June/July 2020

Vol. 19 / No. 6 / June/July 2020

THE MEMBER MAGAZINE OF THE AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY

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Learn more about how to submit your proposal at asbmb.org/meetings-events NEWS FEATURES PERSPECTIVES 2 32 42 PRESIDENT’S MESSAGE ON THE FRONT LINES WHAT WE’VE LOST BY CLOSING ASBMB journals are going open access OF CORONAVIRUS CARE OUR LABS—AND WHAT WE RISK REOPENING THEM 5 36 MEMBER UPDATE PIVOTING FROM CARNIVOROUS PLANTS TO COVID-19 45 10 THE COVID–19 PANDEMIC IN MEMORIAM 40 IS SQUEEZING WOMEN AWARD WINNERS OUT OF SCIENCE 12 40 Corbett goes the extra mile to support HONOR SOCIETY NEWS young scientists Undergrad chapter members honored 41 Jura is inspired by her grandmother, 46 a ‘true pioneer’ OUT OF MY COMFORT ZONE: 14 HOW I USE SCIENCE TO RETROSPECTIVE INFLUENCE POLICY 14 Jerry B. Lingrel (1935 – 2020) 18 Michael J. O. Wakelam (1955 – 2020) 42 49 22 ‘WE WILL NOT BE SILENT’ JOURNAL NEWS 22 A mechanism for remdesivir activity and a platform to test other antivirals 24 More than skin deep 25 How posttranslational modifications affect the DNA sensor cGAS 26 From the journals

NEWS 31 How to catch and kill a coronavirus 46 on a doorknob 32

JUNE/JULY 2020 ASBMB TODAY 1 PRESIDENT’S MESSAGE

THE MEMBER MAGAZINE OF THE AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY ASBMB journals are going OFFICERS COUNCIL MEMBERS Gerald Hart Suzanne Barbour President Joan Broderick open access Toni M. Antalis Matt Gentry President-elect Blake Hill Audrey Lamb By Gerald Hart Wei Yang James M. Ntambi Secretary Takita Felder Sumter Joan Conaway Kelly Ten–Hagen he American Society for Bio- (currently mostly from direct costs) Treasurer JoAnn Trejo chemistry and Molecular Biology and making their papers public, is ASBMB TODAY EDITORIAL Ton Monday announced that it complicated, to say the least. EX-OFFICIO MEMBERS ADVISORY BOARD would make its three peer-reviewed To begin with, it incentivizes Robert S. Haltiwanger Rajini Rao Carla Koehler journals fully open access beginning high-volume publishing, rather than Chair Co-chairs, 2020 Annual Ana Maria Barral in January 2021. As president, I con- high-quality publishing. You’ve prob- Meeting Program Committee Natasha Brooks vened a task force responsible for ex- ably noticed that some open-access Cheryl Bailey Kelly Chacón Chair, Education and Beronda Montgomery ploring how the society could achieve publishers have pretty low standards: Professional Development Bill Sullivan this longstanding goal, and I oversaw The more papers they publish, the Committee Melissa Vaught Daniel Raben Binks Wattenberg the task force’s work. Here, I’d like more money they make. For the Chair, Meetings Committee to explain the reasons for this move, ASBMB, based upon the volume of Sonia Flores ASBMB TODAY why we decided to partner with a papers it currently publishes in its Chair, Minority Affairs Angela Hopp Committee Executive Editor commercial publisher, and what this three journals, subscriptions provide Nicole Woitowich [email protected] all means for the society. more income than author fees will. Chair, Science Outreach and Comfort Dorn I’ve written before about the The society is willing to take that Communication Committee Managing Editor Terri Goss Kinzy [email protected] intensifying pressure on scholarly financial hit to do what’s right for the Chair, Public Affairs Lisa Schnabel publishers to make their journals fully community. It is not willing, how- Advisory Committee Graphic Designer open access. Researchers, funding ever, to lower its standards in order Ed Eisenstein [email protected] Chair, Membership Committee John Arnst agencies, patients and other members to increase volume. Let me be very Susan Baserga Science Writer of the public believe that taxpayer- clear about this: ASBMB journals are [email protected] Chair, Women in Biochemistry funded research should be accessible committed to publishing papers that and Molecular Biology Laurel Oldach Committee Science Writter to all. The ASBMB shares this belief, our reviewers, all of whom are active [email protected] Sandra Weller which is why our journals — Journal scientists, deem important, relevant, Chair, Publications Ed Marklin Committee Web Editor of Biological Chemistry, Journal rigorous and reproducible. [email protected] Lila M. Gierasch of Lipid Research and Molecular On top of loss of subscription Editor-in-chief, JBC Allison Frick Multimedia and Social Media & Cellular Proteomics — have for revenue, open-access publishing re- A. L. Burlingame Content Manager years made accepted manuscripts quires different workflows, platforms Editor, MCP [email protected] freely available and have encouraged and technologies. As authors, we don’t Nicholas O. Davidson Barbara Gordon Editor-in-chief, JLR Executive Director authors to post their manuscripts often think about these operational [email protected] Kerry-Anne Rye in public repositories. Still, those requirements for publishing, but it’s Editor-in-chief, JLR measures aside, the writing is on the important to get them right. While wall: In the future, anything short the task force explored the possibility For information on advertising, contact Pharmaceutical Media Inc. at 212-904-0374 or [email protected]. of full open access isn’t going to of ASBMB cobbling together new cut it. and existing systems on its own, it Although both subscription determined that even if the society and open-access models are funded could line everything up for a January by research grants, moving from a launch, it would immediately lag www.asbmb.org/asbmbtoday subscription model, in which institu- behind the competition. Frankly, we PRINT ISSN 2372-0409 tional libraries pay for journal access did the math, and ASBMB simply

Articles published in ASBMB Today reflect solely the authors’ views and not (mostly from indirect costs, F&A), to does not have the finances to go open the official positions of the American Society for Biochemistry and Molecular an open-access model, in which au- access on its own. If we want to do Biology or the institutions with which the authors are affiliated. Mentions of products or services are not endorsements. thors pay the full cost of publishing this quickly and keep pace thereafter,

2 ASBMB TODAY JUNE/JULY 2020 PRESIDENT’S MESSAGE

I have written before about why we should review for and publish in society-owned journals, and my position remains unchanged. JBC, JLR and MCP are still society-owned journals, and they need your contributions now more than ever. the task force determined, we need JBC alone has been publishing for we should review for and publish help. more than a century. It’s important in society-owned journals, and my The task force then produced a to us that we continue to be good position remains unchanged. JBC, request for proposals, making it clear stewards of that archive of knowl- JLR and MCP are still society-owned that the society needed a publishing edge, and Elsevier has committed to journals, and they need your contri- partner with experience transition- preserving it. butions now more than ever. ing subscription journals to open A key point in our negotiations Below are some key points to access and with the ability to do it was pricing, and the good news is remember: by January. The task force evaluated that it will be cheaper for everyone, • All ASBMB journals will be gold seven proposals and shortlisted four but ASBMB members especially, open access beginning in January. potential partners to present to the to publish open-access papers in • The ASBMB will continue to ASBMB Council in February. While our journals. The standard article own 100% of its three journals. each proposal had its own strengths, processing charge will be $2,500, • All editorial decisions will remain Elsevier’s was the strongest. The task and ASBMB members will pay only with the society. force recommended that the society $2,000. This is a very good price • All peer review will continue to partner with Elsevier, and Council in the current marketplace and is be done by working scientists — voted unanimously in April to do so. much cheaper than most open-access YOU (no nonscientist gatekeepers). Now, it’s fair to say that Elsevier journals. • All appointments of editors- has a number of critics in our commu- Finally, given the subscription in-chief, associate editors and nity, in some cases because of histori- revenue we’ll be losing, Elsevier editorial board members will cal practices and in some cases because promised us a short-term income continue to be the society’s to of more recent ones. I’m not here to guarantee that will hold us over while make. defend Elsevier; I am here to explain the journals, after becoming open • There will be a new and improved to you why it was our best choice. access, gradually reach new readers manuscript tracking and submis- For starters, Elsevier has extensive and authors. sion system. experience working with societies. What does all this mean for the • There will be improvements to Many of you likely publish in the ASBMB? the author experience. Biophysical Journal, which is owned The most important thing I want • Fast turnaround will remain a top by the Biophysical Society but pub- to emphasize is that the ASBMB priority. lished in partnership with Cell Press, retains ownership and complete • There will be improvements in an imprint of Elsevier. In just the past editorial control of its journals. We operations. year, Elsevier has worked to make will continue to select our edi- • All ASBMB journals will be in at least 100 journals open access, tors-in-chief, associate editors and full compliance with Plan S and almost half of them with societies. editorial board members. We will other open-access initiatives, In addition, Elsevier has submis- continue to manage the peer-review resulting in greater global reach sion, production, online publishing, process. We will make editorial and visibility. analytics and marketing systems that decisions based upon merit, not • There will be improved search we can immediately adopt and then flashiness or volume. We will always functionality within the board tailor as needed. be scientists working to support other to find the best reviewers for ASBMB journals, as you likely scientists. There will be no nonscien- manuscripts. know, have significant archives that tist gatekeepers. Making our journals fully open must be migrated to any new system. I have written before about why access is the right thing to do to

JUNE/JULY 2020 ASBMB TODAY 3 PRESIDENT’S MESSAGE

advance science, but — as explained coming mandates for open access due You may still have questions above — it will result in a substantial to loss of revenue. We are indeed for- about this decision and its impact. loss of revenue (subscription income). tunate that both the current and past We are doing our best to provide The society will continue its many ASBMB managers have been great information and be as transparent as programs that support our members, stewards of our financial resources. possible. You can find a list of fre- including education, public affairs, In short, open access is not only great quently asked questions here, and outreach and many other activities for science, but also the ASBMB will I also invite you to contact me or that support our field. We have deter- survive this transition in great shape! any of the journal editors with your mined that, with careful stewardship The decision to go open access thoughts, questions and concerns. of the ASBMB’s resources, we will be was not made lightly and involved able to keep the society in great shape the hard work of many people who Gerald Hart (gerald.hart@ uga.edu) is a professor in perpetuity. Unfortunately, as I considered all of the options. As pres- and Georgia Research have stated in earlier columns, many ident, I would like to thank the many Alliance eminent scholar at the University of small society journals and societies people who put in long hours to Georgia and president of themselves won’t likely survive the develop our plans for this transition. the ASBMB.

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The Promoting Research Opportunities for Latin American Biochemists (PROLAB) program allows Latin American graduate students and postdoctoral fellows to spend up to six months in U.S. or Canadian laboratories.

Apply at asbmb.org/career-resources/ awards-grants-fellowships/prolab

4 ASBMB TODAY JUNE/JULY 2020 MEMBER UPDATE

Baserga named Bryant receives recognition among plant biologists Fleming professor Donald Bryant, professor of biochemistry and molecu- Susan J. lar biology at The Pennsylvania State University and a mem- Baserga, chair ber of the Journal of Biological Chemistry editorial board, of the American has received the Charles Kettering Award from the American Society for Society of Plant Biologists in recognition for his work on Biochemistry bacterial photosynthesis. and Molecular Bryant, who also holds the Ernest C. Pollard Biology’s Women professorship in biotechnology, joined the Penn State Bryant in Biochemistry faculty in 1981. His lab studies cyanobacteria and other Baserga and Molecular chlorophotoautotrophs. Biology Bryant has studied the physiology, metabolism and ecology of cyanobac- Committee, was recently appointed teria for nearly 50 years. Recently, his group discovered the process of far-red as the William H. Fleming, M.D. ’57 light photoacclimation, or FaRLiP, in which the expression of a 20-gene operon professor of molecular biophysics and allows cyanobacteria to modify their photosynthetic apparatus to enable growth biochemistry at Yale University. in far-red light, something previously thought to be impossible. The acclima- Baserga is also the director of tion process involves the synthesis of two new types of chlorophyll, d and f, medical studies in the department of and substantial modifications of phycobilisomes and photosystems I and molecular biophysics and biochem- II. Biotechnologists hope that this discovery may someday be used to improve istry and program director of the productivity in crop plant predoctoral program in cellular and The biannual Kettering Award, supported by the Kettering Foundation, molecular biolåogy at Yale. She per- was established in 1962 to recognize excellence in photosynthesis research with formed postdoctoral work with Joan a monetary prize. Steitz, and began her academic career as an assistant professor of thera- Butler named UCSB faculty research lecturer peutic radiology and of genetics at Alison Butler has been awarded the Faculty Research Lecture Award for 2020 the Yale School of Medicine. She by the University of California, Santa Barbara, Academic Senate. became a full professor in 2007. Her Butler, who studies metallobiochemistry in marine laboratory examines the fundamental microbes and algae, is a distinguished professor in UCSB’s aspects of ribosome biogenesis and its department of chemistry and biochemistry. Her research impacts on cell growth, cell division focuses on microbial iron acquisition through secreted chela- and cancer. tors called siderophores. In 2018, Baserga was elected as Among her many honors, Butler has received the Ameri- a fellow of the National Academy can Chemical Society’s 2019 Cope Scholar Award and 2018 of Inventors. She has received the Alfred Bader Award and the Royal Society of Chemistry’s Connecticut Technology Council Butler 2019 Inorganic Reaction Mechanisms Award. She previously Women of Innovation in Research served as president of the Society for Biological Inorganic Chemistry and was and Leadership Award, the Charles elected as a fellow of both the American Academy of Arts and Sciences and the W. Bohmfalk Prize for basic science Royal Society of Chemistry in 2019. teaching at the Yale School of Med- “I congratulate Alison on receiving the highest honor bestowed by UC icine and the ASBMB’s William C. Santa Barbara’s faculty senate,” Pierre Wiltzius, executive dean of the college Rose Award for outstanding research of letters and science, said to the UCSB Current. “As a pioneer in the field and commitment to training young of metallobiochemistry, and a leading scholar on this campus, she is most scientists. deserving of this recognition.” The William H. Fleming, M.D. ‘57 professorship was established Have you recently been promoted or honored? Do you have good news to share? in 2009 to help Yale maintain the highest standard of excellence in the Email it to us at [email protected] — and don’t forget to include a photo! biological sciences.

JUNE/JULY 2020 ASBMB TODAY 5 MEMBER UPDATE

AAAS announces new members

The ASBMB members recently named to the American Academy of Arts and Sciences are, top, from left, Catherine Drennan, Christopher Hill, Kathleen Collins, Joseph Heitman and Blossom Damania; bottom, from left, Thomas Wellems, Trisha Davis, George Stark, Susan Wallace and Thoru Pederson.

The American Academy of Arts won the Protein Society’s Dorothy including the discovery of FKBP12 and Sciences announced recently that Crowfoot Hodgkin Award. She was and TOR as targets of rapamycin. 276 artists, scholars, scientists, and nominated in the mathematical and leaders in the public, nonprofit and physical sciences class, chemistry Biochemistry, biophysics and private sectors have been elected to section, and in the biological sciences molecular biology section the academy in the areas of mathe- class, biochemistry, biophysics, and Kathleen Collins is a professor matical and physical sciences, biomolecular biology section. of molecular and cell biology at the logical sciences, social and behavioral Among this year’s new members University of California, Berkeley, sciences, humanities and art, and in the biological sciences class are historically focused on the structure public affairs, business and adminis- nine members of the ASBMB. and regulation of the telomerase en- tration. They include 10 members of zyme and now focused on the reverse the American Society for Biochemis- Microbiology and immunology transcriptases and biology of retroele- try and Molecular Biology. section ment mobility. She is also the founder Among this year’s new mem- Blossom Damania is a professor of a company developing enzymatic bers in the interclass section is one of immunology and microbiolo- tools for RNA sequencing. She was ASBMB member. gy, molecular bases of disease and a member and chair of the ASBMB Catherine Drennan is a profes- signal transduction at the Univer- Publications Committee from 2012 sor of chemistry and biology at the sity of North Carolina at Chapel to 2016. Massachusetts Institute of Technol- Hill. Her work focuses on under- Christopher Hill is a distin- ogy and a Howard Hughes Medical standing the molecular pathogenesis guished professor of biochemistry and Institute investigator. Her lab studies of oncogenic viruses, including Kapo- vice dean of research at the University the structural biology of metalloen- si’s sarcoma-associated herpesvirus. of Utah School of Medicine. Hill’s zymes, using X-ray crystallography Joseph Heitman is the James structural biology lab studies protein– to investigate how conformational B. Duke professor and chair of the protein interactions and catalysis changes enable catalysis and how department of molecular genetics in a variety of contexts, including these enzymes might be targeted. and microbiology at Duke University proteasome activity, gene expression As a postdoctoral fellow, Drennan School of Medicine. His research and protein quality control. started the undergraduate poster focuses on sexual reproduction and George Stark is a distinguished competition at the ASBMB’s annual evolution of pathogenic eukaryotic scientist in the Cleveland Clinic Le- meeting, and she has maintained microorganisms, antimicrobial drug rner Research Institute. His interests an interest in pedagogy, developing resistance via RNAi-dependent include interferons and cytokines, active lectures and research-based un- epimutation, and targets and mech- signal transduction, p53 and mam- dergraduate courses. In March, she anisms of action of natural products malian cell mutants.

6 ASBMB TODAY JUNE/JULY 2020 MEMBER UPDATE

Seven ASBMB members elected to NAS Susan Wallace is a distinguished professor emerita of microbiology and molecular genetics at the University of Vermont. Her research interests include oxidative DNA damage and repair and the interaction between DNA damages and DNA polymerases.

Cellular and developmental biology section Trisha Davis is the Earl W. Da- vie/Zymogenetics professor and chair The ASBMB members elected to the National Academy of Sciences are, top, from left, Janet Smith, of biochemistry at the University of Christopher Lima, Joan Conaway and Ivet Bahar; bottom, from left, Peter Tontonoz, Michael Rosen Washington. Her lab investigates and Kim Orth. mechanisms of chromosome dynamics, including chromosome capture and movement and microtubule The National Academy of Sciences mechanisms that regulate initiation nucleation and organization during announced the election of 120 mem- and elongation of mRNA transcripts mitosis. bers and 26 international members. by the enzyme RNA polymerase II. Seven of them are members of the She shared ASBMB’s Amgen award Intersection American Society for Biochemistry with her husband, Ron, in 1997 Thomas Wellems is chief of the and Molecular Biology.Here’s a little and that same year was named an Laboratory of Malaria and Vector about each: associate investigator of the Howard Research at the National Institute of Ivet Bahar is a distinguished pro- Hughes Medical Institute, a position Allergy and Infectious Diseases at the fessor and the founding John K. Vries she held until 2001. She was elected National Institutes of Health. He was chair at the University of Pittsburgh in 2002 to the American Academy of nominated in the medical sciences School of Medicine’s computational Arts and Sciences. She has served as section and the section of cellular and and systems biology department. an associate editor for the ASBMB’s developmental biology. His research Bahar developed widely used elastic Journal of Biological Chemistry and focuses include antimalarial drug network models for protein dy- as a member of the ASBMB Council, response and protection conferred by namics. She co-founded the com- finance committee and meetings human hemoglobinopathies and red putational biology Ph.D. program committee. Today she is the society’s cell polymorphisms. offered jointly by the University of treasurer. Thoru Pederson is the Vitold Pittsburgh and Carnegie Mellon Uni- Christopher D. Lima is a Arnett professor of cell biology versity. Just last year, Bahar won the Howard Hughes Medical Institute and a professor of biochemistry Kadir Has Outstanding Achievement investigator and holds the Alfred P. and molecular pharmacology at the Award, which recognizes outstanding Sloan chair as member and chair of University of Massachusetts Medical accomplishments Turkish scien- the structural biology program in the School. He was nominated in the tists have made at the national and Sloan Kettering Institute of Memorial biochemistry, biophysics and molec- international level. Bahar is an elected Sloan Kettering Cancer Center. He is ular biology section and the cellular member of the European Molecular also a professor at the Weill Cornell and developmental biology section. Biology Organization. Graduate School of Medical Sciences. His lab’s research focuses on the func- Joan W. Conaway holds the Lima’s laboratory studies the mech- tional significance of specific protein– Helen Nelson distinguished chair anisms underlying RNA processing RNA interactions in eukaryotic gene at the Stowers Institute for Medical and post-translational modification expression, with emphasis on RNA Research in Kansas City, Mo. She by ubiquitin and ubiquitinlike traffic and processing. studies the mechanisms of gene tran- proteins, such as SUMO. Lima was scription, and her work helped define elected to the American Academy of

JUNE/JULY 2020 ASBMB TODAY 7 MEMBER UPDATE

Arts and Sciences in 2017. Texas Southwestern Medical Center’s method and its single-wavelength Kim Orth is a Howard Hughes biophysics department. Rosen’s counterpart (SAD) and is the Medical Institute investigator and lab studies how the interior of the scientific director of the GM/CA@ the Earl A. Forsythe chair in biomed- cell is organized and, in particular, APS beamlines for crystallography at ical science at the University of membrane-independent compart- the Argonne synchrotron. She was Texas Southwestern Medical Center’s mentalization. His group uses a elected as a fellow of the American molecular biology department. Orth range of techniques to investigate the Association for the Advancement works to elucidate the activity of assembly, composition, and function of Science in 2007 and won her bacterial virulence factors on the of biomolecular condensates. In university’s Distinguished Faculty molecular level, providing insights February, he was recognized with the Lectureship Award in Biomedical into how bacteria cause disease and Wiley Prize in Biomedical Sciences. Research in 2016. how eukaryotic host cells signal in Read our 2015 feature on Rosen’s Peter Tontonoz is the Frances response to infection. She has served career path. and Albert Pianksy chair at the Uni- on the ASBMB awards committee Janet L. Smith is the Margaret versity of California, Los Angeles, and is currently on the nominating J. Hunter collegiate professor at the pathology and laboratory medicine committee. She won the ASBMB– University of Michigan Life Sciences department. Tontonoz studies lipid Merck Award in 2018 and the Institute and professor of Biologi- metabolism and metabolic disease. ASBMB Young Investigator Award cal Chemistry. Her lab uses X-ray He is a member of the editorial in 2012. Read an essay in the Journal crystallography to solve protein board for the ASBMB’s Journal of of Biological Chemistry by Orth structures of natural product biosyn- Lipid Research. In 2017, he gave the about her career. thetic enzymes as well as viral and Havel Lecture at the society’s Deuel Michael K. Rosen is a Howard antiviral proteins. She is regarded as Conference on Lipids, and in 2019 Hughes Medical Institute investi- a key developer of the multi-wave- he was a program co-chair for the gator and chair of the University of length anomalous diffraction (MAD) conference.

Bumpus named department chair

Namandjé Bumpus has been appointed chair of the department of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine after a nationwide search. As director, Bumpus will hold the E.K. Marshall and Thomas H. Maren professorship in pharmacology. She is the first Black woman to chair a department at the school of medicine. Bumpus joined the Hopkins faculty in 2010 after earning her Ph.D. from the Univer- sity of Michigan and completing postdoctoral work at the The Scripps Research Institute (now called Scripps Research). Since then, she has advanced into leadership roles, becom- Bumpus ing the first associate dean of institutional and student equity at Hopkins and then the school of medicine’s associate dean for basic research. Bumpus’ research focuses on drug metabolism, specifically of antiretroviral drugs used to treat and prevent HIV. The work includes investigating genetic variation in kinases that activate certain anti-HIV drugs and liver cytochromes that facilitate drug clearance, as well as developing assays to measure drug metabolites and model their distribution into various tissues. Accolades for Bumpus’ work include the PECASE (Presidential Early Career Award for Scientists and Engi- neers) from the NSF, a Presidential Early Career Award, invited lectureships at the National Institute of General Medical Sciences and the Congressional Biomedical Research Caucus, and awards from the American Society for Pharmacology and Experimental Therapeutics.

8 ASBMB TODAY JUNE/JULY 2020 MEMBER UPDATE

Regev takes leadership position at Genentech

Aviv Regev is leaving the Broad Institute of the Massachusetts Institute for Technology and Harvard University to become Genentech’s research and early development chief in August. She also will be a member of the executive committee for Roche, Genentech’s parent company. In a statement, Severin Schwan, chief executive officer of Roche, said of Regev’s appointment: “She brings a rare combination of expertise that will help us unlock even more possibilities in data-based drug discovery and development.” Regev’s lab uses experimental and computational approaches to study molecular circuits governing the function of mammalian cells and tissues in health and disease. Regev Regev won the American Society for Biochemistry and Molecular Biology’s Earl and Thressa Stadtman Scholar Award in 2014, the same year she became a Howard Hughes Medical Institute investigator. She is also a founding co-chair of the Human Cell Atlas initiative, which aims to map the location and gene expression of all human cell types, and founding director of the Klarman Cell Observatory at the Broad. She was elected to the National Academy of Sciences and won FASEB’s Excellence in Science Mid-Career Investigator Award last year. She earned her master’s degree and Ph.D. in computational biology at Tel Aviv University. She joined MIT’s biology department as a faculty member and a core member of the Broad in 2006. She has served on advisory boards of several biotechnology and pharmaceutical companies, as well as research centers, institutes and hospitals. Regev will be based at Genentech’s South San Francisco headquarters.

Lemire, McGaunn named rising researchers Among the eight undergraduates Junior Fellow award. at the University of Massachusetts Joseph McGaunn, a graduating Amherst to receive Spring 2020 Rising senior with a double major in bio- Researcher awards are Colin Lemire chemistry and molecular biology and and Joseph McGaunn, both members psychology in the Commonwealth of the UMass American Society for Honors College, has worked on five Biochemistry and Molecular Biology research projects in Alexander Suvor- Student Chapter. ov’s lab. He has investigated the role of Lemire Colin Lemire, a graduating bio- McGaunn molecular mechanisms in mediating chemistry and molecular biology ma- interactions between an individual’s jor in the Commonwealth Honors College, is involved in genetics and their environment and in transferring nonge- independent research in Sibongile Mafu’s lab focusing on netic information from one generation to the next, as well the biosynthesis of natural products in plants and fungi. as the potential clinical applications for such mechanisms. His work involves gene discovery and pathway reconstruc- This includes investigating the effect of paternal exposure tion of terpene molecules in fungi that have demonstrated to chemicals such as phthalates on offspring behavior and activity as antimicrobials, with a goal of better understand- metabolism using a mouse model. ing the metabolic pathways of natural products for future McGaunn has presented his work at the Northeast research into their function and potential pharmaceutical Society of Toxicology Regional Chapter annual meeting applications. and the annual meeting of the Society of Toxicology and is In addition to this award, Lemire has received a grant a coauthor on four manuscripts that will be published by from the UMass Amherst Center for Agriculture, Food Suvorov’s lab. and the Environment; an ASBMB Student Chapter Travel The 2020 Rising Researcher awards celebrate these Award to present his research at the 2020 ASBMB Annual students for their unconventional and inspiring approach- Meeting (since canceled); and a UMass Life Sciences es to research, scholarship and creative activity.

JUNE/JULY 2020 ASBMB TODAY 9 IN MEMORIAM

Jan Miernyk Peter Lengyel

Jan A. Miernyk, a Peter Lengyel, a supervisory research professor of molecular molecular biologist biophysics and chem- whose career spanned istry at Yale University 33 years at the U.S. De- for more than four partment of Agriculture, decades, died April 21. died April 2. He was 72. He was 90. Born Oct. 4, 1947, Lengyel was in Boulder, Colorado, born May 24, 1921 in Miernyk attended Fort Budapest, Hungary. He Lewis College in Durango and his parents sur- and the University of Colorado, Boulder before earning a B.A. vived the Holocaust, but many of their relatives perished. He in biology and an M.S. in plant physiology at West Virginia graduated from the Technical University of Budapest in 1951, University. He earned his Ph.D. in plant cell biology at Arizona then served two years in the Hungarian army before returning State University, Tempe in 1980, then completed a postdoc in to his studies. He and his wife, Suzanna, moved to the U.S. in biology research at Queen’s University in Kingston, Ontario. 1956 after the collapse of the Hungarian uprising against the Miernyk began his career with the USDA at the Northern USSR, settling in New York City where he pursued his Ph.D. Regional Research Center, in Peoria, Illinois. He transferred to under Severo Ochoa. He did a postdoc with Jacques Monod in the Plant Genetics Research Unit at the University of Missouri Paris and worked briefly on the faculty of New York University in 1999, where he was also an adjunct professor in the depart- before being recruited to Yale in 1965. ment of biochemistry. He loved his work and was known for his According to an article by Robert Forman on the Yale expertise, with 156 scientific publications and 3,351 citations. website, Lengyel “was famous at Yale for his tremendous He was elected an American Association for the Advancement recall, vast knowledge of science and all things cultural, and of Science fellow in 2007. his meticulous, precise, and fluent lectures delivered without A major focus in Miernyk’s lab was systems biology. He notes, using only chalk and a blackboard to convey the most used a descriptive platform to define periods of cell divi- complex subjects.” sion and specialization, lipid and protein accumulation and Lengyel’s graduate work on deciphering the genetic preparation for quiescence in soybeans, then isolated and code resulted in the correct determination of the nucleotide compared total proteins from each stage. After analyzing composition of codons for 18 amino acids. At Yale, his lab was patterns of change in protein abundance, the lab used systems the first to demonstrate that formylMet-tRNA was required cartography to describe relationships among protein function, for the translation of bacteriophage f2 RNA in a cell-free expression, localization, and biological interaction for an system. He spent many years studying protein synthesis, the evolving cartograph. interferon system and the regulation and modulation of cell In his younger years, Miernyk was a wrestler and football proliferation and differentiation. Research from his laboratory player. He later earned a black belt in Okinawan karate, and he led to the discovery, of an RNase activated by interferons as a taught free martial arts classes at Mizzou for students and fac- defense against infecting viruses. He also studied the proteins ulty. A longtime fan of muscle cars, in retirement he restored p202, a regulator of transcription, and p204, a modulator of and modified a ’62 Ford Falcon. He was a craft beer enthusiast cell proliferation and differentiation. and enjoyed cataloguing new breweries he encountered on his In 2014, Lengyel retired from the Yale faculty and was travels. named professor emeritus. “His erudition, refined manner, Miernyk is survived by his wife, Elizabeth Hoyos–Miernyk, polite friendliness, abundant curiosity, and sincere concern and his daughter, Briana Saucier, and her family. for others were considered to be among his defining features,” Forman wrote.

10 ASBMB TODAY JUNE/JULY 2020 IN MEMORIAM

Tomoko Ohnishi Paul Marks

Tomoko Ohnishi, a Paul Marks, a professor of biochemis- cancer researcher try and biophysics at the who helped turn Me- University of Pennsyl- morial Sloan Kettering vania for more than 52 Cancer Center into a years, died March 17. world-class research She was 88. institution, died April A native of Kobe, 28 from pulmonary Japan, Ohnishi was a fibrosis and lung competitive figure skater cancer. He was 93. and downhill slalom skier Marks was born in her youth. She earned a bachelor’s degree in chemistry in Mahanoy City, Pennsylvania, on Aug. 16, 1926. After in 1956 and a master’s in biochemistry in 1958, both from Marks’ mother died when he was 4 years old, his father Kyoto University. She earned a Ph.D. in biochemistry in 1962 disappeared, leaving his son to a transient life staying with from Nagoya University and did a postdoc in Osaka with Bunji aunts, uncles and grandparents. His father reappeared with a Hagihara. new wife and son five years later and took Marks back. Ohnishi arrived at the Johnson Research Foundation in th Marks attended high school in Brooklyn and, with a ae Penn School of Medicine in 1967 to work as a postdoctoral teacher’s encouragement, applied to Columbia University. He fellow with its director, Britton Chance, who called her “the was accepted and awarded a full scholarship. At Columbia, queen of iron sulfur.” She remained at Penn, where she built a he became interested in genetics and clinical research. He world-class research laboratory that produced more than 200 graduated with his bachelor’s degree in 1945 and his med- publications, the last one when she was 87. ical degree from the university’s College of Physicians and According to Kristen Lynch, chair of Penn’s department Surgeons in 1949. He then performed postdoctoral work at of biochemistry and biophysics, Ohnishi was “a true pioneer” the National Institutes of Health before returning to Columbia in understanding the inner workings of the respiratory electron in 1955 to work on glucose metabolism. He served as univer- transport chain that couples oxidation to the production of sity’s medical school as dean from 1970 to 1973 and as vice ATP. Her work provided a map with which to locate dysfunc- president for medical sciences from 1973 to 1980. tion of that ETC’s complex I in neurodegenerative diseases, When Marks joined MSKCC in 1980 as the center’s neuromuscular diseases and aging. president —a position he would hold for the next two “She appreciated, before most, that understanding the in- decades — he sought to apply the strengths and techniques ner workings of Complex I is crucial for the future of medicine of molecular biology research to cancer research. He helped and devoted her life’s work and passion to deciphering the oversee a top-to-bottom renovation of the center that includ- mysteries of how this key component of the respiratory chain ed revising its tenure system, recruiting emerging talent and, supports life,” Lynch said. most crucially, refocusing its research priorities from surgical In addition to science, Ohnishi loved music. She took sing- innovations to the molecular basis of cancer. ing lessons for many years and enjoyed singing for colleagues He retired in 1999, having published more than 350 at scientific conferences around the world. She spoke some scientific articles and received numerous accolades that French, German and Russian as well as fluent Japanese and included the National Medal of Science in 1991. English. Marks is survived by his wife, Joan Rosen, whom he mar- Ohnishi was married for 60 years to S. Tsuyoshi Ohnishi, ried in 1953; his daughter, Elizabeth; his sons, Andrew and who died in 2018. She is survived by her children, Hiroshi Matthew; six grandchildren; and two great-grandchildren. (and wife Bonnie) and Noriko Lovasz (and husband John); and grandchildren Megumi, Lorelei, Akira and Gavin.

JUNE/JULY 2020 ASBMB TODAY 11 HONOR SOCIETY NEWS

Undergrad chapter members honored

By Stephanie Paxson

he American Society for Biochemistry and Molecular ASBMB’s Student Chapters program also presents an Biology Honor Society, Chi Omega Lambda, recog- Outstanding Chapter award each year to recognize a Stu- Tnizes exceptional undergraduate juniors and seniors dent Chapter that demonstrates leadership in education pursuing degrees in the molecular life sciences at colleges or activities, exceptional commitment to increasing public universities with ASBMB Student Chapters. Students are scientific awareness, interaction with other campus events, recognized for their scholarly achievement, research accom- and participation in regional and national meetings. This plishments and outreach activities. ASBMB usually holds year’s winner is the Northeastern University Student an induction ceremony during the annual meeting, but the Chapter, advised by Kirsten Fertuck. 2020 meeting was canceled due to COVID-19 so inductees instead will be recognized on the society’s website.

2020 HONOR SOCIETY INDUCTEES

Nana Aikins Kevin DiMagno, Marjan Khan Wei-Shin Lu Rochester Institute Rochester Institute of Marymount Manhattan Otterbein University of Technology Technology College Ryan Maki Emily Aleksandrovic Daniel Do Charya Khun University of Wisconsin– Hartwick College Stockton University Wesleyan University Lacrosse Ivy Antunes Madison Donovan Rochelle Knier, Megan McClain St. Mary’s College University of Tampa University of Wisconsin– Otterbein University of Maryland Stout Danielle Duryea Erin McNell Jacob Boyer Otterbein University Sunnie Kong St. Bonaventure University Purdue University Boston University Ryan Fink Victoria Miller-Browne Alon Brown Monmouth University Austin Lai Northeastern University Marymount Manhattan Emory College Zachary Fralish Daniela Molina College Florida Southern College Noah Langenfeld Palacios, University of Nina Bui University of Wisconsin– Massachusetts Wihib Hankore University of Nebraska– Stevens Point University of Nebraska– Victoria Momyer Lincoln Lincoln Renee Lawrence Boston University Nhu Chau University of San Diego Cassidy Illum Rachel Muti St. Mary’s College of Marymount Manhattan Colin Lemire Otterbein University Maryland College University of Kathleen Ngo Lillian Cool Massachusetts Amherst Bailey Jameson Stockton University Otterbein University Stephen F. Austin State Rebecca Leuschen, Tenzin Ngodup Alexis Craft University University of Nebraska– Wesleyan University Lane College Lincoln Rachel Jansen Brett Palmero Allison Cruikshank University of Sean Lewis Lake Forest College University of Nebraska– Massachusetts Rochester Institute of Lincoln Technology Surya Pulukuri Meera Joshi Boston University Wesleyan University Christopher Lore Manhattan College Gwendolyn Pyeatt Boston University

12 ASBMB TODAY JUNE/JULY 2020 HONOR SOCIETY NEWS NORTHEASTERN UNIVERSITY STUDENT CHAPTER

Dr. Sloan Devlin, an assistant professor of biological chemistry and molecular pharmacology at Harvard Medical School, was the keynote speaker at a Student Chapter regional meeting at Northeastern University titled “The Active Site: Promoting Favorable Interactions Among Undergraduates” and also attended by students from Roxbury Community College. Pictured, from left, are Faith Boyd-Mutinga of Roxbury CC; Julian Amirault, Kathleen Merritt and Evan Mun of Northeastern; Sloan Devlin; Anders Lindberg, Ariella Bourdeau, and Jared Subiono of Northeastern; and Lleyan Hashim, Roxbury CC.

Paige Richards Sashrika Saini Huong Trinh Stephanie University of University of Nebraska– Paxson (spaxson Stockton University @asbmb.org) Massachusetts Amherst Lincoln is the ASBMB’s Ashley Robinson diversity and Hamline University Diana Sanchez-Zevallos Chiemeka Uwakwe undergraduate Stockton University St. Johns University coordinator. Catherine Rojas Follow her on Stockton University Sharon Shania Gina Wade Twitter @stephaniepaxson. University of San Diego University of Wisconsin– Jordyn Ross Lacrosse Stevenson University Raheed Sunesra Trinity College Braeden Sagehorn University of Massachusetts Amherst

JUNE/JULY 2020 ASBMB TODAY 13 RETROSPECTIVE

Jerry B. Lingrel (1935 – 2020) By Anil G. Menon & Gary E. Shull

Jeffrey Robbins, Eric A. Schon, Tim M. Jerry Lingrel earned his Ph.D. Townes and John Orlowski in biochemistry from the Ohio contributed to this State University in 1962 and retrospective. then moved on to postdoctoral studies at the California COURTESY OF LYNNE LINGREL–PARTIN COURTESY OF LYNNE Institute of Technology, where he developed a deep interest erry B. Lingrel, a pioneer in the in molecular biology. He field of molecular biology, died subsequently spent a year as a JFeb. 22 at the age of 84. He visiting fellow at the University served with distinction as a mem- of Cambridge in the famed LMB, ber of the faculty of the University or Laboratory of Molecular of Cincinnati College of Medicine Biology. from 1962 to 2019, rising to become chair of the department of molecular genetics, biochemistry, and microbiology, serving in this position for thinking about them.” over 30 years and, subsequently, as gene duplication and evolution in — William Lawrence Bragg interim chair of the department of mammals. cancer and cell biology for three Jerry poured himself into science To provide historical context, years. with fearless intellectual curiosity. In the use of recombinant DNA Jerry was an associate editor of a career spanning 60 years, he was technology was viewed with the Journal of Biological Chem- a pioneer in the invention and use considerable public suspicion in the istry for 28 years; served on and of molecular biological techniques 1970s, and Jerry, with characteristic chaired numerous study sections at and recombinant DNA technology. integrity, was a pioneer in making the National Institutes of Health; Beginning in the mid-1960s, he and sure that procedures, institutional chaired national and international his trainees were among the first to review boards and safeguards were scientific conferences; published identify and characterize mRNA. in place. In the 1980s, he and groundbreaking work; and was an He identified hemoglobin mRNAs, his collaborators were the first to exemplary mentor to dozens of ju- demonstrated their translation into demonstrate that a human gene nior colleagues, postdoctoral fellows protein using a reticulocyte cell- (beta-globin) can function with and graduate students. All who knew free system and determined that correct developmental and tissue him remember him fondly not only hemoglobin mRNA had a poly-A specificity in a transgenic mouse. for his outstanding scientific contri- sequence at its 3´ terminus. His This work established a foundation butions but also for his exceptional work contributed to new ways of for the production of mouse work ethic, humility, integrity and understanding RNA splicing and models of human hereditary decency. stabilization. He later demonstrated disorders and provided an that hemoglobin genes occurred in experimental system in which the “The important thing in science clusters, and his contributions led to molecular mechanism of the switch is not so much to obtain new the hemoglobin genes becoming a from fetal to adult hemoglobin could facts as to discover new ways of paradigm for our understanding of be defined.

14 ASBMB TODAY JUNE/JULY 2020 RETROSPECTIVE

“Within the infant rind of productive set of studies of the physi- that an endogenous ligand regulates this small flower, poison hath ological and developmental functions Na,K-ATPase activity and elucidated residence and medicine power” of these cation pumps in the living some of the physiological functions — William Shakespeare animal. The members of this team of these important ligands. He Jerry was especially skilled at went on to publish groundbreaking generously shared the gene-target- identifying critical bottlenecks in work as independent scientists and ed animals that he developed with science. For example, hunters long earned Cincinnati an international researchers around the world, and used ouabain, the active ingredient reputation as a center of excellence many of them are still being used in arrow poison, to kill prey, but for transgenic and gene-targeting today in a wide variety of studies. traditional healers also used it to studies. treat heart disease. Similarly, digoxin, Jerry fearlessly explored cut- “Chance favors the prepared the active ingredient from the fox- ting-edge gene-targeting techniques mind” — Louis Pasteur glove (digitalis) family of plants, is for making global and conditional Jerry exemplified the alert mind toxic at doses that are barely above gene knockouts and for gene mod- that scans a wide scientific landscape, therapeutic doses. Breakthroughs in ifications, and he identified unique chooses questions carefully and then the 1960s had shown that ouabain functions of the Na,K-ATPase marshals the best forces to answer and digoxin both acted by bind- isoforms in heart and skeletal muscle them. His team made major con- ing sodium–potassium adenosine and the brain. His gene modification tributions to the understanding of triphosphatase, or Na,K-ATPase, studies provided conclusive evidence atherosclerosis from his serendipitous the critical ATP-dependent pump that maintains sodium and potassium gradients across the plasma membrane of every cell in the body. However, further understanding of the physiology of this key ion pump had reached a bottleneck because the

genes encoding its subunits were still LINGREL–PARTIN COURTESY OF LYNNE unidentified, and there was no way to evaluate gene function in vivo. Using cDNA cloning techniques, Jerry determined the sequence of the multiple Na,K-ATPase isoforms and identified the amino acid residues involved in cation transport and the binding of inhibitory drugs such as ouabain and digitalis. Then he made an inspired leap of imagination to take advantage of the then-nascent technology to create gene-targeted mice. Before any such mice had been Jerry Lingrel with his two children, Doug and Lynne, sit on a tractor during a visit to the family farm in the early generated, Jerry quickly assembled a 1970s. His background as a farmer contributed to the work habits that served Lingrel and all who worked with him gene-targeting team at the University throughout his career. of Cincinnati and started a highly

JUNE/JULY 2020 ASBMB TODAY 15 RETROSPECTIVE

listened to and acted on good ideas, and pursued new directions, with new grant submissions often resulting from this process. Jerry enjoyed challenging his

COURTESY OF LYNNE LINGREL–PARTIN COURTESY OF LYNNE mentees and being challenged by them in turn. His genuine enthusiasm and wonder at where the scientific path was taking him and what could be learned were both delightful and inspiring. He was eager to embrace new technologies but only in the pursuit of a “good biological question,” and he had a farmer’s good sense for quickly sizing up scientific papers and grants. This kept the lab fresh and productive as Jerry continued to make important Jerry Lingrel was an avid gardener, both outside, where he grew many vegetables and flowers, contributions to the literature well and inside his greenhouses, where he grew an astonishing array of orchids and cacti. into his 80s. Jerry believed and acted on the principle that everyone was capable discovery, decades earlier, of the zinc “The meeting of two of coming up with new ideas and finger transcription factor Krup- personalities is like the contact approaches. When it was time to pel-like factor 2, or KLF2. The key of two chemical substances: if prepare a new grant submission or observation was that KLF2 is highly there is any reaction, both are a renewal application, he expected expressed in endothelial cells that transformed.” —Carl Gustav everyone in the laboratory who are subjected to high hemodynamic Jung was working in that area, including shear stress, and this prompted them The contribution for which Jerry graduate students, to participate. first to identify the DNA sequence Lingrel will be remembered most He made it clear that this was not that responded to shear stress in is his transformative impact on the merely a training exercise but a result the KLF2 gene and then to identify many graduate students, postdoc- of his belief that everyone in the lab higher order transcription factors toral fellows and medical fellows was fully capable of participating in a that regulate its expression. whom he trained. Lab meetings were shared scientific endeavor. Using gene targeting, the team held every week without fail, and showed that loss of KLF2 in myeloid everyone from the newest graduate “The poetry of the earth is never cells results in a significant increase student to the most experienced dead” — John Keats in atherosclerosis due to an increase postdoc would be in the rotation to Jerry loved the poetry of the in migration and adhesion of both present their latest findings and to earth and the rich soil of Ohio. He neutrophils and macrophages to en- discuss any difficulties they had en- was born and raised on a farm in dothelial cells. They further showed countered. In these meetings, there Byhalia, Ohio, which he visited that widely used statin drugs induce was remarkably little pressure; one frequently. It remains in the Lingrel KLF2 and likely confer some of the was simply presenting data and ideas family to this day. He had an interest protective effects of statins (beyond to a group of interested friends and in farming, gardening and landscap- inhibiting cholesterol biosynthesis) colleagues. Regardless of experience, ing that he pursued throughout his by reducing inflammation, a major everyone was treated as an equal. life. risk factor in atherosclerosis. Jerry actively sought out opinions, Jerry was deeply devoted to Sally,

16 ASBMB TODAY JUNE/JULY 2020 RETROSPECTIVE

Jerry Lingrel was an associate editor of the Journal of Biological Chemistry for 28 years.

his wife of 60 years, and to his chil- “No bubble is so iridescent or dren, Doug and Lynne. His devotion floats longer than that blown Anil G. Menon (menonag @ucmail.uc.edu) is a and loyalty extended to colleagues by the successful teacher” — professor of molecular who worked in his laboratory, de- William Osler genetics, biochemistry and molecular genetics partment and university, and indeed All who contributed to this nar- and associate dean for around the world. Shortly after his rative were Jerry’s trainees and knew baccalaureate education at the University of Cincinnati death, Sally told us that hundreds him at a deep and personal level over College of Medicine. of daffodils Jerry had planted were many decades as a teacher, colleague blooming in their yard. This image and friend. While our zone of com- Gary E. Shull (shullge reminds us of the great good that fort is writing scientific papers guided @ucmail.uc.edu) is a one individual can do on his journey by data, writing this retrospective was professor emeritus of molecular genetics, from a farm boy to a leading scientist guided by emotions and memories. biochemistry and and educator — a flowering that This is a final act of gratitude to Jerry, microbiology at the University of Cincinnati transcends death and that lives in all our teacher, whose influence on our College of Medicine. who have had the privilege of know- scientific and personal success cannot ing him. He will be greatly missed. be expressed in mere words.

Upcoming ASBMB events and deadlines

JUNE

1–30 2020 ASBMB Annual Meeting virtual content: Visit asbmb.org/meetings-events/2020-annual-meeting for a full schedule

JULY

1 Deadline to vote in ASBMB Election

1–7 2020 ASBMB Annual Meeting virtual content: Visit asbmb.org/meetings-events/2020-annual-meeting for a full schedule

10 Virtual meeting: Best practices in online teaching for BMB classrooms

JUNE/JULY 2020 ASBMB TODAY 17 RETROSPECTIVE

Michael J. O. Wakelam (1955 – 2020) By Valerie B. O’Donnell & Edward A. Dennis

Robin F. Irvine, Dan Raben, Friedrich Spener and Shankar Subramaniam provided vignettes included in this article. COURTESY OF SIMON RUDGE

ichael Wakelam, a noted British biochemist, institute Mdirector and associate editor of the Journal of Lipid Research, who pioneered studies into elusive signaling lipids in health and disease including developing innovative ways to measure them, died March 31 in the United Kingdom.

Education and career Michael was born July 15, 1955. Following his secondary education, he attended the University of Birmingham, graduating in 1977 with a B.Sc. in medical biochemistry. He stayed on at Birmingham Michael Wakelam works in his laboratory at Birmingham University in 2006 with one of his for his Ph.D., graduating in 1980. beloved mass spectrometers. This photo was taken for a press release, most likely that During this time, Michael met announcing his move to the Babraham Institute. Jane Fensome, who became his wife in December 1980. After his Ph.D., Michael moved with Jane to Babraham Institute, Cambridge, as 32 Konstanz, Germany, for postdoctor- Reflections on P, IP3 and mass al studies, followed by a return to institute director. During this time, spectrometry London in 1983 on a Beit Memorial Jane and Michael welcomed their During Michael’s time in Ger- Fellowship. sons, Alex and Patrick, into the many, he became interested in lipids Michael worked in the depart- world. because of his work on the sugar ment of biochemistry at Imperial The Biochemical Society molecule inositol, the headgroup College until 1985, when he moved awarded Michael the Morton Award for phosphoinositide phospholipids. to the University of Glasgow as a Lectureship in 2018 for outstanding Measuring inositol phosphates was lecturer. He returned to Birmingham contributions to research in lipid not trivial and required 32P-labeled as a professor of molecular pharma- biochemistry. He was elected a IP3, which was generated from red cology in 1993 and was based there member of the Academia Europaea blood cell ghosts (as invented by Pe- until 2006, when he moved to the in 2019. ter Downes). But the 32P half-life of

18 ASBMB TODAY JUNE/JULY 2020 RETROSPECTIVE

two weeks was an issue, and Michael Lipid Research and Nature Methods, friendliness; he always was laughing. had to keep generating new batches describing methods for phosphoinos- Michael and Dan Raben shared before using up the previous one. itide analysis that included crucial an interest in signaling lipids and When Michael and Robin Irvine steps that stabilized the molecules regulation of their enzymes. The met up in London in the mid-1980s, sufficiently for MS analysis. two met at American Society for they discovered both were making Biochemistry and Molecular Biology the same thing, and from then on Importance of scientific annual meetings, the Lipid Gordon they coordinated their efforts; each conferences Research Conferences, and Federa- time one made a batch, they would Michael enjoyed scientific meet- tion of American Societies for Exper- split it and send half to the other, ings with other lipidologists, many imental Biology conferences, where which cut the number of times they of whom were close collaborators the excitement of their scientific made batches by half. The thought and friends. During a 1998 Keystone discussions was complemented by that they were happily sending 32P symposium on lipids in Taos, New Michael’s humor and caring de- through the post makes Robin a little Mexico, Michael and Robin Irvine meanor. Dan always will remember wobbly at the knees now. set out to go skiing, but neither Michael’s enthusiasm, intelligence Michael continued his work on could ski so they decided to hire and generosity of scientific spirit. inositols after his move to Glasgow. snowshoes and go for a hike high Michael was also a scholar. His He made several seminal discover- in the mountains instead. Michael deep-rooted interest in philosophy ies, including that diacylglycerol is no doubt enjoyed the sunshine and of science led him to read up on the generated from phosphatidylcholine. snow while talking science with col- conceptual foundations of quantum Working with Susan Pyne (then leagues. We will remember him for mechanics. One of his last passions Palmer), he developed a mass assay his wonderful sense of humor and was discussing with his colleagues for IP3, which subsequently was marketed by Amersham. Michael’s lab was known for being exciting, vibrant and hardworking. His infectious passion for research abounded, and results were discussed over beers COURTESY OF ROBIN IRVINE on Byres Road almost in real time. When Michael returned to Birmingham in 1993, he had moved fully into lipid mass spectrometry, leaving behind thin-layer chroma- tography for new approaches that produced unprecedented information about how lipids behave in cells, particularly in cancer. He developed state-of-the-art methods that enabled key discoveries concerning the roles of PLD1 and PLD2 in signaling, un- covering the role of the PH domain Michael Wakelam (right) went snowshoeing with fellow conferees at the Keystone Symposium on Signal in PIP2 regulation. He published Transduction and Lipid Second Messengers in Taos, New Mexico, in 1998. seminal papers in the Journal of

JUNE/JULY 2020 ASBMB TODAY 19 RETROSPECTIVE COURTESY OF EDWARD DENNIS COURTESY OF EDWARD

The first meeting of the LIPID MAPS International Lipid Classification and Nomenclature Committee was held in July 2006 in La Jolla, California. Pictured, from left to right, are Christian Raetz, Masahiro Nishijima, Takao Shimizu, Eoin Fahy, Edward Dennis, Manish Sud, Michael Wakelam, Fritz Spener, Robert Murphy, Yousuke Seyama, Gerrit van Meer and Shankar Subramaniam.

the philosophical foundations of ber Michael as a terrific role model of lipids and lipid–protein interac- the field, having read “Are Quanta who lived for his research and the tions in mammalian cells.” Then Mi- Real” by J.M. Jauch during a systems good of the wider institute as well chael’s group and 20 other investiga- biology conference in Crete in 2019. as a consensus seeker who used his tors submitted a successful application Discussions (particularly with Shan- emotional intelligence to great effect for the LipidomicNet project in 2008. kar Subramaniam, who introduced and hardly ever overruled others. Spener shared that the project’s him to the book) went on late into Michael became heavily involved coordinator dubbed Michael and the evening. in the lipidomics movement around other LipidomicNet leaders the “Vi- the time he moved to Babraham. ennese Coffee Club” because their Babraham onward and LIPID MAPS According to Fritz Spener of Graz, sometimes diverging opinions led In 2007, Michael became direc- Austria, who shared with us an to hilarious and, in the end, fruitful tor of the Babraham. He was moti- obituary he wrote with Christian discussions. For example, Viennese vated to take this role by both the Wolfrum and Wolf Reik for Nature Coffee Club members got irritated challenge of leading a large institute Metabolism, “Editorials about lipid- with literature reporting incorrect and proximity to cutting-edge phos- omics appeared in Europe in 2003, MS data, as the levels of structural phoinositide researchers who could but when news arrived from the U.S. elucidation claimed for lipid species benefit from his analytical capabili- that under Ed Dennis’ leadership the were not in accord with the existing ties. He successfully juggled multiple huge Lipid Metabolites and Pathways instrumental resolving power. As a roles, including rapidly developing a Strategy, or LIPID MAPS, project was result, a shorthand annotation for campus with a significant industrial granted, this started a major under- the correct presentation of lipid MS footprint while overseeing a success- taking. In response, Michael helped data was developed and published ful lipidomics facility. Colleagues convince the Directorate General in the Journal of Lipid Research in at Babraham, including Wolf Reik, 12 of the European Union to solicit 2013 with Michael as senior author. Simon Rudge, Phillip Hawkins, Len applications for a large collaborative This publication subsequently Stephens and Simon Cook, remem- project on high-throughput analysis was adopted by the LIPID MAPS

20 ASBMB TODAY JUNE/JULY 2020 RETROSPECTIVE COURTESY OF VALERIE O’DONNELL COURTESY OF VALERIE

The first meeting of the LIPID MAPS Wellcome Trust principal investigators (front row) and the International Lipid Classification and Nomenclature Committee was held in the Cardiff Castle in Cardiff, U.K., in March 2017. Pictured in front, from right to left, are Michael Wakelam, Edward Dennis, Valerie O’Donnell and Shankar Subramaniam; in back are Takao Shimizu, Fritz Spener, Marcus Wenk, Al Merrill, Robert Murphy and Eoin Fahy.

International Lipid Classification develops not only the informative ship in late 2020, and we were excit- and Nomenclature Committee, or website but also precious databases. ed that this would allow Michael to ILCNC. Certainly, the competence of manag- get back in the lab and spearhead the The LipidomicNet project ing big databases at Babraham is an LIPID MAPS renewal application. strengthened E.U.–U.S. relations; asset, as was Michael’s relation to the It feels especially tragic for us all that European researchers, among them European Bioinformatics Institute in Michael won’t be part of our next Michael, took on active roles in the Cambridge. phase of LIPID MAPS. ILCNC and were invited to be co-au- When the grant was funded, Note: Edward Dennis and Valerie thors of two fundamental classifica- Michael’s reaction was to say, “That O’Donnell also have published a memo- tion papers published in the Journal is absolutely brilliant! Well done, rial article about Michael Wakelam in of Lipid Research in 2005 and 2009. Valerie.” the Journal of Lipid Research. By 2013, though, the LipidomicNet As part of the new funding, the grant from the EU had ended, and LIPID MAPS databases were moved Valerie B. O’Donnell the long-running LIPID MAPS grant to Babraham. Michael’s input was es- (O-DonnellVB @cardiff.ac.uk) is co- in the U.S. was ending as well. sential, providing the new informatics director of the Systems Michael and Valerie O’Donnell home for the project and working Immunity Research Institute at Cardiff from Cardiff University teamed closely with Valerie O’Donnell, Ed- University, U.K. up with Ed Dennis and Shankar ward Dennis, Shankar Subramaniam

Subramaniam from the University of and the ILCNC advisory committee. Edward A. Dennis (edennis California, San Diego, to secure a fol- Michael was intimately involved in @ucsd.edu) is a low-up LIPID MAPS grant from the planning the next renewal cycle for distinguished professor of chemistry and biochemistry, British Wellcome Trust in 2017. This the LIPID MAPS grant to the Well- and of pharmacology and was a big relief for lipidologists, in come Trust. chancellor and chair in chemistry and biochemistry particular those involved in lipidom- Michael had planned to step at the University of ics; this grant safeguards and further down from the Babraham director- California, San Diego.

JUNE/JULY 2020 ASBMB TODAY 21 JOURNAL NEWS

A mechanism for remdesivir activity and a platform to test other antivirals Public–private research partnership between Gilead, Canadian scientists reveals a key residue in the SARS-Cov-2 polymerase

By Laurel Oldach

esearchers who showed in and the FDA rapidly issued emer- ta in Edmonton, joined the lab in February that remdesivir blocks gency use authorization for the drug. September 2019. When he began the Rcoronavirus polymerases are Now, using enzymes from the MERS study in October, the risk of a reporting in the Journal of Biolog- novel coronavirus SARS-nCoV-2 pandemic was still theoretical. By the ical Chemistry that the finding also itself instead of the related virus that time the authors were ready to write applies to the novel coronavirus — causes MERS, the research team has up their finding that the MERS poly- and they think they can explain the shown that remdesivir blocks the merase easily incorporates remdesivir molecular mechanism for how the SARS-nCoV-2 replicase in a test but stumbles to a halt a short time drug gums up the virus’ gears. tube. They also examined a selection later, the first cases of COVID-19 In their earlier paper, graduate of other nucleotide analogs to under- had been reported in Hubei prov- student Calvin Gordon and profes- stand more about whether and how ince, China. And by the time they sor Matthias Götte of the University each might work against infection. published the discovery, Italy was in of Alberta and co-authors demon- The Götte lab studies viral enzy- lockdown and cases had been report- strated that remdesivir can inhibit mology, and Götte has developed a ed in both the U.S. and Canada. the viral replicase of the coronavirus system for expressing large quantities As soon as the first SARS-CoV-2 that causes Middle East Respiratory of viral polymerases from insect genome was published in January, Syndrome, or MERS. The study cells to enable rapid enzymology Egor Tchesnokov, a research associ- included co-authors from Gilead studies, informed by a World Health ate in the lab and co–first author on Sciences, the company that makes Organization pandemic-preparedness the new paper, got to work cloning the drug. blueprint, which regularly updates a it into their expression system and In the ensuing months, remde- list of the most concerning patho- preparing to test remdesivir’s effect sivir, an adenosine-mimicking nucle- gens. “Coronaviruses like SARS on those enzymes. Their new study, otide analog developed to treat other and MERS were always on the list,” published in April, confirms that, viruses, has emerged as the most Götte said. as it did in MERS, the drug works promising small-molecule treatment Most graduate students don’t against the enzyme complex the for COVID-19. In late April, the finish a paper in their first year in novel coronavirus uses to replicate National Institute for Allergy and the lab — let alone two papers. its genome. This time, thanks to a Infectious Diseases reported qualified Calvin Gordon, a first-year graduate molecular modeling study run by success of a clinical trial of the drug, student at the University of Alber- Gilead’s Jason Perry, the authors ROBERT KIRCHDOERFER, JBC 2020 A cartoon rendition shows how remdesivir stops forward motion by the polymerase from the novel coronavirus.

22 ASBMB TODAY JUNE/JULY 2020 JOURNAL NEWS GILEAD SCIENCES

Workers in a manufacturing facility at Gilead produce remdesivir.

are able to explain how it nucleotide (analog) out there that tested in fifteen clinical trials around happens. would cause a stronger termination.” the world for efficacy as a COVID-19 Using the crystal structure To find out, the researchers treatment. Like sofosbuvir and of the polymerase enzyme from assessed the effect of a variety of other remdesivir, favipiravir is a nucleo- another coronavirus — as it hap- known nucleotide analogs — some tide analog that has been shown to pened, researchers from China and of which are in clinical trials — on inhibit other RNA viruses. However, Australia published a cryo-EM the viral polymerase. This allowed as with sofosbuvir, the SARS-CoV-2 structure of the novel coronavirus’ them both to pinpoint the effect of polymerase showed strong selectivity replicase on the same day as the the drug on a chemical modification for the natural ribonucleotide over fa- second Götte study — and a crystal at the 1’ in its ribose by comparing vipiravir, raising some concern about structure showing how a hepatitis the features of molecules that did and whether favipiravir will have antiviral virus enzyme interacts with remde- did not inhibit the polymerase and to activity against the new coronavirus. sivir, Perry and other researchers at make some predictions about other Götte said, “I think it’s very import- Gilead put together a computational nucleotide analog drug candidates. ant to reconcile the biochemical data model of how remdesivir fits into the For example, they found that, un- with antiviral data.” active site of the novel coronavirus’ like polymerases from other viruses, Whether or not remdesivir replicase. the enzyme did not recognize drugs proves to be an effective treatment “As the enzyme incorporates with a 2’ ribose modification as RNA for COVID-19, the researchers hope one, two, three more nucleotides, building blocks. For a drug to inhibit their enzyme platform will help the incorporated remdesivir moves the viral replicase, the replicase must speed up assessment of novel drug back, so to speak,” Götte said. As it recognize it as a building block of candidates as they are developed. reaches the third position away from new RNA, and for realistic dosing, They also plan to seek therapeutic the enzyme’s active site, the drug en- it’s best if the enzyme picks up the combinations of nucleotide inhibitors counters — or causes — a blockage. drug more easily than the drug’s and drugs with other mechanisms, Because of its unusual 1’ modifica- natural counterpart. The researchers which could reduce the chances that tion, it crashes into a specific amino found that the SARS-CoV-2 poly- resistance will develop, Götte said. acid, a serine conserved among most merase does not prefer a Gilead drug coronavirus polymerases, which for hepatitis, sofosbuvir, to its natural prevents the enzyme from moving counterpart, UTP. In a competition one step forward to incorporate the assay, Götte said, “UTP wins, by far. Laurel Oldach (loldach next RNA base. So it is very unlikely based on our @asbmb.org) is a science writer for the ASBMB. “It’s not perfect chain termina- data that we would expect potent Follow her on Twitter tion; there’s a little read-through,” antiviral activity from sofosbuvir.” @LaurelOld. Götte said. “The specific wish would They also investigated the influ- be to see whether there’s any other enza drug favipiravir, which is being

JUNE/JULY 2020 ASBMB TODAY 23 JOURNAL NEWS

More than skin deep Novel bacterial lipase structure may lead to new acne treatments

By Nathalie Gerassimov

cne can have an enormous social and emotional effect on the 85% Aof adolescents and 40% of adults who have it. Hyo Jung Kim and

colleagues in the Republic of Korea JUNG KIM AE-RAN KWON & HYO recently published a paper in the Journal of Lipid Research describing the molecular structure of a key enzyme involved in the skin disorder. This research has the potential to pave a path for new acne treatments. Acne research focuses on strains and types of Cutibacterium acnes and their lipase secretion and The top two skin layers are the activity. South Korean researchers solved the structure of a highly conserved C. acnes lipase. epidermis, forming the waterproof barrier, and the dermis, consisting ated strongly with acne and displays Acne treatments such as benzoyl of hair follicles and sweat glands higher lipase secretion and activity peroxide, retinoid and antibiotics surrounded by connective tissue. In than C. acnes type II, which is asso- focus only on symptoms and can the dermis next to hair follicles are ciated with healthy skin. Excessive have undesirable side effects. Kwon, sebaceous glands that secret sebum, a production of fatty acids can promote Kim and colleagues at Daegu Haany complex mixture of lipids including inflammation, so differences in lipase University and Woosuk University triglycerides and their derivatives. secretion and activity could be a ma- are working to design compounds Acne is chronic inflammation of the jor driver in acne development. that selectively block this lipase. sebaceous follicles, resulting in skin In this study, the investigators “Since the lipase is secreted elevations such as papules, pustules solved the structures of C. acnes type protein, this can be a good target for and cysts that can lead to scarring. II lipase by X-ray crystallography topical treatment,” Kim said. “We Research into causes of acne in three states: closed, blocked and can limit the application area to a focuses on Cutibacterium acnes, a open. Corresponding author Ae-Ran local site of infection.” Gram-positive bacterium typically Kwon explained the research strate- Kim recalled suffering from mild found on healthy human skin, where gy: “The structures solved by X-ray acne breakouts when she felt stressed it helps block pathogens. Specifically, crystallography are often compared to as a teen. “I would get so self-con- C. acnes secretes lipases that break still images. Once you combine sev- scious, lose confidence in face-to-face down lipids in the sebum and release eral images together you can extract conversation and even postpone my fatty acids that form a protective information analogous to a moving dates,” she said. layer on the skin surface. However, animation, so you can see how the She is confident about the high C. acnes colonization of inflamed protein works.” market demand for improved acne sebaceous follicles contributes in an Specifically, the researchers found treatments. as-yet-unknown way to the develop- a novel active site gating mechanism, DOI: 10.1194/jlr.RA119000279 ment of acne. with two key phenylalanine residues Nathalie Gerassimov Recent research supports the idea forming a lid on top of the active site (nathalie.gerassimov that acne is caused by imbalances in that controls lipase activity. Since @gmail.com) is a postdoctoral researcher at the C. acnes subtypes and their re- this lipase is highly conserved across the Carnegie Institution of spective lipases. Specifically, C. acnes C. acnes subtypes, this research also Washington department of type I subclass, called IA, is associ- applies to the acne-associated IA. embryology.

24 ASBMB TODAY JUNE/JULY 2020 JOURNAL NEWS

How post-translational modifications affect the DNA sensor cGAS By John Arnst

hen a pathogen finds its way inside the human body, the Winnate immune system springs into action, thanks to pattern-recog-

nition receptors that pick up on mo- BERNARD HEYMANN /NIAMS & NIH lecular patterns associated with the pathogen’s genetic material and the damage that they cause. While one of these DNA sensors, cyclic GMP- AMP synthase, or cGAS, has been characterized in recent years as a key part of an immune signaling axis that upregulates the cytokine type I inter- The image on the left is the outer protein shell of the herpes simplex virus type 1, the virus that causes feron, the role that factors including cold sores. The image on the right is the mature capsid of the same virus, which Ileana Cristea and her post-translational modifications play colleagues at Princeton University have used to examine the effect of post-translational modifications in its recruitment and activation have on the DNA sensor cGAS. remained unclear. To figure out how PTMs regulate to THP-1 macrophage-like cells, through parallel reaction–monitoring cGAS, a laboratory at Princeton STING-HEK293T cells that had mass spectrometry, that acetylation of University led by Ileana Cristea has been immune-stimulated and human Lys198 decreases during infection with identified and functionally analyzed primary fibroblasts before and after both HSV-1 and human cytomegalo- phosphorylations and acetylations of the cells were infected with herpes virus, which highlights the residue as a cGAS in various cell types. They pub- simplex–type I virus, finding a total regulatory point during virus infection. lished their findings in the journal of six phosphorylations and eight “This area of immunity has Molecular & Cellular Proteomics. acetylations. To assess the functional advanced significantly with the recent “I am fascinated by our co-evo- relevance of each of these PTMs, identification of different DNA lution with the diverse array of viral Cristea’s lab then generated a series sensors,” Cristea said. “Next we pathogens that are part of our eco- of single-point cGAS mutations in need to determine their unique and system,” said Cristea, whose research stable cell lines constructed to express redundant functions and whether involves the proteomics of host–virus cGAS with amino acid substitutions they evolved to recognize diverse interactions. “A growing body of that would either present phos- pathogens in a biological state- or tis- evidence points to post-translational phorylation and acetylation or that sue-specific manner. This information modifications as modulators of DNA mimicked the modified states. is critical for understanding human sensor functions, but this area of They found that an acetyl-mimic immunity, autoimmune disorders investigation is still in early stages, so mutation at Lys198, where lysine and our ability to combat infections.” we aimed to expand the understand- was swapped to glutamine, increased ing of the cGAS PTM landscape and cGAS-dependent interferon sig- John Arnst (jarnst of how these PTMs impact the ability naling compared to a control, and @asbmb.org) is an of cGAS to induce immune responses they showed that two acetyl-mimic ASBMB Today science writer. Follow him on and apoptosis.” mutations at Lys384 and Lys414 can Twitter @arnstjohn. The researchers enriched cGAS by inhibit the ability of cGAS to induce applying immunoaffinity purification apoptosis. The researchers also found,

JUNE/JULY 2020 ASBMB TODAY 25 From the journals

By Himanshi Bhatia, Arti Dumbrepatil, & Anand Rao

We summarize a selection of Cholesterol and the ABCs The evolutionary recent papers from the Journal of of ATP signaling emergence of PD-L2 Biological Chemistry, the Journal The extracellular signaling of ATP The programmed cell death 1, of Lipid Research and Molecular & is implicated in a variety of important or PD1, receptor ligands PD-L1 and Cellular Proteomics. physiological and pathophysiological PD-L2 are transmembrane proteins roles, but the mechanisms responsible that play critical roles in modulating Nonspecific nicking for regulating ATP release are not immune system activation. Howev- by Cas12a well understood. Researchers at Yale er, little is known about the specific The discovery of the CRISPR- University are helping to solve this function of each ligand and when based genome editing system has mystery by identifying a link between their roles differentiated. driven innovation in personalized cholesterol and the release of ATP. In a paper recently published in medicine and incited increased In a paper published in the the Journal of Biological Chem- scrutiny of the precision and Journal of Biological Chemistry, istry, Elliot Phillips of New York specificity of the methodologies Patrick Dunn and colleagues used University School of Medicine and being employed. Cas12a, an hypotonic conditions to induce ATP collaborators explore what makes RNA-guided endonuclease in the release by volume-regulated anion PD-L2 unique and describe its bacterial type V-A CRISPR-Cas channels in HEK-293 cells and moment of evolutionary divergence. anti-phage immune system, recently mouse cerebellar granule neurons. Using site-directed mutagenesis, has emerged as an alternative gene- They then performed a gain-of- surface plasmon resonance and editing tool capable of binding function screen for modulators of crystallography, the authors identified and cutting double-stranded DNA ATP release and identified two ATP- an unexpected loss- and gain-of-in- targets with high specificity, but this binding cassette subfamily G member teraction mutations that resulted in described specificity is paradoxical to 1 variants as modulators. These structural differentiation from PD-L2 the function of Cas12a as an immune transporters are involved in regulating without affecting function. But why responder fighting against rapidly cellular cholesterol, suggesting that did this protein diverge structurally evolving pathogens. how cells handle cholesterol may without an alteration in function? Using high-throughput cleavage affect their extracellular signaling. The authors use phylogenetic analysis assays, Karthik Murugan of Iowa The authors tested this by using to answer this question, revealing that State University and colleagues methyl-beta-cyclodextrin to deplete the new structural features appeared observed widespread cuts to single cellular cholesterol levels, resulting in simultaneously with the emergence strands of double-stranded DNA, ATP export. of placental mammals. Their results known as nicking, and found that These findings raise interesting suggest that the emergence of PD-L2 these nicks occur nonspecifically questions, such as whether from PD-L1 may be important to when Cas12a binds to a target DNA. individuals afflicted with cholesterol- immune system adaptations required Their results, which appear linked diseases present with abnormal for placental gestation. in a recent paper in the Journal extracellular ATP release, and the DOI: 10.1074/jbc.AC119.011747 of Biological Chemistry, provide results could be instrumental in important details about the natural developing improved therapeutic Getting oxidized nucleotides role of Cas12a and demonstrate regimens for the treatment of out of the pool its potential for nonspecific cholesterol-related maladies. Human MuT homologue 1, editing. DOI: 10.1074/jbc.RA119.010699 or MTH1, reduces genotoxicity by DOI: 10.1074/jbc.RA120.012933 removing oxidized nucleotides from the nucleotide pool to prevent their

26 ASBMB TODAY JUNE/JULY 2020 JOURNAL NEWS

Handing over heme for degradation

Heme is a ring-shaped complex formed by four pyrrole molecules In a recent paper in the Journal of Biological Chemistry, Angela that bind iron, and it is an indispensable oxygen-carrying component Fleischhacker and colleagues at the University of Michigan School of of hemoglobin in blood and myoglobin in muscle cells. The breakdown Medicine write that they have detected a protein-mediated transfer of of heme into biliverdin, carbon monoxide and iron plays a number of heme between the HRMs and the HO2 core. Using hydrogen–deuterium important physiological roles. Biliverdin is a precursor to bilirubin, a exchange mass spectrometry, the authors monitored the dynamics of natural antioxidant, and endogenous carbon monoxide is a vasodilatory HO2 with and without iron-containing heme bound to the HRMs and gas that has anti-inflammatory properties. Furthermore, heme itself at to the catalytic core, and they detected conformational changes in the high concentrations can be toxic, promoting oxidative stress and lipid core only when it was in an unbound state. Moreover, the researchers peroxidation. Thus, regulating heme levels is critical for human health, observed heme being transferred to the core from the HRMs and vice but the mechanisms responsible for signaling its degradation are not versa, achieving equilibration. well known. Based on these findings, the authors present a new heme transfer Human heme oxygenase-2, or HO2, is an enzyme that converts model that ascribes functional significance to heme binding of HRMs in heme to biliverdin when heme binds to the enzyme’s core catalytic addition to the catalytic site on HO2. They suggest that this mechanism active site. HO2 also contains two short amino acid sequences known may be essential for toggling between the degradation and maintenance as heme regulatory motifs, or HRMs, that can bind iron-containing of physiological heme levels. heme and are involved in governing heme function. DOI: 10.1074/jbc.RA120.012803 —Anand Rao

This image shows the crystal structure of heme oxygenase-2 in complex with heme. MASAKAZU SUGISHIMA, YAMAGATA UNIVERSITY MASAKAZU SUGISHIMA, YAMAGATA

incorporation into the genome. MTH1 catalyzes the hydrolysis of Lipid swaps alter MTH1 also actively removes nucle- N6-methyl-dATP to N6-methyl- membrane nanodomains otides that have undergone meth- dAMP to prevent its incorporation The plasma membrane has a ylation, a post-translational modifi- into DNA. The authors also identify highly asymmetric distribution of cation. This is an important feature the structure of N6-methyl-dAMP– lipids and contains dynamic nano- because, if allowed to incorporate bound human MTH1, revealing domains surrounded by a different into the DNA, methylated nucleo- why N6-methyl-dATP is a good liquid microenvironment. These tides could have detrimental effects MTH1 substrate. nanodomains play a role in the vital on cellular epigenetic programming. Their work, published in the functions of cells and organisms. Using mutant zebrafish, crys- Journal of Biological Chemistry, However, researchers do not yet tallography, mass spectrometry and reveals a mechanism that helps to understand how these liquid-ordered enzyme kinetic assays, Emma Rose prevent the impaired regulation lipid domains, or rafts, in the plasma Scaletti of Stockholm University of epigenetic control and RNA membrane are formed, which limits and collaborators demonstrate that metabolism. study of their biological functions.

JUNE/JULY 2020 ASBMB TODAY 27 JOURNAL NEWS

Metabolic labeling of bacterial membranes

Continuous use of antimicrobial drugs in medicine, agriculture and PLs are indirect, low-throughput and labor-intensive. aquaculture to treat or prevent infections has led to the emergence Inga Nilsson and an international team of researchers from the of multidrug resistance, or MDR, in both humans and farmed animals. Novartis Institutes for BioMedical Research have used metabolic label- Pathogenic bacterial species that have acquired MDR cause infections ing to detect a compromised OM in intact bacteria. Naturally occurring that are effectively untreatable and present a serious threat to public Escherichia coli lipids are difficult to label, so the researchers explored health. phosphatidylcholine, or PC, labeling by fluorescent click reagents, Gram-negative bacteria are intrinsically resistant to many because PC is present in most pathogenic bacteria. Their recent study antibiotics because of their unique membrane architecture. Phospho- published in the Journal of Lipid Research showed successful metabol- lipids, or PLs, constitute the inner layer of the outer membrane, or OM, ic labeling of cellular PC with 1-azidoethyl-choline to visualize phospho- while the outer layer is composed of lipopolysaccharides. The OM’s lipids in intact E. coli cells with a biorthogonal fluorescent method. strict asymmetry functions as a permeability barrier, protecting the In the future, this assay could be used to identify compounds that cells from the immune system as well as blocking many toxic interfere with OM lipid asymmetry, thus facilitating the discovery of new compounds. This barrier affects drug screening–related research and antimicrobial compounds. The authors suggest that it can be scaled generally results in a low hit rate when screening compound libraries. up to a medium- to high-throughput whole-cell screening assay for OM Consequently, identifying effective new antibiotics or small-molecule asymmetry, phospholipid externalization and OM permeability defects. inhibitors against Gram-negative bacteria has been a major challenge. DOI: 10.1194/jlr.RA120000654 Existing assays to identify a compromised OM by detecting bacterial —Arti Dumbrepatil

Escherichia coli cells are grown with 1-azidoethyl- choline and treated with Alexa488-sDIBO to allow fluorescent detection. ADAPTED FROM NILSSON ET AL./JLR

A research team led by Guangtao domain-forming properties than Reducing cholesterol in Li at Stony Brook University write intact cells. This study improves a corneal disease in their latest study in the Journal understanding of the inherent ability Schnyder crystalline corneal of Lipid Research that the propen- of plasma membrane lipids to form dystrophy, or SCD, is a rare disease sity of plasma membranes to form ordered nanodomains and implies characterized by deposits of choles- ordered domains can be modulated that lipid substitutions in nano- terol and phospholipid in the cornea. by membrane lipid substitutions. To domains can be used to alter biolog- Most cases of SCD lack an obvious understand the properties of plasma ical processes. With further research, systemic disorder, but high choles- membrane lipids and proteins, the insights from this research could be terol levels are common. As SCD researchers generated giant plasma applied to enhance the utility of lipid progresses, an opaque disc of corneal membrane vesicles, or GPMVs, exchange as a method to probe the crystals or other lipids forms, result- in mammalian cells, which repre- functions of membrane domains in ing in impaired vision and ultimately sent a natural membrane system. living organisms. in the need for a corneal graft. GPMVs are easier to investigate for DOI: 10.1194/jlr.RA119000565 SCD is caused by mutations

28 ASBMB TODAY JUNE/JULY 2020 JOURNAL NEWS

Algorithm identifies active kinases for AML treatment

Continuous use of antimicrobial drugs in medicine, agriculture and Acute myeloid leukemia, or AML, is a cancer of the bone marrow ics combined with INKA analysis to identify hyperphosphorylated active aquaculture to treat or prevent infections has led to the emergence and blood that progresses rapidly if left untreated. An estimated kinases. Due to the heterogeneous signaling in these cell lines, the anal- of multidrug resistance, or MDR, in both humans and farmed animals. 19,000 new cases will be diagnosed this year with a five-year survival ysis identified multiple phosphopeptides. INKA analysis of individual cell Pathogenic bacterial species that have acquired MDR cause infections rate of 28.1%. Small-molecule kinase inhibitors are a potential treat- lines identified specific driver kinases, including PDGFRA, JAK2, KIT and that are effectively untreatable and present a serious threat to public ment strategy for AML patients. However, due to molecular heterogene- FLT3. Using this approach, the researchers identified and functionally health. ity in AML, no single molecule has been clinically effective. verified active tyrosine kinases in 10 cell lines. For the remaining six cell Gram-negative bacteria are intrinsically resistant to many In their recent study published in the journal Molecular & Cellular lines without a tyrosine kinase driver, they identified MAPK signaling as antibiotics because of their unique membrane architecture. Phospho- Proteomics, Carolien van Alphen and colleagues at the Amsterdam a potential drug target. lipids, or PLs, constitute the inner layer of the outer membrane, or OM, University Medical Center relied on an integrative inferred kinase The authors concluded the study by applying their analytical while the outer layer is composed of lipopolysaccharides. The OM’s activity, or INKA, algorithm to identify prospective small-molecule strategy to clinical samples. Despite the lower amount of input sample, strict asymmetry functions as a permeability barrier, protecting the kinase inhibitors. For each given kinase, INKA performs a four-compo- phosphoproteomic and INKA analysis identified similar driver kinases cells from the immune system as well as blocking many toxic nent analysis by determining the phosphorylation status of the kinase in patient samples to those in the cell lines. The in-depth analysis compounds. This barrier affects drug screening–related research and itself, its activation loop and all its possible substrates. INKA assigns a performed in this study provides a basis for future clinical applications generally results in a low hit rate when screening compound libraries. nonzero score to kinases with both kinase-centric and substrate-cen- for personalized treatment of AML patients. Consequently, identifying effective new antibiotics or small-molecule tric phosphorylation status. DOI: 10.1074/mcp.RA119.001504 inhibitors against Gram-negative bacteria has been a major challenge. A panel of 16 AML cell lines was chosen for pY-phosphoproteom- —Himanshi Bhatia Existing assays to identify a compromised OM by detecting bacterial

This schematic representation shows INKA analysis for a panel of acute myeloid leukemia cell lines. CAROLIEN VAN ALPHEN ET AL./MCP. CAROLIEN VAN

JUNE/JULY 2020 ASBMB TODAY 29 JOURNAL NEWS

in the gene encoding UbiA pren- detailed workflow for LCM-based brains, proline-arginine, or poly-PR, yltransferase domain-containing proteomic analysis of the substantia and glycine-arginine, or poly-GR, protein-1, or UBIAD1. The disease nigra, a region of the brain rich in exhibit greater levels of cellular tox- is characterized by inhibition of the dopaminergic neurons and implicat- icity. The toxicity has been attributed SCD-associated UBIAD1 degra- ed in Parkinson’s disease. The authors to repeat-associated non-AUG-ini- dation via the endoplasmic reticu- have unraveled the substantia nigra tiated translation that results in lum–associated degradation pathway. proteome using limited quantities of production of abnormal translation This significantly contributes to the tissue samples. products of varying lengths. While it dysregulation of cholesterol synthe- Eva Griesser and colleagues at is reported that these polymers stall sis. A new study published in the the University of Dundee, U.K., first the ribosomal translation machinery Journal of Lipid Research sheds optimized their protocol for isolating and ribosome biogenesis, not much light on the SCD etiology and its proteins from tissue samples. They is known about the identity of the importance in improving the efficacy performed comparative analysis for affected proteome. For a recent study of cholesterol-lowering statin therapy, testing LCM efficiency in five healthy published in the journal Molecular for which the major limitation is the donors who each provided intact & Cellular Proteomics, Mona Rad- UBIAD1-mediated dysregulation tissue and 3,000 cells, which were wan and colleagues at the University of cholesterol synthesis. A multide- isolated with LCM. Bioinformatic of Melbourne, Australia, performed partment team at the University of analysis identified neuron-specific whole proteomic profiling to probe Texas Southwestern Medical Center proteins and gene ontology, or GO, the interacting partners of these toxic led by Dong-Jae Jun postulates that cellular components to be enriched in polymers of varying lengths. accumulation of SCD-associated the microdissected samples. Using a combination of immu- UBIAD1 via sequestration in the ER Application of this optimized noprecipitation, mass spectrometry results in a buildup of cholesterol. protocol to the substantia nigra and green fluorescent protein-labeled Identification of agents that accelerate from 15 healthy donors identified peptides, the authors identified the degradation of SCD-associated 5,677 protein groups with GO multiple cellular pathways through UBIAD1 may help to prevent cho- terms ranging from substantia nigra which Arg-rich polymers manifest lesterol accumulation and the corneal development and neurotransmitter cellular toxicity. The affected protein opacity associated with SCD. secretion (high intensity) to lysosome machinery for poly-PR and poly-GR DOI: 10.1194/jlr.RA119000551 and trans-Golgi network (low inten- ranged from cytoskeletal proteins sity). This methodology will facilitate to arginine methylases PRMT1 and (Laser)-capturing the proteomic analysis of different brain PRMT5, which was in striking con- substantia nigra proteome regions in the course of neurodegen- trast to the partners of inert polymers Many challenges hinder the erative disorders. like poly-GA. The effect was further analysis of tissue sections, includ- DOI: 10.1074/mcp.RA119.001889 pronounced with varying lengths ing their heterogeneous nature and of these polymers, with 101x DPRs limited cell numbers in distinct cell Promiscuous binding in inducing marked ribosome stalling populations. Laser capture microdis- motor neuron disease and toxicity. These insights into the section, or LCM, is a technique that Arginine-based dipeptide repeat multiple pathophysiological mecha- purifies small cell populations from polymers, or DPRs, are a unique nisms inherent in MND pave a path mixed samples. In a study published characteristic of motor neuron for deeper understanding of neurode- in the journal Molecular & Cellular disease, or MND. Among the ab- generation. Proteomics, the authors present a normally expressed DPRs in patient DOI: 10.1074/mcp.RA119.001888

Himanshi Bhatia (himanshi.b Arti Dumbrepatil Anand Rao @gmail.com) is a ([email protected]) ([email protected]) is a postdoctoral research is a science writer covering science communicator associate at the Washington topics ranging from for the ASBMB. Follow University in St. Louis and nanorobots to virology. She him on Twitter is passionate about science has a Ph.D. in biochemistry @AnandRaoPhD. communication. and writes for Microbiome Digest and Bio Voice News.

30 ASBMB TODAY JUNE/JULY 2020 NEWS

How to catch and kill a coronavirus on a doorknob

By John Arnst

ore than two months after the treme, we can make purely synthetic World Health Organization de- materials that have an incredibly long Mclared the outbreak of the new lifetime but don’t have any biological coronavirus a global pandemic, we function.” lather and scrub our hands — sing- According to Page, another chal- Rick Page ing Happy Birthday, twice, or maybe lenge will be ensuring that functional the chorus to Mr. Brightside — to groups remain active in the environ- wash away the possibility that we’ll ment where the materials are tested. bring the virus into our mouths and “We typically think of them lungs from a contaminated handrail acting in water, but we’re going to or doorknob. To cut off these routes be putting them on a surface where of indirect transmission, researchers they may very well be getting dried,” at Miami University in Ohio are de- he said. “(We’re) trying to figure out Dominik Konkolewicz veloping polymer coatings for public how much of these we need to put surfaces that have the potential to contact with biological species and on the surface and if we can keep the capture and inactivate SARS-CoV-2, how biological membranes inter- groups functional so they are still able the virus that causes COVID-19. act with the polymers, as sticking to sequester a virion.” Rick Page and Dominik macromolecules to a synthetic surface Like researchers at most univer- Konkolewicz, who specialize in pro- can cause changes in the combined sities, Page and Konkolewicz have tein biochemistry and polymer chem- 3-D net-like structure that affect the had their labs — which are around istry, respectively, recently received performance of both materials. 1,400 square feet each — closed since $181,849 from the National Science “We can change how closely we mid-March. However, they recently Foundation for this work. They plan pack the net elements and where we received approval to begin working to develop protein–polymer mate- place different groups,” Konkolewicz on their NSF-funded project in June, rials that can use peptides to either said. “If we change the structure in which will entail researchers working capture the virus by grabbing onto its a systematic fashion, how does that in shifts and maintaining appropriate spike proteins or inactivate the virus impact the material’s performance?” distance from one another. by disrupting its outer lipid layer, or The researchers also intend to “I think it’s going to start off do both. evaluate the overall durability of with a few graduate students coming “We’re taking two reasonably dif- the polymer–protein coatings once back,” Page said. “We’re doing all of ferent areas of chemistry and putting they’ve been applied to a surface; a the intro work that we can (for the them together to make advances on coating that rubs off the first time COVID-19 project) at home … to both sides,” Page said. “Neither of someone touches it would be of little try to get things ready to go so that us would be able to do this on our practical use. come June 1, we can hit the ground own.” “We can put the peptides (right) running.” Page and Konkolewicz have been on surfaces … but there’s very little

collaborating for more than six years chance that the peptide would stay John Arnst (jarnst and have worked on applying func- on the surface for the length of time @asbmb.org) is an tional groups that can disrupt vesicles that we want it to. So if we’re looking ASBMB Today science writer. Follow him on and other lipid layers to polymer at a doorknob, and you touch the Twitter @arnstjohn. coatings. They investigate both how doorknob, the peptide’s gone,” synthetic macromolecules behave in Konkolewicz said. “On the other ex-

JUNE/JULY 2020 ASBMB TODAY 31 FEATURE

On the front lines of CORONAVIRUS CARE Recent months have been challenging, tiring and exciting for Mike Gillette, an By John Arnst ICU physician and Molecular & Cellular Proteomics associate editor

ore than two decades ago, Michael Gillette How has working in the intensive care units been since noticed that patients being treated in the the coronavirus outbreak hit Massachusetts? intensive care units at Massachusetts General Well, next to New York and New Jersey, Massachu- MHospital for the same condition responded setts has had a particularly difficult time with the pandem- differently to the same drugs. Reasoning that different ic. The state is now approaching 100,000 confirmed cases molecular processes underlay common syndromes, he and 7,000 deaths, but we’re fortunately on the downward became interested in better aligning the treatment with the slope, at least until the impact of trying to reopen things is specific pathology — what we now call precision medicine. fully realized. Since then, he has juggled his work at Mass General with The intensive care unit that I work in most of the translational and biomarker research at the Broad Institute time, the main medical intensive care unit, is an 18-bed of the Massachusetts Institute of Technology and Harvard unit. And there’s another mixed medical–surgical intensive and teaching duties at the hospital and Harvard Medical care unit I often attend on that typically has an additional School. But with the outbreak of COVID-19 in Massachu- 10 or 12 medical ICU patients. setts, the critical care physician has spent all of his working We will sometimes occupy several beds in the cardiac hours, and most of his waking ones, treating coronavirus intensive care unit, particularly in the winter in the mid- patients in the now single-purpose intensive care units. dle of flu season. So, when things are bad, we might have Gillette’s professional path was more circuitous than 32 or 34 beds for medical ICU patients. We got up to most. After graduating from Carleton College in Minne- more than 180 at our peak occupancy in April. sota with a B.A. in biology and philosophy, he attended Our cardiac intensive care unit became a COVID-19 Oxford University as a Rhodes scholar, where he earned unit. Our neuro ICU became a COVID-19 unit. Our master’s degrees in philosophy and experimental psychol- burn unit became a COVID-19 unit. We had adult ogy and in human biology. He then earned both an M.D. COVID-19 patients being managed in the pediatric in- and a Ph.D. from Harvard Medical School, going on to tensive care unit. Half of the postoperative acute care unit train at Mass General with a specialization in pulmonary was a COVID-19 unit. and critical care medicine. Two general floors in one of our buildings have the A longtime colleague of Molecular & Cellular Pro- appropriate physical infrastructure — gas lines, electrical teomics Deputy Editor Steven Carr, Gillette became an panel, stuff like that — and were converted to COVID-19 MCP associate editor in 2018. He recently spoke with units. And that’s just accounting for the critically ill John Arnst, an ASBMB Today science writer, about work- patients. A number of hospital floors were dedicated ing in the intensive care unit at Mass General during the COVID-19 floors for those who just needed general sup- pandemic. Earlier this year, they talked about how Gillette portive care and supplemental oxygen. came to work in proteomics. These interviews have been All kinds of doctors and nurses were stepping in edited for clarity and length. outside of their normal roles and their normal practice to

32 ASBMB TODAY JUNE/JULY 2020 FEATURE

After graduating from Harvard Medical School in 1995, Gillette did his residency, then a fellowship, at Massachusetts General Hospital, where he continues to work today.

assist — nurses who don’t normally do critical care were Another thing that has been really striking is the de-

JENNIFER GILLETTE doing critical care; physicians who don’t normally do crit- gree to which the pandemic is revealing the fracture lines ical care were doing critical care. We’ve had surge staffing in our social fabric. You read these things in the newspa- in place now for several months, which is supposed to be per: “This is another manifestation of systemic racism and five days on and five days off, although the five days off is class disparities.” But it’s really evident in the hospital be- often interrupted with time on. cause the things that are associated with severe disease — hypertension, diabetes, obesity and heart disease, and to a What did that look like for ICU docs? lesser degree, actually, lung disease — are disproportion- The ICU-trained docs were trying to put together ately represented in black and Latino populations where detailed protocols to guide other practitioners and were the health care needs have historically been systematically consulting across all the units. Even ICU triage, which under-addressed. is normally a little side role when you’re on service in the intensive care unit, became a dedicated role, and it took How is the surge in COVID-19 patients affecting the rest a critical care expert working full time to keep up with of the hospital’s operations? where patients were, what the capacity was, how to redis- There was a time when, whichever intensive care tribute them and how to load balance across hospitals. unit you walked into, everybody was critically ill from It’s really been an extraordinary time — lots of people COVID-19. And that was it. stepped up in other ways, even within their domain of And they all have the same stories. There’s basically expertise. For instance, these critically ill patients often one narrative: seven days of malaise, myalgias, a fever need a fair number of procedures done; they need central and dry cough. Then progressive shortness of breath that line access and arterial lines and things like that. brings them to the hospital, where some of them stabilize Normally, that’s all part of our practice. But when you’re and others relatively quickly worsen and end up needing as busy as we have been, it’s really difficult to be admitting to be intubated for acute respiratory distress syndrome. and managing critically ill patients all over the hospital and Part of what was so strange is that we normally are getting the procedures done and supervised. And that’s very busy and have full intensive care units without especially true given that we usually rely on residents to be patients with COVID-19 and ARDS. The conditions stepping in and doing some of these lower-level procedures we normally treat didn’t disappear with the onset of once they’re trained; but there was a real objective, especially COVID-19. So the question became: Where were they all? earlier on in the epidemic, to try to keep trainees out of It really can’t be a good thing that all of the critically ill pa- direct patient-contact situations. Attending-level surgeons tients that I would normally be taking care of weren’t there. and other expert proceduralists formed a specialized team to There have been a lot of COVID-19 deaths where get this work done quickly and safely. we’ll never know, because of a lack of testing, whether

JUNE/JULY 2020 ASBMB TODAY 33 they were directly attributable to COVID-19. But there from that experience. I think the playbook really is there is a still larger impact of people who delayed seeking care — how you develop that kind of surge capacity quickly — for other conditions and then came in later than they nor- and there are going to be a lot more practitioners who are mally would, sometimes past the point when you could familiar with the drill, if you will. actually help them anymore. Without wanting to seem strange and macabre, it was Now that COVID-19 cases are starting to ratchet kind of exciting to be dealing with this in the early going. down, we’re starting to see the patients with liver failure I was working really long hours, but I would not have and the patients with strokes, the patients with heart at- wanted to be doing anything else. I felt like this was stuff tacks showing up again, so it’s just really clear that people I’m trained for. were laying low and deciding that it was better to suffer at But the caveat to that is that I do think practitioner home than to go in and risk being infected if they weren’t fatigue is going to be a pretty serious issue, in addition to already infected. And that’s a scary thing. the existing concerns about stress and mental health in the A lot of these COVID-19 patients who are now general front-line community. While that’s not something getting better from their critical illness are going to need that personally I deal with, I am getting tired. If we get sustained periods of rehab. Those numbers are huge, and I a month off and then the cases start to uptick a little bit don’t think the rehab capacity really exists for that. It’s like and then by fall we’re back to this full-surge programming a wave; it just keeps going to the next level of care and the again, that’s going to be hard. Even though we’ll have the next level of care and the next level of care. playbook, I think that’s going to be, in many ways, harder than the first time. What about accounts of people who have recovered from COVID-19 but are now experiencing pain or loss of How did you become interested in proteomics and sensation in their extremities? biomarkers? There’s just a lot we still don’t really understand about We have syndromes that we treat, like severe sepsis. the disease. But one thing has been pretty clear: The Severe sepsis means that you have either a strong suspicion patients who get critically ill and have respiratory failure of an infection or evidence of an infection, and some sort have needed ventilatory support for quite a long time, of multisystem organ dysfunction. That has all kinds of even relative to severe cases of ARDS. different manifestations and different molecular underpin- Regular influenza can sometimes cause severe ARDS, nings in terms of the host response. It remains a relatively but for the most part, it’ll be a bacterial infection or lethal condition. pancreatitis or something similar that sets it off. And we’re Although progress has been made because of improve- treating the underlying cause at the same time that we’re ments in supportive care and our deployment of critical supporting the patient through the ARDS. But if you early interventions, it’s still something where, depending don’t have anything that actually treats COVID-19 — I on the center, 25% to 40% of patients who present with mean, we’ve got encouraging news about remdesivir but severe sepsis succumb to it during their hospital stay. not enough remdesivir to be giving it to everybody — if With those kinds of numbers, as you’d imagine, phar- you aren’t treating the underlying disease, then it’s going macologic interventions have been investigated and pro- to continue to drive the illness for a longer period of time. posed, and a lot of drugs have gotten into various clinical The longer you’re critically ill and the longer you’re trials, with some of them in advanced clinical trials. At this intubated, the more debilitated you’re going to be. And so, point, there are no drugs that are FDA approved for severe even without these other strange complications of coronavirus sepsis. There was one, Xigris, that became FDA approved infection that we’re just beginning to understand and tally, and made it into clinical use; it has since been withdrawn there are going to be patients who need a long time to recover. for a lack of efficacy and concerning side effects. The issue is probably not that we have never had As you’re scaling back in the hospital, do you feel like drugs that might work but that we have never known the you’re better prepared for when things ramp back up in patients to give them to. I was really interested, from that a few months? perspective, in precision medicine before it was a kind I think there’s the direct answer, and then there’s a sort of of buzzword. So 20 years ago, I came over from Mass caveat. The direct answer is: absolutely. General and started working at the Center for Genome The foresight and the leadership at our institution Research, which became the Broad Institute. were amazing, partly because they had forewarning that I wanted to work on understanding the molecular New York didn’t have, partly because they were learning underpinnings of disease so that we could stratify patients

34 ASBMB TODAY JUNE/JULY 2020 and could begin to say, even if it’s a retrospective analysis, And he said, “I think you should go to medical school that there are subgroups that we can define molecularly because biology and medicine are cool.” He was going with biomarkers. to go to medical school. And so I just decided, sitting up there in the thin atmosphere, “Medical school sounds How has your background as a physician informed that really interesting; I’ll bet I’d really like that.” And I was research? probably in my second year of medical school before I I think having a clinical sense of where the important started to grapple with the idea that, as things would questions lie and what a clinician would want to know is naturally progress, I was probably going to end up being a really central, particularly on the biomarker side of things doctor. I was very interested in brain and mind stuff that but probably also on the biological discovery side of things. combined all of my interests in biology, philosophy and I find that when I’m working with my proteomics experimental psychology. colleagues, my clinical perspective is constantly valuable in I ended up doing a Ph.D. in neuroscience in the middle helping make sure that people are thinking about the right of medical school, and I expected to do neurosurgery and sorts of samples that we’d want to collect, what the right sort combine that with neurophysiology, but I couldn’t line of controls are and which relevant variables we’re going to up enough surgical rotations early enough to actually do manage throughout the course of a treatment or project. a surgical internship without postponing a year. And I thought, “Well, I’m going to get on with it; I’ll do a medical Was cardiopulmonology, or being a physician in general, internship and then I’ll apply in surgery.” In my early something you thought you were going to do from a young age? rotation as a medical intern at Mass General, I was in the No, it wasn’t one of these things where I grew up intensive care unit, and the people there were great and the having any idea what I was going to do. physiology was really cool. And I liked the combination of I’m a little bit, dispositionally, a dilettante. I had a really sick patients and fascinating ethical problems. So a lot biology/philosophy double major as an undergraduate. of circumnavigation to get where I ended up. I have a master’s degree in philosophy and experimental psychology, and I have a master’s degree in biological Do you have any advice for early-career scientists who anthropology. I have an M.D., and my Ph.D. is in neu- are starting out? rophysiology. I thought coming out of college that I was I would say it’s important to really be assertive and either going to do environmental law or marine biology. advocate for yourself. I also think you should, at all stages, I had a friend who was going to medical school while focus on working with the people you’re excited about and I was at Oxford at the time I was collecting these random working on problems that you’re passionate about. degrees. During a trip, we were literally sitting on top of John Arnst ([email protected]) is an ASBMB Today Mount Kenya, and it was a gorgeous morning. We were Doscience you writer. have Follow him any on Twitter advice @arnstjohn. for early- exhausted, and I was getting increasingly concerned in career scientists the background about what I was going to do when I left who are starting out? Oxford because I really hadn’t made up my mind at all. I would say it’s important to really be asser-

JENNIFER GILLETTE

In less demanding times, Gillette and his wife Jennifer — with whom he has two sons and recently began fostering a third — enjoy hiking, fishing and skiing, among other hobbies.

JUNE/JULY 2020 ASBMB TODAY 35 FEATURE

If you want to find interesting enzymes, a carnivorous plant is a really good place to look,” said UCI professor Rachel Martin, who has applied her lab’s expertise in cysteine proteases from sundew plants to study the cysteine protease of SARS-CoV-2. Image credit: Noah Elhardt/Wikimedia

36 ASBMB TODAY JUNE/JULY 2020 FEATURE

Pivoting from carnivorous plants to COVID-19 UCI professors team up to seek protease inhibitors

By Laurel Oldach

ou might not think that research units that replicate the viral genome, hijack into how carnivorous plants digest the host cell’s immune response and carry out their meals would be remotely other nonstructural roles. Yuseful in responding to a pandemic. Protease inhibitors have been successful But that’s the thing about basic research: Its treatments for other viral infections, such

applications are unpredictable. as HIV. Drug repurposing studies such as MARTIN COURTESY OF RACHEL Before the COVID-19 pandemic, Rachel the World Health Organization’s Solidarity Martin, a biophysical chemist at the Uni- Trial are testing the HIV protease inhibi- versity of California, Irvine, studied diverse tors ritonavir and lopinavir in patients with proteases, including from the carnivorous COVID-19 to see whether they give clinical sundew plant, for a different purpose, to benefit. explore ways to break down harmful, pro- But existing drugs developed for other tease-resistant aggregates such as amyloid viral proteases may fail to block Mpro. Even plaques. if they do work, there’s a possibility that their Now, Martin is leading many of the labs effect will be limited or that widespread use University of California, Irvine, in her department in a research consortium will promote viral resistance. In all likeli- chemistry professor Rachel Martin in that aims to design new protease inhibitors hood, cocktails of multiple antivirals will be her lab. specific for the coronavirus protease. Working needed, so scientists around the world are six feet apart in the lab or from home using racing to find compounds that inhibit MPro software for virtual screens, the team hopes activity and might become, or inspire, future to contribute to a future arsenal of antivirals drugs. That’s where Martin, vice chair of the against SARS-CoV-2, the virus that causes chemistry department at UCI, comes in: A COVID-19. protease expert whose lab is conversant in both computational and biochemical studies, A hunt for protease inhibitors she saw an opportunity to contribute to the Proteases play an important role in hunt for protease inhibitors. COVID-19 infection. The novel coronavirus translates much of its RNA genome into two Proteases from carnivorous plants long polyproteins. It requires a protease called Martin studies the biophysics of protein COURTESY OF RACHEL MARTIN COURTESY OF RACHEL MPro, or the main protease, to cleave that aggregation, which is linked to human diseas- long polyprotein into 16 individual active es such as Alzheimer’s. One possible strategy

JUNE/JULY 2020 ASBMB TODAY 37 FEATURE

to reverse harmful aggregation would be to An assay for robust inhibition introduce new proteases. To find proteases The consortium includes two compu- with new functions, Martin and colleague tational labs and six experimental labs in Carter Butts sequenced the genome of the addition to Martin’s from the UCI chemistry

COURTESY OF RACHEL MARTIN COURTESY OF RACHEL sundew Drosera capensis, a plant that traps department. The team has two research goals; and slowly digests insects that land on its the first is to find one or more inhibitors that sticky hairs. specifically inhibit the SARS-CoV-2 main “If you want to find interesting enzymes, protease. a carnivorous plant is a really good place to Much like the sundew protease project, look,” Martin said. Unlike animals, which the work starts with computational mod- break down food mechanically and digest eling. The team takes a structure — the it in specialized organs, she said, a carnivo- European protein database currently lists rous plant “has to perform all of its digestive 124 reports on the structure of the protease, functions right out in the open, where it’s in including many in complex with ligands — competition with bacteria and fungus. … All and uses molecular simulations to predict it has are really amazing enzymes.” other possible conformations. Then, they Once Martin and her team identified dock ligands numbering in the thousands 44 new cysteine proteases in the sundew ge- from libraries curated by DrugBank, UC Ir- nome, they needed to predict each protease’s vine and other academic institutions around Marquise Crosby, a graduate student in substrate selectivity to decide where to focus the world to see which are best able to bind Martin’s lab, has shifted from studying their biochemical resources. to the enzyme’s active site. This lets them sundew to producing protease. After using a program called Rosetta to narrow down the dizzying list of potential predict the structure of each protease and molecules to strong candidates to be tested in refining those predictions manually, the team the wet lab. used molecular docking simulations and ma- To test how well the modeled chemicals chine learning to predict the substrates each work in a test tube, the consortium needs enzyme might be able to bind and cleave. huge quantities of purified protease, which When COVID-19 struck, Martin said, Martin’s lab is producing and characteriz- The stereotype she realized that the pipeline her team used ing, and adequate amounts of each of the of“ a lab scientist to search for substrates could be converted promising compounds, which the depart- is somebody who’s to seek inhibitors instead. After all, she said, ment’s synthetic labs are producing. They also socially maladjusted “If you think about it, an inhibitor is just a need to monitor how active the protease is substrate that doesn’t do the chemistry.” in the presence of each candidate inhibitor. and has no friends, Martin knew her lab could contribute. Researchers in Nowick’s lab synthesized a but that’s not how As most of the UCI campus prepared to shut probe that had been published, but was not it works at all. down, she prepared her team to launch a yet available for sale. When the protease Experimentalists are socially distanced research project. James No- cleaves the probe, it fluoresces, allowing wick, a chemistry professor in a neighboring high-throughput testing of candidate inhibi- very social! lab, was ticking through a shutdown checklist tors in a 96-well plate format. says RachelMartin.” when Martin stopped in to ask that he leave the shared ultrapure water system on—she Mapping mutational landscapes was going to need it. Nowick said, “It was The consortium is pursuing a second goal like a lightbulb went on — that biomedical in tandem with the first: to identify inhibi- scientists should be putting all hands on deck tors or combinations that make it difficult for to solve this problem.” the virus to develop resistance. He wasn’t the only fellow professor to sign The team has started by working to up to help; the consortium quickly grew to ten understand what Martin calls the mutation- labs. Martin said, “Basically every colleague al landscape of the protease in circulating that I told about it said, ‘What can I do?’” coronavirus strains. If there is already a strain

38 ASBMB TODAY JUNE/JULY 2020 FEATURE

in circulation that can resist a candidate protease inhibitor, that’s crucial information for moving forward. Similarly, if resistance is just a mutation or two away, the scientists would like to know that. COURTESY OF RACHEL MARTIN COURTESY OF RACHEL Every day, undergraduate T.J. Cross, who joined Martin’s lab just days before the university shut down, and graduate student Gemma Takahashi comb an epidemiological sequencing database in search of new mutations to the protease. Each time a laboratory submits a sequence to the Global Initiative on Sharing All Influenza Data, or GISAID, Undergraduate T.J. Cross helps monitor a global epidemiological sequencing database for that includes a new protease mutation, the new mutations to the SARS-nCoV-2 protease. team uses molecular dynamics simulations to model how it affects the protein’s shape, movements and interaction with selected at a time, the work seems to move achingly compounds. In May, the team posted a slowly. Every stint at the bench must be care- If you want to preprint analyzing 79 known variants of the fully coordinated in the lab’s Slack channel. find“ interesting protease. Members of the lab also miss sharing ideas, enzymes, a “Right now, we are simulating every sin- technical advice and the simple pleasure of carnivorous plant gle one,” Martin said. “And yes, it is expen- each other’s company. sive. Yes, we’re doing it. We know that it may “The stereotype of a lab scientist is is a really good not be sustainable long term … but we’re somebody who’s socially maladjusted and has place to look, going to do the best we can for a while.” no friends, but that’s not how it works at all,” says Rachel ” Martin told the audience of a recent webinar. Martin. Logistics of a big consortium “Experimentalists are very social!” Martin’s salary, those of her faculty col- Martin has also stayed in close contact leagues and their students and postdocs, are with other teams working on protease inhib- funded by grants, and she said that program itor development. Around the world, teams officers have been happy to support their at the University of Hamburg, the University pivot to COVID-19 research. Covering of Science and Technology of China, the the cost of reagents and computer time has Swiss Federal Institute of Technology, and the been more of a challenge. The university has University of California, San Francisco, and dedicated some discretionary funding and led other international consortia are working to crowdfunding efforts to support the project, develop protease inhibitors. but to keep it going long-term, the group “We’re keeping in touch to make sure will need more funding. That’s a challenge, that we’re not duplicating efforts,” Martin as grant cycles move much more slowly than said. “Everybody I’ve talked to from all over this project has. the world … has been very collaborative and Martin has led research consortia before, eager to solve the problem.” but never one that came together so fast. Within eight weeks of conceiving of the project, she was supervising the first positive Laurel Oldach ([email protected]) is control assays remotely. Soon, she said, the a science writer for the ASBMB. Follow her on Twitter @LaurelOld. team hopes to test its first candidate compounds. At the same time, she added, because just two people can safely work in the lab

JUNE/JULY 2020 ASBMB TODAY 39 AWARD WINNERS AWARD WINNERS

ASBMB MID-CAREER LEADERSHIP AWARD Corbett goes the extra mile to support young scientists By Nivedita Uday Hegdekar

nita Corbett understands first- hand how early influences can Unraveling human diseases Ashape a young scientist’s career with systems biology research path. A high school chemistry teacher named Mrs. Broadway encouraged Anita Corbett’s research group focuses on Corbett’s interest. understanding the molecular basis for diseases, “I liked science and was good at particularly how missense mutations in proteins it, but that was about it,” she said. lead to distinct disease phenotypes. “However, she saw something special Studies have shown that mutations in me that I didn’t. She appointed in multiple genes encoding structural RNA me as the captain of Science Bowl exosome subunits are linked to disease. In one Anita Corbett team and encouraged me to develop project, following a successful collaboration my leadership skills and scientific with clinicians, the Corbett group was the first to link mutations in a gene encoding one acumen.” particular subunit of the RNA exosome, EXOSC5, to clinical outcomes (developmental As an undergrad at Colgate delays, cerebellar hypoplasia and motor weakness). University, Corbett said, her conversa- In a recent study, the Corbett group collaborated to combine various genetic models, tions with Roger Rowlett helped her including budding yeast and zebrafish, as well as biochemical techniques to characterize develop as a researcher and science how changes in the protein found in people with EXOSC5 mutations ultimately affected advocate. “I was one of Roger’s earliest the function of the RNA exosome complex. trainees and loved working in his lab. As the RNA exosome subunits are expressed ubiquitously in every cell, so are the He had confidence in my abilities and pathogenic variants. Thus, the lab also further determines the requirement for the RNA was such a positive influence.” exosome in specific tissues/cell types and provides insight into how defects in RNA While pursuing her Ph.D. in exosome function contribute to specific clinical manifestations. Neil Osheroff’s lab at Vanderbilt University, Corbett learned to love teaching and mentoring. “His lab Young Investigator Award, Christine help your fellow researchers. The rest welcomed many undergraduate Dunham. will follow through.” researchers,” she said, “and I gained “When shortlisting seminar Anita Corbett is the inaugural a lot of experience through training speakers at Emory University, I focus recipient of the ASBMB Mid-Career and mentoring people from different on inviting junior faculty, particu- Leadership Award recognizing an walks of life.” larly women, whose careers would individual at the full professor or In 2003, Corbett was the first benefit from another invitation on senior scientist level with a strong com- woman to receive tenure in the their CV,” she said. mitment to advancing the careers of department of biochemistry at Emory Corbett describes the research women in biochemistry and molecular University School of Medicine. She in her lab as “model system fluid” biology. This award will be presented is now a professor in the biology because high school students, unat the 2021 ASBMB Annual Meeting department and co-director of several dergraduates, graduate students and in Indianapolis. prominent programs at Emory Uni- postdoctoral fellows with expertise in versity. various model organisms all collabo- Corbett is passionate about rate on certain projects. Nivedita Uday Hegdekar is a increasing diversity and inclusion After 23 years as a professor, graduate student at the University of Maryland in science and goes the extra mile Corbett has this advice: “Always pur- working toward a Ph.D. in to support the career development sue an area of work that fulfills you; biochemistry and molecular biology and an M.S. in of young scientists. She nominated don’t shy away from asking for help patent law. the recipient of the 2019 ASBMB when required; and always, always

40 ASBMB TODAY JUNE/JULY 2020 AWARD WINNERS AWARD WINNERS

ASBMB EARLY-CAREER LEADERSHIP AWARD Jura is inspired by her grandmother, a ‘true pioneer’ By Kerri Beth Boggs

hen she was a child, Natalia Jura traveled from Krakow to Chasing high resolution Wnorthern Poland to spend the structures of elusive cell summer months with her grand- receptors mother. Her grandmother was a pharmacist, and she gave Jura small Natalia Jura aims to understand how tasks to help serve her customers. cells communicate with each other and the Jura learned how to weigh and mix environment. Her lab addresses this ques- chemicals for her grandmother’s for- tion by studying the structure of single-pass mulations. She became curious about transmembrane proteins, which serve as how the medicines worked. cell surface receptors. Receptor tyrosine Natalia Jura “I wondered, ‘How does she kinases, or RTKs, represent leading clinical know what to mix so that people get targets since they are often hijacked by cancers and viruses. The long-term goal of Jura’s better?’” Jura said. lab is to develop therapeutic strategies to target these receptors in human diseases. Jura now considers her grand- RTKs eluded structural investigation for many years because they are difficult to mother a true pioneer. After leaving express and analyze via X-ray crystallography. Jura’s lab developed techniques to improve university to have children, Jura’s the purification of these receptors. They use cryo-electron microscopy to study different grandmother returned to finish her conformations of the proteins. One goal of Jura’s lab is to reconstruct the architecture degree and become a pharmacist. of RTK signaling complexes to understand how they promote cell proliferation, division, Her determination and ambition movement and other crucial processes. inspired Jura to take on new chal- Jura’s lab also studies the molecular and structural mechanisms by which pseudoki- lenges. nases communicate signals. These highly conserved proteins evolved parallel to catalytic “She would always tell me, ‘Your kinases, and they represent another important group of disease targets. Although pseu- brain is your biggest asset,’” Jura dokinases are members of the protein kinase superfamily, they primarily utilize noncatalytic said. “Growing up as a girl, that was mechanisms for signaling. Jura hopes that understanding the structure and function of these an important message.” proteins will open doors for development of inhibitors to target pseudokinases linked to Jura created a home laboratory. disease. She tested acids and bases with pH indicators and observed the color changes. Her mind thrived on figur- biology as a postdoc at the University careers of women in biochemistry and ing out how things worked. of California, Berkeley. molecular biology along with demon- Jura’s scientific interests grew Now an associate professor at strated excellence in research, discovery stronger throughout school, so she the University of California, San and/or service. Due to the cancellation pursued a master’s in molecular Francisco, Jura said she is grateful for of the 2020 ASBMB Annual Meeting, biology from Jagiellonian University the collaborations she has built since this award will be presented at the in Poland. Though the university had she started her lab in 2010. 2021 ASBMB Annual Meeting in little funding, Jura’s professors carved “The ultimate beauty of science Indianapolis. out projects to give their students is when we team up and work to- research experience. Jura learned that gether on something.” she could accomplish goals in science Natalia Jura is the inaugural Kerri Beth Boggs (kerri. even when resources were sparse. recipient of the ASBMB Early-Career [email protected]) is a graduate student in the Jura earned her Ph.D. in mo- Leadership Award honoring an indi- biochemistry department at lecular and cellular biology at Stony vidual who is an associate professor, the University of Kentucky. Follow her on Twitter Brook University in New York. She assistant professor or equivalent with a @KB_Boggs. then entered the world of structural strong commitment to advancing the

JUNE/JULY 2020 ASBMB TODAY 41 PERSPECTIVES

What we’ve lost by closing our labs — and what we risk reopening them By Audrey L. Lamb & Graham R. Moran

hen our university campuses emergency remote instruction. The science should be solid. With labs closed in March, we realized first was a 75-student metabolism closed, requesting additional experi- W that, although we can adapt class for juniors and seniors taught ments may slow publication of good much of our instruction material to via team problem-solving using white work by months or longer. deliver it effectively via the web, the boards. She converted the material medium is wholly different from the to individual problem-solving with Our lab members classroom and cannot replace what flexibility to complete timed exams. Our undergrads, living in the pe- students learn at the bench. The tech- While course evaluations indicated tri dish of dorms and community eat- nical skills we teach in a laboratory this was an acceptable solution, most ing (buffets and food courts) were the simply do not translate, and the loss students said they preferred in-per- most likely to spread the disease, not of experimental inquiry inevitably son, team-based instruction. The sec- unlike people on cruise ships or in has significant impact to undergradu- ond, a graduate class on professional prisons. Therefore, they were evacuat- ates, graduate students, postdocs and development, adapted more readily ed first, leaving our campuses largely us, the faculty. All this uncertainty to remote instruction, as it included empty. Undergraduate researchers raises many questions, most of which outside speakers who already were in both our labs no longer were able we cannot answer fully at this stage. slated to present remotely. Before the to pursue their projects. For seniors, Scientists are natural planners, and stay-at-home order, the speakers were this meant final experiments were not not knowing how to develop a plan the only people on a screen, but now completed. Continuing undergrads is the most frustrating aspect of this everyone participated online. are also unlikely to be able to resume shutdown. Graham’s lab scattered to a variety their work safely in the coming In the absence of experiments, of locations (both nearby and distant semester as rules for reopening labs at scientific skills are abstract. We may from campus) and began working both our institutions strictly forbid or be able to teach the concept of how on the backlog of manuscripts. This severely limit undergraduate research- to perform a titration online, but proved to be a productive period, ers. One set of guidelines actually the skill of using a pipette to deliver with six manuscripts prepared. states that the PI is responsible for accurate volumes requires intellectual However, two require confirmatory “communicating expectations for and muscle memory synergy that can experiments and cannot be submitted behavior on and off campus” includ- be imprinted only by tactile stimuli. until research activity resumes. ing requiring the student to agree to Similarly, though students easily can Both of us have been helping “Avoid violations of social distancing grasp the concept of aseptic tech- students prepare dissertations and norms (e.g., attending parties that in- nique for microbiology, the elaborate serving on committees for candida- volve large groups and close contact)” choreography required to prevent cy exams and dissertation defenses. and “Timely disclosure if roommates’ contamination is only learned by do- These exams are now fully online, contacts or behaviors increase the risk ing. How many of us could learn to which can seem impersonal, and for exposure.” juggle without rhythmically lofting explanation of data is limited when The most novice lab members objects? a student can’t easily go to the board need the closest supervision — they and show their thinking. We also must learn laboratory safety risks — Remote work have been reviewing manuscripts for and frequently are not allowed in When in-person instruction academic journals, which requires a the lab alone until trained. The new and research abruptly ceased in balancing act when considering the restrictions will prevent individual March, Audrey immediately had to need for additional experiments: We undergraduates from conducting adapt two active-learning classes to don’t want to hinder progress, yet the research and have additional conse-

42 ASBMB TODAY JUNE/JULY 2020 PERSPECTIVES CREDIT IS OUSA CHEA/UNSPLASH

quences for our disciplines. A student this critical stage. After providing in- the granting period if universities are who can’t experience the scientific struction on the software the lab uses less than fully operational in the near process directly will have difficulty for analysis, Graham created mock term? More importantly, will this deciding to pursue higher degrees in data for the student to analyze. This limit future employment opportu- the field, and graduate school admis- activity filled eight weeks but now nities of these individuals, lengthen sions committees will have even more largely is exhausted. We both seek to their career progression or both? difficulty assessing the likelihood find constructive ways to maintain of success for students without lab involvement with laboratory projects The prospect of reopening experience. and continue each student’s learning. Laboratories are hives of activity From our perspective as pro- We have concerns about the use and interaction and were not designed fessors, a graduate student may of funds granted specifically to sup- to be left fallow and empty. Research experience little consequence with a port the research activities of junior labs must conduct experiments; the one-semester delay; however, this per- investigators. Both of us employ indi- system requires that graduate students spective is not shared by the graduate viduals who oversee many day-to-day and postdocs in biochemistry and mo- students. The young and ambitious laboratory functions and activities. lecular biology develop technical skills perceive time differently. Neverthe- These researchers present a unique and perform a body of experimental less, all agree that a year or more set of problems. Once all writing op- work. Publications remain the primary would impede project progression, portunities are exhausted, is it correct currency of the sciences, and we are particularly for first- and second-year and prudent to continue to pay their funded to complete specific objectives. Ph.D. candidates. Graham has a very salaries? Morally, the answer is easy; With grants running and experiments engaged first-year graduate student they should be supported. But what designed, we are keen to get back into who had to halt research activity at does it mean for productivity within the lab.

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Reopening will require additional repeatedly. Dangers also exist from training on COVID-19 transmission and for our home lives. If Audrey’s and proper use of personal protec- son rejoins his soccer team on the tive gear (to prevent viral spread as pitch, will she have to be isolated opposed to providing experimental from him when he returns home? safety), establishing calendars to min- Graham worries about commuting imize or prevent overlap of personnel home to Milwaukee, potentially car- Audrey’s research team has the in the lab, and new guidelines for rying the virus from the higher risk green light to return to her laborato- sanitizing workspaces between users. population in Chicago. If he returns ry, whereas Graham’s is expected to We have moved benches and equip- to work, should he not travel to see return in a limited capacity in mid- ment to put greater distance between his family? June. However, the two of us are not workspaces. Some labs are installing Social distancing is effective at in the first wave of people allowed to plastic sheeting between back-to-back reshaping the infection curve but, return to campus. Most universities benches, akin to the sneeze guards in the absence of a vaccine or a have decided that people who pre- now prevalent at drive-through treatment, doesn’t change the area dominantly work in offices (includ- restaurants and the grocery check- beneath that curve. Avoiding contact ing professors) should continue to out. Can we be safe in a laboratory with others ensures only that the work remotely. Audrey is genetically without community immunity? Even number infected does not spike and predisposed to lung infections and with all of our efforts to promote overwhelm our capacity to respond. therefore considered high risk. We safety, we can’t control all outcomes. Obviously, we must all commit to have discussed at length the logistics Our lab colleagues will be at signifi- less contact and stringent hygiene, of both conforming to the regulations cant risk regardless of what we do to but in doing so we dramatically pro- set by our institutions and defining mitigate. long the threat. So the resumption of additional protocols within the lab to Collaborative work or common scientific activity worldwide appears minimize the chance of community instrumentation compounds these to be contingent on the develop- spread. dangers. Will that incubator that ment of a vaccine or drug against Limiting the number of people everyone borrows to grow bacteria COVID-19. Without such a remedy, in the lab will slow productivity. We become a node for viral transmis- we must weigh the value of our work train our personnel, answer questions sion? The same is true for shared against the potential cost to health and help to solve problems in labs of instruments and spaces such as the and life. about 12 people. Having one or two nuclear magnetic resonance or mass Graham R. Moran working at a time, with the faculty spectrometry lab or the cold room. ([email protected]) is a providing remote, discontinuous and Audrey’s team is prioritizing projects professor of biochemistry and Carl Moore endowed iterative supervision, will be much that do not require the NMR but research chair at Loyola less efficient. Slow is better than instead can be accomplished using University Chicago. nothing but not what we expect for equipment within the Lamb lab. reasonable productivity. Some grad students from other labs

Labs have thousands of surfaces, use our equipment regularly, and we Audrey L. Lamb many of them touched by all group have included them in the calendar- ([email protected]) is a professor of biochemistry members and some that cannot easily ing system as if they were full-time in the department of be sprayed with an alcohol solution employees to reduce overlap. molecular biosciences at without damage (absolutely do not The risks will be cumulative as the University of Kansas. spray the microscope, for example). each of us passes from home to work

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The COVID-19 pandemic is squeezing women out of science By Marina K. Holz

n the early days of working from The professional slide for women in family and friends. It is clear that the home during the pandemic, science has started to emerge. majority of the child care burden will Ibefore everyone discovered virtual While many male scientists, fall on the female heads of household, backgrounds, I noticed something unencumbered by their usual travel who will remain at home while their peculiar. My male coworkers joined and other distractions, have hit their male colleagues return to their offices meetings from bookshelf-lined offic- productivity peak, a disproportionate and labs reenergized. Summer, one of es, while my female colleagues logged number of women have experienced the most productive seasons for scien- in from kitchen tables and living a productivity deficit — women over- tists, effectively is canceled for many rooms. “My husband and I are both whelmingly picking up the house- women in science. professionals who work from home, hold responsibilities associated with It truly would be revealing to see yet somehow, he is holed up in the caring for children and aging parents the gender breakdown of grant appli- upstairs office, while — as you can under the dictate to shelter in place. cations to the National Institutes of see — I am here in the dining room,” Women scientists were surprised Health (the primary federal funder of one of my coworkers remarked how swiftly this happened to highly research) submitted for the June and during a recent video conference. educated, self-aware professionals July deadlines. The adverse effects on In the last two decades, we who have long advocated for equity female scientists’ productivity — few- have achieved remarkable gains in in science but fell into the all-con- er papers, fewer grants —likely will equalizing the standing of women in suming role of the caregiver in their have long-lasting and wide-ranging science. The numbers of women as own homes. To be clear, many of consequences. Papers and grants are lead authors on research papers and us acknowledge that our wonderful the main currency for competitive recipients of major research grants, spouses, who have been supportive of fellowships, tenure-track appoint- in the senior ranks of the tenured our careers, shouldering the burdens ments, promotions and awards, the professoriate, and in academic lead- along the way, did not exactly force lack of which will affect women ership have been on the rise. I am us into this domestic role. It just hap- scientists disproportionately. one of these success stories, being the pened that they took over the home While men return to the active first female dean at my institution, office and shut the door. practice of science in all of its glori- one of many to come. There is still Institutions across the nation ous forms, a large fraction of women much progress to be made, but we gradually are reopening their research will not, perhaps permanently. started 2020 with great hopes for the programs, and scientists with school- Whether or not academic institutions new decade. The pandemic abruptly aged children are scrambling to and research funders urgently address caused research laboratories to shut- come up with child care solutions, this issue now will determine the pro- ter, and working from home became as daycares and summer camps will fessional futures of women in science the new normal for most academics. not return to business as usual this for decades to come. “Great, we will finally have the time summer. Running a backyard child to write all the papers we always care operation while managing a lab Marina K. Holz (mholz wanted,” the scientists hopefully is not an option. Hiring a nanny @nymc.edu) is the dean of the proclaimed. on a graduate student stipend or a Graduate School of Basic But startling posts shared on so- postdoc salary is impossible. Scien- Medical Sciences and professor of cell biology and anatomy cial media by journal editors suggest tists are notoriously nomadic as they at New York Medical College that the share of papers submitted by progress from grad school to postdoc and a member of the Women in Biochemistry and Molecular female scientists has dropped signifi- and faculty positions, leaving them Biology Committee of the American Society cantly during the last two months. without a local network of reliable for Biochemistry and Molecular Biology.

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Out of my comfort zone: How I use science to influence policy By Amanda Koch

once had a meeting with a sena- to understand what was happening support from the university admin- tor’s staff member while he walked in the political world. Watching the istration. Then we talked to our city Idown a hall to another meeting. news and the presidential debates, council members about how we, as The staffer came out of his office, I realized that government officials scientists, could best serve them. We looked at me, asked my name and often do not make evidence-based developed relationships with our state then said, “follow me” as he turned decisions and many do not support senators and representatives so we into the hall. Frazzled, I gathered all science. I decided then that I wanted could share our scientific opinions on my things; I was carrying too much my scientific voice to be heard in current legislation. We also started and not wearing the right shoes for politics. keeping our eyes open for legislation hurrying to catch up with someone. Over the past 50 or so years, at the federal level and discussed it But I caught up. Wordlessly, the staff- there have been times the govern- with our senators’ local staff mem- er opened his hand, clearly expecting ment increased science funding bers. For example, our group recently something from me. I put my sweaty because a policymaker thought a cer- has been advocating for a federal palm into their open hand and then tain area of research was important. bill, the Scientific Integrity Act. To realized he were not expecting a President John F. Kennedy wanted encourage a “yes” vote on this bill, we handshake. A business card! Right. Americans to be the first to the moon met multiple times with the staffs of As I dug around in my oversized — NASA received increased funding. Rep. Joe Neguse, D-Colo., and Sens. bag for my card, he said, “Sorry, but Vice President Joe Biden’s son died Cory Gardner, R-Colo., and Michael another important meeting came up. of cancer — the National Institutes Bennet, D-Colo. Our advocacy We are going to have to chat on my of Health increased funding for worked. The bill since has passed the way.” cancer research. But scientists don’t House and is now in the Senate to be I was there to tell the staffer why have to convince the president or discussed. the senator should support funding vice president of the United States At first, science advocacy seemed for scientific research. I had to do it that scientific research is important. daunting, but it ended up being in three minutes. Advocacy can start at a city council straightforward and fun, especially From what I’ve seen as a senior or a state capitol. with a great group and a growing Ph.D. student, many scientists avoid And it doesn’t have to be a network. policy issues. But government leaders solo endeavor. Scientists can form Here, I’ll walk through my ad- make policy decisions that directly coalitions to advocate collectively. vocacy protocol and describe actions affect scientific research. Every year, I know I work better in a group, I’ve taken to push myself out of my Congress creates a federal budget that so with my new passion for science lab and make my voice heard in the includes science funding. As scien- advocacy I reached out to my fellow policy world. tists, we need to step up and talk to Ph.D. students and professors (also policymakers who may not see the motivated to take action from the Be part of a group importance of our research. 2016 elections) to form an advocacy This means leaving the lab for a My motivation to advocate group. Together we brainstormed, few hours to connect with people. for science came during the 2016 learned about federal and state I started by having conversations elections. At that time, I was study- budgets, and developed an advocacy with people I worked with who were ing hard for my qualifying exams, game plan. First, we created a tight politically aware or already engaged. developing a thesis project, conduct- and trustworthy network within our Those conversations evolved into ing experiments that seemed to fail university. We locked down funding forming a university organization constantly and all the while trying for our advocacy group and garnered for graduate students and postdocs

46 ASBMB TODAY JUNE/JULY 2020 PERSPECTIVES ANDY FELICIOTTI/UNSPLASH

around science policy and commu- Most scientific societies, including from the office for science.” nication. A group with similar goals the American Society for Biochem- • The ask. “I am here today to ask may exist already on your campus. istry and Molecular Biology, have that you encourage the senator to In that case, do not start an identical advocacy initiatives and policy continue supporting science by group; a bigger collective voice is experts on staff. These groups provide voting to maintain (or increase) more powerful than scattered voices. amazing resources and are important the budget for scientific agencies allies. They will train you, explain such as the National Institutes of Develop a message the policy issues and give you needed Health and the National Science When you go into a meeting with empowerment. Foundation.” an elected official, what’s the ask? • The funding. “I am a Ph.D. This can be challenging; it’s hard to Be clear and concise student from Colorado State keep up with the news and decipher In developing an ask, I’ve learned University and have been funded complicated legislation. I started with to avoid complex terminology. The through the NIH and NSF for letter-writing campaigns encourag- message must stick with the poli- the past four years.” ing my senators to support science cymaker, and science jargon is not • The basic idea of the research. funding and to seek out scientific the way to do that. Also, be aware “Through that funding, I study experts when making policy deci- of how much time you have. In the how viruses replicate within host sions. Both of these asks align with three-minute meeting described cells.” most scientific disciplines. To develop above, I covered these six steps. • The 10-year goal. “This work can more specific asks, I partnered with • The thank you. “Thank you for be used to test which drugs stop national science policy organizations. your time. This shows support a virus from spreading without

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As scientists, we may feel removed from policy issues. But I believe science My final recommendation for simply that my concerns were passed can and should inform developing a message, which will along. Maintaining contact builds a policy. That’s why it is crit- come easily to scientists, is to do relationship with the policymaker or ical, especially during this background research. Knowing about staff member. election year, to step out of a policymaker’s past decisions helps As scientists, we may feel the lab and be the voice for me formulate my message with confi- removed from policy issues. But science. dence and makes the conversation go I believe science can and should more smoothly. inform policy. That’s why it is critical, especially during this election year, to The follow-up step out of the lab and be the voice hurting the cells’ normal activity.” Once my nerves settle after a for science. • The wrap-up. “Thank you meeting, I always send a quick email again for your time and for thanking the person for their time your and the senator’s con- and offering further support on the tinued support for science topic if needed. Sometimes, after Amanda Koch ([email protected]) funding and for science in meeting with a senate staff member, is a fifth-year Ph.D student general.” I’ll send them additional resources studying biochemistry and The overall message must be that they can pass along to their molecular biology at Colorado State University. Outside of concise: fund science. To make the senator. They also follow up with research, her passion is specific ask memorable, I say it at me to let me know how the senator science communication and advocacy. In her free time, she enjoys both the beginning and end of the has voted (usually when the senator backpacking, skiing, rock climbing conversation. votes for what I was advocating) or and being with her family.

ASBMB WEBINARS & EVENTS 2020 Annual Meeting Virtual Content

See upcoming and on-demand Spotlight Talks, virtual poster sessions, poster galleries and more at: asbmb.org/meetings-events/2020-annual-meeting

48 ASBMB TODAY JUNE/JULY 2020 PERSPECTIVES

‘We will not be silent’

Dear ASBMB members, We, as members of the ASBMB Minority Affairs Committee, believe in the dignity of all human beings and have chosen to shine a light on injustice, advocate for diversity and equity, and ensure that all voices are heard. We are sickened. Hundreds of years of wealth, housing, and health- care inequality and environmental racism have resulted in Black and other communities of color being disproportionately affected by the COVID-19 pandemic. And yet these workers have disproportionately been the ones picking and processing the foods, delivering the household sta- ples, and providing the services that allow the rest of the nation to stay home and be safe. We are grieving. Last fall, Atatiana Jefferson, a 28-year-old Black woman, was shot by police in her home while playing video games with her nephew. Earlier this month, Ahmaud Arbery, a 25-year-old Black man, was killed by white men while jogging. Breonna Taylor, a 26-year- old Black woman who wanted to become a nurse, was shot by police in her own home while sleeping. Last week, the graphic killing of George Floyd by police and his haunting final words echoed those of Eric Gar- ner in 2014: “I can’t breathe.” We are exhausted. Institutional- ized racism, housing discrimination and educational inequality have prevented African Americans, Latinx, Native Americans and other minority groups from joining our ranks in scientific research and medicine. As a scientific society, we create events and programs to remove barriers and at- tract minority students to our ranks. BANKS/UNSPLASH CLAY

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We try to educate, advocate and serve and intervene, even if our voices shake, ham Lincoln, quoting the Bible, said, as role models. for it is only in just actions that we will “A house divided against itself cannot We are angry. The systemic bias- start correcting some of the historical stand.” As a scientific society, let us es, racial profiling and inequalities in wrongs that our nation has imposed not wait for a beacon, but, through access make our goals almost unat- upon communities of color. our engagement and actions, shine a tainable. The events of the past several We will not be silent. Dr. Martin light on inequities and light a path for months have shaken our belief that Luther King Jr. is often quoted* as everyone to walk on toward a just and the better angels of our nature will having said: “There comes a time equitable future. We must light up the prevail. As we watch and participate when silence is betrayal. Our lives darkness together. in the protests against police killings begin to end the day we become silent Sincerely, of Black people, we understand that about things that matter. In the end, hundreds of years of racism and we will remember not the words of Sonia C. Flores, Chair, ASBMB oppression, starting with the sin of our enemies, but the silence of our Minority Affairs slavery, have culminated in what is friends. Only in the darkness can you Committee currently gripping our nation. In this see the stars.” Vahe Bandarian country, we still struggle to show that We must work together. The force Ruma Banerjee Black lives indeed matter. of American history has crushed the Suzanne Barbour We are united. Together, as lives and hopes of the Black commu- Carlos Castañeda scientists and leaders in our community. We should not act surprised that Joseph Chaney nities, we cannot sit silently. We need finally the cauldron has boiled over, Adela Cota–Gomez to channel our despair and anger. If as, for too many years, our nation’s Kayunta Johnson–Winters you are not a member of a minority top leaders have not only ignored our Carlos Lopez community, become an ally. Offer plight but have added more fuel to the Deborah Neely–Fisher support, listen, amplify their voices, fire. We look to our elected leaders to Lana Saleh and educate your peers. In the words provide the beacon that lights the path Gustavo Silva of Angela Davis: “In a racist society, it to an equitable future. For the first time is not enough to be nonracist, we must in many years, the lights of the White *These likely were not MLK’s be antiracist.” We call on all members House are dark. actual words but rather a synthesis of of the ASBMB to step up, speak out We must walk together. Abra- parts of his speeches.

Cast your vote in the 2020 ASBMB Election!

Learn about the candidates and vote at: asbmb.org/membership/election

Deadline: July 1

50 ASBMB TODAY JUNE/JULY 2020 CLASSIFIEDS

Research Specialist, Protein Structural Biology Assoc. Director/Director, Process Development Howard Hughes Medical Institute Cue Biopharma Austin, Texas, United States Cambridge, Massachusetts, United States

We are currently looking for a highly motivated Research In this newly introduced position at Cue Biopharma, the Director/ Specialist to support the lab of Dr. Keiko Torii at the University Senior Director of Process Development will be tasked with of Texas at Austin in Austin, Texas. The Torii lab has a long- improving and developing robust and scalable manufacturing standing interest to unravel how plant stem cells function and processes, scientifically sound specifications, and associated contribute to growth and development, with specific emphasis analytical methods for our unique biologics. This role will be on signal transduction pathways and underpinning genomic/ expected to support both internal research activities as well as epigenomic mechanisms. In addition to harnessing chemical and work carried out through CMOs. Further, this individual, having synthetic biology, we are designing and building synthetic signal demonstrated expertise and leadership in the field, will have transduction circuits to control plant growth and development the opportunity to build a small team to support upstream, suited for a changing climate. downstream, and assay development activities. This position will report to the Vice President of Protein Therapeutics and will https://careers.asbmb.org/job/research-specialist-protein- collaborate closely with the Head of CMC. structural-biology/54075741/ https://careers.asbmb.org/job/assoc-directordirector-process- development/54168502/

Postdoctoral Associate Technology and Application Consultant University of Pittsburgh Mettler-Toledo AutoChem, Inc. Pittsburgh, Pennsylvania, United States REMOTE, New Jersey, United States

A postdoctoral position is currently available at the Soft The Technical Sales department of METTLER TOLEDO AutoChem Tissue Biomechanics Laboratory (STBL) in the Department of (www.mt.com/autochem) needs a self-motivated, ambitious team Bioengineering under the direction of Professor Jonathan Vande player to fill our Technology and Application Consultant role, ide- Geest. The STBL is currently developing a novel platform to ally located in New Jersey. We are looking for people who love sci- study the mechanobiology of the optic nerve head in primary ence and technology, and excel at building dynamic relationships open angle glaucoma that seamlessly integrates state of the art with people and are interested in expanding their commercial and techniques in regenerative medicine, 3D bioprinting, and intravital business skills. Ideal candidates are problem solvers with a strong imaging. The long term goal of the STBL is to utilize this novel chemistry, chemical engineering, or biochemistry background who platform to improve the mechanistic understanding of how optic will accept challenges, ask questions, research, and engage our nerve head extracellular matrix remodeling is linked to retinal customers. This position will be responsible for providing world ganglion cell death and vision loss and if this understanding can class technical sales consulting services to potential and existing be leveraged to discover the next generation of novel therapeutic customers in the optimization and improvement of particulate targets for glaucoma. process and applications, particularly crystallization. As a recognized expert, you will establish strong peer based relationships https://careers.asbmb.org/jobs/view/postdoctoral- with scientists and engineers in the field, while ensuring sustain- associate/54168278/ able sales growth of the business in their region. https://careers.asbmb.org/jobs/view/technology-and- application-consultant/54168494/

To see a full list of jobs, please visit asbmb.org/careers

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