SPRING 2019

INVESTING IN DISCOVERY EXPANDING LSI-led projects help keep U-M on the THE TOOLBOX cutting edge of basic science research How the LSI is developing new tools to advance scientific discovery LET’S TALK SCICOMM Public engagement in the digital age CONTENTS

DEPARTMENTS Expanding the Toolbox How the LSI is developing new 01 From the Director 8 tools to advance scientific 02 News & Updates discovery 26 Perspectives 30 Victors for Discovery 35 Voices of the Faculty 36 Profiles

40 Inside the LSI Investing in Discovery 46 Year in Photos LSI-led projects help keep U-M 15 on the cutting edge of basic science research

ON THE COVER

New tools help to expand and advance scientific discovery.

Photos: Peng Li (wrench image), Erin Grimm (hammer image), Let’s Talk SCICOMM Stephanie King (saw image) Public engagement in the 21 digital age

LSI Magazine is published annually by the U-M The Life Sciences Institute REGENTS OF THE The University of Michigan, as an equal Life Sciences Institute University of Michigan UNIVERSITY OF MICHIGAN opportunity/affirmative action employer, 210 Washtenaw Avenue Jordan B. Acker, Huntington Woods complies with all applicable federal and ROGER D. CONE, PH.D. Ann Arbor, MI 48109-2216 Michael J. Behm, Grand Blanc state laws regarding nondiscrimination and Director Mark J. Bernstein, Ann Arbor affirmative action. The University of Michigan (734) 763-1200 | [email protected] Paul W. Brown, Ann Arbor is committed to a policy of equal opportunity ANNA SCHORK, J.D. Shauna Ryder Diggs, Grosse Pointe for all persons and does not discriminate Managing Director Send address changes to the above address Denise Ilitch, Bingham Farms on the basis of race, color, national origin, or email. Ron Weiser, Ann Arbor age, marital status, sex, sexual orientation, EMILY KAGEY Katherine E. White, Ann Arbor gender identity, gender expression, disability, Editor & Manager of Communications and Copyright © 2019 Regents of the University Mark S. Schlissel, ex officio religion, height, weight, or veteran status Marketing of Michigan in employment, educational programs and activities, and admissions. Inquiries or IAN DEMSKY complaints may be addressed to the Senior Contributing Editor Director for Institutional Equity, and Title IX/Section 504/ADA Coordinator, Office STEPHANIE KING for Institutional Equity, 2072 Administrative Designer & Illustrator Services Building, Ann Arbor, Michigan 48109-1432, (734) 763-0235, TTY (734) LAURA J. WILLIAMS 647-1388, [email protected]. Director of Development For other University of Michigan information call (734) 764-1817.

LSI MAGAZINE / SPRING 2019 I macromolecules insideofcells.This willberevolutionary. the methodsneededtodetermine the3-Dstructureof in cryo-electrontomography, theyintendtodevelop molecules purifiedfromthecell. Bycreatingaprogram scientists to determine theatomic-levelstructureof the mysteries of the cell. Conventional cryo-EM allows Cianfrocco andJanetSmithtopeerevenfurtherinto funding willallowLSIinvestigatorsMelanieOhi,Michael cryo-electron microscopy(cryo-EM),andBiosciences The UniversityofMichiganisalreadyanationalleaderin microscopy andnaturalproductsdrugdiscovery. critical problemsinthebiosciencesthroughadvanced projects willstrengthentheuniversity’sabilitytosolve U-M BiosciencesInitiativein2018.Thesecross-disciplinary scientific researchproposalsfundedbythepresidential LSI projectswerealsoselectedastwoofthefivemajor enable profoundnewdiscoveriesacrossthebiosciences. chemistry, biophysicsandcomputingthatwillundoubtedly investigators whoaredevelopingnewmethodologiesin article, “Expanding the Toolbox,” focuses on three LSI University ofMichiganand,indeed,theworld.Thecover and corelaboratoriesbringtotheentirefacultyof remarkable discoveryresourcesthatLSIinvestigators DIRECTOR FROM THE This issueofthe into biologicalsystemsandprocesses. electron microscopy,whichwillenableevenfurtherinsight power haveresulted in strikingadvances both lightand the convergenceofchemistry,physicsandcomputational of new technologies in the life sciences. For example, of newtechnologiesinthelifesciences.Forexample, fortunate tobeinaperiodofacceleratingdevelopment to scientists’abilitymakediscoveries—andweare t ishardtooverestimatethepowerthatnewtoolsbring LSI Magazine LSI focuses on some of the focusesonsomeofthe Mary SueColemanDirector,Life SciencesInstitute Roger D.Cone,Ph.D. Sincerely, Twitter, @UMLifeSciences. quarterly e-newslettersandbyjoiningtheconversationon our progressthroughoutthe year by signing up forour into asinglemagazineissue,soIinviteyoutofollow There’s muchmoregoingonattheLSIthanwecanpack discovery willmaketheU-Maleaderandbestinthisfield. unique setoftoolsforsolvingdifficultproblemsindrug overproduce andevenmodifyactivenaturalproducts.This live microbialstrainswiththebiosynthetictoolstoidentify, extracts fromauniquecollectionofapproximately5,000 Sherman andhiscolleaguesarelinkingsemipurified even destroyed,theirnaturalproductscollections. major pharmaceuticalcompanieshavegivenaway,or pharmaceuticals canbedaunting.Consequently,most the chemistry to convert these products into promising malarial treatmentsandmanycancerdrugs);however, often make very good drugs (think antibiotics, anti- investigators. Naturalproductssynthesizedbymicrobes products drugdiscovery,includingacorelabforallU-M Biosciences fundstoadvanceanascentprograminnatural David ShermanandAshootoshTripathiwereawarded

Leisa Thompson Photography NEWS & UPDATES NOT SO FAST THERE S. XU LAB A research team led by the Life Sciences Institute has To better understand how the interactions between uncovered a cause of declining motor function and increasing cells changed as worms aged, Xu and his colleagues frailty in tiny, aging worms — and a way to slow it down. investigated the junctions where motor neurons communicate with muscle tissue. The findings identify a molecule that can be targeted to improve motor function, and indicate that similar They identified a molecule called SLO-1 (for “slowpoke pathways may be at play in aging mammals as well. potassium channel family member 1”) that acts as a regulator for these communications. The molecule As humans and animals age, our motor functions dampens neurons’ activity, slowing down the signals from progressively deteriorate. Millimeter-long nematodes neurons to muscle tissue and reducing motor function. exhibit aging patterns remarkably similar to those of other animals. And they only live about three weeks, making The researchers manipulated SLO-1, first using genetic them an ideal model system for studying aging. tools and then using a drug called paxilline. In both cases, they observed two major effects in the roundworms. Not “We previously observed that as worms age, they gradually only did they maintain better motor function later in life, lose physiological functions,” explains Shawn Xu, Ph.D., they also lived longer than the control worms. professor at the LSI and senior study author. “Sometime around the middle of their adulthood, their motor function begins to decline. But what causes that decline?” Heiti Paves/iStock/Thinkstock

2 LSI MAGAZINE / SPRING 2019 NEWS & UPDATES

PUTTING THE BRAKES ON METABOLISM RESEARCHERS LIN LAB IDENTIFY NEW A hormone produced by the liver tells the body to downshift its metabolism POTENTIAL DRUG when it’s expending a lot of energy, LSI researchers have found. TARGET FOR HUNTINGTON’S Scientists in the lab of LSI professor Jiandie Lin, Ph.D., discovered that DISEASE WEISMAN LAB the hormone tsukushi (or TSK) was elevated in mouse tissue when mice were burning a lot of energy, such as when they needed to maintain body A multi-institutional team of temperature in cold environments. researchers, including the LSI’s Weisman lab, identified a new drug The researchers believe TSK is putting a “brake” on metabolism and target for treating Huntington’s dampening energy expenditure. disease, a fatal neurological disorder for which there currently Removing this brake had metabolic benefits for the mice. When mice were is no cure or preventative therapy. temporarily fasted, those lacking TSK lost significantly more weight than normal mice. And when fed a high-fat diet, normal mice approximately The researchers identified an doubled in weight — while the mice that lacked TSK experienced only about enzyme that, when inhibited, a 30 percent increase in weight and displayed better metabolic parameters. appears to help clear out the mutant proteins that accumulate in cells The research reveals a potential target for treating metabolic disorders. and lead to the disease. The study, which included a fruit fly model of Huntington’s disease, paves the way for mammalian studies — a precursor to eventual development and testing of a drug in humans.

“What’s most exciting here is that not only can the fruit flies tolerate the lack of this enzyme,” says Lois Weisman, Ph.D., “but it’s actually making them better.” Stephanie King, LSI

SCIENTISTS HAVE REVEALED THE FIRST STEPS INVOLVED IN A MICROBE’S SYNTHESIS OF A POTENT NERVE TOXIN. “THE ADVANCE COULD HELP TO MAKE THE COMPOUND, SAXITOXIN, MEDICALLY USEFUL.

—Nature Research Highlights on work led by LSI faculty member Alison Narayan, Ph.D., on an enzyme involved in manufacturing saxitoxin. By modifying the toxin’s precursors, the team aims to transform the deadly poison for beneficial use. ”

LSI MAGAZINE / SPRING 2019 3 NEWS & UPDATES

RECEPTOR PROTEIN IN THE BRAIN CONTROLS THE BODY’S FAT ‘RHEOSTAT’ CONE LAB A team of scientists from the LSI and Vanderbilt experiences some sort of metabolic stress that shifts University has uncovered the function of a protein energy levels — eating too much or too little, for example that has been confounding researchers for more than — MC3R ensures that the balance of energy and fat in the two decades — and has introduced a new concept in body does not drift too far in either direction. metabolism research. This role in rheostasis makes MC3R a promising new drug The protein, called the melanocortin 3 receptor (or MC3R target for treating obesity. “When we lose weight, our for short), maintains what LSI Director Roger Cone, Ph.D., bodies sense that the energy balance has tipped below has termed “energy rheostasis.” the established lower boundary and try to adjust by using less energy and increasing appetite,” explains lead study The discovery opens new doors for developing anti- author Masoud Ghamari-Langroudi, M.D., Ph.D., of the obesity drugs and for understanding weight gain during Vanderbilt University School of Medicine. pregnancy and menopause, says Cone, who was the senior author on the study. A drug that targets MC3R has the potential to reduce the rigidity of that lower boundary, Cone says. “In many ways, A lack of MC3R has almost no effect on mice under it’s an ideal drug target because it could enable people to normal conditions. But mice without this protein lose keep the weight off when they lose weight through diet more weight when fasting and gain more weight when and exercise.” eating a high-fat diet, compared with normal mice.

These seemingly contradictory results stem from the protein’s role in setting the upper and lower boundaries of the body’s ideal energy balance. When the body Stephanie King, LSI

4 LSI MAGAZINE / SPRING 2019 NEWS & UPDATES

DECODING STEM CELLS’ COMPLEX DECISION-MAKING PROCESS LEE LAB Life Sciences Institute researchers have deciphered the be employed to drive certain types of tumor stem cells complex mechanisms that neural stem cells use to shed to give up their stemness, potentially reducing tumor their identity when dividing. growth and relapse.

Neural stem cells have the potential to develop into specific cell types within the body’s nervous system. They do this by dividing into two different types of cells: one exact copy of the stem cell (to maintain the stem cell pool), and one that can differentiate, ultimately becoming a neuron or a glial cell, for example.

Using the model system Drosophila melanogaster, researchers in the lab of Cheng-Yu Lee, Ph.D., identified a multi-dimensional process that the latter cell uses to turn off all gene activities telling it to be a stem cell — not just turning off specific genes, but also removing any stem-related RNA and proteins that those genes have already coded.

The study helps unravel a complex process that is essential for the body’s ability to maintain and create the cells it needs for survival. And the researchers believe that these same mechanisms could eventually Stephanie King ,LSI

CLARIFYING ‘FUZZY’ PROTEINS MAPP LAB Researchers in the lab of Anna Mapp, Ph.D., at the LSI its ability to bind to various different structures, and have developed a new approach to zero in on a type of determined that this region can be targeted with drug- elusive protein-protein interactions, where errors can like molecules. give rise to a host of human diseases. Their findings may create a new approach to drug discovery. The researchers have already found one small molecule that binds well to the region and achieves potent Our bodies build cellular machines to turn on genes interactions in cell cultures, and they are screening the as needed, using an assembly of proteins called extensive small-molecule libraries at the LSI’s Center for transcriptional activators and coactivators. Interactions Chemical Genomics to find more. between these two types of proteins are crucial for proper cell function and health, but are notoriously “We now understand this important class of proteins in difficult to target for therapeutic intervention. a way we didn’t before, which is significant,” Mapp says. “But we also have actionable items that we can use to Transcription coactivators have what Mapp describes discover more effective drug-like molecules.” as “fuzzy” structures, which continue to change shape as they bind with various other proteins, making them challenging to target with small molecules.

Mapp and her colleagues now have identified one region of a transcriptional coactivator that is critical for

LSI MAGAZINE / SPRING 2019 5 NEWS & UPDATES

SCIENTISTS DISCOVER A ROLE FOR ‘JUNK’ DNA YAMASHITA LAB Satellite DNA, long considered to be “junk” DNA, in not use their satellite DNA, they formed micro-nuclei, or fact plays a crucial role in cell survival by ensuring that tiny buds outside the nucleus that included pieces of the chromosomes bundle correctly inside the cell’s nucleus, genome. Without the entire genome encapsulated in the according to new findings from the LSI. And this function nucleus, the cells could not survive. appears to be conserved across many species. The similar findings from both fruit fly and mouse cells “We were not quite convinced by the idea that this is lead Yamashita and her colleagues to believe that satellite just genomic junk,” says Yukiko Yamashita, Ph.D. “If we DNA is essential for cellular survival, not just in model don’t actively need it, and if not having it would give us an organisms but across species that embed DNA into the advantage, then evolution probably would have gotten rid nucleus — including humans. of it. But that hasn’t happened.”

Working in both Drosophila melanogaster (fruit flies) and mouse cells, the researchers found that when germ cells — the cells that develop into sperm or eggs — could

ONE GENE MAY BE ABLE TO PINCH HIT FOR ITS ‘TWIN’ TO FIGHT CONGENITAL ANEMIA GINSBURG LAB Stephanie King, LSI

It may be possible to coax one gene into fixing the have the same function, but they operate in different disease caused by faulty copies of its nearly identical tissues throughout the body. And because the two genes “twin,” U-M researchers have found. have the same functions, one gene could potentially step in to fix problems caused by mutations in the other. The two genes are so-called paralogs, or two genes that evolved from one gene that was duplicated in the “It changes the way we think about these genes,” says genome. Despite the similarities between the genes, David Ginsburg, M.D., LSI professor and senior study mutations in the two bring about very different diseases. author. “And it raises the prospect of this approach for other A mutation in one leads to abnormal bone formation, while human diseases where there are similar paralog genes.” problems with the other cause a type of congenital anemia.

Through a comprehensive set of experiments — ranging from human cell culture, to yeast, to whole-animal studies — the researchers determined that the genes

6 LSI MAGAZINE / SPRING 2019 NEWS & UPDATES

INSTITUTE NEWS NEW FACULTY MEMBERS EXPLORE THE BRAIN One is investigating the neural circuits responsible for breathing. The other is building new tools to track neurons’ response to specific behaviors.

Together, the LSI’s newest faculty members — Peng Li, Ph.D., and Wenjing Wang, Ph.D. — are expanding neuroscience expertise at the institute.

Li, an assistant professor who comes to U-M from a

postdoc at Stanford University, represents the LSI’s Eric Bronson, Michigan Photography first joint appointment with the School of Dentistry. Wang, who also hails from Stanford, holds her joint LSI/HHMI STAFFER NAMED appointment in the Department of Chemistry at the FIRST RHODES SCHOLAR FOR College of Literature, Science, and the Arts. SAUDI ARABIA

You can read more about each of their research Majd Abdulghani — a geneticist working in the lab of LSI programs in this issue. faculty member and Howard Hughes Medical Institute investigator Vivian Cheung, M.D. — will join this year’s class of Rhodes Scholars at the University of Oxford. She will be the first student to represent Saudi Arabia. Abdulghani, who is also an award-winning podcaster, says she hopes to inspire women and girls around the world to pursue science. “I hope that when people see I’m Saudi Arabian, I wear a headscarf, I’m Muslim, I’m a woman — all of these things that they might perceive as obstacles didn’t stand in my way.”

Abdulghani’s story attracted significant media attention and was picked up by the Associated Press, Michigan Radio, Nature news and Saudi Gazette, as well as being shared widely on social media. Leisa Thompson Photography Leisa Thompson Photography

THE LSI KICKS OFF NEW SCICOMM SPEAKER SERIES AT U-M

Science writer Tom Clynes was selected to kick off an ongoing series of LSI-sponsored public talks highlighting the importance of science communication. Clynes, whose work has appeared in National Geographic, Nature, The New York Times and Popular Science, is also the author of The Boy Who Played with Fusion. “Our goal for this series is to focus attention on the importance of communicating and disseminating science beyond the walls of the academy,” says LSI

Director Roger Cone. @TomClynes via Twitter

LSI MAGAZINE / SPRING 2019 7 EXPANDING THE TOOLBOX

How the LSI is developing new tools to advance scientific discovery

BY EMILY KAGEY

8 LSI MAGAZINE / SPRING 2019 LSI MAGAZINE /SPRING2019 9

Leisa Thompson Photography efore Frederick Sanger became only the “But many of these reagents are toxic acids or rare elements fourth person in history to receive two Nobel — metals that have to be mined from meteors, for example,” Prizes, before he created the Sanger method of explains LSI assistant professor Alison Narayan, Ph.D. B sequencing DNA, before he developed a toolkit “One of the reactions my lab is working on traditionally to sequence proteins, he wanted to solve a problem. uses iridium, which is one of the rarest elements on Earth.”

In 1944, Sanger set out to solve the structure of insulin. Narayan’s lab at the LSI is focused on the question of how Scientists already knew that proteins were made up of chains synthetic chemistry can shift away from reagents that are of amino acids, but they lacked an effective technique for toxic and resource-intensive to a greener, more powerful determining the precise order of those amino acids. To approach to chemistry. uncover the structure of insulin, Sanger would need a scientific tool that did not yet exist. Inside an incubator on the fourth floor of the LSI, Escherichia coli bacteria are busy churning out an answer. So he built one: the “jigsaw puzzle method” for determining a protein’s structure, which earned Sanger his first Nobel Prize Chemical reactions occur constantly in nature, without in Chemistry in 1958. the use of dangerous or expensive reagents. Instead, these reactions rely on biocatalysts — enzymes that can initiate a But when he turned his attention to sequencing DNA in the reaction over and over without being depleted. Bacteria, fungi 1970s, Sanger found that, despite its usefulness in analyzing and other microorganisms have spent millennia evolving proteins, this tool could not unravel the thousands of base catalytic tools to build complex, bioactive molecules. Now pairs that comprise all the pieces of the genome. To solve Narayan is recrafting those tools for synthetic chemistry. this new problem, he needed a more sophisticated tool. So he built another one.

The Sanger method of sequencing DNA revolutionized scientists’ ability to analyze genes and understand their functions, and it earned Sanger his second Nobel Prize in WE’RE DEVELOPING A Chemistry in 1980. “ROUTE THAT JUST TAKES Sanger is part of a long tradition of “toolmakers” in the YOU DIRECTLY THERE OR, annals of scientific achievements. Novel discoveries often IN SOME CASES, EVEN GETS result from the novel tools that precede them, and many of YOU TO A DESTINATION science’s top honors and awards have gone to the scientists who built those tools — scientists who, when faced with a THAT WAS PREVIOUSLY research question that could not be answered with existing INACCESSIBLE. options, decided to make their own.

Three faculty members at the University of Michigan Life Sciences Institute are doing just that, developing tools to advance not just their research but also their fields. Researchers in Narayan’s lab start by identifying a complex molecule that organisms can build in nature, but which” is challenging — or impossible — for chemists to develop in BUILDING WITH NATURE’S BLOCKS the lab. Her group studies the transformations that nature When chemists want to develop new materials — new uses to build the compound, identifies the proteins that medicines, for example, or improved plastics — they jump-start those transformations and then harnesses E. coli first must find a way to transform existing molecules. To to manufacture the proteins into tools that chemists can facilitate these transformations, synthetic chemists use apply to their reactions. reagents to coax molecules into reactions that can build new products. “Imagine that you have found a way to get to your desired destination, but it requires 20 stops,” says Narayan, who is

10 LSI MAGAZINE / SPRING 2019 synthetic reagents; sometimes synthetic chemists have a more efficient way to build a molecule than the process used in nature. Instead, she is building an additional set of tools for chemists’ toolbox that will enable researchers to draw from the best of both worlds.

It’s an approach that Narayan is using in her own research to develop potential new medicines from a potent neurotoxin. The shellfish toxin saxitoxin blocks voltage-gated sodium ion channels in neurons, preventing cell function and causing paralysis. If the molecule can be altered to block only very specific ion channels, though, it might have therapeutic applications — such as blocking pain without the use of opioids.

“We’re not constrained to one world or the other,” Narayan says. “We’re taking from both to create a process that’s the most efficient.”

ENGINEERING PROTEIN POWER TOOLS Down the hall from the Narayan lab, LSI assistant professor Wenjing Wang, Ph.D., is also drawing from nature to build new tools, using tiny proteins from sharks and llamas.

Wang wants to investigate how proteins affect cellular processes. But the specific processes she’s interested in,

Leisa Thompson Photography like a neuron’s response to a stress stimulus, happen in microseconds. And the available tools simply take too long Alison Narayan, Ph.D. for the type of dynamic protein processes that Wang and many other scientists want to understand. also an assistant professor of chemistry in the U-M College of Literature, Science, and the Arts. “We’re developing a To overcome this challenge, Wang’s lab at the LSI is evolving route that just takes you directly there or, in some cases, even new tools to study protein functions, using nanobodies gets you to a destination that was previously inaccessible.” — smaller, more stable versions of the antibodies that circulate through our blood, confronting foreign invaders Biocatalysts can perform their work in water and at room such as bacteria and viruses. These tiny molecules can latch temperature. And because they specialize in creating on to one specific, predetermined protein and disrupt its specific bonds, they produce the desired molecules with function immediately, without affecting the activities of fewer unnecessary byproducts, generating less waste while other proteins in the cell. With a structure that is smaller still performing powerful, precise chemical reactions. and more stable than that of antibodies, nanobodies are proving to be the perfect building blocks for those tools. Despite their advantages, biocatalysts have yet to be widely adopted across academia or industry, in part because of the Since their discovery in the early 1990s, nanobodies have wide-ranging chemical and biological prowess needed to demonstrated enormous utility in fields like structural develop them for large-scale use. biology and medicine. More than 40 nanobody-based therapies are currently under development, with several in Using her expertise in both complex molecule synthesis clinical trials. And llama nanobodies played an essential role and biosynthesis, Narayan is making biocatalysts more in revealing the structure of G protein-coupled receptors — accessible to chemists. Her goal is not to fully replace all a discovery that earned the 2012 Nobel Prize in Chemistry.

LSI MAGAZINE / SPRING 2019 11 Leisa Thompson Photography

Wenjing Wang, Ph.D.

More recently, researchers have begun to explore light, the nanobodies stand idle in the cell, awaiting further nanobodies’ power to perturb protein function directly instruction. Researchers can then shine the light source at inside cells. But Wang wants to boost that power further, the exact moment they want to observe — when a neuron building even more precise tools for protein research. fires, for example — and see how the cell responds when the protein loses its function. As soon as the light turns off, Using directed evolution (the technology that was awarded the cell returns to its normal state. the 2018 Nobel Prize in Chemistry), Wang is building a library of nanobodies that are each evolved to target a Wang plans to use the new tools to study processes such as different protein. The nanobody’s DNA can then be inserted how memories form and how depression develops at the into a virus, which in turn inserts itself into a cell — where it molecular level. But she is not limiting her library only to produces nanobodies that are primed to latch onto the one proteins involved in neurological processes. Instead, she protein of interest and prevent it from working. wants to develop a full array of highly responsive, highly specific tools that researchers across scientific fields can use But when you’re studying dynamic processes, like cellular to study dynamic processes within cells. stress responses, it’s not enough to get those nanobodies into the cell or even to make sure they find the specific “Over the past 10 to 20 years, I’ve seen how molecular tools protein being studied. can allow biologists to do what they could not do before and facilitate really fascinating biological discoveries,” she “We don’t want the nanobody to be bound to the protein says. “That’s what I’m trying to do in my lab now: design all the time,” Wang says. “Otherwise, it will perturb the new tools that enable novel research across many fields.” protein’s function constantly, instead of during only the event we want to study.” It’s an ambition shared by a colleague a few floors below.

So she is building the nanobodies to activate only when exposed to a specific light source. Without a signal from the

12 LSI MAGAZINE / SPRING 2019 THAT’S WHAT I’M TRYING TO “DO IN MY LAB NOW: DESIGN NEW TOOLS THAT ENABLE NOVEL RESEARCH ACROSS MANY FIELDS. ” Stephanie King, LSI

BREAKING DOWN BIG DATA BARRIERS The research program of structural biologist Michael Each image the electron microscope captures, which Cianfrocco, Ph.D., reflects his dual interests in answering is actually a movie, is about 5GB of data. Researchers important biological questions and improving access to the typically need tens of thousands of images to reveal the full sophisticated technologies he uses to answer those questions. 3-D structure of the protein they’re studying — adding up to several terabytes of data every time they want to test His lab at the LSI studies how proteins in the cell are able something, Cianfrocco says. to transport various cargos to the right destination within the cell at the right time. He’s specifically interested in That massive amount of data is what led to Cianfrocco’s dynein, a motor protein that carries freight into the center other line of research. As an expert in cryo-EM, he knows of the cell, and its roles in human health and disease. For the technique’s power to answer important biological example, before it can infect the DNA of its target, human questions. But even for many users who have access to the immunodeficiency virus (HIV) has to travel to the nucleus highly specialized equipment, data storage and processing of the cell. Cianfrocco’s lab is studying how the virus hitches still present massive barriers to wider adoption. So he’s a ride on dynein to get to its destination. building tools to democratize cryo-EM.

“We want to know how these motor proteins actually The project has its roots in Cianfrocco’s postdoctoral research work,” says Cianfrocco, who is an assistant professor at the experience, when technological constraints were getting in LSI and an assistant professor of chemical biology at the the way of his ability to answer scientific questions. U-M Medical School. “How does dynein navigate through its environment? That’s the question we’re trying to answer.” “When I was starting out with cryo-EM, you had to know how to code,” he explains. “If you couldn’t code, you To find out, his lab uses the structural biology technique couldn’t solve structures. I had the incentive of wanting to that won the 2017 Nobel Prize in Chemistry: cryo-electron solve a structure, so I learned to code. And then I kind of microscopy (or cryo-EM). This approach employs advanced just kept going.” microscopes to reveal the shapes of proteins that have been flash-frozen in a layer of vitreous ice. When he and his colleagues bumped up against the computing limitations of their institution, he adapted a Cryo-EM enables researchers to study a broad array commercial cloud-computing service for his research needs. of protein structures that are indiscernible using other structural biology techniques — but only if they have access “Our jobs kept dying or crashing — and that’s where the to the specialized electron microscopes, and to enormous whole cloud thing came from,” he says. computing power.

LSI MAGAZINE / SPRING 2019 13 Cianfrocco started using cloud computing to store and at no cost. But researchers interested in processing large process his cryo-EM data more efficiently. To avoid amounts of data at these centers may lack the programming repeating many of the programming steps each time skills to do so. That’s where Cianfrocco’s project comes in. he ran a new data set, he built a software package that automated the process. Then, because it was working The website he is developing will provide a virtual portal well, he decided to make the software available to other to the super computers, removing the need for processing researchers for free (though users still have to pay for the know-how and enabling scientists to upload their data, computing services). analyze it and get results. And unlike commercial solutions, it’s completely free. Now as a faculty member of the LSI, Cianfrocco is continuing his efforts to open cryo-EM to more researchers Cianfrocco believes the tools he’s developing will better and more discoveries. equip the cryo-EM field to answer new, important biological questions. With funding from the National Science Foundation, he is developing a website that will enable researchers to easily “It feels like a thing that we need. The field needs this, and store and process cryo-EM data. no one else is building it,” he says. “So I guess the question I always think about is, ‘If not us, who’s going to do it?’” The NSF has built giant, super-computing centers all around the country, which researchers can apply to use

Michael Cianfrocco, Ph.D., right, with a member of his lab Leisa Thompson Photography

14 LSI MAGAZINE / SPRING 2019 INVESTING IN DISCOVERY LSI-led projects help keep U-M on the cutting edge of basic science research

BY IAN DEMSKY

ack in October 2015, University of Michigan “We’re really pleased by the amazing breadth of science and President Mark Schlissel announced a $150 the transdisciplinary nature of the funded proposals,” says million initiative to cement U-M as a “powerhouse Roger Cone, Ph.D., the vice provost and director of the Bin the biosciences and a global leader in discovery Biosciences Initiative and chair of the 16-member committee and societal impact.” that reviewed and ranked nearly 30 submissions.

Strategically, the initiative’s goals were to bolster emerging “Of course, I’m personally very proud that the proposals areas of strength, invest in core facilities, and create greater from LSI faculty members scored so well,” adds Cone, who opportunities for community, collaboration and coordination is also director of the LSI. “To me, it speaks not only to across units and disciplines. the quality and ambition of the science happening at the institute, but also to our larger role in developing resources Last February, the initiative solicited its first round of and expertise that can serve the entire campus.” high-impact, multidisciplinary research proposals focused on solving critical problems in the biosciences. Now, the The cryo-EM award, for example, will expand access to the first major investments from that effort are being realized technology for U-M researchers across departments on the as the university launches the first round of Biosciences central campus and at Michigan Medicine. And the new Initiative projects — with Life Sciences Institute faculty natural products drug discovery core will participate in the members leading two of five large projects and one of four universitywide efforts of Michigan Drug Discovery to smaller ones. translate faculty members’ biological discoveries into the medicines of tomorrow. One of these projects will enable U-M, already an early adopter of cryo-electron microscopy, to become an Other projects funded by the initiative include a new center international leader in the field and a premier destination for the study of concussions, an institute for global climate for cryo-EM research and training. change biology and an expansion of the Center for RNA Biomedicine. Biosciences Initiative support will also expand natural products drug discovery — the development of new “I am thrilled that our faculty have responded with medicines from microorganisms — at U-M, with the groundbreaking proposals,” Schlissel said when announcing creation of a dedicated core laboratory. the first projects to be funded through the institute. “Our first projects leverage U-M’s comprehensive excellence, And an exploratory grant was awarded for the development catalyze hiring in the biosciences and related disciplines, of a drug repurposing platform that will speed relief to and embrace our mission to conduct research for the benefit patients by finding new uses for drugs that have already of society.” passed the lengthy and rigorous FDA approval process, or that have been found safe in clinical trials. Stephanie King, LSI

LSI MAGAZINE / SPRING 2019 15 16 From left:MichaelCianfrocco,Ph.D.; JanetSmith,Ph.D.;MelanieOhi,Ph.D. LSI MAGAZINE /SPRING2019

Leisa Thompson Photography IN PRAISE OF SMALL THINGS Expanding U-M’s global leadership in cryo-EM

The Royal Swedish Academy of Sciences proclaimed that cryo-electron microscopy had “moved biochemistry into a new era” when it awarded the 2017 Nobel Prize in Chemistry to the imaging tool’s leading developers.

The technique allows structural biologists to study the inner workings of macromolecular “machines” at atomic resolution — and allows for the three-dimensional visualization of important protein complexes that have been impossible to capture using X-ray crystallography.

The new Biosciences Initiative grant positions U-M to further Leisa Thompson Photography Cryo-EM research led by Stephanie Gates and Adam Yokom, then distinguish itself in the field with the addition of cryo-electron graduate students at the LSI, was published in Science in 2017. tomography, known as cryo-ET, and correlative light and electron microscopy, or CLEM. The investment will also “This will empower researchers to answer important questions, increase the availability of cryo-EM resources to researchers like how amyloid plaques in neurodegenerative diseases form, across the university, while expanding educational and how viruses like HIV assemble in cells and how the nuclear training programs for practitioners at U-M and beyond. pore functions inside a living cell,” says Janet Smith, Ph.D., a professor of biological chemistry at the Medical School “Cryo-EM is rapidly building new fundamental knowledge and the LSI, and director of the Center for Structural Biology. about human biology and paving the way for the development of new medicines,” says Melanie Ohi, Ph.D., co-scientific CLEM, meanwhile, overcomes some of the limitations of director of the U-M cryo-EM facility at the Life Sciences electron microscopy by combining it with optical microscopy. Institute and associate professor of cell and developmental biology at the Medical School. Not only does the award draw on cross-campus partnerships and synergies — with, for example, the Medical School; Demand has been running high for the four microscopes College of Engineering; College of Pharmacy; and College currently available in U-M’s multimillion-dollar cryo-EM of Literature, Science, and the Arts — it is also fueled by a facility. Ohi and co-director Michael Cianfrocco, Ph.D., an new partnership with instrument manufacturer Thermo assistant professor of biological chemistry at the Medical Fisher Scientific, which will contribute to the development School and the LSI, noted in their proposal for the initiative of U-M’s facilities and support educational programming. that they had recently consulted on projects for more than 35 faculty members spanning 14 departments across four In June 2018, Ohi and Cianfrocco led an international cryo- schools and colleges. EM image-processing workshop at U-M — the first in what is planned to be an annual event to provide more hands-on “They’re all working on biologically compelling and training to the growing ranks of practitioners across the structurally challenging problems,” Cianfrocco says. “This world. The goal is to make U-M a leading institution and investment will allow us to overcome existing bottlenecks destination for developing the next generation of cryo-EM around capacity and the availability of training — as well as specialists. to push into new, cutting-edge areas.” “The best way to learn is by doing — either by joining or At the top of that list will be the adoption of cryo-ET, a collaborating with an established laboratory, or by paradigm-shifting technique that allows researchers to study participating in a workshop where you can roll up your molecular machines inside intact cells, rather than only sleeves and work with real data in real time,” Cianfrocco says. purified proteins suspended in solution.

LSI MAGAZINE / SPRING 2019 17 18 Ashootosh Tripathi,Ph.D.(left),and David Sherman,Ph.D.(right) LSI MAGAZINE /SPRING2019

Leisa Thompson Photography FROM MICROBES TO MEDICINES Developing a natural products drug discovery core

Professor David Sherman’s expeditions have taken him from the sweltering deserts of Israel to the crags of the Himalayas, from the rainforests of Central America to underwater sites off Costa Rica and Papua New Guinea.

The soil and marine sediment samples that he and his team collect in remote environments have uncovered microorganisms that have evolved to produce antibiotics, anticancer agents and compounds that may aid in the fight against other diseases, including AIDS.

Scientists call these beneficial microbe-made molecules David Sherman, LSI David Sherman, Ph.D., and colleagues collect sediment samples in the Red Sea. “natural products.” And the Sherman group has amassed a unique, 40,000-sample (and growing) library that places to make them patentable — without which there’s no U-M at the forefront of natural products discovery. incentive for an industry partner to invest tens of millions of dollars to bring them to market. “As large pharmaceutical companies have cut back on their early-stage drug discovery efforts, academic institutions “The current bottleneck is in our ability to do natural like U-M have stepped in to fill that void,” says Sherman, products drug discovery at scale and in the lack of metadata Ph.D., a faculty member at the Life Sciences Institute, associated with the complex mixture of compounds in our Medical School and College of Pharmacy. “U-M has spent extract library,” says Ashootosh Tripathi, Ph.D., director the last decade building a really exciting academic drug of the new Natural Products Discovery Core at the LSI, discovery program, and this new investment from the assistant research scientist at the LSI and research assistant Biosciences Initiative will help make the natural products professor in the College of Pharmacy. arm of that enterprise best-in-class.” “The development of a true core laboratory will allow us The drug discovery process often starts with an investigator to create a high-throughput pipeline and establish next- using high-throughput screening to find compounds that generation chemical informatics technology to accelerate will shut down or activate a pathway of interest. the entire path from sample to drug prospect,” he adds.

For example, U-M microbiologist Kathleen Collins, M.D., Funding from the Biosciences Initiative will support Ph.D., has been searching for compounds that can inhibit infrastructure for the new core, as well as three new faculty Nef, a protein produced by HIV and a key player in the positions to expand research in the natural product sciences. virus’s ability to hide from defenders in the body’s immune The proposal specifically recommends that the new faculty system. When a small-molecule screen failed to turn up any members bring expertise in specialties that are currently potential options, she turned to the LSI’s natural product underrepresented at U-M, such as plant natural products. extract library. A screen of natural products pinpointed several promising results from marine actinomycetes bacteria — “We anticipate extensive interactions with the existing drug spurring an ongoing collaboration with Sherman’s lab. discovery cores at U-M as well as new collaborations with the cryo-EM facility and nuclear magnetic resonance But it’s not enough to simply identify new medicinal spectroscopy core to expand biocatalyst discovery and compounds made by bacteria and fungi. One has to coax engineering efforts,” Sherman says. “This will help us the microbes to produce sufficient quantities of the drug- develop intellectual property at the earliest possible stage like molecules in order to conduct experiments. And they and facilitate identification of leads for ongoing drug have to be modified to improve their effectiveness and also discovery projects.”

LSI MAGAZINE / SPRING 2019 19 HIDING IN PLAIN SIGHT Drug repurposing library will shorten path to new treatments

Nine of out 10 drugs entering clinical trials will fail. Getting a new drug across the finish line is a high-risk, high-reward enterprise that usually takes more than a decade and can cost hundreds of millions of dollars.

This means patients have to wait years for biological discoveries to translate into new, life-saving options in the clinic.

With exploratory funding from the Biosciences Initiative, a group of researchers from U-M aims to shorten that path. Michigan Medicine will team up with Michigan Drug Leisa Thompson Photography Discovery and the Center for Chemical Genomics, located Nick Santoro, Ph.D., analyzes a sample at the U-M Center for at the Life Sciences Institute, to develop a library of Chemical Genomics. compounds that have already been evaluated in clinical trials. Ph.D., director of the Center for Chemical Genomics, “Each drug will have an established safety profile with U-M’s high-throughput screening core. “And it will augment regulatory approval to test in humans, along with our existing small molecule and natural products screening formulation and scale-up manufacturing already figured libraries.” out,” says the project’s lead investigator, Jonathan Sexton, Ph.D., an assistant professor of internal medicine in the The first step will be to purchase an initial set of 5,000 Medical School and of medicinal chemistry in the College compound, including recently discovered entities that are of Pharmacy. “As U-M researchers investigate new biological newer than those typically found in standard library sets. pathways and mechanisms, there’s a good chance these compounds may turn out to be useful in unexpected areas.” The end goal is to make available a complete library of compounds that have already been clinically evaluated or Sexton points to thalidomide — once notorious for causing approved — which would further set U-M apart in the birth defects when used to treat nausea in pregnant women academic drug discovery arena. A recent historical analysis — which has found a second, beneficial life as a cancer by Drug Discovery Today of more than 1,450 FDA-approved drug. There’s also amlexanox, a drug used to treat canker new molecular entities found that U-M was the “largest sores and asthma, which former LSI Director Alan Saltiel, single contributor” among academic institutions. Ph.D., has shown holds promise for treating type 2 diabetes. Only about half of the compounds destined for the new “As Nobel laureate James Black said, ‘The most fruitful library can be purchased, so the rest will need to be produced basis for the discovery of a new drug is to start with an old synthetically, either in-house or with commercial partners, drug,’” Sexton says. Sexton adds.

In drug discovery, a lot of labor and expense goes into “Over 25,000 drugs have entered clinical trials in the U.S., identifying a target, figuring out its mechanism of action, Europe and the Pacific Rim,” says Vincent Groppi, Ph.D., and researching the pharmacology and toxicity of the director of Michigan Drug Discovery. “We will create an compounds. With a repurposing library, however, researchers annotated collection of as many of these drugs as possible begin with a commanding head start since the compounds and make them available to researchers at U-M. This opens have already passed many of the highest initial hurdles. new possibilities for research here, while also helping to deliver new therapies to patients quickly and cost-effectively.” “A highly annotated library like this one is invaluable in accelerating the drug discovery process,” says Andrew Alt,

20 LSI MAGAZINE / SPRING 2019 LET’S TALK SCICOMM Public engagement in the digital age

BY IAN DEMSKY

Attabey Rodríguez Benítez, graduate student, Narayan lab Leisa Thompson Photography

LSI MAGAZINE / SPRING 2019 21 hen the zombie apocalypse comes, chemist In the midst of a rapidly changing media landscape, Raychelle Burks, Ph.D., is going to increased competition for public funding and a growing camouflage herself with death-scented awareness of the lack of diversity within STEM fields, W cologne. It will be made using two natural SciComm efforts can open discussion to a wider range of polyamines — aptly named putrescine and cadaverine. She voices and encourage collaboration between researchers may even save the rest of us if her plan to mass-produce who might not interact in traditional scientific forums. this eau de death using Escherichia coli bacteria pans out. Grad students and postdocs at the U-M Life Sciences And if the undead hordes fail to rise, she will still have Institute are using science communication in a variety of accomplished her goal of inspiring vibrant scientific forms to broaden outreach, convey the importance of basic discussion using pop culture as a jumping-off point. research and inspire future generations of scientists. Beyond helping to organize events like ComSciCon-Michigan, they Burks, an assistant professor at St. Edward’s University, are participating in campus SciComm interest groups, delivered the keynote for ComSciCon-Michigan 2018, a meeting with federal lawmakers, giving media interviews, graduate-student-organized science communications maintaining vibrant social media channels and visiting conference held at the University of Michigan’s Ann Arbor elementary school classrooms — to give just a few examples. campus last summer. She is among a growing vanguard of researchers promoting expanded science communications Roger Cone, Ph.D., vice provost and director of U-M’s — often shorthanded as SciComm — to spur conversation Biosciences Initiative and director of the LSI, believes such among both the scientific community and the general public. efforts are an important aspect of the wider processes for sharing proven scientific findings and studies. “Part of our Raychelle Burks, Ph.D., visits U-M for ComSciCon. job as scientists is to help the public understand the value of the investment they’ve made both in public universities like U-M and in federal institutions like the National Institutes of Health,” he says.

FROM THE LAB TO THE LEGISLATURE Communicating the value of scientific discovery to the public extends to helping public leaders translate such discoveries into effective policy.

Politicians aren’t hearing enough from constituents about the importance of science or of funding research — which can have real-world consequences for human health, for regional economic prosperity and for developing future scientific leaders, says Mary Woolley, president of Research!America, a leading science advocacy group.

Changing political and funding landscapes have inspired more scientists to engage in increased public outreach and activism. The March for Science in April 2017, for example, drew more than 1 million participants across the globe in a unified and vocal pushback against attacks on evidence- based policymaking and threats to drastically slash funding for research.

“Policy isn’t made in the lab,” says U-M graduate student Sarah Kearns, who chaired the ComSciCon-Michigan @DrRubidium via Twitter organizing committee. “We need to clearly communicate

22 LSI MAGAZINE / SPRING 2019 about the science involved — to the people who are affected by these issues, to voters and to the legislators making decisions about them.”

Last fall, Elizabeth Ronan, a doctoral candidate in the U-M Medical School’s Department of Molecular and Integrative Physiology, participated in the American Physiological Society’s “Hill Day,” visiting with lawmakers in Washington, D.C., to discuss the importance of support for academic research. Ronan’s group, which included U-M physiology professor Daniel Michele, Ph.D., met with staff members from several Republican and Democratic members of Congress.

“We went on behalf of APS, but also as individual constituents from each of our respective districts,” says Ronan, who studies sensory biology in the lab of LSI faculty member Shawn Xu, Ph.D. “The staffers seemed very appreciative that we were there to offer a scientist’s perspective. It was clear that scientists don’t meet with them nearly as often as other advocacy groups.”

‘A GREAT EQUALIZER’ Meanwhile, as social media usage grows, the nature of how research is shared and discussed is expanding. Social channels @MicheleLabUM via Twitter have become an increasingly important tool for networking and keeping up with developments in one’s discipline, and Elizabeth Ronan and Daniel Michele, Ph.D., on Capitol Hill have given scientists greater agency in publicizing their research studies. And social media channels like Twitter can amplify not only great research that may get less attention in other “There’s a lot of great science that deserves to be shared, media sources but also voices that have traditionally been beyond just what grabs the biggest headlines in mainstream left out of the scientific conversation. Oleta Johnson, Ph.D. media,” says Kearns (@annotated_sci), who is co-mentored (@oletaknowsstuff), a recent graduate of the U-M Program by Michael Cianfrocco, Ph.D., at the LSI and Kristen in Chemical Biology who is now conducting postdoctoral Verhey, Ph.D., in the Medical School. “Microscopes are research at the University of California, San Francisco, really cool, and telescopes are really cool — and that pure, thinks of it as “a great equalizer.” raw curiosity about the universe should be cultivated more in our society.” “You can have a Laura Kiessling or a Carolyn Bertozzi tweeting at an undergrad or a grad student,” she says. “It makes you feel like you belong to the community of scientists that you admire.”

THERE’S A LOT OF GREAT Johnson joined Twitter as an undergrad — “to keep up “SCIENCE THAT DESERVES TO BE with jokes,” she says — and has since developed a presence SHARED, BEYOND JUST WHAT that champions issues of minority representation in science and social justice causes. GRABS THE BIGGEST HEADLINES. “Existing as a black woman in STEM is inherently a socio- ” political statement, and not by MY choice,” Johnson wrote LSI MAGAZINE / SPRING 2019 23 @AnnaMapp via Twitter

Oleta Johnson celebrates her thesis defense.

in one tweet, amplifying a tweet by #BLACKandSTEM “One of the great things about social media is that it has creator Stephani Page, Ph.D. “Trying to make MY working shifted what gets seen and who gets seen,” Burks says. “And conditions better is not some extracurricular activity. It’s that’s really exciting because, across professions and genres, my survival.” you’re hearing voices and seeing work that weren’t getting highlighted before.” The breadth of voices and experiences available on social media can offer perspectives beyond one’s usual orbit, adds Social media channels also provide an opportunity for Burks (@DrRubidium), whose popular Twitter feed has scientists to discuss their daily activities and the excitement more than 20,000 followers. of making new discoveries in a more personal way, says developmental biologist Yukiko Yamashita, Ph.D. (@ yamashitaflylab), a Howard Hughes Medical Institute investigator and professor at the U-M Medical School and the LSI. ACROSS PROFESSIONS AND “It can give younger people a view of what a scientist’s life “GENRES, YOU’RE HEARING is really like,” she says. VOICES AND SEEING WORK THAT WEREN’T GETTING SCIENCE IN MORE THAN 280 CHARACTERS Of course, while opening science to more audiences, social HIGHLIGHTED BEFORE. media can also provide a forum for knee-jerk reactions, fringe beliefs and even personal attacks on scientists and their research. The peer-review process remains essential in promoting accuracy and transparency in both scientific ” research and reporting.

24 LSI MAGAZINE / SPRING 2019 And even outside of traditional peer-reviewed publishing Making science more accessible is what led Attabey routes, editors still maintain a key role in improving how Rodríguez Benítez, a Program in Chemical Biology student science is communicated effectively. Vikramjit Lahiri, a and member of the Narayan and Smith labs at the LSI, to graduate student in U-M’s Molecular, Cellular and launch her SciComm blog, “Arroz y Habichuelas.” Developmental Biology Department whose mentor is LSI faculty member Daniel Klionsky, Ph.D., found this when In this longer-form venue, Rodríguez Benítez, who hails submitting an article to The Scientist called “Eat yourself from Puerto Rico, explores scientific topics in both Spanish to live: Autophagy’s role in health and disease.” and English — contributing to the availability of accurate science stories in her native tongue. “It took two to three months to write what I thought was a very, very transparent draft,” Lahiri says. “Then the editor “We need to continue to make science more accessible if came back and said the part on the mechanics and basic we want people to understand how it’s important to their biology was too dense. We went through several rounds of lives,” she says. revisions, which was pretty frustrating; but, in the end, I feel that all those changes made it a lot more accessible.”

From left: Yukiko Yamashita, Ph.D.; Sarah Kearns; Attabey Rodríguez Benítez; Elizabeth Ronan; Vikramjit Lahiri Leisa Thompson Photography

LSI MAGAZINE / SPRING 2019 25 26 LSI MAGAZINE /SPRING2019

Leisa Thiompson Photography PERSPECTIVES

IF WE DON’T SIGH, WE DIE

We sigh all the time — when we’re annoyed, discouraged, exhausted or just trying to calm down. But sighing isn’t just useful for expressing emotion; it’s essential for keeping us alive. Sighs are so important, in fact, that they have to be programmed into ventilators to keep patients’ lungs functioning properly.

Peng Li, Ph.D., an assistant professor at the University of Michigan Life Sciences Institute, is probing the neural circuits that control all types of sighing to learn more about how the brain regulates sighs for sentiment versus sighs for survival, and how disruptions in those circuits lead to serious conditions like sleep apnea and sudden infant death syndrome (SIDS).

LSI MAGAZINE / SPRING 2019 27 PERSPECTIVES

Q: Why is sighing so important? During my postdoctoral work, we began investigating A: Our lungs contain hundreds of millions of balloon-like different neuronal types within the breathing control centers structures called alveoli sacs, which are involved in the exchange in the brain, to determine their role in controlling breathing. of oxygen and carbon dioxide. But these sacs can collapse; We identified about 200 neurons in the brain stem expressing and if too many collapse, the lungs no longer function properly. a particular neuropeptide, a molecule that neurons use to Sighing reopens the alveoli, and so we need to sigh about once communicate with each other. Interestingly, the receptor of every five minutes just to maintain normal pulmonary this neuropeptide is expressed in a small group of neurons function. We don’t have to think about these so-called basal in the breathing pacemaker region. We thought this sighs. They just continue autonomously, in addition to our neuropeptide pathway may underlie some function in intentional sighs. Misregulated sighing is also implicated in controlling breathing. When we injected the neuropeptide disorders like chronic anxiety disorder and SIDS. into the breathing pacemaker region, we discovered that it induced elevated sighing without affecting normal breathing. That told us that this neural circuit has a dedicated function Q: What inspired you to start studying sighing? in controlling sighing. And that’s how we got into sighing. A: We came to study sighing somewhat by chance. I’m interested in how the brain controls breathing, more broadly. We breathe about 20,000 times per day, maintaining our Q: What major questions is your lab tackling at the LSI? body homeostasis. And to a certain extent, we also have A: There are a couple of research directions we are pursuing voluntary control over our breathing, like when we hold to better understand how the brain controls breathing, and our breath. Our breathing also changes in response to how breathing is regulated by various biological and certain emotions and even in response to activities like emotional conditions. talking, swallowing, laughing, coughing, crying — for all of these, our breathing pattern has to adjust in response to Just like regular breaths, sighs occur without us having to other behaviors. It’s a really unique function of our body, think about them, and are also regulated by our states — such at the intersection of physiology and neuroscience. as emotion- or stress-induced sighing. So sighing is not just

Molecular dissection of a brain center that regulates homeostasis Peng Li, LSI

28 LSI MAGAZINE / SPRING 2019 PERSPECTIVES

an essential physiological function of our body, but also can serve as emotional or social interaction signals between individuals.

With the sigh circuit we discovered, now we can trace up to study how sighing is regulated by different inputs. We found that the neuropeptide pathway that underlies basal sighing also mediates emotion-induced sighing. In addition, there is another input pathway that can control our sighs only in response to emotional or stress cues, and it does not affect basal sighs.

We now want to figure out how sighing is regulated by different inputs and neural circuits in various conditions. To this end, we are using cutting-edge technologies to trace and manipulate the neural circuits to determine what kind of inputs the neurons are receiving from other parts of the brain

to control sighing. This approach may allow us to identify egyjanek/shutterstock

behavioral circuits in the brain that have previously resisted Consistent sighs must be programmed into ventilators to keep identification, due to difficulties in modeling certain human patients’ lungs functioning properly. behaviors in the mouse.

In addition to sighing, my lab is generally interested in Q: What are the challenges of this type of research? understanding how breathing behaviors are controlled in A: One challenge in understanding how breathing is different physiological and emotional contexts and delineating modulated — and how it is impaired in various pathological the different cell types and molecular pathways in the conditions — is our lack of knowledge about which neuron breathing control circuit. Our discovery on the neural circuit types control breathing, and how they function. Many regions for sighing demonstrates that breathing control is genetically in the brain stem are critical in controlling breathing. And and molecularly tractable. We hypothesize that there are unlike other brain regions that have a clear structure, the other discrete neurons and circuits dedicated to controlling brain stem contains diverse neural populations intermingled other breathing behaviors. with each other, often with no clear boundary between different neuron types.

With the recent advances in molecular biology and neurogenetics, though, we can now begin to study neuron populations with greater precision. We can genetically target only a couple hundred neurons in the entire mouse brain to SIGHING IS NOT JUST AN visualize their activity during behaviors, explore what other “ESSENTIAL PHYSIOLOGICAL neurons they listen to and talk to, and test their function by FUNCTION OF OUR BODY, BUT manipulating their activity. This will lead to a better understanding of the neural types and circuits involved in ALSO CAN SERVE AS EMOTIONAL controlling various aspects of breathing. OR SOCIAL INTERACTION SIGNALS BETWEEN INDIVIDUALS. Our hope is that if we find the molecular pathways that underlie this essential behavior, we can discover potential targets that could be manipulated to relieve breathing-related disorders, like SIDS or sleep apnea. ” Interview by Emily Kagey

LSI MAGAZINE / SPRING 2019 29 HAIL TO THE VICTORS FOR DISCOVERY

n late 2018, the University of Michigan wrapped up the results — from helping high school and undergraduate five-year Victors for Michigan campaign that shattered students discover a love of science to supporting faculty records for fundraising at a public university. members in their pursuit of novel discoveries that advance I human health and society. Thanks to the tremendous generosity of donors, the U-M Life Sciences Institute raised more than $30 million during the campaign, enabling the creation of innovative EDUCATION educational and research programs, and allowing the LSI to Diversifying STEM: Aspirnaut at Michigan support its trainees with best-in-class resources to accelerate The LSI is getting ready to bring on its second summer their careers. cohort of Aspirnauts, high school students from under- resourced school districts across Michigan who spend six “We’re grateful to have such an amazing group of weeks conducting research internships in LSI labs. The philanthropists, many of them scientific leaders in their students live on campus and participate in college counseling, own right, who share our passion for bold, innovative standardized test preparation and social activities. Two discovery, for improving human health and for creating undergraduate students also serve as mentors and chaperones transformative educational experiences,” says LSI Director while participating in the six-week research internship. Roger Cone, Ph.D. “I love being in the lab, and that has been a really big “The energy and opportunities generated by these new realization for me during this program,” says Katie Emery, resources and programs has just been tremendous,” he adds. who participated in the program as both a high school Many of the campaign gifts are already delivering exciting student and then a mentor.

Aspirnaut students are welcomed to the LSI during a white-coat ceremony. From left: Martin Philbert, Ph.D; Roger Cone, Ph.D.; Selena Pacheco; Esperanza Gonzales; Diogenes Lopez-Urioso; Mack Williams; Miriam Li; Amarri Johnson; Cammy Truong; Katie Emery; Julie Hudson, M.D.; Billy Hudson, Ph.D. Stephanie King, LSI

30 LSI MAGAZINE / SPRING 2019 VICTORS FOR DISCOVERY

Jim Flynn and his wife, Kerianne, have supported the In most cases, graduate tuition is paid by faculty members, program for a three-year launch. using grant funding or startup funds. In 2018, the LSI Leadership Council collectively made gifts to improve Summer science jobs: Rosen Fellows financing mechanisms for graduate students at the LSI and Terry Rosen, Ph.D., and his wife, Victoria, have funded a make U-M more competitive with top peer institutions, fellowship to support undergraduate students working in many of which pay some or all of the tuition costs for their LSI labs over the summer, with a preference for students graduate students. placed through the U-M Undergraduate Research Opportunities Program (UROP). The program provides a To date, the Graduate Student Support Fund is sufficient to stipend to allow students to continue working on research provide tuition for one grad student per lab, per year. The projects, rather than seek nonacademic summer jobs. institute is continuing to fundraise for graduate students beyond the Victors for Michigan campaign. “I have gained a great community of people in the LSI, who motivate and inspire me to pursue more both academically Connecting students to the scientific community: David and personally,” says neuroscience major Erkina Sartbaeva, and Michelle Kroin Family Scholarship Fund reflecting on her Rosen Fellow experience in 2017. To open opportunities and enrich the LSI experience for more young researchers, David and Michelle Kroin created Fueling discovery: Graduate students a fund that provides scholarships to graduate students and At any given time, approximately 60 graduate students are postdocs to participate in their larger research communities gaining valuable lab experience in the LSI, working under through scientific conferences. Nearly 20 early-career the guidance of the institute’s faculty members in pursuit scientists have attended a conference with support from of a Ph.D. from U-M’s Rackham Graduate School, and this program, meeting mentors, hearing new research and ultimately a career as a high-impact scientific leader in presenting their work. academia or industry.

Vikram Shende, a graduate student in the Sherman lab, received funding from the David and Michelle Kroin Family Scholarship Fund to present his research at an international conference. Stephanie King, LSI Scott C. Soderberg, Michigan Photography

LSI MAGAZINE / SPRING 2019 31 VICTORS FOR DISCOVERY

RESEARCH Leading the charge: Future faculty Paul and Susan Meister have made a substantial commitment to faculty support.

“We appreciate the Meisters’ tremendous support of the LSI and ongoing commitment to our research and education programs,” Cone says.

Understanding cancer: Margolies Discovery Fund In the lab of Stephen J. Weiss, M.D., who studies the molecular underpinnings of cancer and metastasis, philanthropic support from Yoshiko and Greg Margolies has led to key discoveries related to cancer, particularly to the molecular mechanisms of metastasis. The Weiss lab developed a new strategy for producing anticancer antibodies — a very promising potential therapy that uses a patented method to specifically target the ability of cancerLeisa Thompson Photography cells to metastasize.

Seeding innovation: Klatskin-Sutker Discovery Fund With support from the Klatskin-Sutker Discovery Fund — established by a philanthropic gift from Charles and Lynne Klatskin and their daughter and son-in-law, Deborah Ian Demsky, U-M Klatskin and Burton Sutker, M.D. — two LSI faculty May-Walt Life Sciences Fellow Brittany Morgan, Ph.D., with David R. Walt, Ph.D. members are advancing innovative projects with great potential, and a third project is set to be announced soon. Launching leaders: May-Walt Life Sciences Fellows A novel “super-postdoc” program at U-M is preparing In the first project funded by this program, LSI faculty exceptional early-career researchers to launch successful member Alison Narayan, Ph.D., created the first known independent research careers, thanks to a leading gift from Michele D. May and David R. Walt, Ph.D. Deborah Klatskin and Burton Sutker, M.D.

The Michigan Life Sciences Fellows program is a multi- department program that attracts top postdoctoral fellows to U-M by providing robust professional development and funds to support independent research.

As part of the program, the first May-Walt Life Sciences Fellow, Brittany Morgan, Ph.D., is conducting research at the LSI into signaling biology in triple negative breast cancer, with the goal of opening new therapeutic avenues for cancers that are resistant to first-line treatments.

Additional funding in the LSI is provided through a bequest from Michigan alumna Rita L. Willis (AB ’45), who established an endowed fund in honor of her father, U-M alumnus Sidney Morse Willis. Photo courtesy of Deborah Klatskin and Burton Sutker

32 LSI MAGAZINE / SPRING 2019 VICTORS FOR DISCOVERY Daryl Marshke, Michigan Photography

From left: David Sherman, Ph.D.; Roger Cone, Ph.D.; Alan Saltiel, Ph.D; and George Church, Ph.D, at the 2017 Saltiel Life Sciences Symposium. library of chemicals containing guanidine, a compound possible by the generous support of the LSI’s faculty, produced by microorganisms — and notoriously difficult Leadership Council, Scientific Advisory Board and to work with in the lab. Narayan’s library makes possible friends. The name recognizes the leadership and scientific research into new potential drugs for treating epilepsy, contributions made by former LSI Director Alan R. cardiac arrhythmias and central nervous system disorders. Saltiel, Ph.D., during his 13-year tenure.

The fund also is supporting researchers in the lab of LSI Sparking international collaboration: Kaplan Scholars faculty member Bing Ye, Ph.D., to create a legion of fruit Later in 2019, researchers from U-M and Israel will begin flies to advance understanding of Down syndrome. collaboratively assembling a library of compounds made naturally by microorganisms collected in the deserts and The cause of Down syndrome — an extra copy of seas of Israel to use in the discovery of new drugs. The chromosome 21 — has long been known. But much less project is funded by the David and Meredith Kaplan is known about which of the 200 genes on chromosome Michigan-Israel Visiting Scholars program, which 21 drive the specific conditions that affect patients with stimulates research in life sciences by supporting one or Down syndrome. more researchers from U-M at the Weizmann Institute of Sciences or the Technion-Israel Institute of Technology in Ye’s lab developed different strains of the common model Israel — or supporting researchers from the Weizmann system Drosophila melanogaster, or fruit flies, each Institute of Sciences or the Technion-Israel Institute of representing a different gene mutation on chromosome 21, Technology at U-M. to connect physical conditions to gene mutations. Identifying which genes may be responsible for the various conditions Other gifts received during this record-breaking campaign will help make further research in mammals more efficient. are funding the LSI Cubed program that supports trainee-led projects spanning multiple LSI labs, the LSI Carrying the conversation: Saltiel Life Sciences Grads Group, the Innovation Partnership, international Symposium collaborations and many other resources that make the In 2016, the annual LSI symposium was named the Saltiel LSI the singular scientific community it is today. Life Sciences Symposium thanks to an endowment made

LSI MAGAZINE / SPRING 2019 33 34 ENGINEERING PROTEIN & BiologicalDesign PALMER COMMONS SEPTEMBER 25,2O19 SALTIEL SYMPOSIUM LIFE SCIENCES FREE ANDOPENTOTHEPUBLIC myumi.ch/lsi-protein-engineering VICTORS FORDISCOVERY LSI MAGAZINE /SPRING2019 Odra Noel

Stephanie King, LSI VOICES OF THE FACULTY EXPANDING OPPORTUNITIES REQUIRE EXPANDED SUPPORT FOR GRADUATE STUDENTS BY ANNA MAPP

n 2018, the National Academies of Sciences, Although the career paths are disparate, there are common Engineering, and Medicine (NASEM) issued a report skills that link them and that are core components of the outlining how the U.S. graduate education system can Ph.D. itself: critical thinking, speaking, writing, working Ibetter respond to the needs of its students, and to the effectively in diverse teams, creative problem-solving. But nation’s need for well-trained scientists across academia, there also are skills and experiences that are unique to government, industry and other sectors. each field. A strategy that I recently adopted is to complete a mentoring agreement with each new student who joins the Opportunities for doctoral scientists in the government and lab. The Program in Chemical Biology, based in the LSI, is industry sectors have rapidly expanded in recent decades now implementing a program-wide mentoring agreement — as has the realization that a scientific Ph.D. offers great that will serve as a framework and living document for each benefits to employees and employers across a range of student — one that will facilitate productive conversations fields. This broadening of options is reflected in the careers with their mentor and thesis committee members. that graduates are pursing after earning their Ph.D., with more than half now entering fields beyond academia. Graduate students are an essential element of the LSI’s research mission, and supporting them is critically important to the growth of scientific discovery and to academia’s wider impact on the society we serve. Right now, graduate student support GRADUATE STUDENTS ARE AN comes largely from individual faculty members’ funding from ESSENTIAL ELEMENT OF THE LSI’S federal agencies. Yet current funding restrictions are making it “ increasingly challenging for us to give students the full support RESEARCH MISSION. and experience needed to prepare them to lead their fields.

The NASEM report calls for graduate education to be Today’s students have opportunities to drive advancements fundamentally reoriented to focus on helping graduate in academic research, the national economy and the students “develop skills to advance the frontiers of discovery, overall scientific enterprise — ”and our approaches to contributing to the growth of the U.S. economy, its national helping them reach the top of their scientific fields, in all security, and the health and well-being of its people.” sectors, have to keep pace. That type of focus will require a combination of At the Life Sciences Institute, we are committed to developing greater financial and programmatic support from their the next generation of scientific leaders, and that starts institutions, as well as more specific support from their with helping graduate students discover a path to scientific mentors to prepare them to become the next generation excellence and leadership. In response to the growing career of scientific leaders. landscape, for example, I have worked to evolve my mentoring approach to more proactively help students build strengths Anna Mapp, Ph.D., is a chemical and skills appropriate for their career path. When someone biologist and a professor at the is interested in joining my research group, one of my first University of Michigan Life Sciences questions is always about their career goals. These goals will Institute and in the Department of help shape their decision-making process, the type of science Chemistry at the U-M College of they pursue and the skills we need to focus on building. Literature, Science, and the Arts. She is also the director of the U-M Currently, students in my lab have interests ranging from Program in Chemical Biology. academia to industry, from education to entrepreneurship. Leisa Thompson Photography

LSI MAGAZINE / SPRING 2019 35 PROFILES PROFILES ADVANCING BOLD SCIENCE — AND SCIENTISTS

There was a time Janet Smith thought science just wasn’t “Learning how to manage a group of people is one thing; for her. As a chemistry major in college, she had no plans first you need to learn how to be a scientist,” Smith says. to pursue graduate school until her senior year, when a “And probably the most important part of becoming a seminar on protein evolution sparked an interest in scientist is learning how to run a project.” biochemistry and her advisor urged her to apply for Ph.D. programs. Even after earning her doctorate in biochemistry, That’s why everyone in Smith’s lab has their own project, she still did not see herself running a lab in academia. and why so many trainees leave her lab prepared to drive innovative, forward-thinking science. “But then I got a good postdoc position with someone who’s a leader in the field,” Smith recalls, “and I learned a “Janet treated me more like a colleague than a graduate heck of a lot.” student,” recalls John Tesmer, Ph.D., one of Smith’s first graduate students and eventually her colleague as a professor Once Smith embarked on her independent research career, at the Life Sciences Institute, before returning to Purdue she quickly established herself as one such leader in her University as a professor of biological sciences. “She gave me field. In addition to developing novel structural biology a great project, and she let me become the owner of it, which methods, her lab has solved the structures of nearly 200 made me fearless about future projects.” proteins — including a cellular protein that fights the human immunodeficiency virus (HIV), and proteins that The effects of Smith’s mentoring have rippled far beyond her allow Dengue fever, West Nile fever and the Zika virus to own lab, extending to her colleagues. As the assistant director replicate and spread infection. of the LSI, she guides mentoring and career advancement activities for junior faculty members at the institute. “One of these structures has opened a whole new area of flavivirus biology,” Smith says. “It doesn’t look like any other She’s also lending her expertise in leading shared resource protein, so it was not previously possible to even make a projects — through her work with the Argonne National hypothesis about what it was doing.” Laboratory’s Advanced Photon Source and as the director of the LSI’s Center for Structural Biology — to a new Now, with the 3-D structure Smith’s lab defined, researchers project to expand the LSI’s nationally leading cryo-EM are discovering new and unexpected functions for the protein. program, funded by the U-M Biosciences Initiative.

Beyond defining novel protein structures and activity, Smith “Janet has always been a source of terrific professional advice,” is known for another central aspect of her research program: Tesmer says. “And if you’re going to advance as a scientist her mentoring. and as an academic, you need someone like that. She has the experience, and she knows how to be successful.” “I’m proud of the advances we’ve made in the science — and I’m proud of the students,” she reflects. “I’ve had the opportunity to train some really fantastic students.”

In just the past year, Smith’s graduate students have gone on to postdoctoral positions at the Dana-Farber Cancer Institute, Harvard Medical School and the Massachusetts Institute of Technology.

Her approach to mentoring derives from her experiences as a graduate student. When selecting a graduate lab and project, she knew that having her own project would better prepare her to take ownership of her research in the future. Janet Smith, Ph.D. Stephanie King, LSI TENURED FACULTY PROFILE

36 LSI MAGAZINE / SPRING 2019 PROFILES

FINE-TUNING DRUG DISCOVERY

After enrolling in U-M’s pharmacology graduate program, Alt’s desire to answer novel research questions at a molecular level led him to the lab of John Traynor, Ph.D.

“We both were, and still are, interested in how drugs work at the very fundamental level of cells and proteins,” says Traynor, who is now the associate chair of research and Edward F Domino Research Professor of Pharmacology in the U-M Medical School, and a professor of medicinal chemistry in the U-M College of Pharmacy. “Andy is very bright and very enthusiastic. So when the two of us got together, the research raced off.” Andy Alt, Ph.D.

Stephanie King, LSI The same ambition that drove his research throughout graduate school and 15 years in the pharmaceutical industry In Andy Alt’s office at the University of Michigan Life Sciences ultimately brought Alt back to U-M, to advance cutting- Institute, two rows of caps form a visual résumé for the edge drug discovery projects at the LSI’s Center for Chemical scientist — graduate school at U-M, postdoc at Indiana Genomics. The center provides high-throughput screening University, and then an extensive stint working with some of small molecules and natural product libraries for drug of the pharmaceutical industry’s biggest names (Eli Lilly, discovery projects. Pfizer, Bristol-Meyers Squibb) before returning to U-M to lead the LSI’s Center for Chemical Genomics. Drawing on his years of experience in industry, Alt is expanding the scope and reach of the center to help accelerate Throughout each of those cap changes, Alt has been driven drug discovery projects across the university — where he by an ambition to translate new knowledge into innovative sees the greatest opportunity for more experimental research therapeutic solutions. that can lead to groundbreaking discoveries.

“I want to work on projects that involve really novel mechanisms, truly different drugs,” Alt explains. “As a scientist, that is what’s most interesting to me, because it feels like I’m having a tangible impact on the world.” MORE AND MORE, I THINK THE “HIGH-RISK, HIGH-REWARD It was this ambition that first led Alt, then a college senior RESEARCH IS GOING TO BE DONE majoring in psychology and violin performance, to start conducting pharmacology research. IN ACADEMIA.

During a chance conversation with his behavioral pharmacology professor, Alt mentioned his two majors. The professor thought that Alt’s manual dexterity from playing “More and more, I think the high-risk, high-reward research violin would be a great fit for the small-animal surgery his is going to be done in academia,” Alt says. “We have” the lab conducted, studying the effects of a blood pressure flexibility here to work on projects that are more likely to medicine. He immediately recruited Alt to join the lab. have a massive impact on patients’ lives. And at the end of the day, that’s what I want to work on.” “That was my introduction to doing scientific research,” Alt says. “And for the first time, I realized that we were working on questions that nobody knew the answer to. All of a sudden, the work felt more meaningful and more important.” RESEARCH FACULTY PROFILE

LSI MAGAZINE / SPRING 2019 37 PROFILES

THE SIGNIFICANCE OF STRUCTURE in cultivating a diverse workforce, improving professional development for women and broadening access for individuals from underrepresented groups. To help young scientists build stronger paths to higher education and careers in STEM (science, technology, engineering and math) fields, she mentors middle and high school students from under- resourced communities in Detroit.

And in 2018, Sanders and classmate Omari Baruti, a fellow researcher in the Mapp lab, co-founded STEM in Color at U-M. The student-run group provides its 200-plus participants with a scholarly and professional space tailored to serving the academic and professional needs of students from diverse backgrounds. Melody Sanders

Stephanie King, LSI “How can we equip and empower our participants with tools to address things like identity issues, and micro- and macro- Ask Melody Sanders what drew her to study the protein aggressions? These are things that we’re going to encounter, complexes that activate genes, and she will tell you it was a and there’s very little training on how to address them,” fascination with structure. Sanders says. “We want to provide that training.”

“I like to understand how structure influences function, Sanders’ activism is motivated by her desire to make a because it is critical to every single process,” explains the meaningful contribution to her society and community. But, fourth-year graduate student in the University of Michigan’s more directly, she also knows that this work will improve Program in Chemical Biology. the chances of success for herself and, eventually, for her three children. Her understanding of the role that structure plays in biological processes has enabled Sanders to forge a research project that spans the fields of biochemistry and cryo-electron microscopy. I LIKE TO UNDERSTAND HOW Working jointly in the labs of Anna Mapp, Ph.D., and STUCTURE INFLUENCES FUNCTION, Melanie Ohi, Ph.D., at the U-M Life Sciences Institute, she “ BECAUSE IT IS CRITICAL TO EVERY is elucidating the architectural dynamics that enable proteins to turn genes on and off, so that individual cells function SINGLE PROCESS. properly. Defects in the specific proteins she is studying have been found in leukemia and other forms of cancer. By understanding how their form and organization impact “There are institutional barriers that may not allow me to do function, Sanders hopes to shed light on how structural science in a way that someone from a different group can defects can lead to human diseases. — and until I can address those, I cannot effectively” do science to my maximum potential,” she explains. “This is a change Ask Sanders about her activism, and you’ll discover again that is necessary for myself, it is necessary for my colleagues, that it’s all about structure. and it’s necessary for my family.”

Outside the lab, she is examining societal and institutional And how does she make room for her research, her scholarship structures that create barriers to success — and finding ways and her activism? to remove these barriers. “Structure,” she says. “Structure is so important.” Sanders leads workshops to guide various industry groups STUDENT PROFILE

38 LSI MAGAZINE / SPRING 2019 PROFILES

EXPLORING THE UNEXPECTED In Bethany Strunk’s lab at Trinity University, researchers While in Weisman’s lab, Strunk began her deeper exploration are investigating a type of lipid-modifying enzymes in yeast of lipid-modifying proteins, while training undergraduate — not for their ability to target lipids, but for what Strunk and graduate students in the lab. calls their “unexpected roles.” “Beth’s postdoctoral studies were ambitious and innovative,” “These proteins tend to take on additional roles in the cell, says Weisman, who is also a professor of cell and and in some cases these other roles are at least as important developmental biology in the U-M Medical School. “And as their lipid-modifying functions,” she explains. “So we her passion for research is matched by her dedication to are exploring how — even though we think of them as training and mentoring.” lipid-targeting enzymes — some of their most influential functions might come from the way they interact with At Trinity, Strunk is now using those passions to develop other proteins in the cell.” her own student-centered research program, where undergrads can drive innovative research while receiving In many ways, this openness to exploring unexpected roles hands-on mentoring and instruction. is what led Strunk to her current position as an assistant professor of biology at Trinity University. And like her approaches to research and teaching — which have been fed by her wide-ranging experiences in the lab, Strunk’s interest in science began during outdoor walks in Tanzanian classrooms and in simply observing nature with her father when she was a child. — Strunk’s dedication to mentoring is inspired by her experiences with devoted mentors. “He would bring home weird insects, frogs, turtles — I think it just got me kind of obsessed with wildlife and “So many of my successes have come from applying myself nature,” she recalls. in ways I never would have attempted without the encouragement of my mentors,” she explains. “I have been That obsession stayed with Strunk as she began college, so fortunate to have mentors who demanded that I aim planning to become a wildlife veterinarian. But as she took much higher than even my own expectations.” more advanced classes examining different scientific subjects, her interests continued to zoom in — from whole-animal By building a cutting-edge research program for health to the molecular interactions taking place within undergraduate students, she now hopes to similarly motivate cells. She followed those changing interests, eventually future scientists to continue exploring the unexpected. switching her major to biochemistry.

“Something about the problem-solving aspect of biochemistry fascinated me,” she says. “The idea of being able to look at some phenomenon and determine how it worked down to the molecular level really hooked me.”

Strunk knew she wanted to pursue graduate school after finishing college, but first she had another role she wanted to explore: serving in the Peace Corps, where she spent four years teaching high school science in Tanzania.

Her explorations eventually led Strunk to the University of Michigan’s Program in Chemical Biology, where she earned her Ph.D., and then to the lab of Life Sciences Institute faculty member Lois Weisman, Ph.D., for a postdoctoral fellowship. Bethany Strunk

ALUM PROFILE Bethany Strunk, Ph.D., (right) in her lab with research students Alejandra Muñoz-Rivera (left) and Hannah Reeves (center)

LSI MAGAZINE / SPRING 2019 39 40 THE LSI INSIDE LSI MAGAZINE /SPRING2019

Stephanie King, LSI INSIDE THE LSI

LSI FACULTY

M.D. LSI Ph.D. LSI Ph.D. LSI MED MED LSA HHMI MED

Vivian Cheung Michael Cianfrocco Roger D. Cone Research Professor Research Assistant Professor Mary Sue Coleman Director Research Professor

Frederick G.L. Huetwell Professor Assistant Professor of Biological Vice Provost and Director, U-M of Pediatrics and Communicable Chemistry, Medical School Biosciences Initiative; Professor Diseases, Professor of Human of Molecular and Integrative Genetics, Medical School; Physiology, Medical School; Howard Hughes Medical Institute Professor of Molecular, Cellular, Investigator and Developmental Biology, College of Literature, Science, and the Arts

Research areas: RNA biology, Research areas: cryo-electron Research areas: neurobiology genetics, neurodegeneration microscopy, single molecule of obesity, energy homeostasis, methods, biochemistry, intracellular cachexia, anorexia nervosa transport

M.D. LSI M.D., Ph.D. LSI Ph.D. LSI Ph.D. LSI MED MED LSA MED HHMI

David Ginsburg Ken Inoki Daniel J. Klionsky Cheng-Yu Lee Research Professor Research Associate Professor Research Professor Research Associate Professor

James V. Neel Distinguished Roger C. Wiggins Collegiate Alexander G. Ruthven Professor of Robert H. Bartlett Collegiate University Professor of Internal Professor in the Life Sciences; Life Sciences; Professor of Professor in the Life Sciences; Medicine, Human Genetics and Associate Professor of Internal Molecular, Cellular and Associate Professor of Internal Pediatrics, Warner-Lambert/ Medicine and Molecular and Developmental Biology, College of Medicine, and Cell and Parke-Davis Professor of Medicine, Integrative Physiology, Medical Literature, Science, and the Arts Developmental Biology, Medical Medical School; Howard Hughes School School Medical Institute Investigator

Research areas: hematology, Research areas: metabolism, Research areas: autophagy, cell Research areas: stem cells, blood clotting, genetics mTOR pathway signaling, biology neurological disease nephrology

Tools & Model Systems

Computational biology Cryo-EM Drosophila Mice Stem cells Yeast Zebrafish Leisa Thompson Photography

LSI MAGAZINE / SPRING 2019 41 INSIDE THE LSI

LSI FACULTY

Ph.D. LSI Ph.D. LSI Ph.D. LSI Ph.D. LSI DENT MED LSA LSA MED MED

Peng Li Jiandie Lin Anna Mapp Rowena Matthews Research Assistant Professor Research Professor Research Professor Research Professor Emerita

Assistant Professor of Biologic and Bradley M. Patten Collegiate Edwin Vedejs Collegiate Professor G. Robert Greenberg Distinguished Materials Sciences, Dental School; Professor in the Life Sciences; of Chemistry, College of University Professor Emerita of Assistant Professor of Molecular Professor of Cell and Literature, Science, and the Arts; Biological Chemistry, Medical and Integrative Physiology, Developmental Biology, Medical Director, Program in Chemical School; Professor Emerita of Medical School School Biology Chemistry and Research Professor Emerita of Biophysics, College of Literature, Science, and the Arts

Research areas: molecular Research areas: obesity-associated Research areas: synthetic organic Research areas: vitamin-derived neuroscience, breathing and sighing metabolic disease, signaling and chemistry, chemical biology, cofactors in the catalysis of gene transcription, metabolic tissue molecular biology complex chemical reactions development

Ph.D. LSI Ph.D. LSI Ph.D. LSI Ph.D. LSI LSA MED LSA LSA MED MED PHARM

Alison Narayan Melanie Ohi David H. Sherman Janet L. Smith Research Assistant Professor Research Associate Professor Research Professor Associate Director Research Professor

Assistant Professor of Chemistry, Rowena G. Matthews Collegiate Hans W. Vahlteich Professor of Margaret J. Hunter Collegiate College of Literature, Science, Professor in the Life Sciences; Medicinal Chemistry, College Professor in the Life Sciences; and the Arts Associate Professor of Cell and of Pharmacy; Professor of Professor of Biological Chemistry, Developmental Biology, Medical Microbiology and Immunology, Medical School; Professor of School Medical School; Professor of Biophysics, College of Literature, Chemistry, College of Literature, Science, and the Arts; Director, Science, and the Arts Center for Structural Biology

Research areas: biocatalysis, Research areas: cryo-electron Research areas: natural product Research areas: X-ray complex molecule synthesis, microscopy, biochemistry, genetics biosynthesis, synthetic organic crystallography, viruses and natural products chemistry, marine microorganisms, infectious disease, drug discovery drug discovery

Tools & Model Systems

Cryo-EM Mice Natural products Stem cells X-ray crystallography Yeast Leisa Thompson Photography

42 LSI MAGAZINE / SPRING 2019 INSIDE THE LSI

LSI FACULTY

Ph.D. LSI Ph.D. LSI M.D. LSI Ph.D. LSI LSA MED MED MED

Wenjing Wang Lois Weisman Stephen J. Weiss Jun Wu Research Assistant Professor Research Professor Research Professor Research Assistant Professor

Assistant Professor of Chemistry, Sarah Winans Newman E. Gifford and Love Barnett Upjohn Assistant Professor of Molecular College of Literature, Science, Collegiate Professor in the Life Professor of Internal Medicine and and Integrative Physiology, and the Arts Sciences; Professor of Cell and Oncology; Director, Postdoctoral Medical School Developmental Biology, Medical Research Training Program, School Medical School; Associate Director for Basic Science Research, U-M Comprehensive Cancer Center

Research areas: chemical biology, Research areas: organelles, Research areas: cancer, Research areas: “beige” thermo- protein engineering, neuroscience, neurodegeneration metastasis, stem cell functions, genic fat cells, metabolism optogenetics angiogenesis, inflammation

Ph.D. LSI Ph.D. LSI Ph.D. LSI Ph.D. LSI MED LSA MED MED MED HHMI

X.Z. Shawn Xu Zhaohui Xu Yukiko Yamashita Bing Ye Research Professor Director, Undergraduate Training Research Professor Research Associate Professor Research Associate Professor

Bernard W. Agranoff Collegiate Associate Professor of Biological James Playfair McMurrich Burton L. Baker Collegiate Professor in the Life Sciences; Chemistry, Medical School; Collegiate Professor in the Life Professor in the Life Sciences; Professor of Molecular and Associate Professor of Biophysics, Sciences; Professor of Cell and Associate Professor of Cell and Integrative Physiology, Medical College of Literature, Science, Developmental Biology, Medical Developmental Biology, Medical School and the Arts School; Howard Hughes Medical School Institute Investigator

Research areas: sensory Research areas: structural Research areas: stem cells, Research areas: neuronal transduction, synaptic mechanisms biology, protein folding, molecular developmental biology, cell division development, neurodevelopmental underlying behavior and addiction, chaperones and differentiation diseases aging and longevity

Tools & Model Systems

C. elegans Cancer cells Drosophila Mice Stem cells X-ray crystallography Yeast Leisa Thompson Photography

LSI MAGAZINE / SPRING 2019 43 INSIDE THE LSI

LSI AFFILIATE FACULTY

Ph.D. LSI Ph.D. LSI Ph.D. LSI MED MED LSA MED

Ryoma “Puck” Ohi Carole Parent Matthew Soellner Adjunct Research Associate Professor Adjunct Research Professor Adjunct Research Assistant Professor

Associate Professor of Cell and Raymond W. Ruddon Collegiate Research Assistant Professor of Developmental Biology, Medical Professor of Cancer Biology Internal Medicine, Medical School; School and Pharmacology, Professor of Assistant Professor of Chemistry, Cell and Developmental Biology, College of Literature, Science, Medical School and the Arts

Research areas: mitosis, Research areas: cancer biology, Research areas: bioorganic cytokinesis, microtubules, cell biology, pharmacology, chemistry, chemical biology, reconstitution chemotactic signaling organic chemistry

Tools & Model Systems

Cancer cells Dictyostelium Mammalian cells Mice

BEHIND THE SCENES Victoria Orr and Jeanne Stuckey, Ph.D., analyze a western blot in the Center for Structural Biology. Leisa Thompson Photography

44 LSI MAGAZINE / SPRING 2019 INSIDE THE LSI

HONORS & AWARDS

Roger Cone Daniel Klionsky Jiandie Lin Elected to the American Academy of Arts Elected to the American Academy of Arts Elected Fellow of the American Association and Sciences and Sciences for the Advancement of Science

Alison Narayan Melanie Ohi Shawn Xu Named 2019 Sloan Research Fellow; 2019 Elected Director of Biological Sciences for Elected Fellow of the American Association Cottrell Scholar Award recipient the Microscopy Society of America for the Advancement of Science

Zhaohui Xu Yukiko Yamashita Carole Parent Appointed LSI Director of Undergraduate Howard Hughes Medical Institute Elected Fellow of the American Association Training Investigator renewed appointment for the Advancement of Science Leisa Thompson Photography

LSI MAGAZINE / SPRING 2019 45 YEAR IN PHOTOS All photos by Stephanie King unless otherwise noted

Expanding educational programs High school students in the newly expanded Aspirnaut program pose for a selfie. Leisa Thompson Photography

Undergrads in the lab New efforts, including naming a director of undergraduate education, will bolster the experience of undergrads at the LSI.

Strengthening diversity Collaboration, cubed Graduate students Omari Baruti and Melody Sanders receive an award Graduate students Amy Fraley and Tyler Beyett for STEM in Color, a professional development organization focused on used a new cross-lab grant program, LSI Cubed, to supporting students from diverse backgrounds. investigate a natural product’s impact on a pathway linked to cardiac hypertrophy. 46 LSI MAGAZINE / SPRING 2019 One wild ride Outreach Halloween is always the peak of the LSI social calendar. In 2018, the Postdoc Jon Nelson shares the excitement of science with Operations team stole the show with their roller-coaster costume. children at the Ann Arbor Hands-On Museum.

Leadership in cryo-EM Last June, the LSI held its first hands-on cryo-EM workshop for academic and industry scientists from across the country.

Bringing thought-leaders to campus Baldomero Olivera, who studies cone snail venom in search of new therapeutics, was one of more than a dozen luminary scientists invited to campus in 2018.

LSI MAGAZINE / SPRING 2019 47 The Power of One The 2018 Saltiel Life Sciences Symposium explores the frontiers of single cell biology.

Lift off Graduates of the Program in Chemical Biology’s master’s degree program were among the many students in the LSI community to earn degrees last year.

48 LSI MAGAZINE / SPRING 2019 ADVISORY BOARDS

LEADERSHIP COUNCIL SCIENTIFIC ADVISORY BOARD • Rajesh Alva, Managing Director, New Mountain Capital • Susan G. Amara, Ph.D., Scientific Director, National • L. Kay Chandler, Partner, Cooley LLP Institute of Mental Health, National Institutes of Health • Richard Douglas, Ph.D., Board of Directors, Novavax Inc.; • Benjamin F. Cravatt, Ph.D., Gilula Chair of Chemical Biology Advisor, Red Sky Partners and Professor of Chemistry, The Skaggs Institute for • James Flynn, Partner, Deerfield Management Co. Chemical Biology, The Scripps Research Institute • Lawrence G. Hamann, Ph.D., Vice President and Global • James E. Crowe, Jr., M.D., Director, Vanderbilt Vaccine Head of Chemistry, Celgene Corp. Center; Ann Scott Carell Chair and Professor of Pediatrics, Pathology, Microbiology and Immunology, Vanderbilt • Christopher J. Kirk, Ph.D., President and CSO, Kezar Life University School of Medicine Sciences • Vishva M. Dixit, M.D., Vice President, Physiological • David E. Kroin, Co-Founder and Managing Director, Great Chemistry, Genentech Inc. Point Partners LLC • Justin Du Bois, Ph.D., Henry Dreyfus Professor of Chemistry • Shiraz Ladiwala, Vice President, Strategy and Corporate and Professor of Chemical and Systems Biology, Stanford Development, Thermo Fisher Scientific University • Bruce Leuchter, Managing Partner, PJT Partners • Joel Elmquist, D.V.M., Ph.D., Professor of Internal Medicine • Greg Margolies, Senior Partner and Head of Capital Markets and Pharmacology; Maclin Family Distinguished Professor Group, Ares Management LLC in Medical Science; Carl H. Westcott Distinguished Chair • Joel Martin, Ph.D., President and CEO, Dauntless in Medical Research; Director, Division of Hypothalamic Pharmaceuticals Inc. Research, University of Texas Southwestern Medical Center • Paul M. Meister, President, MacAndrews & Forbes Holdings • Helen H. Hobbs, M.D., Howard Hughes Medical Institute Inc.; Co-Founder, Liberty Lane Partners LLC Investigator; Professor, Department of Internal Medicine • Roger Newton, Ph.D., Founder, Executive Chairman and and Molecular Genetics, University of Texas Southwestern Chief Scientific Officer, Esperion Therapeutics Medical Center • John E. Osborn, Executive in Residence, Warburg Pincus; • C. Ronald Kahn, M.D., Chief Academic Officer, Joslin Affiliate Professor, University of Washington, Seattle; Diabetes Center and Section Chief of Integrative Physiology Contributor, Forbes.com and Metabolism; Mary K. Iacocca Professor of Medicine, • Julia C. Owens, Ph.D., President and CEO, Millendo Harvard Medical School Therapeutics Inc. • Laura Kiessling, Ph.D., Novartis Professor of Chemistry, • Atul Pande, M.D., Chief Medical Advisor, PureTech Health Massachusetts Institute of Technology • Craig C. Parker, CEO, Surrozen • Jeffrey Leiden, M.D., Ph.D., Chairman, CEO and President, • Liam Ratcliffe, M.D., Ph.D., General Partner, New Leaf Vertex Pharmaceuticals Venture Partners LLC • Paul M. Meister, President, MacAndrews & Forbes Holdings • Terry Rosen, Ph.D., CEO, Arcus Biosciences Inc.; Co-Founder, Liberty Lane Partners LLC • Joseph Schwarz, M.D., Former U.S. Representative, 7th • Eva Nogales, Ph.D., Howard Hughes Medical Institute Congressional District, Michigan Investigator, Professor, Molecular and Cell Biology • Barry Sherman, M.D., Co-Founder, CEO and President, Department, University of California, Berkeley; Senior StemPar Sciences Inc. Faculty Scientist, Molecular Biophysics and Integrated • Michael Staebler, Partner, Pepper Hamilton LLP Bio-Imaging Division, Lawrence Berkeley National Lab • Burton Sutker, M.D., Radiologist, St. Clare’s Health System, • Stuart Orkin, M.D., Howard Hughes Medical Institute New Jersey Investigator, David G. Nathan Professor of Pediatrics, Harvard Medical School • David R. Walt, Ph.D., Core Faculty Member, Wyss Institute at Harvard University; Hansjörg Wyss Professor of • Craig C. Parker, CEO, Surrozen Biologically Inspired Engineering, Harvard Medical School; • Terry Rosen, Ph.D., CEO, Arcus Biosciences Professor, Brigham and Women’s Hospital; Howard Hughes • Randy W. Schekman, Ph.D., Howard Hughes Medical Medical Institute Professor; Founder of Illumina Inc. and Institute Investigator, Professor of Molecular and Cell Quanterix Corp. Biology, University of California, Berkeley; 2013 Nobel • Wendell Wierenga, Ph.D., Independent Consultant and Laureate in Physiology or Medicine former CEO and R&D leader in biotech and pharma • David R. Walt, Ph.D., Core Faculty Member, Wyss Institute • Steve Worland, Ph.D., President, CEO and Director, at Harvard University; Hansjörg Wyss Professor of eFFECTOR Therapeutics Inc. Biologically Inspired Engineering, Harvard Medical School; Professor, Brigham and Women’s Hospital; Howard Hughes Medical Institute Professor; Founder of Illumina Inc. and Quanterix Corp.

BACK COVER Beautiful, but not glamorous. Researchers in the Yamashita lab study the development of cells inside the fruit fly testis to understand the mechanisms that regulate asymmetric stem cell division. These poorly understood processes play important roles in cancer and other diseases.

LSI MAGAZINE / SPRING 2019 49 University of Michigan Life Sciences Institute, Suite 3100 210 Washtenaw Avenue Ann Arbor, MI 48109-2216

BIG IDEAS. BOLD SCIENCE. Yukiko Yamashita Lab