Vol. 19 / No. 9 / October 2020

Milk through the millennia Lipids in potsherds hold clues to lactase persistence The 2021 ASBMB Annual Meeting will be virtual!

Learn Join us more April at asbmb.org/annual-meeting27–30, 2021 Learn more at asbmb.org/annual-meeting

The ASBMB annual meeting is held in conjunction with Experimental Biology. CONTENTS

NEWS FEATURES PERSPECTIVES

2 30 45 EDITOR’S NOTE MILK THROUGH THE MILLENNIA THE ART OF PAPER FOLDING AND THE Wellness—we need it now more than ever Lipids in potshards hold clues to lactase SCIENCE OF PROTEIN FOLDING persistence 3 48 MEMBER UPDATE 38 THE UPS AND DOWNS OF TEACHING PANDEMIC SNARLS RESEARCH IN A PANDEMIC 6 ADMINISTRATION IN MEMORIAM Funders, grant administration offices work 50 together to reassure anxious investigators NATIONAL CERTIFICATION 9 COVER: PHOTO ILLUSTRATION BY EXAM AS FACULTY DEVELOPMENT RETROSPECTIVE PATRICE GALLAGHER, BASED ON A PHOTO EXERCISE BY KATHERINE GRILLO Herb Tabor (1918–2020) Applying large-scale assessment ideas to small classes 15 RESEARCH SPOTLIGHT 51 Understanding the impact “IT ALL COMES DOWN TO WHERE WE of Type 1 diabetes susceptibility genes PLACE OUR BETS” 18 5 questions for Mark Harpel NEWS Nobelists’ former postdocs discover missing link in telomerase evolution 21 JOURNAL NEWS 21 Re-creating coagulation in a lab 30 22 Gut microbiome shaped by dietary sphingolipids 23 Our internal ecology 38 24 From the journals 45

15 50

OCTOBER 2020 ASBMB TODAY 1 EDITOR’S NOTE

Vol. 19 / No. 9 / October 2020

THE MEMBER MAGAZINE OF THE AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY THE MEMBEROFFICERS MAGAZINE OFCOUNCIL THE AMERICAN MEMBERS SOCIETY Wellness – we need it FOR BIOCHEMISTRY ANDSuzanne MOLECULAR Barbour BIOLOGY Toni M. Antalis President Joan Broderick Charles Craik GeraldOFFICERS Hart COUNCIL MEMBERS MattSquire Gentry J. Booker now more than ever PastGerald President Hart Susanna Greer President Victoria J. DeRose Wei Yang AudreyBlake Lamb Hill Secretary Jennifer DuBois JamesAudrey M. Ntambi Lamb By Comfort Dorn Secretary Joan Conaway TakitaJames Felder M. Ntambi Sumter Celia A. Shiffer Toni TreasurerM. Antalis Kelly Ten–Hagen Takita Felder Sumter Treasurer or six weeks, from mid-March shared in these pages. EX-OFFICIO MEMBERS Kelly Ten-Hagen JoAnn Trejo to late April, I slept with a The third iteration of the EX-OFFICIO MEMBERS ASBMB TODAY EDITORIAL Robert S. Haltiwanger thermometer on my night- ASBMB Today wellness issue is RobertCarla S. Haltiwanger Koehler ADVISORY BOARD F ASBMB TODAY EDITORIAL Co-chairs, 2020/2021Carla Annual Koehler RajiniADVISORY Rao BOARD stand. And I did not sleep well. I coming up in 2021, and as we slog MeetingCo-chairs, Program Committee2020 Annual Chair Rajini Rao woke up regularly between 2 and our way through what feels like an Meeting Program Committee Cheryl Bailey AnaChair Maria Barral 3 a.m. Sometimes I went back to endless pandemic, wellness is an Chair, Education and Professional Cheryl Bailey NatashaFloyd Brooks“Ski” Chilton Development Committee sleep. Sometimes not. I’d scroll on ever more important topic. Beyond Chair, Education and KellyHenrik Chacón Dohlman ProfessionalDaniel Development Raben BerondaPeter J.Montgomery Kennelly my phone for hours, checking the protecting ourselves from CO- Committee Chair, Meetings Committee BillBeronda Sullivan Montgomery latest news. Every time I coughed, VID-19, we need to stay physically SoniaDaniel Flores Raben MelissaA. Maureen Vaught Rouhi I took my temperature. I had and mentally strong. For many of Chair,Chair, Meetings Minority Committee Affairs Melissa Vaught Binks Wattenberg whooping cough many decades ago us, the aspects of our lives that used Committee Binks W. Wattenberg Sonia Flores when I was teenager; as a result, I to provide the life part of work–life Chair,Nicole Minority Woitowich Affairs ASBMB TODAY Chair, Science OutreachCommittee and ASBMB TODAY cough a lot. balance, such as home and family, Communication Committee AngelaAngela Hopp Hopp Susannna Greer Executive Editor I’m lucky. I have a job I can now overlap with our work. So Terri Goss Kinzy Executive Editor Chair, Public Outreach [email protected] do from home that still provides where’s the balance? Chair, PublicCommittee Affairs [email protected] Advisory Committee ComfortComfort Dorn Dorn me with a steady paycheck. I can Now, when I wake up at 2 a.m., Matthew S. Gentry ManagingManaging Editor Editor Chair,Ed EisensteinPublic Affairs control my contact with other I no longer look at the latest news [email protected]@asbmb.org Chair, MembershipAdvisory Committee Committee people. I don’t have to worry about on my phone. I keep a soothing JohnJohn Arnst Arnst SusanSandra Baserga Weller supervising children or caring for book and a few Sudoku puzzles on ScienceScience Writer Writer Chair, WomenChair, in Biochemistry Publications [email protected] and Molecular Biology [email protected] elderly relatives. But I’m still kind my nightstand instead of a ther- Committee Laurel Oldach Committee Laurel Oldach of a mess. mometer. I don’t always go back to Lila M. Gierasch Science Writter Sandra Weller [email protected] Writter In the age of COVID-19, well- sleep, but I’m calmer. Editor-in-chief, JBC [email protected] Chair, Publications Ed Marklin A. L. Burlingame ness has taken on a new meaning. What about you? How are Committee Ed WebMarklin Editor Editor, MCP Many of us are grappling not only you coping? How are you keep- Lila M. Gierasch Web [email protected] Editor NicholasEditor-in-chief, O. Davidson JBC [email protected] Frick with a scary virus but also with ing yourself, your colleagues, your Editor-in-chief, JLR AllisonMedia Frick Specialist A. L. Burlingame social isolation, uncertain job and students well in body, mind and [email protected] and Social Media Kerry-AnneEditor, MCP Rye money prospects, the need to care spirit? We want to hear from you, Editor-in-chief, JLR ContentBarbara Manager Gordon Nicholas O. Davidson [email protected] Director for and educate our children at and we want to share your stories Editor-in-chief, JLR [email protected] Gordon home. We don’t want to get sick, and strategies in the January issue. Kerry-Anne Rye Executive Director Editor-in-chief, JLR [email protected] but everything we’re doing to avoid Please send your submissions to getting sick might be making us a [email protected] or via our little unwell. website by Nov. 2. ForFor information information on on advertising, advertising, contact contact Pharmaceutical Pharmaceutical A couple of years ago, the staff And, as always, I wish you well. Media Inc. at 212-904-0374 or [email protected]. Media Inc. at 212-904-0374 or [email protected]. of this magazine decided to start each year with a January wellness issue. We asked our readers to share Comfort Dorn (cdorn@ asbmb.org) is the managing their strategies for keeping their editor of ASBMB Today. Follow minds and bodies healthy in the her on Twitter @cdorn56. www.asbmb.org/asbmbtoday www.asbmb.org/asbmbtoday pressure-cooker world of scientific PRINT ISSN 2372-0409 PRINT ISSN 2372-0409 research. We received wonderful,

ArticlesArticles published published in ASBMB in ASBMB Today Today reflect reflect solely solely the authors’the authors’ views viewsand not varied, heartfelt responses that we theand official not the official positions positionsof the American of the SocietyAmerican for BiochemistrySociety for Biochemistry and Molecular and BiologyMolecular or Biologythe institutions or the institutions with which with the authorswhich the are authors affiliated. are affiliated. Mentions of productsMentions or of services products are or not services endorsements. are not endorsements.

2 ASBMB TODAY OCTOBER 2020 MEMBER UPDATE

De La Cruz appointed chair phate,” was awarded an honorary 1999 for services to molecular biology. Doctor of Science. He is a fellow of the Royal Society and at Yale Walker has been emeritus director a foreign associate of the National Enrique M. and professor at Cambridge’s Medi- Academy of Sciences. In 2012, he was De La Cruz cal Research Council Mitochondrial awarded the Copley Medal. became chair of Biology Unit since 2015. His cur- Developmental biologists Edith the Department rent work focuses on understanding Heard and Elizabeth Robertson and of Molecular the molecular mechanism of how mathematical physicist Roger Penrose Biophysics and ATP is made, specifically, how the were also nominated for honorary Biochemistry at rotation of ATP synthases is gener- degrees in science this year. The 2020 Yale University in ated and how these synthases differ awards ceremony was canceled due to in humans and bacteria in their the coronavirus pandemic. DE LA CRUZ July. De La Cruz, structure, function and regulation, an associate editor for the Ameri- with the goal of devising drugs that Parker to head can Society for Biochemistry and can kill pathogenic bacteria without BioFrontiers Institute Molecular Biology’s Journal of harming humans. Biological Chemistry, studies the A fellow at Sidney Sussex College Biochemist Roy Parker is the new actin cytoskeleton, molecular motor at Cambridge and an honorary director of the BioFrontiers Institute at proteins and nucleotide signaling fellow at Oxford’s St. Catherine’s the University of Colorado Boulder. enzymes. College, Walker was knighted in He has taken over after eight years as In August, De La Cruz was ap- pointed to the advisory board for the ASBMB Maximizing Opportu- Ma wins astronaut foundation scholarship nities for Scientific and Academic Stella Ma, an undergraduate at the University of Wisconsin–Madi- Independent Careers, or MOSAIC, son, has won a scholarship from the Astronaut Scholarship Foundation. program. He is a member of the Now a fourth-year student in the biochemistry department, Ma spent society’s Minority Affairs Commit- summers as a rising high school senior and incoming undergraduate tee and Meetings Committee. He in Emery Bresnick’s lab at UW-Madison, studying molecular mecha- previously served on the Publica- nisms underlying hematopoietic stem and progenitor cell development tions Committee. and differentiation. In 2019, she won ​funding from the provost’s office De La Cruz was tapped to lead to work in the lab of Anna Huttenlocher, where she studies immune Yale’s Branford College in 2017 and interactions with wounds and cancer. Also in 2019, she won a bio- won the Biophysical Society’s Emily chemistry undergraduate summer research award to work in the lab of Gray Award in Education in 2018. Helen Blackwell, where she studies bacterial communication​ and, in collaboration with the Huttenlocher lab, how Cambridge gives Walker bacteria may use communication to evade honorary degree the immune system. In 2020, she received a Goldwater Scholarship. Molecular biologist John The Astronaut Scholarship Foundation was Walker is one of eight individuals started in 1986 when the founding Mercury that Cambridge University present- 7 astronauts each sponsored a $1,000 ed with honorary scholarship and began to raise funds for degrees this year. future awards. The astronauts also donated MA Walker, who proceeds from their speaking engagements, shared the 1997 and the program now awards more than 50 scholarships each year Nobel Prize valued at up to $15,000 each. for chemis- “I’m so grateful to the Astronaut Scholarship Foundation for this try with Paul D. honor — I’m still half-trying to convince myself it’s real,” Ma said Boyer and Jens C. “Beyond the financial support, the networking opportunities and WALKER Skou for “elu- professional development advice ASF offers are spectacular. I’m also cidation of the especially grateful to my PIs and to the Biocore honors biology program enzymatic mechanism underlying faculty and my classmates for their support.” the synthesis of adenosine triphos-

OCTOBER 2020 ASBMB TODAY 3 MEMBER UPDATE

a distinguished professor at CU that get built up when we all get translation. This work also led the Boulder, succeeding Nobel laureate busy,” Parker said. lab to discover P bodies, cytoplas- and fellow RNA researcher Thomas Parker has spent much of his mic granules that contain RNA and Cech. career focused on messenger RNA. proteins and can regulate translation. The interdisciplinary research After graduating from Carnegie Related particles, called stress gran- institute, founded in 2009, counts Mellon University in Pittsburgh ules, can form when something is physics, and earning a Ph.D. in genetics wrong in the cell, pausing translation computer from the University of California, — and their dysregulation seems science, San Francisco, he trained briefly to link to pathology in diseases like life sci- as a postdoc in three different labs amyotrophic lateral sclerosis, also ence and before launching his own, studying known as Lou Gehrig’s disease. chemistry eukaryotic mRNA turnover at the Parker joined the faculty at CU researchers University of Arizona. Boulder in 2012, after 22 years at among its Starting from an interest in the University of Arizona. He is a PARKER 19 faculty unstable mRNAs in yeast, Parker’s fellow of the American Academy of and about lab described the pathways of RNA Arts and Sciences, a member of the 100 staff and trainees. “To really degradation involving deadenyl- National Academy of Sciences and make progress in science today, you ation and decapping, as well as a Howard Hughes Medical Institute need to incorporate new ways of showing a fundamental competi- investigator. He served as president thinking and break down the silos tion between RNA degradation and of the RNA Society in 2010.

ASCB awards for Trejo, Olzmann, Farber The American Society for Cell Biology has announced interest in the proteins that regulate lipid storage and its annual awards for 2021, and three American Society mobilization from inside these organelles. He also won a for Biochemistry and Molecular Biology members are 2019 Presidential Early Career Award for Scientists and among its slate of awardees. Engineers. Joann Trejo, a professor and assistant vice chancel- Steven Farber, a principal investigator at the Carn- lor for health sciences faculty affairs at the University of egie Institution for Science embryology department and California, San Diego, School of Medicine, has received adjunct professor in the Johns Hopkins University biol- the ASCB’s prize for excellence in inclusivity, which ogy department, shares this year’s Bruce Alberts Award recognizes a scientist who champions inclusion and for Excellence in Science Education with Jamie Shuda. diversity in science with a $5,000 award to further their Farber and Shuda are the co-creators of an outreach inclusion activities. In addition to studying protease- educational program, Project BioEYES, which has used activated receptor and G-protein–coupled receptor hands-on experiments with zebra fish to teach science signaling in vascular inflammation and breast cancer to more than 130,000 students in grades 4 through progression, Trejo is dedicated to mentoring of both 12. Farber’s lab studies digestive organ physiology in faculty and trainees; the award is the latest in a series of developing zebra fish larvae with a focus on the cell and mentoring and inclusivity awards recognizing her work molecular biology of lipids. from ASCB, ASBMB and UCSD. James Olzmann, an associate professor at the Uni- versity of California, Berkeley, has received the Günter Blobel Early Career Award, which honors a researcher less than seven years into an independent career. (The ASCB recently renamed the award in honor of Blobel, a cell biologist and Nobel laureate who died in 2018). Olzmann’s lab studies lipid droplet function with special TREJO OLZMANN FARBER

4 ASBMB TODAY OCTOBER 2020 MEMBER UPDATE

ASM career awards for Wickner, Moss The American Society for Microbiology has an- chaperones can also participate in protein disaggregation, nounced the recipients of its 2021 awards, including helping cells respond to stress. Wickner is a member of American Society for Biochemistry and Molecular Biol- the National Academy of Sciences and a fellow of the ogy members Sue Wickner and Bernard Moss among American Academy of Arts and Sciences. the honorees. Both are distinguished investigators who Bernard Moss, head of the genetic engineering lead laboratories at the National Institutes of Health in section of the National Institute for Bethesda. Allergy and Infectious Disease, was Sue Wickner, head of the DNA Molecular Biol- honored with a Lifetime Achievement ogy Section at the National Cancer Award, which recognizes a career of Institute, has received the ASM award sustained contribution to the field of for Basic Research, which recognizes a microbiology. Moss, a virologist and scientist “whose discoveries have been former president of the American fundamental to advancing our under- Society for Virology, is known for standing of the microbial world.” Her MOSS research into viral mRNA capping; work focuses on heat-shock proteins, immune evasion through expression a family of ATP-dependent molecular of proteins that resemble host cytokines; and the use of WICKNER chaperones that participate in protein vaccinia-based vectors for vaccines. He is a member of folding and proteolysis in both pro- the National Academy of Sciences and a fellow of the karyotic and eukaryotic cells. Her lab found that these American Academy of Arts and Sciences.

ASBMB CAREER CENTER

Make your next move.

Browse jobs in academia and industry and get a free résumé review.

careers.asbmb.org

OCTOBER 2020 ASBMB TODAY 5 IN MEMORIAM

Harold Scheraga Deborah Zamble

Cornell University professor Deborah Zamble, a profes- emeritus of chemistry Harold A. sor at the University of Toronto, Scheraga died Aug. 1 in Ithaca, died July 6 following a brain New York. He was 98. hemorrhage. Over his seven-decade Zamble was born in 1971 career, Scheraga pioneered the and grew up in Kingston, Ontario. application of physical chemistry to protein science — what She earned her bachelor’s degree at the University of Toronto, is now known as protein biophysics — to decipher how amino where she conducted undergraduate research with Bibudhen- acid sequences influence the three-dimensional folding path- dra Sarkar on zinc-finger proteins. She went on to earn a Ph.D. way, thermodynamics and biological activity of proteins. He in 1999 at the Massachusetts Institute of Technology, where published more than 1,300 papers about protein chemistry, she worked with Stephen J. Lippard studying the anticancer the most recent of which appeared in June. drug cisplatin. She completed a postdoctoral fellowship in the Scheraga was born Oct. 18, 1921, in Brooklyn to Samuel lab of Christopher T. Walsh at Harvard Medical School, where and Etta Scheraga. He grew up in Monticello, New York, but she studied the zinc-containing protein component of the the family moved back to Brooklyn after his father lost his antibiotic microcin B17 synthetase. radio and musical instrument store to the 1929 economic Zamble started her lab at Toronto in 2001 and focused on crash. Scheraga later credited the Great Depression and the how pathogenic microorganisms use nickel. severe financial strain it put on his family with shaping his The chemistry department at Toronto tweeted a thread af- outlook and career aspirations. ter her death that said, in part: “Deborah gave tirelessly, sup- After earning a bachelor’s of science from City College of porting co-workers and students in their research, advancing New York in 1941 and a Ph.D. from Duke University in 1946, our department and the bioinorganic chemistry community. Sheraga was awarded a one-year postdoctoral fellowship at She was also a highly skilled, caring and enthusiastic instruc- Harvard Medical School. The following year, he was hired as tor. We are diminished as a department because of her loss.” an instructor teaching quantitative analysis at Cornell. He be- Zamble served as a member of the editorial board of the came an assistant professor in 1950, an associate professor ASBMB’s Journal of Biological Chemistry, on the council of the in 1953 and a full professor in 1958. In 1965, he was named Society of Biological Inorganic Chemistry and on the executive the Todd professor of chemistry. He served as chair of the board of the Royal Canadian Institute. chemistry department from 1960 to 1967, during which time In a remembrance, the RCI noted that Zamble valued he led the department’s expansion into materials science and science outreach: “Deborah was passionate about making sci- molecular biology, as well as initiated construction of the S.T. ence available to everyone, particularly people outside of the Olin Chemistry Research Laboratory. scientific and academic community, and especially kids. She Scheraga’s wife of 76 years, Miriam, who died in Janu- was always available to help ensure everything went smoothly ary, worked for the Cornell University Library for 30 years. at our events, often bringing her own young family. At our fam- Scheraga is survived by his brother, David; three children; ily programs in particular, Deborah made sure that all of the five grandchildren; and four great-grandchildren. children attending found something fun and interesting to do.” Friends and colleagues said she enjoyed cooking, reading and gardening in her free time. Zamble is survived by her husband, Brian Murray; children, Matthew and David; her parents, a sister and a niece and nephew.

6 ASBMB TODAY OCTOBER 2020 IN MEMORIAM

Norbert Swislocki George Ronald Williams

Biochemist Norbert I. Swislocki University of Toronto Scarbor- died at his home in Grand View- ough professor emeritus and on-Hudson, New York, on June former principal George “Ron” 21 after a long illness. Williams died in July. Swislocki was born in 1936 Born in 1928 in Liverpool, in Warsaw, Poland. He and his England, Williams attended mother fled in 1939 to Vilnius, Lithuania, where they met Merchant Taylors’ School and earned his Ph.D. from the up with his father, a journalist following the Polish Army. University of Liverpool. After pursuing postgraduate work at In Vilnius, the family obtained a visa from the Japanese the University of Toronto, the University of Pennsylvania and diplomat Chiune Sugihara, who helped as many as 6,000 the University of Oxford, he became a faculty member at the Jews escape the Nazi regime, and crossed the Soviet Union University of Toronto in 1956. to reach Kobe, Japan. From there, they took a boat to Williams chaired the department of biochemistry Shanghai, where they remained throughout World War II. from 1970 to 1977. Under his leadership, the department In 1947, Swislocki’s family moved to the United expanded undergraduate instruction in biochemistry to States, settling in Los Angeles, where he would obtain his include students in other disciplines as well as larger num- bachelor’s, master’s and doctoral degrees in biochemistry bers of biochemistry specialist students. During his tenure from the University of California, Los Angeles. Swislocki then as chair, members of the department received Canadian completed a postdoctoral fellowship at Brandeis University. Biochemical Society Ayerst awards on three occasions. Swislocki took a position at Memorial Sloan Kettering Williams served as the sixth principal of what was then Cancer Center in New York, where he conducted research known as Scarborough College from 1984 to 1989. He loved on red blood cells and aging. He was later appointed chair to hike, and combined his passion for biochemistry with of the department of biochemistry at the University of Medi- concern for the environment in a book published in 1996, cine and Dentistry of New Jersey, which in 2013 merged “The Molecular Biology of Gaia,” about the stability of the with Rutgers University to become the Rutgers School of Earth’s environment. Biomedical and Health Sciences. Williams loved the arts, including chamber music, Although he never hunted, Swislocki was an excel- opera, theater, the visual arts, poetry and novels: “His joy lent marksman, according to his obituary in a Palisades, flowed from professional artists, but also from local amateur N.Y., newsletter, and made it to the Olympic trials in target groups and, especially, children,” according to his obituary. shooting. Paul Gooch chaired the division of humanities at the Swislocki is survived by his wife of 29 years, Jane University of Toronto from 1977 to 1982. “Ron Williams was Lattes–Swislocki; his brother, Arthur; children, Madeline a dear and lovely man, always positive, interested in all the and Mark; four stepchildren, Jain, Lisa, Abigail and Conrad; world has to offer,” Gooch said in a remembrance. “He had and 14 grandchildren. the mind of a scientist and the heart of a humanist.” Williams is survived by his wife, Joyce; children, Geoff, Glynis, and Tim; grandchildren, Jeremy, Dave, and Jano; and great-grandchildren, Nia and Lila.

OCTOBER 2020 ASBMB TODAY 7 IN MEMORIAM

Danica Dabich Soll Berl

Danica Dabich, Soll Berl, a neurochem- professor emeritus ist, psychiatrist and professor of biochemistry at emeritus of neurology at Mount the Wayne State Sinai Medical Center, died June University School of 7 at his home in Pittsboro, N.C., Medicine, died June five days before his 102nd birthday. 20. She was 89. Born in Brooklyn in 1918, Berl earned degrees from St. Born August John’s University School of Pharmacy and the University of 6, 1930 in Detroit, Dabich received her bachelor’s degree Wisconsin before World War II. During the war, he served as in chemistry from the University of Michigan in 1952 and a an Army medical technician and was part of a research effort master’s of science from Ohio State University in 1955. She to mass-produce penicillin for Allied troops. He attended earned a doctoral degree in philosophy from the University medical school at Case Western Reserve University after of Illinois in 1960. his discharge, then did a residency at New York University Dabich began her career as an analytical chemist at Bellevue Medical Center, and a National Institutes of Health Phillips Petroleum Co. in 1952, then worked as a research postdoctoral fellowship at the New York State Psychiatric assistant at the E.B. Ford Research Institute for Medical Institute. Research. She was a postdoctoral fellow at the University of Berl began his career as an assistant professor and later Freiburg in Germany before taking a position as a research associate professor of neurology and neurosurgery at Colum- associate at Wayne State in 1961. She became an assistant bia University’s College of Physicians and Surgeons. He also professor in 1966 and was promoted to associate professor maintained a private part-time practice as a psychiatrist. He in 1970. joined the department of neurology at Mount Sinai in 1974 Throughout her research career, Dabich explored the and retired in 1989 as professor emeritus. He co-authored biochemistry of early mammalian development, working more than 100 papers with a research focus on brain amino primarily with pre-implanted mouse embryos. acid and protein metabolism. Dabich was a member of the American Chemical In retirement, Berl and his wife ran a bed-and-breakfast Society. In her spare time, she enjoyed reading, gardening for 20 years in the Hudson Valley of New York. They later trav- and music. eled extensively, spending time in Amagansett, N.Y., Vermont She is survived by her sister, Lyubica Dabich, and and North Carolina. An amateur artist, Berl also loved tennis, brother, Sam Dabich. literature and the theater. He was admired for his cooking and was known to enjoy a very dry martini, especially on the beach at sunset, according to an obituary. He is survived by his wife, Terry, four children and one granddaughter.

8 ASBMB TODAY OCTOBER 2020 RETROSPECTIVE Herb Tabor (1918–2020)

By F. Peter Guengerich

n Aug. 20, the biochemistry ASBMB community lost one of its giants Owith the passing of Herb Tabor at the age of 101. Herb was a unique individual, and he definitely will be missed. Others knew him better than I did, but he outlived most of his contem- poraries, so I was asked to write this Retrospective. I met Herb at a Journal of Biological Chemistry editorial board meeting when I joined the board for the first time in 1984, and we became acquainted later during my time on the American Society for Biochemistry and Molecular Biology council. I got to know him better af- ter 2006, when I became an associate After he retired as editor-in-chief of the Journal of Biological Chemistry, Herb Tabor continued with the editor at JBC. title of co-editor and helped assign manuscripts even after his 100th birthday. Herb was one of the finest individ- uals I have known in this field. Several obituaries already have appeared, and passion for research. His first paper In 1943, Herb was transferred to a detailed autobiographical account in JBC was published in 1943 on the U.S. Public Health Service, at of Herb and his late wife, Celia, ap- this work, measuring the ionization first working under the direction of peared in the 1999 Annual Review of constant of magnesium phosphate. Sanford Rosenthal, beginning his 77- Biochemistry. I will try not to repeat His last JBC paper (which I acted as year career at the National Institutes too many things. I will write about associate editor for) was published in of Health. He became a lab chief and my experiences with Herb and what I 2015, 72 years after his first. I doubt continued in that role until 1999, know about him. this record ever will be eclipsed. when he was succeeded by Reed Herbert Tabor was born in New Herb’s medical degree did not lead Wickner, who had trained with him. York City on Nov. 28, 1918, which he to a long clinical career, but while an In the early 1940s, the NIH was new, told me was Thanksgiving Day that intern at Yale in 1942, he was the first and the NIH intramural program was year. World War I had just ended, and individual to inject a new antibiotic small, located in Bethesda, Maryland. there was a viral pandemic then too. I called penicillin into a patient. The There, Herb and Celia Tabor began do not know much about his child- patient’s recovery from severe strep- their pioneering research on poly- hood, but obviously, he was a real tococcal septicemia was remarkable, amines, a topic that is still very inter- prodigy, attending the City College of and this and other successes led to the esting and was featured in a special New York for two years and then Har- scaling up of fermentation and use of collection in JBC edited by Tony Pegg vard College, graduating from Har- the drug in the war effort. Herb also to celebrate Herb’s 100th birthday. vard at the age of 18. He obtained an spent time during World War II as the In the early days at the NIH, a M.D. from Harvard Medical School only medical officer on a U.S. Coast group of what were to become stellar at the ripe old age of 22 in 1941. Guard cutter ship, part of convoys in scientists would meet to eat lunch During his last year of medical the North Atlantic. Despite a scare daily over presentations and lively school, Herb worked in the lab of or two, he said, he did not have to do discussions of current literature in the A. Baird Hastings and developed his any surgeries. growing field of biochemistry. The

OCTOBER 2020 ASBMB TODAY 9 RETROSPECTIVE COURTESY OF ED MARKLIN Award. I was asked to provide com- ments on his research program for an NIH intramural review. That was a humbling experience — how could I critique this great man? I was asked how his success compared with his contemporaries, but he had outlasted all of them. In 1961, Herb joined the editorial board of JBC, and he became an asso- ciate editor in 1969. By today’s stan- dards, JBC was still a small enterprise, although it was certainly a premier journal in the field. When Bill Stein developed health issues, Herb took over as acting editor-in-chief and then as editor-in-chief in 1971, a job he would hold until 2010. If you knew Herb, you could only be impressed by his organizational skills, his work ethic and his dedica- tion to fairness. During his nearly 40-year tenure as editor-in-chief, JBC This photo of a young Herb and Celia Tabor hung in the kitchen of the duplex the family lived in since grew tremendously. Herb assigned 1949 on the National Institutes of Health campus. The couple met on a Boston streetcar in 1940 and all of the manuscripts out for review were married in 1946. by himself, with the average rising to more than 50 per day at the peak of our submissions. In line with what group included Herb Tabor, Arthur the work himself. I also recall an Kornberg, Leon Heppel, Bernard account (not from Herb) of an NIH Horecker, and later others such as investigator in the 1980s who went to If you knew Herb, you Earl and Thressa Stadtman, Christian Herb’s office to complain about a JBC Anfinsen, Alton Meister, Osamu submission that had been declined. could only be impressed Hayaishi and Bruce Ames. I would He wound up having to follow Herb have loved to be part of that exciting all around the lab because Herb was by his organizational skills, time. Today, our field, in part because in the middle of some work, transfer- of its success, has become so broad ring rotors. The author finally felt his work ethic and his that it is difficult if not impossible embarrassed about bothering him. for an individual scientist to follow Herb and his family lived at the dedication to fairness. everything in any detail. NIH starting in 1949 in one of the Herb and Celia were essentially duplexes built for staff. The big ad- he construed was his obligation to free of most administrative respon- vantage was the ease of getting to and his job at the NIH, he did none of sibilities at the NIH. There was no from work. Herb told me he used to this during the workday — and it grant writing, teaching, attending walk home for breakfast (presumably, was much harder to do the necessary faculty meetings or serving on com- he went to the lab early). He lived in editorial work in the pre-electronic mittees, and they relished this. Herb the same house at the NIH until his era. Assistants from the JBC of- routinely did much of his own lab death. Living on the NIH campus fice would leave a big sack of paper work. Late in his life, at one of our is not so attractive today due to the manuscripts at the back door of his JBC associate editors’ meetings, some security checks needed to enter; trust house every evening. Sometimes, he editors were comparing problems me — it’s like the airport. would use the pay phone at the NIH with their eyeglasses. Herb said he was Herb was elected to the U.S. lab to call the JBC office (during his having problems in the lab with his National Academy of Sciences in lunch break), have titles read to him own glasses when he was transferring 1977, and in 1995, Herb and Celia and make assignments (an early effort bacteria, which meant he was doing received the ASBMB William C. Rose at e-communication). He handled

10 ASBMB TODAY OCTOBER 2020 RETROSPECTIVE

complaints from authors and manu- script controversies on the weekends. In addition, he hosted three associate REMEMBRANCES editor meetings each year. As JBC grew, in the late 1980s, I was very fortunate to be a postdoc down the hall from Herb from we heard pessimistic forecasts at our 1989 to 1995. I warmly recall Herb and Celia eating lunch during editorial board meetings regarding our weekly seminar series. She would open up their lunch bag, hand whether we could ever deal with the him half a sandwich and take the other half. When that was finished, growing page volume. The JBC did not make too many mistakes dur- she would then take out a piece of fruit, cut it in half and give him ing Herb’s tenure, but one was the his half. It was so wonderful to see their love for one another. And attempt at “miniprint” (go back to fortunately, one of his postdocs, David Balasundaram, and I cooked some 1980s JBC papers if you are up a collaboration that ended up as a couple of papers. To be a co- too young to remember that). The author with Herb was a great honor. Herb always had an open issue later was resolved by institut- door and an open ear, and he asked the best questions. He was a force ing electronic publishing, where JBC led the field. Although Herb was no of nature. longer a young man, he adapted well Jonathan D. Dinman, University of Maryland to the electronic systems with his Mac and really pushed this new venture. As an associate editor, I knew that After our first publication on a key enzyme in polyamine biosynthesis, my new assignments (now electronic) Herb was among those whose comments encouraged me to shift much would start rolling out every evening emphasis in my lab toward the study of polyamines. In the subsequent at about 6 p.m. Eastern time, when 10 years, I met many good friends and colleagues at stimulating Herb got home from work. Even and entertaining meetings in the U.S., Europe, Japan and Israel. through the heavy submission years, Eventually, mitochondria regained my attention. Thus, I have not Herb was a hands-on editor, and he assigned papers to himself for review seen many of my “polyamigos” for some time, but I retain wonderful as well as to the associate editors. memories. Herb stands out among them as a giant role model in He did delegate aspects of the JBC research and service to science. operations to Barbara Gordon and later to Nancy Rodnan, the ASBMB Herb also was responsible for my selection to the editorial board of publications directors, both of whom the JBC. The 10 years I spent on the board were challenging but most he greatly admired. However, Herb rewarding and satisfying. was a nuts-and-bolts guy who drove the journal. Immo Scheffler, University of California, San Diego Herb worked well with the associ- ate editors. He invited our input and In the fall of 2009, Herb Tabor phoned to ask if I would write the was supportive in any problems we National Academy of Sciences biographical memoir of the biochemist encountered dealing with authors, Mahlon Hoagland (1921–2009). I think he was doing so as chair although he certainly wanted to be fair to the authors too. At the associ- of NAS Section 21 at the time. He quickly added, “You are in a ate editors’ meetings, he let us all unique position to do this.” Sensing my puzzlement, he said, “You have our input but was able to reach are still alive.” a consensus and then to make us all feel that we had been part of his final We both laughed, and I accepted of course. But what added to the decision (“I think you will all agree combined poignancy and comedy of this phone call was that Herb with me that …”). himself was in his early 90s at the time. From this experience — in As he indicated in his Annual which I felt his vigor, intelligence, kindness and sense of humor — I Review of Biochemistry article, his hoped that he would be around for much longer, and indeed he was. objective for JBC was not to restrict publication to the most exciting Thoru Pederson, University of Massachusetts Medical School research areas; we had a policy of

OCTOBER 2020 ASBMB TODAY 11 RETROSPECTIVE COURTESY OF F. PETER GUENGERICH

Herb Tabor, left, poses with ASBMB Publications Director Nancy Rodnan and F. Peter Guengerich. Tabor would delegate aspects of the JBC operations to Rodnan, but he was a nuts-and-bolts guy, Guengerich writes.

accepting all manuscripts that made a exciting when published, but they biomedical science community will substantial biochemical contribution. stood the test of time and had great miss him. Herb was truly a person That is, we wanted to publish excit- impact. to emulate. The ASBMB already has ing papers but not at the expense of After retiring as editor-in-chief, recognized him with the Herbert solid contributions that are important Herb continued with the title of co- Tabor Research Award for excellence for the development of science. He editor and was helping assign manu- in biological chemistry and molecu- resisted pressure to allow exceptions scripts even after his 100th birthday. lar biology and contributions to the to our policy of considering all manu- We sometimes would talk about as- community of scientists and the JBC scripts equally, without any preselec- signments of problematic manuscripts Herbert Tabor Early Career Investiga- tion or commitment for expedited or whether a submitted paper really tor Awards given to first authors of publication of favorite authors or fit our journal best — his instincts exceptional JBC papers. subjects. Some JBC Classics papers, were almost always right. I never Herb was preceded in death by his for example, might not have seemed have heard anyone say anything bad wife, Celia White Tabor, in 2012. He about Herb, although there must have is survived by his four children, Ed- been some complaints; when you are ward, Marilyn, Richard and Stanley, After retiring as editor- an editor, you cannot accept all the as well as 10 grandchildren and six papers, and he must have annoyed great-grandchildren. in-chief, Herb continued someone along the way. Publishing is So long, Herb. You are really changing rapidly today, and I doubt if missed. Thanks for the memories, on with the title of co-editor any editor will ever match the 40-plus behalf of all of your admirers. years Herb ran JBC. and was helping assign I was privileged to know and work with Herb Tabor. He was in essence F. Peter Guengerich ([email protected]) manuscripts even after his a humble man. Beyond his family, is deputy editor of the Journal of Biological Chemis- he focused everything on science and try and the Tadashi Inagami chair in biochemistry at 100th birthday. JBC. The ASBMB and the entire Vanderbilt University.

12 ASBMB TODAY OCTOBER 2020 RETROSPECTIVE

REMEMBRANCES

Herb Tabor was one of a kind. When he took hold Herb’s achievements in polyamine research in of the JBC, it was already an iconic institution, but health and disease were substantial and significant. he took it so much farther. I value the three years I As the editor-in-chief of JBC for 40 years, his spent on the ASBMB Publications Committee, where accomplishments set a golden mark on the scientific I treasured my interactions with Herb. His wisdom community. I suspect that no other scientist has had was much appreciated when I had to handle a couple as much influence on the scientific community as of ethics issues. The JBC has stayed on a high plane, he has. In 2004, he and Celia participated in the but Herb was indispensable in getting it there and International Polyamine Conference held in Chiba, keeping it there. Japan, and after the meeting they visited Osamu Hayaishi (president of Osaka Bioscience Institute My first research publication, as a third-year at that time, now deceased), who had been a close graduate student, was in the JBC, as was my last, friend since their NIH era. Herb and Celia came to as a long-retired professor. The JBC, and Herb, visit me also, and he presented an excellent lecture enriched my career and my life. at Osaka University. Many of our researchers were Christopher K. Mathews impressed by his talk. Oregon State University I remember when I met Herb at a JBC editorial board meeting, and I was amazed to learn that he Herb Tabor was a unique and deeply memorable personally handled over 400 submitted manuscripts person — gracious leader, dedicated scientist, to JBC and assigned each paper to a suitable visionary with deep insight, devoted husband associate editor. He was 81 years old at that time. and father, and above all exceptionally kind I think that he is now renewing his friendship with and generous. In my years as an associate editor, Professor Osamu Hayaishi in Heaven. his ability to guide a group of independent (and sometimes fractious) editors ever so clearly and yet Tani Naoyuki Taniguchi, Osaka gently into the best decisions was amazing. His daily University and Osaka International dispersal of all incoming JBC submissions with just Cancer Institute the right connection to each of the associate editors seemed an impossible task — but he always did it. Not only was Herb a brilliant and dedicated Herb Tabor’s personal ethos is reflected in the JBC scientist, but he was a gentleman, who taught me today in a way that I hope will be transmitted into a few lessons way back when I was a graduate the future as a living memorial of his contributions. student about how to conduct yourself when facing And even more amazing, his commitment to his own a not-so-friendly audience. Also, he was a devoted research and students thrived in the midst of these husband and father. His legacy is as multifaceted as responsibilities. He mentored a multitude of students his contributions and the extent of peoples’ lives he and colleagues with his quintessential example that touched. brought together exceptional brilliance, dedication and kindness. His absence in our world is our great We will hold his memory and his family in the loss, but his example is forever before us. Light.

Kathleen S. Matthews, Rice University Ed Eisenstein, University of Maryland

OCTOBER 2020 ASBMB TODAY 13 RETROSPECTIVE

REMEMBRANCES

Herb and the JBC were a huge part of my • Being on the editorial board drew me into professional career. Since he was editor-in-chief service on the ASBMB Publications Committee, throughout my career, I think of JBC = Tabor. which I chaired for a year or two. There I saw up Here are some highlights: close and personal how the JBC functioned and what made it great. • When I was a graduate student with Sidney Udenfriend, I felt I had finally made it when I I am grateful for Herb’s outstanding service published in the JBC, which was considered the editing one of the premier scientific journals. It is gold standard. inconceivable how many lives he touched and how • My postdoc from 1970 to 1973 was in the lab many careers he promoted. of Bob Schimke who himself had been a postdoc Bob Rhoads, Louisiana State University in Herb’s lab. Because of this, I always thought of Health Sciences Center Herb as my scientific grandfather and reminded him of this every time I saw him. My first paper with Bob Schimke was in the JBC. During the time when JBC was trying to decide • When I was a faculty member at University of if they were going to go online or not, Herb was Kentucky Medical Center, my quest for tenure was undecided and argued for quite a while not to go substantially aided by publication of another JBC online until he could be convinced that it would paper. be good for the journal and the readership. One day when he was in his office, he went to look • My first two graduate students, Lee-Yun Chu and up an article in a bound volume of past issues. Larry Malek, published their major findings in the The volume was so heavy that it slipped out of JBC. his hands and fell on his foot. It broke a toe and • My career received a major boost when I was helped him make the decision to move the journal appointed to the editorial board of the JBC in online. 1990. I suspect this was one reason I was hired as head of biochemistry and molecular biology at Herb loved to tell that story as an example of Louisiana State University Health Sciences Center higher authorities (like gravity) sometimes being in 1992, a position I held for over 21 years until needed to help make important decisions. I closed my lab and went from active to emeritus Charles Craik, University of California, faculty status. San Francisco • One of the best papers by one of my postdocs, Barry Lamphear, was in the JBC.

14 ASBMB TODAY OCTOBER 2020 RESEARCH SPOTLIGHT Mentoring and metabolism Sharifa Love–Rutledge studies the impact of Type1diabetes susceptibility genes and supports young scientists COURTESY OF SHARIFA LOVE– RUTLEDGE

By Kerri Beth Boggs

hen Sharifa Love–Rutledge was a little girl in Moss Point, WMississippi, her brother re- ceived a science kit for Christmas. She convinced him to let her help make borax bouncy balls from the kit, and seeing simple ingredients transformed into a tangible product changed her life. “I hadn’t done any science demos up to that point,” she said. “It was ex- citing to have something that worked come from the experiment.” She wanted to do more. In fifth grade, Love–Rutledge Indications from her graduate and postdoc studies that an overlap existed between Type 1 diabetes and joined her school district’s gifted prediabetes inspired Sharifa Love–Rutledge’s research focus at the University of Alabama at Huntsville. program, which provided an outlet to explore her interest in science. She thought about becoming an ophthal- biology class. She decided to leave me now!” mologist and designed a papier-mache the department of natural science, Love–Rutledge also found men- eyeball to present in class. Though she and her professors, who had noticed tors through the National Science sometimes tried to avoid attention, something special in her, wondered Foundation’s Louis Stokes Alliance for the teachers in the program helped why she disappeared. Minority Participation and the U.S. Love–Rutledge find her voice. “They saw something in me that I Department of Education’s McNair “In some classes, I wanted to fade didn’t see in myself,” she said. into the background. My eighth-grade Fate stepped in when Love–Rut- science teacher, Mrs. Stevenson, made ledge returned to the department to She found her niche me feel seen,” she said. “She encour- take an organic chemistry class in her studying chemical aged me to ask questions and partici- sophomore year. She found her niche pate. I felt like I was valuable in that studying chemical mechanisms and mechanisms and using space.” using analytical problem solving. Her analytical problem professors recognized her talents and Guardian angels decided to make a long-term invest- solving. Her professors ment in her success. recognized her talents Love–Rutledge’s teachers put her “Once I came back, they weren’t on a path to pursuing a biology degree going to let me leave,” she said. “I had and decided to make a at Tougaloo College in Hinds County, several professors that would strategi- long-term investment in Mississippi, but she struggled with cally check in on me. My organic rote memorization in her freshman chemistry professor still checks in on her success.

OCTOBER 2020 ASBMB TODAY 15 RESEARCH SPOTLIGHT

Scholars Program, both designed to working with undergraduates. She school. She began to wonder if an help underrepresented minority stu- watched students become defeated overlap existed between Type 1 dents achieve academic success. by their science classes and give diabetes and prediabetes. “Those two programs working up on themselves. She managed to These observations inspired her together was really great,” she said. “I help save some of them, but others research focus at the University of was able to pool two sets of resources slipped through the cracks, beyond Alabama at Huntsville, where she that helped me reach my end goal.” her grasp. is now an assistant professor in the “Now that I’m a professor, I have chemistry department. the ability to save more students that Continued work with the rat Becoming the angel have the potential to succeed,” she model from her postdoc showed Love–Rutledge graduated from said. that the animals are susceptible Tougaloo with a degree in chemistry Love–Rutledge learned that many to Type 1 diabetes when they are and went on to pursue a Ph.D. in students, particularly those in minor- young through an immune-driven biochemistry at the University of ity groups, struggled to believe in event. As the animals age, they Alabama. themselves and find their potential. develop prediabeteslike symptoms. She stepped into unfamiliar ter- She recognized the need for students Love–Rutledge’s research suggests ritory in her first-year biochemistry to see people like themselves in the that these changes are connected to course. The students gave presenta- positions they hoped to reach one a Type 1 diabetes susceptibility gene tions and offered feedback to each day. that is associated with kidney disease other, but the competitive environ- “I hadn’t met an African American in African Americans and cancer ment caught Love–Rutledge off female with a Ph.D. until I was in risk. She plans to explore the role guard. Some students put others graduate school,” she said. of this susceptibility gene in aging down to make themselves look better. and lipid metabolism. Since this Love–Rutledge, who already ques- Rats, humans and diabetes gene can make humans and rodents tioned if she should be in graduate In 2014, Love–Rutledge complet- susceptible to Type 1 diabetes, it school, felt like an imposter. ed her graduate work on chromium may also enhance their susceptibility Once again, her mentors came nutrition and its relation to Type to other pathologies. to the rescue, helping her break free 2 diabetes. She was the first Black Love–Rutledge’s lab uses bio- from the paralyzing lies of imposter woman to earn a Ph.D. in chemistry chemical techniques to correlate the syndrome so she could blossom as from the University of Alabama. metabolic changes at multiple stages a scientist. Though she sometimes At Michigan State University, she of life due to the susceptibility gene wanted to give up, Love–Rutledge completed a postdoc in the physiol- to find translational biomarkers said that her “guardian angels” en- ogy department, studying a virus- linked to increased diabetes suscep- couraged her to stick with her path. inducible Type 1 diabetes rat model. tibility. They also study the proteins As a graduate teaching assistant, She saw changes in the rats that expressed from Type 1 diabetes Love–Rutledge came face-to-face resembled the Type 2 diabetes mod- susceptibility genes to understand with her own challenges while els she had worked with in graduate how they affect pancreatic beta cells and insulin-sensitive tissues such as the liver, skeletal muscle and fat.

About the Research Spotlight Giving back Outside the lab, Love–Rutledge The American Society for Biochemistry and Molecular Biology’s Research Spotlight serves as a mentor for students highlights distinguished biomolecular and biomedical scientists from diverse back- through her church and a youth symposium program where she or- grounds as a way to inspire up-and-coming scientists to pursue careers in the molecular ganizes science demonstrations and life sciences. Eligible candidates include Ph.D. students, postdoctoral fellows, and new programming. She wants to expose young students to science and be or established faculty and researchers. To nominate a colleague for this feature, contact a resource for them as they think us at ASBMB Today at [email protected]. about their education and career options. “Kids’ choices are often limited to

16 ASBMB TODAY OCTOBER 2020 RESEARCH SPOTLIGHT COURTESY OF SHARIFA LOVE– RUTLEDGE

Members of the Love-Rutledge lab display their research: top, left to right, Helen Gibson and Anna Hart; center, Jamya Patterson; bottom, left to right, Sidney Martin and Laura Catherine Wright.

what they’re exposed to. They may her mentees that Rome wasn’t built never get to leave their hometown,” in a day. Kerri Beth Boggs is a graduate student in the biochemistry she said. “I want to help them “It takes time to build all the ac- department at the University of realize that the world is bigger than colades you see for the people around Kentucky. Follow her on Twitter what they’ve seen.” you,” she said. “It’s easy to place @KB_Boggs Love–Rutledge hopes to make unrealistic expectations on yourself. a difference in the lives of young Be okay with gradual changes and scientists, just like the mentors who gradual improvement. Pace yourself. never gave up on her. She reminds You can’t force things to happen.”

OCTOBER 2020 ASBMB TODAY 17 NEWS Nobelists’ former postdocs discover missing link in telomerase evolution

By Nivedita Uday Hegdekar COURTESY OF DOROTHY SHIPPEN

n 1983, Carol Greider and her Ph.D. advisor, Elizabeth Black- Iburn, discovered telomerase, the enzyme that replenishes telo- meres. For this, they were awarded the 2009 Nobel Prize in physiology or medicine, and their seminal work opened the gateway for decades of work that has advanced our under- standing of aging and human lifespan — including new research by their own former postdocs. Those postdocs, Dorothy Shippen and Julian Chen, knew each other long before their first collaborative project, a study published in Pro- ceedings of the National Academy of At work in the Shippen lab at Texas A& M are, left to right, Dorothy Shippen, first author of the recent Sciences. paper Jiarui ‘Gerry’Song and Claudia Marcela Castillo-Gonzalez. “Julian and I came out of Carol Greider and Elizabeth Blackburn’s their ongoing research projects. Those determining telomere length, particu- research labs, respectively,” said conversations resulted in a collabora- larly in aging cells. Shippen, a university distinguished tion that led to a pivotal discovery Many researchers have focused professor and regents fellow in Texas about telomerase RNA. on the use of telomerase in cancer A&M’s department of biochemistry and anti-aging treatments. However, and biophysics. “Due to our similar About telomerase much is unknown about the telo- research interests, we kept crossing merase, particularly its evolution. The paths at various research confer- Telomeres are repetitive DNA enzyme is markedly different across ences for many years. Our respective sequences that safeguard the ends of various kingdoms, making it impor- research groups used different tools linear chromosomes. Healthy somatic tant to understand the components to answer fascinating questions about cells have a limited replicative life- that contribute to these evolutionary telomerase, and Julian and I devel- span, and as they age, their telomeres differences and their role in telomere oped a mutual admiration for each shorten, leading to eventual cellular maintenance. other’s work.” senescence and/or apoptosis. How- Telomerase complexes contain two At the 2019 Cold Spring Harbor ever, the ribonucleoprotein enzyme core components: a catalytic protein Telomeres and Telomerase Meeting, telomerase counteracts this shrinking subunit and an RNA subunit. The members of Shippen’s group met process and helps lengthen telomeres catalytic protein subunit — telomer- up with Chen’s lab team (Chen is a by adding short DNA repeats, thus ase reverse transcriptase — has been professor of biochemistry at Arizona extending the life of the cell. The level well characterized. The RNA subunit State University), and they discussed of telomerase activity is crucial in serves as a template for the addition

18 ASBMB TODAY OCTOBER 2020 NEWS

of new telomeric DNA repeats by tions to fundamental biological chal- Plant telomerases may the reverse transcriptase. Researchers lenges,” she said. “Plant telomerases ‘‘ first isolated it in 1991 in ciliates and may tell us something new about tell us something new about later discovered its homologs in yeast longevity and aging and how hu- and humans. man telomerase could be regulated. longevity and aging and how Hence, it was essential to discover Uncovering a missing link this missing subunit.” human telomerase could be Shippen previously had identi- “The telomerase RNA in these fied the reverse transcriptase subunit regulated. three different kingdoms — cili- in plants. In 2019, her team, led by ’’DOROTHY SHIPPEN ate, yeast and humans — are very graduate student Jiarui Song, suc- different with regard to transcription cessfully isolated telomerase RNA machinery, sequence, etc.,” Chen from the thale cress plant, Arabidop- said. “A long-standing question in sis thaliana. To isolate this telomerase Chen and his team played a crucial the telomerase biology field is, how RNA, termed AtTR, the researchers role.” did these various telomerase RNAs used a protein purification approach Chen and his team worked with evolve so differently?” using deep sequencing of RNAs asso- the Shippen lab to determine the Researchers tried for years to ciated with telomerase activity. structure, perform functional analysis isolate telomerase RNA from plant “Our investigations began with of the isolated AtTR and identify its species. They included Shippen, who some genetic and phylogenetic homologs in many other plant spe- believed the plant kingdom held analysis of AtTR,” Shippen said. “We cies. the key to unanswered questions in then decided to follow up by further These analyses, coupled with stud- telomerase evolution. characterizing this subunit and find- ies in cells and animal models, uncov- “Plants often evolve unique solu- ing new homologs. This is where Dr. ered a startling revelation: The plant telomerase RNA was an intermedi- VANAE GOHEEN-HOLLAND ate between telomerase RNA from humans and from lower eukaryotes. The subunit contained signature marks from both animal and protist kingdoms. “We called this intermediate plant telomerase RNA the ‘missing link’ between ciliates and vertebrates,” Chen said. “It significantly expanded our knowledge about telomerase evolution.” Delving deeper, moving forward The complete identification of plant telomerase allows researchers to study telomerase evolution in a new way. While ciliate and plant telo- merase RNA are transcribed by RNA polymerase III, vertebrate and fungal telomerase RNA are transcribed by RNA polymerase II. How did telom- erase RNA evolve to be transcribed by two different RNA polymerases, and how did they make this transition? Pictured in the Chen lab at Arizona State are, from left, Yang Li, a research assistant professor; Dhenu- To answer this question, Chen gen Logeswaran, a postdoctoral fellow; and Julian Chen. All were authors on the recent PNAS paper. said, “Our next step will be to study

OCTOBER 2020 ASBMB TODAY 19 NEWS COURTESY OF JULIAN CHEN

This image represents the relationship between aging and telomerase. The structure and function of a missing component of telomerase enzyme from plants hold promise for aging and cancer research.

telomerase RNA in several ancestral metabolism.” Chen and Shippen believe that ap- plant species to characterize their Shippen and Chen will continue plications of their findings in humans structure and determine which RNA collaborating to study plant telome- are years away, but they are optimis- polymerase they were transcribed rase. They expect future research into tic about the future of telomerase by. Hopefully, we will soon have a the plant system to have translational research. comprehensive picture about how application in humans, particularly “We see a lot of opportunities telomerase RNA has evolved along for cancer and anti-aging treatments. ahead,” Chen said. “This is indeed different eukaryote lineages.” While plant and human telo- an exciting time to be working in the Shippen wants to delve deeper merases differ, understanding the field of telomere biology and telo- into the telomerase ribonucleoprotein plant telomerase mechanism and its merase evolution.” complex. She believes that a differ- evolution might help researchers en- ent group of proteins associate with gineer new strategies to regulate and the reverse transcriptase to make it manipulate human telomerase. For Nivedita Uday Hegdekar functional in plants. example, higher levels of telomerase (nivedita.hegdekar@umaryland. “By uncovering these accessory immortalize cancer cells, enabling edu) is a graduate student at the components,” she said, “we will gain them to live and grow much longer University of Maryland working toward a Ph.D. in biochemistry insight into the interface between than normal cells. Targeted inhibi- and molecular biology and an the canonical telomerase function tion of telomerase in cancer might M.S. in patent law. Follow her on and other cellular functions such as have therapeutic benefit. Twitter @NiveditaHegdek1.

20 ASBMB TODAY OCTOBER 2020 JOURNAL NEWS Re-creating coagulation in a lab A positive step for the horseshoe crab

By Kian Kamgar-Parsi KALDARI/WIKIMEDIA COMMONS

hen considering modern med- icine’s fight against infections, The horseshoe crab Wa horseshoe crab is likely not has been around for the first thing that comes to mind. 450 million years and However, the dwindling number of is more closely related these ancient arthropods is cause for to spiders than other concern in the biomedical industry. crabs. Use of horseshoe Bacterial lipopolysaccharide, or crabs’ blue blood (called LPS, is a toxic molecule that can cause hemolymph) for medical life-threatening infectious reactions in tests threatens a species humans. Horseshoe crab hemolymph already pressured by (a blood equivalent) is extremely sen- environmental change sitive to LPS, coagulating in response and human development. to even trace amounts. Due to this property, hemolymph is used in the erase B; chelicerase B in turn activates represent the core components, three Limulus test, a critical tool to ensure proCE into the clotting enzyme that proteins alone cannot mimic hemo- medical devices and drugs are free of coagulates the hemolymph. Kawabata lymph perfectly. “Some cofactors, LPS contamination. Unfortunately, previously engineered functional environmental proteins or some the harvesting of hemolymph pits proC and proB; in this new research, preservatives must be indispensable,” medical and conservation interests his lab also made a functional proCE Kawabata said. against each other. without the use of hemolymph for It is also important to ensure that Shun-Ichiro Kawabata, a researcher the first time. the cascade cannot be triggered by at Kyushu University in Japan, seeks “We have overcome several difficul- other environmental substances, a solution to this conflict. “(The) raw ties in preparing these recombinant something that will require further materials of Limulus test are totally proteins, and now we have (all) testing and optimization. dependent on the limited natural three recombinants: proC, proB, Although questions remain, Kawa- resource,” he said. “As an alternative and proCE,” Kawabata said. Using bata and his team already are working approach, we have been doing studies these three proteins to reconstitute with companies in Japan “to make a to develop a next-generation Limulus the coagulation cascade, the team more sensitive and convenient test … test using recombinant (engineered) discovered that specific regions and and ensure a continuous supply of the proteins.” amino acids in proB and proCE are best materials,” he said. Recent research published by key for activation. Now they are using In time, the proteins developed in Kawabata and his colleagues in the their set of recombinant zymogens the Kawabata lab could bring medical Journal of Biological Chemistry and these recent data to improve on and conservation concerns into har- represents an important step toward a nature’s designs. mony, protecting the horseshoe crab hemolymph-free Limulus test. “We are pushing this work forward population while providing a power- In their study, Kawabata’s team to prepare more effective and stable ful tool to prevent infections. focused on the main catalytic pathway recombinants of the protease zymo- of hemolymph coagulation: three gens applicable for the detection of Kian Kamgar-Parsi received a zymogens (inactive enzyme precur- LPS,” Kawabata said. Ph.D. in biophysics from the University of Michigan and works sors) called proC, proB and proCE. In Challenges remain before a fully as a consultant for the pharma- the presence of LPS, proC is activated synthetic hemolymph substitute can ceutical industry. into an enzyme called alpha-chelic- be used for the Limulus test. While erase C that converts proB into chelic- the proteins developed by the team

OCTOBER 2020 ASBMB TODAY 21 JOURNAL NEWS Gut microbiome shaped by dietary sphingolipids By Nivedita Uday Hegdekar This bar graph shows the sphin- he gut microbiome comprises golipid interactors trillions of symbiotic micro- of the microbiome Torganisms that reside in our in decreasing order gastrointestinal tract and perform from left to right, biochemical functions that affect with Bacteroi- metabolic health. Each microbiome des, Prevotella, is unique, and microbiome imbalance Lactobacillus and is associated with disorders such as Bifidobacterium inflammatory bowel disease and celiac being the top four disease. interactors. Diet influences gut microbiome composition, and macronutrients such as carbohydrates, protein and click chemistry. Fluorescence-activat- opment of the infant microbiome. fats are key mediators of this influ- ed cell sorting and 16S rRNA gene Min-Ting, is first author on the ence. Lipids are a major macronutri- sequencing isolated and identified paper published in the Journal of ent, yet scientists know little about microbes that took up the alkyne- Lipid Research. how individual classes of dietary lipids tagged sphingolipid metabolites and “We will next investigate the mo- interact with the microbiome. those that did not. lecular consequences of sphingolipid Elizabeth Johnson studies sphingo- The team found that the dietary consumption in infants and in our lipids, a class of lipids that consist of sphingolipids largely were taken up by mouse models,” she said. “Further- a sphingoid backbone attached to a Bacteroides and Prevotella spp., two more, we will be using our BOSSS fatty acid via an amide bond. Sphin- key players in the human gut micro- methodology to investigate how other golipids not only are present in most biome. Metabolomic analysis revealed lipids, for instance cholesterol, can foods and synthesized from scratch by that non–sphingolipid-producing shape the microbiome.” the host tissue but also are produced microbes such as Bifidobacterium, a Such work has implications for by gut microbes themselves. This major microbiome component, could microbiome-related nutrition, John- raises some questions: How do dietary process the sphingolipids in ways son said. sphingolipids interact with the micro- similar to the sphingolipid-producing “By determining how the micro- organisms that do and do not produce microbes such as Bacteroides and also biome might be interacting with dif- sphingolipids? Are they assimilated in unique ways. ferent metabolites, we can ultimately into the microbiome? If so, how do Because the foods we eat are assim- use diet to positively influence our they influence microbial metabolism? ilated by our microbiomes, this work microbiome composition. This way The Johnson lab developed a could have consequences for health we can really revolutionize the field method called bioorthogonal labeling- and, importantly, in development of of precision medicine.” sort-seq-spec, or BOSSS, for identi- the infant microbiome. Sphingolipids DOI: 10.1194/jlr.RA120000950 fication and fate-mapping of dietary comprise approximately 0.2% to 1% sphingolipids in the gut microbiome. of the total lipids in human milk. In Nivedita Uday Hegdekar The researchers synthesized and fed breastfed infants, human milk and (nivedita.hegdekar@umaryland. alkyne-tagged sphingolipids (distin- microbiome development are inti- edu) is a graduate student at the guishable from the body’s sphingolip- mately related in the first six months University of Maryland working toward a Ph.D. in biochemistry ids and those in the host microbiome) of life. Johnson and her group and molecular biology and an to mice and conjugated fluorescent hypothesize that sphingolipids in milk M.S. in patent law. Follow her on dyes to the tagged metabolites using could influence positively the devel- Twitter @NiveditaHegdek1.

22 ASBMB TODAY OCTOBER 2020 JOURNAL NEWS Our internal ecology Ecosystem models help explain the diversity of the gut microbiome By Laurel Oldach

ccording to a recent estimate, LEYUAN LI if you sample enough humans’ Aintestines, almost 40,000 types of microbe can be found. Any individual may have 100 trillion individual micro-organisms in one or two thousand taxonomic groups. How does the microbiome maintain such diversity? One model to explain the enor- mous variety borrows from studies of larger ecosystems. A well-known theory in ecology, nonequilibrium coexistence of competitors, suggests that as an environment fluctuates, different species gain an edge over neighbors — but their ascendance rarely lasts long. Intestinal nutrients fluctuate as the human host eats and excretes, in Macro- and microecosystems may have more in common than we might think. time with the physiology of sleep– wake cycles, and along the length of the gut. A layer of mucus that Li. “The gut is actually a heteroge- community, to identify the bacteria, protects host cells from commensal neous system … so we need to start fungi and archaea that are present. microbes introduces new oligosac- thinking about the gut microbiome Li thinks metaproteomics also may charides as a fuel source and also like a rainforest.” help researchers road-test increasingly separates microbial communities Li, who conducted her Ph.D. popular ex vivo experimental models into mucosal and luminal niches. studies building artificial ecosystems, of the microbiome to make sure they As conditions change, species in the now studies gut microbiome dynam- match up to the real thing. microbiome shift in abundance and ics in health and diseases such as in- “Using metagenomics, you know jockey for survival, and the constant- flammatory bowel disease in the lab who are there and what they can do,” ly changing competitive edge keeps of Ottawa professor Daniel Figeys. Li said. “With metaproteomics you the ecosystem diverse. In a recent review in the journal know who are there and what they are According to University of Ot- Molecular & Cellular Proteomics, doing.” tawa postdoctoral fellow Leyuan the pair offer an introduction to DOI: 10.1074/mcp.R120.002051 Li, the time is ripe for microbiome microbiome ecology. studies to apply population model- The review highlights the ing and systems dynamics from potential for metaproteomics, macroecology to this more intimate which characterizes the proteins of Laurel Oldach (loldach@asbmb. org) is a science writer for the ecosystem. whole communities of microbes, to ASBMB. Follow her on Twitter “Most of the time we study the describe microbial function. Most @LaurelOld. gut microbiome as a whole: We microbiome studies use metagenom- sequence one sample as if it were ics, ribosomal RNA sequencing of representative of our whole gut,” said the mixed population of a microbial

OCTOBER 2020 ASBMB TODAY 23 JOURNAL NEWS

From the journals By Nuala Del Piccolo, Latavia Hill & Anand Rao

We offer summaries of recent source of energy. Dysregulation of ing to an increase in plasma triglyc- papers in the Journal of Biological triglyceride metabolism and storage eride levels, a decrease in the activity Chemistry, the Journal of Lipid is associated with metabolic diseases, of enzymes that break down triglyc- Research and Molecular & Cellular including Type 2 diabetes. Age also erides, changes in the distribution of Proteomics. increases the risk for metabolic dis- fat cells in the body, and alterations in ease. The combined impact of these inflammation-associated lipid storage Risk factors for metabolic two factors rarely is considered. and release processes. In a recent Journal of Lipid Re- The authors assert that supple- disease search review paper, Kathryn Spitler menting the existing literature with Following a meal, the human body and Brandon Davies of the University mechanistic studies at the molecular, rapidly converts extra calories into of Iowa summarize the current litera- cellular and physiological levels will triglycerides. These fatty acids then ture on the relationship between aging answer open questions about how are stored in the bloodstream and fat and triglyceride metabolism/storage. aging and triglyceride metabolism/ cells, where they serve as an accessible They write about studies that link ag- storage cause metabolic disease and

Pinpointing the proteases that make flu go viral CENTERS FOR DISEASE CONTROL INFLUENZA LABORATORY There are four main types of influ- or TMPRSSs, known as TM- enza viruses — A, B, C and D — and PRSS4 and TMPRSS13. nearly every winter in the U.S. the The researchers used protease influenza A and B viruses cause the inhibitors alongside transfec- disease epidemic known as flu season. tion of TMPRSS13, hepsin and Globally, influenza A and B account prostasin in double-knockout for over 300,000 deaths and 3 million Tmprss2-/-Tmprss4-/- cells to to 5 million cases of severe respira- identify differences in HA reliance tory illness each year, according to the on protease cleavage. They found World Health Organization. that HA proteases overlap in the Hemagglutinin, or HA, is a two influenza viruses but dem- glycoprotein located on the surface onstrate functional differences. of influenza viruses. HA is activated Finally, the authors extended their by cleavage by host cell proteases and work from mouse airway tissue to is essential for initiating the entry human tissue, finding that human of influenza virus into host cells. orthologs of hepsin and prostasin Understanding the mechanisms of Researchers are studying the proteases respon- cleave influenza B HA extensively HA protein cleavage is important for sible for cleaving the influenza A and B glycopro- but not influenza A HA. development of flu therapies, but the tein hemagglutinin, found in viruses such as H1N1 The researchers’ data suggest proteases involved in the activation of influenza, shown here in a colorized image. that influenza A and B strains many viral strains remain unknown. have overlapping sets of proteases In a recent paper published in the ing, infection of mouse cell lines and that cleave HA differently and Journal of Biological Chemistry, plaque assay analysis, the authors that protease activity differs in Anne Harbig of Philipps-University analyzed the collection of proteases mice and humans. Identifying the Marburg and an international team present in mouse lower airway tissues factors responsible for influenza revealed a collection of proteases and identified four candidate prote- HA activation has both basic that process HA and govern protease ases responsible for influenza A and B science and potential therapeutic functionality against specific HA HA activation: hepsin, prostasin and applications. glycoproteins. Using RNA sequenc- two transmembrane serine proteases, DOI: 10.1074/jbc.RA120.012635

24 ASBMB TODAY OCTOBER 2020 JOURNAL NEWS HELENE HOFFMAN inform strategies to mitigate these risk factors. DOI: 10.1194/jlr.R120000922 Ribosomes don’t rewire protein folding reactions To function properly, proteins must adopt and maintain specific confor- mations. They typically reach their final structure by cycling through preferred intermediate conformations, a process that starts during protein synthesis. But how the ribosome af- fects protein folding remains unclear. Using a ribosomal force-profiling assay, Madeleine Jensen of the University of California, Berkeley, and collaborators at the University of Male iguanas secrete substances from their femoral glands to attract female mates. Cambridge showed that ribosomal interactions have little impact on the folding pathways of RNase H, sug- Immune function of femoral glands in marine gesting that the ribosome does not in- iguanas fluence protein folding. Additionally, the authors found that the ribosome Femoral glands play a key role in chemical signaling in many lizards promotes RNase H unfolding while and amphibian species, including marine iguanas. Male iguanas secrete the growing protein chain is close to substances from their femoral glands to attract female mates, and the ribosome, which may limit the researchers hypothesize that certain lipids in these secretions aid in detrimental effects of RNase H mis- territory marking and male quality communication. Recently, Fredrick folding and assist in folding fidelity. Tellkamp, Franziska Lan and a team of German researchers published These results, reported in a recent a paper in the journal Molecular & Cellular Proteomics that focused paper in the Journal of Biological on identifying the function and identity of proteins found in femoral Chemistry, provide new insights into gland secretions using a comprehensive proteomic approach. how ribosomes affect the folding of The researchers developed the first transcriptome data set and used nascent proteins. this information to identify various phospholipase isoforms in marine DOI: 10.1074/jbc.RA120.013909 iguanas. They used prediction software to characterize unidentifiable proteins and learned that two of the 15 candidates were enriched in A new way to study femoral gland secretions. Next, they used several biochemical methods, including mass spectrometry analysis, to characterize these compounds Parkinson’s further. This analysis revealed several thousand hits, and further experi- mentation identified epidermis-specific proteins, lipid-binding proteins Parkinson’s disease is a progres- and immune-responsive proteins. sive, neurodegenerative disorder that The work also yielded femoral gland proteins that have antimicrobi- causes involuntary loss of control over al properties. This finding led to the generation of a library of antimi- some body functions. The causative crobial peptides, and the researchers selected 17 AMPs for analysis. Of agents of some Parkinson’s cases are these 17 AMPs, peptide 4 showed strong antimicrobial effects against mutations in the leucine-rich repeat E. coli and Bacillus subtilis in growth rate reduction experiments. The kinase 2, or LRRK2. These changes researchers speculate that AMPs and immune cells in femoral gland se- lead to increased kinase activity, which cretions provide protection against bacterial infection and degradation enhances the phosphorylation of an when the femoral gland opens during male iguana territory marking, important protein known as Rab10 which is crucial to survival. involved in disease manifestation. DOI: RA120.001947 Recent work published in the journal Molecular & Cellular Proteomics by

OCTOBER 2020 ASBMB TODAY 25 JOURNAL NEWS

How does CETP modulate cholesterol transport?

Plasma lipoproteins are particles that make NATIONAL HEART, LUNG AND BLOOD INSTITUTE lipid-based nutrients and waste products soluble for transport in the bloodstream. They are critical for transporting triglycerides, or TGs, and cholesteryl esters, or CEs, throughout the body. TGs are an essential fuel source, and CEs are the dietary form of cholesterol, which is a necessary component of healthy cells. Each class of plasma lipoprotein is responsible for a specific function, which can include transport of CEs or TGs from the intestines to peripheral tissues or removal of excess CE from the tissues and bloodstream through the liver. Cholesteryl ester transfer protein, or CETP, is a bidirectional lipid transfer protein that catalyzes the transfer of CE from lipoproteins that bring nutri- ents to peripheral tissues to lipoproteins that clear excess material through the liver; it also can catalyze the transfer of TG in the reverse direction. An ex- cess of CE in lipoproteins that provide tissues with nutrients (or a paucity of CE in lipoproteins that Dysregulation of cholesterol transport by plasma lipoproteins remove waste) has been linked to atherosclerosis increases a person’s risk for atherosclerosis. and other cardiovascular diseases in humans. Based on its ability to modulate the dynamic equilibrium lipoproteins that provide tissues with nutrients carry among plasma lipoproteins, CETP has emerged as more CE. At the same time, the concentration of an enticing therapeutic target. lipoproteins that remove waste is reduced drasti- A new study reported in the Journal of Lipid cally, and these particles carry less CE and more Research examines how CETP’s preference for TG TG. Further, hepatic expression of genes involved or CE affects plasma lipoproteins. The report takes in cholesterol uptake and metabolism is reduced. In advantage of the natural difference in human and contrast, in animals overexpressing hamster CETP, hamster CETP’s preferences for CE and TG cargo, analyses of plasma lipoproteins and gene expression respectively. Richard Morton and Yan Liu of the matched wild-type measurements. Cleveland Clinic overexpressed each gene in ham- These findings highlight the central role of CETP sters and then probed the utility of the new model — specifically, its cargo preference — in plasma system by assessing the distribution and content of lipoprotein-mediated cholesterol transport and in- plasma lipoproteins. form the design of future CETP-targeted therapies. In animals overexpressing human CETP, the DOI: 10.1194/jlr.RA120000691

Ozge Karayel of the Max Planck Insti- coupled with in-gel digestion, the re- this work provides new knowledge tute of Biochemistry and an interna- searchers detected small differences in about the role of Rab10-Thr73 tional team focused on determining LRRK2 activity in mouse fibroblast in LRRK2-associated Parkinson’s. the stoichiometry of Rab10-Thr73 in cells. Next, they tested Rab10 levels Furthermore, these findings can aid Parkinson’s patient samples. before and after LRRK2 inhibition the development of new medications The researchers developed a highly in both human peripheral blood that will treat disease progression, not sensitive, mass spectrometry–based and Parkinson’s patients and found just the symptoms. Lastly, the mxSIM assay, mxSIM, to show that Rab10 increased Rab10-Thr73 phosphoryla- technology can be used to study other phosphorylation is a direct readout tion levels in the patients as com- diseases. for LRKK2 activity. Using mxSIM pared to healthy controls. Overall, DO: RA120.002055

26 ASBMB TODAY OCTOBER 2020 JOURNAL NEWS

An adaptor protein prompts zymes — EPT1 and CEPT1 —that similarity metric and determined the catalyze the last step of the cytidine hemagglutinin glycosylation similari- membrane protrusion diphosphate-ethanolamine pathway, ties for the wild-type SWZ13 strain Invadopodia — protrusions from in which ethanolamine phosphate is versus a SW13 mutant. The mutant the membranes of cancer cells that are transferred to a lipid acceptor. The strain contained the same sequons as rich in the cytoskeletal protein actin authors show that EPT1 is localized the wild type, but at the whole gly- — are essential for metastasis. The in the Golgi apparatus, synthesizes PE coprotein level the two strains were role of transforming growth factor species (including plasmenyl-PE) with measurably distinct in glycosylation beta, or TGF-beta, in metastasis has long fatty acid chains, and prefers the due to alteration of head group gly- been well established, but how TGF- lipid acceptor 1-alkyl-2-acyl-glycerol, cosylation. The researchers concluded beta signaling is linked to cancer or AAG. CEPT1, on the other hand, that the Tanimoto similarity metric cell motility as well as its relation to is found in the endoplasmic reticu- is useful for determining alterations invadopodia remain unknown. lum, synthesizes PE species with short in glycoprotein glycosylation from Alex Kiepas of McGill University fatty acid chains, and prefers the lipid bottom-up glycoproteomics data. and collaborators at Laval University acceptor 1,2-diacylglycerol, or DAG. This work will aid future vaccine revealed that Src-homology/collagen The findings identify complemen- production. adaptor protein initiates the dynamic tary roles for the CEPT1 and EPT1 DOI: RA120.002031 adhesion complexes necessary for enzymes in PE synthesis and provide invadopodium formation in a TGF- a basis for future studies into main- Lab-grown amyloidosis beta–dependent manner. tenance of PE species in mammalian These findings, published in a re- membranes, including why mutations model measures up cent study in the Journal of Biologi- and loss of exons in EPT1 are linked Systemic amyloidosis is a rare cal Chemistry, further researchers’ to neurodegenerative diseases. hereditary disorder that commonly understanding of cancer metastasis DOI: 10.1194/jlr.RA120000898 manifests in heart, kidney, liver and and open new avenues for cancer nerve complications, sometimes lead- drug discovery. ing to organ failure. Systemic amyloi- DOI: 10.1074/jbc.RA119.011903 Measuring glycosylation dosis is caused by misfolded proteins, in influenza A such as transthyretin, resisting the Enzymes collaborate to Influenza A is an RNA virus that body’s catabolic processes and build- affects birds and mammals. Strains ing up outside cells. Studies seeking synthesize phospholipids of this virus caused the 1918 Span- to identify the biological mechanisms The lipid composition of mem- ish flu pandemic and the more recent underlying this condition require branes is essential to cell function, 2009 H1N1 swine flu outbreak. clinically relevant disease models. affecting everything from membrane This virus has a high mutation rate, In recent work published in the protein activity to cellular homeo- which ultimately helps it to evade the Journal of Biological Chemistry, stasis. Hence, lipid composition in host immune response. This is why Sara Raimondi of the University cells is orchestrated carefully through researchers create new flu vaccines an- of Pavia and an international team constant synthesis, degradation and nually. Influenza vaccine development compared the characteristics of fibrils recycling of lipid species. Cellular takes advantage of antigenicity of the generated experimentally with natural synthesis of ethanolamine phos- influenza A envelope protein hemag- transthyretin fibrils to assess their pholipids, or PEs, the second most glutinin, or HA, and its glycosylation value as a model for systemic amy- abundant lipid in human cells, takes state. loidosis. The authors found that the place through the phosphatidylser- Recent work published in the experimentally generated fibrils are ine decarboxylation and cytidine journal Molecular & Cellular Pro- thermodynamically and structurally diphosphate-ethanolamine pathways. teomics focused on determining if similar to naturally occurring amyloid The latter is the focus of a new study there is a difference in glycosylation fibrils. reported by Yasuhiro Horibata and at the protein level in two related These results show that laboratory- a team of researchers from Dokkyo influenza strains, using a statistics- grown transthyretin fibrils are a useful Medical University. based approach. Deborah Chang model for investigating the patho- Their Journal of Lipid Research of Boston University and a team of physiology of amyloidosis. paper characterizes the two en- U.S. researchers used the Tanimoto DOI: 10.1074/jbc.RA120.014026

OCTOBER 2020 ASBMB TODAY 27 JOURNAL NEWS

Sorting out sensor domains and MecR1. lactamase inhibitor that blocks the In a recent paper published in the activity of the beta-lactamase enzyme to inhibit MRSA Journal of Biological Chemistry, J. produced by S. aureus. Infections by methicillin-resistant Andrew N. Alexander of the Universi- These findings reveal the presence Staphylococcus aureus, or MRSA, ty of British Columbia and colleagues of a secondary sulfate-binding pocket bacteria are notoriously difficult to at the University of Maryland and San that could be exploited in the design treat due to the bacteria’s resistance to Francisco General Hospital solved the of future inhibitors capable of treating several antibiotics. Contributing to X-ray crystallographic structures of MRSA. MRSA’s antibiotic resistance are two the BlaR1 and MecR1 sensor domains DOI: 10.1074/jbc.RA120.013029 integral membrane proteins, BlaR1 in complex with avibactam, a beta-

Nuala Del Piccolo Latavia Hill ([email protected]) Anand Rao (arao@asbmb. ([email protected]) is a graduate student studying org) is an ASBMB science is a postdoctoral scholar in microbiology at the University of communicator. Follow him on the biomedical engineering Kansas. Twitter @AnandRaoPhD department at the University of California, Davis. She earned her Ph.D. in materials science and engineering at Johns Hopkins University.

ASBMB CAREER CENTER

Find the next great addition to your lab.

ASBMB Regular and Industry members can post jobs for free.

careers.asbmb.org

28 ASBMB TODAY OCTOBER 2020 Connect your community with a virtual scientific event Interested in hosting a virtual event? The ASBMB is here to help. The ASBMB provides a platform to share scientific research and to discuss emerging topics and technologies in an interactive, virtual setting.

When you host a virtual event with the ASBMB, your event will: n accommodate up to 500 attendees n be marketed to the ASBMB’s 11,000 members n reach the ASBMB’s network of journal authors and meeting attendees

Learn more about how to submit your proposal at asbmb.org/meetings-events

OCTOBER 2020 ASBMB TODAY 29

ASBMB_TODAY_AUGUST_PRINT_V1.indd 2 8/5/20 3:08 PM Milk through the millennia

30 ASBMB TODAY OCTOBER 2020 FEATURE Lipids in potsherds hold clues to lactase persistence

By John Arnst FIONA MARSHALL/WUSTL

ixty-six million years ago, primitive animals with mammary glands man- aged to ride out a mass extinction event, with the eventual result that today humans have to pay bills and Sponder our own mortality. However, we are the only mammals that can di- gest lactose into adulthood and blunt these pains with industrial quantities of cheddar cheese, so the verdict is out on whether this situation is a net positive or negative. But for nearly two-thirds of adults worldwide who are lactose intolerant, milk, cheeses and other dairy prod- ucts cause a different kind of pain. In the absence of lactase, the enzyme that cleaves lactose into glucose and galactose once the sugar enters our small intestines, lactose passes through whole and becomes food for the microbes that live in our large in- testines, whose byproducts then cause bloating, nausea, stomach pains and digesting lactose was such a strong This Pastoral Neolithic bowl from the Bromshead diarrhea. Moreover, digesting the milk evolutionary advantage in pastoralist archaeological site in Kenya’s portion of the Great protein casein in adulthood releases societies that alleles for it indepen- Rift Valley is an example of Elmenteitan pottery, a insulin growth factor-1, a hormone dently developed in human popula- lithic and pottery tradition. The bowl is housed in that can, in excess, cause cystic acne. tions in both Northern Europe and the Fitzwilliam Museum at Cambridge University Production of lactase also can fall off Eastern Africa, with subgroups from and was photographed by Fiona Marshall, an an- suddenly in adulthood, although the the latter — in what are today Tanza- thropologist at Washington University in St. Louis. role that diet — say, eating a brick nia, Kenya and Sudan — developing of feta cheese every day for lunch for three distinct polymorphisms. several months — may play in this is Genetic analyses of modern pasto- K. GRILLO/UNIVERSITY OF FLORIDA unclear. ralists have helped revise our under- The persistence of lactase in 35% standing of where lactase persistence of adults is due to single nucleotide developed, but they give a broad polymorphisms in the gene that codes range— 6,800 to 2,700 years before for the enzyme. Several thousand the present day — for when those years ago, the ability to continue traits emerged.

OCTOBER 2020 ASBMB TODAY 31 FEATURE K. GRILLO/UNIVERSITY OF FLORIDA

To pinpoint when humans began consuming milk By analyzing the lipid residues on samples in 1976 when French sci- in East Africa, researchers, including anthropolo- 125 fragments of ceramic pots recov- entists used gas chromatography to gist Katherine Grillo and organic geochemist Julie ered from sites in Kenya and Tan- detect trace amounts of fatty acids — Dunne, looked for lipid residues on 125 pottery zania, scientists at the University of byproducts of oil — in fragments of shards, or sherds, that were found at archaeologi- Bristol, the University of Florida and jars used to transport goods in cal sites in Kenya and Tanzania and are similar to the University of Dar es Salaam have the ancient Mediterranean. Their these. Sherds A–E come from the site Jarigole, uncovered cultural contexts behind work appeared in the journal while sherds F and G come from the site Dongo- the genetic phenomenon that date its Archaeometry. dien, both of which are located in the Turkana emergence in East Africa to approxi- Today, Julie Dunne, an analytical basin in Kenya. Sherds H–K come from the site mately 5,000 years ago. chemist at the University of Bristol Luxmanda in north-central Tanzania. Sherds L “Advances in ancient DNA recov- uses GC–MS to examine the lipids and M, which come from the site Ngamuriak in ery and processing have really helped embedded in the matrices of ancient the Great Rift Valley in southwestern Kenya, are us pinpoint when we think selection shards of pottery. examples of Elmenteitan pottery. for these alleles appeared and evolved. “If you think about an unglazed We now know from the genetic ceramic pot, and if you had to put record that this probably happened some milk in it, or even meat, and during a key time period known just boil it up, what you would actu- as the Pastoral Neolithic, which ally see is fat globules floating on the roughly dates to between 5,000 and top,” Dunne said. “Those globules of 2,000 years ago in East Africa,” said Katherine Grillo, an anthropologist at the University of Florida. “But what we didn’t understand previously is the context in which selection for those alleles actually happened.” Atomizing pottery That context is provided by gas chromatography–mass spectrometry. Chromatography first was used to analyze residues in archaeological JULIE DUNNE

32 ASBMB TODAY OCTOBER 2020 FEATURE

fat, lipids, absorb into the unglazed had been searching for new archaeo- ceramic matrix during cooking.” logical sites in northern Tanzania Unlike proteins, which are too when a collaborator, Agnes O. Gidna large to fit in ceramic matrices, lipids from the National Museums of Tan- are small and can survive in the ma- zania in Dar Es Salaam, took a short trices of ceramic pots for more than trip home to her family’s farm near 10,000 years. the town of Luxmanda on the Mbulu “They sit very nicely in the pot Plateau, farther south in north-central until people like me come along and Tanzania. grind up broken potsherds, which are “We had spent weeks and weeks generally only what survives anyway,” surveying for new sites much farther Dunne said. “I’ve analyzed pottery north, and towards the end of a field from Europe and Africa which is season, Dr. Gidna said, ‘You know nearly 10,000 years old, and there is what? I’m just going to go home for a actually pottery in Japan that goes few days. I’ll be back,’ and she went. back more like 15,000 to 17,000 Then she calls us and she said, ‘there’s years and has yielded lipids.” some pottery.’ And pretty soon real- In 2008, the leader of Dunne’s ized we discovered that she had dis- research group, Richard Evershed — covered the biggest Pastoral Neolithic who developed the field of organic site in East Africa,” Grillo said. “It’s in residue analysis — helped determine her mother’s yard.” that the earliest date that pastoral so- After the researchers recover a cieties in Anatolia, now Turkey, began small, two- to three-centimeter sherd Katherine Grillo, an anthropologist at the consuming processed dairy was 9,000 like those Gidna first found at the University of Florida, co-directs two major field years ago. This predates the 5,000 Luxmanda site, they clean its surface projects in East Africa: one examining the social year-old pottery that she and Grillo to remove the oils of more recent significance of monumental “pillar sites” built by recently analyzed. human lives — lotions, sunscreens the region’s earliest herders in the Turkana Basin “If milk is being processed in the and sebum — and pulverize the pot- in northwestern Kenya, and another examining pots, we know humans are consum- tery into dust. They then use an acid the largest Pastoral Neolithic settlement site ing milk,” Dunne said. “And once extraction to separate the lipids from in eastern Africa farther south at Luxmanda, you start processing it and reduce the the sherds. Tanzania. lactose content, then it makes it much easier for humans to digest. So that’s ELIZABETH SAWCHUK/MAX PLANCK INSTITUTE FOR THE SCIENCE OF HUMAN HISTORY happening in the Near East around about 7000 B.C.” From serendipity to eureka The pottery sherds that Grillo and Dunne recently analyzed came from four sites across Kenya and Tanzania that are together repre- sentative of the breadth of Pastoral Neolithic sites in the region. While samples from the three sites located in Kenya — Dongodien, Jarigole and Ngamuriak — were obtained from museum collections in collaboration with Karega–Munene, an anthropolo- gist at the United States International University in Nairobi, sherds from the fourth site were products of serendip- ity. In 2012, Grillo and her colleagues

OCTOBER 2020 ASBMB TODAY 33 FEATURE JJ HARRISON the sherds from the four sites, Dunne, Grillo and their colleagues were able to obtain the first direct evidence that herders in ancient eastern Africa were consuming milk 5,000 years ago. Whether the gradual reduction in lac- tose content by fermentation ended up driving populations to consume more lactose-heavy, however, is a more elusive question. “The development of widespread lactose persistence in herding societies through gene-culture coevolution is a topic now preoccupying scientists worldwide,” Grillo said. “Selection for lactase persistence may have become stronger as herders became even more specialized and dependent on livestock later on.” Milk markets Feta is a softer cheese made from sheep’s milk or “Sometimes when we come to the a mixture of milk from sheep and goats. end of the extraction, you can actually Today, the reduction of lactose see the fat in the little vial coming levels in processed dairy foods means from the animals cooked in the pots someone who is lactose intolerant and thousands of years ago, which is quite no longer can eat softer cheeses like amazing,” Dunne said. feta without first swallowing Lactaid The scientists then run those lipids might be able to eat a sharp block through a gas chromatograph, which of cheddar that has almost all of its lets them know whether the lipids lactose removed. are animal fats and whether they are According to Andrea S. Wiley, a too contaminated to be interpretable. medical anthropologist at the Univer- The process most often yields fats sity of Indiana at Bloomington who from animals, but it also can reveal studies the relationship between milk byproducts of plants and insects, such consumption and child health in the as bees, where lingering traces of wax U.S. and in India, consumption of will indicate that a population likely cheese, butter and similar products harvested honey. After then running was the status quo of dairy produc- the lipids through an isotope mass tion in the U.S. until the late 1800s. spectrometer, the researchers are able “The late 19th to differentiate whether they came century is really from a ruminant — cattle, sheep or when milk con- goats — or nonruminants, such as sumption starts pigs, chickens and donkeys. to become more “Then we can also differentiate, common, other most crucially, between milk and than just dairy meat,” Dunne said. “And that was our products, and eureka moment in our lab, probably ANDREA S. WILEY mostly as food 20 years ago now, that’s really enabled for children as a such a body of work on exploiting breast milk substitute,” she said. milk and the evolution of lactase Over the ensuing decades, milk persistence.” producers, working with the National By applying these techniques to Dairy Council, began pitching milk

34 ASBMB TODAY OCTOBER 2020 FEATURE

as a source of nutrients for children. JUERS, D.H., MATTHEWS, B.W; ASTROJAN/PDB; WIKIPEDIA “The Dairy Council was formed in 1915, and that’s when they take the lead role in identifying what is the best food for children, and milk is a central part of that message,” Wiley said. “(They) tried out different nutrient messages, that milk is a good source of X, Y or Z. And the prevail- ing way, certainly beginning in the 1930s and on, was that milk has been understood nutritionally as a source of calcium. And that’s where the link to the strong bones matches up very nicely.” That messaging stuck for decades. Take, for example, the “Got Milk?” ad campaign of the 1990s, which infil- trated billboards, magazines, airwaves, televisions and lunchrooms for more than 20 years to sell a generation and their parents on the belief that milk builds strong bones in children. Wiley said. “Milk is what mammals Lactase, an enzyme found in the small intestines While the link between cow’s produce, or female mammals produce, of mammals, splits the sugar lactose into glucose milk and strong bones is dubious, and it sustains infants when it’s all and galactose. the connection does have a scientific they consume.” basis in breast milk: In infancy, breast milk acts as a source of calcium, and Lactase emergence its whey and casein proteins act as growth promoters. Over the past two decades, our But a wildly successful ad cam- understanding of lactose intolerance paign couldn’t reverse a downward as an enzymatic matter also has been trend that started after World War transformed and revised, according II, which marked the high point for to Sarah Tishkoff, a geneticist at the American production and consump- University of tion of milk. The dairy industry today Pennsylvania’s is in dire straits, with more than Perelman School 2,700 dairy farms having gone out of of Medicine who business in the last two years and the studies genetic amount of liquid milk consumed per variation in East capita plummeting more than 40% African popula- since 1975. tions. “We’re really back to where we SARAH TISHKOFF In 2002, the were around the early 20th century geneticist Leena in terms of milk consumption in the Peltonen and her colleagues created U.S.,” Wiley said. But despite the a map of genetic variants in Finnish plummet in overall consumption of families that were lactose intolerant, cow’s milk, she thinks milk as a sub- a rarity in Northern Europe. This stance still inspires a certain cultural discovery was essential to understand- reverence. ing the genetic mechanisms of lactase “Milk has always been positioned, persistence. I think, as a very special food. And, “They thought of lactose intoler- you know, in one way, it really is,” ance like a disease, basically,” Tishkoff

OCTOBER 2020 ASBMB TODAY 35 FEATURE MARION_SMITH / ISTOCKPHOTO.COM humans has changed over the past 10,000 years, the enzymatic activity of bovine stomachs has not, making modern cows proxies for the ancient cattle of pastoralists past. A plant that passes through a cow’s stomach in significant quantities today will make the same subtle imprint on the chromatographic character of its milk that its identical ancestor did millen- nia ago. This has yielded insights that cattle and assorted mammals in ancient Europe tended to eat very temper- ate vegetation known as C3 plants, named after the number of carbon Herd of African cattle grazing on Masai Mara said. “It was interesting because (the molecules in the first compound plains, Masai Mara, Kenya. mutations) were not in the lactase formed by the Calvin cycle of carbon gene, they were upstream in front of fixation, but African mammals tended a neighboring gene. And at that time, to eat more arid-friendly C4 plants very little was known about gene like sorghum and amaranths. regulation. It was a rare example of “We see, for example, the animals finding a regulatory mutation that were eating lots of C4 grasses, and influences this well-known common so we think in East Africa at this trait.” time, there were some environmental Four years later, Tishkoff and her shifts happening,” Grillo said. “Even colleagues, working with Tanzanian, if people weren’t able to be farmers Kenyan and Sudanese ethnic groups, because of unpredictable or patchy found that lactase persistence evolved rainfall, they may have had milk or at least four times in human popula- something like it.” tions. They described this convergent By providing glimpses into past evolution of lactase persistence in the periods of climate and habitat disrup- journal Nature and expanded upon it tion, forces that will continue to in 2014 in the American Journal of shape the lives of pastoralists in com- Human Genetics. ing decades, Grillo hopes the long- “We saw this very strong genomic preserved lipids may make the case for footprint of selection,” Tishkoff said. a more resilient lifestyle. “And that was one of the earliest “It’s getting harder to be a herder genomic signatures of selection, and in many areas (that are) drying out, still one of the strongest signals in the but it’s actually much easier to be a human genome.” herder when the climate is getting really unpredictable and arid than it is Lipid whispers to be a farmer,” Grillo said. “We can build a much more holistic picture Today, pastoralist societies in East- of what life was like for these people ern Africa still rely on milk and milk because of the residue analysis.” products from cattle, sheep, goats or camels; some groups are estimated to derive up to 60% or even 90% of John Arnst (jarnst@asbmb. org) is an ASBMB Today their total calories from milk prod- science writer. Follow him ucts, which they complement with on Twitter @arnstjohn. meat, maize, beans and seasonally available plants. While the digestive chemistry of

36 ASBMB TODAY OCTOBER 2020 ASBMB career center Find your next hire. ASBMB Regular and Industry members can post jobs for free.

career.asbmb.org

OCTOBER 2020 ASBMB TODAY 37

ASBMB_TODAY_AUGUST_PRINT_V1.indd 4 8/5/20 3:24 PM FEATURE Pandemic snarls research administration Funders, grant administration offices work together to reassure anxious investigators

ERIC KUONG/STANFORD MEDICINE By Laurel Oldach

reed Stary was in a difficult position. As his research lab at CStanford gradually reopened, the physician–scientist realized he had to choose which of two grant propos- als to focus on; his team wouldn’t have enough time to complete both on schedule. Stary’s lab of two technicians and two postdocs is supported by an R01, a five-year grant of about half a million dollars from the National In- stitutes of Health, along with smaller individual grants to the postdocs. He needs to show the NIH continued annual progress on that major grant. In the meantime, hedging his bets, Stary also had submitted an applica- tion for a second R01 in February of this year. The pandemic upset his plans to revise that grant in response to reviewers’ concerns and resubmit it in October. “We have to try to get the data for our existing R01, try to get the data for our new R01 revision, try to get the data for my postdoc’s grant that he’s finishing up, and also try to get the data for a new grant he’s submit- ting this fall,” Stary said. With limited time in the lab, his team couldn’t run all of the experiments to collect all of the data they needed on the timeline he had hoped for. Tenure-track, but not yet tenured faculty like Creed Stary of Stanford University have expressed Stary wasn’t the only PI scrambling concerns about keeping their labs funded through the pandemic. to rework his funding strategy. As the pandemic continues to beleaguer the U.S., in most of the country lab work has remained slow, stripped to the minimum hours required to keep crit- ical research going. Now, as research-

38 ASBMB TODAY OCTOBER 2020 FEATURE LAUREL OLDACH /ASBMB TODAY

For principal investigators at research universities, R01 grants are a major source of funding. Most PIs spend several months developing a research proposal and budget and work with university grant administration offices to compile and submit the complex proposal packages. There are three annual deadlines to submit an R01 application: early in October, February and June. Four to five months after the application deadline, a study section of peers who have read a group of applications meets to review and score applications. Funding decisions, based on reviewers’ scores and institutional priorities, are determined at the next NIH advisory council meeting. After those decisions are finalized, several more months can pass before funds are transferred.

ers and administrators prepare for the maintained funding; and additional As the pandemic continues next set of major grant application proposed legislation, called the Health deadlines in early October, many are and Economic Recovery Omnibus to beleaguer the U.S., in most especially concerned about principal Emergency Solutions or HEROES investigators like Stary — relatively Act, would add over $4 billion in of the country lab work has young, pre-tenure and vulnerable to supplemental research spending to the a serious disruption if just one grant NIH’s budget if passed. remained slow, stripped to the application should be denied. However, gaining access to that minimum hours required to money can be a challenge. Winning The big picture research grants is a complex and time- keep critical research going. consuming task. Up to a year can pass Funding to the NIH has not from when an applicant submits an faltered during the pandemic. “There investigator-initiated grant to when is a lot of money available if you’re — if the application is successful — doing research on SARS-CoV-2,” the funds are released. About 79% of explained Ben Corb, the American all applications for R01 grants across Society for Biochemistry and Molecu- the NIH are unsuccessful. Too many lar Biology’s public affairs director, consecutive unsuccessful applications during a recent webinar hosted by can force a researcher to close a lab the society. “If not, there is continued and walk away from a research career funding available at the same levels, despite decades of training. and we expect an increase in fiscal Principal investigators spend year 2021.” months preparing applications and The Coronavirus Aid, Relief and years learning grantsmanship, the Security or CARES Act, passed in unwritten rules for success in the fed- March, included about $1.65 billion eral funding system. They also spend in additional funding for the NIH significant time planning ahead to for COVID-19 research. As of mid- keep their labs funded continuously. September, fiscal year 2021 budget Many, like Stary, are concerned about proposals from the White House the effect of research disruptions on and House of Representatives call for their funding.

OCTOBER 2020 ASBMB TODAY 39 FEATURE

Working below full capacity, Federal officials at the NIH stress director of the Office of Sponsored that they are sensitive to these con- Research and an assistant vice presi- researchers are trying to cerns and are working hard to find dent for research at the University solutions. In a statement, the Office of Texas at Austin, said that even as focus on doing the work of External Research wrote, “We other support staff faced furloughs are deeply concerned and mindful and layoffs, her office has worked that’s most important about how the spread of COVID-19 harder from home, handling expedit- while also taking care to has affected the biomedical research ed requests for COVID-19 research enterprise and we have implemented funds along with an uptick in non– avoid starting monthslong various administrative flexibilities.” pandemic-related grant applications. Some of those flexibilities, like Likewise, the NIH reported a 10% experiments that might extended deadlines to submit grants increase in the number of grant appli- in the spring, were short-term. Oth- cations received from May to June in have to be abandoned ers, like relaxation of strict rules for 2020 compared to the same funding career-stage grants for postdocs and cycle in previous years. if local public health early-career independent investigators, Phased reopenings have brought have continued. researchers back into once-shuttered mandates change. labs slowly. Not all researchers were Research down, grant able to return to work full-time (see ‘The parent trap’ on page 41). writing up For those who could, reagents were When university campuses closed back-ordered, animal colonies had across the country in March, many to be reestablished, and laboratories researchers turned to writing, data are operating at restricted capacity to analysis and other projects to stay pro- prevent crowding. The slowdown may ductive while shut out of their labs. last many more months. Bill Sonntag, who directs a research Working below full capacity, center at the University of Oklahoma researchers are trying to focus on Health Science Center, said, “I tell the doing the work that’s most important faculty in my department … ‘While while also taking care to avoid starting we’re shut down and you have to be monthslong experiments that might home, can you write a grant?’” have to be abandoned if local public That flurry of writing is reflected in health mandates change. submission systems. Renee Gonzales, “Starting out the year, you have these grand plans about planning out LAUREL OLDACH /ASBMB TODAY experiments,” Stary said. But this year, “you don’t have the luxury of all that labor that you were relying on.” Reporting progress At the end of each year of a funded grant, the principal investiga- tor must submit a progress report explaining what work has been done, According to a blog post what money has been spent and any by NIH Deputy Director unexpected interruptions. University for External Research and federal program officers review Mike Lauer, R01 and that report before disbursing the next research project grant year’s funding. applications were both Renee Gonzales’ staff typically up by about 10% over reviews progress reports for two red previous years in the June flags: investigators giving less effort 2020 application cycle. than expected or spending less than

40 ASBMB TODAY OCTOBER 2020 FEATURE

Scientists with young children lost more time than their childless peers, and mothers of young children lost more time than fathers.

The parent trap

A study published in the journal Nature Human Behavior in July confirmed what many scientists report anecdotally: The cost of the pandemic to research time isn’t equal across fields or life stages. Scientists with young children lost more time than their childless peers, and mothers of young children lost more time than fathers.

School districts across the country remain closed for in-person classes. Daycare facilities are providing a fraction of their normal enrollment to limit crowding and the risk of spreading the virus. (Campus daycare options often are overbooked already, with yearslong wait lists.) And many grandparents, who can be at heightened risk from infection, are sitting out this round.

Some large universities, such as Yale, the University of California system and the University of Chicago, have invested in or beefed up backup childcare benefits for their faculty and staff and sometimes also trainees. These programs subsidize an in-home caretaker for days when a normal care plan falls through unexpectedly. However, ham- mering out that normal care plan is a significant challenge; young parenthood overlaps with the precarious early-career stage that lasts well into most researchers’ forties; and many are concerned that the result will squeeze parents, especially mothers, out of science altogether.

“I have one very productive postdoc who decided not to come back (to the lab) in the end,” said Lynne Maquat, a professor and director of the RNA biology center at the University of LYNNE MAQUAT Rochester. Concerned about taking care of children and two sets of aging parents, the researcher reduced his hours to one day a week, conducted remotely, to focus on care responsibilities and begin consulting as a freelancer. Others in the lab have picked up the project he was working on.

OCTOBER 2020 ASBMB TODAY 41 FEATURE

three-quarters of the annual budget. unknowns.” This year, she said, both problems are As the pandemic continues, Gon- commonplace. zales thinks the NIH should consider Oleg Barski, a retooling the progress report. “If I feel program officer this way in my office, I can imagine in biochemistry what they feel like when they get at the National thousands and thousands of these re- Institute for ports. What’s the point of asking the General Medi- question (about plans) when there’s cal Sciences, said no answer?” repeatedly in an Early in the pandemic, Gonzales OLEG BARSKI interview that said, her office frequently fielded the NIH has questions about whether research- no intention of penalizing funded ers could keep paying their staff and researchers for disruptions caused by their trainees (see ‘Can I pay my COVID-19. technicians?’on page 44). Later, other “These projects, and these PIs, were questions rose to prominence — such carefully selected through a very rigor- as what to do if money runs out ous process,” Barski said. “We are here before a lab can return to working at to do everything possible to ensure full capacity. the success of these scientists, not to Even with labs closed, PIs have punish them for the delay.” continued to pay personnel costs such The progress report form leaves PIs as stipends, tuition and benefits, and an opportunity to explain why they most universities still charge overhead made less progress or fewer purchases to keep lights and freezers on and pay than planned and how they plan to support staff such as Gonzales’ team. address the setback. But the cur- Gonzales said that some researchers rent environment makes it difficult have expressed concern that those to plan. Gonzales said that progress fixed costs, which, unlike experi- reports are full of statements such as, ments, were not interrupted, might “‘I don’t know when I can get back drain grants, which could make it up to (full) spending; I don’t know impossible to complete the full scope if I’m going to be able to complete of work once their labs are back to the project.’ There are just so many full capacity. If time runs out on a grant before

LAUREL OLDACH/ATODAY a lab can complete the project, the investigator can apply for more time. If the money runs out, the NIH plans to make supplementary funding avail- able — but current guidance suggests that researchers wait to apply for that boost until the pandemic’s full cost to their labs is clear. A plurality of 130 NIH-funded principal Landing new grants investigators polled start Meanwhile, the NIH continues to their R01 applications shepherd grants through the review three months or more in process, including this spring’s bum- advance, but many start per crop of new grants for research closer to the deadline. projects not related to COVID-19. Respondents were For these new applications, some con- polled via Twitter in cessions were made to the pandemic. September 2020. For example, researchers can submit

42 ASBMB TODAY OCTOBER 2020 FEATURE

additional preliminary data after HTTPS://UNSPLASH.COM/PHOTOS/NAQHDUS5MNO otherwise finalizing a grant. So far, only the round of grant applications submitted, like Stary’s, before the full effects of the pan- demic were felt in the U.S. have been reviewed. Stary has to convince peer reviewers, organized into a study section, that his proposed project is scientifically interesting and poised to succeed. “They were locked at home, read- ing a stack of grants,” Stary mused. “I wonder if they took that into consideration, in terms of saying ‘He should do this, this and this before resubmitting’?” According to Barski, study sections have not changed dramatically, even as they’ve gone from meeting on the Bethesda campus of the NIH to vid- eoconferencing via Zoom. Reviewers, he said, have received instructions “to assume that issues resulting from the pandemic will be resolved prior to the Labs across the country sat empty for months, and many still are working at less than full capacity. award — and to show understanding that everybody has been affected.” At the same time, reviewers are questions that would require more ex- Barski reminds researchers asked to be rigorous. Barski reminds perimentation. While he initially had researchers that they should submit hoped to submit a revised application that they should submit the the very best grant application they in November, he has had to accept can muster, which may mean delaying that the lab will be unable to get it all very best grant application submission by one or more cycles. done in time. “Reviewers are still tasked to deter- Meanwhile, Stary also spent time they can muster, which may mine if the premise and feasibility of this summer reviewing grants submit- mean delaying submission by the project are solid,” Barski said. “It’s ted during the spring cycle. “I know unfortunate, but if that crucial experi- how difficult it’s going to be to get the one or more cycles. ment, for example showing proof of data that I would like to see,” he said principle, has not been done — and a week before his deadline to submit therefore the feasibility or the premise his appraisals. He said he planned of the project is questionable — I to ask himself, “What’s the absolute think the PI should wait until they’re most critical thing they need to ad- able to submit the best proposal pos- dress here?” sible.” According to a study section mem- Reviewers generally have the pre- ber who preferred to remain anony- rogative to request more experiments mous, reviewers are in a confusing to bolster the preliminary data that position. They are not well equipped PIs present. Collecting those data can to determine how the pandemic pay off; in 2019, only about 17% of might have affected an individual grant proposals were funded after first lab’s ability to collect preliminary being submitted, whereas about 33% data. Many also are concerned about of resubmissions made the cut after whether the pandemic’s impact on a second round of review. The study different fields of research and regions section that reviewed Stary’s grant had can be mitigated fairly.

OCTOBER 2020 ASBMB TODAY 43 FEATURE

COURTESY OF CREED STARY Ensuring continuity Some universities have stepped in to help their professors make it through. For example, Yale and the University of Pennsylvania have in- troduced recovery grants up to tens of thousands of dollars to help research- ers whose funding was interrupted by the pandemic or doesn’t cover costs of closing down and starting back up again. Just how great those costs will be has yet to be seen. Kathryn Kirkland Stary’s lab includes two postdocs and two technicians. Snider, a grants administrator at the University of Colorado Boulder, said, “Can I pay my technicians?” “Given that we still don’t really have a good clear image of what the eco- In June, the National Institutes of Health passed on guidance from the federal nomic impact of COVID will be long Office of Management and Budget stating that, if grant-funded workers couldn’t term on the economy … I think it’s work on the funded projects, universities needed to use up other sources of funding going to be a while before we really before applying grant funds to continue paying salaries. know the full impact (on research).” “I’ve found that NIGMS-funded For some researchers, this was not a problem. “My people were busy,” said PIs are an extremely resilient and an Lynne Maquat of the University of Rochester. Even among the scientists who were extremely creative group,” said Barski. not involved in keeping animal colonies and other essential functions running, “I “Yes, I hear concerns, of course. But never had anyone furloughed in the sense that they weren’t working. We wrote com- what I see more, is not ‘what are we mentaries, we wrote reviews, we wrote fellowships, we worked on manuscripts.” supposed to do?’ but ‘what we are The guidance did not apply to researchers supported by training grants, even if going to do in order to do the best possible science in the situation.’” they could not work directly on the projects outlined in their grants. For profes- Although the future is uncertain, sional staff, such as technicians and lab managers, funded from a federal source, Stary, Maquat and other researchers guidelines applied across the federal government demanded that they be paid from said, in light of the economic hard- other sources, such as laboratory startup funds, until those other sources were ship the pandemic has caused, they exhausted. feel fortunate to be in a relatively According to Stanford professor Creed Stary, the announcement was a chal- stable situation for now. “There’s a lot of heartache out lenge, especially since it applied retroactively. Startup money in his department there,” Stary said. “We’re among the generally comes from hospital income. With elective and nonemergency surgeries lucky ones.” canceled for months, that revenue evaporated. “The hospital was losing millions of dollars a month,” Stary said. “That profit sharing that the department can normally rely on … was essentially gone. So, sud- denly everyone was very nervous about being able to support their staff.” As far as he knows, no one working in a lab at Stanford was laid off or fur- Laurel Oldach (loldach@asbmb. org) is a science writer for the loughed. But he’s concerned about year-end accounting and the effect on his lab’s ASBMB. Follow her on Twitter startup fund, a source that many PIs rely on as a sort of savings account against a @LaurelOld. gap in funding.

44 ASBMB TODAY OCTOBER 2020 ESSAY The art of paper folding and the science of protein folding By Sudha Neelam SUDHA NEELAM

The author’s son Nikhil gets started on an origami project. Precise measurements are key to successful paper folding.

n a world where we glorify busy- found numerous tutorials on how SUDHA NEELAM ness, slowing down can be a chal- to fold paper. These videos got my Ilenge. In recent months, an invis- teenager hooked. Our floors soon ible enemy has forced many of us to were covered in large sheets of paper slow down and shut down our usual as we learned about precreasing, fold- routines. As the parent of a teenager, ing, collapsing and all sorts of other I’ve had my own set of challenges. origami tidbits. Kids, especially teens, need to be This activity has kept my son engaged, motivated and entertained. Nikhil engaged. He spends hours When we were brainstorming ways trying to get accurate measurements to make the most of our time during on a square of paper; a fraction of an the spring lockdown, an origami inch off will make him start all over jumping frog on the internet caught again. He insists that the success of an our attention. We were drawn to the origami structure lies in the precision simplicity of origami; all we needed with which the paper is measured and Titled “Walking in the rain,” this origami structure was paper and some basic folding folded. Watching him meticulously folded by the author’s son Nikhil portrays a skills. We turned to what we thought measure, fold, collapse and shape woman carrying an umbrella. The author and was the only reliable source to help paper made me think of our own Nikhil like being able to fold people depicting us learn about it — YouTube — and biological origami and the science of feelings and emotions.

OCTOBER 2020 ASBMB TODAY 45 ESSAY SUDHA NEELAM protein folding. Proteins, the essential building blocks of life, can only func- tion if they are folded properly. This idea piqued my scientific curiosity and I wanted to explore the similari- ties between paper folding and protein folding.

A brief history of origami Origami, the ancient Japanese art of paper folding, has entertained generations with its beautiful simplic- These PowerPoint images depict how protein folding affects the function of the protein. The single chain ity. Origami used to be called orikata. of amino acids must be folded into 3D structures to create functional proteins. The word “origami” comes from two Japanese words; “oru” means “to fold,” and “kami” means “paper.” Paper was invented in China around 105 A.D., and Japanese origami originated when Buddhist monks carried paper from China to Japan sometime in the sixth century. Origami paper was difficult to make and therefore expensive. In Japan, handmade paper was a luxury used only on specific religious occasions. Before the invention of paper, people did recreational folding with Changes or mishaps in the folding of the single chain result in a misfolded or nonfunctional protein. materials such as cloth or leather. As with most art forms, new techniques have evolved. Origami is no longer functional protein. starts with a bird base. This structure folded exclusively with origami paper. Initially, proteins are synthesized has a square base and petal folds. If People use printer paper, wrapping as a long chain of amino acids. The we make a mistake in one of the folds paper, old newspapers, junk mail sequence of amino acids and their or switch a petal fold for a mountain and even scrapbook paper. Unlike properties determine how the proteins fold, we will end up with an unstable, traditional origami, modern variations are folded. Proteins are at the core inaccurate and perhaps disfigured involve cutting, shaping and even of all the biological and molecular crane. using glue to make the structure more machinery in our bodies. They must Robert Lang, an origami pioneer, sturdy and stable. be synthesized, assembled and folded creates incredible design patterns accurately to perform the critical func- from plain paper. I find it fascinat- Proteins: Our own biological tions that keep us alive. ing to look at his crease patterns and Misfolded, unfolded or inaccurate- envision how one particular diagonal origami ly folded proteins are nonfunctional, crease will be folded into the tentacles Proteins, the building blocks of life, and they form a sticky, gooey mess. of a bug, or how one mountain fold also are folded. However, in the case The sticky, misfolded, obsolete protein or valley fold will become the base of of proteins, they fold spontaneously becomes a hindrance to our bodies’ a 3D structure. based on a series of codes in the form normal functioning. Similarly, our DNA carries crease of amino acids, which are akin to the patterns in the form of a genetic code crease patterns and folds of origami. The yin and yang of folds that determines the type and sequence This biological origami depends on of amino acids. Like origami crease the correct genetic code, accurate as- Each type of fold in origami has its patterns and folds, our biological ori- sembly of amino acids and the precise own distinct pattern and purpose. For gami depends on folding the correct folding of the amino acids into a example, the popular origami crane sequence of amino acids into pristine

46 ASBMB TODAY OCTOBER 2020 ESSAY SUDHA NEELAM

CORRECT FOLDING PATTERNS INCORRECT FOLDING PATTERNS

Similar to protein folding, mishaps or mistakes in origami folding can result in mismatched structures. These PowerPoint images show correct and incorrect folding patterns for an origami crane and how each affects the final structure.

functional proteins. A group of dis- Folds of life and art origami is a mirror reflecting the orders known as proteopathies occur invisible folds of our life. when the proteins are misfolded due A protein starts off as a flat sheet to incorrect assembly of the amino before being folded into a 3D struc- acids, genetic changes or abnormal ture. The protein sheet is similar to folding patterns. In neurodegenera- origami paper. Both need to be mea- Sudha Neelam (neelam.sudha@ tive diseases such as Alzheimer’s and sured and folded accurately. Precision, gmail.com) is a research scien- tist in the field of cell biology. Parkinson’s disease, the proteins are perfection and patience are of utmost She is interested in studying the misfolded and become nonfunctional. importance in creating the simple yet mechanisms of protein synthesis, Knowing the structure and folding beautiful, pristine folds of life and art. how misfolded proteins cause patterns of proteins is vital to under- As scientists continue to explore diseases and how therapeutics can correct damage caused by standing their functions, and this in protein folding, and while Nikhil and misfolded proteins. She also turn will help in designing therapeu- I experiment with the art of paper loves to cook, which she believes tics for these diseases. folding, I can’t help but wonder if is a form of science.

ASBMB CONFERENCE SERIES Call for proposals Learn more at asbmb.org/propose-event.

OCTOBER 2020 ASBMB TODAY 47 ESSAY The ups and downs of teaching in a pandemic

By Victoria Del Gaizo Moore

am an associate professor in the COURTESY OF VICTORIA MOORE chemistry department at Elon IUniversity. I teach undergraduate students and have an undergraduate research lab. We currently are operat- ing on campus. The university has put protocols in place for faculty, staff and students: wearing masks on campus when indoors or outside if we are unable to maintain 6 feet or more distance, wiping down work stations when we finish, limiting student numbers in a classroom or lab based on the size of the room. Wipes and hand sanitizer stations are in every classroom, and most classrooms are upgraded with cameras to record or livestream class through Zoom or Webex. The university is administering COVID-19 tests at random each In Victoria Moore’s lab, student Seth McKee, pictured at the cell culture hood, is investigating chemore- week and posting results on a dedi- sistance in pancreatic cancer, and Maggie Canavan, pictured with Moore at the microscope, is studying cated website. On that website we chemosensitivity in acute myeloid leukemia. also can find total numbers of student and faculty cases, how many students are in quarantine (at least one entire for hybrid and remote teaching, and the other half of the class can view dorm is dedicated to quarantine) faculty were incentivized to participate later what occurred. I don’t use the and how many days’ supply of wipes, with a small stipend. whole class periods on Monday and hand sanitizer and other supplies are Due to limits on how many Wednesday, because the students have on campus. We get a weekly update students can be in a classroom, many video lectures to watch and other from the vice president of communi- faculty can have only half of their class projects to work on for our Friday cations with info about the situation. in person at a time. I have adapted my meetings, which usually are reserved The administration instructed the class to be hybrid, with half the stu- for group work and presentations. faculty to set up our courses so we dents attending on Monday, the other I am framing my entire medicinal could pivot quickly to fully remote, half attending on Wednesday; we are and pharmaceutical chemistry course if needed, and encouraged hybrid all remote and meet during class time around COVID-19. For example, or flipped classrooms. The Center on Zoom on Fridays. I prerecord lec- instead of looking at random clinical for the Advancement of Teaching tures using an electronic white board trials, we are using COVID-19 clini- and Learning and the teaching and and post 20- to 25-minute lectures cal trials to learn about trial phases. learning technologies department staff of material on Moodle and then use Also, one topics project is centered on provided several three-day online ses- in-class time to answer questions and COVID-19 topics, and I will intro- sions in late July and early August for dive deeper into the material. I record duce major principles of pharmacoki- faculty to learn about best practices and post each in-person session so netics and dynamics using drugs that

48 ASBMB TODAY OCTOBER 2020 ESSAY

are being used to treat COVID-19 grammatic review or five-year plan- patients. I also adopted a grading ning that ordinarily would be done. contract policy with less emphasis on All committee meetings are online. points and more emphasis on doing After taking the initial extra time a good job and learning the material. and effort to figure out how I would Students will take all exams synchro- teach hybrid courses, the fall semester nously online through Moodle. has been a little easier than normal We are teaching the general chem- for me, being a mom of two school- istry lab sections in pods — groups aged children. I can record lectures of nine students that cycle through whenever and from wherever I want. Learn in-person labs, virtual prerecorded With office hours on Zoom, I don’t lab videos with data analysis and off have to go to my actual office; I can weeks so we can get all the students in be at home with my kids after school something person for a few hands-on labs. hours. The same holds for committee I had to purchase my own voice meetings — I can be at home and be new. projector/microphone, as the univer- working. sity did not supply one. It is abso- My prerecorded lectures allow me lutely necessary when trying to teach to focus on student understanding Watch on-demand with a mask on. All office hours are when we are in person rather than through Zoom. just delivering the concepts, which is webinars and events I have one lecture student who actually really nice from a pedagogical including scientific is completely remote; students with standpoint. I also don’t feel the pres- presentations and health concerns could apply for this sure to give a performance, because I discussions on topics option but had to be vetted through a am sharing small snippets of material. committee. I assigned this student an I can have all of my notes and the related to career in-person buddy. I also have one vir- textbook laid out in front of me, and development, tual lab student who uses prerecorded I always can pause the recording if education, funding video lectures for all the labs — the needed. and more. chemistry department paid a few stu- We never would have explored dent workers to run through all of the these new ways of conducting the fall semester general chemistry labs semester had there not been the asbmb.org/ and record them for virtual students pandemic. We have learned we don’t or in case the entire university has to need to be together physically to be meetings-events/ transition to all remote. productive, which offers flexibility to on-demand working parents. Once we are back The upside to normal (not wearing masks and without a strictly limited number of My research lab is forging ahead as students in the classroom), I hope that usual but with masks on and limiting we can retain some of the practices the number of people in the research we’ve put in place. I certainly will space at any given time. We are consider continuing the flipped lec- interested in understanding chemo- turing and grading contracts for my resistance and chemosensitivity in courses in the future. different types of cancer, specifically Read more COVID-19 on campus looking at apoptosis and mitochon- essays at asbmb.org/asbmb-today. drial metabolism. I’m grateful that this aspect of the fall semester is Victoria Del Gaizo Moore undisrupted. ([email protected]) is an Committee work has been reduced associate professor in the to essential work only. Curriculum chemistry department at Elon committees are reviewing propos- University. als for new courses to be taught this academic year but not taking on pro-

OCTOBER 2020 ASBMB TODAY 49 ESSAY National certification exam as faculty development exercise Applying large-scale assessment ideas to small classes ASBMB

By Brian Chiswell I have learned a few things from colleagues who are members of or work at the ASBMB. These les- f you are considering volunteering sons ensure fairness to the student, to serve on a team involved in the promote consistency in grading, and IAmerican Society for Biochemistry bring deserved attention to question and Molecular Biology certification and rubric details. exam, I strongly recommend it based on my own experience. LESSON 1: The person or committee Five years ago, I helped to score that writes an exam question ideally a single question for the ASBMB should not be the one to write the certification exam, which is offered to rubric or score the answers. When we college juniors and seniors enrolled in write a question, we are already biased ASBMB-accredited programs and is toward an answer. designed to test their understanding LESSON 2: The exam should be anony- of the core competencies in biochem- The ASBMB in each of the last two years scored mous when graded, especially if you istry and molecular biology. Little did almost 1,000 exams. Here, ASBMB staff members know the student. I know the effect this activity would Quira Zeidan, Kirsten Block and Stephanie Paxson have on my thinking and the impact LESSON 3: Exams should be scored by prepare the exams for mailing. it would have on my own test ques- more than one scorer and interrater ample, choose your toughest question tion writing. Since that time, I have reliability should be calculated and to grade and ask a few colleagues to worked each year on small commit- addressed. score an answer to check if interrater tees of bright, motivated faculty to LESSON 4: Questions should be reliability is an issue. Instead of ask- write new questions for the ASBMB reevaluated and improved after each ing a peer to take one of your exams, exam and to create and refine rubrics time the test is administered. ask them to take a five-question quiz for existing questions. containing the five new questions you Working with the ASBMB has al- LESSON 5: Each question should be are vetting for this year’s final. Also, lowed me to take a hard look at three graded from all exams at the same another professor teaching the same important components of written time. subject could help you with a rubric assessment: writing questions, writing LESSON 6: Questions should target to make sure it is objective, not overly rubrics and scoring answers. My class- different levels of Bloom’s taxonomy biased toward what you remember room instruction is guided mainly by to create an exam that also can be a saying in lecture. how I want students to think their useful teaching diagnostic tool. We Written assessments are difficult to way through an answer. Without each should aspire to teach students to develop, and we should develop them component of the written assessment analyze, evaluate and create, so catego- together. aligning and synergizing with the oth- rizing questions in this manner will ers, there is a risk that the questions diagnose how well we are teaching are not fair, not actually assessing Brian Chiswell (brian. these skills. [email protected]) is an what I had hoped or not requiring associate professor at Touro the students to think. Working on The ASBMB in each of the last two College in Manhattan. In his these exam committees has changed years scored almost 1,000 exams, so undergraduate research lab, it is a large-scale process. The ideas students study the molecular my mindset, so I am more aware of detail of cell signaling in stom- these issues when working on my own above can be applied on a smaller ach cancer oncogenesis. Follow exams. scale in your department. For ex- him on Twitter @BPChiswell jbc.org/site/vi/women_in_jbc/ 50 ASBMB TODAY OCTOBER 2020 PERSPECTIVES

“It all comes down to where we place our bets” 5 QUESTIONS WITH MARK HARPEL By Laurel Oldach

rug discovery involves coming Tell me about a day up with a safe and effective in your life. Dmolecule — but first, you have to figure out what part of the cell you Primarily, I’m a matrix program can mess with to get your desired 3leader for one particular program. I result in disease. Mark Harpel of set the strategy and get it approved, GlaxoSmithKline is a scientific leader make sure we have the appropriate in a unit that does exactly that. resources and handle the day to day. I also evaluate new targets — so a lot You work on novel human of my day is spent reading journal articles and talking to people — and genetics. What does that provide expertise on business develop- mean? ment opportunities. 1One of the most important parts of drug discovery, at least in terms of What traits do you investment, is getting the target right. look for in a potential We draw on genetics to pick targets employee? Mark Harpel that have a disease basis in actual hu- man data. 4It has to go beyond the resume. CURRENT POSITION Our research unit evaluates targets What’s most important to me is a gen- Scientific leader, novel human that come out of genetic analyses and uine sense of interest and excitement; genetics, GlaxoSmithKline advances them through validation the other skill I look for is adaptabil- into a discovery program and, if we’re ity. There’s no guarantee that what CAREER PATH successful, to the point of early clini- we’re doing today will be of interest Ph.D., University of Minnesota, cal studies. three months from now. If we find a 1990 It all comes down to where we reason why we should not be working Postdoctoral research: protein engi- place our bets. We use genetics to on something, we’ll walk away from neering, Oak Ridge National Lab help us select targets, but then build it. There has to be an understanding FIRST JOB OUTSIDE OF ACADEMIA the package to understand them and up front that that could happen. Chemical enzymologist, DuPont identify the early kill experiments Pharmaceuticals that could stop us from investing in When has networking something that ultimately will not FAVORITE MOLECULE OR PROTEIN work out. really worked for you? “Non-heme iron containing oxygen- I had an opportunity to join either ases, the first enzyme I purified … or What’s a kill 5DuPont Pharmaceuticals or DuPont RuBisCo: it’s a dog of an enzyme.” experiment? Basic Research — my contact was someone at Basic Research that I Read an extended version of this inter- Any experiment that would let us knew well from various meetings. He view at asbmb.org/asbmbtoday. 2say whether the hypothesis is good or brought me in to interview for his en- bad moving forward. That could be zymology group, but he made sure my working with human cells to reduce resume made its way up to DuPont Laurel Oldach (loldach@asbmb. expression of a protein. It could also Pharma, and I had a dual interview. org) is a science writer for the be down the road: If we run a high- I ended up not working with him di- ASBMB. Follow her on Twitter @LaurelOld. throughput screen and we don’t get rectly — but what he did really speaks anything out, we’ve either run the to people wanting to do good things wrong screen or the target’s no good. for other people.

OCTOBER 2020 ASBMB TODAY 51 ASBMB Today call for submissions Online teaching: ASBMB Today is accepting submissions Practices and for two upcoming special issues. resources

asbmb.org/education/ The wellness issue online-teaching January 2021 Deadline: November 2, 2020 Access a collection of best practices on: With our lives upended by a worldwide pandemic, how have you kept yourself well? If you are a • Organizing course professor, investigator or supervisor, how have you materials looked after your students’ and workers’ wellness? • Collaboration and Write about the physical and mental challenges you peer review faced and overcame in 2020. • Online assessments • Online lab work The reimagining issue These resources were collected by a group of June/July 2021 dedicated educators and Deadline: March 15, 2021 ASBMB members. When the world reopens after COVID-19, it will be a different place. It’s a good time to reimagine To submit resources to the ways the scientific enterprise could be more collection, visit sensible and just. We want your ideas for how to asbmb.org/education/onlin e-teaching and fill out the do that. Think about the systems around you. Can form. they be improved? Should they be replaced? Tell us what you would do to make them better.

For information, email [email protected] or go to asbmb.org/asbmbtoday and click SUBMIT.

52 ASBMB TODAY OCTOBER 2020 classifieds

Senior Scientist, Cell Therapy Postdoctoral Associate Simcere Innovation, Inc. Weill Cornell Medicine

Simcere Innovation is one of the internal inno- The Postdoctoral Associate position (avail- vation arms of Simcere Pharmaceutical group able immediately) is for a full-time researcher with focuses on the discovery and development to work on molecular identification of lipid of novel cell therapies for oncology and im- transporters for protein glycosylation’ using munology indications. We believe that the pharmaceutical and venture biochemistry, chemical biology and cell biology approaches. The project capital global community needs a new way to explore and facilitate is a collaboration between the Menon laboratory at Weill Cornell Medical R&D in the ever-changing field of medicinal science. We provide an en- College in New York City, and the Bütikofer and Häner laboratories at vironment where all the talents can pursue and foster their aspirations the University of Bern, funded by the Swiss National Science Foundation. outside the traditional organization box. Our disruptive operation model The main approach will be to use available photoclickable analogs of can help scientists tackle challenging scientific problems, while minimiz- dolichyl phosphate to capture and identify lipid transporters (scram- ing risk. Together, we aim to develop a truly transformative model that blases) involved in the flip-flop of dolichol-linked oligosaccharides and would benefit our patients and revolutionize scientific society. monosaccharides across the endoplasmic reticulum (ER) membrane for protein N-glycosylation. Scramblase candidates captured by photoclick The Senior Scientist will participate in early drug discovery and devel- chemistry will be identified by quantitative proteomics, and their role opment projects with a focus on immuno-oncology. The candidate will will be validated by biochemical and genetic approaches. The Menon characterize and develop large and small molecules in close collabora- laboratory was the first to demonstrate the scramblase activity of a puri- tion with partner lines as an integral member of drug discovery teams. fied membrane protein and provides an excellent environment for this Ideal applicants will employ and develop new cutting-edge in vivo project. mouse and human cancer models. The individual will provide technical and scientific expertise in in vivo pharmacology to the Cancer Immunol- The ideal candidate will have first author publications and direct experi- ogy Discovery department to enable target identification, validation, ence in biochemistry, chemical biology and/or cell biology. The candidate prioritization and efficient drug discovery. Ideal applicants will be collab- should be self-motivated, able to work independently as well as part orative and team-oriented, possess excellent communication, leader- of a collaboration, possess reasonable quantitative skills and a strong ship and organizational skills, critical problem-solving abilities, and a attention to detail. Prior experience with protein purification, biochemical commitment to excellence. reconstitution, and/or yeast genetics would be beneficial. careers.asbmb.org/job/senior-scientist-cell-therapy/54764024/ careers.asbmb.org/job/postdoctoral-associate/54664256/

HowardAssociate/Sr. Hughes Associate, Medical Assay Institute AppliedAssistant BioMath, Professor LLC of Biology PostdoctoralDevelopment Associate -and Lefkowitz Quality Lab Control Analytics AugustanaSenior Scientist, University Mathematical Modeler Cepheid

CepheidWe are currently is a leading seeking molecular a forward-thinking, diagnostic Augustana University, a selective, private, companyinventive andthat resultsis an operating driven Postdoctoral company within Asso - liberal arts institution invites applications for Danaherciate within Corporation’s the lab of Dr. Diagnostics Robert Lefkowitz at platform. a tenure-track Assistant Professor position CepheidDuke University is dedicated in Durham, to improving NC. The healthcare Lefkow- in the Department of Biology beginning byitz developing,lab studies themanufacturing, molecular and and regulatory marketing accurate yet easy-to-use September 2021. A Ph.D. is expected; postdoctoral experience is molecularproperties systemsof G protein-coupled and tests. By automatingreceptors (GPCRs), highly sophisticatedalso known as and preferred. time-consumingseven transmembrane manual spanning procedures, receptors the company’s (7TMRs). solutions Current work deliver in Duties typically include teaching 2 lectures and 2 labs each semester athe better lab focuses way for on institutions understanding of any how size GPCR to perform cell signaling, sophisticated by biased mo- and a January term course. These will include a team-taught genetics lecularor unbiased diagnostic ligands, testing is mediated for organisms through and GPCRs genetic-based and their transducdiseases.- course and a molecular biology course in alternating semesters, as Throughers, the G its proteins strong andmolecular β-arrestins. biology The capabilities, lab utilizes the techniques company rangingis well as other courses based on the needs of the department and focusingfrom biophysics on those to applications pharmacology where to cell accurate, biology rapid, to in andvivo actionableanimal qualifications of the applicant. testdisease results models are needed– and more most, information such as managing on their infectiousresearch can diseases be found andon their website. cancer. While teaching is a major component of the position, produc- tive research involving undergraduates is expected and is a long- TheWe aresuccessful targeting applicant candidates will whowork have as a amember strong backgroundof the Protein in Reagenta variety standing tradition in the department. The college is situated in an Developmentof biochemical, and biophysical, Production and Department cell biological to develop techniques. and manufacture The lab area experiencing rapid growth in biomedical, biotech, agricultural, recombinantthrives on developing protein reagents novel solutions including to recombinant challenging problemsenzymes. He/She– so we and environmental research, offering collaboration opportunities in willneed mainly someone contribute who isn’t to proteinafraid to reagent both think assay outside development the box and and qual chal-- various research areas. A research startup will be provided as well as itylenge control the status analytics. quo. We feel science moves forward best when you aren’t afraid to question everything and embrace creative experimental access to extensive existing research equipment ($1,350,000 in new approachescareers.asbmb.org/job/associatesr-associate-assay-development- – and we want team members who are as enthusiastic purchases in the department over the last decade). and-quality-control-analytics/54763578/ about that approach as they are about our science. careers.asbmb.org/job/assistant-professor-of-biology/54764154/ careers.asbmb.org/job/postdoctoral-associate-lefkowitz-

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

Call for nominations: the first class of ASBMB fellows

DEADLINE: JAN. 4, 2021

Selection as a fellow of the American Society for Biochemistry and Molecular Biology is an honor to be bestowed upon our most distinguished members. Fellows will be recognized for their meritorious efforts to advance the molecular life sciences through sustained outstanding accomplishments in areas such as scientific research, education, mentorship, commitment to diversity and service to the society and scientific community.

The ASBMB Fellows Program encourages nominations that reflect the breadth and diversity of the society’s membership.

Nominees must be regular, industry or emeritus members of the ASBMB.

asbmb.org/about/asbmb-fellows