,

Michigan, and it includes members from Johns Hopkins University, Memorial Sloan

Kettering Cancer Center, Fox Chase Cancer Center/Temple University, University of

Southern California, and Rigshospitalet/University of Copenhagen. The American

Association for Cancer Research (AACR), as SU2C’s scientific partner, reviews

projects and provides objective scientific oversight.

RECENT PUBLICATIONS

Chaiappinelli, Katherine B., Pamela L. Strissel, Alexis Desrichard, Huili Li, Christine Henke, Benjamin Akman, Alexander Hein, Neal

S. Rote, Leslie M. Cope, et al. 2015. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including

endogenous retroviruses. Cell 162(5): 961–973.

32 Van Andel Research Institute | Scientific Report


PETER A. JONES, PH.D., D.SC.

Dr. Jones received his Ph.D. from the University of London. He

joined the University of Southern California in 1977 and served as

director of the USC Norris Comprehensive Cancer Center between

1993 and 2011. Dr. Jones joined VARI in 2014 as its Chief Scientific

Officer and Director of the Center for Epigenetics.

STAFF

MINMIN LIU, PH.D.

HITOSHI OTANI, PH.D.

ROCHELE TIEDEMANN, PH.D.

WANDING ZHOU, PH.D.

ADJUNCT FACULTY

RONALD CHANDLER, JR., PH.D.

FEYRUZ RASSOOL, PH.D.

RESEARCH INTERESTS

Epigenetics may be defined as mitotically heritable changes in gene expression that

are not caused by changes in the DNA sequence itself. Epigenetic processes establish

the differentiated state of cells and govern how genes are used to allow organs and

cells to function correctly and inherit their properties through cell division. In the case

of diseases such as cancer, these processes can go wrong, changing the behavior of

cells to adverse effect. However, many of these changes are potentially reversible by

treatment with drugs. Because epigenetic processes are at the root of biology, they

have implications for all of human development and disease.

Our laboratory studies the mechanisms by which epigenetic processes become

misregulated in cancer and contribute to the disease phenotype. We focus on the role

of DNA methylation in controlling the expression of genes during normal development

and in cancer. Our work has shifted to a holistic approach in which we are interested in

the interactions between processes such as DNA methylation, histone modification, and

nucleosomal positioning in the epigenome, and we want to determine how mutations

in the genes which modify the epigenome contribute to the cancer phenotype. We

have had a long-term interest in the mechanism of action of DNA methylation inhibitors,

both in the lab and in the clinic. We are working with several major institutions to bring

epigenetic therapies to the forefront of cancer medicine.

RECENT PUBLICATIONS

Lay, Fides D., Yaping Liu, Theresa K. Kelly, Heather Witt, Peggy J. Farnham, Peter A. Jones, and Benjamin P. Berman. 2015.

The role of DNA methylation in directing the functional organization of the cancer epigenome. Genome Research 25(4): 467–477.

Roulois, David, Helen Loo Yau, Rajat Singhania, Yadong Wang, Amavaz Danesh, Shu Yi Shen, Han Han, Gangning Liang, Peter

A. Jones, et al. 2015. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous

transcripts. Cell 162(5): 961–973.

Statham, Aaron L., Phillippa C. Taberlay, Theresa K. Kelly, Peter A. Jones, and Susan J. Clark. 2015. Genome-wide nucleosome

occupancy and DNA methylation profiling of four human cell lines. Genomics Data 3: 94–96.

CENTER FOR EPIGENETICS 33


STEFAN JOVINGE, M.D., PH.D.

Dr. Jovinge received his M.D. (1991) and his Ph.D. (1997) at

Karolinska Institute in Stockholm. Since December 2013 he has

been the Medical Director of Research at the Frederik Meijer Heart

and Vascular Institute and a Professor at VARI. He also directs

the DeVos Cardiovascular Research Program, is a Professor at the

MSU College of Human Medicine, and is a Consulting Professor at

Stanford University.

STAFF

PAULA DAVIDSON, M.S.

DAWNA DYLEWSKI, B.S.

ELLEN ELLIS

EMILY EUGSTER, M.A.

JENS FORSBERG, PH.D.

LISA KEFENE, M.A., MB(ASCP), RLAT

ERIC KORT, M.D.

BRITTANY MERRIFIELD, B.S.

HSIAO-YUN YEH (CHRISTY) MILLIRON, PH.D.

JORDAN PRAHL, B.S.

LAURA TARNAWSKI, M.S.

MATTHEW WEILAND, M.S.

LAURA WINKLER, PH.D.

RESEARCH INTERESTS

The DeVos Cardiovascular Research Program is a joint effort between VARI and

Spectrum Health. The basic science lab is the Jovinge laboratory at VARI, and a

corresponding clinical research unit resides within the Fred Meijer Heart and Vascular

Institute.

Cardiovascular diseases are among the major causes of death and disability worldwide.

While the incidence of ischemic heart diseases has started to decline, congestive heart

failure is still rising. Medical treatment for the latter is supportive, and the only available

therapy is heart transplantation.

To regenerate myocardium after disease or damage is one of the major challenges in

medicine. Our group is working on true heart muscle regeneration along two axes:

external and internal (cardiac) cell sources. The most robust external source for

generating heart muscle cells has been stem cells, either from an embryonic stem

cell (ESC) system or from reprogrammed pluripotent stem cells (iPSCs). The main

drawback to the stem cell approach is that their differentiation will generate a multitude

of different cell types at different stages of development. A mixed cell population of

undifferentiated cells always has the potential to create tumors. Also, the use of ESCs

creates a need for lifelong immunosuppressive treatment. iPSCs, however, could be

generated from the patient’s own peripheral blood cells, a technique established by our

group in Grand Rapids. To be able to use these sources, we have developed strategies

based on establishing surface marker expression—similar to those for bone-marrow

cells—to help select homogenous, safe populations to transplant.

34 Van Andel Research Institute | Scientific Report


The second axis we focus on is endogenous generation

within the heart. Although adult human heart muscle cells

are to a small extent generated after birth, the internal

source of such cells and their cell cycle regulation are

unknown. Some data indicate that cardiac progenitors

could be involved, and other data suggest that differentiated

heart muscle cells might be the source. We and our

collaborators have rejected the view that adult heart muscle

cells are not capable of undergoing a complete cell division.

With the use of 14 C dating, the adult heart has been shown

to have a regenerative capacity. This has opened a

completely new field of induced local generation of heart

muscle cells, which is now being explored.

The final phase of patient studies will involve the

administration of cells or compounds to stimulate

endogenous regeneration. To prepare cells for

transplantation into humans, an accredited Good

Manufacturing Practice facility will be established in

collaboration with Stanford University, and the first safety

studies (Phase II) will be followed by studies evaluating the

best route for delivering the treatment and the best timing.

In the final stage, randomized prospective clinical trials will

be launched.

Our program’s eventual aims are clinical concept studies

of heart muscle cell regeneration in patients, either by cell

transplantation or stimulation of endogenous sources. The

program’s clinical side involves a multistep process to

prepare for these studies. Patients with the most severe

heart disease, i.e., those needing mechanical support, are

being studied to optimize treatments that will be used in

later safety studies. We have already derived mortality

prediction algorithms for patients on bedside heart-lung

machines.

RECENT PUBLICATIONS

Bergmann, Olaf, Sofia Zdunek, Anastasia Felker, Mehran Salehpour, Kanar Alkass, Samuel Bernard, Staffan L. Sjostrom,

Mirosława Szewcykowska, Teresa Jackowska, et al. 2015. Dynamics of cell generation and turnover in the human heart.

Cell 161(7): 1566–1575.

Raulf, Alexandra, Hannes Horder, Laura Tarnawski, Caroline Geisen, Annika Ottersbach, Wilhelm Röll, Stefan Jovinge, Bernd

K. Fleischmann, and Michael Hesse. 2015. Transgenic systems for unequivocal identification of cardiac myocyte nuclei and

analysis of cardiomyocyte cell cycle status. Basic Research in Cardiology 110(3): 33.

Tarnawski, Laura, Xiaojie Xian, Gustavo Monnerat, Iain C. Macauley, Daniela Malan, Andrew Borgman, Sean M. Wu, Bernd

K. Fleischmann, and Stefan Jovinge. 2015. Integrin based isolation enables purification of murine lineage committed

cardiomyocytes. PLoS One 10(8): e0135880.

CENTER FOR EPIGENETICS 35


PETER W. LAIRD, PH.D.

Dr. Laird earned his Ph.D. in 1988 from the University of Amsterdam

with Piet Borst. Dr. Laird was a faculty member at the University of

Southern California from 1996 to 2014, where he was Skirball-Kenis

Professor of Cancer Research and directed the USC Epigenome

Center. He joined VARI as a Professor in September 2014.

STAFF

KELLY FOY, B.S.

TOSHINORI HINOUE, PH.D.

KWANGHO LEE, PH.D.

ZHOUWEI ZHANG, M.S.

WANDING ZHOU, PH.D.

STUDENT

NICOLE VANDER SCHAAF, B.S.

RESEARCH INTERESTS

Our goal is to develop a detailed understanding of the molecular basis of human

disease, with a particular emphasis on the role of epigenetics in cancer. Cancer is often

considered to have a primarily genetic basis, with contributions from germline variations

in risk and somatically acquired mutations, rearrangements, and copy number

alterations. However, it is clear that nongenetic mechanisms can exert a powerful

influence on cellular phenotype, as evidenced by the marked diversity of cell types

within our bodies, which virtually all contain an identical genetic code. This differential

gene expression is controlled by tissue-specific transcription factors and variations in

chromatin packaging and modification, which can provide stable phenotypic states

governed by epigenetic, not genetic, mechanisms. It seems intrinsically likely that an

opportunistic disease such as cancer would take advantage of such a potent mediator

of cellular phenotype. Our laboratory is dedicated to understanding how epigenetic

mechanisms contribute to the origins of cancer and how to translate this knowledge

into more-effective cancer prevention, detection, treatment, and monitoring.

We use a multidisciplinary approach in our research, relying on mechanistic studies

in model organisms and cell cultures, clinical and translational collaborations,

genome-scale and bioinformatic analyses, and epidemiological studies to advance our

understanding of cancer epigenetics. In recent years, we participated in the generation

and analysis of high-dimensional epigenetic data sets, including the production of

all epigenomic data for The Cancer Genome Atlas (TCGA) and the application of

next-generation sequencing technology to single-base-pair-resolution, whole-genome

DNA methylation analysis. We are leveraging this epigenomic data for translational

applications and hypothesis testing in animal models. A major focus of our laboratory

is to develop mouse models for investigating epigenetic mechanisms and drivers of

cancer and to develop novel strategies for single-cell epigenomic analysis.

36 Van Andel Research Institute | Scientific Report


RECENT PUBLICATIONS

Cancer Genome Atlas Research Network. 2016. Comprehensive molecular characterization of papillary renal-cell carcinoma.

New England Journal of Medicine 374(2): 135–145.

Ceccarelli, Michele, Floris P. Barthel, Tathiane M. Malta, Thais S. Sabedot, Sofie R. Salama, Bradley A. Murray, Olena Morozova,

Yulia Newton, Arnie Radenbaugh, et al. 2016. Molecular profiling reveals biologically discrete subsets and pathways of

progression in diffuse glioma. Cell 164(3): 550–563.

Levine, A. Joan, Amanda I. Phipps, John A. Baron, Daniel D. Buchanan, Dennis J. Ahnen, Stacey Cohen, Noralane M. Lindor,

Polly A. Newcomb, Christophe Rosty, et al. 2016. Clinicopathological risk factor distributions for MLH1 promoter region

methylation in CIMP positive tumors. Cancer Epidemiology, Biomarkers and Prevention 25(1): 68–75.

Ryland, Katherine E., Allegra G. Hawkins, Daniel J. Weisenberger, Vasu Punj, Scott C. Borinstein, Peter W. Laird, Jeffrey R.

Martens, and Elizabeth R. Lawlor. 2016. Promoter methylation analysis reveals that SCNA5 ion channel silencing supports Ewing

sarcoma cell proliferation. Molecular Cancer Research 14(1): 26–34.

Cancer Genome Atlas Research Network. 2015. The molecular taxonomy of primary prostate cancer. Cell 163(4): 1011–1025.

Ciriello, Giovanni, Michael L. Gatza, Andrew H. Beck, Matthew D. Wilkerson, Suhn K Rhie, Alessandro Pastore, Hailei Zhang,

Michael McLellan, Christina Yau, et al. 2015. Comprehensive molecular portraits of invasive lobular breast cancer. Cell 163(2):

506–519.

CENTER FOR EPIGENETICS

37


GERD PFEIFER, PH.D.

Dr. Pfeifer earned his M.S. in pharmacology in 1981 and his Ph.D. in

biochemistry in 1984 from Goethe University in Frankfurt, Germany.

He most recently held the Lester M. and Irene C. Finkelstein Chair in

Biology at the City of Hope in Duarte, California, before joining VARI

in 2014 as a Professor.

STAFF

ZHIJUN HUANG, PH.D.

SEUNG-GI JIN, PH.D.

JENNIFER JOHNSON, M.S.

JIYOUNG YU, PH.D.

RESEARCH OVERVIEW

The laboratory studies epigenetic mechanisms of disease, with a focus on DNA

methylation and the role of 5-hydroxymethylcytosine in cancer and other diseases.

Specifically, the lab studies hypermethylation in cancer genes with the intent of

determining the mechanisms and significance of CpG island methylation. The work

centers on the hypothesis that CpG island hypermethylation in tumors is driven by one

or a combination of the following: carcinogenic agents, inflammation, imbalances in

methylation and demethylation pathways, oncogene activation leading to epigenetic

changes, and dysfunction of the Polycomb repression complex.

The removal of methyl groups from DNA has recently been recognized as an important

pathway in cancer and possibly in other diseases. Our lab studies mechanisms of

5-methylcytosine oxidation.

DNA methylation in cancer

To effectively study genome-wide DNA methylation patterns, we previously developed

the methylated CpG island recovery assay (MIRA), which is used in combination with

sequencing to identify commonly methylated genes in human cancers and normal

tissues. We investigate mechanisms of cancer-associated DNA hypermethylation using

DNA-methylation and chromatin-component mapping in normal and malignant cells, as

well as bioinformatics approaches and functional studies.

38 Van Andel Research Institute | Scientific Report


Tet3 and related proteins

We have identified three different isoforms of the Tet3

5-methylcytosine oxidase and characterized them using

biochemical, functional, and genetic approaches. We

observed that one isoform of Tet3 specifically binds

to 5-carboxylcytosine, thus establishing an anchoring

mechanism of Tet3 to its reaction product, which may aid in

localized 5-methylcytosine oxidation and removal. We also

study several Tet-associated proteins, trying to understand

their biological roles.

5-methylcytosine oxidation and

neurodegeneration

Using ChIP sequencing, we mapped one of the isoforms of

Tet3 in neuronal cell populations. Tet3 has a rather limited

genomic distribution and is targeted to the transcription

start sites of defined sets of genes, many of which function

within the lysosome and autophagy pathways. We know

these pathways are defective in neurodegenerative

diseases. We are exploring the mechanistic consequences

of 5-methylcytosine oxidation in this disease group, with the

long-term goal of determining whether neurodegeneration

has an epigenetic origin.

RECENT PUBLICATIONS

Jin, Seung-Gi, Zhi-Min Zhang, Thomas L. Dunwell, Matthew R. Harter, Xiwei Wu, Jennifer Johnson, Zheng Li, Jiancheng Liu,

Piroska E. Szabó, et al. 2016. Tet3 reads 5-carboxylcytosine through its CXXC domain and is a potential guardian against

neurodegeneration. Cell Reports 14(3): 493–505.

Jung, Marc, Seung-Gi Jin, Xiaoying Zhang, Wenying Xiong, Grigoriy Gogoshin, Andrei S. Rodin, and Gerd P. Pfeifer. 2015.

Longitudinal epigentic and gene expression profiles analyzed by three-component analysis reveal down-regulation of genes

involved in protein translation in human aging. Nucleic Acids Research 43(15): e100.

Jung, Marc, Swati Kadam, Wenying Xiong, Tibor A. Rauch, Seung-Gi Jin, and Gerd P. Pfeifer. 2015. MIRA-seq for DNA

methylation analysis of CpG islands. Epigenomics 7(5): 695–706.

CENTER FOR EPIGENETICS

39


SCOTT ROTHBART, PH.D.

Dr. Rothbart earned a Ph.D. in pharmacology and toxicology from

Virginia Commonwealth University in 2010. He joined VARI in April

2015 as an Assistant Professor.

STAFF

EVAN CORNETT, PH.D.

BRADLEY DICKSON, PH.D.

ROCHELLE TIEDEMANN, PH.D.

STUDENT

ROBERT VAUGHAN, B.S.

RESEARCH INTERESTS

Two major epigenetic marks regulating the structure and function of eukaryotic

chromatin are the methylation of DNA and post-translational modifications (PTMs) of

histone proteins. Breakthroughs in our understanding of chromatin function have been

made through the identification of protein machineries that incorporate (write), remove

(erase), and bind (read) these epigenetic marks. Chromatin modification and remodeling

shape cellular identity, and it is becoming increasingly apparent that deregulation of

epigenetic signaling contributes to, and may cause, the initiation and progression

of cancer and other human diseases. Unlike genetic abnormalities, chromatin

modifications are reversible, making the writers, erasers, and readers of these marks

attractive therapeutic targets. The goal of our research is to define the molecular details

of chromatin accessibility, interaction, and function. We are particularly interested in

understanding how DNA and histone modifications work together as a language or

code that is read and interpreted by specialized proteins to orchestrate the dynamic

functions of chromatin. We hope our studies will lead to a better understanding of

the etiology of disease and will contribute to the discovery of effective therapeutic

approaches that target the epigenetic machinery.

Mechanics of chromatin interaction

It appears that many chromatin-associated factors have multiple known (or

predicted) chromatin regulatory domains, both within a single protein and within the

subunits of complexes. There is a diverse and exciting potential here, a previously

underappreciated layer of complexity and specificity to chromatin recognition and

regulation. Our studies are using expertise in biochemistry, computational and

molecular biophysics, and cell biology to define the molecular underpinnings of

multivalency and allostery in chromatin interaction and function.

40 Van Andel Research Institute | Scientific Report


Mechanisms regulating the inheritance of DNA

methylation

Application of microarray technology to the

study of histone PTMs.

The faithful inheritance of DNA methylation patterns is

essential for normal mammalian development and long-term

transcriptional silencing. We recently discovered that

the E3 ubiquitin ligase UHRF1 is a key regulator of this

process through its interaction with a histone signature of

transcriptionally silent heterochromatin. Current studies are

focused on defining the molecular interconnections between

UHRF1, DNMTs, and chromatin, and on elucidating the role of

UHRF1 deregulation in tumor initiation and progression.

We recently developed a histone peptide microarray platform

that has greatly improved our understanding of histone

PTM function in development and disease, as well as during

the fundamental processes of transcription, chromatin

organization, and DNA repair. We are developing several

new microarray-based platforms to enable high-throughput

discovery of histone PTM function. Two areas of focus are

to expand the utility of our current histone peptide array in

defining the influence of the “histone code” on writers and

erasers of these marks and to develop a multiplex array assay

for comparative profiling of histone PTM patterns in stages of

differentiation and disease.

RECENT PUBLICATIONS

Rothbart, Scott B., Bradley M. Dickson, Jesse R. Raab, Adrian T. Grzybowski, Krzysztof Krajewski, Angela H. Guo, Erin K. Shanle,

Steven Z. Josefowicz, Stephen M. Fuchs, et al. 2015. An interactive database for the assessment of histone antibody specificity.

Molecular Cell 59(3): 502–511.

Simon, Jeremy M., Joel S. Parker, Feng Liu, Scott B. Rothbart, Slimane Ait-Si-Ali, Brian D. Strahl, Jian Jin, Ian J. Davis,

Amber L. Moseley, and Samantha G. Pattenden. 2015. A role for widely interspaced zinc finger (WIZ) in retention of the G9a

methyltransferase on chromatin. Journal of Biological Chemistry 290(43): 26088–26102.

Zhang, Zhi-Min, Scott B. Rothbart, David F. Allison, Qian Cai, Joseph S. Harrison, Lin Li, Yinsheng Wang, Brian D. Strahl, Gang

Greg Wang, and Jikui Song. 2015. An allosteric interaction links USP7 to deubiquitination and chromatin targeting of UHRF1.

Cell Reports 12(9): 1400–1406.

CENTER FOR EPIGENETICS

41


Mapping of the mammalian 5-methylcytosine oxidase Tet3.

Top left: Ribbon representation of the mTet3 CXXC domain (light blue) bound to CcaCG DNA (tan). The zinc ions in the CXXC domain

and the carboxylates in DNA are shown as green and red spheres, respectively. Top right: Electrostatic surface representation, with

positive charge shown as blue and negative charge as red.

Bottom: ChiP-seq data shows that Tet3FL peaks center on transcription start sites (horizontal arrows) for four lysosome-related genes.

The peaks from neuronal progenitors (NPC) and mouse brain cells correspond to the locations of low 5-methylcytosine content in the

DNA sequence of NPCs and mouse embryonic stem cells (Stadler et al., 2011). Figure from the Pfeifer laboratory.

42

Van Andel Research Institute | Scientific Report


HUI SHEN, PH.D.

Dr. Shen earned her Ph.D. at the University of Southern California

in genetic, molecular, and cellular biology. She joined VARI in

September 2014 as an Assistant Professor.

STAFF

HUIHUI FAN, PH.D.

WANDING ZHOU, PH.D.

RESEARCH INTERESTS

The laboratory focuses on the epigenome and its interaction with the genome in various

diseases, with a specific emphasis on female cancers and cross-cancer comparisons.

We use bioinformatics as a tool to understand the etiology, cell of origin, and epigenetic

mechanisms of various diseases and to devise better approaches for cancer prevention,

detection, therapy, and monitoring. We have extensive experience with genome-scale

DNA methylation profiles in primary human samples, and we have made major

contributions to epigenetic analysis within The Cancer Genome Atlas (TCGA).

DNA methylation is ideally suited for deconstructing heterogeneity among cell types

within a tissue sample. In cancer research, this approach can be used for cancercell

clonal evolution studies or for quantifying normal cell infiltration and stromal

composition. The latter can provide insights into the tumor microenvironment, and

in noncancer studies it can be a useful tool for accurately estimating cell populations

and providing insights into lineage structures and population shifts in disease. In

addition, we are interested in translational applications of epigenomic technology. To

this end, we bring markers emerging from our bioinformatics analysis into clinical assay

development, marker panel assembly, and optimization, with the ultimate goal of clinical

testing and validation.

RECENT PUBLICATIONS

Cancer Genome Atlas Research Network. 2016. Comprehensive molecular characterization of papillary renal-cell carcinoma.

New England Journal of Medicine 374(2): 135–145.

Ciriello, Giovanni, Michael L. Gatza, Andrew H. Beck, Matthew D. Wilkerson, Suhn K Rhie, Alessandro Pastore, Hailei Zhang,

Michael McLellan, Christina Yau, et al. 2015. Comprehensive molecular portraits of invasive lobular breast cancer. Cell 163(2):

506–519.

Yao, Lijing, Hui Shen, Peter W. Laird, Peggy J. Farnham, and Benjamin P. Berman. 2015. Inferring regulatory element landscapes

and transcription factor networks from cancer methylomes. Genome Biology 16: 105.

CENTER FOR EPIGENETICS

43


PIROSKA E. SZABÓ, PH.D.

Dr. Szabó earned an M.Sc. in biology and a Ph.D. in molecular

biology from József Attila University, Szeged, Hungary. She joined

VARI in 2014 as an Associate Professor.

STAFF

FUJUNG CHANG, M.S.

JI LIAO, PH.D.

TIE-BO ZENG, PH.D.

STUDENT

NICK PIERCE

RESEARCH INTERESTS

Our laboratory studies the molecular mechanisms responsible for resetting the

mammalian epigenome between generations, globally and specifically in the context of

genomic imprinting. We focus on how genomic imprints are established at differentially

methylated regions (DMRs) in germ cells and how they are maintained in the zygote and

in the soma. Our main hypothesis is that cytosine 5-hydroxymethylation, chromatin

composition, and noncoding RNAs are essential components of the imprint cycle, being

involved at the DNA methylation imprint-maintenance phase in the zygote and in the

soma, as well as at the imprint-erasure and -establishment phases in the germline.

Epigenetic mechanisms that maintain imprinting in the zygote

and in the soma

In somatic cells, the parental DMR alleles are differentially marked by covalent histone

modifications, including H3K79 methylation. To test whether these methylation marks

maintain imprinting in the soma, we will measure allele-specific gene expression,

chromatin composition, and DNA methylation in embryos and placentas having targeted

inactivation of histone methyltransferase genes (for example, of Dot1L). We and others

have shown that oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine

(5hmC) plays a role in global demethylation in the paternal pronucleus of the zygote.

H3K9 dimethylation protects some paternal methylation imprints from TET3-mediated

oxidation in the zygote, but it is not known whether maternal imprints are similarly

protected. In addition, 5hmC may be important in the maintenance of hypomethylation

of one DMR allele after fertilization and in the soma, because it is not recognized by the

maintenance methyltransferase. In agreement with this hypothesis, we have detected

allele-specific 5hmC marks at some imprinted DMRs in somatic cells. We will follow up

with genetic experiments to determine the exact role of 5hmC and H3K9 methylation at

the phase of imprint maintenance in the zygote and in the soma.

44 Van Andel Research Institute | Scientific Report


The role of transcription and chromatin in

imprint establishment in the germline

To understand how imprint establishment at specific loci is

related to global epigenetic remodeling events, we recently

mapped dynamic changes in DNA CpG methylation,

transcription, and chromatin in fetal male germ cells. We

found broad, low-level transcription across paternal DMRs

prior to DNA de novo methylation in prospermatogonia.

We are testing genetically whether such transcription

is required for paternal imprint establishment. Active

chromatin marks such as H3K4 methylation diminish

at paternal DMRs prior to establishment of the DNA

methylation imprint. We are generating conditional mutant

mice and prospermatogonia-specific inducible Cre-deletor

mice to test whether removing H3K4 methylation is

essential for paternal imprint establishment. Maternal

DMRs are occupied by H3K4 methylation peaks in

prospermatogonia. We are testing genetically whether this

mark is sufficient to protect maternal DMRs from de novo

DNA methylation.

RECENT PUBLICATIONS

Jin, Seung-Gi, Zhi-Min Zhang, Thomas L. Dunwell, Matthew R. Harter, Xiwei Wu, Jennifer Johnson, Zheng Li, Jiancheng Liu,

Piroska E. Szabó, et al. 2016. Tet3 reads 5-carboxylcytosine through its CXXC domain and is a potential guardian against

neurodegeneration. Cell Reports 14(3): 493–505.

Iqbal, Khursheed, Diana A. Tran, Arthur X. Li, Charles Warden, Angela Y. Bai, Purnima Singh, Xiwei Wu, Gerd P. Pfeifer, and

Piroska E. Szabó. 2015. Deleterious effects of endocrine disruptors are corrected in the mammalian germline by epigenome

reprogramming. Genome Biology 16: 59.

CENTER FOR EPIGENETICS 45


STEVEN J. TRIEZENBERG, PH.D.

Dr. Triezenberg earned his Ph.D. at the University of Michigan. He

was a faculty member at Michigan State University for more than 18

years before joining VAI in 2006 as the founding Dean of Van Andel

Institute Graduate School and as a VARI Professor.

STAFF

GLEN ALBERTS, B.S.

CAROLYN BOTTING, M.S.

KRISTIE VANDERHOOF, B.S.

STUDENT

NIKKI THELLMAN, D.V.M.

RESEARCH INTERESTS

Our research explores the mechanisms that control how genes are expressed inside

cells. Some genes must be expressed more or less constantly throughout the life

of any eukaryotic cell; others must be turned on (or off) in particular cells at specific

times or in response to specific signals or events. Regulation of gene expression helps

determine how a given cell will function. Our laboratory explores the mechanisms

that regulate the first step in that flow, the process of transcription. We use infection

by herpes simplex virus as an experimental context for exploring the mechanisms of

transcriptional activation in human cells.

Transcriptional activation during herpes simplex virus infection

Herpes simplex virus type 1 (HSV-1) causes the common cold sore or fever blister. The

initial lytic or productive infection by HSV-1 results in the obvious symptoms in the

skin and mucosa, typically in or around the mouth. Like all viruses, HSV-1 relies on

the molecular machinery of the infected cell to express viral genes so that the infection

can proceed and new copies of the virus can be made. This process is triggered by a

viral protein known as VP16, which stimulates the initial expression of viral genes in the

infected cell. Much of our work over the years has explored how VP16 activates these

genes during lytic infection.

After the initial infection resolves, HSV-1 finds its way into nerve cells, where the virus

can remain in a latent mode for long periods of time—essentially for the entire life of the

host. Occasionally, some triggering event (such as emotional stress or damage to the

nerve from a sunburn or a root canal operation) will cause the latent virus to reactivate,

producing new viruses in the nerve cell and sending them back to the skin to cause a

recurrence of the cold sore. We are investigating the role that VP16 might play during

such reactivation.

46 Van Andel Research Institute | Scientific Report


Chromatin-modifying coactivators in

reactivating latent HSV

The strands of DNA in which the human genome is encoded

are much longer than the diameter of a typical human cell.

To help fit the DNA into the cell, cellular DNA is typically

packaged as chromatin, in which the DNA is wrapped

around “spools” of histone proteins and then further

arranged into higher-order structures. When genes need to

be expressed, they are partially unpackaged by the action

of chromatin-modifying coactivator proteins, which either

chemically change the histone proteins or physically slide

the histones along the DNA.

Transcriptional activator proteins such as VP16 can

recruit these chromatin-modifying coactivator proteins to

specific genes. We have shown that this process is not

very important during lytic infection, because viral DNA in

either the viral particle or the infected cell is not effectively

packaged into chromatin. However, in the latent state,

few viral genes are expressed because the viral DNA is

packaged much like the silent genes of the host cell. Our

present hypothesis is that the coactivators recruited by

VP16 are required to open up chromatin as an early step in

reactivating the viral genes from latency. We are currently

testing this hypothesis in quiescent infections of cultured

human nerve cells.

Regulating the regulatory proteins: posttranslational

modification of VP16

The activity of a given protein is not only dependent on

being expressed at the right time, but also on chemical

modifications of that protein. Proteins can be posttranslationally

modified by adding chemical groups,

including phosphates, sugars, methyl or acetyl groups,

lipids, or small proteins such as ubiquitin. Each of these

modifications can affect how the protein folds, how it

interacts with other proteins, and how stable it remains in

the cell.

We know that VP16 can be phosphorylated, and we have

already identified several sites within the VP16 protein

where this happens. We are now testing whether these or

other modifications affect how VP16 functions, either as a

transcriptional activator protein or as a structural protein of

the HSV-1 virion. In some experiments, we make mutations

that either prevent phosphorylation or that introduce an

amino acid that mimics phosphorylation, and then we test

the effects of these mutations on VP16 functions. In other

experiments, we inhibit the enzymes, such as kinases,

that apply the modifications. We expect that this work

will lead to new ideas about ways to selectively inhibit

the modification of VP16 using small-molecule drugs and

thereby prevent or shorten infection.

Other cellular regulators of HSV infections

When HSV makes use of cellular proteins to promote its

infection, infected cells take defensive measures to inhibit

the virus. We would like to find ways to block the cellular

proteins that support the virus or boost the cellular proteins

that inhibit it. Because some of the cellular proteins that

normally repair damaged DNA in the host cell become active

upon HSV infection, we predicted that the DNA damage

response might be important for the growth of the virus,

but our experimental results don’t support that hypothesis.

We have also found that a number of protein kinases from

the host cell help with early steps in the infection process.

Some of those seem to be involved in the entry of the virus

into the cell; we are now testing whether chemical inhibitors

of those kinases might be useful treatments for cold sores.

Other kinases seem to affect viral infection at later stages,

but we don’t yet know why. We are studying each of these

potential participants to find out what roles they play in virus

infection and whether drugs that block these kinases might

be useful in treating viral infection in humans.

RECENT PUBLICATIONS

Botting, Carolyn, Xu Lu, and Steven J. Triezenberg. 2016. H2AX phosphorylation and DNA damage kinase activity are

dispensable for herpes simplex virus replication. Virology Journal 13: 15.

CENTER FOR EPIGENETICS

47


48 Van Andel Research Institute | Scientific Report


CENTER FOR

NEURODENERATIVE SCIENCE

Patrik Brundin, M.D., Ph.D.

Director

The Center’s laboratories focus on the development

of novel treatments that slow or stop the progression

of neurodegenerative disease, in particular

Parkinson’s disease. The work revolves around

three main goals: disease modification, biomarker

discovery, and brain repair.

Neurons from the brain of a mouse model of Parkinson's disease.

The neurons are stained green, cell nuclei are stained blue with DAPI, and pathological

inclusions of α-synuclein are stained red. (Image by Nolwen Rey of the Patrik Brundin lab.)

49


LENA BRUNDIN, M.D., PH.D.

Dr. Brundin earned her Ph.D. in neurobiology and her M.D. from Lund

University, Sweden. In 2012, she arrived at VARI as an Associate

Professor and she now holds a full-time appointment.

STAFF

AUDREY ANDERSON, B.S.

ELENA BRYLEVA, PH.D.

STAN KRZYZANOWSKI, B.A.

KEERTHI RAJAMANI, PH.D.

ANALISE SAURO, B.S.

DAN TUINSTRA, B.A.

STUDENTS

JAMIE GRIT, B.S.

SARAH KEATON, M.S.

RESEARCH INTERESTS

Our laboratory works with the hypothesis that inflammation in the brain causes

psychiatric symptoms such as depression and thoughts of suicide. This hypothesis

stems from the fact that people with infections such as the flu often develop behavioral

symptoms known as sickness behavior. We have shown that individuals who attempt

suicide have high levels of inflammation and toxic products of inflammation in both the

blood and the cerebrospinal fluid. The higher the degree of inflammation, the more

depressed and suicidal is the affected patient. Therefore, we think that the biological

mechanisms of sickness behavior and the disease traditionally known as psychiatric

depression are similar, involving activation of the inflammatory response in the brain

and subsequent effects on nerve cells. In a recent clinical study, we showed that

when depression is successfully treated, it is associated with a significant decrease of

inflammation products in the blood.

The laboratory is conducting clinical studies on patients in the Grand Rapids

area and translational experiments in the laboratory at VARI, trying to detail what

inflammatory mechanisms are responsible for the effects on emotion and behavior.

Such mechanisms could be the foundation of novel treatments directed at depression

and suicidal behavior. The medications used today are based on principles identified

about 50 years ago in the monoamine hypothesis of depression. Unfortunately, these

medications help only about 50% of affected patients. If anti-inflammatory agents

could be used to treat depressive and suicidal symptoms, it would be a huge step

toward helping patients suffering from so-called treatment-resistant depression.

50 Van Andel Research Institute | Scientific Report


In recent years, we have identified some infections and

genetic variants associated with a higher risk for suicidal

behavior and depression. Intriguingly, we found that

infection with the parasite Toxoplasma gondii is associated

with a sevenfold risk of attempted suicide. Some 10-20%

of all Americans are infected with this parasite, which

was previously considered harmless to everyone except

pregnant women and immunocompromised individuals.

After initial infection by ingesting undercooked meat or

contaminated soil, the parasite enters the brain and resides

in nerve cells. The parasite may be the cause of subtle

behavioral changes in the infected hosts, perhaps due to

low-grade chronic brain inflammation. Toxoplasma infection

may be treatable using current medications, but it still

needs to be proved in clinical trials that such treatment has

a beneficial effect on depressive and suicidal behavior.

Our laboratory is currently conducting two clinical

studies in Grand Rapids. The first is a collaborative

study of perinatal depression (depression during and

after pregnancy) together with Pine Rest Christian Mental

Health, Spectrum Health, and Michigan State University.

This multi-institutional NIH-sponsored effort, led by Dr.

Brundin, investigates the possible role of inflammation of

the placenta in the development of depression in pregnant

women. The goals of the study are to understand the cause

of depression during pregnancy, something that is currently

unknown, and to find biomarkers in the blood to identify

women who are at risk for depression during and after

pregnancy. If we know which women are at risk, they can

be closely monitored during pregnancy for symptoms and

receive prompt support and help. Finally, if we uncover

the trigger of depression in pregnancy, we will be optimally

positioned for developing novel therapies to target the

cause of the disease.

The second clinical study is called the Heart Failure and

Inflammation in Depression (HFIND) study. With Spectrum

Health, we will look at the co-morbidity of cardiovascular

disease and depression. We predict that patients suffering

from heart failure who have a high level of inflammatory

products in their blood will also suffer from depression. Our

hypothesis is that if we treat the inflammation, the patient’s

mood and cardiovascular status will both improve, giving a

doubly beneficial effect.

RECENT PUBLICATIONS

Ventorp, Filip, Cecillie Bay-Richter, Analise Sauro, Janelidze Shorena, Viktor Sjödahl Matsson, Jack Lipton, Ulrika Nordström, Åsa

Westrin, and Lena Brundin. 2016. The CD44 ligand hyaluronic acid is elevated in the cerebrospinal fluid of suicide attempters

and is associated with increased blood–brain barrier permeability. Journal of Affective Disorders 193: 349–354.

Bay-Richter, Cecillie, Shorena Janelidze, Analise Sauro, Richard Bucala, Jack Lipton, Tomas Deierborg, and Lena Brundin. 2015.

Behavioural and neurobiological consequences of macrophage migration inhibitory factor gene deletion in mice. Journal of

Neuroinflammation 12: 163.

Bay-Richter, Cecillie, Klas R. Linderholm, Chai K. Lim, Martin Samuelsson, Lil Träskman-Bendz, Gilles J. Guillemin, Sophie

Erhardt, and Lena Brundin. 2015. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate

receptor in depression and suicidality. Brain, Behavior, and Immunity 43: 110–117.

CENTER FOR NEURODEGENERATIVE SCIENCE

51


PATRIK BRUNDIN, M.D., PH.D.

Dr. Brundin earned both his M.D. and Ph.D. at Lund University

in Sweden. He was a professor of neuroscience at Lund before

becoming a Professor and Associate Research Director of VARI

in 2012.

STAFF

KIM COUSINEAU, MPA

SONIA GEORGE, PH.D.

NOLAN REY, PH.D.

EMILY SCHULTZ, B.S.

JENNIFER STEINER, PH.D.

TREVOR TYSON, PH.D.

ADJUNCT FACULTY

WILLIAM BAER, M.D., PHARM.D.

RESEARCH INTERESTS

The mission of the laboratory is to understand why Parkinson’s disease (PD) develops

and to use cellular and animal PD models to discover new treatments that slow or

stop disease progression. To achieve this goal, the laboratory has several ongoing,

externally funded projects that study the pathogenic processes of PD.

Misfolded variants of the protein α-synuclein (α-syn) are the main constituent

of the protein aggregates that make up intraneuronal Lewy bodies, the major

neuropathological hallmark of PD. Mutations in the gene encoding α-syn underlie

rare forms of inherited PD, and these mutations trigger α-syn aggregation in neurons.

Furthermore, genetic changes that increase the amount of α-syn in neurons also

result in α-syn aggregation and cause neurodegenerative disease. The molecular

mechanisms that cause cell death when α-syn aggregates are poorly understood. Our

team was one of the first to propose and demonstrate that intercellular propagation

of abnormal α-syn protein might drive the progression of symptoms by involving more

brain regions. Several of our projects aim to identify the mechanisms underlying α-syn

transmission and to clarify the role of this process in PD development.

One project uses C. elegans to examine α-syn transfer and assembly into small

aggregates. We have created a genetically modified worm in which α-syn coupled

to a truncated fluorescent reporter protein is expressed in one set of neurons, while

α-syn coupled to the remaining part of the fluorescent reporter is expressed in different

neurons that are anatomically connected to the first set. When α-syn transfers from

one neuron to a neighboring one, it can assemble with the α-syn protein already

present, allowing the reporter protein to reconstitute and fluoresce. We are continuing

to modify these worms to study the genetic pathways that control intercellular transfer

and assembly of α-syn.

52 Van Andel Research Institute | Scientific Report


We also use mouse models to evaluate α-syn transmission

between brain regions. In one model, mice are first

engineered to express large amounts of human α-syn

protein in the nigrostriatal pathway. Immature neurons

lacking human α-syn (graft) are transplanted into the

striatum. After several weeks, human α-syn can be found

in the transplanted neurons, which could only occur by

transmission from the host brain to the grafted neurons.

We are currently defining how inflammation contributes to

α-syn spread in this model. We hypothesize that microglia

remove extracellular α-syn that is available for transfer from

cell to cell, and that the activation of microglia (as occurs in

PD) will influence the efficacy of clearance of α-syn from the

extracellular space.

We have developed another mouse model based on

injections of misfolded α-syn into the olfactory bulb. The

loss of olfaction is an early change in PD, and the olfactory

bulb has been proposed to be a starting point of Lewy body

pathology, possibly due to an environmental insult. In our

model, α-syn aggregate pathology gradually spreads along

olfactory pathways, causing progressive olfactory deficits.

Given that α-syn transmission between cells is thought to

drive PD progression, interfering with this process might

slow the worsening of symptoms. We have partnered with

GISMO Therapeutics Inc. and obtained funding from the

Michael J. Fox Foundation to evaluate the ability of heparan

sulfate proteoglycan (HSPG) inhibitors to prevent transfer of

α-syn between cells in cell culture and in mouse models.

Genetic factors other than α-syn also influence PD

risk. Recent genetic studies have identified the enzyme

aminocarboxy-muconate semialdehyde decarboxylase

(ACMSD) as a modifier of PD risk. This enzyme is a key

regulator of the kynurenine pathway, which regulates

neuroinflammation. The Michael J. Fox Foundation funds a

joint project with Dr. Lena Brundin in which we are exploring

whether overexpression of ACMSD in a rat model of PD can

reduce neuroinflammation and be neuroprotective.

We are also exploring whether modulation of the

mitochondrial pyruvate carrier (MPC) can protect neurons

from death. We use the compound MSDC-0160, which is

an MPC modulator originally developed as an anti-diabetic

agent. Thanks to funding from the Cure Parkinson’s Trust

UK, the Campbell Foundation, and the Spica family, we

have shown that MSDC-0160 is a powerful protectant

against neurodegeneration in several toxin and genetic

models of PD. The compound influences the capacity

of the neurons to carry out the autophagy process (a cell

stress response that is altered in PD), promoting their

survival, and it also inhibits neuroinflammation. Given the

favorable safety profile of MSDC-0160, the drug is already

under consideration for PD clinical trials, demonstrating its

high potential for clinical translation.

RECENT PUBLICATIONS

Brundin, Patrik, Graham Atkin, and Jennifer T. Lamberts. 2015. Basic science breaks through: new therapeutic advances in

Parkinson’s disease. Movement Disorders 30(11): 1521–1527.

Nordström, Ulrika, Geneviève Beauvais, Anamitra Ghosh, Baby Chakrapani Pulikkaparambil Sasidharan, Martin Lundblad,

Julia Fuchs, Rajiv L. Joshi, Jack W. Lipton, Andrew Roholt, et al. 2015. Progressive nigrostriatal terminal dysfunction and

degeneration in the engrailed1 heterozygous mouse model of Parkinson’s disease. Neurobiology of Disease 73: 70–82.

Reyes, Juan F., Tomas T. Olsson, Jennifer T. Lamberts, Michael J. Devine, Tilo Kunath, and Patrik Brundin. 2015. A cell culture

model for monitoring α-synuclein cell-to-cell transfer. Neurobiology of Disease 77: 266–275.

CENTER FOR NEURODEGENERATIVE SCIENCE

53


GERHARD A. COETZEE, PH.D.

Dr. Coetzee earned his Ph.D. in medical biochemistry from the

University of Stellenbosch, South Africa, in 1977. He was a

professor in the Departments of Urology, Microbiology, and

Preventive Medicine at the Keck School of Medicine at USC before

joining VARI as a Professor in November 2015.

STAFF

ALIX BOOMS, B.S.

KIM COUSINEAU, MPA

STEVE PIERCE, PH.D.

TREVOR TYSON, PH.D.

J.C. VANDERSCHANS, B.S.

RESEARCH INTERESTS

Our laboratory focuses on applying genome-wide association studies (GWAS)

to uncovering the roles of genetic risk variants in Parkinson’s disease. GWAS of

complex phenotypes have become more powerful as the sample sizes of cases and

controls have increased and meta-analyses have been employed. Additionally, as

next-generation sequencing techniques have become more feasible and increasingly

affordable, more single nucleotide polymorphisms (SNPs) with lower minor allele

frequencies have been identified. Thus, association signals at any given locus have

become increasingly complex, in large part due to the many candidate risk SNPs

correlated with each other due to linkage disequilibrium (LD). Consequently, it is

virtually impossible to assign functionality, let alone causality, to any given SNP at a

risk locus. This dispiriting situation is only made more daunting by the unexpected

finding that for many complex diseases, more than 80% of the risk SNPs are located

in noncoding DNA. To address these issues, we and others have used chromatin

biofeatures to inform potential functionality on the original discovery SNPs (known to

the field as “index SNPs”) and their many surrogate SNPs—the former revealed by

GWAS and the latter defined by the r 2 of the population-specific LD.

54 Van Andel Research Institute | Scientific Report


VIVIANE LABRIE, PH.D.

Dr. Labrie received her Ph.D. in genetics and neuroscience from the

University of Toronto. She was an assistant professor at University

of Toronto before joining VARI in early 2016.

STAFF

AUDREY ANDERSON, B.S.

JENNIFER JAKUBOWSKI, M.S.

RESEARCH INTERESTS

Our goal is to gain an in-depth understanding of the primary molecular causes of

Alzheimer’s disease and Parkinson’s disease in order to help develop new treatments.

Specifically, we study epigenetic involvement in these neurodegenerative illnesses.

Epigenetic marks act like a layer over the top of the DNA sequence code, controlling gene

activities without changing the DNA sequence. Epigenetic marks are partially stable:

i.e., they have the capacity to change in response to environmental signals and over

time. This dynamic aspect is highly relevant, because advanced age is the best-known

risk factor for both Alzheimer’s and Parkinson’s disease. It takes years before symptoms

arise in patients, and after disease onset, the pathological features and symptoms worsen

with time. We propose that aberrant epigenetic changes, accumulating with age at key

genomic regions, contribute to the etiology of these diseases.

We perform genome-wide searches for epigenetic abnormalities in genomic regulatory

elements such as enhancers, which affect the complex spatial and temporal expression

of genes. Under the influence of regulatory elements, genes can be highly expressed

in certain tissues or cell types and weakly or not at all in others. By activating or

repressing regulatory elements, epigenetic marks can modify the abundance, timing,

and cell-specific patterns of gene expression, which is central to healthy brain function.

By applying epigenomic and next generation sequencing–based techniques in human

samples, we aim to identify epigenetically misregulated regulatory elements in Alzheimer’s

and Parkinson’s disease. We also examine the interaction between DNA sequence

factors (SNPs) and epigenetic marks to determine whether certain disease risk variants

help coordinate epigenetic misregulation at regulatory elements.

Once the regulatory elements that bear epigenetic disturbances are identified, functional

studies help to understand how these elements contribute to disease susceptibility. We

look for changes in 3D chromatin conformation and in gene transcripts to identify the

genes and pathways affected. We also use genome editing techniques (CRISPR-Cas9)

in cell lines and mice to determine the extent to which epigenetically disrupted regulatory

elements contribute to disease pathology and symptoms. Through this research we can

uncover new genomic regions causally involved in Alzheimer’s and Parkinson’s disease.

CENTER FOR NEURODEGENERATIVE SCIENCE

55


Double calcein-labeled bone cross section from a six-month-old female Hrpt2 cKO mouse.

Bones were labeled ten days apart to measure the bone formation rate. The large cortical pits

outlined in green stain are due to mature osteoblasts and osteocytes lacking the Hrpt2 gene, which

is required for proper regulation of transcription. Image by Casey Droscha of the Williams lab.

56 Van Andel Research Institute | Scientific Report


JIYAN MA, PH.D.

Dr. Ma earned his Ph.D. in biochemistry and molecular biology from

the University of Illinois at Chicago. He was at Ohio State University

from 2002 until he joined VARI in November 2013 as a Professor.

STAFF

ROMANY ABSKHARON, PH.D.

AUDREY ANDERSON, B.S.

KATELYN BECKER, M.S.

AMANDINE ROUX, PH.D.

JUXIN RUAN, PH.D.

FEI WANG, PH.D.

XINHE WANG, PH.D.

RESEARCH INTERESTS

Protein aggregation is a key pathological feature of a large group of late-onset

neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. Our

overall goals are to elucidate the molecular events leading to protein misfolding in

the aging central nervous system; to understand the relationship between misfolded

protein aggregates and neurodegeneration; and, to develop approaches to prevent,

stop, or reverse protein aggregation and neurodegeneration in these devastating

diseases.

We study protein aggregates in prion diseases (transmissible spongiform

encephalopathies). These are true infectious diseases that can spread from

individual to individual and cause outbreaks. We have established an in vitro system

to reconstitute prion infectivity with bacterially expressed prion protein plus defined

cofactors. We use this system to dissect the essential components and the structural

features of an infectious prion and to uncover the molecular mechanisms responsible

for the prion strain and species barrier.

Recently, the concept of prions has expanded to Parkinson’s and Alzheimer’s

diseases. α-Synuclein has been suggested to spread the disease pathology in a prionlike

manner from a sick cell to healthy ones. We want to understand the similarities

and differences between prions and amyloidogenic proteins. We are investigating

cellular factors that affect α-synuclein aggregation and the connections between

various α-synuclein aggregated forms, their prion-like spread, and dopaminergic

neuron degeneration.

RECENT PUBLICATIONS

Yu, Guohua, Ajun Deng, Wanbin Tang, Junzhi Ma, Chonggang Yuan, and Jiyan Ma. In press. Hydroxytyrosol induces phase II

detoxifying enzyme expression and effectively protects dopaminergic cells against dopamine- and 6-hydroxydopamine induced

cytotoxicity. Neurochemistry International.

Yu, Guohua, Huiyan Liu, Wei Zhou, Xuewei Zhu, Chao Yu, Na Wang, Yi Zhang, Ji Ma, Yulan Zhao, et al. 2015. In vivo protein

targets for increased quinoprotein adduct formation in aged substantia nigra. Experimental Neurology 271: 13–24.

CENTER FOR NEURODEGENERATIVE SCIENCE 57


DARREN J. MOORE, PH.D.

Dr. Moore earned a Ph.D. in molecular neuroscience from the

University of Cambridge, U.K., in 2001 in the laboratory of Piers

Emson. He was at Johns Hopkins (2002–2008) and at the Swiss

Federal Institute of Technology (EPFL) in Lausanne (2008–2014) before

joining the VARI faculty as an Associate Professor in early 2014.

STAFF

AUDREY ANDERSON, B.S.

XI CHEN, PH.D.

LINDSEY CUNNINGHAM, B.S.

SHARIFUL ISLAM, PH.D.

JEN KORDICH, M.S.

NATE LEVINE, B.S.

AN PHU TRAN NGUYEN, PH.D.

ERIN WESTON, B.A.

LESLIE WYMAN, B.S.

RESEARCH INTERESTS

Our laboratory studies the molecular pathogenesis of Parkinson’s disease, with

the long-term goal of developing novel, targeted, disease-modifying therapies and

neuroprotective strategies. Although most cases of PD are sporadic, 5–10% of cases

are inherited, with causative mutations identified in at least 12 genes. We focus on the

cell biology and pathophysiology of several proteins that cause inherited PD, including

the dominantly inherited leucine-rich repeat kinase 2 (LRRK2; a multi-domain protein

with GTPase and kinase activity) and vacuolar protein sorting 35 ortholog (VPS35; a

component of the retromer complex), as well as the recessive proteins parkin (a RINGtype

E3 ubiquitin ligase) and ATP13A2 (a lysosomal P 5B

-type ATPase). We seek to

explain the normal biological function of these proteins in the mammalian brain and the

molecular mechanism(s) through which disease-associated variants produce neuronal

dysfunction and eventual neurodegeneration in inherited forms of Parkinson’s.

We employ a multidisciplinary approach that combines molecular, cellular, and

biochemical techniques in experimental model systems such as human cell lines,

primary neuronal cultures, Saccharomyces cerevisiae, and human brain tissue. We also

have developed several unique rodent-based models (transgenic, knock-out, knock-in)

for mechanistic studies of these proteins.

58 Van Andel Research Institute | Scientific Report


Some of our current projects focus on

• the contribution of enzymatic activity and protein aggregation to neurodegeneration in novel, adenoviral-based, LRRK2

rodent models of PD;

• neuroprotective effects of pharmacological kinase inhibition in LRRK2 rodent models;

• genome-wide identification of genetic modifiers of LRRK2 toxicity in S. cerevisiae;

• identification of novel GTPase effector proteins and kinase substrates for LRRK2;

• the role of ArfGAP1 in mediating LRRK2-induced neurotoxic pathways; and

• the development of novel rodent models of VPS35-linked PD and the pathological interactions of VPS35 with

α-synuclein and LRRK2.

RECENT PUBLICATIONS

Daniel, Guillaume, and Darren J. Moore. 2015. Modeling LRRK2 pathobiology in Parkinson’s disease: from yeast to rodents.

In Behavioral Neurobiology of Huntington’s Disease and Parkinson’s Disease, Hoa Huu Phuc Nguyen and M. Angela Cenci, eds.

Current Topics in Behavioral Neurosciences series, Vol. 22. Berlin: Springer Verlag, pp. 331–368.

Daniel, Guillaume, Alessandra Musso, Elpida Tsika, Aris Fiser, Liliane Glauser, Olga Pletnikova, Bernard L. Schneider, and Darren

J. Moore. 2015. α-Synuclein-induced dopaminergic neurodegeneration in a rat model of Parkinson’s disease occurs independent

of ATP13A2 (PARK9). Neurobiology of Disease 73: 229–243.

Tsika, Elpida, An Phu Tran Nguyen, Julien Dusonchet, Philippe Colin, Bernard L. Schneider, and Darren J. Moore. 2015.

Adenoviral-mediated expression of G2019S LRRK2 induces striatal pathology in a kinase-dependent manner in a rat model of

Parkinson’s disease. Neurobiology of Disease 77: 49–61.

CENTER FOR NEURODEGENERATIVE SCIENCE 59


JEREMY VAN RAAMSDONK, PH.D.

Dr. Van Raamsdonk completed a Ph.D. in medical genetics at

the University of British Columbia in 2005. He joined VARI as an

Assistant Professor in 2012.

STAFF

AUDREY ANDERSON, B.S.

DYLAN DUES, B.S.

MEGAN SENCHUK, PH.D.

STUDENTS

JASON COOPER, B.S.

EMILY MACHIELA, B.S.

RESEARCH INTERESTS

As the average human life span continues to increase, the likelihood of an individual

developing a neurodegenerative disease also increases. Thus, there is a need to

understand the aging process and its role in the development of age-onset disorders

such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Our

research is focused on gaining insight into the aging process and the pathogenesis

of such diseases. Beyond benefit to the individual, this work has potential benefits

for society by decreasing health care costs and helping to maintain productivity and

independence to a later age.

The free radical theory of aging (FRTA) proposes that aging results from the

accumulation of oxidative damage caused by reactive oxygen species (ROS) generated

during normal metabolism. However, recent work in the worm Caenorhabditis elegans

has indicated that the relationship between ROS and life span is more complex.

Superoxide dismutase (SOD) is an enzyme that decreases the levels of ROS, but the

deletion of SOD genes (individually or in combination) does not decrease life span. In

fact, quintuple-mutant worms lacking all five sod genes live as long as wild-type worms

despite a markedly increased sensitivity to oxidative stress. Thus, it appears that while

oxidative damage increases with age, it does not cause aging, and the result with the

quintuple mutants suggests a balance between the pro-survival signaling and the toxic

effects of superoxide.

Recent evidence suggests that increased levels of superoxide can act as a pro-survival

signal that leads to increased longevity. This is demonstrated by life-span increases

following the deletion of the mitochondrial gene sod-2 and the treatment of wild-type

worms with the superoxide generator paraquat. Thus, one of the main goals of

this work is to uncover the mechanism by which superoxide-mediated pro-survival

signaling leads to increased longevity. Using a combination of genetic mutants and

RNA interference, we explore how increases in superoxide trigger the signal, how the

signal is transmitted, and which of the changes the signal introduces lead to increased

life span.

60 Van Andel Research Institute | Scientific Report


The role of aging in Parkinson’s disease

The greatest risk factor for developing Parkinson’s disease

(PD) is advanced age. Even individuals with the inherited

forms of PD live decades without exhibiting symptoms or

neuronal loss, despite the fact that the disease-causing

mutation is already present at birth. This suggests that

changes taking place during normal aging make cells

more susceptible to the mutations implicated in PD. This

conclusion is supported by the fact that the onset of the

disease in animal models is proportional to the life span

of the organism and is not related to chronological time.

Moreover, several changes known to take place during the

aging process have been shown to affect functions involved

in the pathogenesis of PD.

crosses to generate double mutants and will use RNA

interference via feeding to specifically knock down genes

of interest. The health of the resulting worms will be

compared with that of control worms to determine whether

the aging gene affects the disease-like abnormalities. By

examining the role of aging in PD, this project will provide

new insight into the mechanism underlying the disease.

This knowledge will provide novel therapeutic targets that

may lead to an effective treatment.

This work will be conducted using C. elegans PD models,

because these worms have orthologs to almost all of the

genes implicated in PD, including PARK2 (pdr-1), PINK-1

(pink-1), LRRK-2 (lrk-1), DJ-1 (djr-1.1,-1.2), UCHL-1 (ubh-1),

ATP13A2 (catp-6), VPS-35 (vps-35), and GBA (gba-1-4).

Several worm models of PD have been developed,

including chemical models such as 6-OHDA and MPTP

transgenic worms expressing α-synuclein; transgenic

worms expressing mutant LRRK2; and deletion mutants of

pdr-1, pink-1, djr-1.1, and catp-6. These models exhibit a

number of PD-related phenotypes, including aggregation

of α-synuclein, decreased mobility, decreased adaption to

food (a response mediated by dopamine neurons), and,

importantly, degeneration of dopaminergic neurons. The

main goals of this work will be 1) to determine whether

genes that extend life span are beneficial in the treatment of

worm models of PD and 2) to determine whether processes

that show decreased function with age specifically

exacerbate PD-like features. We will use genetic

RECENT PUBLICATIONS

Cooper, Jason F., Dylan J. Dues, Katie K. Spielbauer, Emily Machiela, Megan M. Senchuk, and Jeremy M. Van Raamsdonk. 2015.

Delaying aging is neuroprotective in Parkinson’s disease: a genetic analysis in C. elegans models. npj Parkinson’s Disease 1: 15022.

Schaar, Claire E., Dylan J. Dues, Katie K. Spielbauer, Emily Machiela, Jason F. Cooper, Megan Senchuk, Siegfried Hekimi, and

Jeremy M. Van Raamsdonk. 2015. Mitochondrial and cytoplasmic ROS have opposing effects on life span. PLoS Genetics 11(2):

e1004972.

CENTER FOR NEURODEGENERATIVE SCIENCE

61


62


CORE TECHNOLOGIES

AND SERVICES

Scott D. Jewell, Ph.D.

Director

Staining of mouse bone to visualize bone marrow

(red cells), solid bone with embedded osteocytes

(brown areas) and region of actively growing new

bone (blue-green). Image by Alexis Bergsma.

63


VIVARIUM AND TRANSGENICS CORE

BRYN EAGLESON, M.S., LATG

Ms. Eagleson earned an M.S. degree in laboratory animal science

from Drexel University’s College of Medicine. She worked for many

years at the National Cancer Institute’s Frederick Cancer Research

and Development Center in Maryland before joining VARI as the

Director of Vivarium and Transgenics in 1999.

STAFF

MEGAN BRIGGS, B.S.

THOMAS DINGMAN

NICHOLAS GETZ, B.S.

NAOMI GRABER

AUDRA GUIKEMA, B.S.

TRISTAN KEMPSTON, B.S.

MICHAEL KUBIK

TINA MERINGA, A.A.

DAVID MONSMA, PH.D.

JANELLE POST, B.ED.

MALISTA POWERS

MATHEW RACKHAM

LISA RAMSEY, A.S., LVT

ADAM RAPP, B.S.

APRIL STAFFORD, B.S.

YANLI SU, A.M.A.T.

AURORA THOMS

WILLIAM WEAVER, B.S.

SERVICES

The goal of the VARI Vivarium and Transgenics core is to develop, provide, and maintain

high-quality mouse modeling services. The vivarium is a state-of-the-art facility that

includes a high-level containment barrier. Van Andel Research Institute is an AAALACaccredited

institution, most recently reaccredited in September 2013. All procedures

are conducted according to the Guide for the Care and Use of Laboratory Animals.

The staff provides rederivation, surgery, dissection, necropsy, breeding, weaning,

tail biopsies, sperm and embryo cryopreservation, animal data management, project

management, and health-status monitoring. Transgenic mouse models are produced

on request for project-specific needs. The creation of gene-targeted mice using the

CRISPR/Cas9 systems has recently been implemented. We also provide therapeutic

testing and preclinical model development services. Projects include pharmacological

testing, target validation testing, patient-derived xenograft (PDX) development,

orthotopic engraftment model development, and subcutaneous xenograft/allograft

model development.

64 Van Andel Research Institute | Scientific Report


PATHOLOGY AND BIOREPOSITORY CORE

SCOTT D. JEWELL, PH.D.

Dr. Jewell earned his Master’s and Ph.D. degrees in experimental

pathology and immunology from The Ohio State University. He

served there as director of the Human Tissue Resource Network in

the Department of Pathology. He joined VARI in 2010 as a Professor,

as well as Director of the Program for Technologies and Cores and of

the Program for Biospecimen Science.

STAFF

BREE BERGHUIS, B.S.

ALEX BLANSKI, B.S.

ERIC COLLINS, B.S.

MELISSA DEHOLLANDER, M.B.A., B.S.

BRIANNE DOCTER, M.S.

KRISTIN FEENSTRA, B.S.

PHIL HARBACH, M.S.

MEGHAN HODGES, B.S.

GALEN HOSTETTER, M.D.

ERIC HUDSON, B.S.

CARRIE JOYNT, B.S., HT

JULIE KOEMAN, B.S., CG(ASCP) CM

ROB MONTROY, B.S.

LORI MOON, M.B.A.

CHELSEA PETERSON, B.S.

DANIEL ROHRER, M.B.A., B.S.

LISA TURNER, B.S., HT, QIHC(ASCP)

DANA VALLEY, B.A., CPIA

ANTHONY WATKINS, A.S.

SERVICES

The Pathology and Biorepository Core integrates anatomic pathology expertise with

biorepository and biospecimen science in order to assist in VARI’s research. We build

upon historical strengths in standard histology, microscopy, and biobanking, and we

use novel technologies to test and apply best practices in biospecimen science. The

pathology discipline provides complementary emphasis on high-quality biospecimens

and interpretable results with which to validate experimental models and extend them

to clinical samples, thereby advancing our common translational mission.

Dr. Jewell, with his expertise in experimental pathology, immunology, and biobanking,

and Dr. Hostetter, who is board-certified in anatomic pathology, together provide a wide

range of expertise to the VARI laboratories. Currently, they are studying the effects of

preanalytical variables in tissue collection and transport on the integrity of downstream

analytes. The assessment of tumor suppressors and immunomodulators in tumor

tissues and the application of genomic and epigenomic assays for biospecimens

are among the services provided by the core. The VARI biorepository is nationally

and internationally recognized, serving as the NCI Comprehensive Biospecimen

Resource for the Cancer Human Biobank (caHUB). In 2015, it was designated as

the Biorepository Core Resource for the NCI Clinical Proteomic and Tumor Analysis

Consortium (CPTAC) and as the biorepository for the Tuberous Sclerosis Alliance.

In addition, we are moving into our sixth year of providing biorepository services for

the Multiple Myeloma Research Foundation’s CoMMpass Study. The biorepository

is serving the VARI/SU2C consortium for epigenetics clinical trials biobanking,

collaborating with Drs. Jones and Baylin. Dr. Jewell serves as a committee member for

the College of American Pathologist (CAP) Biorepository Accreditation Program (BAP).

The VARI biorepository has been a CAP BAP-accredited biorepository since 2012 and

was reaccredited in 2015.

CORE TECHNOLOGIES AND SERVICES

65


Pathology Core services

Biorepository Core services

• Histology and diagnostic tissue services,

including morphology, immunohistochemistry, in

situ hybridization, and multiplex fluorescent IHC

assays

• Pathology review and annotation of clinical

samples from VARI’s prospective and retrospective

tissue collections

• Design and construction of tissue microarrays

• Digital imaging and spectral microscopy coupled

with image analysis tools

• Biobanking services for VARI investigators, the

National Cancer Institute, the Multiple Myeloma

Research Foundation, and the Tuberous Sclerosis

Alliance

• Biospecimen kit construction, shipping, and

tracking

• Clinical trials biobanking coordination

• Quality management program

• Cell fractionation and biospecimen processing

• Laser capture microdissection

• Cytogenetics

• Ion Torrent genomic technology

RECENT PUBLICATIONS

The GTEx Consortium. 2015. The Genotype-Tissue Expression (GTEx) analysis: multitissue gene regulation in humans. Science

348(6235): 648–660.

Melé, Marta, Pedro G. Ferreira, Ferran Reverter, David S. DeLuca, Jean Monlong, Michael Sammeth, Taylor R. Young, Jakob M

Goldmann, et al. 2015. The human transcriptome across tissues and individuals. Science 348(6235): 660–665.

Rivas, Manuel A,. Matti Pirinen, Donald F. Conrad, Monkol Lek, Emily K. Tsang, Konrad J. Karczewski, Julian B. Maller, Kimberly

R. Kukurba, et al. 2015. Effect of predicted protein-truncating genetic variants on the human transcriptome. Science 348(6235):

666-669.

66 Van Andel Research Institute | Scientific Report


FLOW CYTOMETRY CORE

HEATHER SCHUMACHER, B.S., MT

(ASCP)

Heather Schumacher has a B.S. in medical technology from

Ferris State University and is certified by the American Society of

Clinical Pathologists as a generalist (MT). She has over 12 years of

experience in hematology/flow cytometry and is proficient on three

major vendor platforms, including eight different flow cytometers.

She joined VARI as the Flow Cytometry Core manager in 2012.

SERVICES

The core provides comprehensive flow cytometry analysis and sorting services

in support of VARI research. Additional services include assistance with protocol

development and training in data analysis. Flow cytometry services are provided using

a Beckman Coulter MoFlo Astrios and Beckman Coulter CytoFLEX S. Other equipment

for blood analysis includes a VetScan instrument, a VetScan HMII, and a Shandon

Cytospin 3.

CORE TECHNOLOGIES AND SERVICES

67


BIOINFORMATICS AND BIOSTATISTICS CORE

MARY E. WINN, PH.D.

Dr. Winn earned her Ph.D. from the University of California, San Diego.

She became VARI’s Bioinformatics and Biostatistics Core manager in 2013.

STAFF

MEGAN BOWMAN, PH.D.

BENJAMIN JOHNSON, PH.D.

ZACHARY MADAJ, M.S.

STUDENTS

MICHELE GORT

MARGARET KLEIN

ZACHARY WEBER

NICOLE ZOLMAN

SERVICES

Established in April 2013, the Bioinformatics and Biostatistics Core serves the analytical

needs of VARI by providing efficient, high-quality computational and statistical

support for VARI research labs wrestling with the analysis and interpretation of data.

The broader mission of the BBC is to strengthen and maintain bioinformatics and

biostatistics techniques across all VARI laboratories. The BBC maintains sequencing

pipelines for processing and analyzing genomic data sets; provides access to a variety

of proprietary and open-source resources; supports the design, planning, conduct,

analysis, and reporting of research; and more.

We provide statistical consulting; experimental design (including research proposal

development, sample size determination, and randomization procedures); analysis,

interpretation, and presentation of small and large data sets; manuscript preparation

and data deposition; genomic variant detection and annotation; transcript/isoform

differential expression; and DNA copy number determination. We also perform

systems-level analysis such as gene-set or network-based analysis. We support the

greater educational mission of the Institute, helping students and staff develop an

analytic approach and skills in experimental design through seminars, lectures, and

workshops.

The BBC maintains external collaborations with various academic and industrial

partners, including Michigan State University and Henry Ford Health Systems.

RECENT PUBLICATIONS

Osgood, Christy L., Nichole Maloney, Christopher G. Kidd, Susan Kitchen-Goosen, Laura Segars, Meti Gebregiorgis, Girma M.

Woldemichael, Min He, Savita Sankar, et al. In press. Identification of mithramycin analogs with improved targeting of the EWS-

FLI1 transcription factor. Clinical Cancer Research.

Sameni, Mansoureh, Elizabeth A. Tovar, Curt Essenburg, Anita Chalasanik, Erik S. Linklater, Andrew Borgman, David M. Cherba,

Arulselvi Anbalagan, Mary E. Winn, et al. 2016. Cabozantinib (XL184) inhibits growth and invasion of preclinical TNBC models.

Clinical Cancer Research 22(4): 923–934.

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Van Andel Research Institute | Scientific Report


CONFOCAL MICROSCOPY AND

QUANTITATIVE IMAGING CORE

STAFF

KRISTIN FEENSTRA, B.S.

ERIC HUDSON, B.S.

JEFFREY KORDOWER, PH.D.

ANDERSON PECK, M.S.E.

SERVICES

Established in October 2013, the core provides optical imaging services for Van Andel

Research Institute and collaborating institutions, as well as the expertise and analytical tools

to use them effectively. Our services include live-cell imaging and biosensor studies of cell

signaling in cancer and brain tissue; the measurement of gene expression, protein transport,

and protein-protein interactions; and 3D reconstruction of large fluorescent structures in

tissue blocks. Training in these techniques and in the management of the data obtained is

provided. We have two scanning confocal microscopes, a Nikon A1-RSi with coded stage

and a Zeiss 510 META-MP instrument. The core has collaborations with academic partners

at nearby universities, including Michigan State University and Western Michigan University.

The core allows users of all experience levels to perform quantitative research at or

exceeding the professional standards of their field. We have implemented a comprehensive

solution for the collection, management, and processing of all imaging data for researchers

at VARI.

A suite of commercial and open-source image analysis programs on a powerful Z620

workstation is available. Options include deconvolution and complex 3D visualization

(Huygens Professional), neuron tracing (IMARIS Suite), high-throughput phenotype

quantitation, machine learning (CellProfiler and CPAnalyst), sophisticated mathematical

analysis options (MATLAB), and image manipulation or figure preparation software such

as Fiji/Image J, Photoshop, and GIMP.

The core has also added a PerkinElmer Vectra, a multi-modal, automated imaging system

for scanning tissue sections and acquiring multispectral images. IT supports workflows

including whole-slide scanning, annotation, and review through a simple, intuitive interface.

It includes an operator-centric system for performing whole-slide scans and acquiring

multispectral images in regions of interest. Regions for image acquisition can be selected

using inForm Tissue Finder software for fully automated operation.

CORE TECHNOLOGIES AND SERVICES

69


SMALL-ANIMAL IMAGING FACILITY

STAFF

ANDERSON PECK, M.S.E.

SERVICES

The Small-Animal Imaging Facility focuses on the development of preclinical imaging

technologies that offer anatomic and functional information to biomedical investigators. We

also aim to develop imaging technologies capable of monitoring organ/tissue activity at the

molecular level in order to advance clinical applications such as early detection and staging

of cancer. By combining new tracers, imaging analysis, and genomic information, we are

assisting investigators in non-invasive imaging technologies for translational research. Our

technologies include digital X-ray, high-resolution microCT, microSPECT/CT, microPET/CT,

micro-ultrasound, optical imaging, radiochemistry, and custom tracers. Our comprehensive

facility management system was designed to provide real-time analysis capabilities for

imaging studies. This system allows researchers to group mice based on results from

previous time points, enhancing the study’s overall quality and making effective use of

resources.

We have developed 1) an automated system to quantify tail residual activity for correction of

standard uptake value–related calculations in PET and SPECT imaging; 2) a QA/QC protocol

to evaluate whether an optical imager with certain characteristics is adequate for Cherenkov

luminescence imaging acquisition; 3) an in vivo, non-invasive, high-resolution imaging

method for Kupffer cell migration in response to early liver metastasis; and 4) a method

to reduce respiratory artifacts in microCT imaging by using a high-frequency oscillatory

ventilation system.

70 Van Andel Research Institute | Scientific Report


AWARDS FOR

SCIENTIFIC ACHIEVEMENT

71


JAY VAN ANDEL AWARD FOR OUTSTANDING

ACHIEVEMENT IN PARKINSON’S DISEASE RESEARCH

This award was established to honor distinguished researchers in the field of Parkinson’s disease and is named after Van Andel

Institute founder Jay Van Andel, who passed away in 2004 after a long struggle with the disease. Awardees are selected on the

basis of their scientific achievements and renown as a leader in Parkinson’s research or in research on closely related neurodegenerative

disorders.

2015 Award Recipients

Robert Nussbaum, M.D., FACP, FACMG

Maria Grazia Spillantini, Ph.D., FMedSci, FRS

Dr. Nussbaum was the senior author on a 1997 Science paper

that first linked a mutation in the gene that codes for α-synuclein

to an inherited form of Parkinson’s disease. Later that year, Dr.

Spillantini and her colleagues published a paper in Nature that

identified α-synuclein as the main component of Lewy bodies

in all forms of Parkinson’s, not just inherited cases. These

discoveries were groundbreaking, opening a new, crucial area of

research into the role of this protein in Parkinson’s disease. Dr.

Nussbaum holds the Holly Smith Distinguished Professorship in

Science and Medicine and is Chief of the Division of Genomic

Medicine at the University of California, San Francisco. Dr.

Spillantini is a Professor of molecular neurology at the University

of Cambridge’s Department of Clinical Neuroscience.

Drs. Spillanti and Nussbaum at the award ceremony.

Prior Recipients

Andrew John Lees, M.D., FRCP, FMedSci 2014

Alim-Louis Benabid, M.D., Ph.D. 2013

Andrew Singleton, Ph.D. 2012

72 Van Andel Research Institute | Scientific Report


HAN-MO KOO MEMORIAL AWARD

Dr. Han-Mo Koo joined the Van Andel Research Institute in 1999 as one of its founding investigators. He established important

projects to identify genetic targets for anticancer drugs against melanoma and pancreatic cancer, and he worked tirelessly to

contribute to the Institute's mission to improve health and enhance lives. In May 2004, Dr. Koo passed away following a six-month

battle with cancer. To honor his memory and scientific contributions, the Han-Mo Koo Memorial Award and Lecture was established

in 2010. Awardees are selected based upon their scientific achievements and their contributions to human health and research that

align with the scientific legacy of Han-Mo Koo.

2015 Award Recipient

Eric S. Lander, Ph.D.

Dr. Eric Lander is founding director of the Broad Institute,

Professor of biology at Massachusetts Institute of Technology,

and Professor of systems biology at Harvard Medical School.

As one of the principal leaders of the Human Genome Project,

Lander and his colleagues created many of the key tools for

the study of human genomics and have applied these tools

in pioneering new ways to understand cancer, diabetes, and

inflammatory diseases. In 2009, President Obama appointed

him to co-chair the President’s Council of Advisors on Science

and Technology. He is a member of the U.S. National Academy

of Sciences, among many other honors. Dr. Lander earned his

B.A. in mathematics from Princeton University and his Ph.D. in

mathematics from Oxford University as a Rhodes Scholar.

Dr. Lander delivering his Dr. Han-Mo Koo Award address.

Prior Recipients

Frank P. McCormick, Ph.D., F.R.S 2013

Phillip A. Sharp, Ph.D. 2012

73


EDUCATIONAL AND

TRAINING PROGRAMS

74 Van Andel Research Institute | Scientific Report


VAN ANDEL INSTITUTE

GRADUATE SCHOOL

Steven J. Triezenberg, Ph.D.

President and Dean

Van Andel Institute Graduate School develops future leaders in biomedical research

through an intense, problem-focused Ph.D. degree in cellular, molecular, and genetic

biology. VAIGS has created an innovative curriculum that guides doctoral students

to think and act like research leaders through problem-based learning. In doing so,

students develop key skills of finding and evaluating scientific knowledge and of

designing experimental approaches to newly arising questions. We also foster the

development of leadership skills and professional behavior, and we seek to integrate

graduate students into the professional networks and culture of science. VAIGS

currently has 23 students and seeks to admit five to six students each year. VAIGS

alumni have gone on to postdoctoral positions at leading biomedical research

institutions throughout the United States. VAIGS is accredited by the Higher Learning

Commission (www.hlcommission.org; 1-800-621-7440).

Julie Davis Turner, Ph.D., Associate Dean

Kathy Bentley, B.S.

Patty Farrell-Cole, Ph.D.

Michelle Love, M.A.

Christy Mayo, M.A.

Nancy Schaperkotter, A.M., LCSW, CEAP

Kristie Vanderhoof, B.A.

75


POSTDOCTORAL FELLOWSHIP PROGRAM

Van Andel Research Institute provides postdoctoral training opportunities to advance the knowledge and

research experience of new Ph.D.s while at the same time supporting our research endeavors. Each fellow is

assigned to a scientific investigator who oversees the progress and direction of research. Fellows who worked

in VARI laboratories in late 2015 and in 2016 are listed below.

Romany Abskharon

Virje University, Egypt

VARI mentor: Jiyan Ma

Xiangqi (Neil) Meng

Sun Yat-sen University, China

VARI mentor: Xiaohong Li

Laura Tarnawski

Lund University, Sweden

VARI mentor: Stefan Jovinge

Xi Chen

University of Liverpool, UK

VARI mentor: Darren Moore

An Phu Tran Nguyen

Universität Tübingen, Germany

VARI mentor: Darren Moore

Rochelle Tiedemann

Georgia Reagents University, Augusta

VARI mentor: Peter Jones/Scott Rothbart

Evan Cornett

University of Central Florida, Orlando

VARI mentor: Scott Rothbart

Hitoshi Otani

Tokyo Medical and Dental University

VARI mentor: Peter Jones

Elizabeth Tovar

Wayne State University, Detroit, Michigan

VARI mentor: Carrie Graveel

Paul Daft

University of Alabama, Tuscaloosa

VARI mentor: Xiaohong Li

Kuntal Pal

National University of Singapore

VARI mentor: Eric Xu

Laura Winkler

University of Wisconsin, Madison

VARI mentor: Stefan Jovinge

Kristin Dittenhafer-Reed

University of Wisconsin, Madison

VARI mentor: Jeff MacKeigan

Keerthi Thirtamara Rajamani

The Ohio State University, Columbus

VARI mentor: Lena Brundin

Jiyoung Yu

Seoul National University, South Korea

VARI mentor: Gerd Pfeifer

Sourik Ganguly

University of Kentucky, Lexington

VARI mentor: Cindy Miranti/Xiaohong Li

Nolwen Rey

University of Lyon, France

VARI mentor: Patrik Brundin

Tie-Bo Zeng

Harbin Institute of Technology, China

VARI mentor: Prioska Szabó

Shariful Islam

Max Plank Institute for Heart

and Lung Research, Germany

VARI mentor: Darren Moore

Amandine Roux

University of Pierre and Marie Currie,

France

VARI mentor: Jiyan Ma

Wanding Zhou

Rice University, Houston, Texas

VARI mentor: Peter Jones/Peter Laird/

Hui Shen

Yanyong Kang

Institute of Biophysics,

Chinese Academy of Sciences

VARI mentor: Eric Xu

Juxin Ruan

Shanghai Institute for Biological Sciences,

Chinese Academy of Sciences

VARI mentor: Jiyan Ma

76 Van Andel Research Institute | Scientific Report


INTERNSHIP PROGRAMS

The Summer Internship Programs are designed

to provide undergraduate college students

opportunities to be mentored by professionals in

their chosen research field, to become familiar with

the use of state-of-the-art scientific equipment and

technology, and to learn valuable interpersonal and

presentation skills. The goal of these programs is

to expose aspiring researchers and clinicians to

exciting advances in biomedical sciences that will

help define their career paths. Internships last 10

weeks, with two cohorts per summer.

Since 2001, hundreds of VARI internships have

been generously supported through the Frederik

and Lena Meijer Summer Internship Program.

Meijer interns are noted in the listing below by

an asterisk (*).

Van Andel Education Institute also partners with

United Negro College Fund (UNCF) to match

students interested in biomedical research careers

with summer research internships at VARI.

2015 UNDERGRADUATE INTERNS

Amherst College,

Amherst, Massachusetts

Michael Bessey (Williams)

Aquinas College,

Grand Rapids, Michigan

Hannah Jablonski (D, C, and M)

Caitlin Rietsema (D, C, and M)

Calvin College,

Grand Rapids, Michigan

Amy Bohner (Graduate School)

Rachel Buikema (Willliams)

Michael DeMeester (Laird)

Matthew Hollowell (Wu)

John Lensing (Williams)

Megan VanBaren (MacKeigan)

Central Michigan University,

Mount Pleasant

Alyssa Shepard (Sempere)

Clemson University,

Clemson, South Carolina

Leland Dunwoodie (Haab)

Dillard University,

New Orleans, Louisiana

Latisha Franklin, (Duesbery)

Ferris State University,

Big Rapids, Michigan

Shayna Donoghue (Sempere)

Luke Gillespie (Facilities)

Grand Valley State University,

Allendale, Michigan

Daniela Gomez (Sempere)

Margaret Klein (Winn)

Austin Meadows (Li)

Madison Schmidtmann

(Glassware/media)

Megan Thompson (Duesbery)

Hope College,

Holland, Michigan

Zachary DeBruine (Melcher)

Claire Schaar (Van Raamsdonk)

Philip Versluis (Rothbart)

Kalamazoo College,

Kalamazoo, Michigan

Reid Blanchett (Triezenberg)

Michigan State University,

East Lansing

William Hanrahan (MacKeigan)

Joseph Kretowicz (Haab)

Jack Pfeiffer (Yang)

Purdue University,

Lafayette, Indiana

Eric Li (Xu)

University of Michigan,

Ann Arbor

Christian Cavacece (Melcher)

John Cooper (Ma)

Kellie Spahr (Miranti)

University of Pennsylvania,

Phildelphia

Elizabeth Goodspeed (P. Brundin)

Washington University in St. Louis,

Missouri

Saranya Sundaram (Moore)

Wayne State University,

Detroit, Michigan

Ethan Cutler (Library)

Western Michigan University,

Kalamazoo

Nathan Morgan (Logistics)

Wheaton College,

Wheaton, Illinois

Devon Jeltema (Jewell)

77


2015 Summer Interns

Kneeling, left to right: Cavacece, Versluis, Gillespie, Morgan, Meadows, Dunwoodie, Shepard, Cutler. Standing, left to right: Lensing,

DeBruin, Hanrahan, DeMeester, Bohner, Kretowicz, Goodspeed, Li, Sundaram, Klein, Pfeiffer, Rietsema, Schmidtmann, Blanchett,

Spahr, Cooper, Buikema, Schaar, VanBaren, Jeltema, Bessey, Donoghue, Thompson, Hollowell, Franklin

Academy of Modern Engineering

The Academy of Modern Engineering (AME) is one

of four specialized programs within Innovation

Central High School administered by Grand

Rapids Public Schools. It provides selected high

school students who plan to major in science or

engineering the opportunity to work in a research

laboratory. Since 2000, VARI has mentored 55

students in this program and its predecessor,

GRAPCEP.

The 2015 AME interns, Vanessa Baraza and Yesenia Barnel.

78 Van Andel Research Institute | Scientific Report


VARI AND JAY VAN ANDEL SEMINAR SERIES

January 2015

Tiago Fleming Outeiro,

University Medical Center,

Göttingen, Germany

“From the baker to the bedside:

unraveling the molecular basis

of neurodegeneration”

February

Steven Finkbeiner, Gladstone

Institute of Neurological

Disease, University of California,

San Francisco

“Unraveling mechanisms

of neurodegeneration with

genomics, single-cell analysis,

and human iPSCs models”

March

Nora M. Navone, M.D. Anderson

Cancer Center, Houston, Texas

“Prostate cancer cell–stromal

cell crosstalk via FGFR1

mediates antitumor activity of

dovitinib in bone metastases”

Jie Shen, Harvard Medical

School, Boston, Massachusetts

“Insights into Alzheimer's and

Parkinson's diseases from

genetic approaches”

April

Robert Stroud, University of

California, San Francisco

“Wiggle wiggle, not a trickle:

how do transmembrane

transporters work”

Gerry Coetzee, USC Norris

Comprehensive Cancer Center,

Los Angeles

“Unlocking the secrets of

enhancer biology with GWAS”

May

Michael F. Clarke, Stanford

Institute, Stanford, California

“Degenerative diseases and

cancer: the yin and yang of

stem cells”

Matthew J. Farrer, University of

British Columbia, Vancouver

“Parkinson's disease: pathology,

ontology, and etiology”

June

Douglas R. Spitz, University of

Iowa, Iowa City

“Metabolic oxidative stress in

cancer biology and therapy:

from the bench to the bedside”

August

Amy Manning-Bog, Sangamo

BioSciences, Inc., Richmond,

California

“Unsuspected pathogenetic

interactions in parkinsonism”

September

Chuan He, University of

Chicago

“Reversible RNA and DNA

methylation in gene expression

regulation”

October

Yifan Cheng, Howard Hughes

Medical Institute, University of

California, San Francisco

“Structures of TRP ion channels

by single particle cryo-EM: from

blob-ology to atomic structures”

Anne C. Ferguson-Smith,

University of Cambridge,

England

“Parental origin effects and the

epigenetic control of genome

function”

November

Li-Huei Tsai, Picower Institute

for Learning and Memory,

Cambridge, Massachusetts

“Epigenetic mechanisms of

neuronal gene expression and

memory”

December

Yang Shi, Harvard Medical

School, Boston Children’s

Hospital

“Histone methylation regulation,

recognition, and link to human

disease”

Ali Shilatifard, Northwestern

University, Evanston, Illinois

“Enhancer malfunction in

cancer”

79


80 Van Andel Research Institute | Scientific Report


ORGANIZATION

81


David L. Van Andel

Chairman and CEO, Van Andel Institute

VARI Board of Trustees

David L. Van Andel, Chairman and CEO

Tom R. DeMeester, M.D.

James B. Fahner, M.D.

Michelle Le Beau, Ph.D.

George F. Vande Woude, Ph.D.

Ralph Weichselbaum, M.D.

Max Wicha, M.D.

Board of Scientific Advisors

The Board of Scientific Advisors advises the CEO and

the Board of Trustees, providing recommendations and

suggestions regarding the overall goals and scientific

direction of VARI. The members are

Michael S. Brown, M.D., Chairman

Richard Axel, M.D.

Joseph L. Goldstein, M.D.

Tony Hunter, Ph.D.

Phillip A. Sharp, Ph.D.

82 Van Andel Research Institute | Scientific Report


Office of the Chief Scientific Officer

Van Andel Research Institute

Peter A. Jones, Ph.D., D.Sc.

Chief Scientific Officer

Patrick Brundin, M.D., Ph.D.

Associate Director

Staff

External Scientific Advisory Board

Aubrie Bruinsma, B.A., Events and Meetings Coordinator

David Cabrera, M.S., Chief of Staff

Kayla Habermehl, B.A., B.S., Science Communications

Speciaist

Jennifer Holtrop, B.S., Scientific Administrator

Chelsea John, B.S., Research Department Administrator

David Nadziejka, M.S., Science Editor

Aaron Patrick, B.S., Research Operations Supervisor

Bonnie Petersen, Executive Assistant

Beth Resau, B.A., M.B.A., Events and Meetings Supervisor-

Daniel Rogers, B.S., CCRC, CIP, Clinical Research

Administrator

Ann Schoen, Senior Executive Assistant

Tony Hunter, Ph.D.

Marie-Francoise Chesselet, M.D., Ph.D.

Howard J. Federoff, M.D., Ph.D.

Theresa Guise, M.D.

Kristian Helin, Ph.D.

Rudolf Jaenisch, Ph.D.

Max S. Wicha, M.D.

83


ADMINISTRATIVE ORGANIZATION

The departments listed below provide administrative support to both the Van Andel Research Institute and the Van Andel

Education Institute.

Executive

David Van Andel, Chairman and CEO

Christy Goss, Senior Executive Assistant

Operations

Jana Hall, Ph.D., M.B.A., Chief Operations Officer

Ann Schoen, Senior Executive Assistant

Legal

David Whitescarver, Vice President and Chief Legal Officer

Business Development and Extramural Administration

Thomas DeKoning

Robert Garces, Ph.D.

Compliance

Gwenn Oki, Director

Jessica Austin

Ryan Burgos

Angie Jason

Emily Koster

Andrea Poma, M.P.A.

Laura Kersjies

Dave Lutkenhoff

Communications and Marketing

Beth Hinshaw Hall, Director

Frank Brenner

David Jackiewicz

Rachel Harden

Development

Patrick Placzkowski, Director

Hannah Acosta

Kim Bosko

Aubrie Bruinsma

Sarah Murphy Lamb

Teresa Marchetti

Ashley Owens

Megan Schroeder

Angie Stumpo

Facilities

Samuel Pinto, Director

Tim Bachinski

Amber Baldwin

Maria Bercerra-Mota

Schuyler Black

Rob Cairns

Marilouise Carlson

Jeff Cooling

Deb Dale

Jason Dawes

Katherine Delacruz

Lupe Delgado

Ken DeYoung

Art Dorsey

Michelle Fraizer

Kristi Gentry

Hodilia Jimenez

Matthew Jump

Hannah Kaiserlian

Todd Katerburg

Tracy Lewis

Lewis Lipsey

Merriebelle Martinez

Dave Marvin

Samanthat Meekie

Joan Morrison

Anjayala Newland

Jamison Pate

Karen Pittman

Amber Ritsema

Tyler Rosel-Pieper

Jose Santos

Amber Smith

Ebony Taylor

Amber TenBrink

Rich Ulrich

Jeff Vadeboncouer

Pete Van Conant

Erik Varga

Jeff Wilbourn

LeeAnn Winger

Finance

Timothy Myers, Vice President and Chief Financial Officer

Katie Helder, VAI/VAEI Finance Director

Rich Herrick, VARI Finance Director

Kathryn Bishop

Mark Denhof

Sandi Dulmes

Nate Gras

Tess Kittridge

Angie Lawrence

Jessica Parker

Leah Postema

Susan Raymond

Cindy Turner

84 Van Andel Research Institute | Scientific Report


Human Resources

Security

Linda Zarzecki, Vice President

Ryan DeCaire

Deirdre Griffin

Eric Miller

Pamela Murray

John Shereda

Kevin Denhof, CPP, Director

Jonathan Fey

Adam Garvey

Katee McCarthy

Brian Nix

Andriana Vincent

Information Technology

Bryon Campbell, Ph.D., Chief Information Officer

David Drolett, Manager Jason Kotecki

Candy Wilkerson, Manager Ben Lewitt

Bill Baillod

Deb Marshall

Terry Ballard

Randy Mathieu

Tom Barney

Matt McFarlane

Phil Bott

Bruce Racalla

James Clinthorne

Thad Roelofs

Dan DeVries

Michael Stolsky

Sean Haak

Lisa VanDyk

Kenneth Hoekman

Sponsored Research

David Ross, Director

Marilyn Becker

Kathy Koehler

Sara O’Neal

Contract Support

Caralee Lane, Librarian

(Grand Valley State University)

Michele Quick

Heather Wells

Barbara Wygant

Innovation and Collaboration

Jerry Callahan, Ph.D., M.B.A., I&C Officer

Norma Torres

Investments Office

Kathy Vogelsang, Chief Investment Officer

Ted Heilman

Turner Novak

Karla Mysels

Austin Way

Materials Management

Richard M. Disbrow, C.P.M., Director

Matt Donahue

Cheryl Poole

Tracey Farney

Bob Sadowski

Heather Frazee

Kyle Sloan

Chris Kutschinski

Kim Stringham

Emily McPherson

John Waldon

Shannon Moore

85


VAN ANDEL INSTITUTE

Van Andel Institute Board of Trustees

David Van Andel, Chairman

John C. Kennedy

Mark Meijer

Board of Scientific Advisors

Michael S. Brown, M.D., Chairman

Richard Axel, M.D.

Joseph L. Goldstein, M.D.

Tony Hunter, Ph.D.

Phillip A. Sharp, Ph.D.

Van Andel Research Institute

Board of Trustees

David Van Andel, Chairman

Tom R. DeMeester, M.D.

James B. Fahner, M.D.

Michelle Le Beau, Ph.D.

George F. Vande Woude, Ph.D.

Ralph Weichselbaum, M.D.

Max Wicha, M.D.

Chief Executive Officer

David Van Andel

Van Andel Education Institute

Board of Trustees

David Van Andel, Chairman

James E. Bultman, Ed.D.

Donald W. Maine

Juan R. Olivarez, Ph.D.

Gordon L. Van Harn, Ph.D.

Van Andel Research Institute

Chief Scientific Officer

Peter A. Jones, Ph.D., D.Sc.

Chief Operations Officer

Jana Hall, Ph.D., M.B.A.

VP Business Development

Jerry Callahan, Ph.D.

VP and Chief Financial Officer

Timothy Myers

VP Human Resources

Linda Zarzecki

Vice President and

Chief Legal Officer

David Whitescarver

Communications

and Marketing

Beth Hinshaw Hall

Development

Patrick Placzkowski

Facilities

Samuel Pinto

Security

Kevin Denhof

86 Van Andel Research Institute | Scientific Report


The Van Andel Institute and its affiliated organizations (collectively the “Institute”) support and comply with applicable laws prohibiting

discrimination based on race, color, national origin, religion, gender, age, disability, pregnancy, height, weight, marital status, U.S. military

veteran status, genetic information, or other personal characteristics covered by applicable law. The Institute also makes reasonable

accommodations required by law. The Institute’s policy in this regard covers all aspects of the employment relationship, including recruiting,

hiring, training, and promotion, and, if applicable, the student relationship.


333 Bostwick Avenue, N.E., Grand Rapids, Michigan 49503

Phone 616.234.5000 Fax 616.234.5001 www.vai.org

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