Vol. 18 / No. 11 / December 2019

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

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www.jbc.org NEWS FEATURES PERSPECTIVES 2 34 56 EDITOR’S NOTE ANTS IN THE LAB NIGHT SHIFT Ending an elemental year Using social insects to study e nightlife of a scientist–mother 3 behavior and aging PRESIDENT’S MESSAGE 42 Beware the unintended consequences OXYGEN SENSING AND ALTITUDE of mandatory open access Semenza shares 2019 Nobel Prize 5 48 MEMBER UPDATE GIFT GUIDE 34 10 RETROSPECTIVES 10 Roberta F. Colman (1938 – 2019) 14 Sydney Brenner (1927 – 2019) 18 NEW MEMBERS 42 56 20 LIPID NEWS Crystal building blocks of triglycerides 21 YEAR OF (BIO)CHEMICAL ELEMENTS Rounding out the year with nickel and zinc 22 JOURNAL NEWS 22 Tor comes to the fore in autophagy ANNUAL MEETING 24 Paving the way for disease-resistant rice 25 Secrets of fat and the lymph node 26 When prions are personal 51 28 From the journals 2020 MEETING TO HIGHLIGHT JLR JUNIOR ASSOCIATE EDITORS RAY BLIND ...... 52 ON THE COVER ROTONYA CARR ...... 53 A carpenter ant climbs on the bud of a native sleepy hibiscus at Sweetbay Natural Area in BRANDON DAVIES ...... 54 Palm Beach Gardens, Florida. BOB PETERSON/WIKIMEDIA COMMONS GISSETTE REYES–SOFFER ...... 55

DECEMBER 2019 ASBMB TODAY 1 EDITOR’S NOTE

THE MEMBER MAGAZINE OF THE AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY Ending an elemental year OFFICERS COUNCIL MEMBERS Gerald Hart Suzanne Barbour By Comfort Dorn President Joan Broderick Matt Gentry Toni M. Antalis Blake Hill President-elect Audrey Lamb eaders of a certain age may is a teacher, and she o ered to write Wei Yang James M. Ntambi remember Tom Lehrer’s song a series of articles for ASBMB Today Secretary Takita Felder Sumter Kelly Ten–Hagen R“ e Elements,” in which the highlighting elements of signi cance Joan Conaway JoAnn Trejo Treasurer then-Harvard math professor and in the biochemical realm. ASBMB TODAY EDITORIAL musical satirist patter-sang, a la Gil- ere’s nothing an editor likes EX-OFFICIO MEMBERS ADVISORY BOARD bert and Sullivan, the name of every better than the promise of a timely Robert S. Haltiwanger Rajini Rao element in the periodic table. series (and guaranteed content), so Carla Koehler Chair Co-chairs, 2020 Annual Ana Maria Barral When I was a musical theater I was delighted, but Quira gave us Meeting Program Committee Natasha Brooks nerd in high school, I co-directed a something more than that. As regu- Kelly Chacón Cheryl Bailey musical revue in my senior year. e lar ASBMB Today readers know, she Chair, Education and Beronda Montgomery Professional Development Bill Sullivan other directors and I thought we had has provided a wonderfully coherent Committee Melissa Vaught Binks Wattenberg the whole thing precast, but during series of lessons that clearly explain Daniel Raben auditions, a hitherto unremarkable everything from where the elements Chair, Meetings Committee ASBMB TODAY Sonia Flores singer bowled us over with her rendi- originate to their roles in human Angela Hopp Chair, Minority A airs Executive Editor tion of this serious tongue twister. (I’ll health. Every month, I’ve looked Committee [email protected] link to a video of Lehrer singing it on forward to learning something new Nicole Woitowich Comfort Dorn the ASBMB Today website so you can from this series. And on page 21 of Chair, Science Outreach and Managing Editor Communication Committee [email protected] hear for yourself how impressive this this issue, with nickel and zinc, I’m Terri Goss Kinzy Lisa Schnabel was.) We borrowed a lab coat and a sad to see it end. Chair, Public A airs Graphic Designer Advisory Committee wall-sized copy of the periodic table is month may mark the end [email protected] Ed Eisenstein John Arnst from the school’s science department of the (bio)chemical elements in Chair, Membership Committee Science Writer to hang behind her. At every perfor- ASBMB Today, but plans are afoot Susan Baserga [email protected] mance, that song brought the house to build educational programs Chair, Women in Biochemistry Laurel Oldach and Molecular Biology Science Writter down. e big chart disappeared after around these 11 articles — complete Committee [email protected] closing night, and one of my fellow with experiments. If this resource Sandra Weller Ed Marklin Chair, Publications Web Editor directors either had to pay for it or would be useful to you or any of Committee [email protected] forfeit her diploma. your colleagues, contact Quira at Lila M. Gierasch Allison Frick Editor-in-chief, JBC Multimedia and Social Media at was the last time I thought [email protected]. A. L. Burlingame Content Manager about the periodic table until an anks to all our readers for [email protected] Editor, MCP ASBMB Today planning meeting celebrating the International Year of Barbara Gordon Nicholas O. Davidson Executive Director late last year when Quira Zeidan, the the Periodic Table with us — and Editor-in-chief, JLR [email protected] society’s education and public out- thank you, Quira, for being as cool a Kerry-Anne Rye Editor-in-chief, JLR reach coordinator, told us that 2019 teacher as Tom Lehrer. was the 150th anniversary of the year For information on advertising, contact Pharmaceutical Comfort Dorn Media Inc. at 212-904-0374 or [email protected]. Dmitri Mendeleev  rst published his ([email protected]) is the tabular display of the elements. managing editor of ASBMB She wasn’t just sharing science Today. Follow her on Twitter @cdorn56. trivia. In her heart of hearts, Quira

www.asbmb.org/asbmbtoday PRINT ISSN 2372-0409 CORRECTION Articles published in ASBMB Today re ect solely the authors’ views and not The Lipid News article in the November issue contained incorrect terminology. the o cial positions of the American Society for Biochemistry and Molecular Biology or the institutions with which the authors are a liated. Mentions of It should have stated that platelet activating factor is a plasmanylcholine. products or services are not endorsements.

2 ASBMB TODAY DECEMBER 2019 PRESIDENT’S MESSAGE

Beware the unintended consequences of mandatory open access By Gerald Hart

n 2018, a group of research While the American Society for Plan S: “ e Funders do not support funding organizations with the Biochemistry and Molecular the ‘hybrid’ model of publishing. Isupport of the European Re- Biology favors moving toward However, as a transitional pathway search Council, or ERC, launched a model where scientific towards full Open Access within a cOAlition S, a plan to require full clearly dened timeframe, and only as literature is freely available to open access to published research part of transformative arrangements, papers on work they had funded. everyone (open access), the Funders may contribute to nancially eir mandate: “With eect fact remains that someone supporting such arrangements.” from 2021, all scholarly publica- has to pay for the reviewing, If open access for nal versions of tions on the results from research redaction, quality control papers is mandated across the board, funded by public or private grants and eventual publication of libraries will no longer need to pay provided by national, regional and to subscribe to journals. In the U.S., research findings. international research councils and all costs of publication will need to funding bodies, must be published be borne by authors, generally from in Open Access Journals, on Open direct costs from grants. e cost to Access Platforms, or made immedi- ble, Open Access publication fees are authors to publish likely will increase ately available through Open Access covered by the Funders or research substantially. Repositories without embargo.” institutions, not by individual re- Mandated open access benets Most major funding agencies in searchers; it is acknowledged that all for-prot publishers, several of whom Europe have endorsed this plan. researchers should be able to publish already are making lots of money While the American Society for their work Open Access.” from open-access journals. ese Biochemistry and Molecular Biol- us far, U.S. funding agencies, publishers, especially the so-called ogy favors moving toward a model such as the National Institutes of high-impact journals and their where scientic literature is freely Health and the National Science cascade journals, can receive exor- available to everyone (open access), Foundation, have not adopted Plan bitant funds to publish a paper, and the fact remains that someone has S, but it seems likely that open access the more papers they publish, either to pay for the reviewing, redac- eventually will become mandatory in the parent journal or its cascade tion, quality control and eventual worldwide for scientic literature. siblings, the more money they make. publication of research ndings. ASBMB journals are already open One side eect is that the quality Under the current system, most access. In the Journal of Biological of publications might drop because publication costs (at least in the Chemistry, the Journal of Lipid more money is to be made by pub- U.S.) are born by library subscrip- Research, and Molecular & Cellu- lishing more papers. tions, helping keep authors’ costs to lar Proteomics, the papers in press, In contrast, complete open access a minimum. At U.S. universities, or PIPs, go online the day they are likely will have a deleterious eect on library subscriptions are paid by accepted, and they remain online for scientic societies, and small societ- indirect costs (nance and account- free indenitely. However, this model ies with limited budgets will be hit ing, or F&A) that funding agencies is not acceptable to Plan S propo- particularly hard. Most societies are provide to the universities within nents, who demand that the nal nonprot, but they do use some of grants. redacted versions of papers also must the funds generated by their journals As stated in one of the Plan S be available for free. to support science, such as travel 10 key principles, “Where applica- Another key principle listed in awards for students, community

DECEMBER 2019 ASBMB TODAY 3 PRESIDENT’S MESSAGE

outreach and education, as well as to forth by the European agencies and because we scientists continue to advocate for government support of provide funds to help defray the cost play the impact factor game — even scienti c research. Open access not of publication. Perhaps indirect costs though nearly all of us agree that a only will eliminate funds used for (F&A) supporting library subscrip- journal’s impact factor says nothing these functions, but many specialty tions might be redirected to help about the quality of papers published journals published for or by small keep costs low for authors publishing in it. societies likely will cease to exist due in open-access journals? to lack of revenue. It is aso important that we Gerald Hart If complete open access of the scientists not allow the for-pro t ([email protected]) is a professor and Georgia type mandated by Plan S is adopted publishers to demand exorbitant fees Research Alliance eminent within the U.S., then the NIH, the to publish in their journals. ese scholar at the University of Georgia and president of the NSF and other U.S. funding agencies publishers can, and often do, demand ASBMB. must follow a model like that set lots of money to publish simply

Call for 2021 ASBMB Symposia proposals

Planning a meeting can be daunting. The ASBMB o ers its members the opportunity to work directly with its meetings department to plan and promote niche scientifi c meetings through the ASBMB Symposia program. asbmb.org/special symposia/proposals/

4 ASBMB TODAY DECEMBER 2019 MEMBER UPDATE

Member update

By ASBMB Today Sta

Hartl, Lee win Breakthrough Prize Two of the ve winners of the 2020 Breakthrough Prize in Life Sciences are members of the American Society for Biochemistry and Molecular Biology.

F. Ulrich Hartl, managing director Lee is a John H. Ware endowed of the Max Planck Institute of Bio- professor in Alzheimer’s research at the chemistry, and Virginia Man-Yee Lee, Perelman School of Medicine, director a professor in Alzheimer’s research at the of the Center for Neurodegenerative University of Pennsylvania, are among Disease Research and co-director of the Hartl the recipients of the $3 million award, Lee Marian S. Ware Center for Alzheimer’s one of three awarded annually by the Drug Discovery Program. She is hon- Breakthrough Prize Foundation and known collectively ored for discovering TDP43 protein aggregates in fron- as the “Oscars of Science.” e foundation also selected totemporal dementia and amyotrophic lateral sclerosis recipients in physics and mathematics. and for showing that dierent forms of alpha-synuclein Hartl shares the honor with Arthur L. Horwich of in dierent cell types underlie Parkinson’s disease and the Yale School of Medicine and the Howard Hughes multiple system atrophy. Medical Institute, for discovering functions of molecular Jerey M. Friedman and David Julius also received chaperones in mediating protein folding and preventing the life sciences prize. e recipients were honored at protein aggregation, which can be a precursor to cancer an awards ceremony in November at the NASA Ames and neurodegenerative diseases. Research Center in California.

Cell biology society names fellows Five members of the American Society for Georgia, Athens. Biochemistry and Molecular Biology are among the 16 Vassie Ware, professor of biological sciences and fellows elected to the American Society for Cell Biology co-director, HHMI biosciences program and distance in 2019. e fellows, who are selected by their peers, are education program, Lehigh University, Bethlehem, recognized not only for their contributions to research Pennsylvania. involving cell biology and to its community of scientists Susan Wente, professor of cell and developmental but also for their commitment to the mission of the biology, provost, interim provost and vice chancellor ASCB. Congratulations to these ASBMB members: for academic aairs, Vanderbilt University, Nashville, David Asai, senior director for science education, Tennessee. Howard Hughes Medical Institute, Chevy Chase, e 16 new fellows will be recognized at the ASCB/ Maryland. European Molecular Biology Organization meeting to be Mary Dasso, senior investigator in the Section on Cell held in Washington, D.C., this month. Cycle Regulation, National Institutes of Health, Bethesda, Maryland. Erin Dolan, professor of biochem- istry and molecular biology and Georgia Athletic Association professor of innovative science education, University of Asai Dasso Dolan Ware Wente

DECEMBER 2019 ASBMB TODAY 5 MEMBER UPDATE

National Academy of Medicine elects new members Velasquez, Torres land Five members of the American Society for Biochemistry and Molecu- Gilliam fellowship lar Biology are among the 90 new regular members and 10 new interna- Erick Velasquez, tional members elected to the National Academy of Medicine. a Ph.D. student in the biochemistry, e newly elected members include: molecular and struc- Beverly L. Davidson, professor of pathology and lab- tural biology pro- oratory medicine, Perelman School of Medicine, Univer- Velasquez gram at the Universi- sity of Pennsylvania, and director, Raymond G. Perelman ty of California, Los Center for Cellular & Molecular erapy, Children’s Angeles, and Jorge Hospital of Philadelphia. Torres, a a professor Davidson in the department of chemistry and bio- Raymond N. DuBois Jr., dean of the college of chemistry at UCLA medicine and professor of biochemistry and medicine, Torres are among this year’s Medical University of South Carolina, Charleston. 44 pairs of Gilliam fellows, selected by the Howard Hughes Medical Institute. DuBois Gilliam fellowships for advanced J. Silvio Gutkind, professor of pharmacology and study are unique in supporting advi- associate director of basic science, Moores Cancer Center, sor-student pairs rather than profes- University of California, San Diego. sors or trainees in isolation. Designed to foster diversity and inclusion in science and train future scientic Gutkind leaders, the awards support fellows Krzysztof Palczewski, director of the Center for in their later years of graduate school Translational Vision Research, Irving H. Leopold chair and provide training for their faculty in ophthalmology and a professor of physiology and mentors. biophysics at the University of California, Irvine School Under Torres’ supervision, of Medicine. Velasquez plans to apply machine Palczewski learning to proteomics data sets to understand protein-protein interac- Anil K. Rustgi, professor of medicine and director, tions in mitosis. Herbert Irving Comprehensive Cancer Center and asso- Torres studies proteins that ciate dean of oncology, department of medicine, Vagelos direct the assembly and function College of Physicians and Surgeons, Columbia University, of the mitotic spindle and uses New York City. multidisciplinary approaches to Rustgi develop new anti-cancer drugs. He received the American Society for e newly elected members bring the NAM’s total membership to Biochemistry and Molecular Biology’s more than 2,200 and the number of international members to approxi- 2019 Ruth Kirschstein Diversity in mately 180. Science Award.

6 ASBMB TODAY DECEMBER 2019 MEMBER UPDATE

Fleming recognized Biophysical Society announces honors for diversity work American Society for Biochemistry and Molecular Biology members Karen Fleming, G. Marius Clore, Dan Herschlag and Alexandra C. Newton are among a professor of the recipients of the 2020 Biophysical Society awards. ASBMB members biophysics at Johns Cynthia Wolberger and Hao Wu have been named 2020 BPS fellows. Hopkins University, Clore, a National Institutes of Health distinguished investigator and received the chief of the Protein Nuclear Magnetic Resonance Section of the National Fleming university’s Provost’s Institute of Diabetes and Digestive and Kidney Diseases, will receive the Prize for Faculty BPS Innovation Award in recognition of his contributions to the develop- Excellence in Diversity in May. ment of nuclear magnetic resonance imaging for determining 3D struc- e $50,000 prize recognizes tures of macromolecules in solution and his work on the development of faculty eorts to promote gender and paramagnetic and relaxation-based NMR experiments to characterize rare, racial diversity. In Fleming’s case, that transient and previously invisible states of macromolecules. advocacy work includes starting a Herschlag, a professor of biochemistry at Stanford University, will journal club for gender equity, teach- receive the society’s Founders Award for his fundamental contributions ing fellow Hopkins professors about to RNA folding and enzymology. “ e Founders Award allows us to call best practices for inclusive pedagogy attention to outstanding achievements in biophysics that are now accept- and holding equity workshops at ed and used by others, whether that acceptance was immediate or over a scientic society meetings. period of years,” BPS President Dave Piston stated. “Dan’s work on RNA “We all need to plug the leaks folding and enzymology has had a ripple eect on the eld, leaving a last- in the STEM pipeline through our ing impact on the entire breadth of molecular biophysics.” actions and words each and every Newton, a professor in the department of pharmacology at the University day,” Fleming said in her remarks on of California, San Diego, will received the BPS Award in the Biophysics of receiving the award. Health and Disease in recognition of her paradigm-shifting discoveries that Fleming, whose research focuses showed how disease mutations that inhibit protein kinase C activity cause on membrane protein folding and cancer while those that activate PKC are drivers of neurodegenerative diseases. the involvement of chaperones in Wolberger is a professor of biophysics and biophysical chemistry at that process, serves as an associate the Johns Hopkins University School of Medicine. Her research in ubiqui- editor of the Journal of Biological tin signaling and regulation of transcription has transformed understand- Chemistry. ing of molecular mechanisms underlying genes regulation through elegant structural studies. Brown University Wu is the Asa and Patricia Springer professor in the department of honors Gordon biological chemistry and molecular pharmacology at Harvard Medical Sharona School. Her use of structural immunology has revised the view of intracel- Gordon, a professor lular signaling and cellular organization through discovering supramolec- of physiology and ular signalosomes formed by innate immune signaling proteins, mech- biophysics at the anisms that govern cooperative assembly, and proximity-driven enzyme University of Wash- activation. Gordon ington in Seattle, was awarded Brown Uni- versity’s 2019 Horace Mann Medal. e prize, named after a poli- tician and education reformer who attended Brown in the early 19th century, recognizes signicant contri- Clore Herschlag Newton Wolberger Wu butions of Brown graduate alumni to

DECEMBER 2019 ASBMB TODAY 7 MEMBER UPDATE

their elds and was conferred at the in certain cancers, where it contrib- university’s commencement ceremo- utes to resistance to apoptosis, but ny in May. also in traumatic injury, which in- Gordon, whose research focuses creases its activity and can contribute on the physiology of ion channels to stress-induced diabetes. in the TRP family, serves as the edi- While leading that research, tor-in-chief of the Journal of General Boehning also held several leadership Physiology. Last year she founded roles at UTHealth, most recently Below the Waterline, a grassroots directing two graduate programs. His organization aimed at improving accolades include awards for teaching the culture of science by addressing excellence and for being an outstand- gender harassment, and she published ing faculty member. a study on the development of scien- Follow us tic identity among postdocs. Biophysical Society elects In their announcement of the Moores to council on Twitter prize, the award committee noted Carolyn A. Gordon’s commitment to the scien- Moores of Birk- Stay up to date on tic community along with her own beck College, part scientic achievements. of the University of the latest science London, has been published in Boehning moves Moores elected to the gov- ASBMB journals. to Rowan University erning council of the Darren Biophysical Society. She will begin a Boehning, until three-year term in February 2020. recently a professor A professor of structural biology of biochemistry and whose lab studies microtubule orga- molecular biology nization and dynamics, Moores runs @jbiolochem Boehning at the University of the biological sciences department at Texas Health Science Birkbeck and recently was appointed Center at Houston, has joined the interim dean at the college. She also Cooper Medical School of Rowan is the academic head of the electron University in Camden, New Jersey. microscopy and image processing lab. @jlipidres He will serve as head of the school’s With more than 9,000 members department of biomedical sciences around the world, the Biophysical and assistant dean for research. Society develops and shares knowl- Boehning’s research focuses on edge in biophysics. Its members apoptosis, investigating how the ino- elected a new president-elect and four @molcellprot sitol triphosphate receptor calcium council members, including Moores, channel contributes to cell death. in August. is receptor is not only dysregulated SEND US YOUR NEWS Do you have good news to share with fellow ASBMB members? Email it to us at [email protected] — and don’t forget to include a photo!

8 ASBMB TODAY DECEMBER 2019 MEMBER UPDATE

IN MEMORIAM John Oates

John Oates, a physician–scientist on the team that discovered the rst blood pressure–lowering drug and who went on to become a pioneer in the study of pros- taglandins, died in July in Nashville at age 87. Oates was raised in Fayetteville, North Carolina, by a former schoolteacher mother and lawyer–historian father. He earned his bachelor’s degree in 1953 at what was then Wake Forest College (now University) and his M.D. in 1956 at the college’s Bowman Gray School of Medicine. He did a stint in the Merchant Marines, at which time he was based in and became fond of New York, and went on to complete his residency at the New York Hospital–Cornell Medical Center. Though he was prepared to join the U.S. Air Force as part of the so-called “doctor draft” that sent thousands of medical professionals to the Korean War battle eld, he learned from a peer that working at the Oates moved to Vanderbilt University in 1963 and National Institutes of Health was an alternative. His is credited with founding one of the rst divisions of chair arranged for him to take a position at the National clinical pharmacology, which he led until 1996. Heart Institute, according to a 2013 interview in the Oates’ team at Vanderbilt did groundbreaking Journal of Clinical Investigation. research on prostaglandins, members of the eicosanoid In 1959, he and colleagues at the NIH were family derived from fatty acids. They determined the studying the synthesis and metabolism of aromatic role prostaglandins play in renin release by the kid- amines (for example, norepinephrine and serotonin) to neys, showing that, parallel to the adrenergic nervous better understand their roles in high blood pressure. system, they affected renin release and blood pressure They discovered, quite unexpectedly, that the Merck regulation. drug methyldopa (brand name Aldomet), which the They also found that prostaglandin D2 is a major company had synthesized as part of a cancer research inammatory mediator produced by mast cells, which screen, lowered blood pressure in animal models. kicked off drug-development studies for allergic rhinitis “The pharmacologists at Merck had completed and asthma. toxicology studies and commented to us that they had Oates also is recognized for elucidating the concept given rabbits doses of up to one gram per kilogram of rst-pass metabolism, which affects drug concen- without lowering blood pressure or having any adverse tration. And, in his later years, his group studied small effect,” he told Vanderbilt University’s Leigh MacMillan molecules that could be used for diseases driven by in 2005. “They said it can’t possibly be pharmacologi- oxidative stress, including Alzheimer’s and coronary cally active.” artery disease. Methyldopa ended up being used to treat severe Oates’ publication list is long, his awards numer- hypertension and, though more effective therapies for ous, and his academic progeny widespread. He is high blood pressure have since emerged, still is used survived by his wife, Meredith, three children and four today in certain cases, in particular during pregnancy. grandchildren.

DECEMBER 2019 ASBMB TODAY 9 RETROSPECTIVE

Roberta F. Colman (1938 – 2019)

By Hal White & Judith G. Voet

oberta (Bobbie) Colman, Willis department of biological chemistry F. Harrington professor emerita at Harvard Medical School. She left

Rof chemistry and biochemistry Harvard as an associate professor in KENDE PAUL at the University of Delaware, joined 1973 to become a full professor of what then was the UD chemistry biochemistry at UD. department in 1973 as its fth bio- During her highly productive chemist and remained there until her career, Bobbie published more than retirement in 2009. 260 articles in journals such as the In 1985, Bobbie became the rst Journal of Biological Chemistry, woman to receive the Francis Alison Biochemistry, Archives of Biochemis- Award, UD’s highest faculty honor, try and Biophysics, Nature Genetics and the university awarded her an and Protein Science. Many of her honorary doctor of science degree at publications dealt with the struc- commencement in 2014. Her hon- ture of the active sites of enzymes orary degree citation recognized her and the function of various amino for her roles as a revered educator and acid side chains in enzyme catalysis. Pictured here in June 2012, Bobbie Colman had a prolic researcher and also saluted She pioneered the use of particular colorful fashion sense. her work in mentoring women and reactive nucleotide analogs as anity minority students. labels to probe enzyme active sites. e citation concluded, “Your As a world authority on the struc- Award from the ASBMB for scientic pioneering undoubtedly changed ture and function of nicotinamide achievement. She served as chair of and enriched the scientic world in adenine dinucleotide-linked and the division of biological chemistry of academe; it also has enriched the nicotinamide adenine dinucleotide the American Chemical Society from larger society because of the many phosphate-linked isocitrate dehydro- 1998 to 2000. She was on the edi- contributions that you have made to genases and other enzymes such as torial board of Archives of Biochem- your eld.” glutamate dehydrogenase, pyruvate istry and Biophysics for 27 years, Bobbie’s distinguished career in kinase, glutathione S-transferase including 17 years as an executive research started in high school when and adenylosuccinate synthase, she editor. She was an associate editor of she received a Westinghouse Science established numerous collaborations the Journal of Protein Chemistry for Talent Search Award. She graduated and received many honors. six years and served on the editori- from Radclie College summa cum Bobbie was a fellow of the al boards of several other journals laude and went on to graduate school American Association for the Ad- including the Journal of Biological at Harvard University, where she vancement of Science and a member Chemistry and Protein Science. earned a Ph.D. under the direction of of numerous professional societies. roughout her career at UD, the renowned physical organic chem- Among other positions, she was Bobbie maintained a well-funded ist Frank Westheimer. After post- treasurer of the American Society for research group of about 10 peo- doctoral fellowships at the National Biological Chemists (the precursor ple, including research assistants, Institutes of Health and Washington of the American Society for Bio- undergraduates, graduate students, University in St. Louis, she joined chemistry and Molecular Biology) postdoctoral fellows and visiting the faculty in the department of from 1981 to 1985. She served on faculty members. Nearly 30 graduate biological chemistry at Washington the ASBMB Executive Council students completed their dissertations University in 1966. A year later, she from 1993 to 1996, and in 1996 under her guidance. Many of these became an assistant professor in the she received the Herbert A. Sober associates have gone on to distin-

10 ASBMB TODAY DECEMBER 2019 University of Delaware Board of Trustees Chairman Gil Sparks presents Bobbie Colman with an honorary doctor of science degree at the university’s 2014 commencement ceremony. EVAN KRAPE EVAN COURTESY OF JUDITH G. VOET COURTESY

Enjoying a meal together in February 2019 are, from left, Bobbie and Bob Colman, Don and Judy Voet, Paul and Frances Kende, and Liz and Ed Thornton.

DECEMBER 2019 ASBMB TODAY 11 RETROSPECTIVE

guished careers elsewhere. In addi- then discovering early in her career a Her fashion sense was very color- tion, she was the program director large salary discrepancy between her- ful and often extended to clothing of UD’s NIH-funded chemistry-bi- self and similarly qualied male fac- acquired on her travels. ology interface graduate program ulty members, Bobbie took a special After her retirement in 2009, from 1993 to 2009. Students in her interest in nurturing and enabling Bobbie regularly attended classes at laboratory received excellent training. the careers of women and under- UD’s Osher Lifelong Learning Insti- In addition to her graduate students represented minority scientists. She tute, where she continued to cultivate and postdoctoral fellows, many of did this through mentoring students her many interests. the undergraduates who worked in in her own laboratory and through She is survived by her husband; her laboratory became co-authors on service on national committees such her children, Sharon and David; and scientic publications. as the Committee on Women in Bio- her two grandchildren, Lexi Green- Graduate students and un- chemistry and the Educational Aairs berg and Jason Greenberg. dergraduates from over the years Committee of the ASBMB.

remember Bobbie as their teacher Bobbie enjoyed traveling. With Hal White ([email protected]) is a professor in graduate-level biochemistry core her husband, Robert, she used emeritus of chemistry and biochemistry at the courses. She also taught elementary summer vacations to travel the world University of Delaware. biochemistry for nonmajors and from the Antarctic to Asia and Africa. mechanisms of enzyme regulation. In each country, she took in the Judith G. Voet ([email protected]) is the J.H. Hammons professor emerita of After being one of the only wom- local culture and natural history and chemistry and biochemistry at Swarthmore en in her college science classes and returned with photographs to share. College.

To their friends, Bobbie and Bob Colman were “joined at the hip,” attending movies, concerts and plays together, as in this April 2013 photo. PAUL KENDE PAUL

12 ASBMB TODAY DECEMBER 2019 KATHY F. ATKINSON BOBBIE COLMAN’S INFLUENCE

Mayura Dange, former graduate student: “She is the reason I am what I am … Not only a U.S.-graduated scientist, but also a feminist, a travel lover, a hobbyist photographer …. Her scientic excellence is all over the web, but her personality was far beyond science labs and books …. She was a constant learn- er, who after her retirement at the age of 71, started taking music appreciation and architecture classes at the university. She would subtly emphasize how a woman has to take extra eorts to prove herself while strongly reminding us that being a woman does not entitle you to any freebies or sympathy. ere are many life lessons I learned under her guidance, but more personal to me was when I had tried and failed over and over in one part of my project. She was someone who would never give up, but she told me ‘sometimes we have to let go of something that is not working out and focus on what is working. It’s not giving up, it’s being practical.’” Anastasia évenin, doctoral student: “Rest in peace, dearest Dr. Colman — my Ph.D. adviser. I would not be where I am today without your help and guidance. You were the kindest, most caring person I knew, and your positivity was my guiding light during my Ph.D. You will always be the kind of scientist and a woman I will aspire to be.” Mark Segall, former postdoctoral researcher: “Dr. Colman was an ideal mentor, extraordinarily knowledgeable, but also very willing to consider and discuss the ideas of scientists at earlier stages of their careers. She provided an environment that brought out the very best in her graduate students and post- docs. ere was never a single day that I did not feel supported, encouraged and eager to move ahead with my project and determine the outcome of the next experiment. Even years after I left her laboratory, Dr. Colman remained extremely supportive and an enduring role model to me.” Don Dennis, a faculty colleague for many years, remembers a conversa- Bobbie Colman, pictured here in 2004, took tion with a visiting speaker who noted that Dr. Colman was such a competent a special interest in nurturing and enabling scientist and that she only talked about substantive issues. e visitor then the careers of women and underrepresented wondered if she ever engaged in small talk. Dennis responded that she did, minority scientists. but she never initiated it because “she had more respect for others’ time than they did for themselves.” Dennis also noted that since the age of 17, Roberta routinely got and did not need more than ve hours of sleep a night. Judy Voet, who, with her husband, Don, and Liz and Ed ornton and Frances and Paul Kende, was a close personal friend of Bobbie and Bob Colman, writes, “To us, they were joined at the hip. ey took courses and studied together, took trips together, went to movies, concerts and plays together and gave wonderful dinner/slide-shows of their travels together. ey even created a joint out-going phone message/greeting! Bobbie was a wonder- ful, creative cook and often coordinated meals to go with their travel presen- tations, with Bob being primarily the sous chef. But with the slide shows that ‘togetherness’ ended. ey were each ercely protective of their own photos, and we often wound up with a two-act show!” Bobbie’s daughter, Sharon Greenberg, writes, “My mother was a person with a true love of life, discovery of the world and learning. She was a very positive, optimistic individual who instilled in me a passion for travel and learning. Her grandchildren loved her excitement and enthusiasm. We miss her immensely.”

DECEMBER 2019 ASBMB TODAY 13 RETROSPECTIVE

Sydney Brenner (1927 – 2019)

By Terrence Sejnowski

orn in South Africa in 1927, code was based on triplets of base say something like this: First you must Sydney Brenner started medi- pairs, which he called codons, and he choose the right place for your work B cal school at such an early age found two of the stop codons. with generous sponsors to support you. that he was too young to practice is led to a third turning point. Cambridge and the Medical Research medicine at the conclusion of his Sydney shared an oce at the LMB Council will do. en you need to dis- training. is gave him time to take with Francis Crick, and they had cover the right animal to work on — a classes in anatomy and physiology long discussions about biological worm such as C. elegans for example. that included bench experiments. He questions. What do you do for your Next, choose excellent colleagues who abandoned medicine and went on to next project after discovering the are willing to join you in the hard write a master’s thesis in the eld of structure of DNA and working out work you will need to do. How about cytogenetics, which served him well the genetic code? Francis decided John Sulston and Robert Horvitz for when he became a molecular biolo- to focus on the human brain, and a starter. You must also make sure gist. is was the rst turning point Sydney inaugurated a new model that they can nd other colleagues and in his remarkable life. organism, Caenorhabditis elegans, students. Everybody will have to work In 1953, Sydney was pursuing a roundworm that is one millimeter hard. Finally, and most important of doctoral research at Oxford when he long and has only 302 neurons. He all, you must select a Nobel Committee heard about the DNA model that wanted a species that could serve as a which is enlightened and appreciative Jim Watson and Francis Crick had Rosetta stone for decoding how neu- and has an excellent chairman with constructed, based on experimental rons give rise to complex behaviors. unquestioned discernment.” data from Rosalind Franklin. Along e neurons’ small size and other Sydney once counseled me not with Leslie Orgel and Jack Dunitz, he technical problems delayed that to retire until I had my next job drove to Cambridge to see the model. study until optogenetic techniques lined up. is was his way of keeping He described this experience in a were invented, but in the meantime active in science long into his 80s. lecture near the end of his life: the worm’s genetics were the starting After retiring from the LMB, he had “And I have to tell you that it was point for many breakthroughs in un- an experimental project in Singa- just a moment of absolute enlighten- derstanding how a creature develops pore sequencing the highly compact ment, that’s all I can say. I had seen the from an embryo by following every genome of the fugu, a puersh. light, and I spent the whole of the next cell in its body over time. He was the founding president of day, before we went back, talking to Sydney was famous for his wit. the Okinawa Institute of Science Jim Watson … And I resolved to work He received the Nobel Prize for and Technology, a distinguished on this subject and, of course, there physiology or medicine in 2002 for professor at the Salk Institute and wasn’t much I could do at that time. I establishing C. elegans as a model a senior fellow at both the Janelia started to think, as indeed we began to system. At the Nobel banquet, he Research Campus of the Howard talk then, about the genetic code. What delivered a short after-dinner talk: Hughes Medical Institute and the is this code? What does this sequence “But now I come to what I want to Crick–Jacobs Center for eoretical mean?” say. And the best way I can say it, is to and Computational Biology at the is was a second turning point. tell you about a letter I’ve received. A Salk Institute. Sydney had reinvented Francis Crick recruited Sydney to the Nobel Prize winner gets many letters. himself again, this time as a Johnny Laboratory of Molecular Biology, or is was from a student in China. His Appleseed for science. He wrote in LMB, where he embarked on a series e-mail said: ‘Dear Dr. Sydney Brenner, “My Life in Science,” his autobiog- of experiments that eventually con- I wish also to win a Nobel Prize. raphy: “I think my real skills are in tributed to deciphering the genetic Please tell me how to do it.’ I have getting things started. In fact, that’s code. His discoveries proved that the been considering the reply which will what I enjoy most, the opening game.

14 ASBMB TODAY DECEMBER 2019 OIST/WIKIMEDIA COMMONS

Sydney Brenner speaks at a 2011 symposium at the Okinawa Institute of Science and Technology.

And I’m afraid that once it gets past magazine editorial, “Understanding pioneering piece of 21st century that point, I get rather bored and want the Human Brain,” he wrote: “Like connectomics in the 20th century. to do other things.” most elds in biology, neuroscience In October 2017, I served as Sydney gave three lectures at the is succumbing to an ‘epidomic’ of interlocutor for four lectures Sydney Salk Institute on “Reading the Hu- data collecting.” At a symposium gave to a small group of young man Genome” in 2009. ey were at the University of California, researchers in Singapore, during a tour de force, delivered without a San Diego, on the emergence of which he reminisced about his career single slide or prop. He did not need omics, when asked which of all the and the art of doing science. He props to hold an audience spell- omics was the most important, his stressed the importance of giving bound. He said that no human ever immediate reply was “economics.” younger scientists resources to set had read the entire human genome, On another occasion he was asked out in new directions as he had done base pair by base pair — only com- about the use of pipelines for drug early in his career. e average age puters. Sydney made it his goal to discovery. His comment was “High of researchers receiving their rst do just that and in so doing discov- throughput: No input, no output.” National Institutes of Health grant ered interesting similarities between Despite these comments, we should is now 45, halfway to retirement. At stretches of DNA in dierent genes remember that he was responsible the Crick-Jacobs Center at Salk, we and across species. for the complete reconstruction of hatched a scheme to give promis- Sydney was skeptical about the the C. elegans brain from electron ing young scientists a junior fellow rise of omics in biology. In a Science microscopic sections in 1968, a position directly after their Ph.D.,

DECEMBER 2019 ASBMB TODAY 15 RETROSPECTIVE SCOTTED400/WIKIMEDIA COMMONS COURTESY OF TERRENCE SEJNOWSKI COURTESY

Sydney Brenner’s last lectures, delivered in Singapore in 2017, were published in book form in 2018.

Wang Jian, founder of the genome sequencing company BGI, shows Sydney Brenner around the BGI headquarters in Shenzhen, Guangdong, China, in November 2010.

providing them with independence “I shared an o ce with Francis is a little man in overalls with a large and mentoring, bypassing years of Crick for twenty years in Cambridge. spanner in his back pocket. ‘God,’ postdoctoral apprenticeships. ese At one time he was interested in says the angel, ‘ is is Dr. Crick; Dr. fellows  ourished and went on to embryology and spent a lot of time Crick, this is God.’ ‘I am so pleased to brilliant careers. e Salk Institute thinking about imaginal discs in meet you,’ says Francis. ‘I must ask you extended the fellows program to Drosophila. One day, he threw the this question. How do imaginal discs other research areas with equal suc- book he was reading down onto his work?’ ‘Well,’ comes the reply, ‘We took cess. Sydney’s in uence lives on there desk with an exasperated cry. ‘God a little bit of this stu and we added and at other institutions he helped knows how these imaginal discs work.’ some things to it and … actually, we launch and advise. In a  ash I saw the whole story of don’t know, but I can tell you that I visited Sydney in Singapore Francis arriving in heaven and Peter we’ve been building  ies up here for in January 2017 along with family welcoming him with ‘Oh Dr. Crick, 200 million years and we have had no and friends from all stages of his life you must be tired after your long complaints.” to celebrate his 90th birthday. He journey. Do sit down, have a drink Sydney Brenner died in April, was no longer able to travel, but he and relax.’ ‘No,’ says Francis, ‘I must joining Francis Crick in Paradiso. He was well cared for by his family and see this fellow, God; I have to ask him had an enormous impact on science Singaporean friends and was staying a question.’ After some persuasion, the and in uenced many careers. We have at the Shangri La Hotel. He was us- angel agrees to take Francis to God. lost a great scientist and a good friend. ing a wheelchair, and his health was ey cross the middle part of heaven, Terrence Sejnowski ([email protected]) failing, but he was as lively as I ever and  nally right at the back, across the holds the Francis Crick chair at the Salk have seen him. I asked him to tell us railway tracks, they come to a shed, Institute for Biological Studies and is a distinguished professor in the division of my favorite Sydney Brenner story, with a corrugated iron roof, surround- biological sciences at the University of “Francisco Crick in Paradiso”: ed by junk. And in the back part, there California, San Diego.

16 ASBMB TODAY DECEMBER 2019 DECEMBER 2019 ASBMBASBMB TODAY 17 NEW MEMBERS

Olayinka Adebayo, Monica Bonilla, Colleen Doci, Emily Jones, Morehouse School College of William and Mary Marian University University of Dayton of Medicine William Booth, Daniel Dyroff, Adrianna Jones, Louisiana Bukola Adedayo, Johnson C. Smith University Truman State University State University A&M Federal University of Technology, Akure Justice Brakache, Brandon Easparro, Jennifer Jossart, Kennesaw State University Omni International University of California, Goodness Adekoya, Riverside Providence College Madeleine Bristow, Timothy Ezeorba, Providence College University of Nigeria, Shania Kalladanthyi, Lauren Aden, Nsukka Kennesaw State University Truman State University Ashli Brown, Mississippi State University Thomas Fedrigoni, Chamithi Karunanayake, Oluwaseyefunmi Adeniran, College of the Holy Cross Miami University Sefako Makgatho Health Summer Burns, Sciences University Kennesaw State University Erin Flaherty, Christopher Kim, University College of the Holy Cross of Massachusetts Boston Chidinma Adiele, Mary Butler, Kennesaw State University Truman State University Jaime Freire-Arvelo, Sarah Kim, Emory University University of Puerto Rico, Nilanthi Adikari, Courtney Layne Buttram, Medical Science Campus Minje Kim Australian National Kennesaw State University University Neil Ganguli, Caitlin Kirkpatrick, Esmeralda Carrera, Tulane University Kennesaw State University Melika Ahmadian, Mount Saint Mary’s Memorial University of University Matthew Gasparrini, Michael Kobor, University Newfoundland College of the Holy Cross of British Columbia Clement Chan, Furyal Ahmed, University of Texas at Tyler Nicholas Gay, Christopher Kowalski, Agnes Scott College University of Cambridge College of the Holy Cross Yen-Shan Chen, Heba Ali, Indiana University–Purdue Chelsea George, Patrick Lackey, Florida International University Indianapolis University of Texas Westminster College University at El Paso Aaliaya Coke, Kennesaw Austin Lai, Emory University Varsha Chowdary Anche, State University Bradford Gibson, Amgen Alabama A&M University Zachary Landis, Jake Collins, Josie Gottsponer, University of Alabama Anthonia Anowai, Truman State University Tulane University at Birmingham University of Calgary Brett Colson, Mohammad Haddad, Nico Lang, University Gallage Ariyaratne, University of Arizona Ghalib University of Wisconsin–La Crosse Montana State University Benoit Coulombe, Ellie Hall, Philipp Lange, Demos Athanasopoulos, Montreal Clinical Research College of William and Mary University of British Pace University Institute Columbia Collin Hansen, Saheed Ayodeji, Charles Crawley, Truman State University Acasia Lanzaderas, Wayne State University Georgia State University University of Texas Grace Harrington, Florida at San Antonio Sigal Bakun, Carolyn Dang, Institute of Technology Kennesaw State University Kennesaw State University Isabelle Lee, Ronald Hills, Tulane University Ryan Barrett, Saumitra Das, University of New England College of the Holy Cross Indian Institute of Science Cameron Lewis, Angel Jaimes, Tulane University Joseph Baugher, Nicholas Dash, Kennesaw State University U.S. Food and Drug Providence College Aileen Li, Administration Praveen Jaiswal, University of Hawaii Sneha Dass, Louisiana State University Mark Beery, College of William and Mary Health Sciences Center Wenshe Liu, Appalachian State Shreveport Texas A&M University University Jesse Davila–Calderon, Case Western Reserve Bella Jankowski, Connor Long, Oana Boldura, University College of the Holy Cross University of Tennessee Banat University of Agricultural Sciences Laura Diaz–Martinez, Xiaoxu Jiang, Adriana Lopez, and Veterinary Medicine Gonzaga University Nicholls State University Tulane University

18 ASBMB TODAY DECEMBER 2019 NEW MEMBERS

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DECEMBER 2019 ASBMB TODAY 19 LIPID NEWS

Crystal building blocks of triglycerides

By Michael Airola

rancis Crick once said, “If you want to understand function, Fstudy structure.” Do you agree? I certainly do, and I would argue that most lipid biologists do too. Just MICHAEL AIROLA consider the eort to dene chemical structures for the many thousands of lipids that exist and the hypoth- eses about individual lipid function that this structural information has generated. What has lagged behind is the characterization of the structures of the proteins that modify, transport or interact with these lipids, but times are changing. For example, when I started my postdoc in Yusuf Han- nun’s lab, only a handful of sphingo- Beautiful structures of proteins involved in triglyceride metabolism and storage. lipid-metabolizing enzymes had been structurally characterized, and these were mainly from bacteria. While e researchers revealed an unexpect- membrane protein that is a key player many questions remain open (hey, ed lipid-binding cavity and provided in the formation of cytoplasmic ceramide synthase — we can’t wait to insight into disease mutations as well lipid droplets. Two groups (Renhong see what you look like!), work from as pharmacological inhibition of this Yan and colleagues and Xuewu Sui several labs has dened the structures therapeutic target. and colleagues), using cryo-electron and mechanisms for many human e second is the crystal structure microscopy, found that 11 or 12 enzymes in sphingolipid metabolism. of lipoprotein lipase, or LPL, the seipin molecules (dependent on the A similar revolution appears to be major lipase that clears triglycerides species) come together to form a ring happening with triglycerides. As most in the blood. Gabriel Birrane and that spans the endoplasmic reticulum of you know, triglycerides serve as a colleagues and Risha Arora and membrane, can bind phosphatidic reservoir for energy storage, but when colleagues separately determined the acid and may stabilize the formation they accumulate excessively, they can LPL structures, overcoming the rela- of nascent lipid droplets. cause health problems, including obe- tive instability of LPL by complexing What’s next? Who knows, but I’m sity, diabetes and heart disease. ree it with its binding partner glyco- darn sure we’re all gonna love it. new structures in particular have sylphosphatidylinositol-anchored caught my attention. high-density lipoprotein-binding e most recent is a crystal protein 1. ese structures, along structure of microsomal triglyceride with other biochemical data, suggest Michael Airola (Michael. transfer protein complex, which LPL is active as a monomer, challeng- [email protected]) transfers neutral lipids into apolipo- ing the long-standing paradigm that is an assistant professor of biochemistry and cell protein B-containing lipoproteins. LPL was only active as a dimer. biology at Stony Brook e arduous crystallography required e last notable structure is that University. to conduct this work is impressive. of seipin, a homo-oligomeric integral

20 ASBMB TODAY DECEMBER 2019 A YEAR OF BIOCHEMICAL ELEMENTS

Rounding out the year with nickel and zinc

By Quira Zeidan

o complete our celebration of the 150th anniversary of Dmitri T Mendeleev’s periodic table, we look at nickel and zinc, two metallic elements with chemical symbols Ni E. JABRI ET AL/WIKIMEDIA COMMONS and Zn and atomic numbers 28 and 30, respectively. NICKEL AND ZINC Nickel can exist in oxidation states ranging from -2 to +4. e most abundant — Ni+2 — com- This ribbon diagram shows the 3D structure of the enzyme urease in coordination with two nickel ions bines with common anions such as depicted in green. sulfate, sulde, carbonate, nitrate and hydroxide. In contrast, zinc predom- inates in the oxidation +2 almost ex- Both nickel and zinc are essen- Proteus mirabilis. It breaks down clusively, acting as a strong reducing tial for life and are present in many urea and produces ammonia, which agent. Zinc forms binary compounds organisms. Nickel is recognized and increases the pH of the surrounding with most nonmetal and metalloid transported into the cell by a variety environment from neutral to basic elements with the exception of noble of mechanisms: nonspecic inux and becomes toxic in the liver, the gases. across membrane proteins in bacteria stomach lining, the kidneys and the Nickel is produced with iron in and yeast, high-anity uptake via blood stream. the nal stages of nuclear reactions transporters and permeases in certain Cells transport, use and sequester during violent explosions deep inside bacteria, and incorporation through zinc much as they do other divalent supergiant stars. As a result, these channels that preferentially carry metals. Photosynthetic bacteria of the two elements are mixed abundantly other divalent cations — such as genus Acidiphilium contain a purple in the interior of meteorites. e magnesium and calcium — in fungi chlorophyll pigment that uses zinc as astrophysical origin of zinc is not en- and humans. Inside cells, nickel cofactor instead of the more common tirely understood, but it might have is inserted into the active site of magnesium. Zinc-dependent phos- involved the asymmetric explosion of many enzymes such as hydrogenase, pholipases C in Clostridia, Bacillus the universe’s earliest supernova. nickel superoxide dismutase, carbon or Listeria species may contribute to Nickel makes up only 0.008% of monoxide dehydrogenase, cis-trans toxicity by breaking down host cell the Earth’s crust and occurs often as isomerase and urease. Toxic excess membranes. e coordination of one an alloy with iron in the planet’s core. intracellular free nickel is neutralized or more zinc ions by particular amino It also exists in minerals in combina- by binding to negatively charged acids forms a zinc-nger motif that tion with sulfur and arsenic. Zinc is molecules such as polyphosphate and stabilizes the 3D structure of many the 24th most common element in sequestration of nickel-containing proteins that bind DNA, such as the Earth’s crust, where it is found complexes into vacuoles. nucleases and transcription factors. primarily as zinc sulde and as a e nickel-containing protein binary alloy with metals including urease is important in the patho- Quira Zeidan aluminum, gold, iron, lead, silver and physiology of liver cirrhosis, peptic ([email protected]) is nickel. Mineral weathering dispers- ulcers and urinary stones. Urease is the ASBMB’s education and public outreach coordinator. es small amounts of zinc into soil, produced by bacteria that infect the Follow her on Twitter seawater and the atmosphere. gastrointestinal and urinary tracts, @quirazeidan. including Helicobacter pylori and

DECEMBER 2019 ASBMB TODAY 21 JOURNAL NEWS

Tor comes to the fore in autophagy

By Martin J. Spiering

ealthy cells are expert recyclers, In a 1998 paper published in rapidly breaking down worn-out the Journal of Biological Chem- Hor surplus macromolecules and istry and now recognized as a JBC reusing their building blocks. Several Classic, Takeshi Noda and Yoshinori pathways, such as the proteasomal Ohsumi at the National Institute for degradation route for protein break- Basic Biology in Japan uncovered this down, specically pick out those missing link, reporting that the target damaged or expendable molecules. of rapamycin, or Tor, protein in yeast

ese selective degradation path- suppresses autophagy in cells that are COMMONS GOVERNMENT OF JAPAN/WIKIMEDIA ways usually operate in cells that have growing in nutrient-rich conditions. ready access to nutrients. But when cells encounter crises such as severe A facile biological system Yoshinori Ohsumi and colleagues discovered that nutrient shortages, they activate an Researchers had known since the the Tor protein controls autophagy in emergency recycling strategy. In these early 1990s that two Tor proteins of yeast cells. cells, a bulk degradation pathway Saccharomyces cerevisiae, or budding indiscriminately breaks down mac- yeast, respond to the nutritional state romolecules and entire cytoplasmic of the cell and regulate cell cycle organelles and ribosomes. progression. Noda and Ohsumi’s referees asked for additional exper- is process is called autophagy discovery that Tor also controls auto- iments to verify that what he and (Greek for “self-eating”) — or some- phagy was a milestone in unraveling Ohsumi saw under the microscope times, more specically, macroauto- how bulk degradation is regulated in was indeed autophagy. phagy to distinguish it from spe- eukaryotic cells. e extra work paid o. “We cialized forms of autophagy that are Ohsumi chose yeast for his main clearly showed that cytoplasmic more restricted and selective. It’s the studies in part because it has a large enzymes are incorporated into the rough equivalent of a wood chipper vacuole (a structure analogous to the isolated vacuole during this process,” that shreds chairs, tables and creden- lysosome in mammalian cells) that Noda said; these additional ndings zas wholesale for use in plywood or as is easy to study by light microscopy. convinced the referees and secured replace fuel. In 1992, his team discovered that the paper’s publication. Autophagy also represents an in nutrient-starved cells of yeast e referees’ requests prompted important quality-control mechanism mutants that cannot degrade proteins Noda to develop more specic and that eliminates long-lived proteins via the proteasomal pathway, the sensitive methods. “After the expe- and damaged organelles in some vacuoles quickly ll up with spherical rience with the rst paper, I realized cells, such as neurons, whose total structures. that we needed a quantitative assay destruction by other processes such as ese membrane-bound for measuring autophagy activity,” apoptosis would harm the organism. structures contained ribosomes, he said. Defects in autophagy have been mitochondria, lipids and cytosolic linked to neurodegenerative diseases enzymes, suggesting that they were A revised view and cancer, highlighting that this signs of autophagy; the researchers In a follow-up paper, Noda and recycling mechanism is essential for named them autophagic bodies. others in the Ohsumi lab developed keeping cells healthy and alive. How- Noda, the rst author of the an assay that measures the activity ever, how the cellular nutrient status Classic paper, was a graduate student of a genetically engineered alkaline is communicated to the autophagy in the Ohsumi lab. During peer phosphatase, or ALP, that becomes machinery was long unknown. review of the 1992 paper, he said, the active only when moved to the yeast

22 ASBMB TODAY DECEMBER 2019 JOURNAL NEWS

vacuole as it is during autophagy. in the Tor-inhibited cells, and using colleagues reporting that Tor phos- “Having this system in hand, I light microscopy, they also observed phorylates the autophagy-related got interested in studying the regu- the tell-tale autophagic bodies in the yeast protein Atg13, interfering with latory mechanism of autophagy in vacuoles. Atg13’s ability to activate another more detail,” Noda said. Using a yeast strain that carried a kinase, Atg1, required for autophagy Noda came across a 1996 paper mutated TOR2 gene encoding a tem- induction. from Michael Hall’s group at the perature-sensitive Tor2 variant, the A 2009 paper by the Ohsumi lab University of Basel, Switzerland, authors  rmed up these observations, reviewed how using the facile yeast reporting that Tor in yeast controlled  nding that the TOR2-mutant strain system has helped pinpoint many cellular processes that typically are exhibits autophagy when grown at other key players in autophagy. induced in response to starvation. temperatures that inactivated the Despite great strides in clarifying “As autophagy is induced by mutated Tor2 variant. autophagy mechanisms in both yeast starvation, I was eager to use our ALP “Our discovery of Tor’s role in and mammalian cells, more work assay to test the hypothesis that Tor autophagy revised prevailing views at is needed. In particular, to prevent might also regulate autophagy,” the time, showing that Tor regulates self-destruction, cells must avoid Noda said. not only anabolic processes, but also excessive degradation during autoph- Noda and Ohsumi grew yeast catabolic ones,” Noda said. “ is agy, Noda said, meaning they need cells in nutrient-rich culture condi- coupling of anabolic and catabolic to have mechanisms that terminate tions that typically inhibit autoph- processes has been a key game chang- autophagy at the right time. agy. e researchers then added the er in the research  eld.” “We are currently investigating Tor inhibitor rapamycin to the cell this question,” Noda said, “and cultures. Using their ALP-based auto- In search of a mechanism already got some good candidate phagy assay, they detected autophagy ey next turned to the question molecules” that might stop of how Tor might control autophagy. autophagy. e Ohsumi lab previously had gen- For work that helped uncover the erated 14 autophagy-de cient yeast molecular mechanisms in autophagy, strains, and Noda found that rapamy- Ohsumi was awarded the Nobel Prize cin did not restore autophagy in these in physiology or medicine in 2016. mutants, indicating that these genes, called ATG, all act downstream of JBC Associate Editor Paul Fraser Tor. at the University of Toronto nominated e Classics paper could not re- the paper as a Classic. Read this and solve the question of how Tor might other JBC Classics at jbc.org JOURNAL OF BIOLOGICAL CHEMISTRY regulate the ATGs, but there was a promising hint — Tor was known to have a kinase domain essential for cell cycle regulation. is suggested When yeast cells are depleted of nutrients, that Tor might control autophagy by Martin J. Spiering autophagic bodies (small dark spherical phosphorylating and thereby inhib- ([email protected]) structures) start to accumulate in their vacuoles is the technical editor at iting autophagy-associated proteins the Journal of Biological (light gray structure). Noda and Ohsumi showed such as the ATGs. Chemistry. Follow him that the Tor protein inhibits autophagy in is was borne out by a 2000 on Twitter @spieringmj. nutrient-rich conditions. study published by Ohsumi and

DECEMBER 2019 ASBMB TODAY 23 JOURNAL NEWS

Paving the way for disease-resistant rice

By Jonathan Grin

esearchers have uncovered an unusual protein activity in rice Protein crystals and a rice panicle Rthat might give plants an edge depicted against a backdrop of rice in the evolutionary arms race against grains represent the structural rice blast disease, a major threat to biology and plant pathology aspects rice production. of a study that found a new way to Magnaporthe oryzae, the fungus combat rice blast disease. that leads to the disease, creates lesions on rice plants that reduce the yield and quality of grain, causing

a loss of up to a third of the annual MARINA FRANCESHETTI AND PHIL ROBINSON global rice harvest. A sustainable approach to ward known as eectors inside rice cells. but the experiments showed that o the fungus has not yet been devel- In response, rice plants have evolved plants expressing this NLR also par- oped. Cost and environmental con- genes that encode nucleotide-bind- tially reacted to AVR-Pia. cerns limit the use of toxic fungicides. ing leucine-rich repeat proteins, or Looking at the unexpected And a phenomenon called linkage NLRs, which are intracellular im- pairing using X-ray crystallography, drag, where undesirable genes are mune receptors that bait specic fun- the authors saw that the rice NLR transferred along with desired ones, gal eectors. After an NLR receptor’s possessed two separate docking sites makes it dicult to breed varieties specic fungal eector binds to the for AVR-Pia and AVR-Pik. with improved disease resistance that bait, signaling pathways are initiated Pikp causes meager immune reactions still produce grain at a desired rate. that cause cell death. after binding AVR-Pia; however, the Gene-editing technologies that e cells “die in a very localized receptor’s DNA could be modied to precisely insert genes in rice plants area so the rest of the plant is able to improve its anity for mismatched eventually could overcome linkage survive,” Baneld said. “It’s almost eectors, Baneld said. “If we can drag, but rst, genes that boost rice like sacricing your nger to save the nd a way to harness that capabili- immunity need to be identied or rest of your body.” ty, we could produce a super NLR engineered. After learning that the fungal ef- that’s able to bind multiple pathogen Mark Baneld at the John Innes fectors AVR-Pia and AVR-Pik have eectors.” Centre and a team of researchers in similar structures, the researchers As an ultimate endgame, gene-ed- Japan and the U.K. report in the sought to nd out whether any rice iting technologies could be used to Journal of Biological Chemistry NLRs known to bind to one of these insert enhanced versions of NLRs — that a particular rice immune recep- eectors might also bind to the other, such as Pikp — into plants, Baneld tor — from a class of receptors that Baneld said. said, which could tip the scale in typically recognize single patho- e team introduced dierent favor of healthy rice crops. genic proteins — triggers immune combinations of rice NLRs and reactions in response to two fungal fungal eectors into tobacco (a model

proteins. e genes encoding this for studying plant immunity) and Jonathan Grif n receptor could become a template also used rice plants to show if any (jonmgrif n93@gmail. com) is a freelance science for engineered receptors that detect unusual pairs could elicit immune writer. Follow him on Twitter multiple fungal proteins and thereby responses. An AVR-Pik-binding rice @spelledjon. improve disease resistance. NLR called Pikp triggered cell death Rice blast fungus deploys proteins in response to AVR-Pik as expected,

24 ASBMB TODAY DECEMBER 2019 JOURNAL NEWS

Secrets of fat and the lymph node

By Laurel Oldach

hen you eat a high-fat meal, your gut exports the fat into W chylomicrons, which join the ow of lymph in the surrounding vessels. is combined uid, which resembles cream, passes rapidly through the lymph nodes and into the blood stream, where the fat is ab- COURTESY OF SANDER KERSTEN COURTESY sorbed by cells that need energy, like heart muscle cells, or that can store fat for the long term, like adipose tissue. Sander Kersten, a professor and department chair at Wageningen A cartoon Kersten uses for teaching shows how saturated fat from the diet enters the lymph node as University in the Netherlands, stud- chylomicrons and how lymph node resident macrophages respond to the fat. ies that rapid uptake system, which depends on a protein called lipopro- ANGPTL4 uctuates in response to to high fat in the bloodstream. But tein lipase, or LPL for short. LPL fasting, cold exposure and exercise, ANGPTL4 in macrophages appears breaks down triglyceride fat mole- helping to control the body’s lipid use. to work dierently than in fat cells. cules, allowing them to be absorbed. Drug developers hoped that Although ANGPTL4 reduces LPL Kersten’s latest study in the Journal reducing ANGPTL4 would be a activity and fat uptake in macro- of Lipid Research shows that LPL good way to reduce the risk of heart phages, it doesn’t seem to alter LPL regulation varies among tissues. disease, but this research hit a snag. level — suggesting that it does not Too much fat in the blood can Mice that were bred to have no act by targeting LPL for degradation cause problems such as heart disease. ANGPTL4 appeared healthy at rst, but by another mechanism. Exactly erefore, right after a meal, it is but that health was fragile. how ANGPTL4 aects macrophages, benecial for adipose tissue to absorb “If you place these animals on a Kersten said, remains to be deter- fat rapidly for storage. at means diet that’s rich in fat, they develop mined. bumping up LPL levels. But during complications which were unantici- “After 20 years of studying a long fast, limited LPL activity in pated,” Kersten said. Lymph carrying ANGPTL4, there are some things adipose tissue helps ensure that fat chylomicrons escapes into their ab- that are very, very clear about this stays available to cells that need it for domens, eventually killing the mice. protein,” Kersten said. “And I’m hap- energy. It is important that our bod- Whether this would happen in hu- py to have contributed to that.” ies can tune LPL activity in dierent mans if you blocked their ANGPTL4 Other questions remain. “We’re systems in response to how much isn’t known — it’s an experiment no not still 100% sure about what is food we eat. one is willing to risk. going on in the lymph nodes.” Some 20 years ago, as a post- e Kersten lab’s latest paper doc, Kersten isolated a protein, examines why loss of ANGPTL4 has Laurel Oldach ANGPTL4, that acts as a control this eect. e work focuses on mac- ([email protected]) is a science writer for the dial for LPL. Later, his lab demon- rophages, the cells that populate the ASBMB. Follow her on strated that the protein targets LPL lymph node. Like fat cells, macro- Twitter @LaurelOld. for degradation in adipose cells. phages express ANGPTL4, and like Researchers since have found that fat cells, they turn it up in response

DECEMBER 2019 ASBMB TODAY 25 JOURNAL NEWS

When prions are personal

Researchers on a quest for a cure publish new assay for monitoring protein level in folding disease

By Laurel Oldach

research team with an especially personal stake in prion diseases NIAID Ahas developed a new measure- ment that may be useful in testing the treatments they aim to pioneer. Almost everyone produces the prion protein known as PrP, which is found in the brain and cerebro- spinal uid. Like most proteins, PrP folds into a characteristic structure when it is produced. But sometimes that structure can change. When one copy of PrP adopts a misfolded shape, other prion proteins it comes into contact with tend to adopt the same shape. e misfolded proteins spread like an infection, and they tend to clump together, damaging the brain. For husband and wife team Sonia Vallabh and Eric Vallabh The prion protein forms fibrils like the ones shown here. Minikel, prions became personal when Vallabh’s mother died in her early fties of a mysterious, rapidly Alliance, a nonprot dedicated to a potential treatment is working? advancing neurodegenerative disease. nding a cure. With support from “ e rst and most basic thing An autopsy showed that the cul- leaders at Boston’s Broad Institute, you do in a clinical trial that’s the rst prit was a genetic prion disorder, a they enrolled in Harvard Medical in humans is you try to nd a dose variant in PrP that makes the protein School, and last spring they defended that is potent and tolerated,” Minikel more likely to adopt a misfolded pri- their Ph.D. theses, which focused on said. on conformation. A test revealed that the mechanisms of prion disease, in To measure a drug candidate’s po- Vallabh, who is now in her thirties, back-to-back seminars. Now they’re tency, researchers usually test for how had the gene too. looking ahead toward testing much it aects its target. In this case, “She has a very high probability treatments. that would mean looking for a drop of developing the same disease by Researchers hope that if they can in PrP after treatment. However, in midlife,” Minikel said. “And once it nd a way to reduce the amount of the normal course of this disease, strikes, it’s rapidly fatal.” prion protein in a person predisposed the amount of detectable PrP drops After that genetic test, Vallabh to prion disease, they can reduce dramatically after a person begins to and Minikel changed their lives. the chances that person will develop show symptoms. ey started taking night classes in the disease, or they might be able to “It’s very nonintuitive … trying biology and took entry-level jobs in delay the onset of symptoms. to lower a thing that already goes laboratories. ey founded the Prion But how will researchers know if down at the onset of disease,”

26 ASBMB TODAY DECEMBER 2019 JOURNAL NEWS

Minikel said. at means that even if the protein hope it will reduce the damage done If disease progression and an has changed shape, the assay can by misfolded PrP. e early trials give eective drug candidate had the still detect it. e work recently was Minikel hope, he said: Mice with ge- same eect on circulating PrP level, published in the journal Molecular netic prion disorders, if treated before researchers would need to test the & Cellular Proteomics. they show symptoms, survive longer drug long before the disease began. Using this new assay to measure without disease. And they weren’t even sure if the biobanked samples from patients, Even if this drug candidate PrP drop in the test results reected Minikel and his colleagues conrmed doesn’t prove eective, Minikel looks reality. e most common test relies that PrP in the cerebrospinal uid with pride at the groundwork they’ve on an interaction between PrP and an drops in the course of prion disease. laid. antibody that recognizes its shape. As Where the PrP goes is still an open “We’ve made tremendous prog- PrP refolds, the researchers won- question. But with greater condence ress in making this a what people in dered, could it become invisible to that it is indeed dropping when the industry would call a ‘developable the antibody while still present in the disease starts, the team has a roadmap disease,’” he said. “And I think that’s cerebrospinal uid? for the best possible clinical tests a really promising step forward no As part of his thesis work, for the drugs that they’re starting to matter what happens with the anti- Minikel helped develop a new test to develop: ey need to test poten- sense oligonucleotides.” resolve this question. With colleagues tial drugs in people at risk of prion at the Broad Institute who specialize diseases who have not yet shown in proteomics, he came up with a symptoms. way to detect PrP that doesn’t depend Working with a commercial part- Laurel Oldach on the protein’s shape. Instead, using ner, Vallabh and Minikel have started ([email protected]) is a science writer for the a mass spectrometry technique called testing drug candidates in mice ASBMB. Follow her on multiple reaction monitoring, the using antisense oligonucleotides, a Twitter @LaurelOld. approach breaks the protein into bits technology that should suppress the and measures its constituent parts. production of prion protein. ey

JLR THEMATIC REVIEW SERIES ADIPOSE BIOLOGY

jlr.org/site/collections/adipose_biology/

DECEMBER 2019 ASBMB TODAY 27 JOURNAL NEWS

From the journals By John Arnst, Jonathan Grin, Angela Hopp, Kian Kamgar–Parsi & Laurel Oldach

Probing progesterone- Profiling stem cells of the Institut für Biochemie und producing cells in pregnancy in differentiation Molekularbiologie and colleagues Extravillous trophoblasts, or Mesenchymal stem cells, or established two mouse models, each EVTs, support formation of the pla- MSCs, can dierentiate into various with a specic mutation that disrupts centa, and EVT dysfunction has been cell types and have strong thera- one of SECISBP2’s two selenopro- associated with pregnancy complica- peutic potential for autoimmune tein-producing functions. In the tions. However, the unique character- disease and other disorders, but their Journal of Biological Chemistry, istics of EVTs compared to other cell development from embryonic stem they write that they found that while types such as villous cytotrophoblasts, cells remains poorly understood. one mutation nullied SECISBP2 or vCTBs, are not well understood. In a recent paper published in the function, the other mutation had Research published in the Journal of journal Molecular & Cellular tissue-dependent eects, suggesting Lipid Research provides new infor- Proteomics, a global research team that diering clinical phenotypes mation on the metabolic characteris- led by Anja Billing of Weill Cornell may be caused by varying SECISBP2 tics of these key cells. Medicine-Qatar writes that they stability in dierent tissues. Austria- and California-based improved a protocol for develop- DOI: 10.1074/jbc.RA119.009369 researchers led by Sigrid Vondra ge- ing MSCs from ES cells and then nomically proled EVTs and vCTBs used this system to prole changes Functions of a kidney from rst-trimester human placentas in the transcriptome, proteome regulator enzyme and found higher cholesterol levels in and phosphoproteome during Cytochromes CYP27B1 and EVTs as well as signicant dierences dierentiation. e work identies CYP24A1 are known regulators of in genes associated with cholesterol numerous regulatory changes that vitamin D in the kidney. However, metabolism. ey found that EVTs include changing expression of HOX the regulatory mechanism of the have higher levels of the enzyme transcription factors, long noncoding latter enzyme, which carries out HSD3B1, which is responsible for a RNAs and signaling proteins. e separate functions in renal and nal step in producing progesterone multiomics approach also allowed nonrenal tissues, has not been (a key pregnancy hormone) from the authors to appreciate, for exam- clear. Mark B. Meyer, Seong Min cholesterol. rough additional anal- ple, that the proteins most phos- Lee and colleagues in Wisconsin yses, the researchers discovered that phorylated are also the most strongly and Canada used ChIP-Seq and EVTs produced and secreted high upregulated. CRISPR/Cas9 genome editing levels of progesterone to support DOI: 10.1074/mcp.RA119.001356 to probe the genomic basis of placental health and that they relied CYP24A1 regulation in kidney and on their higher cholesterol levels to How protein stability nonrenal target cells, or NRTCs. support this biological role. Perhaps shapes disease ey uncovered regulatory regions most signicantly, they found that Mutations in SECISBP2 — a downstream of the Cyp24a1 gene HSD3B1 levels were decreased in protein necessary for selenoprotein that, when specically deleted, placental samples from miscarriage, synthesis — are linked to human revealed a chromatin-based linking the EVTs’ progesterone disease, but patients with these mechanism responsible for the production directly to pregnancy mutations exhibit a high degree of CYP24A1’s diering functions in health. Further studies could provide phenotypic heterogeneity. To gain the kidney and NRTCs. eir study warning signs and drug targets for insight into how dierent mutations was published in the Journal of healthy pregnancy management. inuence SECISBP2 function and Biological Chemistry. DOI: 10.1194/jlr.P093427 clinical phenotypes, Wenchao Zhao DOI: 10.1074/jbc.RA119.010173

28 ASBMB TODAY DECEMBER 2019 JOURNAL NEWS

Chasing tails: improving structural analysis of histones

Histones are essential for chromatin organization, but Malvina Papanastasiou and colleagues treated the four structural details for their N-terminal tails — which play a core histones — H2A, H2B, H3 and H4 — with the prote- crucial role in epigenetic regulation by way of post-trans- ase cathepsin-L, which helps improve coverage of histone lational modi cations — have proven elusive for crys- tails, before subjecting them to HX-MS. tallographic characterization. To obtain these structural They found that cathepsin-L demonstrated unique details, researchers at the Broad Institute and the National cleavage patterns for each of the histones that were Institute of Standards and Technology turned to hydrogen/ pH-dependent and that it generated overlapping N-terminal deuterium-exchange mass spectrometry. peptides about 20 amino acids long for the core histones The technique, abbreviated as HX-MS, takes advan- H2A, H3 and H4. Taken together, the authors believe these tage of the tendency of hydrogens in certain proteins to results prove the protease’s suitability for the analysis of trade places constantly with nearby hydrogen atoms when histone tail dynamics. in aqueous solutions. When these proteins, such as his- “Overall, this novel strategy opens new avenues for tones, are exposed to heavy water that contains deuterium, investigating the dynamic properties of histones that are not a hydrogen isotope twice the mass of normal hydrogen, apparent from the crystal structures, providing insights into they wind up incorporating it in exposed positions on their the structural basis of the histone code,” they write in their surface. Once there, the deuterium atoms then can be recent paper in the journal Molecular & Cellular Proteomics. used to probe protein conformation. DOI: 10.1074/mcp.RA119.001325 —John Arnst

Histones such as H3, shown here in pink during the metaphase stage of mitosis, package and order DNA in structural units called nucleosomes. LAURA TRINKLE-MULCAHY

DECEMBER 2019 ASBMB TODAY 29 JOURNAL NEWS

Sterol metabolism a mammalian sugar-binding domain, saccharide called group A carbo- in the nematode but there have been conicting hydrate, or GAC, to infect human e metabolism of cholesterol reports regarding the receptor’s hosts. In a paper published in the is fundamental to eukaryotic life, sugar-binding activity. Sabine A. Journal of Biological Chemistry, as cholesterol contributes to hor- F. Jégouzo, Hadar Feinberg and Azul Zorzoli and Benjamin H. mone signaling, metabolism and colleagues in the U.S. and U.K. Meyer of the University of Dundee maintaining cell structure. Given its used solid-phase binding compe- and colleagues in Scotland and importance in cellular function as tition assays, glycoprotein blotting Russia write that they used molecular well as its complexity, the cholesterol experiments and glycan array analysis and synthetic biology approaches, metabolism pathway is the subject to investigate the binding activity biochemistry, radiolabeling and of signicant research to identify of various mammalian CD23s, they other techniques to show that the key divergences and elucidate major write in the Journal of Biological enzyme GacB performs a critical step evolutionary points in eukaryotic Chemistry. While no sugar binding in GAC biosynthesis. e results life. Wenxu Zhou, Paxtyn Fisher and was detected for human CD23, a also indicated that the enzyme is a team in W. David Nes’ lab at Texas range of sugars were found to bind conserved across the Streptococcus Tech have studied the cholesterol to cow and mouse CD23. e genus, including those with other metabolism pathways of nematode ndings suggest that CD23 may play types of surface carbohydrates, and worms (a common, well-character- various roles across dierent species. may provide an opportunity to target ized test organism) to elucidate the DOI: 10.1074/jbc.RA119.010572 early steps of GAC biosynthesis in S. specic processes therein. pyogenes infections. In research published in the Glycan markers assigned DOI: 10.1074/jbc.RA119.009894 Journal of Lipid Research, the re- with beam search searchers used a variety of biochemi- Many antibodies used to rec- The upshot of blocking cal and spectroscopic tools to follow ognize stem cells recognize glycan ubiquitination the evolution of cholesterol and epitopes on surface proteins or lipids. Proteins modied by ubiquitin sterol intermediates in the worms. To understand these reagents better, and small ubiquitinlike modier, ey already knew that sterol metab- an international team led by Nian or SUMO, proteins are pivotal in olism occurs along two evolutionari- Wu of Imperial College London myriad essential cellular processes ly divergent branches in the worms, used glycans synthesized in the lab and are elevated under proteotoxic leading to either C4-methyl stanol or to determine what these antibodies conditions such as heat shock, but C4-methyl stenol products. Experi- bind to with greatest ecacy. Using the reason why has not been clear. ments in this study showed that the a computing approach called a beam To understand better the basis for enzyme sterol C4alpha-methyltrans- search, which enables rapid search- this eect, Zhe Sha and a team ferse was responsible for regulating ing through large data sets, in this from Harvard Medical School and sterol ux through these divergent case a glycan microarray, the authors the Leiden University Medical pathways via a novel mechanism. resolve uncertainty about exactly Center blocked ubiquitination in is additional knowledge of the what these antibodies bind to. e human cell lines with a selective cholesterol pathway could pro- results, which were published in inhibitor of ubiquitin-activating vide insights into the evolutionary the journal Molecular & Cellular enzyme. e treatment led to a development of eukaryotic sterol Proteomics, also shed light on stem large accumulation of SUMOylated metabolism. cell glycobiology. proteins located in special nuclear DOI: 10.1194/jlr.RA119000317 DOI: 10.1074/mcp.RA119.001309 bodies. ese unexpected results, which were published in the Journal Does this receptor How strep prepares to infect of Biological Chemistry, oer really bind sugars? Streptococcus pyogenes — the insight into the interplay between Recent work has shown that bacterium responsible for strep ubiquitination and SUMOylation a domain of the immunoglobulin throat and a diverse array of other under stress. E-binding receptor CD23 resembles diseases — relies on a surface poly- DOI: 10.1074/jbc.RA119.009147

30 ASBMB TODAY DECEMBER 2019 JOURNAL NEWS

Lipid effects on endoplasmic reticulum structure

The endoplasmic reticulum, or ER, is a key organ- decreases in DAG skewed the rod-sheet split toward elle in all eukaryotic cells and plays essential roles in cell sheets. signaling and protein synthesis. The structure of the ER is Further experiments con rmed that the reintroduction integral to its function, and a number of human diseases of DAG recovered the normal balance, as did the addition including Alzheimer’s, Type 2 diabetes and certain cancers of other lipids that energetically favor highly curved rodlike are associated with changes in that structure. Previous membranes, such as phosphatidylethanolamine. These ER research primarily has focused on the role of proteins in structural modi cations were independent of any changes maintaining ER structure, while the role of lipids (the main in the number or type of proteins in the ER membrane, structural element of cell membranes) is less well studied. showing that the physical properties of the lipids them- A new paper by Gabriela Ulloa and an international selves were driving the structural reformatting of the ER team, published in the Journal of Lipid Research, high- directly. lights the important role that lipids play in mediating ER Beyond contributing to a deeper understanding of ER structure. structural modi ers, this research could have applications The researchers changed ER membrane lipid com- in medicine. While most drugs target speci c proteins, positions in relatively inert sea urchin oocytes. By  uores- little drug development has targeted lipids directly to exert cently labeling the ER membrane and using advanced therapeutic bene t. With further study and more pre- microscopy techniques, they were able to follow changes cise techniques, lipid-based targets for future therapies in the proportion of two main types of ER structure:  at could emerge as a promising avenue in the treatment of sheets and curved rods. Through this microscopy-based ER-structure–associated human pathologies. approach, diacylglycerol, or DAG, was identi ed as a key DOI: 10.1194/jlr.RA119000210 lipid in mediating ER structure, as the researchers found —Kian Kamgar–Parsi OPENSTAX/WIKIMEDIA COMMONS OPENSTAX/WIKIMEDIA

The endoplasmic reticulum surrounds the nucleus (a), and has a structure including both sheetlike (b) and rodlike (c) sections that contribute to its function.

DECEMBER 2019 ASBMB TODAY 31 JOURNAL NEWS

Breaking down bacterial biofi lm adhesion

Cholera is caused by consuming water or food contam- deleted, though, the cell clusters cannot attach to surfaces. inated with the bacterium Vibrio cholerae. The study by Katherine Kaus and colleagues in Rich Like nearly all other bacteria, Vibrio cholerae forms a Olson’s lab at Wesleyan, however, suggests there may be bio lm — a bacterial community stitched together with nuanced, though important, differences in RbmC and a glue of polysaccharides, proteins and nucleic acids. It Bap1. produces these bio lms in water while it awaits its thirsty The team found that Bap1 has a different binding host and then, once ingested, to protect against the acidic activity than RbmC; Bap1 prefers anionic polysaccharides environment of the stomach, allowing it to survive and over complex N-glycans. These results indicate that Bap1 enter the small intestine, where it produces the toxin that and RbmC may play critical but different roles in bio lm causes severe diarrhea, dehydration and even death. surface attachment. Becoming a bio lm has its bene ts. Bunches of “These studies in conjunction with structures of Bap1 bacteria are less vulnerable than singletons to predation complexed with carbohydrate ligands will provide a frame- by protozoa and bacteriophages. They’re also more potent: work for understanding the network of complex molecular Bio lms pack higher doses of bacteria and hyperinfective interactions that underlie bio lm assembly and adhesion in cells. V. cholerae,” the authors wrote in JBC. Scientists at Wesleyan University have been studying Kaus, now a postdoctoral researcher at the University the bits and pieces of Vibrio cholerae bio lms found in of Texas Medical Branch in Galveston, said, “Our study is water and the gut, and they recently reported a new nding an exciting step forward in understanding the speci c roles about two components of the bio lm matrix in the Journal played by Bap1 and RbmC within the bio lm and how the of Biological Chemistry. slight differences in the two proteins might lead to import- Previous studies have suggested that the matrix pro- ant functional differences within the various environments teins RbmC and Bap1 have redundant functions. When encountered throughout the Vibrio cholerae lifecycle.” either is deleted, the bio lm grows as usual; when both are DOI: 10.1074/jbc.RA119.008335 — Angela Hopp

32 ASBMB TODAY DECEMBER 2019 JOURNAL NEWS

Elucidating a cervical John Arnst Kian Kamgar–Parsi cancer trigger ([email protected]) is an ([email protected]) ASBMB Today science studied biophysics at the e degradation of tumor sup- writer. Follow him on University of Michigan pressor p53 by human papillomavi- Twitter @arnstjohn. and is a consultant for the rus, or HPV, oncoprotein E6 is a key pharmaceutical industry. step in the development of HPV-pos- itive cervical cancer. E6 triggers the ubiquitination of p53 by associating Jonathan Grif n with the ubiquitin ligase E6AP, but Laurel Oldach (jonmgrif n93@gmail. ([email protected]) is the function of the ligase is not well com) is a freelance science a science writer for the understood. By analyzing the p53 writer. Follow him on Twitter ASBMB. Follow her on @spelledjon. Twitter @LaurelOld. polyubiquitinated by E6AP in vitro, Yuji Masuda of Nagoya University and a team in Japan were able to elucidate details of the process. ey Angela Hopp found that p53 is multipolyubiquiti- (ahopp@asbmb. nated with short chains and hypoth- org) is the ASBMB’s esize that this is done in a stepwise communications director and executive editor of manner. Together, the  ndings could ASBMB Today. Follow inform the development of treat- her on Twitter @angelahopp. ments for HPV-positive cervical can- cer. e research was published in the Journal of Biological Chemistry. DOI: 10.1074/jbc.RA119.008374

a season of giving Support young scientists and their mentors by making an end-of-year donation to the ASBMB travel award fund or Marion B. Sewer Scholarship fund. You may donate by contacting the ASBMB Membership Department at [email protected]

DECEMBER 2019 ASBMB TODAY 33 ANTS in the lab Using social insects to study behavior and aging

By Alyson Smith

34 ASBMB TODAY DECEMBER 2019 FEATURE

or more than a decade, researchers Danny Reinberg and Shelley Berger have stud- ied ant communities to learn about links between epigenetics, gene expression and complex biological processes — and they have built their own cooperative scientic community in the process. e two rst met in the early 1990s, when Reinberg was a professor at the Univer- sity of Medicine and Dentistry of New Jersey and Berger was a postdoctoral fellow at FHarvard. Both studied transcription and gene expression, Reinberg by working out biochemical mechanisms and Berger by searching for new genes. At the time, Reinberg, Berger and other scientists were uncovering the nuts and bolts of epigenetics: how chemical tags attached to DNA and surrounding proteins control DNA packaging to specify which genes each cell within an organism expresses. “We had very lively conversations debating the utility of biochemistry compared to genet- ics,” Berger recalled. “Over the years, I think it would be fair to say we developed a lot of respect for one another.” eir shared interest in ants began in 2005 at an epigenetics conference in Mexico City when a strike tied up trac and trapped them for hours in a cab they were sharing. ey agreed that Reinberg’s experimental system of mammalian cells and Berger’s work with yeast limited their ability to dissect the role of epigenetic tags in complex processes such as neuroscience, aging and animal behavior. ey needed a better model organism. At one point, Berger’s eyes lit up. On a recent family vacation to Costa Rica, she had seen leaf-cutter ants in action. ese ants run agrarian societies, nding and harvesting leaves that they use to grow their fungal food. As an undergraduate, Berger had learned that individual ants of the same species are are closely related sisters: ey share 75% of their DNA but can adapt radically dierent traits and behaviors when exposed to dierent environments. “ e vast dierences in the way ants look and the way they act are due to epigenetic regula- NEW YORK UNIVERSITY COURTESY OF SHELLEY BERGER COURTESY

As a Howard Hughes Medical Institute investigator, Danny Reinberg applied Shelley Berger, pictured here in her lab at the University of Pennsylvania, for the HHMI Collaborative Innovation Award, a four-year grant supporting suggested to Danny Reinberg in 2005 that ants could be a powerful model investigators who form teams to pursue outside-the-box projects. organism to study epigenetics. BOB PETERSON/WIKIMEDIA COMMONS

DECEMBER 2019 ASBMB TODAY 35 FEATURE

tion.” Berger said. “ ey have similar DNA, eusocial animals divide labor among two but during their lifetimes they can change or more morphologically and behaviorally because of environmental dierences which distinct castes; reproductive castes produce lead to their aging dierently or maybe even ospring while worker castes care for young, dying of dierent diseases.” maintain and defend the hive, and forage Berger suggested that ants held the prom- for food. ise of becoming a uniquely powerful model Ant colonies are superorganisms: Each organism to study epigenetics in action. Re- caste functions like an organ — an ovary, a re- inberg instantly agreed that they should work productive tract, a muscle or a stomach — to on ants together. accomplish what the colony needs to survive. In a recent paper in the Annual Review Within its caste, each ant functions like a cell, of Genetics, Reinberg shared some of what relying on inter-organism communication they’ve learned about the molecular mecha- and environmental cues to dictate behavior nisms underlying social behavior since that and maximize colony success. eir unique cab ride. social structure makes ants wildly successful; they are found on nearly every landmass on A powerful model Earth, and their global biomass rivals that Like termites, many bees and wasps, of humans. Ants are also capable of feats snapping shrimp, and naked mole rats, ants of cooperation: foraging for food over long are eusocial, exhibiting the highest levels of distances, building bridges with their own cooperation found in animals. Ants and other bodies and managing colonies of fungi or KARL GLASTAD

Among carpenter ants, there are two worker castes. On the left is the minor forager, and on the right is the major soldier.

36 ASBMB TODAY DECEMBER 2019 other insects to produce food. With only one or a few reproducing queens in each ant colony, all colony mem- bers are closely related siblings. Despite similar genetics, castes may have distinct

sizes, brains, body plans, behaviors and social UNIVERSITY STATE JACOB MAYFIELD/ARIZONA interactions. Like genetically identical cells in a multicellular organism, the identity and behavior of individual ants depend less on DNA sequence than on how signal inputs at key points in dierentiation and development act on that sequence. Ants’ unique genetic makeup allows Reinberg, Berger and their collaborators to study epigenetic factors behind development, behavior and other processes in isolation from the genetics. When Shelley Berger and Danny Reinberg approached him about his work with ants, Jürgen Liebig, pictured in his lab at Arizona State University, was excited to combine his knowledge Building a team of ant biology with their experience in biochemistry and genetics to study behavior at the After forming their partnership during molecular level. the cab ride, Reinberg and Berger knew they needed a large and unconventional funding source, because none of the ant genomes much better.” had been sequenced. In 2007, the Howard e carpenter ant has two types of work- Hughes Medical Institute announced the ers (major and minor), while the jumping ant Collaborative Innovation Award, a four-year has two types of reproductive castes (queens grant funding HHMI investigators to form and pseudoqueens). e scientists agreed that teams of scientists and pursue ambitious, Berger would study the carpenter ant, and outside-the-box projects. Reinberg, an HHMI Reinberg would study the jumping ant — to investigator, suggested they apply. exploit the species’ unique caste structures eir rst step was to nd a collaborator and study dierent facets of epigenetics. who had experience working with ants in Liebig suggested that they study the epi- the lab. Berger’s friend Laurence Zwiebel, an genetics of aging in addition to behavior. In insect biologist at Vanderbilt, recommended many ant species, the queen lives much longer ant biologist Jürgen Liebig of Arizona State than nonreproductive castes, sometimes up University. Liebig was studying the carpenter to 30 years. Liebig knew that carpenter ant ant Camponotus oridanus and the jumping queens live at least 17 years, while worker ant Harpegnathos saltator. He was excited to females live only two years. He also knew that combine his knowledge of ant biology with when jumping ant queens died, nonrepro- Reinberg’s and Berger’s experience in bio- ductive workers could become reproductive chemistry and genetics to study behavior at pseudoqueens that maintained the colony and the molecular level. lived ve times longer than normal workers. “You can study a whole society in a Petri In the laboratory, Liebig had worked out dish or a shoe box when you work with ants,” protocols to switch jumping ant workers to Liebig said. “ is makes it much easier to pseudoqueens and back again, with concomi- study the organization of societies as you tant changes in longevity. can control and replicate the experiments e HHMI reviewers recognized that

DECEMBER 2019 ASBMB TODAY 37 FEATURE

studying epigenetics in ants could uncover When worker ants determined to forage mysteries behind human health, behavior and for food manage break to out of their nest, aging at a level not available in other model they cannot reproduce and do not survive organisms. Reinberg and his team received for long, especially if they encounter hostile the Collaborative Innovation Award in 2008 workers from a dierent colony. and 2012, jumpstarting their entry into ant Using the genomics technology available epigenetics. at the time, it took the team two years to sequence, annotate and compare the carpen- Making a model organism ter and jumping ant genomes and transcrip- By the time they received the HHMI tomes. ey discovered that the two types of funds, Reinberg had moved to the New York ants had two common epigenetic tags (DNA University School of Medicine and Berger methylation and histone acetylation) and en- to the University of Pennsylvania School zymatic machinery to add and remove them. of Medicine. ough ant colonies are rare Interspecies and intercaste dierences in medical school labs, the deans at NYU in epigenetic tag prevalence and the expres- and Penn, like the HHMI, understood the sion of acetylating and methylating enzymes potential impacts this research could have on suggested that epigenetics plays a role in the

COURTESY OF ROBERTO BONASIO OF ROBERTO COURTESY human health. e deans provided Reinberg social structure of each species. e scientists and Berger with the nancial support to build hypothesized that changing epigenetic tags temperature-controlled ant rooms capable of could change behavior. Liebig’s lab began Molecular biologist housing dozens of ant colonies in clear plastic feeding carpenter ants epigenetic drugs in Roberto Bonasio, now an boxes. their water. is strategy made the foragers independent investigator Two intrepid postdocs agreed to lead the more active but did not change the soldiers’ at the University of labs’ rst studies in carpenter and jumping behavior. Pennsylvania, led the ants: molecular biologist Roberto Bonasio As in other animals, the brains of young Reinberg lab’s studies of in Reinberg’s lab and computational biolo- ants are more plastic than those of adults; jumping ants when he was gist Daniel Simola in Berger’s lab. Bonasio they are still developing and easier to change a postdoc. and Simola learned to use each species’ with drugs and other interventions. e unique reproductive strategy to maintain the researchers decided to switch from feeding colonies. ey also learned how to conduct adult ants drugs to injecting the drugs into and interpret assays that quantify foraging, the brains of young ants. When they injected scouting and other social behaviors for later newly hatched carpenter ant soldiers with use in epigenetics research. inhibitors of deacetylation enzymes, the ants “ e two of them really were the reason behaved like foragers instead of soldiers. e

COURTESY OF SHELLEY BERGER COURTESY we got this going so beautifully in our two behavioral switch happened after injection labs,” Berger said of Bonasio and Simola. “We with drugs that blocked several epigenetic en- struck it rich in getting two really brilliant zymes and with RNA molecules that blocked As a postdoc, trainees.” specic enzymes. computational biologist e two labs clean the nests in their ant “Although the drugs are very short-lived Daniel Simola, now colonies once a week and feed the ants mul- (lasting only a few hours), we could get a an investigator with tiple times per week. e carpenter ants get long-lasting epigenetic switch of behavior that GlaxoSmithKline, led the sugar-water, mealworms and protein supple- could last 50 days,” Berger said. “ e soldiers Berger lab’s first studies in ments; the jumping ants get live crickets. To would now forage as long as we could assay carpenter ants. meet U.S. Department of Agriculture require- them.” ments, the ants live in escape-proof containers “ ere was only a very small window with slippery walls in a sealed containment in development in which we could change facility lled with oil traps. the phenotype,” Reinberg said. “Once the

38 ASBMB TODAY DECEMBER 2019 BOB PETERSON/WIKIMEDIA COMMONS

Two carpenter ants on a sleepy hibiscus bud at Juno Beach, Florida. ant acquired the change, it was stable. at colonies of mutant ants without relying on immediately told us that, yes, epigenetics is limited numbers of true queens. Learning to important.” inject jumping ant embryos with the CRIS- Armed with their knowledge of ant ge- PR-Cas9 machinery necessary to remove the netics and gene expression, Reinberg, Berger, Orco gene and then raise the resulting larvae Liebig and their collaborators turned to the to healthy, reproducing adults took years of gold standard in establishing a model organ- trial and error. e researchers had to make ism: generating a heritable genetic mutation. tough decisions about which strategies to In the fruit y and other insects, the olfactory pursue. co-receptor Orco is required for olfactory “A lab is a company with one mission to function but not for survival. e team there- accomplish,” Reinberg said. “We needed to fore decided to target Orco to generate adult abort some projects to make sure we could mutant jumping ants that could demonstrate accomplish the mission. It was a very step-by- the role of Orco in social behaviors. step learning experience.” e ability to produce reproductive Finally, postdoc Hua Yan, grad student pseudoqueens from mutant jumping ant Comzit Opachaloemphan and NYU professor workers would make it possible to establish and fruit y expert Claude Desplan estab-

DECEMBER 2019 ASBMB TODAY 39 FEATURE BOB PETERSON/WIKIMEDIA COMMONS JÜRGEN LIEBIG Reinberg, Berger and Liebig are proud of the work their teams have done to establish new model systems to study epigenetics. “Each of us had to leave their comfort zone and engage in something new,” Liebig said. “ is allowed cross-fertilization from ge- netics, epigenetics and behavioral ecology and A Harpegnathos worker next to a cocoon and a larva. led to a boost in both areas. Ants have now become a new model system in genetics.” lished a successful CRISPR-Cas9 protocol. “I was hoping that the brain was going to Jumping ants missing the Orco gene had be plastic enough that we could manipulate reduced sensitivity to odorant chemicals and it and change the behavior,” Berger said, “but loss of brain regions responsible for processing I’ve been amazed that we can alter the brain olfactory signals. e mutant ants also dis- using these methods. I think we’ll be able to played impaired social interactions with other accomplish the same thing in aging as well.” ants, wandering outside the nest but not “ ere is nothing impossible in science if foraging for food and less able to mate, re- you are persistent and passionate,” Reinberg produce and care for their young. is study said. “Now I have to convince the entire sci- paved the way for future work on the role of entic community that it was a success.” olfaction in eusocial behavior and established A lot has changed since that long cab ride the jumping ant as a genetic model organism. in Mexico City. Reinberg and Berger, with the help of their collaborators and trainees, The future of ant epigenetics moved epigenetics research out of the test Reinberg and Berger continue to build on tube and into a complex model organism. their decade of experience in ant epigenetics. Roberto Bonasio and Hua Yan are now After the HHMI Collaborative Innovation independent investigators; together with Re- Award program ended in 2016, they secured inberg, Berger, Liebig and Desplan, they will traditional National Institutes of Health carry ant epigenetics research decades into the funding from the National Institute on Aging future. to apply their genetic and epigenetic tools in “With every model system we have used aging research. over the years,” Reinberg said, “we have COURTESY OF SHELLEY BERGER COURTESY eir labs are working to dene gene learned a lot from each of them that can expression changes behind caste development, be applied to humans. I do not know what behavior and aging, especially in the brain. exactly we are going to learn, but I know that Postdoc Karl Glastad was Led by postdoc Karl Glastad, they are den- we will learn at least two or three important first author on a recent ing epigenetic pathways that change the brain things.” paper out of Shelley to control caste identity. ey hope to nd Berger’s lab on epigenetic epigenetic tags that persist as an ant transi- pathways that change tions from one caste to another and continue Alyson Smith the brain to control social to aect the ant’s behavior, anatomy and/or ([email protected]) is a behavior in ants. longevity. In the future, they hope to expand scientist and scienti c writer at Vala Sciences Inc. in San Diego, the genetic toolkit of carpenter and jumping California. Follow her on Twitter ants to rival that of more established model @cellbionerd. organisms, such as the fruit y.

40 ASBMB TODAY DECEMBER 2019 BOB PETERSON/WIKIMEDIA COMMONS

A jumping ant carries a flower for nest entrance decoration in Wynaad, India.

DECEMBER 2019 ASBMB TODAY 41 FEATURE

OXYGEN SENSING AND ADAPTING TO ALTITUDE

Gregg L. Semenza is one of three physician–scientists awarded the 2019 Nobel Prize for physiology or medicine.

42 ASBMB TODAY DECEMBER 2019 Semenza shares 2019 Nobel Prize in physiology or medicine By John Arnst

ll cells of the human body, even cancerous normal oxygen levels. ones, live or die by their access to oxygen. Semenza and his lab since have probed the role that When that gaseeous molecule is in short HIF-1 and a related protein, HIF-2, play in sites across supply, the body responds by upregulating the the body, including the breast cancer tumor microenvi- hormone erythropoietin, or EPO, to pump out ronment. He also has taken an interest in how variants in more red blood cells, as well as proteins that HIF pathway proteins have been selected over millennia Aaect wound healing, metabolism, embryonic develop- in populations in Tibet that have adapted to living at high ment and altitude adjustment. is response also plays a altitudes. role in anemia, stroke, infection, myocardial infarction “We started with a really specic goal,” Semenza said. and cancer. “We wanted to understand expression of one gene and is year, the Nobel committee awarded its prize how that gene responded to changes in oxygen in partic- for physiology or medicine to a trio of physician-scien- ular cells. And then, as we went on, the role of the HIFs tists — Gregg L. Semenza at Johns Hopkins University, just continued to expand and expand.” William G. Kaelin Jr. at the Dana-Farber Cancer Institute Like many laureates before him, Semenza missed the and Peter J. Ratclie at Oxford University — for their rst early-morning phone call from the Nobel committee roles in discovering how cells sense and adapt to oxygen in October. availability. “I was so sound asleep that, by the time I got to the In 1993, Semenza characterized the protein complex phone, it had stopped ringing. So I went back to sleep,” he hypoxia-inducible factor, or HIF, which controls the said. “It was actually quite some time later that the second production of EPO and other proteins made in response call came and I thought ‘I better be quicker this time.’” to hypoxia, or reduced oxygen levels. In 1995, he iden- e news was an exceptionally welcome bright spot in tied the genes that encode the two subunits of HIF. 2019. “It was a pretty bad year up until a few weeks ago,” During that time, his lab and Ratclie’s lab independently Semenza said during a mid-October interview in his lab at found that the oxygen-sensing mechanism is present in Hopkins. all bodily tissues rather than only in the kidney, where In May, he fell down a ight of stairs and broke his EPO is produced. Kaelin and his lab then found that neck. Hopkins was, by his account, a good place to be for the protein VHL, named after the inherited syndrome that injury, from which he has recovered and has few com- von Hippel-Lindau’s disease, was involved in controlling plications. “Fortunately, we have an excellent neurosurgery responses to hypoxia. Ratclie’s group subsequently found department,” he said. that VHL interacts with one of the two subunits of HIF, Winning the Nobel was exciting, but for Semenza,

JOHNS HOPKINS MEDICINE HIF-1 alpha, and tags it with ubiquitin for degradation at ever since he decided as an undergrad to study genetics,

DECEMBER 2019 ASBMB TODAY 43 FEATURE COURTESY KAROLINSKA INSTITUTE COURTESY

When oxygen levels are low (hypoxia), HIF-1 alpha is protected from degradation and accumulates in the nucleus, where it associates with ARNT and binds to specific DNA sequences (HRE) in hypoxia-regulated genes (1). At normal oxygen levels, HIF-1 alpha is degraded rapidly by the proteasome (2). Oxygen regulates the degradation process by the addition of hydroxyl groups (OH) to HIF-1 alpha (3). The VHL protein then can recognize and form a complex with HIF-1 alpha, leading to its degradation in an oxygen-dependent manner (4).

the focus always has been on how his research might aect FINDING EPO patients’ well-being. “One of the benets of being trained as a physician is The French physician Paul Carnot and his grad- that that also gives you a certain perspective … and you uate student Clotilde-Camille Deandre proposed see what patients and their families go through,” Semenza hormonal regulation of red blood cell production in said. “ en an experiment that doesn’t work is not such an 1906 after investigating the effects of bloodletting on end-of-the-world thing.” red blood cell concentration in rabbits. In 1948, Finn- Semenza and his wife waited a few hours to tell their ish scientists Eva Bonsdorff and Eeva Jalavisto named adult children about the Nobel committee’s call. In the the hormone erythropoietin for the erythrocyte blood meantime, he headed to his lab for an early-morning precursors found in bone marrow. champagne toast. Eugene Goldwasser’s lab at the University of Chicago puri ed EPO in 1977. In collaboration with Homing in on HIF the biopharmaceutical company anemia in people After graduating from Harvard University in 1978, Se- with kidney disease. The U.S. Food and Drug Ad- menza enrolled in an M.D.–Ph.D. program at the Univer- ministration approved the drug, sold as Epogen, in sity of Pennsylvania. When he arrived at Hopkins in 1986 1989. Amgen, Goldwasser then isolated the EPO gene for a postdoctoral fellowship — fresh o a pediatrics resi- and expressed it in an epithelial cell line. This paved dency at Duke University Medical Center — he intended the way for the drug epoetin alfa, developed to treat to continue studying his thesis topic, the molecular basis anemia in people with kidney disease. The U.S. Food of the hemoglobin deciency disorder beta-thalassemia in and Drug Administration approved the drug, sold as transgenic mice. However, Semenza’s mentor at Hopkins, Epogen, in 1989. Haig Kazazian, and his colleague Stylianos Antonarakis had shifted to studying mutations in the factor VIII gene,

44 ASBMB TODAY DECEMBER 2019 which is essential to blood clotting. Semenza decided to focus on EPO expression (see box: KAELIN, RATCLIFFE AND VHL Finding EPO); at the time, the hormone was believed to be expressed in the liver during early development but William Kaelin, who shared the Nobel Prize with only in the kidney during adulthood. Gregg Semenza and Peter Ratcliffe, discovered the e research team took advantage of the EPO gene’s von Hippel-Lindau, or VHL, protein — named for a ge- small size by inserting a fragment containing the whole netic disease — when he was investigating its effects gene and small anking sequences, for a total of about 4 in families who had inherited a mutated form of it and, kilobases of DNA, into transgenic mice. As hoped for, this as a consequence, suffered dramatically increased yielded expression of EPO in the liver of adult specimens. risk of certain cancers. He found that cancer cells that Due to the presence of both the human and mice did not express VHL expressed high levels of genes EPO genes, the mice produced too many red blood cells, a normally regulated by hypoxia, such as those related condition called polycythemia. to angiogenesis, and thus tumor growth. “But the gene was not expressed in a regulated way However, the oxygen-dependent mechanisms in the kidney,” Semenza said. “And it was expressed in a that told VHL when to tag HIF-1 alpha with ubiquitin lot of places where we thought it shouldn’t be expressed, remained a mystery until 2001, when Kaelin and including the brain.” Ratcliffe simultaneously found that, at normal oxygen e researchers then inserted a larger piece of DNA, levels, oxygen-sensitive enzymes called prolyl-hydrox- which curtailed some of the extraneous EPO expression. ylases modify HIF-1 alpha with hydroxyl groups that When they inserted an even larger fragment, which in- interact with VHL, bringing the entire mechanism into cluded important anking sequences, they found that the focus. protein was expressed exclusively in the broblast kidney cells where endogenous EPO is expressed. “It was only then, after we had done all those experi- ments, that I began to think about the mechanisms for regu- tagged with ubiquitin by the von Hippel-Lindau protein lating the gene according to oxygen tension,” Semenza said. (see box: Kaelin, Ratclie and VHL). e researchers soon found that a short DNA se- quence downstream of the EPO gene, which they named Adaptations to altitude the hypoxia-response element, controlled the increase of Since puzzling out how HIF allows cells to sense EPO gene transcription in response to hypoxia. Over the oxygen levels, Semenza has wanted to know how that following years, Semenza and his postdoc Guang Wang system adapts to the reduced oxygen in high-altitude identied, characterized and puried a protein that bound environments such as Tibet and the Bolivian Andes. to the HRE, which Semenza named HIF-1, and identied When someone whose family has lived for generations at the sequence of its two subunits, designated as HIF-1 low elevation rapidly ascends to altitudes above 8,000 feet, alpha and HIF-1 beta. e papers in which they character- they can develop symptoms of acute mountain sickness, ized and puried HIF-1 were published in the Journal of such as headaches, dizziness, nausea and exhaustion. Over Biological Chemistry in 1993 and 1995, respectively. time, this can develop into chronic mountain sickness, At low oxygen levels, HIF-1 alpha accumulates in which is characterized by polycythemia and increased the nucleus, where it and HIF-1 beta, which is identical blood pressure; in severe cases, this becomes high-altitude to the protein ARNT, bind to and upregulate the EPO pulmonary edema. gene, stimulating production of hemoglobin. However, “As the red blood cell count goes up, the blood at normal oxygen levels, HIF-1 alpha rapidly is degraded becomes more viscous and may be more likely to cause by proteasomes, which target the protein once it has been complications, particularly in pregnancy,” Semenza said.

DECEMBER 2019 ASBMB TODAY 45 FEATURE

Were it not for that rst mutation, the second one, which was associated with low levels of hemoglobin,

JOSEF PRCHAL would have been impossible to develop. “He calculated that this second mutation occurred 8,000 years ago on the background of this C-SNP (cyste- ine single nucleotide polymorphism),” Semenza said. In a subsequent study, Prchal and colleagues at the University of Copenhagen found that a similar mutation had evolved in populations in the Bolivian Andes. “Nobody went from Tibet to the Andes and said, ‘I’ve got a few variants you might need,’ right? is occurred independently,” Semenza said. Independent groups also have found that HIF-2 alpha is mutated in both Tibetan mastis and Tibetan sheep. “ is is how you get to the best state under high alti- tude, right?” Semenza said. “You make a variant right in this gene … medicine, biology, evolution — it’s amazing.”

Partners and mentors Gregg L. Semenza, left, and Josef Prchal, right, have been collaborators Prchal, a hematologist at the University of Utah and for over 30 years. In 2017, they visited a Mongolian nomad settlement on native of the Czech Republic, has been collaborating with the Tibetan Plateau in China’s Qinghai Province with Ge Ri-Li, director of Semenza since the latter was a postdoc at Hopkins. the Research Center for High Altitude Medicine at Quighai University, and “He’s an extremely focused and driven person,” Prchal high-altitude anthropologist Cynthia M. Beall. said. “If I need any advice about some very dicult biological puzzle, I don’t think anybody can give me better advice than Gregg.” “When you think about it, the problem is not too few red In 1995, shortly after Semenza published his seminal blood cells, it’s too little oxygen.” work on HIF regulation of EPO expression, he and Prchal In 2014, Semenza and his collaborator Josef Prchal collaborated on a paper in the journal Nature Genetics sequenced the HIF-containing genomic regions of 26 about mutations causing familial polycythemia in the people from Tibet. To the researchers’ surprise, they found Chuvash, a Turkic ethnic group in western Russia. that hemoglobin levels don’t spike in the Tibetans and that By Prchal’s account, he is one of a small handful of a mutation was responsible for a lower oxygen threshold scientists Semenza has collaborated with continuously over for HIF to signal EPO production. the years, outside of Semenza’s mentors and mentees. “It was basically gain of function in Tibetans of neg- “I’ve been very fortunate to have had really superb ative regulators of HIFs,” Prchal said. “So in hypoxia, the mentors at every step of my career,” Semenza said. “I was Tibetans downregulated HIF.” really inspired by a school biology teacher; her name was According to Semenza, Prchal was interested in Dr. Rose Nelson, and she started me on the way to my nding mutated HIF variants after noticing that previous career in science.” studies sequencing the genomes of people in Tibet were all While Semenza encourages independence in his train- missing a specic sequence. ees, he continues to collaborate with a number of them. “He found that that was very dicult to sequence, One of his former postdocs, Daniele Gilkes, who studies so he developed a protocol for getting it,” Semenza said. the hypoxic breast tumor microenvironment, started as an “And lo and behold, there was a polymorphism there that assistant professor at Hopkins in 2015. aected the amino acids. And remarkably, it occurred on “Having a mentor that was both a clinician and a the background of a gene that already had a variant at scientist was extremely important and impactful for my another site in the protein.” training,” Gilkes said. “Gregg helped me to focus on

46 ASBMB TODAY DECEMBER 2019 Daniele Gilkes’ research at was very interested in the work that I was doing and that Johns Hopkins University it was important to him. But it’s dicult to emulate.” focuses on the genetic alterations that happen Beyond the lab under hypoxic conditions In addition to their value as basic research, Semenza, COURTESY OF DANIELE GILKES COURTESY and how they can both Ratclie and Kaelin’s discoveries about oxygen sensing have contribute to tumor helped pave the way for drugs, now in advanced clinical progression and be trials, that could kill cancer cells by starving them of oxygen prevented. through inhibiting the prolyl hydroxylases that modify HIF or inhibiting HIF-1 alpha outright. While some have been approved in China, the drugs have yet to be marketed. research that could make a true impact on improving “I think in the U.S., we’ll probably have an answer in outcomes.” one to two years from these trials,” Semenza said. Semenza pointed out early in her postdoctoral fel- “We’re doing those experiments because we hope that lowship that metastasis, rather than the primary tumor, is we’re going to be able to do something that’ll impact on what kills patients with breast cancer. Gilkes then focused public health. We haven’t gotten there yet, so we’ll just her research eorts on oxygen’s role as a critical determi- keep going.” nant in the metastatic process. She noted that even with as many as 15 people in the John Arnst ([email protected]) is an ASBMB Today science writer. Follow him on lab, Semenza always responded quickly to her questions. Twitter @arnstjohn. “I try to do that for my students, because that was really important to me,” she said. “It made me feel like he

IN MEMORIAM: Paul Greengard

As we celebrate Gregg Semenza’s Nobel prize, we look back on laureates Paul Greengard and Sydney Brenner who died earlier this year. A retrospective of Brenner is on page 14. Neuroscientist Paul Greengard, who won the Nobel Prize in physiology or medicine in 2000 for discovering how brain cells react to dopamine, died April 13 at the age of 93. Greengard was born in Brooklyn on Dec. 11, 1925. After graduating from high school, he enlisted in the Navy, where he became an electronic technician and was as- signed to a team at the Massachusetts Institute of Technology that worked on early-warning radar system to protect American ships in World War II. He then went to Hamilton College, where he majored in physics and mathematics. He received his Ph.D. in biophysics from Johns Hopkins University in 1953, and joined the faculty at Yale University in 1968 after years of postdoctoral work and a stint in the pharmaceutical industry. At Yale, he conducted his then-underappreciated groundbreaking research on neurochemical signal transduction, which went against the prevailing notions that nerve cells communicated solely through electrical signals. He started at The Rockefeller University in 1983, where he served as the founding director of the Fisher Center for Research on Alzheimer’s Disease, a topic he researched, along with Parkinson’s disease, depression and schizo- phrenia, until his death. Greengard and his wife Ursula von Rydingsvard used the $400,000 Nobel award to found an annual prize at Rockefeller University for outstanding female biomedical scientists. The Pearl Meister Greengard Prize, named after Greengard’s mother, who died giving birth to him, has been awarded since 2004. Greengard is survived by his wife Ursula, sister Linda Greengard, three children and six grandchildren.

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NOVEMBERDECEMBER 2019 ASBMB TODAY 49 ASBMB professional-development resources

Jobs board Careers blog asbmb.org/careers asbmb.org/careers/blog The ASBMB jobs board has listings from academia, Every week, our jobs blog presents insights into the government and industry. Looking for your next hire? current job market. Members can post jobs for free. Webinars Grant-writing training asbmb.org/careers/webinars asbmb.org/grantwriting We offer live webinars and recordings of past This D.C.-based summer workshop yields impressive webinars on topics including: getting funding, salary results; 75% of participants end up with successful negotiation, research careers in industry and more. grants within two years. Video tutorials Communications training asbmb.org/careers/careerdevelopment/tutorials asbmb.org/outreach/training/asc Our video series has tips on networking, dressing Can’t travel for training? Take the ASBMB’s “The Art professionally, building a personal brand and more. of Science Communication” online course to gain the skills, knowledge and mindset necessary to become a great presenter.

Small meetings asbmb.org/specialsymposia Small meetings are offered throughout the year on a wide range of scientific topics. Interested in asbmb.org/careers organizing a meeting? Members can work with the ASBMB to plan and organize a special symposium.

50 ASBMB TODAY DECEMBER 2019 Annual Meeting

Annual meeting to highlight JLR junior associate editors

By George M. Carman & Robert V. Stahelin

The Journal of Lipid Research recently recruited four outstanding ear- ly-career scientists to serve as junior associate editors: Raymond Blind of the George M. Carman ([email protected]) Vanderbilt University School of Medicine, Gissette Reyes–Soffer of the Colum- is the founding director bia University Irving Medical Center, Brandon Davies of the University of Iowa of the Rutgers Center for Lipid Research, a Journal Carver College of Medicine and Rotonya Carr of the University of Pennsylvania of Lipid Research associate Perelman School of Medicine. editor and co-director of the ASBMB Lipid Research The JLR instituted the junior associate editors program to facilitate develop- Division. ment of review skills and associated editorial activities. Since their appointments, these four junior AEs not only have been involved with the review process but Robert V. Stahelin also have organized a series of virtual issues highlighting the cutting-edge ([email protected]) is the research published by the journal on lipoprotein clearance, sphingolipids and Retter professor of pharmacy at Purdue University and co- lipoprotein (a). A fourth virtual issue is due to be published this month. director of the ASBMB Lipid When the American Society for Biochemistry and Molecular Biology Research Division. Meetings Committee asked us to organize the JLR session for the upcoming annual meeting in San Diego, it seemed obvious that there was no better way to highlight the journal’s commitment to early-career scientists than to have a session centered around our junior AEs. The JLR session, titled “Lipid Diversity and Disease: Spotlight on Journal of Lipid Research Junior Associate Editors,” will highlight their lipid-based research ranging from basic to clinical studies. As co-chairs of this JLR session, we invite you to read in the following pages about our junior AEs and the exciting work they will present on April 7 at the 2020 ASBMB Annual Meeting.

DECEMBER 2019 ASBMB TODAY 51 ANNUAL MEETING

JLR JUNIOR ASSOCIATE EDITOR RAY BLIND Becoming an active citizen and scientist

By Elizabeth Stivison

ne thing becomes apparent quickly when talking to Ray The many facets of nonmembrane OBlind, an assistant professor of lipids medicine, biochemistry and phar- macology at Vanderbilt University Ray Blind’s lab studies aspects and Journal of Lipid Research junior of what nonmembrane phospho- associate editor: He doesn’t isolate inositide lipids can do in the cell and himself in an ivory tower. how they do those things. In partic- Since he was a grad student at ular, the lab is interested in these New York University, Blind has lipids acting as signaling molecules reached out to students of all ages in the nucleus. Ray Blind and abilities who need a mentor One main arm (among many) of or a teacher, especially those who this work takes structural biology approaches, elucidating the structures otherwise might be unable to forge of lipid-binding nuclear receptors as well as the nuclear lipid signaling their way into science. He tutored enzyme inositol polyphosphate multikinase, or IPMK. This work suggested learning-disabled undergraduates, potential roles for the disordered domains in IPMK that previously had mentored high schoolers and taught been somewhat mysterious to scientists. evening classes at Berkeley. During Another branch of the lab’s work is looking at the potential role lipid his postdoc at the University of signaling enzymes like IPMK and PTEN have in chromatin remodeling California, San Francisco, he worked and gene expression. They investigate genomewide binding of these mole- as a National Institutes of Health cules to understand how these proteins, traditionally thought to act only institutional research and academic on membrane-bound lipids, may be regulating chromatin and transcrip- career development, or IRACDA, tion directly. fellow, teaching at a local college and sharing his insights about higher ed- ucation. He also took time out of his postdoc work to teach at an under- staed medical school in Tanzania. important traits for the parents of a an “outstanding young scientist” as “ e students who didn’t go to future scientist, but they were not well as a “good citizen to the lipid private schools, the ones who had part of the elite academic world, so community.” Judging from Blind’s to work through college and maybe Blind had to make his own way. career of service, he appears to be didn’t have all the privileges other He initially thought he’d pursue a good citizen of the wider science students had, I wanted to do what- a teaching career at a smaller liberal community as well. ever I could to help people like that,” arts college but soon realized he he said. wanted to do more research, and Blind sees himself in those he has ourished since starting his

students; his mother emigrated from lab. He hasn’t forgotten his mission Elizabeth Stivison (elizabeth. Paraguay as a teenager after working of service, though; he is working [email protected]) is a careers columnist for the outside her home since age 9, and to establish an IRACDA teaching ASBMB and a postdoc at his father built machine parts for postdoc program at Vanderbilt. Columbia University studying General Motors. Both were curi- Blind’s mentor at the JLR, mechanisms of DNA repair. ous, adventurous problem solvers, George Carman, describes him as

52 ASBMB TODAY DECEMBER 2019 JLR JUNIOR ASSOCIATE EDITOR ROTONYA CARR Blending clinical, research perspectives to define early lipid disease

By Courtney Chandler

otonya Carr had little research experience before she began her Understanding lipid crosstalk Rmedical residency fellowship at in fatty liver disease the University of Pennsylvania 11 years ago. After four years in med Fatty liver disease, or FLD, is school and another four as a prima- the most common liver disease in ry care physician, Carr joined the the U.S. and is estimated to affect university’s gastroenterology spe- more than 30% of the population. cialization program, which includes The liver, the body’s largest internal emphasis on the liver. organ, has myriad important roles, Carr was interested in metab- including converting food to fuel Rotonya Carr olism and endocrinology, so she and processing fat. FLD can have elected to work in the lab of Rexford alcohol-related and non-alcohol-related origins. Ahima, who since has moved to While the disease often is hard to diagnose in the early stages, Johns Hopkins University. Ahima this is exactly where Rotonya Carr has focused her research. Carr and was starting to focus on diseases colleagues have found that crosstalk between lipid droplets, which are related to fatty livers, and Carr dove lipid-rich cellular organelles, and lipid metabolism in the liver may relate to right in. the development of FLD. She has identi ed a speci c lipid droplet protein “It was the best decision I made called perilipin 2 as a potential therapeutic target in alcoholic FLD and has in my career,” Carr said. “I learned related it to sphingolipid metabolism. Her lab is one of the only ones to how to do bench science and learned identify ceramides, a speci c family of lipid molecules, in lipid droplets. about fatty liver disease from a Carr’s talk at the American Society for Biochemistry and Molecular clinical perspective and from a basic Biology annual meeting will focus on the crosstalk among sphingolipid biology perspective too.” metabolism, lipid droplets and cellular components and how it relates Now an assistant professor in to FLD. the UPenn department of medicine’s division of gastroenterology, Carr has made fatty liver disease her career. As a testament to her contributions to questions related to the biology of “Have passion about your area the eld of lipid biology, she recently their disease,” she said. “I can explain of work and surround yourself with was selected as a junior editor for the what’s going on in their bodies, and supportive colleagues,” she said. Journal of Lipid Research. once they understand this connec- “Your success will depend on you Fatty liver disease, or FLD, is tion between biology and disease, we and your drive.” dened by the presence of fat in more see better results with their treatment than 5% of liver cells. Carr researches plans.” the early stages of FLD and wants to Mentorship at the bench is understand how dysregulation of lip- important to Carr; she takes pride Courtney Chandler id metabolism in the liver promotes in supporting trainees who, like her, (courtneyec19@gmail. com) is a postdoctoral disease. As a practicing clinician, she may have started with limited lab researcher at Johns works with patients who have the experience. Her top two pieces of Hopkins University and a careers columnist for the disease she studies. advice are useful for researchers and ASBMB. Follow her on “My patients have so many clinicians alike. Twitter @CourtneyEChan.

DECEMBER 2019 ASBMB TODAY 53 ANNUAL MEETING

JLR JUNIOR ASSOCIATE EDITOR BRANDON DAVIES Unraveling regulation of lipid partitioning

By Isha Dey

ood mentoring along his aca- demic and professional journey A protein that regulates Ghelped shape Brandon Davies’ lipid partitioning career as a research scientist right from the start. Lipids in the foods we eat are “I had a really good AP Biology packaged into chylomicrons for teacher in high school who turned circulation in the blood; from there, me on to science,” Davies said. they are taken up by many tissues His older brother Sean, a pro- including the heart, skeletal muscle, fessor and researcher at Vanderbilt adipose tissue, and the liver. Improp- University, was Davies’ rst career er partitioning of lipids to tissues is Brandon Davies mentor. Watching his brother go associated with conditions such as through the process of attending diabetes, atherosclerosis and obesity. graduate school, doing a postdoc and A protein called lipoprotein lipase, or LPL, is a key determinant of lipid then getting a job showed Davies partitioning in the human body; the greater the LPL activity in a partic- what it takes to establish a career in ular tissue, the greater the uptake of triglycerides by the same. Davies’ science and guided him along his lab seeks to understand how a group of proteins called angiopoietinlike own path. proteins, or ANGPTL, regulate LPL activity. One such protein, ANGPTL4, “I was blessed with excellent inhibits LPL activity in the adipose tissue and shifts the delivery of fat away mentors during my Ph.D. and from adipose tissue to the heart and muscles, contributing to conditions postdoc,” he said. ough they each such as atherosclerosis and muscle insulin resistance. had dierent styles of mentoring and Davies and his colleagues study the tissue-speci c activity of leadership, Davies said, they always ANGPTL4. They have discovered that knocking out ANGPTL4 in the liver wanted him to succeed and genuine- or adipose tissue of mice causes an age-dependent shift in fat partition- ly supported his desire to be a career ing. This is relevant because, with age, chances of developing metabolic scientist. disorders such as diabetes increase. This nding, when extrapolated to After majoring in biology and humans, could help explain the biology behind such metabolic disorders. English as an undergraduate at the University of Utah, Davies earned a Ph.D. from the University of California, Berkeley, where he the group,” Young said. “He was When not in the lab, Davies en- studied the role of two transcription calm, diligent, organized, honest and joys mountain biking and spending factors in ergosterol synthesis. As a creative.” time with his three children. postdoc in the lab of Stephen Young Now an associate professor of at the University of California, Los biochemistry at the University of Angeles, he simultaneously worked Iowa studying the regulation of lipid on two projects: the role of nuclear partitioning within the body, Davies Isha Dey (ishaadey@gmail. lamins in health and disease and advises budding researchers not to com) is a scientist at Thermo Fisher Scienti c in India. the function of a protein called get discouraged with failure but to GPIHBP1 in the metabolism of learn from their mistakes. “Look for triglyceride-rich proteins. a mentor who looks out for you,” he “Brandon was a joy to have in said.

54 ASBMB TODAY DECEMBER 2019 JLR JUNIOR ASSOCIATE EDITOR GISSETTE REYES–SOFFER The rich rewards of a steep learning curve

By Pingdewinde Sam

issette Reyes–Soer spent the rst four months of her post- Studying lipid-altering proteins Gdoctoral fellowship in Henry N. in disease Ginsberg’s lab pipetting lipoproteins by the bubbling method, a tech- Gissette Reyes–Soffer’s lab uses nique that is crucial for accurate and stable isotopes to examine lipid and consistent results, while Ginsberg lipoprotein metabolic pathways with watched over her shoulder, making established and newly developed a 20-minute process feel like it was methodologies of mass spectrometry. taking hours. The lab has developed key analytical He had reason to be watchful. methods to examine lipid-altering Gisette Reyes-So¨er At the time, Reyes–Soer had no proteins that regulate cardiovascular previous lab experience. After earning and liver diseases. an M.D. in the Dominican Repub- Heart disease is the leading cause of death for both men and women lic, her homeland, she moved to the in the U.S. Reyes–Soffer and her team have shown the relationship that U.S. She joined Ginsberg’s lab at the exists between lipid and lipoprotein metabolism and the most common Columbia University Irving Insti- cause of cardiovascular disease, atherosclerosis. Atherosclerosis, or tute for Clinical and Translational hardening of arteries, is caused by a buildup of fatty plaques that prevents Research in 2004. e early stage of oxygen-rich blood from owing normally to organs and tissues, and the her transition to translational research condition can lead to heart attack, stroke and death. came with a steep learning curve, she The Reyes–Soffer lab also is working to improve the health of the recalls. Bench work required per- largest organ in the human body, the liver, which in adults is about the sistence, which she had. size of a football. The liver is involved in food digestion, storing energy and Reyes–Soer is now an assis- eliminating toxic substances. The lab is enlarging their research to include tant professor in the department of proteins other than lipoprotein (a) that might be involved in nonalcoholic medicine in the division of preventive fatty liver disease and body fat accumulation. medicine and nutrition with her own lab at the Columbia University Irving Medical Center Vagelos College of Physicians and Surgeons, mostly with a new hypothesis and nd new the success of her colleagues and her involved in clinical and translational answers to the problem.” own trainees and, most importantly, research. Medical school satised Ginsberg mentored Reyes–Soer a ‘glass is full’ love of life that makes the human aspect of her interest in for 15 years, from postdoctoral fellow working with her a joy.” health, while research has given her to R01-funded assistant professor. a solid career path to inquire into “What has remained constant is Pingdewinde Sam ([email protected]) disease states and mechanisms that her enthusiasm for research, which is a Ph.D. candidate regulate them. is only exceeded by her boundless in the department of “When an experiment in the lab energy and determination to be a cellular and molecular physiology at the Johns gives us expected results, we smile successful, independent investigator,” Hopkins University big,” she said. “When it gives us he said. “ ese characteristics, which School of Medicine and the founder of Teêbo.org. unexpected results, we smile broad- are not uncommon in academics, Follow him on Twitter er. is means we need to come up are combined with her concern for @samestry.

DECEMBER 2019 ASBMB TODAY 55 The nightlife of a scientist–mother

By Teisha Rowland

y half-awake mind dismissed maternity leave, he was already back derail it? What gaps remained? Did the gentle rustling, but the at work. As a university professor we have the time ll them before I left Mmovement persisted. Groggily and department chair, he’d need to the lab for months? Tick tick tick. If I remembered the newest member of be ready for a full day of teaching, we didn’t make this deadline, would our family. My hand slipped between mentoring, back-to-back meetings we be scooped? If we succeeded, would the crib bars, trying to soothe my and directing the bucket brigade to the reviewers appreciate the signicance nearly three-month-old son. put out the usual departmental res. of the ndings in such a niche eld? Hadn’t I just fallen asleep? Not long ago, I’d stayed up late Would they be right not to appreciate A glance at the clock conrmed too. But now I was up at all hours. A them? that once again my mind had quiet, private time with our in- Somehow, we’d kept the momen- deceived me; a couple of hours had fant. And the manuscript. tum going, even across multidisci- passed. ese awakenings interrupted My eyes adjusted while I checked plinary collaborations. Somehow, my sleep three or four times a night. for new emails from my collabora- I’d managed, even with increasing And every time, it felt like I had just tors. A few replies had arrived. ey fatigue and new aches and pains, to dozed o. thought the revised gures looked collect the data before I’d left. It was a A plaintive crying joined the good and the cover letter justied crazy plan. Somehow, it worked. increasingly frantic ailing inside the the novelty of our ndings. e way After giving birth, I worked from crib. My son was hungry. And if I we explained that unexpected result home to nish writing the paper. I waited much longer, he might wake in the discussion section would scraped together the free moments of up the entire household. have to be good enough for now; my day — between diapers, laun- Time to move quickly. my co-authors agreed that we could dry, scarng meals my husband had I pulled back my warm sheets wait to do the experiment later, after prepared and trying to soothe a fussy and, like an automaton, carried out seeing reviewer responses. I couldn’t new being. I was grateful to collabora- the protocol that, though still new, do experiments now, in any case, and tors who continued to wrap up loose had become familiar. I sat up, situat- was starting a new job soon after my ends in the lab and communicate via ed him on my lap and reached for my maternity leave ended. We would aim email. Face-to-face meetings (even phone. Even on its dimmest setting, to submit later in the week. It would virtual ones) were out of the question the screen seemed bright. Squinting, be my rst paper as a postdoc in the (I was still trying to teach my new- I navigated to the baby app and start- lab. I was thrilled to have created a born what a schedule was; perhaps ed the nursing timer. paper with a Nobel laureate. by the time he went to college he’d My husband remained sound I wished I could share the news get it). Luckily, he was healthy and asleep. I’d crawled into bed early, with my husband, but I dared not napped well. I often nursed him at after getting the baby down, while disturb him. my computer; he’d fall asleep on my he stayed up entertaining our toddler I thought back to the frantic lap, and I hardly noticed the hours until her bedtime. I missed the months in the lab, all of us racing passing as I focused on the manu- evenings with them, but this was against the clock to collect the data script. I pecked away at the keyboard the easiest way for me to accumulate before my due date. Were the gures with one hand. I fought for each spare maybe six hours of sleep, combining we’d outlined on the whiteboard at that second. Outlining, writing, editing, interrupted chunks plus sleeping in. rst manuscript meeting still the best rewriting, making gures, tweaking My husband didn’t have the lux- way to tell this story? Did the surprising gures, retweaking gures and editing ury of sleeping in — while I was on results complement the narrative or my collaborators’ revisions.

56 ASBMB TODAY DECEMBER 2019 Was there an alternative to chas- job, we could not aord our mort- and he let out a satisfying burp. As ing this manuscript, this obsession? gage. One postdoc I knew could not I was changing his diaper, he woke Motherhood. I wanted what was best aord full-time daycare and had to up. In the dark room, my hands for my baby, to bond with this tiny juggle taking baby care with their went through the familiar motions. fascinating life. At the same time, I partner. Yet another postdoc said He softly cried, and again I tried to felt like I was ghting for my identity she couldn’t have kids because she calm him before the wails woke my as a scientist against potentially couldn’t aord the childcare on her husband and toddler. He was ready all-consuming motherhood. It did salary. A female professor once told for round two. not surprise me to learn of a recent me that, nancially, it was better to Sitting back in bed, I started the study published in Nature showing wait until landing a tenure-track job timer again. that more than 40% of full-time fe- before having kids, but with fertili- What would I be doing when I got male scientists quit science or became ty rates dropping in a woman’s 30s back to lab? I opened my action items part-time after having their rst child (more steeply after 35), and most and added a few more bullet-pointed (compared to 23% of new fathers). postdocs being 30-34 years old, and experiments to the long list. I’d have Being a new parent is exhausting. most rst tenure-track positions be- only one week in lab before starting And there’s the guilt. Was I still ing landed at age 33-36, it is denite- my new job. Five days to wrap it all being a good mother? Was my drive ly tight timing. Tick tick tick. up. If I made the cDNA on Monday to publish diminishing my mother- My phone vibrated. “Have fed morning, assuming the RNA was still hood? Would my children grow up to for 15 minutes,” a pop-up told me. good, how many qRT-PCR plates could resent me because I have a career? e baby was asleep, his lips barely I run? Where would that put me by My return to full-time work was moving. Gently I lifted him, pat- Wednesday, and then by Friday, as- also a matter of nances; without my ting him close against my shoulder, suming I wasn’t so sleep-deprived that I

DECEMBER 2019 ASBMB TODAY 57 Suddenly, I heard a gentle rustling, followed by a plaintive cry. Hadn’t I just fallen asleep? I looked at our clock. No, more than two hours had passed, once again. At least it’s easy to fall asleep when one is so sleep deprived. botched the experiments? I opened my fewer experiments, but I’d have more I set my phone back on the night- calendar app and blocked out time meetings and teaching obligations, stand. Gently lifting my son to my for the runs. so picking up sick kids still would shoulder, I patted him a few times en I shifted the times I already be a careful dance with my husband and he burped. I held him a little had blocked o for running to the and his busy schedule. Having my longer, feeling his cheek against lactation room, roughly every 2-3 own oce meant I could pump at mine. Who will you be someday? hours. (If I spaced the times out more, my desk, with little disruption to my Will you become a scientist like your would there still be enough milk to work. parents, try to answer the dicult avoid formula for a while?) I tried I opened my action items for get- questions of our time or build tools to to remember which incubation ting the stem cell center o to a good help humanity — or wisely run from steps were at least 20 minutes long, start. Move forward with purchasing the profession? allowing for a lactation room visit. the specialized tissue culture incuba- He settled in his crib, and I inking about a recent study show- tors. Look for a refurbished, used or settled back into bed. Emails I ing that the time of day that milk is demo microscope to save funds. Set up wanted to send and action items to produced acts as a circadian cue to the center’s website to attract users. Get add to my lists still buzzed through the infant, I set a reminder to label the word out on the training that will my brain, but I resisted picking the my bottles when I pumped, and I be oered. I wanted everybody to phone back up. Soon, the gentle hoped daycare could follow such know about this new resource where breathing of my husband and baby labeling instructions too. It would be people could grow their own cells, do lulled me back to sleep. nice if that helped him sleep through their research and receive hands-on Suddenly, I heard a gentle rus- the night. training. I dreamed of it being busy tling, followed by a plaintive cry. Keeping busy would at least help with users conducting world-class re- Hadn’t I just fallen asleep? distract me from missing him. We search and forging multidisciplinary I looked at our clock. No, more liked the day care center but didn’t collaborations. How would I get there? than two hours had passed, once know our baby’s caregivers. I hoped How long would it take? again. At least it’s easy to fall asleep he’d be in good hands, that they’d My phone vibrated. “Have fed when one is so sleep deprived. get him to take his bottles well, that for 15 minutes.” I listened to the I placed my baby on my lap and if he managed to roll onto his belly baby’s rhythmic, peaceful breathing. reached for my phone. during a nap they’d make sure he didn’t suocate. I hoped he wouldn’t catch a cold from the onslaught of Teisha Rowland ([email protected]) is director of the Stem Cell Research and Technology Resource day care germs, and then I felt guilty Center at the University of Colorado Boulder. She is as I realized I was worried about how passionate about science education; Women in Science and Education, or WiSE, efforts; helping scientists become his illness might disrupt my carefully better communicators; and being a geek. Rowland was a planned experimental schedule. postdoc in Thomas R. Cech’s laboratory while on maternity I’d have more exibility at my leave, and the manuscript she writes about was published in PNAS. new job as director of a new shared stem cell center. It was focused on my specialty – researching human pluripotent stem cells. I’d be doing

58 ASBMB TODAY DECEMBER 2019 2020 ASBMB–Deuel Conference on Lipids Fat in Liver and Beyond

MARCH 3 – 6, Hotel del Coronado, Coronado, Calif. Learn more, register and submit your abstract at www.asbmb.org/deuelconference/

Feb. 4: Abstract submission deadline

PROMOTING RESEARCH OPPORTUNITIES FOR LATIN AMERICAN BIOCHEMISTS

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.

Sign up for updates at asbmb.org/pabmb

DECEMBER 2019 ASBMB TODAY 59 NEW! ASBMB Today call for submissions

ASBMB Today is publishing a new essay series in 2020 SERVICE BEYOND SCIENCE A career in the life sciences is demanding, but some researchers find time to give back to their communities — often in surprising ways. Do you do volunteer work that is unrelated to your life in the lab? Tell us about what you do and why.

Email [email protected] for more information, or submit at asbmb.org/asbmbtoday.

Upcoming ASBMB events and deadlines

2–8 National Influenza Vaccination Week 5 ASBMB–Deuel Conference on Lipids early registration deadline DECEMBER

1–31 National Mentoring Month 30 Deadline for last-chance abstracts for 2020 annual meeting 30 Deadline for scientific outreach abstracts for 2020 annual meeting 31 Deadline for Student Chapters Honor Society applications JANUARY

4 World Cancer Day 4 Deadline for ASBMB–Deuel Conference on Lipids abstract submission 14 Deadline for ASBMB Outstanding Chapter Award applications 19 Deadline for ASBMB–Deuel Conference on Lipids registration

FEBRUARY 29 Rare Disease Day

60 ASBMB TODAY DECEMBER 2019 CLASSIFIEDS

Umea University Wake Forest Baptist Medical Center Senior Lecturer / Chair, Department of Biochemistry Associate Professor in Cell Biology

The Department of Molecular Biology (MB) at Umeå University has The Chair must be a passionate advocate for the Department’s initiated a search for a quali ed cell biologist. The position will come trainees, students, and faculty. They will be a major institutional with automatic tenure at the Faculty of Science and Technology. We leader, strengthening existing collaborative relationships throughout are interested in outstanding individuals who have the potential to the health system and working with the Dean’s OŽ ce in in‘ uencing develop an innovative, independent research program that comple- the academic enterprise for WFBMC. The next Chair of Biochemistry ments and enhances our existing strengths. has the opportunity to build a leading 21st century department on Candidates with research interests and teaching experience in exciting a foundation of renowned training and research excellence, while areas of mammalian cell biology and using a variety of molecular serving as an advocate for the organization in all of its missions. experimental approaches and model systems are encouraged to apply. Quali ed candidates will possess a PhD, MD, or MD/PhD (or equiv- alent); be eligible for appointment as a full professor; have demon- http://www.asbmb.org/Careers/Jobs/81990/ strated leadership experience; and have national, and preferably international, recognition in biochemistry. http://www.asbmb.org/Careers/Jobs/81982/

Vanderbilt University Western New England University Tenure Track Faculty Positions Director of Forensic Science - Assistant/Associate Professor

The Department of Molecular Physiology & Biophysics (MPB) at Responsibilities of the position include teaching lecture and labora- Vanderbilt University invites applications for a tenure-track faculty tory sections of introductory and advanced forensic science courses, appointment. MPB has a long and distinguished scienti c history developing upper-level electives, and guiding undergraduate student and currently has 23 primary faculty members with active research research projects and internships. In addition, the Director helps the programs studying biophysics, gene regulation, genetics, membrane Department Chair with program assessment, staŽ ng, and scheduling. transport, metabolic/endocrine disorders, neuroscience, signal While primarily a teaching institution, scholarly activity is required for transduction, single-cell biology, and structural biology. Applicants tenure consideration. must have a Ph.D. and/or M.D. degree and an outstanding record of Candidates should have a Ph.D. in forensic science, molecular scholarly achievement that demonstrates the potential to establish a biology, analytical chemistry, or other closely related  eld, a strong highly productive and innovative research program. A generous start- commitment to undergraduate education, and demonstrated teaching up package will be provided to facilitate cutting-edge investigations abilities. Extensive professional work experience working in a forensic into fundamentally signi cant biomedical research questions. Ap- science laboratory or in a molecular biology/analytical chemistry pointment is expected to be at the Assistant Professor (tenure-track) laboratory focused on forensic science applications is required. level, although applicants may also be considered for more senior appointment. http://www.asbmb.org/Careers/Jobs/81908/ http://www.asbmb.org/Careers/Jobs/81959/

To see a full list of jobs, please visit asbmb.org/careers ANNUAL MEETING SAN DIEGO | APRIL 4-7, 2020

Discover Common Bonds Session tracks at the ASBMB Annual Meeting Daily morning sessions at the ASBMB annual meeting are divided into eight tracks addressing different topics in biochemistry; stay in your lane or explore other domains.

BIOCHEMISTRY OF LIPIDS AND MEMBRANES NEW DEVELOPMENTS IN METABOLISM • Novel roles of lipids in health and disease • NAD synthesis, salvage and sirtuins in tissue health • How lipids impact the structure and function of • Control of cell fate by metabolic intermediates membrane proteins • New insights into control of metabolism by • Membrane biogenesis and trafficking transporters

GLYCOSYLATION AND EXTRACELLULAR RNA AND DISEASE MATRIX IN DEVELOPMENT, REPAIR • Noncoding RNAs and disease AND DISEASE • RNA modifications and disease • Glycosylation and extracellular matrix in • RNA binding proteins and control of RNA development, repair and cancer biogenesis in disease • Glycosylation and extracellular matrix in immunologic, inflammatory and infectious disease RE-IMAGINING STEM: WHO WE ARE • Glycosylation and extracellular matrix in neurologic AND WHAT WE DO and metabolic diseases • Who we are: Creating a culture of wellness in science MOLECULAR MACHINES — STRUCTURE • What we do: Choosing pedagogy over content AND FUNCTION • Molecular machines: New paradigms in structure, UNDERSTANDING THE RULES OF LIFE function and engineering • Cell decision making • Molecular motors • Regulation of gene expression • Molecular motors in transport, biosynthesis and • Best practices for preventing/managing incidences energy transduction of harassment in the workplace

MOLECULAR MECHANISMS OF CELL SIGNALING • Mechanosignaling • Posttranslational modifications/signaling • Emerging mechanisms of signaling