2016 Scientific Report

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 

iii

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 

IV 

Van Andel Research Institute | Scientific Report

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 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. 

2 


3

4

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. 

6 


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. 


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 

7

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. 


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. 

8 


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. 


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. 


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. 


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. 

10 


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. 


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. 


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. 


11

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. 


NEIL (XIANGQI) MENG, PH.D. 

ALEXANDRA VANDER ARK, M.S. 

JIE WANG, M.D. 

QI ZENG, M.D. 


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. 

12 Van Andel Research Institute | Scientific Report

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. 


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. 


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 


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. 


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. 


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 


XIN GU, M.S. 

JIYUAN KE, PH.D. 

AMANDA KOVACH, B.S. 

EDWARD ZHOU, PH.D. 


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); 


• 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. 


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. 


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. 


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

STUDENTS 

SHAYNA DONOGHUE 

DANIELA GOMEZ, B.S. 

ALYSSA SHEPARD 


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. 


• 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. 


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. 


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. 


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. 


MARIE MOONEY, M.S. 

MATT PRIDGEON, M.D. 


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. 


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. 


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). 



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. 


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. 


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. 


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. 


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. 


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. 


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. 


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. 


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 


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. 


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. 


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. 


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 


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. 




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. 


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 


JIANSHUANG LI, B.S. 

JIE LI, PH.D. 

HUADIE LIU, M.S. 

DI LU, M.S. 

KEVIN WEAVER, B.S. 


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. 


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. 



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 

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. 


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. 


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. 


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. 


RONALD CHANDLER, JR., PH.D. 

FEYRUZ RASSOOL, PH.D. 


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. 


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. 


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. 


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. 


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. 


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. 


STUDENT 

NICOLE VANDER SCHAAF, B.S. 


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. 



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. 


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. 


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. 


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. 


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. 


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. 


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. 


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 


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. 



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. 


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. 


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 


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. 


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. 


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. 


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. 


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. 


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. 


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. 


47


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. 


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. 


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. 


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. 


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


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. 


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. 


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. 


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. 


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. 


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 


JENNIFER JAKUBOWSKI, M.S. 


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. 


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. 


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. 


KATELYN BECKER, M.S. 

AMANDINE ROUX, PH.D. 

JUXIN RUAN, PH.D. 

FEI WANG, PH.D. 

XINHE WANG, PH.D. 


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. 


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 


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. 


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. 


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. 


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 


DYLAN DUES, B.S. 

MEGAN SENCHUK, PH.D. 

STUDENTS 

JASON COOPER, B.S. 

EMILY MACHIELA, B.S. 


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. 


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 


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. 


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. 


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 


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. 


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. 


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. 


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. 

68 


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. 


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. 


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 


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 


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 


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 


Amandine Roux 

University of Pierre and Marie Currie, 

France 


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 



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. 


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


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. 


Office of the Chief Scientific Officer 

Van Andel Research Institute 


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 


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 


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. 


Phillip A. Sharp, Ph.D. 


Board of Trustees 


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 


James E. Bultman, Ed.D. 

Donald W. Maine 

Juan R. Olivarez, Ph.D. 

Gordon L. Van Harn, Ph.D. 


Chief Scientific Officer 


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 


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

2016 Scientific Report

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