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Van Andel Research Institute<br />

<strong>Scientific</strong> <strong>Report</strong> <strong>2018</strong>


Cover image: The yeast Mcm2-7 double hexamer, the core of the<br />

DNA replication helicase. A complete view of this cryo-EM structure is<br />

found on p. 35.


Van Andel Research Institute<br />

<strong>Scientific</strong> <strong>Report</strong> <strong>2018</strong><br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | i


Published March <strong>2018</strong>.<br />

Copyright <strong>2018</strong> by Van Andel Institute: all rights reserved.<br />

Van Andel Institute, 333 Bostwick Avenue, N.E.<br />

Grand Rapids, Michigan 49503, U.S.A.<br />

ii | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


In Memoriam<br />

Arthur S. Alberts, Ph.D.<br />

1964–2016<br />

Art Alberts passed away in December 2016 after a<br />

courageous eight-year battle with brain cancer. He<br />

was a passionate, deeply inquisitive scientist who<br />

joined VARI in 2000 as one of its first scientific<br />

investigators. Art was brought up in Southern<br />

California, but he never seemed to allow Michigan<br />

winters to intimidate him into forgoing flip-flops<br />

and shorts. He was a friend, mentor, and<br />

collaborator, a man who loved the purity of science,<br />

the thrills of a dangerous mountain bike trail, and a<br />

good IPA. He is deeply missed.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | iii


Table of Contents<br />

2017 At-A-Glance vi<br />

Introduction 1<br />

Center for Cancer and Cell Biology 4<br />

JUAN DU, Ph.D. 6<br />

PATRICK J. GROHAR, M.D., Ph.D. 7<br />

BRIAN B. HAAB, Ph.D. 8<br />

XIAOHONG LI, Ph.D. 9<br />

WEI LÜ, Ph.D. 10<br />

KARSTEN MELCHER, Ph.D. 11<br />

LORENZO F. SEMPERE, Ph.D. 12<br />

MATTHEW STEENSMA, M.D. 13<br />

BART O. WILLIAMS, Ph.D. 14<br />

NING WU, Ph.D. 15<br />

H. ERIC XU, Ph.D. 16<br />

TAO YANG, Ph.D. 17<br />

Center for Epigenetics 20<br />

STEPHEN B. BAYLIN, M.D. 22<br />

PETER A. JONES, Ph.D., D.Sc. 23<br />

STEFAN JOVINGE, M.D., Ph.D. 24<br />

PETER W. LAIRD, Ph.D. 25<br />

HUILIN LI, Ph.D. 26<br />

GERD PFEIFER, Ph.D. 27<br />

SCOTT ROTHBART, Ph.D. 28<br />

HUI SHEN, Ph.D. 29<br />

PIROSKA E. SZABÓ, Ph.D. 30<br />

TIMOTHY J. TRICHE, JR., Ph.D. 31<br />

STEVEN J. TRIEZENBERG, Ph.D. 32<br />

iv | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Center for Neurodegenerative Science 36<br />

LENA BRUNDIN, M.D., Ph.D. 38<br />

PATRIK BRUNDIN, M.D., Ph.D. 39<br />

GERHARD (Gerry) A. COETZEE, Ph.D. 40<br />

JEFFREY H. KORDOWER, Ph.D. 41<br />

VIVIANE LABRIE, Ph.D. 42<br />

JIYAN MA, Ph.D. 43<br />

DARREN J. MOORE, Ph.D. 44<br />

Educational and Training Programs 62<br />

VAIGS GRADUATE STUDENTS 64<br />

SUMMER INTERNSHIP PROGRAM 65<br />

POSTDOCTORAL FELLOWSHIP PROGRAM 66<br />

Organization 68<br />

MANAGEMENT 70<br />

ADMINISTRATIVE DEPARTMENTS 72<br />

ORGANIZATIONAL CHART 74<br />

Core Technologies and Services 48<br />

MARIE ADAMS, M.S. 50<br />

Genomics<br />

MEGAN BOWMAN, Ph.D. 51<br />

Bioinformatics and Biostatistics<br />

BRYN EAGLESON, M.S., LATG 52<br />

Vivarium and Transgenics<br />

CORINNE ESQUIBEL, Ph.D. 53<br />

Confocal Microscopy and<br />

Quantitative Imaging<br />

SCOTT D. JEWELL, Ph.D. 54<br />

Pathology and Biorepository<br />

RACHAEL SHERIDAN, Ph.D. 55<br />

Flow Cytometry<br />

GONGPU ZHAO, Ph.D. 56<br />

Cryo-Electron Microscopy<br />

Awards for <strong>Scientific</strong> Achievement 58<br />

JAY VAN ANDEL AWARD FOR OUTSTANDING 59<br />

ACHIEVEMENT IN PARKINSON’S<br />

DISEASE RESEARCH<br />

HAN-MO KOO MEMORIAL AWARD 60<br />

TOM ISAACS AWARD 61<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT |v


2017 At-A-Glance<br />

Record-breaking funding<br />

115 total active awards totaling $97 million<br />

32 new awards in 2017 totaling $33 million<br />

Of those, 13 awards, for $25 million,<br />

are federal grants<br />

A growing scientific impact<br />

145 2017 publications,<br />

132 peer-reviewed<br />

Prestigious faculty<br />

In 2017, the Institute celebrated Chief <strong>Scientific</strong> Officer Dr. Peter Jones’s election to the American<br />

Academy of Arts and Sciences, placing him in the elite company of more than 250 Nobel Laureates<br />

and 60 Pulitzer Prize winners. Director’s Scholar Dr. Stephen Baylin also earned the honor of being<br />

elected to the National Academy of Sciences, an independent and nonpartisan advisor to the<br />

federal government on matters related to science and technology. In all, VARI is home to<br />

2 fellows of the American Academy of Arts & Sciences<br />

2 members of the National Academy of Sciences<br />

3 fellows of the American Association for the Advancement of Science<br />

3 fellows of the American Association for Cancer Research Academy<br />

A collaborative effort<br />

383 collaborating organizations<br />

32 countries in which<br />

VARI collaborates<br />

A growing team<br />

384 total employees<br />

223 total research employees<br />

31 faculty<br />

43 postdoctoral fellows<br />

27 Van Andel Institute Graduate School Ph.D. students<br />

vi | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Introduction<br />

In many ways, 2017 was a record-breaking year for Van Andel Research<br />

We continue to build critical<br />

mass, thanks to an ambitious<br />

recruiting effort conducted<br />

in accordance with our<br />

Strategic Plan.<br />

Institute. We experienced incredible growth in all aspects of our<br />

scientific enterprise, from an all-time high in scientific publications to<br />

an incredible increase in peer-reviewed federal funding, the most ever<br />

awarded in our 21-year history. Several new faculty have arrived and<br />

more will be joining us soon, which will bolster our existing research<br />

programs and support the establishment of new ones. And, we continue<br />

our collaborations with other leading institutions both in the U.S.A. and<br />

abroad to translate lab discoveries into the clinic.<br />

STRATEGIC GROWTH<br />

We continue to build critical mass, thanks to an ambitious recruiting effort<br />

conducted in accordance with our Strategic Plan. The Center for Cancer and Cell<br />

Biology added two new faculty in 2017, Wei Lü in March and Juan Du in October.<br />

The Lü lab uses single-particle cryo-electron microscopy and other methods to<br />

study the structures and mechanisms of ion channels and transmembrane receptors.<br />

The Du lab focuses on excitatory neuronal receptors, studying their structure and<br />

function via cryo-EM, electrophysiology, and X-ray crystallography. The Center for<br />

Neurodegenerative Science welcomed Wouter Peelaerts, who joined Patrik Brundin’s<br />

lab in 2017, becoming the first Fulbright Scholar to join the Institute.<br />

In September 2017, the Center for Epigenetics welcomed Timothy J. Triche, Jr.,<br />

whose lab develops statistical and mathematical methods to better understand<br />

pediatric and adult cancers, with a special focus on cancers of the blood in children.<br />

We look forward to the arrival of two more faculty in early <strong>2018</strong>—Drs. Xiaobing Shi<br />

and Hong Wen, both experts in cancer epigenetics.<br />

A major milestone was the establishment of the Institute’s David Van Andel<br />

Advanced Cryo-Electron Microscopy Suite in early 2017. This state-of-the-art<br />

facility places VARI in elite company: the suite’s most powerful microscope, the<br />

Titan Krios, is one of fewer than 120 in the world and can visualize structures down<br />

to the atomic level. The investment, made possible by CEO David Van Andel, is<br />

already bearing fruit. Two new structures that were solved using its instruments<br />

were published in the last quarter of 2017. Huilin Li’s lab and collaborators published<br />

the paper “Cryo-EM structure of Mcm2-7 double hexamer on DNA suggests a<br />

lagging-strand DNA extrusion model” in the Proceedings of the National Academy of<br />

Sciences USA, and Wei Lü’s lab published “Electron cryo-microscopy structure of a<br />

human TRPM4 channel” in Nature. These were among the 132 peer-reviewed articles<br />

from VARI in 2017, a new annual high for the Institute. Selected publications are<br />

listed for each Center and the Cores.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 1


Introduction (cont.)<br />

Grant funding hit an<br />

all-time high in 2017 with 32<br />

new awards totaling over<br />

$33 million.<br />

FUNDING GROWTH<br />

Our growth also is reflected in grant funding, which hit an all-time high in 2017<br />

with 32 new awards totaling over $33 million. Of these, 13 were peer-reviewed<br />

federal awards accounting for over $25 million. These funds will support a plethora<br />

of basic and translational research endeavors aimed at making life-changing<br />

advances. Of note, VARI had the second highest growth in grant funding over 2016-<br />

2017 among 72 comparable independent research institutes.<br />

On the clinical front, we are thrilled that Van Andel Research Institute–Stand Up<br />

To Cancer Epigenetics Dream Team scientists received two of the ten inaugural<br />

SU2C Catalyst awards, which pair Dream Teams with industry support. Totaling<br />

nearly $5.5 million, these funds will fuel new, collaborative clinical trials designed<br />

to evaluate powerful epigenetic and immunotherapy drug combinations as potential<br />

cancer treatments. One grant is funded by Merck & Co. against non-small-cell lung<br />

cancer, one of the most common and deadly types of cancer, and the second is<br />

funded by Genentech against bladder cancer, a disease that claims thousands of lives<br />

annually.<br />

Among the major National Institutes of Health awards were a seven-year R35/<br />

Outstanding Investigator Award from NIH/NCI to Peter Jones; to Patrik Brundin, an<br />

R01 from NIH/NIDCD, an R21 from NIH/NINDS, and a Department of Defense award;<br />

to Scott Rothbart, an R35/Maximizing Investigators’ Research Award from NIH/<br />

NIGMS; to Peter Laird, an R01 from NIH/NCI; to Darren Moore, an R01 from NIH/<br />

NINDS; to Ning Wu, an R01 from NIH/NCI; to Huilin Li, an R01 from NIH/NIGMS;<br />

and to Jiyan Ma, an R21 from NIH/NINDS.<br />

Several of VARI’s postdoctoral fellows and graduate students also received funding<br />

in 2017. Xi Chen, of the Moore laboratory, now has a fellowship from the Parkinson’s<br />

Foundation supporting her studies into a new model for familial Parkinson’s disease.<br />

An Phu Tran Nguyen and Md Shariful Islam, also in the Moore Lab, received grants<br />

from the American Parkinson’s Disease Association. VARI Fellow Xiaotian Zhang<br />

was the recipient of an American Society of Hematology Fellow Scholar Award in<br />

basic and translational research—the first ASH fellowship to a VARI scientist—and<br />

Rochelle Tiedemann, of the Jones and Rothbart labs, received the Institute’s first<br />

American Cancer Society fellowship.<br />

Nicole Vander Schaaf, a graduate student in the Laird lab, received an F31<br />

predoctoral training fellowship from the National Institutes of Health for<br />

her project, “The role of polycomb target gene DNA methylation in intestinal<br />

tumorigenesis.” F31 grants are highly competitive fellowships that support<br />

promising graduate students as they work on their dissertations. Nicole is our first<br />

graduate student to be awarded an F31.<br />

2 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


By harnessing new knowledge<br />

born out of revolutionary<br />

scientific innovation and<br />

technology and working<br />

together against disease, we<br />

can—and will—change human<br />

health for the better.<br />

AWARDS AND SYMPOSIA<br />

VARI’s Chief <strong>Scientific</strong> Officer Peter Jones was elected to the American Academy of<br />

Arts and Sciences in April, and Stephen Baylin was elected to the National Academy<br />

of Sciences in May. Congratulations to both!<br />

In May, the Institute presented U.S. Rep. Fred Upton with a Legislative Champion<br />

Award on behalf of the Association for Independent Research Institutes (AIRI).<br />

Upton, along with U.S. Rep. Diana DeGette, spearheaded the 21 st Century Cures Act,<br />

which passed with bipartisan support and infused more than $6 billion in new<br />

funding to the National Institutes of Health.<br />

VARI hosted several scientific symposia in 2017. Among those events were<br />

“Osteoporosis: An Impending Public Health Crisis”; “New Frontiers in Cancer<br />

Metabolism”; “Frontiers in Reproductive Epigenetics”; “Origins of Cancer”; “A<br />

Celebration of the Cryo-EM Revolution"; and “Grand Challenges in Parkinson’s<br />

Disease” and its parallel patient meeting, “Rallying to the Challenge”. We also held<br />

the second “Epigenomics at VARI” graduate student workshop during the summer.<br />

A BRIGHT TOMORROW<br />

As we move into the future, we do so with a renewed commitment to improving<br />

human health through rigorous science. This mission is an urgent one: as the<br />

world’s population continues to grow and age, the incidence of cancer and<br />

neurodegenerative diseases also are slated to rise. Improved preventative strategies,<br />

diagnostic techniques, treatments, and—ultimately—cures are desperately needed<br />

for the millions around the world who face these diseases today or who will face<br />

them tomorrow.<br />

The past decade has encompassed a scientific renaissance of sorts, one that can be<br />

seen in research organizations around the world, including VARI. By harnessing<br />

new knowledge born out of revolutionary scientific innovation and technology and<br />

working together against disease, we can—and will—change human health for the<br />

better.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 3


Center for Cancer and Cell Biology<br />

Bart O. Williams, Ph.D.<br />

Director<br />

The Center’s scientists<br />

study the basic<br />

mechanisms and<br />

molecular biology<br />

of cancer and other<br />

diseases, with the goal<br />

of developing better<br />

diagnostics and therapies.<br />

4 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


A depiction of arrestin binding by a phosphorylated and active rhodopsin. The cell membrane<br />

lipids are shown as cream colored, rhodopsin is blue, and arrestin is red. The phosphorylated<br />

C-terminal tail of rhodopsin binds to the N-domain (left) of the arrestin molecule. In the main contact<br />

region between the two molecules (central), arrestin accommodates the ICL2 helix of rhodopsin. In<br />

this fully activated state, the tip of arrestin’s C-domain contacts the membrane (right).<br />

Image by Parker de Waal of the Xu lab.


Center for Cancer and Cell Biology<br />

JUAN DU, Ph.D.<br />

Dr. Du earned her Ph.D. at the University of Freiburg. She joined the VARI<br />

faculty in October 2017 as an Assistant Professor.<br />

RESEARCH INTERESTS<br />

The lab is focused on understanding the mechanism and pharmacology of excitatory<br />

neuronal receptors, which are crucially involved in numerous neurological diseases.<br />

A combined approach of single-particle cryo-EM, patch-clamp electrophysiology,<br />

and X-ray crystallography is employed to study the atomic structures and biological<br />

functions of these ion channel receptors.<br />

STAFF<br />

Chen Fan, Ph.D.<br />

Michelle Martin, A.A.<br />

6 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


PATRICK J. GROHAR, M.D., Ph.D.<br />

Dr. Grohar earned his Ph.D. in chemistry and his M.D. from Wayne State<br />

University. He joined VARI in 2015 as an Associate Professor, and he has<br />

clinical and research responsibilities at Spectrum Health and Michigan<br />

State University, respectively.<br />

RESEARCH INTERESTS<br />

Our laboratory studies pediatric sarcomas, and our goal is to develop novel,<br />

molecularly targeted therapies and to translate those therapies into the clinic.<br />

Most pediatric sarcomas are characterized by oncogenic transcription factors that<br />

are required for cell survival. We are developing new approaches to target those<br />

molecules.<br />

STAFF<br />

Elissa Boguslawski, R.L.A.T.<br />

Jenna Gedminas, M.D.<br />

Susan Goosen, B.S., M.B.A.<br />

Mitchell McBrairty, B.S.<br />

Michelle Minard, B.S.<br />

Brandon Oswald, B.S.<br />

Erik Peterson, B.S., M.S.<br />

Katie Sorensen, B.S.<br />

STUDENTS<br />

Maggie Chasse, M.S.<br />

Guillermo Flores, B.S.<br />

Trabectedin is a natural product originally isolated from the sea squirt, Ecteinascidia<br />

turbinata. Our recent work has focused on characterizing the mechanism of<br />

trabectedin’s suppression of the EWS-FLI1 transcription factor in Ewing sarcoma,<br />

identifying second-generation trabectedin analogs, and developing new combination<br />

therapies. We showed that the drug works by redistributing EWS-FLI1 within the<br />

nucleus to the nucleolus. This mechanism provides justification for using a secondgeneration<br />

compound, lurbinectedin, which maintains the nuclear redistribution of<br />

EWS-FLI1 but accumulates to higher serum concentrations.<br />

Over the past year, we have shown convincingly that a targeted combination therapy<br />

of trabectedin plus irinotecan provides cooperative suppression of EWS-FLI1.<br />

Irinotecan augments and sustains suppression of EWS-FLI1 in vivo, leading to the<br />

differentiation of Ewing sarcoma cells into benign tissue. We have also shown that<br />

lurbinectedin maintains both this synergy with irinotecan and the mechanism of<br />

synergy. We have a number of anecdotal responses to treatment with trabectedin<br />

plus irinotecan, and responses to lurbinectedin have been seen in patients in two<br />

independent studies. We are working to formally evaluate these combinations in<br />

phase II studies in the United States.<br />

We have also extensively studied mithramycin, which reverses EWS-FLI1 activity<br />

and blocks the expression of key EWS-FLI1 downstream targets. In a phase I/II trial<br />

at the National Cancer Institute, we found that mithramycin did not achieve serum<br />

levels high enough to block EWS-FLI1 activity. We have now identified secondgeneration<br />

compounds with improved properties that show excellent activity in<br />

Ewing sarcoma cells. We are extending these findings to other tumor types. We have<br />

shown that cells deficient in components of the SWI/SNF chromatin remodeling<br />

complex are hypersensitive to mithramycin. Work is in progress to understand<br />

the mechanism of this hypersensitivity. We are also exploring the interface of<br />

epigenetics and transcription as a drug target.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 7


Center for Cancer and Cell Biology<br />

BRIAN B. HAAB, Ph.D.<br />

Dr. Haab obtained his Ph.D. in chemistry from the University of<br />

California at Berkeley in 1998. He joined VARI as a Special Program<br />

Investigator in 2000, became a <strong>Scientific</strong> Investigator in 2004, and is<br />

now a Professor.<br />

STAFF<br />

ChongFeng Gao, Ph.D.<br />

Zachary Klamer, B.S.<br />

Ying Liu, Ph.D.<br />

Katie Partyka, B.S.<br />

Ben Staal, M.S.<br />

Jeanie Wedberg, A.S.<br />

Luke Wisniewski, B.S.<br />

STUDENTS<br />

RESEARCH INTERESTS<br />

Patients facing a possible diagnosis of cancer need answers to such fundamental<br />

questions as whether a lesion is cancerous and, if so, which treatment will work<br />

best, yet getting the answers can be difficult. The heterogeneity of cancers of a<br />

particular organ is a major source of the difficulty. For example, for pancreatic<br />

cancer, physicians do not have tests that reliably distinguish cancerous from noncancerous<br />

lesions or that group the cancers into specific subtypes. To address this<br />

need, we are 1) seeking molecular markers to identify the subtypes of pancreatic<br />

cancer cells; 2) determining the behavioral and biological differences between<br />

the subtypes; and 3) developing assays to detect the subtypes in a clinical setting.<br />

With such assays, we hope to improve the ability to detect and diagnose pancreatic<br />

cancers, to enable prediction of the behavior of each cancer, and to guide studies<br />

aimed at treating each subtype.<br />

We found that a carbohydrate structure, which we named the sTRA antigen, is<br />

produced by a subtype of pancreatic cancer cell that is different from typical<br />

cancer cells. We also found that another carbohydrate, the well-known CA19-9<br />

antigen, identifies a separate type of pancreatic cancer cell. Individual tumors may<br />

have cancer cells producing one, both, or neither of the antigens. Our research is<br />

revealing that the sTRA-producing cancer cells are more resistant to death and<br />

more aggressive than the CA19-9-producing cells. We are seeking to clarify the<br />

nature and mechanisms of the differences between the subtypes and to determine<br />

optimal treatments for each. Both antigens are secreted into the blood, so we are<br />

investigating the use of blood tests for sTRA and CA19-9 to identify more pancreatic<br />

cancers than previously possible and to determine their subtype. We are also using<br />

new methods of carbohydrate analysis developed in our lab to find markers for<br />

additional subtypes of pancreatic cancer cells.<br />

David Ayala-Talavera<br />

Daniel Barnett, B.A., B.S.<br />

Anna Barry, B.S.<br />

Johnathan Hall<br />

Peter Hsueh, B.S.<br />

Hannah Kalee<br />

8 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


XIAOHONG LI, Ph.D.<br />

Dr. Li received her Ph.D. from the Institute of Zoology, Chinese Academy of<br />

Sciences, in Beijing in 2001. She joined VARI as an Assistant Professor<br />

in September 2012.<br />

RESEARCH INTERESTS<br />

Our laboratory is committed to understanding tumor dormancy and cancer bone<br />

metastasis. Our long-term goals are to develop better therapeutic approaches for<br />

bone metastasis and to prolong a dormancy-permissive bone microenvironment so<br />

that cancer cells can be killed while they are in that state.<br />

STAFF<br />

Sourik Ganguly, Ph.D.<br />

Alexandra Vander Ark, M.S.<br />

Jeanie Wedberg, A.S.<br />

Erica Woodford, B.S.<br />

Project 1. Influence of the bone microenvironment on drug resistance in prostate<br />

cancer bone metastasis. Second-line hormonal therapies such as enzalutamide<br />

improve overall patient survival by only a few months in about 50% of patients,<br />

and almost all patients develop drug resistance. Thus, we need to determine the<br />

mechanisms of drug resistance and to develop new approaches for overcoming it.<br />

Based on our studies, the goals of this project are to determine how enzalutamide<br />

decreases TGFBR2 in osteoblasts, to investigate how loss of TGFBR2 in osteoblasts<br />

promotes the progression of prostate cancer bone metastases, and to target the<br />

underlying mechanism as a novel therapeutic approach to overcoming enzalutamide<br />

resistance.<br />

Project 2. Influence of the bone microenvironment on prostate cancer dormancy.<br />

The majority of cancer patients die of metastases that begin years or decades after<br />

primary diagnosis and treatment. Up to 70% of prostate cancer patients have<br />

disseminated tumor cells in the bone marrow at the time of initial diagnosis, and<br />

these cells can remain dormant and reactivate later. Understanding the underlying<br />

mechanism will provide novel avenues for early preventive and therapeutic<br />

approaches to eradicating metastatic recurrence. We have created a mouse model in<br />

which prostate cancer bone metastasis development is delayed by four weeks, which<br />

is equivalent to three years in humans. Based on our studies, we are proposing to<br />

test the effect of blocking CTHRC1 or of vitamin C treatment on prostate cancer<br />

dormancy and bone metastasis.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 9


Center for Cancer and Cell Biology<br />

WEI LÜ, Ph.D.<br />

Wei Lü earned his Ph.D. from the University of Freiburg in the laboratory<br />

of Oliver Einsle. He then was a postoctoral fellow in the laboratory of Eric<br />

Gouaux (HHMI/Vollum Institute) before joining VARI as an<br />

Assistant Professor in 2017.<br />

RESEARCH INTERESTS<br />

We use single-particle cryo-electron microscopy and other biophysical/biochemical<br />

methods to study the structure and mechanism of ion channels and transmembrane<br />

receptors that are linked to neurological diseases and cancers. We recently<br />

determined the cryo-EM structure of the human TRPM4 channel.<br />

STAFF<br />

Yihe Huang, Ph.D.<br />

Michelle Martin, A.A.<br />

Paige Winkler, Ph.D.<br />

STUDENT<br />

Wooyoung Choi<br />

10 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


KARSTEN MELCHER, Ph.D.<br />

Dr. Melcher earned his master's degree in biology and his Ph.D. in<br />

biochemistry from the Eberhard Karls Universität in Tübingen, Germany.<br />

He was recruited to VARI in 2007, and in 2013 he was promoted to<br />

Associate Professor.<br />

RESEARCH INTERESTS<br />

Our laboratory studies the structure and function of proteins that have central<br />

roles in cellular signaling. To do so, we employ X-ray crystallography and cryoelectron<br />

microscopy in combination with biochemical and cellular methods to<br />

identify mechanisms of signaling and frameworks for the rational design of new<br />

and improved drugs against diseases such as cancer, diabetes, and neurological<br />

disorders.<br />

STAFF<br />

Xin Gu, M.S.<br />

Michelle Martin, A.A.<br />

STUDENTS<br />

Zachary DeBruine, B.S.<br />

Yan Yan, B.S.<br />

VISITING SCIENTIST<br />

Feng Zhang, Ph.D.<br />

AMP-activated protein kinase (AMPK)<br />

AMPK is a central regulator of energy homeostasis and important drug target for<br />

the treatment of metabolic diseases, including diabetes, obesity, and cancer. AMPK<br />

senses the energy state of the cell by competitive binding of AMP, ADP, and ATP to<br />

three sites in its γ subunit. We are determining the structural mechanisms of AMPK<br />

regulation by direct binding of AMP, ADP, ATP, and various drugs, as well as by<br />

post-translational modifications.<br />

Plant hormone signaling<br />

We are studying perception, signal transduction, and target gene regulation for<br />

hormones that reprogram plants in response to drought and other abiotic stresses<br />

(abscisic acid), to herbivorous insects and microbial pathogens (jasmonates), and to<br />

mineral nutrient stresses (strigolactones). These stresses are responsible for major<br />

crop losses worldwide and have a large impact on human malnutrition.<br />

WNT reception and signaling<br />

WNTs are morphogens that have key roles in human development and stem cell<br />

maintenance; components of the WNT signaling pathway are frequently mutated<br />

in cancers, as well as in bone and retinal diseases. This pathway is therefore an<br />

important therapeutic target. Yet, how to therapeutically target the docking of a<br />

WNT to its cell surface receptor complex, and the molecular mechanism of how such<br />

docking transduces signals to the inside of the cell, have remained elusive. We are<br />

using a combination of structural and live-cell analysis to determine the structure of<br />

the intact receptor complex and the mechanism of WNT transmembrane signaling.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 11


Center for Cancer and Cell Biology<br />

LORENZO F. SEMPERE, Ph.D.<br />

Dr. Sempere obtained his B.S. in biochemistry at Universidad Miguel<br />

Hernández, Elche, Spain, and earned his Ph.D. at Dartmouth under Victor<br />

Ambros. He joined VARI in January 2014 as an Assistant Professor.<br />

STAFF<br />

Josh Schipper, Ph.D.<br />

Jeanie Wedberg, A.S.<br />

Jenni Westerhuis, M.S.Ed., M.S.<br />

STUDENTS<br />

Sudakshina Chakrabarty<br />

Joyce Goodluck<br />

RESEARCH INTERESTS<br />

Our laboratory pursues complementary lines of translational research to explain the<br />

etiological role of microRNAs and to unravel microRNA regulatory networks during<br />

carcinogenesis. We investigate these questions in clinical samples and preclinical<br />

models of breast cancer and pancreatic cancer. MicroRNAs can regulate and<br />

modulate the expression of hundreds of target genes, some of which are components<br />

of the same signaling pathways or biological processes. Thus, functional modulation<br />

of a single microRNA can affect multiple target mRNAs (i.e., one drug, multiple hits),<br />

unlike therapies based on small interfering RNAs, antibodies, or small-molecule<br />

inhibitors. The laboratory has active projects in the areas of cancer biology and<br />

tumor microenvironment, with a translational focus toward improving diagnostic<br />

applications and therapeutic strategies.<br />

Because tissue samples are the direct connection between cancer research and<br />

cancer medicine, detailed molecular and cellular characterization of tumors provides<br />

the opportunity to translate scientific knowledge into useful clinical information. We<br />

use innovative multiplexed immunohistochemical and in situ hybridization assays<br />

to implement diagnostic applications of microRNA biomarkers. Molecular biology<br />

and cell biology studies help to identify microRNA targets and regulatory networks.<br />

Recent projects include the following.<br />

• Clinically validating tumor compartment-specific expression of miR-21 as a<br />

prognostic marker for breast cancer. There is focused interest in the stromal<br />

expression of miR-21 in triple-negative breast cancer, for which prognostic<br />

markers and effective targeted therapies are lacking.<br />

• Developing integrative diagnostics for pancreatic cancer using information from<br />

cancer-associated microRNAs and protein glycosylation. Integrative marker<br />

analysis should enhance diagnostic power and interpretation.<br />

• Developing methods for isolating microRNA/target mRNA interactions in in vitro<br />

and in vivo systems.<br />

• Evaluating the miR-21 activity required in cancer cell and tumor stromal<br />

compartments to support aggressive and metastatic features in animal models<br />

of breast and pancreatic cancer.<br />

12 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


MATTHEW STEENSMA, M.D.<br />

Dr. Steensma received his B.A. from Hope College and his M.D. from Wayne<br />

State University School of Medicine in Detroit. He is a practicing surgeon<br />

in the Spectrum Health Medical Group, and he joined VARI as an<br />

Assistant Professor in 2010.<br />

STAFF<br />

Patrick Dischinger, B.S., MB(ASCP) CM<br />

Curt Essenburg, B.S., LATG<br />

Carrie Graveel, Ph.D.<br />

Michelle Minard, B.S.<br />

Elizabeth Tovar, Ph.D.<br />

RESEARCH INTERESTS<br />

Our laboratory conducts research into new treatment strategies for sarcomas.<br />

Specifically, we are interested in determining the mechanisms underlying tumor<br />

formation in sporadic bone and soft-tissue sarcomas and in neurofibromatosis<br />

type 1, a hereditary disorder caused by mutations in the neurofibromin 1 (NF1)<br />

gene. Neurofibromin is considered a tumor suppressor that suppresses Ras<br />

activity by promoting Ras GTP hydrolysis to GDP. People with mutations in the<br />

NF1 gene develop benign tumors called neurofibromas and have an elevated risk<br />

of malignancies ranging from solid tumors (including sarcomas) to leukemia. The<br />

disease affects 1 in 3000 people in the United States, of whom 8–13% will ultimately<br />

develop a neurofibromatosis-related sarcoma in their lifetime. These aggressive<br />

tumors typically arise from benign neurofibromas, but the process of benign-tomalignant<br />

transformation is not well understood, and treatment options are limited,<br />

leading to poor five-year survival rates.<br />

Our current research efforts include the development of genetically engineered<br />

mouse models of neurofibromatosis type 1 tumor progression, most notably NF1-<br />

related MPNSTs and breast cancer; the identification of targetable patterns of<br />

intratumoral and intertumoral heterogeneity through next-generation sequencing;<br />

genotype–phenotype correlations in neurofibromatosis type 1 and related diseases;<br />

and mechanisms of chemotherapy resistance in bone and soft-tissue sarcomas.<br />

STUDENTS<br />

Eve Gardner<br />

Jamie Grit, B.S.<br />

Candace King, M.A.<br />

Courtney Schmidt<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 13


Center for Cancer and Cell Biology<br />

BART O. WILLIAMS, Ph.D.<br />

Dr. Williams received his Ph.D. in biology from Massachusetts Institute<br />

of Technology in 1996, where he trained with Tyler Jacks. Following<br />

postdoctoral study with Harold Varmus, he joined VARI in July 1999. He is<br />

now a Professor and the Director of the Center for Cancer and Cell Biology.<br />

STAFF<br />

Cassie Diegel, B.S.<br />

Gabrielle Foxa, B.S.<br />

Mitch McDonald, B.S.<br />

Megan Michalski, D.D.S, Ph.D.<br />

Michelle Minard, B.S.<br />

Alex Zhong, Ph.D.<br />

STUDENTS<br />

Isaac Izaguirre<br />

Katie Krajnak, M.S.<br />

Adam Racette<br />

RESEARCH INTERESTS<br />

We are studying how alterations in the WNT signaling pathway cause human<br />

disease. Given that WNT signaling functions in the growth and differentiation<br />

of most tissues, it is not surprising that changes in this pathway are among the<br />

most common events in human cancer. Other diseases, including osteoporosis,<br />

cardiovascular disease, and diabetes, have also been linked to it. Our work includes<br />

studying the role of WNT signaling in normal bone formation and in the metastasis<br />

of cancer to the bone. We are also interested in identifying the genes that play key<br />

roles in skeletal development and maintenance of bone mass.<br />

Mutations in LRP5, a WNT receptor, have been causally linked to alterations in<br />

human bone development. We have characterized a mouse strain deficient in LRP5<br />

and have shown that it recapitulates the low-bone-density phenotype seen in<br />

human patients who have that deficiency. We have further shown that mice carrying<br />

mutations in both LRP5 and the related LRP6 protein have even more-severe defects<br />

in bone density. We are also examining the effects on normal bone development<br />

and homeostasis of chemical inhibitors of the enzyme Porcupine, which is required<br />

for the secretion and activity of all WNTs. Because such inhibitors are currently in<br />

human clinical trials for treatment of several tumor types, their side effects related<br />

to the lowering of bone mass must be evaluated.<br />

We are addressing the relative roles of LRP5 and LRP6 in WNT1-induced mammary<br />

carcinogenesis. A deficiency in LRP5 dramatically inhibits the development of<br />

mammary tumors, and a germline deficiency in LRP5 or LRP6 results in delayed<br />

mammary development. We are particularly interested in the pathways that may<br />

regulate the proliferation of normal mammary progenitor cells, as well as of tumorinitiating<br />

cells. In another project, we are studying the development of skeletal<br />

osteoblastic metastasis from prostate cancer and the ability of the tumor cells to<br />

become independent of androgen for survival. Finally, part of our work focuses<br />

on developing genetically engineered mouse models, for example, models of<br />

osteoarthritis.<br />

Nolan Redetzke<br />

14 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


NING WU, Ph.D.<br />

Dr. Wu received her Ph.D. from the Department of Biochemistry of the<br />

University of Toronto in 2002. She joined VARI in 2013 as an<br />

Assistant Professor.<br />

RESEARCH INTERESTS<br />

Many human diseases, such as diabetes, neurodegeneration, cancer, and heart<br />

problems, come with old age. Our laboratory studies the interface between cellular<br />

metabolism and signal transduction, focusing on key steps in glucose and lipid<br />

metabolism in order to understand the ways that nutrients can delay aging effects<br />

and thus postpone the onset of disease.<br />

STAFF<br />

Holly Dykstra, B.S.<br />

Althea Waldhart, B.S.<br />

Jeanie Wedberg, A.S.<br />

Glucose is a vital, highly regulated metabolite in the human body. Its concentration<br />

is tightly controlled within a narrow range by factors secreted from several tissues.<br />

Too much glucose uptake leads to systemic problems that partly stem from oxidative<br />

stress generated by the mitochondria. Our lab examines the mechanism by which<br />

cells control glucose uptake, what regulates the flux from glucose to unwanted lipid<br />

accumulation, and how mitochondrial function is affected by glucose concentration.<br />

At the atomic scale, we employ cryo-electron microscopy to solve the structures<br />

of transporter proteins and their regulators. At the cellular level, we investigate<br />

how cells respond to metabolic stress. At the organism level, we integrate the<br />

cellular response with systemic response to understand how diet can modify and<br />

curb unwanted oxidative damage. This research will provide better insight into the<br />

relationship between diet and health and open the possibility of individualized diet<br />

recommendations to delay aging effects.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 15


Center for Cancer and Cell Biology<br />

H. ERIC XU, Ph.D.<br />

Dr. Xu went to Duke University and the University of Texas Southwestern<br />

Medical Center, earning his Ph.D. in molecular biology and biochemistry.<br />

He joined VARI in July 2002 and is now a Professor. Dr. Xu is also the<br />

Primary Investigator and Distinguished Director of the VARI–SIMM<br />

Research Center in Shanghai, China.<br />

RESEARCH INTERESTS<br />

Hormone signaling is essential to eukaryotic life. Our research focuses on the<br />

signaling mechanisms of physiologically important hormones, striving to answer<br />

fundamental questions that have a broad impact on human health and disease.<br />

We are studying two families of proteins, the nuclear hormone receptors and the<br />

G protein–coupled receptors (GPCRs), because these receptors are fundamentally<br />

important for treating major human diseases.<br />

STAFF<br />

Xiang Gao, Ph.D.<br />

Yanyong Kang, Ph.D.<br />

Michelle Martin, A.A.<br />

Kelly Powell, B.S.<br />

Xiaoyin (Edward) Zhou, Ph.D.<br />

STUDENTS<br />

Parker de Waal, B.S.<br />

Yan Yan, B.S.<br />

VISITING SCIENTIST<br />

Ross Reynolds, Ph.D.<br />

Nuclear hormone receptors<br />

The nuclear hormone receptors form a large family comprising ligand-regulated<br />

and DNA-binding transcription factors, which include receptors for the classic<br />

steroid hormones such as estrogen, androgens, and glucocorticoids, as well as<br />

receptors for peroxisome proliferator activators, vitamin D, vitamin A, and thyroid<br />

hormones. These receptors are among the most successful targets in the history<br />

of drug discovery: every receptor has one or more synthetic ligands being used<br />

as medicines. In the last five years, we have developed projects centering on<br />

the peroxisome proliferator–activated receptors (PPARα, β, and γ), the human<br />

glucocorticoid receptor, the androgen receptor, and a number of orphan nuclear<br />

receptors including CAR, SHP, SF-1, COUP-TFII, and LRH-1. We have solved many of<br />

their structures and identified small-molecule ligands for several of them, including<br />

potent ligands for GR, AR, PPARs, and COUP-TFII, which could be developed into<br />

therapeutics against diabetes, cancer, and inflammatory disease.<br />

G protein–coupled receptors<br />

The GPCRs form the largest family of cell-surface receptors (over 800 members)<br />

and account for over 40% of drug targets. There are only a few dozen solved GPCR<br />

structures because they are seven-transmembrane receptors. Many important<br />

questions regarding GPCR ligand binding and activation remain unanswered,<br />

including pressing questions about the assembly of GPCR signaling complexes that<br />

have downstream effects, such as G protein, arrestin, and GPCR kinases. Our group<br />

aims to use rhodopsin, the prototypical GPCR, as a model system for understanding<br />

how an activated GPCR is assembled with the GPCR downstream signaling effectors.<br />

Answering these basic questions could help in the design of pathway-selective GPCR<br />

ligands as drugs.<br />

16 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


TAO YANG, Ph.D.<br />

Dr. Yang received his Ph.D. in biochemistry at the Shanghai Institute of<br />

Biochemistry and Cell Biology, Chinese Academy of Sciences, in 2001. He<br />

joined VARI as an Assistant Professor in February 2013.<br />

STAFF<br />

Jianshuang Li, B.S.<br />

RESEARCH INTERESTS<br />

Our long-term interest is to investigate the signals and cellular processes<br />

orchestrating the activities of mesenchymal stem cells (MSCs) and MSC-derived<br />

cells during skeletal development, homeostasis, regeneration, and degeneration.<br />

The skeletal system develops from mesenchymal cells and is an important reservoir<br />

of MSCs in postnatal life. MSCs play pivotal roles in skeletal tissue growth,<br />

homeostasis, and repair, while dysregulations in MSC renewal, linage specification,<br />

and pool maintenance are common causes of skeletal disorders. Currently, our<br />

lab is focusing on understanding the role of the sumoylation pathway in skeletal<br />

degeneration, aging, and malignancy. We are also studying the role of LRP1 signaling<br />

in osteoporosis, inflammatory bone loss, and skeletal aging.<br />

Huadie Liu, M.S.<br />

Di Lu, M.S.<br />

Jeanie Wedberg, A.S.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 17


Center for Cancer and Cell Biology<br />

RECENT CENTER PUBLICATIONS<br />

Barnett, Daniel, Ying Liu, Katie Partyka, Ying Huang, Huiyuan Tang, Galen Hostetter, Randall E. Brand, Aatur D. Singhi, Richard<br />

R. Drake, and Brian B. Haab. 2017. The CA19-9 and sialyl-TRA antigens define separate subpopulations of pancreatic cancer<br />

cells. <strong>Scientific</strong> <strong>Report</strong>s 7: 4020.<br />

DeBruine, Zachary J., Jiyuan Ke, Kaleeckal G. Harikumar, Xin Gu, Peter Borowsky, Bart O. Williams, Wenqing Xu, Laurence J.<br />

Miller, H. Eric Xu, and Karsten Melcher. 2017. Wnt5a promotes frizzled-4 signalosome assembly by stabilizing cysteine-rich<br />

domain dimerization. Genes and Development 31(9): 916–926.<br />

Droscha, Casey J., Cassandra R. Diegel, Nicole J. Ethen, Travis A. Burgers, Mitchell J. McDonald, Kevin A. Maupin, Agni S. Naidu,<br />

PengFei Wang, Bin T. Teh, and Bart O. Williams. 2017. Osteoblast-specific deletion of Hprt2/Cdc73 results in high bone mass<br />

and increased bone turnover. Bone 98: 68–78.<br />

Grohar, Patrick J., John Glod, Cody J. Peer, Tristan M. Sissung, Fernanda I. Arnaldez, Lauren Long, William D. Figg, Patricia<br />

Whitcomb, Lee J. Helman, and Brigitte C. Widemann. 2017. A phase I/II trial and pharmacokinetic study of mithramycin in<br />

children and adults with refractory Ewing sarcoma and EWS-FLI1 fusion transcript. Cancer Chemotherapy and Pharmacology<br />

80(3): 645–652.<br />

Grohar, Patrick J., Katherine A. Janeway, Luke D. Mase, and Joshua D. Schiffman. 2017. Advances in the treatment of pediatric<br />

bone sarcomas. In 2017 Educational Book, Alexandria, Virginia: American Society of Clinical Oncology.<br />

He, Yuanzheng, Xiang Gao, Devrishi Goswami, Li Hou, Kuntal Pal, Yanting Yin, Gongpu Zhao, Oliver P. Ernst, Patrick Griffin,<br />

Karsten Melcher, and H. Eric Xu. 2017. Molecular assembly of rhodopsin with G protein–coupled receptor kinases. Cell Research<br />

27(6): 728–747.<br />

Klamer, Zachary, Ben Staal, Anthony R. Prudden, Lin Liu, David F. Smith, Geert-Jan Boons, and Brian Haab. 2017. Mining highcomplexity<br />

motifs in glycans: a new language to uncover the fine specificities of lectins and glycosidases. Analytical Chemistry<br />

89(22): 12342–12350.<br />

Lee, Ho-Joon, Mark P. Jedrychowski, Arunachalam Vinayagam, Ning Wu, Ng Shyh-Chang, Yanhui Hu, Chua Min-Wen, Jodene<br />

K. Moore, John M. Asara, Costas A. Lyssiotis, Norbert Perrimon, Steven P. Gygi, Lewis C. Cantley, and Marc W. Kirschner. 2017.<br />

Proteomic and metabolomic characterization of a mammalian cellular transition from quiescence to proliferation. Cell <strong>Report</strong>s<br />

20(3): 721–736.<br />

Li, Jianshuang, Di Lu, Huadie Liu, Bart O. Williams, Paul A. Overbeek, Brendan Lee, Ling Zheng, and Tao Yang. 2017. Sclt1<br />

deficiency causes cystic kidney by activating ERK and STAT3 signaling. Human Molecular Genetics 26(15): 2949–2960.<br />

Ma, Honglei, Jingbo Duan, Jiyuan Ke, Yuanzheng He, Xin Gu, Ting-Hai Xu, Hong Yu, Yonghong Wang, Joseph S. Brunzelle, Yi<br />

Jiang, Scott B. Rothbart, H. Eric Xu, Jiayang Li, and Karsten Melcher. 2017. A D53 repression motif induces oligomerization of<br />

TOPLESS corepressors and promotes assembly of a corepressor-nucleosome complex. Science Advances 3(6): e1601217.<br />

Minciacchi, Valentina R., Cristiana Spinelli, Mariana Reis-Sobreiro, Lorenzo Cavallini, Sungyong You, Mandana Zandian,<br />

Xiaohong Li, Paola Chiarugi, Rosalyn M. Adam, Edwin M. Posadas, Giuseppe Viglietto, Michael R. Freeman, Emanuele Cocucci,<br />

Neil A. Bhowmick, and Dolores Di Vizio. 2017. MYC mediates large oncosome-induced fibroblast reprogramming in prostate<br />

cancer. Cancer Research 77(9): 2306–2317.<br />

Pridgeon, Matthew G., Patrick J. Grohar, Matthew R. Steensma, and Bart O. Williams. 2017. Wnt signaling in Ewing sarcoma,<br />

osteosarcoma, and malignant peripheral nerve sheath tumors. Current Osteoporosis <strong>Report</strong>s 15(4): 239–246.<br />

Sempere, Lorenzo F., Jessica Keto, and Muller Fabbri. 2017. Exosomal microRNAs in breast cancer towards diagnostic and<br />

therapeutic applications. Cancers 9(7): 71.<br />

18 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Valkenburg, Kenneth C., Angelo M. De Marzo, and Bart O. Williams. 2017. Deletion of tumor suppressors adenomatous polyposis<br />

coli and Smad4 in murine luminal epithelial cells causes invasive prostate cancer and loss of androgen receptor expression.<br />

Oncotarget 8(46): 80265–80277.<br />

Waldhart, Althea N., Holly Dykstra, Anderson S. Peck, Elissa A. Boguslawski, Zachary B. Madaj, Jennifer Wen, Kelsey Veldkamp,<br />

Matthew Hollowell, Bin Zheng, Lewis C. Cantley, Timothy E. McGraw, and Ning Wu. 2017. Phosphorylation of TXNIP by AKT<br />

mediates acute influx of glucose in response to insulin. Cell <strong>Report</strong>s 19(10): 2005–2013.<br />

Winkler, Paige A., Yihe Huang, Weinan Sun, Juan Du, and Wei Lü. 2017. Electron cryo-microscopy structure of a human TRPM4<br />

channel. Nature 552(7684): 200–204.<br />

Yan, Yan, Ting-Hai Xu, Kaleeckal G. Marikumar, Laurence J. Miller, Karsten Melcher, and H. Eric Xu. 2017. Dimerization of the<br />

transmembrane domain of amyloid precursor protein is determined by residues around the gamma-secretase cleavage sites.<br />

Journal of Biological Chemistry 292(38): 15826–15837.<br />

Yang, Tao, and Bart O. Williams. 2017. Low-density lipoprotein receptor-related proteins in skeletal development and disease.<br />

Physiological Reviews 97(3): 1211–128.<br />

Yin, Yanting, Parker W. De Waal, Yuanzheng He, Li-Hua Zhao, Dehua Yang, Xiaoqing Cai, Yi Jiang, Karsten Melcher, Ming-Wei<br />

Wang, and H. Eric Xu. 2017. Rearrangement of a polar core provides a conserved mechanism for constitutive activation of<br />

class B G protein–coupled receptors. Journal of Biological Chemistry 292(24): 9865–9881.<br />

Zhang, Feng, Jiyuan Ke, Li Zhang, Rongzhi Chen, Koichi Sugimoto, Gregg A. Howe, H. Eric Xu, Mingguo Zhou, Sheng Yang<br />

He, and Karsten Melcher. 2017. Structural insights into alternative splicing-mediated desensitization of jasmonate signaling.<br />

Proceedings of the National Academy of Sciences U.S.A. 114(7): 1720–1725.<br />

Zhou, X. Edward, Yuanzheng He, Parker W. de Waal, Xiang Gao, Yanyong Kang, Ned Van Eps, Yanting Yin, Kuntal Pal, Devrishi<br />

Goswami, Thomas A. White, Anton Barty, Naomi R. Latorraca, Henry N. Chapman, Wayne L. Hubbell, Ron O. Dror, Raymond<br />

C. Stevens, Vadim Cherezov, Vsevolod V. Gurevich, Patrick R. Griffin, Oliver P. Ernst, Karsten Melcher, and H. Eric Xu. 2017.<br />

Identification of phosphorylation codes for arrestin recruitment by G protein–coupled receptors. Cell 170(3): 457–469.e13.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 19


Center for Epigenetics<br />

Peter A. Jones, Ph.D., D.Sc.<br />

Director<br />

The Center’s researchers study epigenetics and<br />

epigenomics in health and disease, with the<br />

ultimate goal of developing novel therapies to<br />

treat cancer and neurodegenerative diseases.<br />

The Center collaborates extensively with other<br />

VARI research groups and with external partners<br />

to maximize its efforts to develop therapies that<br />

target epigenetic mechanisms.<br />

20 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Methyl (red) and acetyl (light blue)<br />

groups as epigenetic marks on<br />

nucleosomes and DNA. Image by Nicole<br />

Ethen, formerly of the Williams lab.


Center for Epigenetics<br />

STEPHEN B. BAYLIN, M.D.<br />

Dr. Baylin joined VARI as a Professor and Director's Scholar in the<br />

Center for Epigenetics in January 2015. He is co-leader of the VARI-SU2C<br />

Epigenetics Dream Team, and he devotes a portion of his time to VARI. His<br />

primary appointment is at Johns Hopkins University as the Virginia and<br />

D.K. Ludwig Professor of Oncology and Medicine and as co-head of Cancer<br />

Biology at the Sidney Kimmel Comprehensive Cancer Center.<br />

RESEARCH INTERESTS<br />

The Van Andel Research Institute–Stand Up To Cancer (VARI-SU2C) Epigenetics<br />

Dream Team is a multi-institutional effort to develop new epigenetic therapies<br />

against cancer and to move promising therapies to clinical trials. As co-leader, Dr.<br />

Baylin oversees the team’s research, which leverages the combined expertise of its<br />

members.<br />

Epigenetics is the study of how the packaging and modification of DNA influences<br />

the genes that are active or kept silent in a particular cell, and it holds untold<br />

potential for treating cancer and other diseases. Through a detailed understanding of<br />

how normal epigenetic processes work, scientists can identify erroneous epigenetic<br />

modifications that may contribute to the development and progression of cancer.<br />

Epigenetic therapies, which work by correcting these errors, have the potential<br />

to directly treat cancer and to sensitize patients to traditional treatments such as<br />

chemotherapy and promising new immunotherapy approaches.<br />

The VARI-SU2C Epigenetics Dream Team is headquartered at VARI in Grand Rapids,<br />

Michigan. It includes members from Fox Chase Cancer Center, Garvan Institute<br />

of Medical Research, Indiana University, Johns Hopkins University, Memorial<br />

Sloan Kettering Cancer Center, Rigshospitalet/University of Copenhagen, Temple<br />

University, University of Maryland, and University of Southern California. The<br />

American Association for Cancer Research, as SU2C’s scientific partner, reviews<br />

projects and provides objective scientific oversight.<br />

22 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


PETER A. JONES, Ph.D., D.Sc.<br />

Dr. Jones received his Ph.D. from the University of London. He joined the<br />

University of Southern California in 1977 and served as Director of the USC<br />

Norris Comprehensive Cancer Center between 1993 and 2011. Dr. Jones<br />

joined VARI in 2014 as its Chief <strong>Scientific</strong> Officer and Director of the Center<br />

for Epigenetics.<br />

RESEARCH INTERESTS<br />

Our laboratory uses a holistic approach to determine how DNA methylation,<br />

nucleosome positioning, and histone modifications influence each other to bring<br />

about epigenetic changes that contribute to cancer. Some current and recent projects<br />

are summarized here.<br />

STAFF<br />

Brittany Carpenter, Ph.D.<br />

Ashley DeWitt, M.S.<br />

Minmin Liu, Ph.D.<br />

Amy Nelson<br />

Hitoshi Otani, Ph.D.<br />

Stacey Thomas, Ph.D.<br />

Rochelle Tiedemann, Ph.D.<br />

Tinghai (Peter) Xu, Ph.D.<br />

Wanding Zhou, Ph.D.<br />

Both DNA and histone modifications play important roles in suppressing<br />

endogenous retrovirus (ERV) expression in mammalian cells. ERVs, which have<br />

populated the human genome for more than 100 million years, are CpG-rich at the<br />

time of infection, but they have lost CpG content over such long time periods. We<br />

are currently examining ERVs of different ages to determine their mechanism of<br />

silencing and their ability to induce the expression of viral defense genes. The data<br />

suggest that there is an epigenetic switch in the silencing mechanism, such that<br />

older ERVs are predominately silenced by histone modification rather than DNA<br />

methylation.<br />

Following up our finding that DNA methylation inhibitors induce a state of “viral<br />

mimicry” in cancer cells, we have found that treatment of cells with a low dose of<br />

5-azanucleoside plus vitamin C enhanced immune signals, including the increased<br />

expression of ERVs. Because many patients with hematological neoplasia are<br />

vitamin C–deficient, correction of this deficiency may improve patient response to<br />

epigenetic therapy. This work has led to an ongoing VARI-SU2C pilot clinical trial in<br />

adult patients who have MDS or AML, to assess whether vitamin C supplements can<br />

increase patient response to DNA methylation inhibitors.<br />

Another focus of the lab is the noncoding RNA nc886 (vtRNA2-1), which is variably<br />

imprinted by methylation from the mother during development and is strongly<br />

associated with the risk of both obesity and cancer. We will define the mechanism of<br />

this variable imprinting, examine the role of nc886 in normal cell physiology, and<br />

determine how chromatin structure and DNA methylation silence nc886.<br />

Taking advantage of VARI’s latest cryo-EM instrument, the Titan Krios G2, we have<br />

begun work to solve the structures of the DNA methyltransferases DNMT3A and<br />

DNMT3B bound to nucleosomes. This information will increase our understanding of<br />

how DNA methylation patterns are established and maintained by these enzymes.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 23


Center for Epigenetics<br />

STEFAN JOVINGE, M.D., Ph.D.<br />

Dr. Jovinge received his M.D. (1991) and his Ph.D. (1997) at Karolinska<br />

Institute in Stockholm. Since December 2013 he has been a Professor at<br />

VARI and the Medical Director of Research at the Frederik Meijer Heart and<br />

Vascular Institute. He also directs the DeVos Cardiovascular Research<br />

Program, is a Professor at the MSU College of Human Medicine, and is a<br />

Consulting Professor at Stanford University.<br />

RESEARCH INTERESTS<br />

The DeVos Cardiovascular Research Program is a joint effort between VARI and<br />

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

corresponding clinical research unit resides within the Fred Meijer Heart and<br />

Vascular Institute.<br />

STAFF<br />

Lucas Chan, Ph.D.<br />

Shelby Compton<br />

Paula Davidson, M.S.<br />

Lisa DeCamp, M.A., MB(ASCP), RLAT<br />

Ellen Ellis<br />

Emily Eugster, M.S.<br />

Joseph Faski, B.S.<br />

Jens Forsberg, Ph.D.<br />

Eric Kort, M.D.<br />

Olivia Licari<br />

Hsiao-Yun Yeh (Christy) Milliron, Ph.D.<br />

Matthew Weiland, M.S.<br />

To regenerate myocardium after disease or damage is one of the major challenges<br />

in medicine. We have shown that endogenous generation of heart muscle cells<br />

in humans is continuous throughout life. However, it declines rapidly with age<br />

and is far too insufficient to compensate for the large loss of muscle cells seen in<br />

most diseased hearts. Our preliminary data support the concept that preexisting<br />

cardiomyocytes are the source of this endogenous generation. We have now been<br />

able to isolate dividing cardiomyocytes based on their gene expression pattern.<br />

Thus, we are working our way toward control of the endogenous generation of<br />

cardiomyocytes and thereby toward the possibility of developing strategies to<br />

enable the heart to heal itself.<br />

“Rare diseases” affect fewer than 200,00 individuals in the USA; while each patient<br />

group is small, together rare diseases encompass some 30 million individuals. The<br />

generation of drugs for such small populations is very costly, so those who have<br />

such diseases are often left without specific treatment. With the use of the NIH<br />

database LINCS, which screens all FDA-approved drugs for off-target effects, we<br />

have identified a drug that specifically targets the deficiency in patients who have a<br />

rare mutation that causes a severe heart muscle disease. By reprogramming blood<br />

cells and deriving heart muscle cells from these patients, we have been able to verify<br />

the database predictions for the drug, thereby making possible the availability of<br />

new drugs for patients with this rare disease at a reasonable cost.<br />

Using a sophisticated technology, we have been able to reprogram and derive cardiac<br />

pacemaker cells. This year, we were able to use pacemaker cells to create a biological<br />

pacemaker in a culture dish. In another study, we have created a large database that<br />

allows us to optimize treatment for patients who have severe heart failure and are<br />

on mechanical support. We can also create advanced algorithms for predicting the<br />

outcome of support selection and for preventing complications.<br />

24 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


PETER W. LAIRD, Ph.D.<br />

Dr. Laird earned his Ph.D. in 1988 from the University of Amsterdam<br />

with Piet Borst. He was a faculty member at the University of Southern<br />

California from 1996 to 2014, where he was Skirball-Kenis Professor of<br />

Cancer Research and directed the USC Epigenome Center. He joined VARI<br />

as a Professor in September 2014.<br />

STAFF<br />

Kelly Foy, B.S.<br />

Walid Habib, Ph.D.<br />

Toshinori Hinoue, Ph.D.<br />

Manpreet Kalkat, Ph.D.<br />

Liang Kang, A.S.<br />

KwangHo Lee, Ph.D.<br />

Amy Nelson<br />

Wanding Zhou, Ph.D.<br />

STUDENTS<br />

Zack Jansen<br />

RESEARCH INTERESTS<br />

Our goal is to develop a detailed understanding of the molecular basis of human<br />

disease, with a particular emphasis on the role of epigenetics in cancer. Cancer is<br />

often considered to have a primarily genetic basis, with contributions from germline<br />

variations in risk and somatically acquired mutations, rearrangements, and copy<br />

number alterations. However, it is clear that nongenetic mechanisms can exert a<br />

powerful influence on cellular phenotype, as evidenced by the marked diversity of<br />

cell types within our bodies, which virtually all contain an identical genetic code.<br />

This differential gene expression is controlled by tissue-specific transcription<br />

factors and variations in chromatin packaging and modification, which can provide<br />

stable phenotypic states governed by epigenetic, not genetic, mechanisms. It seems<br />

likely that an intrinsically opportunistic disease such as cancer would take advantage<br />

of such a potent mediator of cellular phenotype. Our laboratory is dedicated to<br />

understanding how epigenetic mechanisms contribute to the origins of cancer and<br />

how to translate this knowledge into more-effective cancer prevention, detection,<br />

treatment, and monitoring.<br />

We use a multidisciplinary approach in our research, relying on mechanistic studies<br />

in model organisms and cell cultures, clinical and translational collaborations,<br />

genome-scale and bioinformatic analyses, and epidemiological studies to advance<br />

our understanding of cancer epigenetics. In recent years, we participated in the<br />

generation and analysis of high-dimensional epigenetic data sets, including<br />

the production of all epigenomic data for The Cancer Genome Atlas (TCGA) and<br />

the application of next-generation sequencing technology to whole-genome<br />

DNA methylation analysis at single-base-pair resolution. We are leveraging this<br />

epigenomic data for translational applications and hypothesis testing in animal<br />

models. A major focus of our laboratory is to develop mouse models for investigating<br />

epigenetic mechanisms and drivers of cancer and to develop novel strategies for<br />

single-cell epigenomic analysis.<br />

Nicole Vander Schaaf, B.S.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 25


Center for Epigenetics<br />

HUILIN LI, Ph.D.<br />

Dr. Li earned his Ph.D. in electron crystallography from the University of<br />

Science and Technology Beijing, where he trained with the late K. H. Kuo.<br />

He joined VARI in 2016 from Stony Brook University, New York.<br />

RESEARCH INTERESTS<br />

The work of our lab focuses on the structural basis of DNA replication, the bacterial<br />

proteasome system, and the regulation and modification of the Notch receptor.<br />

STAFF<br />

Lin Bai, Ph.D.<br />

Xiang Feng, Ph.D.<br />

Hao-Chi Hsu, Ph.D.<br />

Amanda Kovach, B.S.<br />

Hua Li, Ph.D.<br />

Michelle Martin, A.A.<br />

Yanting Yin, Ph.D.<br />

Hongjun Yu, Ph.D.<br />

Eukaryotic DNA replication<br />

Replication initiation is tightly regulated, because failure to ensure once-only<br />

initiation per cell cycle can result in uncontrolled proliferation and genomic<br />

instability, which are hallmarks of tumorigenesis. We use structural and biochemical<br />

approaches to uncover the molecular mechanisms underlying eukaryotic<br />

chromosomal replication. Work in our lab over the past year has revealed how<br />

ORC, with the help of Cdc6, loads the Mcm2-7 hexamer and how the Mcm2-7<br />

double-hexamer binds the origin DNA. In the S phase of the cell cycle, the active<br />

Cdc45–Mcm2-7–GINS helicase (CMG) works with the leading strand polymerase<br />

epsilon, the lagging strand polymerase delta, and the primase-polymerase alpha to<br />

synthesize new DNA. We also determined the structure of the 11-protein yeast CMG<br />

helicase and have shown how the helicase interacts with the replication fork DNA.<br />

Proteostasis in Mycobacterium tuberculosis<br />

Tuberculosis kills some 1.5 million people globally every year. Mycobacterium<br />

tuberculosis can be killed by nitric oxide (NO) of the host immune system. The<br />

Mtb proteasome is a key to the organism’s resistance to such attack and thus is a<br />

promising target for the development of anti-TB chemotherapeutics. In the past<br />

year, we have solved the structure of the ATPase-dependent proteasomal activator<br />

Mpa and the ATP-independent proteasomal activator PafE. We also uncovered the<br />

structural basis for the species-selective binding of six N,C-capped dipeptides to<br />

the Mtb proteasome. Our work illuminates the bacterial proteasome system and<br />

facilitates anti-TB chemotherapeutic development efforts.<br />

STUDENTS<br />

Minge Du, M.S.<br />

Ruda Santos, M.S.<br />

Zuanning Yuan, M.S.<br />

26 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


GERD PFEIFER, Ph.D.<br />

Dr. Pfeifer earned his M.S. in pharmacology in 1981 and his Ph.D. in<br />

biochemistry in 1984 from Goethe University in Frankfurt, Germany. He<br />

most recently held the Lester M. and Irene C. Finkelstein Chair in Biology<br />

at the City of Hope in Duarte, California, before joining VARI in 2014 as<br />

a Professor.<br />

RESEARCH OVERVIEW<br />

The laboratory studies epigenetic mechanisms of human diseases, with a focus on<br />

DNA methylation and the role of 5-methylcytosine oxidation by the TET protein<br />

family.<br />

STAFF<br />

Zhijun Huang, Ph.D.<br />

Seung-Gi Jin, Ph.D.<br />

Jennifer Johnson, M.S.<br />

Amy Nelson<br />

Zhi-Qiang (Ken) Wang, Ph.D.<br />

DNA methylation in cancer<br />

This work centers on the hypothesis that CpG islands are protected from<br />

methylation in normal cells by a set of specific proteins, such as 5-methylcytosine<br />

oxidases, CXXC proteins, and the polycomb complex. The protection breaks<br />

down during early stages of malignancy. We investigate mechanisms of DNA<br />

hypermethylation using DNA-methylation mapping and chromatin mapping in both<br />

normal and malignant cells, as well as bioinformatic approaches and functional<br />

studies employing gene inactivation in tissue culture.<br />

TET3 and related proteins in basic biology and human disease<br />

The removal of methyl groups from DNA has been recognized as an important<br />

pathway in cancer and possibly in other diseases. Our lab studies mechanisms<br />

of 5-methylcytosine oxidation. We have identified three isoforms of the TET3<br />

5-methylcytosine oxidase and characterized them using biochemical, functional,<br />

and genetic approaches. We observed that one isoform of TET3 specifically binds<br />

to 5-carboxylcytosine, thus establishing an anchoring mechanism of TET3 to<br />

its reaction product, which may aid in localized 5-methylcytosine oxidation and<br />

removal. We also study several TET3-associated proteins, trying to understand<br />

their biological roles. TET3 has a rather limited genomic distribution and is targeted<br />

to the transcription start sites of defined sets of genes, many of which function<br />

within the lysosome and autophagy pathways. We are exploring the mechanistic<br />

consequences of 5-methylcytosine oxidation in these genes, with the long-term<br />

goal of determining whether neurodegeneration has an epigenetic origin. In another<br />

project, we are exploring the function of a TET3-binding protein and its effect on<br />

TET-mediated processes in embryonic stem cells and in myoblasts. This work has<br />

implications for understanding the mechanisms underlying muscular dystrophy.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 27


Center for Epigenetics<br />

SCOTT ROTHBART, Ph.D.<br />

Dr. Rothbart earned a Ph.D. in pharmacology and toxicology from Virginia<br />

Commonwealth University in 2010. He joined VARI in April 2015 as an<br />

Assistant Professor.<br />

RESEARCH INTERESTS<br />

The long-term goal of my research program is to define molecular mechanisms<br />

regulating chromatin modification signaling. Through a multidisciplinary and<br />

collaborative research program, we hope to translate basic knowledge of epigenetic<br />

mechanisms into therapeutic benefits.<br />

STAFF<br />

Evan Cornett, Ph.D.<br />

Bradley Dickson, Ph.D.<br />

Alison Lanctot, Ph.D.<br />

Amy Nelson<br />

Kevin Shaw, B.S.<br />

Rochelle Tiedemann, Ph.D.<br />

STUDENTS<br />

We are keen on understanding the complex relationship between DNA methylation<br />

and histone post-translational modifications (PTMs); these are two key epigenetic<br />

regulators of genome accessibility, interaction, and function. Within this broad<br />

framework, we ask 1) how are the writers and erasers of chromatin modifications<br />

regulated? 2) how do nuclear proteins and their complexes interface with (i.e., read)<br />

epigenetic marks to perform their chromatin regulatory functions? and 3) how does<br />

deregulation of chromatin signaling contribute to human diseases like cancer?<br />

We fabricate histone peptide microarrays in my lab as an integral part of our effort<br />

to characterize the complex interactions of proteins with the DNA and histone<br />

components of chromatin. We use this platform extensively to characterize the<br />

reader, writer, and eraser activities of chromatin regulators and also the behavior of<br />

antibodies that recognize histones and their PTMs.<br />

We are also developing new functional proteomics techniques to study the writers,<br />

erasers, and readers of lysine methylation signaling. Our studies are providing<br />

crucial systems-level information for the construction of lysine methylation<br />

signaling networks, are aiding drug discovery and development efforts, and are<br />

improving our understanding of lysine methylation function in human health and<br />

disease.<br />

Christine Ausherman<br />

Robert Vaughan, B.S.<br />

Philip Versluis<br />

28 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


HUI SHEN, Ph.D.<br />

Dr. Shen earned her Ph.D. at the University of Southern California in<br />

genetic, molecular, and cellular biology. She joined VARI in September<br />

2014 as an Assistant Professor.<br />

STAFF<br />

Huihui Fan, Ph.D.<br />

Hongbo Liu, Ph.D.<br />

Amy Nelson<br />

Wanding Zhou, Ph.D.<br />

RESEARCH INTERESTS<br />

The laboratory focuses on the epigenome and its interaction with the genome in<br />

various diseases, with a specific emphasis on cancers of women and cross-cancer<br />

comparisons. We use bioinformatics as a tool to understand the etiology, cell of<br />

origin, and epigenetic mechanisms of disease and to devise better approaches<br />

for cancer prevention, detection, therapy, and monitoring. We have extensive<br />

experience with genome-scale DNA methylation profiles in primary human samples,<br />

and we have made major contributions to epigenetic analysis within The Cancer<br />

Genome Atlas (TCGA).<br />

DNA methylation is ideally suited for deconstructing heterogeneity among cell types<br />

within a tissue sample. In cancer research, this approach can be used for cancer<br />

cell clonal evolution studies or for quantifying normal cell infiltration and stromal<br />

composition. The latter can provide insights into the tumor microenvironment, and<br />

in noncancer studies it can be a useful tool for accurately estimating cell populations<br />

and providing insights into lineage structures and population shifts in disease. In<br />

addition, we are interested in translational applications of epigenomic technology.<br />

To this end, we bring markers emerging from our bioinformatics analysis into<br />

clinical assay development, marker panel assembly, and optimization, with the<br />

ultimate goal of clinical testing and validation.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 29


Center for Epigenetics<br />

PIROSKA E. SZABÓ, Ph.D.<br />

Dr. Szabó earned an M.Sc. in biology and a Ph.D. in molecular biology from<br />

József Attila University, Szeged, Hungary. She joined VARI in 2014 as an<br />

Associate Professor.<br />

RESEARCH INTERESTS<br />

Our laboratory studies the molecular mechanisms responsible for resetting the<br />

mammalian epigenome between generations, globally and specifically in the context<br />

of genomic imprinting. We focus on how DNA methylation patterns are established<br />

in germ cells and how some of those are protected in the zygote and in the embryo.<br />

STAFF<br />

Brianna Bixler, B.S.<br />

Ji Liao, Ph.D.<br />

Amy Nelson<br />

Tie-Bo Zeng, Ph.D.<br />

STUDENTS<br />

Brianna Busscher<br />

Yingying Meng, M.S.<br />

The role of broad transcription and dynamic chromatin changes in the germline<br />

Correctly setting up male or female gamete-specific methylation patterns is vitally<br />

important for fertility, development, and health. Our genome-wide mapping results<br />

have revealed that DNA methylation in fetal male germ cells (prospermatogonia)<br />

occurs by default along a profile of broad, low-level transcription. We have also<br />

found that dynamically increasing or diminishing H3K4 methylation at specific<br />

sequences is predictive of escaping or attaining DNA methylation, respectively, in<br />

the male germline. We hypothesize that transcription run-through is required for<br />

establishing default, broad DNA methylation in the prospermatogonia genome,<br />

including paternal imprinted differentially methylated regions (DMRs). Dynamic<br />

changes in H3K4me by H3K4 demethylases (KDMs) and H3K4 methyltransferases<br />

(HMTs), on the other hand, provide a pattern for de novo DNA methylation. We are<br />

addressing these questions using experimental approaches of mouse genetics and<br />

epigenomics.<br />

Maternal effects of histone methyltransferases<br />

Crucial events in the early embryo, such as reaching totipotency and embryonic<br />

genome activation, depend on accurate levels of epigenetic modifiers deposited in<br />

the egg. We are only beginning to understand the underlying epigenetic mechanisms<br />

in these events. We and others have shown that genome-wide DNA demethylation<br />

in the zygote involves sequential TET-mediated oxidation of 5mC to 5hmC, 5fC, and<br />

5caC in the paternal pronucleus. Specific loci and the entire maternal pronucleus,<br />

however, are protected from TET-initiated DNA demethylation; this protection<br />

involves histone H3K9 methylation. Using mouse genetics and epigenomics, we<br />

will genetically identify the mechanistic connections between maternally deposited<br />

HMTs, DNA methylation, and the developmental potential of the embryo.<br />

30 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


TIMOTHY J. TRICHE, JR., Ph.D.<br />

Dr. Triche earned his Ph.D. from the University of Southern California in<br />

2013. He joined VARI in the autumn of 2017 as an Assistant Professor in the<br />

Center for Epigenetics.<br />

RESEARCH INTERESTS<br />

Our laboratory develops statistical and mathematical methods to dissect<br />

pediatric and adult diseases, with a focus on cancers of the blood in children. We<br />

study interactions between genetic factors and environmental factors (deficiencies<br />

and exposures), particularly where epigenetic mediation plays a major role, such<br />

as in immune response and evasion.<br />

STAFF<br />

Amy Nelson<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 31


Center for Epigenetics<br />

STEVEN J. TRIEZENBERG, Ph.D.<br />

Dr. Triezenberg earned his Ph.D. at the University of Michigan. He was a<br />

faculty member at Michigan State University for more than 18 years before<br />

joining VARI in 2006 as the founding Dean of Van Andel Institute Graduate<br />

School and as a VARI Professor.<br />

RESEARCH INTERESTS<br />

Our research explores the mechanisms that control how genes are expressed inside<br />

cells, with a special interest in the processes that activate transcription of genetic<br />

information from DNA into RNA. We study those mechanisms in the context of<br />

infection by herpes simplex virus type 1 (HSV-1), the cause of cold sores.<br />

STAFF<br />

Glen Alberts, B.S.<br />

Susanne Miller-Schachinger, B.B.A.<br />

.<br />

STUDENT<br />

Nikki Thellman, D.V.M. (Ph.D., May 2017)<br />

Some of our work looks at early stages of lytic or productive infection by HSV-1,<br />

which results in the obvious (and painful) cold-sore symptoms near the mouth. We<br />

have explored how a particular viral protein, VP16, activates the first viral genes that<br />

are expressed during lytic infection. We are now looking at proteins of the host cell<br />

that affect the early stages of infection, some of which control how the virus gets<br />

into a cell and some that control how the VP16 protein performs its functions. This<br />

approach may yield new ideas for antiviral drugs that can block HSV infections.<br />

After the initial infection resolves, HSV-1 finds its way into nerve cells, where the<br />

virus can remain in a latent mode for the entire life of the host. Occasionally, some<br />

stressful event will cause the latent virus to reactivate, producing new viruses in<br />

the nerve cell and sending them back to the skin to cause a recurrence of the cold<br />

sore. We are investigating the role that VP16 might play during this reactivation.<br />

We are especially interested in the epigenetic regulators that might be involved in<br />

unpacking the chromatin that silences the latent viral DNA. Our present hypothesis<br />

is that epigenetic coactivators recruited by VP16 are required to open up chromatin<br />

as an early step in reactivating the viral genes from latency. We are currently testing<br />

this hypothesis in quiescent infections of cultured human nerve cells.<br />

32 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


RECENT CENTER PUBLICATIONS<br />

Azad, Nilofer S., Anthony el-Khoueiry, Jun Yin, Ann L. Oberg, Patrick Flynn, Douglas Adkins, Anup Sharma, Daniel J.<br />

Weisenberger, Thomas Brown, Prakriti Medvari, Peter A. Jones, Hariharan Easwaran, Ihab Kamel, Nathan Bahary, George Kim,<br />

Joel Picus, Henry C. Pitot, Charles Erilichman, Ross Donehower, Hui Shen, Peter W. Laird, Richard Piekarz, Stephen Baylin, and<br />

Nita Ahuja. 2017. Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and<br />

entinostat: a phase 2 consortium/Stand Up 2 Cancer study. Oncotarget 8(21): 35326–35338.<br />

Cancer Genome Atlas Research Network, The. 2017. Integrated genomic characterization of oesophageal carcinoma. Nature<br />

541(7636): 169–175.<br />

Cherniack, Andrew D., Hui Shen, Vonn Walter, Chip Stewart, Bradley A. Murray, Reanne Bowlby, Xin Hu, Shiyun Ling, Robert<br />

A. Soslow, Russell R. Broaddus, Rosemary E. Zuna, Gordon Robertson, Peter W. Laird, Raju Kucherlapati, Gordon B. Mills,<br />

The Cancer Genome Atlas Research Network, John N. Weinstein, Jiashan Zhang, Rehan Akbani, and Douglas A. Levine. 2017.<br />

Integrated molecular characterization of uterine carcinosarcoma. Cancer Cell 31(3): 411–423.<br />

Connolly, Roisin M., Huili Li, Rachel C. Jankowitz, Zhe Zhang, Michelle A. Rudek, Stacie C. Jeeter, Shannon A. Slater, Penny<br />

Powers, Antonio C. Wolff, John H. Fetting, Adam Burufsky, Richard Piekarz, Nita Ahuja, Peter W. Laird, Hui Shen, Daniel J.<br />

Weisenberger, Leslie Cope, James G. Herman, George Somlo, Garcia Agustin A., Peter A. Jones, Stephen B. Baylin, Nancy E.<br />

Davidson, Cynthia A. Zahnow, and Vered Stearns. 2017. Combination epigenetic therapy in advanced breast cancer with<br />

5-azacitidine and entinostat: a Phase II National Cancer Institute/Stand Up to Cancer study. Clinical Cancer Research 23(11):<br />

2691–2701.<br />

Cornett, Evan M., Bradley M. Dickson, and Scott B. Rothbart. 2017. Analysis of histone antibody specificity with peptide<br />

microarrays. Journal of Visualized Experiments 126: e55912.<br />

Georgescu, Roxana, Zuanning Yuan, Lin Bai, Ruda de Luna Almeida Santos, Jingchuan Sun, Dan Zhang, Olga Yurieva, Huilin<br />

Li, and Michael E. O’Donnell. 2017. Structure of eukaryotic CMG helicase at a replication fork and implications to replisome<br />

architecture and origin initiation. Proceedings of the National Academy of Sciences U.S.A. 114(5): D697–E706.<br />

Hanley, M.P., M.A. Hahn, A.X. Li, X. Wu, J. Lin, A.H. Choi, Z. Ouyang, Y. Fong, G.P. Pfeifer, T.J. Devers, and D.W. Rosenberg. 2017.<br />

Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia. Oncogene 36(35):<br />

5035–5044.<br />

Helbo, Alexandra Søgaard, Fides D. Lay, Peter A. Jones, Gangning Liang, and Kirsten Grønbaek. 2017. Nucleosome positioning<br />

and NDR structure at RNA polymerase III promoters. <strong>Scientific</strong> <strong>Report</strong>s 7: 41947<br />

Lakshminarasimhan, Ranjani, Claudia Andreu-Vieyra, Kate Lawrenson, Christopher E. Duymich, Simon A. Gayther, Gangning<br />

Liang, and Peter A. Jones. 2017. Down-regulation of ARID1A is sufficient to initiate neoplastic transformation along with<br />

epigenetic reprogramming in non-tumorigenic endometriotic cells. Cancer Letters 401: 11–19.<br />

Lee, Kwang-Ho, Shirley Oghamian, Jin-A Park, Liang Kang, and Peter W. Laird. 2017. The REMOTE-control system: a system<br />

for reversible and tunable control of endogenous gene expression in mice. Nucleic Acids Research 45(21): 12256–12269.<br />

Ma, Honglei, Jingbo Duan, Jiyuan Ke, Yuanzheng He, Xin Gu, Ting-Hai Xu, Hong Yu, Yonghong Wang, Joseph S. Brunzelle, Yi<br />

Jiang, Scott B. Rothbart, H. Eric Xu, Jiayang Li, and Karsten Melcher. 2017. A D53 repression motif induces oligomerization of<br />

TOPLESS corepressors and promotes assembly of a corepressor-nucleosome complex. Science Advances 3(6): e1601217.<br />

Noguchi, Yasunori, Auanning Yuan, Lin Bai, Sarah Schneider, Gongpu Zhao, Bruce Stillman, Christian Speck, and Huilin Li. 2017.<br />

Cryo-EM structure of Mcm2-7 double hexamer on DNA suggests a lagging-strand DNA extrusion model. Proceedings of the<br />

National Academy of Sciences U.S.A. 114(45): E9529–E9538.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 33


Center for Epigenetics<br />

RECENT CENTER PUBLICATIONS (cont.)<br />

Olsson, P., E. Theander, U. Bergström, S. Jovinge, L.T.H. Jacobsson, and C. Turesson. 2017. Multiplex cytokine analyses in<br />

patients with rheumatoid arthritis require use of agents blicking heterophilic antibody activity. Scandanavian Journal of<br />

Rheumatology 46(1): 1–10.<br />

Polak, Paz, Jaegil Kim, Lior Z. Braunstein, Rosa Karlilc, Nicholas J. Haradhavala, Grace Tiao, Daniel Rosebrock, Dimitri Livitz,<br />

Kirsten Kübler, Kent W. Mouw, Atanas Kamburov, Yosef E. Maruvka, Ignaty Leshchiner, Eric S. Lander, Todd R. Golub, Aviad<br />

Zick, Alexandre Orthwein, Michael S. Lawrence, Rajbir N. Batra, Carlos Caldas, Daniel A. Haber, Peter W. Laird, Hui Shen, Leif<br />

W. Ellisen, Alan D. D’Andrea, Stephen J. Chanock, William D. Foulkes, and Gad Getz. 2017. A mutational signature reveals<br />

alterations underlying deficient homologous recombination repair in breast cancer. Nature Genetics 49(10): 1476–1486.<br />

Robertson, A. Gordon, Jaegil Kim, Hikmat Al-Ahmadie, Joaquim Bellmunt, Guangwu Guo, Andrew D. Cherniak, Toshinori<br />

Hinoue, Peter W. Laird, Katherine A. Hoadley, Rehan Akbani, et al. 2017. Comprehensive molecular characterization of muscleinvasive<br />

bladder cancer. Cell 171(3): 540–556.e25.<br />

Shanle, Erin K., Stephen A. Shinsky, Joseph B. Bridgers, Narkhyun Bae, Cari Sagum, Krzysztof Krajewski, Scott B. Rothbart, Mark<br />

T. Bedford, and Brian D. Strahl. 2017. Histone peptide microarray screen of chromo and Tudor domains defines new histone<br />

lysine methylation interactions. Epigenetics and Chromatin 10: 12.<br />

Thellman, Nikki M., Carolyn Botting, Zachary Madaj, and Steven J. Triezenberg. 2017. An immortalized human dorsal root<br />

ganglia cell line provides a novel context to study herpes simplex virus Type-1 latency and reactivation. Journal of Virology<br />

91(12): 00080-17.<br />

Thellman, Nikki M., and Steven J. Triezenberg. 2017. Herpes simplex virus establishment, maintenance, and reactivation:<br />

in vitro modeling of latency. Pathogens 6(3): 28.<br />

Veland, Nicolas, Swanand Hardikar, Yi Zhong, Sitaram Sayatri, Jiameng Dan, Brian D. Strahl, Scott B. Rothbart, Mark T. Bedford,<br />

and Taiping Chen. 2017. The arginine methyltransferase PRMT6 regulates DNA methylation and contributes to global DNA<br />

hypomethylation in cancer. Cell <strong>Report</strong>s 21(12): 3390–3397.<br />

Weng, Xi-Lan, Ran An, Jessica Cassin, Jessica Joseph, Ruifa Mi, Chen Wang, Chun Zhong, Seung-Gi Jin, Gerd P. Pfeifer, Alfonso<br />

Bellacosa, Xinzhong Dong, Ahmet Hoke, Zhigang He, Hongjun Song, and Guo-li Ming. 2017. An intrinsic epigenetic barrier for<br />

functional axon regeneration. Neuron 94(2): 337–346.<br />

Wu, Yujie, Kuan Hu, Defeng Li, Lin Bai, Shaoqing Yang, Jordan B. Jastrab, Shuhao Xiao, Yonglin Hu, Susan Zhang, K. Heran<br />

Darwin, Tao Wang, and Huilin Li. 2017. Mycobacterium tuberculosis proteasomal ATPase Mpa has a β-grasp domain that hinders<br />

docking with the proteasome core protease. Molecular Microbiology 105(2): 227–241.<br />

Yuan, Zuanning, Alberto Riera, Lin Bai, Jingchuan Sun, Saikat Nandi, Christos Spanos, Zhuo Angel Chen, Marta Barbon, Juri<br />

Rappsilber, Bruce Stillman, Christian Speck, and Huilin Li. 2017. Structural basis of Mcm2–7 replicative helicase loading by<br />

ORC–Cdc6 and Cdt1. Nature Structural & Molecular Biology 24(3): 316–324.<br />

Zhou, Wanding, Peter W. Laird, and Hui Shen. 2017. Comprehensive characterization, annotation and innovative use of<br />

Infinium DNA methylation BeadChip probes. Nucleic Acids Research 45(4): e22.<br />

34 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


A side view of the cryo-EM density map of the S. cerevisiae Mcm2-7 double hexamer, with<br />

individual subunits labeled. The two hexamers are stacked at a tilt angle of 14°.<br />

Image from Huilin Li’s laboratory.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 35


Center for Neurodegenerative Science<br />

Patrik Brundin, M.D., Ph.D.<br />

Director<br />

The Center's laboratories focus on developing<br />

novel treatments that slow or halt the progression<br />

of neurodegenerative disease, in particular<br />

Parkinson’s disease. The work involves three main<br />

goals: disease modification, biomarker discovery,<br />

and brain repair.<br />

36 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Neurons from the brain of a mouse<br />

model of Parkinson’s disease. The<br />

neurons are stained green, cell nuclei are<br />

stained blue with DAPI, and pathological<br />

inclusions of α-synuclein are stained red.<br />

Image by Nolwen Rey of the<br />

Patrik Brundin lab.


Center for Neurodegenerative Science<br />

LENA BRUNDIN, M.D., Ph.D.<br />

Dr. Brundin earned her Ph.D. in neurobiology and her M.D. from Lund<br />

University, Sweden. She joined VARI in 2012 and is an Associate Professor.<br />

RESEARCH INTERESTS<br />

We hypothesize that inflammation in the brain causes psychiatric symptoms<br />

such as depression and thoughts of suicide, and we study how inflammation can<br />

damage nerve cells and be involved in neurological conditions such as Parkinson’s<br />

disease. We are conducting clinical studies on patients in the Grand Rapids area<br />

and translational experiments in the laboratory at VARI, trying to understand the<br />

mechanisms by which inflammation affects the brain.<br />

STAFF<br />

Elena Bryleva, Ph.D.<br />

Nils Eastburg, B.S.<br />

Emily Glidden, B.S.<br />

Stan Krzyzanowski, B.A.<br />

Keerthi Rajamani, Ph.D.<br />

Infections may play a role in triggering inflammation and subsequent symptoms in<br />

patients. In collaboration with Pine Rest Christian Mental Health, we are assessing<br />

the role of herpes simplex virus infection in triggering psychiatric symptoms. Our<br />

hypothesis is that patients with depression are more vulnerable to developing mood<br />

symptoms upon reactivation of HSV infection and that the infection could trigger<br />

depressive episodes.<br />

We have found that infection with the parasite Toxoplasma gondii is associated with<br />

a sevenfold risk of attempted suicide. Some 10-20% of all Americans are infected<br />

with this parasite, which may cause subtle behavioral changes, perhaps due to<br />

low-grade chronic brain inflammation. Toxoplasma infection may be treatable using<br />

current medications, but clinical trials are needed to prove that such treatment has a<br />

beneficial effect on depressive and suicidal behavior.<br />

STUDENT<br />

Sarah Keaton, M.S.<br />

We are conducting a study of perinatal depression together with Pine Rest Christian<br />

Mental Health, Spectrum Health, and Michigan State University. This NIH-funded<br />

effort, led by Dr. Brundin, investigates the role of placental inflammation in the<br />

development of perinatal depression. The goals of the study are to understand the<br />

cause of depression during pregnancy and to find biomarkers to identify women<br />

who are at risk for such depression. We have successfully enrolled 199 women and<br />

evaluated them in pregnancy and post partum over the past three years, and we are<br />

now analyzing the data.<br />

We have identified an enzyme, aminocarboxymuconate semialdehyde decarboxylase<br />

(ACMSD), that may regulate the vulnerability to developing psychiatric and<br />

neurological symptoms upon infection or inflammation. A person having low activity<br />

of ACMSD might have difficulties in controlling inflammation. The by-products<br />

of inflammation may cause nerve cell damage and neurological and psychiatric<br />

symptoms. We are studying whether increased amounts of ACMSD can be protective<br />

and prevent symptoms of Parkinson’s disease and depression.<br />

38 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


PATRIK BRUNDIN, M.D., Ph.D.<br />

Dr. Brundin earned his M.D. and Ph.D. at Lund University, Sweden. He was<br />

a professor of neuroscience at Lund before becoming a Professor and<br />

Associate Research Director of VARI in 2012.<br />

RESEARCH INTERESTS<br />

Our research mission is to understand why Parkinson’s disease (PD) develops. We<br />

use cellular and animal PD models to discover new treatments that we hope can slow<br />

disease progression.<br />

STAFF<br />

Kim Cousineau, M.P.A.<br />

Sonia George, Ph.D.<br />

Lindsay Meyerdirk, M.S.<br />

Wouter Peelaerts, Ph.D.<br />

Emmanuel Quansah, Ph.D.<br />

Keerthi Rajamani, Ph.D.<br />

Nolwen Rey, Ph.D.<br />

Emily Schulz, B.S.<br />

Jennifer Steiner, Ph.D.<br />

Misfolded variants of the protein α-synuclein (α-syn) are a main constituent<br />

of intraneuronal Lewy bodies, the protein aggregates that are the major<br />

neuropathological hallmark of PD. The mechanisms underlying α-syn pathology are<br />

poorly understood. We were one of the first groups to propose that abnormal α-syn<br />

might propagate between neurons and drive the progression of symptoms.<br />

Our interests include understanding how α-syn aggregation is triggered, how the<br />

aggregates spread, and how they cause neurological deficits. We have created a<br />

mouse model of the human disease based on injections of misfolded α-syn into<br />

the olfactory bulb. The loss of olfaction is an early change in PD, often preceding<br />

the onset of the classic motor symptoms. In our model, α-syn aggregate pathology<br />

gradually spreads along olfactory pathways, causing progressive olfactory<br />

deficits. We are now defining whether the deficits are due to neuronal death or to<br />

dysfunction in neurons that contain aggregates.<br />

The olfactory bulb model has been proposed to be a starting point of Lewy<br />

body pathology, but the initial trigger is unknown. We are currently exploring<br />

whether airborne environmental pollutants or other proinflammatory stimuli can<br />

cause α-syn aggregate pathology in the olfactory bulb. We are also examining<br />

immunotherapy and repurposed antidiabetic drugs for effects that reduce PD<br />

pathology in animal models. Given the favorable safety profile of antidiabetic agents,<br />

several are already being tested in PD clinical trials, but further animal trials are<br />

needed to understand the mechanism(s) of action.<br />

Our major funders include the National Institutes of Health, the Department of<br />

Defense, the Michael J. Fox Foundation, the Cure Parkinson’s Trust UK, and<br />

H. Lundbeck A/S.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 39


Center for Neurodegenerative Science<br />

GERHARD (Gerry) A. COETZEE, Ph.D.<br />

Dr. Coetzee earned his Ph.D. in medical biochemistry from the University<br />

of Stellenbosch, South Africa, in 1977. He was a professor in the<br />

Departments of Urology, Microbiology, and Preventive Medicine at the Keck<br />

School of Medicine at USC before joining VARI as a Professor in<br />

November 2015.<br />

STAFF<br />

Alix Booms, B.S.<br />

Kim Cousineau, M.P.A.<br />

Steve Pierce, Ph.D.<br />

Trevor Tyson, Ph.D.<br />

J.C. Vanderschans, B.S.<br />

RESEARCH INTERESTS<br />

Our laboratory focuses on exploring genome-wide association studies (GWAS) to<br />

uncover genetic risk mechanisms in breast cancer and Parkinson’s disease (PD);<br />

we call these post-GWAS studies. GWAS of complex phenotypes such as those of<br />

breast cancer and PD have become powerful pointers to genetic predisposition.<br />

Additionally, as next-generation sequencing techniques have become more feasible<br />

and increasingly affordable, mechanisms may be explored genome-wide. A daunting<br />

and unexpected finding was that for many complex diseases, more than 90% of<br />

the risk single nucleotide polymorphisms (SNPs) are located in noncoding DNA.<br />

To address these issues, we and others have used chromatin biofeatures to explore<br />

potential functionality.<br />

Specifically, our laboratory uses cell culture models to probe mechanisms of risk.<br />

Our main hypothesis is that risk resides in enhancers scattered through our genome<br />

that are identifiable within chromatin biofeatures (nucleosome occupancy and<br />

histone covalent modifications). Enhancers are cell type–specific and mediate risk<br />

by specific gene expression control. For example, in one of our projects we used<br />

differentiating dopaminergic neurons (Lund human mesencephalic [LUHMES] cells)<br />

to probe PD risk enhancers. We matched the differention-specific appearance or<br />

disappearance of enhancers with changes in gene expression. We thus identified<br />

22,057 enhancers paired with 6,388 differentially expressed genes by proximity.<br />

These enhancers are enriched with 14 transcription factor response elements driving<br />

a cluster of genes involved in neurogenesis. We found that differentiated LUHMES<br />

cells, but not undifferentiated cells, showed enrichment for PD risk SNPs. Candidate<br />

genes for these loci were associated with the processes of synaptic vesicle cycling<br />

and transport, which implies that PD-related disruption of these pathways is<br />

intrinsic to dopaminergic neurons. We are using gene-editing tools to delve deeply<br />

into how they affect genetic predisposition. Understanding of this kind may lead to<br />

the identification of preventive strategies against PD.<br />

40 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


JEFFREY H. KORDOWER, Ph.D.<br />

Dr. Kordower earned his Ph.D. at City University of New York in 1984. He<br />

joined Rush University Medical Center in 1990, where he currently is the<br />

Alla V. and Solomon Jesmer Professor of Neurological Sciences and<br />

the director of the Rush Research Center for Brain Repair, among other<br />

positions. He joined VARI in January 2016 as a Professor and Director's<br />

Scholar while continuing his primary appointment at Rush.<br />

RESEARCH INTERESTS<br />

There is a close collaboration between the Kordower lab and the scientists in the<br />

Center for Neurodegenerative Science in trying to understand Parkinson’s disease<br />

pathogenesis and to develop novel therapies for the disease. Recently, the lab has<br />

been investigating the prion-like transfer of abnormal α-synuclein from cell to<br />

cell within the brain. The Kordower lab’s collaborative research program, based at<br />

Rush University Medical Center in Chicago, uses insights garnered from this work to<br />

design and carry out crucial preclinical studies, a vital step in translating potential<br />

therapies into clinical trials for Parkinson’s patients.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 41


Center for Neurodegenerative Science<br />

VIVIANE LABRIE, Ph.D.<br />

Dr. Labrie received her Ph.D. in genetics and neuroscience from the<br />

University of Toronto. She was an assistant professor at University of<br />

Toronto before joining VARI in early 2016.<br />

STAFF<br />

Emily Glidden, B.S.<br />

Bryan Killinger, Ph.D.<br />

Peipei Li, Ph.D.<br />

Lee Marshall, Ph.D.<br />

RESEARCH INTERESTS<br />

Our goal is to gain an in-depth understanding of the primary molecular<br />

causes of Alzheimer’s disease and Parkinson’s disease in order to help develop<br />

new treatments. Specifically, we study epigenetic involvement in these<br />

neurodegenerative illnesses. Epigenetic marks such as methyl or acetyl groups<br />

control gene activities without changing the DNA sequence. Such marks are partially<br />

stable, that is, they can change in response to environmental signals and over time.<br />

This dynamic aspect is highly relevant, because advanced age is the best-known risk<br />

factor for both Alzheimer’s and Parkinson’s disease. It takes years before symptoms<br />

arise in patients, and after disease onset, the pathological features and symptoms<br />

worsen with time. We propose that aberrant epigenetic changes, accumulating with<br />

age at key genomic regions, contribute to the etiology of these diseases.<br />

We perform genome-wide searches for epigenetic abnormalities in genomic<br />

regulatory elements such as enhancers, which affect the complex spatial and<br />

temporal expression of genes. Under the influence of regulatory elements, genes<br />

can be highly expressed in certain tissues or cell types but weakly or not at all<br />

in others. By activating or repressing regulatory elements, epigenetic marks can<br />

modify the abundance, timing, and cell-specific patterns of gene expression, which<br />

are central to healthy brain function. By applying epigenomic and next generation<br />

sequencing–based techniques to human samples, we aim to identify epigenetically<br />

misregulated regulatory elements in Alzheimer’s and Parkinson’s disease. We also<br />

study the interaction between DNA sequence factors (SNPs) and epigenetic marks to<br />

determine whether certain disease-risk variants help coordinate such misregulation.<br />

Once we identify disturbed regulatory elements, functional studies will help us<br />

understand how they contribute to disease susceptibility. We look for changes<br />

in 3D chromatin conformation and in gene transcripts to identify the genes and<br />

pathways affected. We also use CRISPR-Cas9 genome editing in cell lines and mice<br />

to determine the contribution of epigenetically disrupted regulatory elements to<br />

disease pathology and symptoms. Through this research, we can uncover new<br />

genomic regions causally involved in Alzheimer’s and Parkinson’s disease.<br />

42 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


JIYAN MA, Ph.D.<br />

Dr. Ma earned his Ph.D. in biochemistry and molecular biology from the<br />

University of Illinois at Chicago. He was at Ohio State University from 2002<br />

until he joined VARI in November 2013 as a Professor.<br />

STAFF<br />

Romany Abskharon, Ph.D.<br />

Katelyn Becker, M.S.<br />

Emily Glidden, B.S.<br />

Amandine Roux, Ph.D.<br />

Juxin Ruan, Ph.D.<br />

Fei Wang, Ph.D.<br />

Xinhe Wang, Ph.D.<br />

RESEARCH INTERESTS<br />

Protein aggregation is a key pathological feature of a large group of late-onset<br />

neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. Our<br />

overall goals are to uncover the molecular events leading to protein misfolding in<br />

the aging central nervous system; to understand the relationship between misfolded<br />

protein aggregates and neurodegeneration; and to develop approaches to prevent,<br />

halt, or reverse protein aggregation and neurodegeneration in these devastating<br />

diseases.<br />

We study protein aggregates in prion diseases (transmissible spongiform<br />

encephalopathies). These are true infectious diseases that can spread from<br />

individual to individual and cause outbreaks. We have established an in vitro system<br />

to reconstitute prion infectivity with bacterially expressed prion protein plus<br />

defined cofactors. We use this system to dissect the essential components and the<br />

structural features of an infectious prion and to uncover the molecular mechanisms<br />

responsible for the prion strain and species barrier.<br />

Recently, the concept of prions has expanded to Parkinson’s and Alzheimer’s<br />

diseases. α-Synuclein has been suggested to spread the disease pathology in a<br />

prion-like manner from a sick cell to healthy ones. We want to understand the<br />

similarities and differences between prions and amyloidogenic proteins such<br />

as α-synuclein. We are investigating cellular factors that affect α-synuclein<br />

aggregation and the connections between various α-synuclein aggregated forms,<br />

their prion-like spread, and dopaminergic neuron degeneration.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 43


Center for Neurodegenerative Science<br />

DARREN J. MOORE, Ph.D.<br />

Dr. Moore earned a Ph.D. in molecular neuroscience from the University of<br />

Cambridge, U.K., in 2001 in the laboratory of Piers Emson. He was at Johns<br />

Hopkins University and the Swiss Federal Institute of Technology (EPFL)<br />

in Lausanne before joining the VARI faculty as an Associate Professor in<br />

early 2014. He was promoted to Professor in 2017.<br />

STAFF<br />

Xi Chen, Ph.D.<br />

Madalynn Erb, Ph.D.<br />

Emily Glidden, B.S.<br />

Md Shariful Islam, Ph.D.<br />

Jennifer Kordich, M.S.<br />

Nate Levine, B.S.<br />

An Phu Tran Nguyen, Ph.D.<br />

STUDENTS<br />

Lindsey Cunningham, B.S.<br />

Allie Weber, B.S.<br />

Erin Williams, B.A.<br />

RESEARCH INTERESTS<br />

Our laboratory studies the molecular pathogenesis of Parkinson’s disease, with the<br />

long-term goal of developing novel, targeted, disease-modifying therapies and<br />

neuroprotective strategies. Although most cases of PD are sporadic, 5–10% of cases<br />

are inherited, with causative mutations identified in at least 13 genes. We focus on<br />

the cell biology and pathophysiology of several proteins that cause inherited PD,<br />

including the dominantly inherited LRRK2 (leucine-rich repeat kinase 2, a multidomain<br />

protein with GTPase and kinase activity) and VPS35 (vacuolar protein<br />

sorting 35 ortholog, a component of the retromer complex), and the recessive<br />

proteins parkin (an E3 ubiquitin ligase), synaptojanin-1 (an endosomal lipid<br />

phosphatase), and ATP13A2 (a lysosomal P5B-type ATPase). We seek to explain<br />

the normal biological function of these proteins in the mammalian brain and the<br />

molecular mechanisms through which disease-associated variants produce neuronal<br />

dysfunction and eventual neurodegeneration in inherited forms of Parkinson’s.<br />

We employ a multidisciplinary approach that combines molecular, cellular,<br />

and biochemical techniques in experimental model systems such as human cell<br />

lines, primary neuronal cultures, Saccharomyces cerevisiae, nematodes, fruit flies,<br />

rodents, and human brain tissue. We have developed several unique rodent models<br />

(transgenic, knock-out, knock-in) for mechanistic studies of proteins.<br />

Some of our current projects focus on<br />

• the contribution of enzymatic activity and protein aggregation to<br />

neurodegeneration in novel, adenoviral-based, LRRK2 rodent models of PD;<br />

• neuroprotective effects of pharmacological kinase inhibition in LRRK2 rodent<br />

models;<br />

• genome-wide identification of genetic modifiers of LRRK2 toxicity in S. cerevisiae;<br />

• identification of novel GTPase effector proteins and kinase substrates for LRRK2;<br />

• the role of ArfGAP1 in mediating LRRK2-induced neurotoxic pathways;<br />

• the functional interaction of LRRK2 with other PD-linked proteins (ATP13A2 and<br />

synaptojanin-1); and<br />

• the development of novel rodent models of VPS35-linked PD and the pathological<br />

interactions of VPS35 with α-synuclein and LRRK2.<br />

Leslie Wyman, B.S.<br />

44 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


RECENT CENTER PUBLICATIONS<br />

Amos, Christopher I., Joe Dennis, Zhaoming Wang, Jinyoung Byun, Frederick R. Schumacher, Simon A. Gayther, Graham Casey,<br />

David J. Hunter, Thomas A. Sellers, Stephen B. Gruber, Alison M. Dunning, . . . , Gerhard A. Coetzee, Dennis J. Hazelett, . . ., and<br />

Douglas F. Easton. 2017. The OncoArray Consortium: a network for understanding the genetic architecture of common cancers.<br />

Cancer, Epidemiology, Biomarkers & Prevention 26(1): 126–135.<br />

Brundin, Patrik, Kuldip D. Dave, and Jeffrey H. Kordower. 2017. Therapeutic approaches to target alpha-synuclein pathology.<br />

Experimental Neurology 298 (Pt. B): 225–235.<br />

Bryleva, E.Y., S.A. Keaton, J. Grit, Z. Madaj, A. Sauro-Nagendra, L. Smart, S. Halstead, E. Achtyes, and L. Brundin. 2017. The<br />

acute-phase mediator serum amyloid A is associated with symptoms of depression and fatigue. Acta Psychiatrica Scandinavica<br />

135(5): 409–418.<br />

Espay, Alberto, Patrik Brundin, and Anthony E. Lang. 2017. Precision medicine for disease modification in Parkinson disease.<br />

Nature Reviews Neurology 13(2): 119–126.<br />

Fernström, Johan, Åsa Westrin, Cécile Grudet, Lil Träskman-Bendz, Lena Brundin, and Daniel Lindqvist. 2017. Six<br />

autoantibodies associated with autoimmune encephalitis are not detectable in the cerebrospinal fluid of suicide attempters.<br />

PLoS One 12(4): e0176358.<br />

Islam, Md. Shariful, and Darren J. Moore. 2017. Mechanisms of LRRK2-dependent neurodegeneration: role of enzymatic activity<br />

and protein aggregation. Biochemical Society Transactions 45(1): 163–172.<br />

Jakubowski, Jennifer L., and Viviane Labrie. 2017. Epigenetic biomarkers for Parkinson’s disease: from diagnostics to<br />

therapeutics. Journal of Parkinson’s Disease 7(1): 1-12.<br />

Killinger, Bryan Andrew, and Viviane Labrie. 2017. Vertebrate food products as a potential source of prion-like α-synuclein.<br />

npj Parkinson’s Disease 3: 33.<br />

Labrie, Viviane, and Patrik Brundin. 2017. Alpha-synuclein to the rescue: immune cell recruitment by alpha-synuclein during<br />

gastrointestinal infection. Journal of Innate Immunity 9(5): 437–440.<br />

Nguyen, An Phu Tran, Guillaume Daniel, Pamela Valdés, Md Shariful Islam, Bernard L. Schneider, and Darren J. Moore. In press.<br />

G2019S LRRK2 enhances the neuronal transmission of tau in the mouse brain. Human Molecular Genetics.<br />

Nguyen, An Phu Tran, and Darren J. Moore. 2017. Understanding the GTPase activity of LRRK2: regulation, function, and<br />

neurotoxicity. In Leucine-rich Repeat Kinase 2 (LRRK2), Hardy J. Rideout, ed. Advances in Neurobiology series, Vol. 14. Cham,<br />

Switzerland: Springer, pp. 71-88.<br />

Oh, Edward, Richie Jeremian, Gabriel Oh, Daniel Groot, Miki Susic, KwangHo Lee, Kelly Foy, Peter W. Laird, Arturas Petronis,<br />

and Viviane Labrie. 2017. Transcriptional heterogeneity in the lactase gene within cell-type is linked to the epigenome.<br />

<strong>Scientific</strong> <strong>Report</strong>s 7: 41843.<br />

Pierce, Steven, and Gerhard A. Coetzee. 2017. Parkinson's disease-associated genetic variation is linked to quantitative<br />

expression of inflammatory genes. PLoS One 12(4): e0175882.<br />

Rey, Nolwen L., Sonia George, Jennifer A. Steiner, Zachary Madaj, Kelvin C. Luk, John Q. Trojanowski, Virginia M.-Y. Lee, and<br />

Patrik Brundin. In press. Spread of aggregates after olfactory bulb injection of α-synuclein fibrils is associated with early<br />

neuronal loss and is reduced long term. Acta Neuropathologica.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 45


Center for Neurodegenerative Science<br />

RECENT CENTER PUBLICATIONS (cont.)<br />

Tyson, Trevor, Megan Senchuk, Jason F. Cooper, Sonia George, Jeremy M. Van Raamsdonk, and Patrik Brundin. 2017. Novel<br />

animal model defines genetic contributions for neuron-to-neuron transfer of α-synuclein. <strong>Scientific</strong> <strong>Report</strong>s 7: 7506.<br />

Ventorp, Filip, Cecillie Bay-Richter, Analise Sauro Nagendra, Shorena Janelidze, Viktor Sjödahl Matsson, Jack Lipton, Ulrika<br />

Nordström, Åsa Westrin, Patrik Brundin, and Lena Brundin. 2017. Exendin-4 treatment improves LPS-induced depressive-like<br />

behavior without affecting pro-inflammatory cytokines. Journal of Parkinson’s Disease 7(2): 263–273.<br />

Wang, Fei, Xinhe Wang, Christina D. Orrú, Bradley R. Groveman, Krystyna Surewicz, Romany Abskharon, Morikazu Imamura,<br />

Takashi Yokoyama, Yong-Sun Kim, Kayla J. Vander Stel, Kumar Sinniah, Suzette A. Priola, Witold K. Surewicz, Byron Caughey,<br />

and Jiyan Ma. 2017. Self-propagating, protease-resistant, recombinant prion protein conformers with or without in vivo<br />

pathogenicity. PLoS Pathogens 13(7): e1006491.<br />

Williams, Erin T., Xi Chen, and Darren J. Moore. 2017. VPS35, the retromer complex and Parkinson’s disease. Journal of<br />

Parkinson’s Disease 7(2): 219–233.<br />

Zamponi, Emiliano, Fiamma Buratti, Gabriel Cataldi, Hector Hugo Caicedo, Yuyu Song, Lisa M. Jungbauer, Mary J. LaDu, Mariano<br />

Bisbal, Alfredo Lorenzo, Jiyan Ma, Pablo R. Helguera, Gerardo A. Morfini, Scott T. Brady, and Gustavo F. Pigino. 2017. Prion<br />

protein inhibits fast axonal transport through a mechanism involving casein kinase 2. PLoS One 12(12): E0188340.<br />

46 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Differentiation of LUHMES cells as a model of human substantia nigra neurons. These human<br />

neural precursor cells were immortalized using a Myc oncogene in a Tet-off system; adding tetracycline<br />

suppresses the expression of the Myc gene and allows differentiation to occur. Differential interference<br />

contrast (DIC) micrographs (100X) of A) undifferentiated LUHMES cells and B) LUHMES cells after 6 days<br />

of differentiation. Images by Trevor Tyson of the Coetzee laboratory.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 47


Core Technologies and Services<br />

Van Andel Research Institute’s Core Technologies<br />

and Services offer a comprehensive range of<br />

advanced technologies and expertise to support<br />

and enhance the research done at the Institute<br />

and with collaborating organizations.<br />

48 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Staining of mouse bone to visualize bone marrow (red cells), solid bone with embedded<br />

osteocytes (tan areas), and regions of actively growing new bone (blue-green).<br />

Image by Alexis Bergsma.


Genomics Core<br />

MARIE ADAMS, M.S.<br />

Ms. Adams earned an M.S. in genetics from Iowa State University and is<br />

an expert in the latest next-generation sequencing techniques. She joined<br />

VARI in September 2016 from the University of Wisconsin Biotechnology<br />

Center, where she managed the next-generation sequencing core.<br />

SERVICES<br />

The Genomics Core provides a comprehensive catalog of sequencing, genotyping,<br />

and cytogenetic services to support research into the genomic, transcriptomic,<br />

and epigenomic bases of diseases such as cancer and neurodegenerative disorders.<br />

Core staff collaborate with over 45 VARI and external investigators to design and<br />

implement robust protocols and experimental design.<br />

STAFF<br />

Julie Koeman, B.S., C.G.(ASCP) CM<br />

Lori Moon, E.M.B.A.<br />

Mary Rhodes, B.S.<br />

STUDENT<br />

Sarah Harrie<br />

Sequencing services offered include whole-genome, exome, and targeted DNA<br />

sequencing; mRNA expression, total RNA transcriptome, translatome, and targeted<br />

RNA sequencing; and ChIP-seq, methyl-seq, whole-genome bisulfite sequencing,<br />

and targeted bisulfite sequencing, all using Illumina sequencing platforms.<br />

Additionally, single-cell and long-read sequencing are facilitated through the 10X<br />

Genomics Chromium system. We constantly evaluate new assays to provide the most<br />

up-to-date service in this evolving field.<br />

High-throughput genotyping services are performed using the Illumina iScan<br />

system and include the MethylationEPIC Array, Omni-series genome and<br />

exome arrays, Neuro Consortium array, and QC array. Other arrays are easily<br />

accommodated on request. We are also available for qPCR and SNP assays.<br />

Cytogenetic capabilities include FISH probe creation, validation, and analysis;<br />

chromosome breakage studies; transgene localization; and trisomy 8 and 11 mouse<br />

embryonic stem cell screens.<br />

50 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Bioinformatics and Biostatistics Core<br />

MEGAN BOWMAN, Ph.D.<br />

Dr. Bowman earned her Ph.D. from the University of Wisconsin – Madison.<br />

She completed postdoctoral research in genomics and bioinformatics<br />

with the United States Department of Agriculture and Michigan State<br />

University prior to joining VARI in 2016.<br />

SERVICES<br />

Established in April 2013, the Bioinformatics and Biostatistics Core serves the<br />

analytical needs of VARI by providing high-quality computational and statistical<br />

support to the research laboratories. The broader mission of the BBC is to strengthen<br />

and advance bioinformatics and biostatistics at VARI through collaboration,<br />

education, and methods development.<br />

STAFF<br />

Benjamin Johnson, Ph.D.<br />

Zachary Madaj, M.S.<br />

Lori Moon, E.M.B.A.<br />

* Mary E. Winn, Ph.D.<br />

Emily Wolfrum, M.P.H.<br />

* Formerly manager of the BBC, now<br />

Program Manager in the Office of the Cores.<br />

The BBC provides statistical consulting and experimental design, including sample<br />

size determination and randomization procedures, and we analyze a wide variety<br />

of data related to next-generation sequencing, such as genomic variant detection<br />

and annotation, differential expression, DNA copy number determination, and<br />

differential methylation analyses. We offer expertise in systems-level analysis,<br />

including gene-set and network-based analyses, time-series data, tumor growth,<br />

drug response, and other small or large data sets using appropriate statistical<br />

and computational methods. We also assist in the preparation of research grants,<br />

manuscripts, and data deposition. The Core focuses on reproducibility and rigor via<br />

robust statistical design, analysis, and the maintenance of version-controlled source<br />

code.<br />

We support the greater educational mission of the Institute, helping students<br />

and staff develop an analytic approach and skills in experimental design through<br />

seminars, lectures, and workshops.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 51


Vivarium and Transgenics Core<br />

BRYN EAGLESON, M.S., LATG<br />

Ms. Eagleson earned an M.S. degree in laboratory animal science from<br />

Drexel University’s College of Medicine. She worked for many years at the<br />

National Cancer Institute’s Frederick Cancer Research and Development<br />

Center in Maryland before joining VARI as the Director of Vivarium and<br />

Transgenics in 1999.<br />

SERVICES<br />

The goal of the VARI Vivarium and Transgenics Core is to develop, provide, and<br />

maintain high-quality mouse modeling services. The vivarium is a state-of-the-art<br />

facility that includes a high-level containment barrier. Van Andel Research Institute<br />

is an AAALAC-accredited institution, most recently reaccredited in November<br />

2016. All procedures are conducted according to the Guide for the Care and Use of<br />

Laboratory Animals. The staff provides rederivation, surgery, dissection, necropsy,<br />

breeding, weaning, tail biopsies, sperm and embryo cryopreservation, animal data<br />

management, project management, and health-status monitoring. Transgenic<br />

mouse models are produced on request for project-specific needs. The creation of<br />

gene-targeted mice using the CRISPR/Cas9 system has been implemented. We also<br />

provide therapeutic testing and preclinical model development services. Projects<br />

include pharmacological testing, target validation testing, patient-derived xenograft<br />

(PDX) development, orthotopic engraftment model development, and subcutaneous<br />

xenograft/allograft model development.<br />

The Small-Animal Imaging Facility provides preclinical imaging technologies that<br />

offer anatomic and functional information to biomedical investigators. Currently<br />

available technologies include high-resolution microCT, micro-ultrasound, and<br />

optical imaging.<br />

STAFF<br />

Megan Briggs, B.S.<br />

Brandon Bonnema, B.S.<br />

Stephen Bowman, M.S.<br />

Charles Bradfield, B.S.<br />

Rita Burdette<br />

Thomas Dingman, B.S.<br />

Nicholas Getz, B.S.<br />

Sara Greenwald, B.S.<br />

Audra Guikema, B.S., LVT<br />

Tristan Kempston, B.S.<br />

Tina Meringa, A.A.<br />

David Monsma, Ph.D.<br />

Lori Moon, E.M.B.A.<br />

Malista Powers, A.S., LVT<br />

Mathew Rackham<br />

Lisa Ramsey, A.S., LVT<br />

Adam Rapp, B.S.<br />

Yanli Su, A.M.A.T.<br />

Aurora Thoms, A.S.<br />

Collin Tidd, A.S.<br />

William Weaver, B.S.<br />

52 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Confocal Microscopy and Quantitative Imaging Core<br />

CORINNE ESQUIBEL, Ph.D.<br />

Dr. Esquibel has a B.S. in biology from Truman State University and a<br />

Ph.D. in molecular and cellular pharmacology from the University of<br />

Wisconsin–Madison. She joined Van Andel Research Institute as the Core<br />

manager in 2017.<br />

SERVICES<br />

Established in October 2013, the Core provides optical imaging services for Van Andel<br />

Research Institute and collaborating institutions. We focus on comprehensive training<br />

of users for every aspect of imaging: experimental design and optimization, data<br />

acquisition, and image analysis. This helps users of all experience levels to perform<br />

quantitative research at or exceeding the professional standards of their field. To do<br />

this, we maintain multiple instruments with a range of imaging capabilities.<br />

STAFF<br />

Kristin Feenstra, B.S.<br />

Lori Moon, E.M.B.A.<br />

A Nikon A1plus laser scanning confocal is an essential instrument within the Core,<br />

designed to generate high-resolution images in multiple dimensions. It is equipped<br />

for imaging in both galvanometric and resonant scanning modes with four solid state<br />

lasers, four high-sensitivity detectors, and a multi-anode spectral detector. The<br />

confocal can achieve optical sectioning of cells and tissue and can image live samples<br />

over time. The computer-coded stage allows for imaging large areas of the sample.<br />

The PerkinElmer Vectra 3.0 Automated Quantitative Pathology Imaging system is<br />

capable of imaging up to 200 slides per session, using a sophisticated multispectral<br />

camera to mathematically unmix up to seven fluorophores in each slide. Trainable<br />

algorithms in the PerkinElmer inForm software allow for automated segmentation<br />

and quantitative phenotyping of slides.<br />

Image analysis is supported not only through consultation and training of users, but<br />

also through the availability of a powerful Silicon Mechanics PC workstation that<br />

contains a suite of commercial and open-source image analysis programs. Analysis<br />

options include 3D-5D visualization (FIJI, Nikon Elements, Imaris), deconvolution<br />

(Huygens Professional), neuron tracing (Imaris), segmentation (Imaris, MATLAB),<br />

machine learning (CellProfiler and CPAnalyst), and figure preparation (FIJI/Image J,<br />

Illustrator, Photoshop). When out-of-the-box solutions are not available, additional<br />

sophisticated mathematical analysis can be written for case-specific applications<br />

(MATLAB).<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 53


Pathology and Biorepository Core<br />

SCOTT D. JEWELL, Ph.D.<br />

Dr. Jewell earned his Ph.D. degree from The Ohio State University.<br />

He joined VARI in 2010 as a Professor, Director of the Program for<br />

Technologies and Cores, and Director of the Pathology and Biorepository<br />

Core.<br />

STAFF<br />

Bree Berghuis, B.S., HTL(ASCP), QIHC<br />

Alex Blanski, B.S.<br />

Melissa Dehollander, M.B.A., B.S.<br />

Brianne Docter, M.S.<br />

Kristin Feenstra, B.S.<br />

Phil Harbach, M.S.<br />

Meghan Hodges, B.S.<br />

Galen Hostetter, M.D.<br />

Eric Hudson, B.S.<br />

Carrie Joynt, B.S., HT<br />

Rob Montroy, B.S.<br />

Lori Moon, E.M.B.A.<br />

Chelsea Peterson, B.S.<br />

Daniel Rohrer, B.S., M.B.A.<br />

Lisa Turner, B.S., HT, QIHC(ASCP)<br />

SERVICES<br />

The Pathology and Biorepository Core integrates anatomic pathology expertise with<br />

biorepository and biospecimen science in order to assist in VARI’s research. We build upon<br />

historical strengths in standard histology, microscopy, and biobanking, and we apply<br />

best practices in biospecimen science. The pathology discipline provides complementary<br />

emphasis on high-quality biospecimens and interpretable results with which to validate<br />

experimental models and extend them to clinical samples, thereby advancing our common<br />

translational mission. The VARI Biorepository has been accredited by the College of<br />

American Pathologists (CAP) since 2012. Dr. Jewell serves as a committee member for the<br />

CAP Biorepository Accreditation Program.<br />

Dr. Jewell, with his experience in clinical trials and biobanking, and Dr. Hostetter, who is<br />

board-certified in anatomic pathology, are currently studying the effects of preanalytical<br />

variables in tissue collection and transport on the integrity of downstream analytes.<br />

The Core provides assessment of tumor suppressors and immunomodulators in tumor<br />

tissues and the application of genomic and epigenomic assays for biospecimens. The<br />

VARI biorepository is nationally and internationally recognized, serving as the NCI<br />

Comprehensive Biospecimen Resource for the Genotype-Tissue Expression Program<br />

(GTEX). In 2015, it was designated as the Biorepository Core Resource for the NCI Clinical<br />

Proteomic and Tumor Analysis Consortium (CPTAC) and as the biorepository for the<br />

Tuberous Sclerosis Alliance. In addition, we are moving into our seventh year of providing<br />

biorepository services for the Multiple Myeloma Research Foundation’s CoMMpass Study.<br />

The biorepository is serving the VARI-SU2C consortium for epigenetics clinical trials<br />

biobanking, collaborating with Drs. Jones and Baylin.<br />

Pathology Core services<br />

• Histology and diagnostic tissue services, including morphology,<br />

immunohistochemistry, in situ hybridization, and multiplex fluorescent IHC assays<br />

• Pathology review and annotation of clinical samples from VARI’s prospective and<br />

retrospective tissue collections<br />

• Design and construction of tissue microarrays<br />

• Digital imaging and spectral microscopy coupled with image analysis tools<br />

• Cell fractionation and biospecimen processing<br />

• Laser capture microdissection<br />

Biorepository Core services<br />

• Biospecimen kit construction, shipping, and tracking<br />

• Clinical trials biobanking coordination<br />

• Quality management program<br />

Dana Valley, B.A., ASQ CMQ/OE, CSSGB<br />

Anthony Watkins, A.S.<br />

54 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Flow Cytometry Core<br />

RACHAEL SHERIDAN, Ph.D.<br />

Rachael Sheridan earned her Ph.D. in biochemistry from the University<br />

of Wisconsin–Madison and also holds a professional cytometry<br />

certification, SCYM(ASCP). Prior to joining Van Andel Research Institute in<br />

October 2016, she was an instrumentation specialist in the University of<br />

Wisconsin Comprehensive Cancer Center Flow Cytometry Laboratory.<br />

STAFF<br />

Lori Moon, E.M.B.A.<br />

SERVICES<br />

The Core provides comprehensive flow cytometry analysis and sorting services<br />

in support of VARI research. Additional services include assistance with protocol<br />

development and training in data analysis. Flow cytometry services are provided<br />

using a Beckman Coulter MoFlo Astrios and Beckman Coulter CytoFLEX S. Available<br />

hematology equipment includes a VetScan instrument, a VetScan HMII, and a<br />

Shandon Cytospin 3.<br />

Kellie Sisson, B.S.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 55


Cryo-Electron Microscopy Core<br />

GONGPU ZHAO, Ph.D.<br />

Dr. Zhao earned his Ph.D. in physics at the University of North Carolina at<br />

Chapel Hill. He joined Van Andel Research Institute in 2016 as manager of<br />

the Cryo-EM Core.<br />

STAFF<br />

Xing Meng, Ph.D.<br />

Lori Moon, E.M.B.A.<br />

SERVICES<br />

Project 1. During replication initiation, the core component of the helicase—the<br />

Mcm2-7 hexamer—is loaded on the origin DNA as a double hexamer. Determining<br />

how the origin DNA interacts with the axial channel could provide key insights into<br />

Mcm2-7 function and regulation. We worked with Huilin Li’s lab to solve a 3.9-Å<br />

cryo-EM structure of the Mcm2-7 double hexamer on DNA, which suggests a laggingstrand<br />

DNA extrusion model.<br />

Project 2. G protein–coupled receptor (GPCR) kinases (GRKs) play key roles in the<br />

desensitization of GPCR signaling. Dysregulation of this process has been associated<br />

with a broad spectrum of diseases. The overall goal of this project is to use rhodopsin–<br />

GRK1 as a model in order to gain structural insight into the GPCR/GRK complex and<br />

its mechanism of GRK-mediated GPCR signaling. We have worked with the Xu lab to<br />

reveal the overall architecture of the rhodopsin–GRK1 complex via negative-stain EM.<br />

Our plans are to use cryo-EM to solve the structure of the complex at high resolution.<br />

Project 3. G protein–coupled receptors are a superfamily of integral membrane<br />

proteins that turn extracellular signals into intracellular responses. The selective<br />

coupling of GPCRs to specific G proteins is crucial for activating the appropriate<br />

physiological response. With the help of state-of-the-art electron microscopy at VARI,<br />

the Core has worked with the Xu lab to determine a 4-Å structure of the rhodopsin–G i<br />

complex, giving the first insights into G i<br />

-mediated GPCR activation. This research also<br />

established a general method for studying GPCR structures in an active confirmation<br />

and will provide guidance for new-generation, biased drug designs that can specifically<br />

trigger beneficial effects and avoid side effects. This work has significant influence on<br />

both basic biological research and translational studies.<br />

56 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


RECENT CORE PUBLICATIONS<br />

Barnett, Daniel, Ying Liu, Katie Partyka, Ying Huang, Huiyuan Tang, Galen Hostetter, Randall E. Brand, Aatur D. Singhi, Richard<br />

R. Drake, and Brian B. Haab. 2017. The CA19-9 and sialyl-TRA antigens define separate subpopulations of pancreatic cancer<br />

cells. <strong>Scientific</strong> <strong>Report</strong>s 7: 4020.<br />

Berger, Penny L., Mary E. Winn, and Cindy K. Miranti. 2017. Miz1, a novel target of ING4, can drive prostate luminal epithelial<br />

cell differentiation. Prostate 77(1): 45–59.<br />

Dues, Dylan J., Claire E. Schaar, Benjamin K. Johnson, Megan J. Bowman, Mary E. Winn, Megan M. Senchuk, and Jeremy M.<br />

Van Raamsdonk. 2017. Uncoupling of oxidative stress resistance and lifespan in long-lived isp-1 mitochondrial mutants in<br />

Caenorhabditis elegans. Free Radical Biology and Medicine 108: 362–373.<br />

He, Yuanzheng, Xiang Gao, Devrishi Goswami, Li Hou, Kuntal Pal, Yanting Yin, Gongpu Zhao, Oliver P. Ernst, Patrick Griffin,<br />

Karsten Melcher, and H. Eric Xu. 2017. Molecular assembly of rhodopsin with G protein–coupled receptor kinases. Cell Research<br />

27(6): 728–747.<br />

Manojlovic, Zarko, Austin Christofferson, Winnie S. Liang, Jessica Aldrich, Megan Washington, Shukmei Wong, Daniel Rohrer,<br />

Scott Jewell, Rick A. Kittles, Mary Derome, Daniel Auclair, David Wesley Craig, Jonathan Keats, and John D. Carpten. 2017.<br />

Comprehensive molecular profiling of 718 multiple myelomas reveals significant differences in mutation frequencies between<br />

African and European descent cases. PLoS Genetics 13(11): e1007087.<br />

Martin, Katie R., Wanding Zhou, Megan J. Bowman, Juliann Shih, Kit Sing Au, Kristin E. Dittenhafer-Reed, Kellie A. Sisson, Julie<br />

Koeman, Daniel J. Weisenberger, Sandra L. Cottingham, Steven T. DeRoos, Orrin Devinsky, Mary E. Winn, Andrew D. Cherniack,<br />

Hui Shen, Hope Northrup, Darcy A. Krueger, and Jeffrey P. MacKeigan. 2017. The genomic landscape of tuberous sclerosis<br />

complex. Nature Communications 8: 15816.<br />

Noguchi, Yasunori, Auanning Yuan, Lin Bai, Sarah Schneider, Gongpu Zhao, Bruce Stillman, Christian Speck, and Huilin Li. 2017.<br />

Cryo-EM structure of Mcm2-7 double hexamer on DNA suggests a lagging-strand DNA extrusion model. Proceedings of the<br />

National Academy of Sciences U.S.A. 114(45): E9529–E9538.<br />

Westrick, Randal J., Kärt Tomberg, Amy E. Siebert, Guojing Zhu, Mary E. Winn, Sarah L. Dobies, Sara L. Manning, Marisa A.<br />

Brake, Audrey C. Cleuren, Linzi M. Hobbs, Lena M. Mishack, Alexander J. Johnston, Emilee Kotnik, David R. Siemieniak, Jishu<br />

Xu, Jun Z. Li, Thomas L. Sauders, and David Ginsburg. 2017. Sensitized mutagenesis screen in Factor V Leiden mice identifies<br />

thrombosis suppressor loci. Proceedings of the National Academy of Sciences U.S.A. 114(36): 9659–9664.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 57


Awards for <strong>Scientific</strong> Achievement<br />

58 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Jay Van Andel Award for Outstanding<br />

Achievement in Parkinson’s Disease<br />

Research<br />

The Jay Van Andel Award for Outstanding Achievement in Parkinson’s Disease<br />

Research was established in 2012 in memory of Van Andel Institute founder<br />

Jay Van Andel, who battled Parkinson’s disease for a decade before his death in<br />

2004. The award is given to scientists who have made outstanding contributions to<br />

Parkinson’s disease research and who have positively impacted human health.<br />

2017 RECIPIENT<br />

J. William Langston, M.D.<br />

Dr. J. William Langston is the <strong>Scientific</strong> Director, Chief <strong>Scientific</strong> Officer, and Founder<br />

of the Parkinson’s Institute in Sunnyvale, California. Dr. Langston gained international<br />

recognition in 1980s for the discovery of the link between a tainted synthetic heroin<br />

and parkinsonism. The discovery of the biologic effects of that compound led to a<br />

renaissance of basic and clinical research into Parkinson’s disease. Dr. Langston’s<br />

current research includes the study of mechanisms of neuronal degeneration, the<br />

etiology of Parkinson’s disease, the development of new strategies to slow or halt<br />

disease progression, and ways to identify the disease in its earliest “pre-motor” stages.<br />

PRIOR RECIPIENTS<br />

2016—Stanley Fahn, M.D.<br />

2015—Robert Nussbaum, M.D., and Maria Grazia Spillantini, Ph.D., FMedSci, FRS<br />

2014—Andrew John Lees, M.D., FRCP, FMedSci<br />

2013—Alim-Louis Benabid, M.D., Ph.D.<br />

2012—Andrew Singleton, Ph.D.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 59


Awards for <strong>Scientific</strong> Achievement<br />

Han-Mo Koo Memorial Award<br />

Dr. Han-Mo Koo joined Van Andel Research Institute in 1999 as one of its founding<br />

investigators, focusing on the identification of genetic targets for anti-cancer drug<br />

development against melanoma and pancreatic cancer. In May 2004, Dr. Koo passed<br />

away following a six-month battle with cancer. To honor his memory and scientific<br />

contributions, the Han-Mo Koo Memorial Award was established in 2010. Awardees<br />

are selected based on scientific achievements, peer recognition, and that their<br />

contributions to human health and research align with the scientific legacy of<br />

Han-Mo Koo.<br />

2017 RECIPIENT<br />

James P. Allison, Ph.D.<br />

Dr. Allison is a professor and the chair of the Department of Immunology at the<br />

University of Texas MD Anderson Cancer Center. His fundamental discoveries include<br />

the definition of the structure of the T cell antigen receptor and the demonstration<br />

that CTLA-4 is an inhibitory checkpoint that inhibits activated T cells. He proposed<br />

that immune checkpoint blockade might be a powerful strategy against many cancer<br />

types and conducted preclinical experiments showing its potential. His development of<br />

the concept of immune checkpoint blockade has transformed cancer therapy and saved<br />

thousands of lives.<br />

PRIOR RECIPIENTS<br />

2016—Matthew L. Meyerson, M.D., Ph.D.<br />

2015—Eric Lander, Ph.D.<br />

2013—Frank P. McCormick, Ph.D., F.R.S.<br />

2012—Phillip A. Sharp, Ph.D.<br />

60 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Tom Isaacs Award<br />

The Tom Isaacs Award is given jointly by Van Andel Research Institute and The Cure<br />

Parkinson’s Trust. The award was established in memory of Trust co-founder and<br />

champion of the Parkinson’s community Tom Isaacs, who passed away in<br />

May 2017. This award recognizes his vision that a cure for Parkinson’s can and will<br />

be found, but that greater value will be gained from working with people who have<br />

Parkinson’s in this quest. In that spirit, recipients of the award must have had a<br />

significant impact on the lives of people with Parkinson’s or have involved people<br />

with Parkinson’s in a participatory way in their work.<br />

Inaugural Recipient<br />

Thomas Foltynie, B.Sc., MBBS, MRCP, Ph.D.<br />

Dr. Foltynie is a consultant neurologist at University College London. He trained<br />

in medicine at UCL, and he undertook his Ph.D. in Cambridge where he studied the<br />

heterogeneity of Parkinson's disease. He is the senior author of a groundbreaking<br />

study that shows the diabetes drug exenatide may interfere with Parkinson’s<br />

progression, something no current medication can do.<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 61


Educational and Training Programs<br />

62 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Van Andel Institute Graduate School<br />

STEVEN J. TRIEZENBERG, Ph.D.<br />

President and Dean<br />

Van Andel Institute Graduate School develops future leaders in biomedical research<br />

through an intense, problem-focused Ph.D. degree in cellular, molecular, and<br />

genetic biology. VAIGS has created an innovative curriculum that guides doctoral<br />

students to think and act like research leaders through problem-based learning. In<br />

doing so, students develop key skills of finding and evaluating scientific knowledge<br />

and of designing experimental approaches to newly arising questions. We also foster<br />

the development of leadership skills and professional behavior, and we seek to<br />

integrate graduate students into the professional networks and culture of science.<br />

VAIGS currently has 27 students. The most recent cohort of seven includes two<br />

international students. In the past year, five students defended their dissertations<br />

and completed their Ph.D. degrees. VAIGS alumni have gone on to postdoctoral and<br />

professional positions at leading biomedical research institutions and companies<br />

throughout the United States. VAIGS is accredited by the Higher Learning<br />

Commission (www.hlcommission.org; 1-800-621-7440).<br />

Julie Davis Turner, Ph.D., Associate Dean<br />

Kathy Bentley, B.S.<br />

Patty Farrell-Cole, Ph.D.<br />

Michelle Love, M.A.<br />

Christy Mayo, M.A.<br />

Susanne Miller-Schachinger, B.B.A.<br />

Nancy Schaperkotter, A.M., LCSW, CEAP<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 63


VAIGS Graduate Students<br />

The following students were enrolled in VAIGS in 2017.<br />

Menusha Arumugam<br />

University of Michigan–Flint<br />

First-year student<br />

Aditi Bagchi, M.D.<br />

Kasturba Medical College,<br />

Mangalore, India<br />

MacKeigan/Jewell labs<br />

Alexis Bergsma<br />

University of Michigan, Ann Arbor<br />

Miranti/Williams labs<br />

Maggie Chassé<br />

Colorado State University, Fort Collins<br />

Grohar lab<br />

Wooyoung Choi<br />

Tsinghua University, Beijing, China<br />

Lü lab<br />

Jason Cooper<br />

University of Texas at Austin<br />

Van Raamsdonk lab (Ph.D., 2017)<br />

Eric Cordeiro-Spinetti<br />

Instituto Federal de Educação, Ciência e<br />

Tecnologia do Rio de Janeiro, Brazil<br />

First-year student<br />

Lindsey Cunningham<br />

Northern Arizona University, Flagstaff<br />

Moore lab<br />

Zachary DeBruine<br />

Hope College, Holland, Michigan<br />

Melcher lab<br />

Parker de Waal<br />

Kalamazoo College, Michigan<br />

Xu lab<br />

Minge Du<br />

Ludong University, Yantai, China<br />

H. Li lab<br />

Jamie Endicott<br />

Michigan State University, East Lansing<br />

First-year student<br />

Guillermo Flores<br />

Hope College, Holland, Michigan<br />

Grohar lab<br />

Jamie Grit<br />

Hope College, Holland, Michigan<br />

Steensma lab<br />

Emily Haley<br />

University of Alabama at Birmingham<br />

First-year student<br />

Candace King<br />

Tougaloo College, Mississippi<br />

Steensma lab<br />

Katie Krajnak<br />

Purdue University Calumet,<br />

Hammond, Indiana<br />

Williams lab<br />

Emily Machiela<br />

Grand Valley State University,<br />

Allendale, Michigan<br />

Van Raamsdonk lab<br />

Lauren McGee<br />

Hanover College, Indiana<br />

First-year student<br />

Kevin Maupin<br />

Grand Valley State University,<br />

Allendale, Michigan<br />

Williams lab (Ph.D., 2017)<br />

Nathan Merrill<br />

University of Michigan, Ann Arbor<br />

MacKeigan lab (Ph.D., 2107)<br />

Eric Nollett<br />

Calvin College,<br />

Grand Rapids, Michigan<br />

Miranti lab (Ph.D., 2017)<br />

Jordan Prahl<br />

Grand Valley State University,<br />

Allendale, Michigan<br />

First-year student<br />

Abbey Solitro<br />

Ferris State University,<br />

Big Rapids, Michigan<br />

MacKeigan lab<br />

Nicole Thellman, D.V.M.<br />

Louisiana State University, Baton Rouge<br />

Triezenberg lab (Ph.D., 2017)<br />

Bailey Tibben<br />

University of Arizona, Tucson<br />

First-year student<br />

Nicole Vander Schaaf<br />

Indiana Wesleyan University,<br />

Marion, Indiana<br />

Laird lab<br />

Robert Vaughan<br />

Grand Valley State University,<br />

Allendale, Michigan<br />

Rothbart lab<br />

Allie Weber<br />

Michigan State University, East Lansing<br />

Moore lab<br />

Erin Williams<br />

Anderson University, Indiana<br />

Moore lab<br />

Leslie Wyman<br />

Grand Valley State University,<br />

Allendale, Michigan<br />

Moore lab<br />

64 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Summer Internship Program<br />

The VARI summer internships are designed to provide undergraduate students to opportunities be mentored<br />

by professionals in biomedical research, to use state-of-the-art scientific equipment, and to learn valuable<br />

interpersonal, workplace, and presentation skills. The goal of this program is to expose aspiring researchers<br />

and clinicians to exciting advances in biomedical science that will help them define their career paths.<br />

Internships last 10 weeks, with two cohorts per summer. Van Andel Education Institute partners with the United<br />

Negro College Fund to match students interested in biomedical research careers with summer internships<br />

at VARI.<br />

Since 2001, hundreds of VARI internships have been generously supported through the Frederik and Lena Meijer<br />

Summer Internship Program. Meijer interns are noted in the listing below by an asterisk (*).<br />

Calvin College, Grand Rapids, Michigan<br />

*Brianna Busscher (Szabo)<br />

*Rachel House (Wu)<br />

*Lucas VanLaar (Melcher)<br />

*Mark Wolf (MacKeigan)<br />

Boston College, Massachusetts<br />

Catherine VanderWoude (Business<br />

Development)<br />

Central Michigan University,<br />

Mt. Pleasant<br />

*Matthew Fini (Li)<br />

Cheyann Oliver (Purple Community)<br />

Claflin University, Orangeburg, South<br />

Carolina<br />

Ricardo Burke (Haab)<br />

Lowell High School, Michigan<br />

Corah Kaufman (Van Raamsdonk)<br />

Ferris State University, Big Rapids,<br />

Michigan<br />

Drew Eder (Facilities)<br />

Sarah Harrie (Genomics)<br />

*Courtney Wernette (Grohar)<br />

Maria Winquest (VAIGS)<br />

Grand Valley State University,<br />

Allendale, Michigan<br />

Sudakshina Chakrabarty (Sempere)<br />

Jessica DeWyse (Finance)<br />

Johnathan Hall (Haab)<br />

Delaney McCarrey (Purple Community)<br />

Hillsdale College, Michigan<br />

*Christine Ausherman (Rothbart)<br />

*Madison Frame (Triezenberg)<br />

*Taylor Zimmer (Ma)<br />

Hope College, Holland, Michigan<br />

Jessica (Jess) Guillaume (MacKeigan)<br />

Philip Versluis (Rothbart)<br />

Indiana Wesleyan University, Marion<br />

*Hannah VanDusen (Haab)<br />

Innovation High School, Grand Rapids,<br />

Michigan<br />

Angelica Velasquez (Jovinge)<br />

Michigan State University, East Lansing<br />

*Joyce Goodluck (Sempere)<br />

*Brandt Gruizinga (Labrie)<br />

*Zachary Jansen (Laird)<br />

*Yamini Vepa (Labrie)<br />

*Yuk Kei Wan (Yang)<br />

Michigan Technological University,<br />

Houghton<br />

*Carly Joseph (Van Raamsdonk)<br />

Rosalind Franklin University, Chicago,<br />

Illinois<br />

Marie Mustert (Jewell)<br />

Stony Brook University, New York<br />

Calvin Li (Information Technology)<br />

University of Alabama - Huntsville<br />

*Sean Zhou Morash (Xu)<br />

University of Chicago, Illinois<br />

Michelle Zhang (Moore)<br />

University of Michigan, Ann Arbor<br />

Schyler Bennett (Haab)<br />

Adrienne (Denise) Bilbao (Yang)<br />

*Kate Blumenstein (Li)<br />

*Nolan Klunder (Jovinge)<br />

*Adam Racette (Williams)<br />

*Nolan Redetzke (Williams)<br />

Western Michigan University,<br />

Kalamazoo<br />

*Megan Callaghan (Steensma)<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 65


Postdoctoral Fellowship Program<br />

Van Andel Research Institute provides postdoctoral training opportunities to advance the knowledge and<br />

research experience of new Ph.D.s while at the same time supporting our research endeavors. Each fellow is<br />

assigned to a scientific investigator who oversees the progress and direction of research. Fellows who worked in<br />

VARI laboratories in 2017 are listed here.<br />

Walid Abi Habib<br />

Université Pierre et Marie Curie,<br />

Paris, France<br />

Laird lab<br />

Romany Abskharon<br />

Vrije Universitiet Brussel, Belgium<br />

Ma lab<br />

Brittany Carpenter<br />

University of Kentucky, Lexington<br />

Jones lab<br />

Xi Chen<br />

University of Liverpool, United Kingdom<br />

Moore lab<br />

Evan Cornett<br />

University of Central Florida, Orlando<br />

Rothbart lab<br />

Madalynn Erb<br />

Oregon Health and Science University,<br />

Portland<br />

Moore lab<br />

Chen Fan<br />

Institute for Nutritional Sciences,<br />

Shanghai, China<br />

Du lab<br />

Huihui Fan<br />

Harbin Medical University, China<br />

Shen lab<br />

Xiang Feng<br />

Baylor College of Medicine, Waco, Texas<br />

H. Li lab<br />

Sourik Ganguly<br />

University of Kentucky, Lexington<br />

X. Li lab<br />

Yihe Huang<br />

Peking University, China<br />

Lü lab<br />

Zhijun Huang<br />

Harbin Institute of Technology, China<br />

Pfeifer lab<br />

Md Shariful Islam<br />

Max Planck Institute for Heart and Lung<br />

Research, Bad Neuheim, Germany<br />

Moore lab<br />

Manpreet Kalkat<br />

University of Toronto, Canada<br />

Laird lab<br />

Bryan Killinger<br />

Wayne State University,<br />

Detroit, Michigan<br />

Labrie lab<br />

Alison Lanctot<br />

Northwestern University,<br />

Evanston, Illinois<br />

Rothbart lab<br />

Hua Li<br />

Guangzhou Institutes of Biomedicine<br />

and Health, China<br />

H. Li lab<br />

Jianshuang Li<br />

Wuhan University, China<br />

Yang lab<br />

Peipei Li<br />

Chungbuk National University,<br />

Cheongju, South Korea<br />

Labrie lab<br />

Hongbo Liu<br />

Harbin Institute of Technology, China<br />

Shen lab<br />

Lee Marshall<br />

Garvan Institute of Medical Research,<br />

Sydney, Australia<br />

Labrie lab<br />

Xiangqi Meng<br />

Sun Yat-sen University Cancer Center,<br />

Guangzhou, China<br />

X. Li lab<br />

Megan Michalski<br />

University of Michigan, Ann Arbor<br />

Williams lab<br />

John Murdoch<br />

Yale University, New Haven, Connecticut<br />

Labrie lab<br />

An Phu Tran Nguyen<br />

University of Tübingen, Germany<br />

Moore lab<br />

Hitoshi Otani<br />

Tokyo Medical and Dental University,<br />

Japan<br />

Jones lab<br />

Kuntal Pal<br />

National University of Singapore,<br />

Singapore<br />

Xu lab<br />

Wouter Peelaerts<br />

Katholieke Universiteit Leuve, Belgium<br />

P. Brundin lab<br />

66 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Steven Pierce<br />

Columbia University,<br />

New York, New York<br />

Coetzee lab<br />

Tinghai Xu<br />

Shanghai Institute of Materia Medica,<br />

China<br />

Jones lab<br />

Emmanuel Quansah<br />

De Montfort University,<br />

Leicester, United Kingdom<br />

P. Brundin lab<br />

Yanting Yin<br />

Shanghai Institute of Materia Medica,<br />

China<br />

H. Li lab<br />

Nolwen Rey<br />

University of Lyon, France<br />

P. Brundin lab<br />

Tie-bo Zeng<br />

Harbin Institute of Technology, China<br />

Szabó lab<br />

Amandine Roux<br />

University Pierre and Marie Curie,<br />

Paris, France<br />

Ma lab<br />

Wanding Zhou<br />

Rice University, Houston, Texas<br />

Shen lab<br />

Juxin Ruan<br />

Shanghai Institute for Biological<br />

Sciences, China<br />

Ma lab<br />

Rajamani Keerthi Thirtamara<br />

Ohio State University, Columbus<br />

L. Brundin lab<br />

Rochelle Tiedemann<br />

Georgia Regents University, Augusta<br />

Rothbart lab<br />

Elizabeth Tovar<br />

Wayne State University,<br />

Detroit, Michigan<br />

Steensma lab<br />

Zhi-Qiang Wang<br />

Laval University,<br />

Quebec City, Canada<br />

Pfeifer lab<br />

Laura Winkler<br />

University of Wisconsin, Madison<br />

Jovinge lab<br />

Paige Winkler<br />

Michigan State University, East Lansing<br />

Lü lab<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 67


Organization<br />

68 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Primary cortical neurons of a rat. Staining is for Map2 (red), a protein found in neural dendrites,<br />

and sortilin (green), a neural receptor typically found in endosomes. DAPI stains the cell nuclei blue.<br />

The large cell to the upper left that has no dendrites is likely an astrocyte.<br />

Image by Erin Williams of the Moore laboratory. Copyright MBF Bioscience; used with permission.


Management<br />

VARI Board of Trustees<br />

David L. Van Andel, Chairman<br />

Tom R. DeMeester, M.D.<br />

James B. Fahner, M.D.<br />

Michelle M. Le Beau, Ph.D.<br />

George F. Vande Woude, Ph.D.<br />

Ralph Weichselbaum, M.D.<br />

Max S. Wicha, M.D.<br />

DAVID L. VAN ANDEL<br />

Chairman and CEO Van Andel Institute<br />

Board of <strong>Scientific</strong> Advisors<br />

The Board of <strong>Scientific</strong> Advisors advises the<br />

CEO and the Board of Trustees, providing<br />

recommendations and suggestions regarding the<br />

overall goals and scientific direction of VARI.<br />

The members are<br />

Michael S. Brown, M.D., Chairman<br />

Richard Axel, M.D.<br />

Joseph L. Goldstein, M.D.<br />

Tony Hunter, Ph.D.<br />

Phillip A. Sharp, Ph.D.<br />

70 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


PETER A. JONES, Ph.D., D.Sc.<br />

Chief <strong>Scientific</strong> Officer<br />

PATRIK BRUNDIN, M.D., Ph.D.<br />

Associate Director<br />

Office of the Chief <strong>Scientific</strong> Officer<br />

Aubrie Bruinsma, B.A., Events and Meetings Coordinator<br />

Ryan Burgos, B.S., Clinical Research Analyst<br />

David Cabrera, M.S., Chief of Staff<br />

Kayla Habermehl, B.A., B.S., Science Communications Specialist<br />

Jennifer Holtrop, B.S., Research Operations Coordinator<br />

Chelsea John, B.S., Research Department Administrator<br />

David Nadziejka, M.S., E.L.S., Science Editor<br />

Aaron Patrick, B.S., Research Operations Supervisor<br />

External <strong>Scientific</strong> Advisory Board<br />

Tony Hunter, Ph.D.<br />

Marie-Françoise Chesselet, M.D., Ph.D.<br />

Sharon Y.R. Dent, Ph.D.<br />

Howard J. Federoff, M.D., Ph.D.<br />

Theresa Ann Guise, M.D.<br />

Kristian Helin, Ph.D.<br />

Rudolf Jaenisch, Ph.D.<br />

Max S. Wicha, M.D.<br />

Bonnie Petersen, Executive Assistant<br />

Beth Resau, B.A., M.B.A., <strong>Scientific</strong> Events and Meetings Supervisor<br />

Daniel Rogers, B.S., CCRC, CIP, Clinical Research Manager<br />

Veronique Schulz, B.S., Research Operations Coordinator<br />

Stephanie Stewart, B.S., Senior Administrative Assistant<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 71


Administrative Departments<br />

The departments listed below provide administrative support to both the Van Andel Research Institute and the<br />

Van Andel Education Institute.<br />

Executive<br />

David Van Andel, Chairman and CEO<br />

Christy Goss, Senior Executive Assistant<br />

Operations<br />

Jana Hall, Ph.D., M.B.A.,<br />

Chief Operations Officer<br />

Ann Schoen, Senior Executive Assistant<br />

Business Development and<br />

Extramural Administration<br />

Thomas DeKoning, Director<br />

Robert Garces, Ph.D.<br />

Andrea Poma, M.P.A.<br />

Christine Timbol, B.A., M.A.<br />

Compliance<br />

Gwenn Oki, Director<br />

Jessica Austin<br />

Angie Jason<br />

Laura Kersjies<br />

Dave Lutkenhoff<br />

Communications and Marketing<br />

Beth Hinshaw Hall, Director<br />

Frank Brenner<br />

Alex Edema<br />

Rachel Harden<br />

Caitlin Smith<br />

Development<br />

Brett Holleman,<br />

Chief Development Officer<br />

Patrick Placzkowski, Director<br />

Hannah Acosta<br />

Betty Alexander<br />

Maddie Eaton<br />

Allyson Huttenga<br />

Ashley Owen<br />

Teresa Reid<br />

Sarah Rollman<br />

Lawrence Rush<br />

Angie Stumpo<br />

Facilities<br />

Samuel Pinto, Director<br />

Beau Burnett, Chef<br />

Jeff Cooling, Manager<br />

Jeff Wilbourn, Manager<br />

Tim Bachinski<br />

Maria Becerra-Mota<br />

Dedefo Bedaso<br />

Nuritu Bedaso<br />

Rob Cairns<br />

Hebib Chakeri<br />

Jessica Copley<br />

Deb Dale<br />

Jason Dawes<br />

Lupe Delgado<br />

Ken DeYoung<br />

Art Dorsey<br />

Kristi Gentry<br />

Tammy Humphreys<br />

Hodilia Jimenez<br />

Matthew Jump<br />

Todd Katerburg<br />

Tracy Lewis<br />

Lewis Lipsey<br />

Micah McNeil<br />

Dave Marvin<br />

Kristina Mason<br />

Jeannette Mendez<br />

Amanda Miller<br />

Joan Morrison<br />

Jamison Pate<br />

Karen Pittman<br />

Amber Ritsema<br />

Tyler Rosel-Pieper<br />

Kristina Schaner<br />

Amber TenBrink<br />

Dalu Tibesso<br />

Rich Ulrich<br />

Pete Van Conant<br />

Finance<br />

Timothy Myers,<br />

Vice President and Chief Financial Officer<br />

Katie Helder, Controller<br />

Rich Herrick, VARI Finance Director<br />

Kathryn Bishop<br />

Mark Denhof<br />

Sandi Dulmes<br />

Nate Gras<br />

Rami Ibrahim<br />

Tess Kittridge<br />

Angie Lawrence<br />

Leah Postema<br />

Susan Raymond<br />

Cindy Turner<br />

Human Resources<br />

Linda Zarzecki, Vice President<br />

Ryan DeCaire<br />

Deirdre Griffin<br />

Eric Miller<br />

Pamela Murray<br />

John Shereda<br />

Erica Siebrasse<br />

Darlene Walz<br />

72 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Information Technology<br />

Bryon Campbell, Ph.D.,<br />

Chief Information Officer<br />

David Drolett, Manager<br />

Zack Ramjan, Manager<br />

Candy Wilkerson, Manager<br />

Bill Baillod<br />

Terry Ballard<br />

Tom Barney<br />

Phil Bott<br />

James Clinthorne<br />

Kim Coan<br />

Dan DeVries<br />

Sean Haak<br />

Kenneth Hoekman<br />

Matt Hoffman<br />

Jason Kotecki<br />

Diana Lewis<br />

Ben Lewitt<br />

Deb Marshall<br />

Randy Mathieu<br />

Matt McFarlane<br />

Rob Montroy<br />

David Mowry<br />

Bruce Racalla<br />

Thad Roelofs<br />

Anthony Watkins<br />

Innovation and Collaboration<br />

Jerry Callahan, Ph.D., M.B.A., I&C Officer<br />

Norma Torres<br />

Investments Office<br />

Kathy Vogelsang,<br />

Chief Investment Officer<br />

Ted Heilman<br />

Karla Mysels<br />

Turner Novak<br />

Austin Way<br />

Legal<br />

Thomas R. Curran, Jr., General Counsel<br />

Materials Management<br />

Richard M. Disbrow, C.P.M., Director<br />

Matt Donahue<br />

Tracey Farney<br />

Heather Frazee<br />

Desaray Fourman<br />

Justin Harper<br />

Cheryl Poole<br />

Shannon Rydel<br />

Bob Sadowski<br />

Kyle Sloan<br />

Kimberly Stringham<br />

John Waldon<br />

Tracey Walker<br />

Security<br />

Kevin Denhof, CPP, Director<br />

Shelly Adamczak<br />

Brian Nix<br />

Chelsea Sturm<br />

Ross Vander Klok<br />

Andriana Vincent<br />

Sponsored Research<br />

Jeff Richardson, Director<br />

Kathy Koehler<br />

Sara O’Neal<br />

Heather Wells<br />

Barbara Wygant<br />

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 73


Van Andel Institute<br />

Board of <strong>Scientific</strong> Advisors<br />

Michael S. Brown, M.D., Chairman<br />

Richard Axel, M.D.<br />

Joseph L. Goldstein, M.D.<br />

Tony Hunter, Ph.D.<br />

Phillip A. Sharp, Ph.D.<br />

Van Andel Institute Board of Trustees<br />

David Van Andel, Chairman<br />

John C. Kennedy<br />

Mark Meijer<br />

Van Andel Research Institute<br />

Board of Trustees<br />

David Van Andel, Chairman<br />

Tom R. DeMeester, M.D.<br />

James B. Fahner, M.D.<br />

Michelle Le Beau, Ph.D.<br />

George F. Vande Woude, Ph.D.<br />

Ralph Weichselbaum, M.D.<br />

Max Wicha, M.D.<br />

Van Andel Research Institute<br />

Chief <strong>Scientific</strong> Officer<br />

Peter A. Jones, Ph.D., D.Sc.<br />

Innovation & Collaboration<br />

Jerry Callahan, Ph.D.<br />

VP Human Resources<br />

Linda Zarzecki<br />

Communications & Marketing<br />

Beth Hinshaw Hall<br />

Compliance<br />

Gwenn Oki, M.P.H.<br />

Facilities<br />

Samuel Pinto<br />

Chief Executive Officer<br />

David Van Andel<br />

Chief Operations Officer<br />

Jana Hall, Ph.D., M.B.A.<br />

Van Andel Education Institute<br />

Board of Trustees<br />

David Van Andel, Chairman<br />

James E. Bultman, Ed.D.<br />

Donald W. Maine<br />

Juan R. Olivarez, Ph.D.<br />

Gordon L. Van Harn, Ph.D.<br />

Van Andel Education Institute<br />

Director<br />

Terra Terrango<br />

VP & Chief Financial Officer<br />

Timothy Myers<br />

General Counsel<br />

Thomas R. Curran, Jr.<br />

Development<br />

Brett Holleman, CFRE, CFRM<br />

Security<br />

Kevin Denhof<br />

74 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


The Van Andel Institute and its affiliated organizations (collectively the “Institute”) support and comply with<br />

applicable laws prohibiting discrimination based on race, color, national origin, religion, gender, age, disability,<br />

pregnancy, height, weight, marital status, U.S. military veteran status, genetic information, or other personal<br />

characteristics covered by applicable law. The Institute also makes reasonable accommodations required by<br />

law. The Institute’s policy in this regard covers all aspects of the employment relationship, including recruiting,<br />

hiring, training, and promotion, and, if applicable, the student relationship.<br />

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