Personalized Protocols

Vol. 18 / No. 6 / June/July 2019

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

PERSONALIZED PROTOCOLS

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CMY K Download for free at jbc.org. CONTENTS

NEWS FEATURES PERSPECTIVES 2 26 44 EDITOR’S NOTE PERSONALIZED PROTOCOLS RESEARCH SPOTLIGHT Magazine life Mental health accommodations can e link between metabolism and aging help some succeed in the lab — 3 but rst they have to ask 46 NEWS FROM THE HILL ESSAY Advocating for more than money 34 Mental illness should not disqualify me 4 LISTENING TO KETAMINE 48 MEMBER UPDATE ESSAY 7 What I wish people understood about ... NEW MEMBERS 50 OUTREACH 10 University program inspires future scientists HONOR SOCIETY INDUCTEES 54 11 ANNUAL MEETING BIOCHEM, WITH A SIDE 26 Scenes from Orlando OF ADVOCACY 12 LIPID NEWS An ever-growing role for a tiny lipid 14 JOURNAL NEWS 14 Out tting T cell receptors for special combat 16 How do protein tangles get so long? 17 Cascading errors 44 50 18 Study shows long-term e ects of weight loss on the proteome 19 From the journals 24 A YEAR OF BIO(CHEMICAL) ELEMENTS Atomic Nos. 6 and 7 34 JUNE/JULY 2019 ASBMB TODAY 1 EDITOR’S NOTE

THE MEMBER MAGAZINE OF THE AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY Magazine life OFFICERS COUNCIL MEMBERS Gerald Hart Squire J. Booker By Comfort Dorn President Victoria J. DeRose Blake Hill Jennifer DuBois Audrey Lamb Secretary James M. Ntambi Toni M. Antalis Celia A. Shi er fter more than two years of cancer. ere were still recipes with Treasurer Takita Felder Sumter Kelly Ten-Hagen procrastinating, I got a library caviar, but there were also sloppy JoAnn Trejo EX-OFFICIO MEMBERS A card last month, and one of joes. e reality of food, in all its Robert S. Haltiwanger ASBMB TODAY EDITORIAL the rst books I checked out was complexity, turned out to be much Carla Koehler ADVISORY BOARD Ruth Reichl’s “Save Me the Plums.” more interesting than the airbrushed Co-chairs, 2020 Annual Rajini Rao Meeting Program Committee In case that name doesn’t ring a fantasy. Chair Cheryl Bailey Ana Maria Barral bell, Reichl has been the food editor And (to bring this back home), Chair, Education and Floyd “Ski” Chilton at the LA Times, restaurant critic I think that’s where magazines Professional Development Henrik Dohlman Committee Peter J. Kennelly for e New York Times and editor belong. Perched between the rst- Daniel Raben Beronda Montgomery of Gourmet magazine. Quite the draft-of-history breathlessness of Chair, Meetings Committee A. Maureen Rouhi dream career for anyone who likes newspapers and the weightiness of Sonia Flores Melissa Vaught Chair, Minority A airs Binks W. Wattenberg food. books, a good magazine can use its Committee Reichl also has written several theme (food, fashion, woodworking, ASBMB TODAY Susannna Greer autobiographical bestsellers, and biochemistry) as a prism for viewing Chair, Public Outreach Angela Hopp Committee Executive Editor this latest is about her stint at the complexities of the world that [email protected] Gourmet. Because I too am a theme inhabits. Matthew S. Gentry Comfort Dorn Chair, Public A airs Managing Editor magazine editor (admittedly on So as much as I love running Advisory Committee [email protected] a vastly di erent scale), I take a stories about amazing science, I have Sandra Weller Lisa Schnabel Chair, Publications Graphic Designer particular interest in her detailed a special fondness for stories about Committee [email protected] descriptions of the job, complete issues: sexual harassment, faculty Lila M. Gierasch John Arnst with quirky coworkers and diversity — or John Arnst’s article Editor-in-chief, JBC Science Writer [email protected] mystifying jargon. Coincidentally, on page 26 about accommodations A. L. Burlingame Editor, MCP Laurel Oldach years ago, I edited a short-lived for scientists with mental illness. Science Writter Nicholas O. Davidson [email protected] magazine that died because we Both kinds of stories really need to Editor-in-chief, JLR Ed Marklin didn’t sell enough ads — so I feel a run in tandem. If we don’t make Kerry-Anne Rye Web Editor Editor-in-chief, JLR [email protected] sad bond reading about Gourmet’s sure that students and early-career Allison Frick demise in 2009. researchers have what they need to Media Specialist [email protected] For most of its 69 years, succeed — be it time o for therapy Barbara Gordon Gourmet was a specialized appointments, noise-canceling Executive Director [email protected] publication, what some would headphones or a dog to raise call a niche product, tightly oxytocin levels — we will never see For information on advertising, contact Pharmaceutical Media Inc. at 212-904-0374 or [email protected]. focused on recipes and restaurants their potentially amazing science. (with a smattering of travel). And, cheesy as it sounds, the My grandmother sent me a gift more we understand the challenges subscription for a decade or so, in our world, the better our chance pre-Reichl, and I loved that escapist of making it better. quality. It was stodgy but soothing. www.asbmb.org/asbmbtoday Under Reichl’s leadership, Comfort Dorn PRINT ISSN 2372-0409 Gourmet came out of its luxe-life ([email protected]) is the managing editor of ASBMB bubble, running articles about the Today. Follow her on Twitter Articles published in ASBMB Today re ect solely the authors’ views and not the o cial positions of the American Society for Biochemistry and Molecular horrors of sh farms or how the @cdorn56. Biology or the institutions with which the authors are a liated. Mentions of products or services are not endorsements. food industry tried to sabotage a scientist who linked trans fats to

2 ASBMB TODAY JUNE/JULY 2019 NEWS FROM THE HILL Advocating for more than money By Benjamin Corb

hen I write about the actions of Congress, I often to support STEM scholarship programs, for example, we focus on appropriations and funding. And rightly know we can go to that member when we want to discuss W so. As glucose fuels the mitochondria in a cell, policies that will support the next generation of scientists. Congress’ support for federal science-funding agencies is year — for the rst time — our advocacy eorts fuels the engine that powers American leadership in have moved beyond Washington, D.C., to state capitals. research and innovation. So it’s no surprise that the 12 Studies show that state legislatures are more eective appropriations bills our legislators wrangle each year get at passing legislation than Congress, with some data the lion’s share of my ink. suggesting states are six times more But Congress can walk and successful at enacting laws than the chew gum at the same time. Hun- Like scientiﬁc federal government. dreds of bills are introduced every research, advocacy With that in mind, the year in both the House and the ASBMB public aairs team Senate, and only a small fraction is a long game. We recently worked with J.P. Sredzins- of those have a direct eect on need persistence ki, a Republican who represents funding the agencies we care about. and patience if we’re the communities of Monroe and In fact, people I talk to are often Sandy Hook in the Connecticut surprised when I tell them we spend going to see future House of Representatives and a at least half our time on Capitol successes. And like friend of mine, to draft legislation Hill talking about things other than working at the bench, supporting a state program to money for science. retain minority STEM students in Right now, the American our eorts include a lot public colleges and universities. We Society for Biochemistry and of trial and error. researched the issue, helped draft Molecular Biology public aairs the bill’s language and testi ed team is tracking more than 100 before a joint committee on higher pieces of legislation; these focus on topics such as sexual education in Hartford, Conn. e legislation received bi- harassment in science; rules partisan support and was passed out of committee before and regulations that dictate how federal advisory it stalled due to the estimated cost of implementation. committees (and review panels) operate; and a package We will review and modify the bill and then work of bills to improve science, technology, engineering and with Sredzinski to reintroduce it in the next legislative mathematics programs in higher education. You may session. While our proposal stalled (like 97% of bills in be familiar with that last bit from our spring advocacy Congress), we built new partnerships that will serve us campaign. well in the future. Many bills are introduced but don’t become law. Like scienti c research, advocacy is a long game. We In the 115th Congress (January 2017 through January need persistence and patience if we’re going to see future 2019), some 13,000 pieces of legislation were introduced, successes. And like working at the bench, our eorts and only 3% (443) were enacted. e failure rate for include a lot of trial and error. legislation is high, but we learn a lot even from bills that never come to a vote. Benjamin Corb ([email protected]) is director of public Introduced legislation helps us identify which mem- affairs at the ASBMB. Follow him on Twitter @bwcorb. bers of Congress truly support the American scienti c enterprise. By tracking who introduces what pieces of legislation, we know where to focus our resources and build relationships. If a member of Congress introduces a bill

JUNE/JULY 2019 ASBMB TODAY 3 MEMBER UPDATE Member update By Erik Chaulk

Ravid named Mass. academy president Strahl, Dohlman honored as mentors Boston University professor Katya Ravid Brian Strahl and Henrik Dohlman has been named a fellow and president of were among 10 faculty members at the the Massachusetts Academy of Sciences. University of North Carolina at Chapel e nonpro t academy seeks to Hill to receive Excellence in Basic Science promote scienti c literacy and awareness Mentoring Awards earlier this year. Ravid and provides a platform for research Strahl Established by the university’s oce of networking across the commonwealth of graduate education, the awards recognize Massachusetts. outstanding faculty members aliated Ravid is a professor of medicine and biochemistry at with the biological and biomedical scienc- the Boston University School of Medicine, a professor of es program who demonstrate excellence in biology and health sciences at Boston University and a mentoring graduate students. Fulbright research scholar. Strahl is a professor and vice chair of Dohlman Her research explores platelet production and func- the department of biochemistry and bio- tion as well as the roles of purine receptors in platelet and physics and an Oliver Smithies investigator. His research vascular biology in health and pathology. focuses on histone proteins. Ravid founded the Evans Center for Interdisciplinary Strahl also serves as faculty director of UNC’s Biomedical Research and is founding director of the Bos- high-throughput peptide synthesis and array facility. ton University interdisciplinary biomedical research oce. Dohlman is the Sanford Steelman distinguished She began her three-year term as president of the professor and chair of the department of pharmacology. academy in 2018. His research is centered on G proteins and G–protein– coupled receptors. Dohlman is an associate editor for the Gierasch wins Merriﬁeld Award Journal of Biological Chemistry. Lila Gierasch, editor-in-chief of the e two were recognized at a ceremony in January. Journal of Biological Chemistry, has received the 2019 Merri eld Award from LaRiviere named associate dean the American Peptide Society. Washington and Lee University associate Named in honor of Nobel laureate professor of chemistry and biochemistry Gierasch R. Bruce Merri eld and his wife, Libby, Fred LaRiviere was appointed associate the award recognizes outstanding lifetime dean of the college in February. achievement in peptide science. In this new role, LaRiviere focuses Gierasch is a distinguished professor of chemistry and LaRiviere on academic performance and support as biochemistry and molecular biology at the University of well as improving faculty development Massachusetts Amherst. Her research focuses on protein programs and strategic priorities. folding, structure and function, with an emphasis on how LaRiviere joined the faculty at Washington and Lee proteins fold in vivo. e American Chemical Society in 2006 after holding postdoctoral research and teaching previously recognized Geirasch for her contributions to positions at Brandeis University and Colby College. peptide science with the Ralph F. Hirschmann Award. His research explores RNA biochemistry, focusing She received the 2014 Mildred Cohn Award in Biological on understanding the fundamental aspects of ribosome Chemistry from the ASBMB. metabolism in eukaryotes. Gierasch received the Merri eld Award and gave a He has supervised more than 35 student–researchers lecture at the 26th American Peptide Symposium in June; during his tenure at Washington and Lee and has received the award includes a $25,000 honorarium. numerous grants and fellowships for his research.

4 ASBMB TODAY JUNE/JULY 2019 In memoriam: Jerard Hurwitz

American biochemist Jerard Hurwitz died in January at the age of 90. Highly regarded for his work on the biosynthesis of DNA and RNA, Hurwitz was one of the discoverers of RNA polymerase, an enzyme that transcribes DNA into messenger RNA. His work on RNA polymerase led to a general understanding of how the genome is replicated in dividing cells and paved the way for future breakthroughs in genetic engineering. After receiving his Ph.D. in biochemistry from Case Western Reserve University, Hurwitz joined the microbiology department at Washington University in St. Louis in 1956. There he began his work on RNA polymerase. Hurwitz joined the faculty at New York University in 1958 as a professor of microbiology. In 1965, he moved to the Albert Einstein College of Medicine, where he was a professor and chair of the department of developmental biology and cancer. In 1984, Hurwitz joined the Memorial Sloan Kettering Cancer Center as chair of the molecular biology program. He served as MSK’s vice chair from 1991 to 2003. Hurwitz was elected to the National Academy of Sciences in 1974 and received numerous awards for his research throughout his career, including the Eli Lilly Award in Biochemistry in 1962 and a Guggenheim Fellowship in 1968.

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JUNE/JULY 2019 ASBMB TODAY 5 James Bangs Isabelle Coppens John Gerlt Ekaterina Heldwein

Robert Kranz Sue Lin-Chao Dominique Missiakas Charles Rock

Eight members named microbiology fellows

Eight members of the American Society for Biochemistry and Molecular Biology are among the 109 newly elected fellows of the American Academy of Microbiology. An honori c leadership group within the American Society for Microbiology, the academy elects new fellows every year on the basis of scienti c achievement in the eld of microbiology. e newly elected fellows join more than 2,400 scientists who have demonstrated scienti c excellence, originality and leadership in microbiology research, teaching, public health, industry and government service. Congratulations to the following ASBMB members. n James Bangs, University at Bualo n Isabelle Coppens, Johns Hopkins Bloomberg School of Public Health n John Gerlt, University of Illinois at Urbana–Champaign n Ekaterina (Katya) Heldwein, Tufts University School of Medicine n Robert Kranz, Washington University in St. Louis n Sue Lin-Chao, Institute of Molecular Biology, Academia Sinica Erik Chaulk ([email protected]) is n Dominique Missiakas, University of Chicago a peer-review coordinator and digital publications web n Charles Rock, St. Jude Children’s Research Hospital specialist at the ASBMB.

6 ASBMB TODAY JUNE/JULY 2019 NEW MEMBERS

Fatih Abasiyanik, Anja Bielinsky, University Joanne Clement, Bruna Ferreira, University of Chicago of Minnesota University of Florida University of Tampa

Aitor Aguirre, Caymee Bigham, University Junru Cui, Johns Hopkins Jennifer Fishovitz, Michigan State University of Texas at Austin School of Medicine Saint Mary’s College

Saadman Ahmad, Jaylin Billie, University Ngozi Dagbaue, Spartan Bethann Flint, California State University, of Central Florida Health Sciences University West Virginia University Northridge Darlene Blount, City Neil Daily, Sona Fokum, University Alby Alex, of Hope National Medical InvivoSciences Inc. of Illinois at Chicago St. Bonaventure University Center Haider Dar, University Lacy Fowler, Hillsborough Anne Alexander, Milwaukee Milena Bone, Rensselaer of Pittsburgh Community College School of Engineering Polytechnic Institute Brandon D’Arcy, University Kasey Freshwater, West Ohoud AlMalki, Matt Borglin, California of South Alabama Virginia University Georgetown University Polytechnic State University at San Luis Srinivasan Dasarathy, Melody Fulton, Nasser Alotaiq, Obispo Cleveland Clinic University University of Glasgow of Georgia Sreyashree Bose, Texas Saptashwa Datta, Justus Alvarez, Stephen A&M University Sri Ramaswamy Memorial Vrushali Furia, Spartan F. Austin State University Institute of Science Health Sciences University Francesco Botre, Sapienza and Technology Trisha Anand, University University of Rome Sachika Gandhi, Spartan of Texas at Austin Michelle Davis, Health Sciences University Sergei Boudko, Vanderbilt Plymouth State University Leonard Anderson, University Medical Center Jian Gao, Morehouse School Samuel DeCero, Medical Second Af liated Hospital of Medicine Maria Boza, University of College of Wisconsin of Dalian Medical Central Florida University Polina Anipchenko, Saint- Victoria Deery, University Petersburg State Academy Aaron Bradford, Regis of Massachusetts Boston Ravisha Gautam, Spartan of Veterinary Medicine College Health Sciences University James Del Signore, Florida Giulia Antoniali, Deanna Broadwater, Institute of Technology Fabio Gomez Cano, University of Udine Michigan State University Michigan State University Mark Vincent dela Cerna, Ludmilla Aristilde, Ol’ha Brovarets, University of Louisville Richardria Goodson, Cornell University Institute of Molecular Huntingdon University Biology and Genetics of Robert Devor, Pablo Artigas, the National Academy of Oklahoma State University Samer Gozem, Texas Tech University Sciences of Ukraine Georgia State University Health Sciences Center Jenelle DeVry, Xavier Kelsey Bruce, University of Louisiana Nicholas Graves, Rahul Awasthi, Spartan Lin eld College University High School Health Sciences University Salonika Dikshit, Spartan Violeta Burns, Health Sciences University Ying Gu, Pennsylvania Joshua Baker, Nashville West Virginia University State University State Community College H. Diessel Duan, Kyle Cavagnini, University of Kentucky Ritik Gupta, Spartan Health Gertrude Bassey, Johns Hopkins Sciences University Maria-Berenice Duran, Bon Secours Mercy Health School of Medicine Keiser University Eric Gurzell, Western Robert Bauer, Madison Champine, Illinois University Jean Elick, Columbia University Winona State University University of Saint Francis Caio Ricardo Gutierrez Ariel Bazzini, Courtney Chandler, Silva, University of North Hannah Erskine, Stowers Institute for University of Maryland, University Carolina at Greensboro Medical Research Baltimore of New Hampshire Emery Haley, Van Andel Saja Fakhraldeen, Nirajan Bhattarai, Karthick Chennakesavan, Institute Graduate School Idaho State University Temple University Kuwait Institute for Scienti c Research Seth Hall, Amanda Biederman, Emily Cianﬂone, Ohio Northern University Brooke Farrugia, Ohio University Winona State University University of Melbourne Mallory Handlin, unaf liated

JUNE/JULY 2019 ASBMB TODAY 7 NEW MEMBERS

Jorg Hanrieder, Katelyn Kerod, Rosann Marattil, University Nicki Nouri, University University of Gothenburg Montclair State University of Illinois at Chicago of Illinois at Chicago

Nancy Hart, Peace Health Jessica Kissinger, Seth Margolis, Johns Sara Nowinski, University St. Joseph Hospital University of Georgia Hopkins University of Utah School of Medicine School of Medicine Andrew Hines, Christopher LaRock, Udochukwu Obodo, Huntingdon College Emory University Lenore Martin, City of Hope University of Rhode Island National Medical Center William Hines, Johan Larsbrink, Chalmers University of New Mexico University of Technology Sara Martire, University Mijung Oh, School of Medicine of Texas Southwestern Samsung Medical Center Thu Le, Katie Hollis, Paci c Lutheran University Michael Marvin, Lindsey Ohmstede, Stephen Van Andel Institute Rockhurst University F. Austin State University Konstantinos Lekkos, Peter Huang, University of Aberdeen James McCarthey, Samuel Okpechi, Van Andel Institute Vanderbilt University Louisiana State University Andreia Leopoldino, Medical Center Health Sciences Center, Tyler Hurd, University of São Paulo New Orleans Merrimack College Caitlin McDermott, Guanyu Liao, University University of Florida Marcos Oliveira, Abhay I, Spartan Health of Wisconsin–Madison São Paulo State University Sciences University Lauren Grace McGee, Yang-Tsung Lin, Huntingdon College Laura Ott, University of Surtaj Iram, South Dakota Michigan State University– Maryland, Baltimore County State University U.S. Department of Energy Antonio Mele, University Plant Research Laboratory of Central Florida Vijayakanth Pagadala, Rabia Islam, Glycan Therapeutics Deakin University Sara Lindén, Richard Melvin, University of Gothenburg University of Minnesota Kinjal Pancholi, Spartan Jane Jackman, School of Medicine Health Sciences University Ohio State University Amelia Linnemann, Indiana University Jagadeeshaprasad Cinta Papke, University of Divya Jain, Spartan Health Mashanipalya South Alabama Sciences University Michael Lisanti, Guddadarangaiah, Penn University of Salford State College of Medicine Sui Par, Georgia Institute Guochun Jiang, of Technology University of North Carolina Pengda Liu, Marissa Mielke, at Chapel Hill University of North Carolina College of St. Scholastica Dhruv R Patel, Spartan at Chapel Hill Health Sciences University Benjamin Johnson, Mary Miller, Van Andel Institute Amber Lobb, Rhodes College Shubham Patel, Spartan Winona State University Health Sciences University Tierra Johnson, University Eric Morrow, of Maryland, Baltimore Benjamin Loef, University Brown University Pruthvik Patel, Spartan School of Medicine of Wisconsin–Stevens Point Health Sciences University Rima Mouawad, Michigan Heather Junqueira, Lucia Lopes, State University Nisha Pawar, University BioScentK9 University of São Paulo of Maryland Baltimore Disha Mukadam, Spartan Hala Kaaki, Arimar Lopez, University Health Sciences University Sandhya Payankaulam, University of South Florida of Central Florida Michigan State University Pratik Mulay, Spartan Malika Kadirova, Tamara Maes, Health Sciences University Stephanie Phillips, University of Utah Oryzon Genomics S.A. El Paso Community College Goutham Narla, Sahithi Kaligota, Spartan Sahil Mahajan, Washington University of Michigan Michael Piacentino, Health Sciences University University in Saint Louis California Institute Premkumar Natraj, of Technology Rishabh Kandwal, Spartan Misa Mai, Jeju National University Health Sciences University Clark University John Pietrzyk, Madeline Niblock, Biolog Inc. Rezaul Karim, Andrew Maliszewski, Michigan State University University of South Florida Georgia Gwinnett College Adrian Pintado, Cole Niebuhr, University of Malaga Richard Kennedy, Lord Dana Malo, University Global Science Directive Fairfax Community College of Illinois at Chicago

8 ASBMB TODAY JUNE/JULY 2019 Kirill Plemyashov, Saint- Joshua Renfroe, Manvendra Singh, Yung-Chun Wang, Petersburg State Academy Lectenz Bio Duke–National University of University of Georgia of Veterinary Medicine Singapore Medical School Christian Reynolds, Zhiyi Wei, Briana Plourde, Waubonsee Wayne State University Olivia Sirpilla, Southern University of Community College School of Medicine Walsh University Science and Technology

Natalia Podlutskaya, Shiva Rijal, Courtney Smith, Abby Wicks, University of Alaska Touro College Brigham Young University Wayne State University Fairbanks Jonathan Roberson, Scott Soleimanpour, Torsten Wittmann, Danielle Porier, Virginia University of Central Florida University of Michigan University of California, Polytechnic Institute San Francisco and State University Carol Robinson, Shanel Sosa, University of Oxford Wesleyan University Wei Xia, Jaideep Prasad, Sun Yat–sen University Michigan State University Shavon Rochester, Wei Sun, Chinese Academy Delaware State University of Medical Sciences Jianfeng Xu, Lynne Prost, University Arkansas State University of Wisconsin–Madison Angela Rogers, Mohammed Houssaini Arizona State University Tahri Squalli, Tulsi Yadav, Spartan Health Jonai Pujol–Giménez, Worcester State University Sciences University University of Bern Norbert Rolland, Centre national de la Avrohom Teitelbaum, Jinyi Yang, Massachusetts Yanrong Qian, recherche scienti que Touro College Institute of Technology Ohio University Rosalind Rosemond, Danelda Theron, Alan Yocca, Li Qiang, Wellstar Health System St. Bonaventure University Michigan State University Columbia University Jerey Sagan, University Christopher Tinkey, Tai-Soon Yong, Weihua Qiu, Virginia of California, Davis Georgia Gwinnett College Yonsei University Commonwealth University College of Medicine Jascinta Santavanond, Sankalp Tripathi, Spartan Ayesha Qureshi, Spartan La Trobe Institute Health Sciences University Sara Young–Baird, Health Sciences University for Molecular Science National Institutes Michael Trites, of Health Muzammil Qureshi, Spartan Matthew Saunders, University of Alberta Health Sciences University Lectenz Bio Xianghui Yu, Sarah Tulin, Jilin University Charles Radlo, Macleod Sawyer, Canisius College U.S. government DNX Research Foundation Lisa Yun, Ayushi Umrigar, Spartan Michigan State University Md Rahman, Gonul Schara, California Health Sciences University Qatar University State University Stanislaus Ningning Zhao, Audrey Uridil, University of Arizona Ana-Maria Raicu, Caitlyn Scherr, Iowa State University Michigan State University Lipscomb University Bin Zhao, Jazmin Urrutia, University Stanford University Sudhanshu Raikwar, Emily Schleicher, of Texas at Austin University of Missouri and Penn State Hershey Chenghao Zhu, University Harry S. Truman Memorial College of Medicine Rachana Vaidya, of California, Davis Veteran’s Hospital University of Massachusetts Sarah Shaban, University Dartmouth Tongtong Zhu, Matthew Rardin, of Illinois at Chicago Icahn School of Medicine Amgen Dylan Valencia, University at Mount Sinai Rameen Shah, of California, Los Angeles Mortezaali Razzaghi, New Jersey City University Christina Zito, University of Iowa Ana Vergara, Washington University of New Haven Simi Sharma, University State University Aviv Regev, of Illinois at Chicago Mark Zweigart, Broad Institute of the Katherine Vest, University of North Carolina Massachusetts Institute of Ben Shurina, University of Cincinnati Technology and Harvard Miami University College of Medicine

Hongxia Ren, Amy Silva, University of Alexandra Votintseva, Indiana University School Wisconsin–Stevens Point Saint-Petersburg State of Medicine Academy of Veterinary Medicine

JUNE/JULY 2019 ASBMB TODAY 9 NEWS 2019 honor society inductees ASBMB ASBMB Student Chapter regional directors Erin Sayer of the University of Nebraska–Lincoln (left) and Debra Martin of Saint Mary’s University of Minnesota (right) ﬂank new Chi Omega Lambda members at the ASBMB annual meeting in Orlando. The pictured students are (from left) Erin Bertone, Rebekah Dalton, Mary Doan, Jerey Gabell, Clark Hamor, Enessa Kalontar, Jovan Mirkovic, Sarah Neshat, Mallory Soska and Giang Vo.

he American Society for Biochemistry and Molecular Biology Honor Society (Chi Omega Lambda) recognizes ex- ceptional undergraduate juniors and seniors pursuing degrees in the molecular life sciences at colleges or universities T with ASBMB Student Chapters. Students are recognized for their scholarly achievement, research accomplishments and outreach activities. An induction ceremony was held in April at the ASBMB annual meeting in Orlando.

Erin Bertone, University Enessa Kalontar, St. John’s Karen Nga Tana, Goucher of Nebraska–Lincoln University College Caleb Carr, University Nicholas Kite, University Meghan O’Neil, Rochester Institute of Massachusetts Amherst of Nebraska–Lincoln of Technology Brett Daiger, Hendrix College Benjamin Laliberte, University Sarah Neshat, Northeastern Rebekah Dalton, Otterbein of Massachusetts Amherst University University Jamie Loughlin, Stockton Rebecca Prest, Missouri Western Mary Doan, Drexel University University Ashlyn Rairdin, University Julia Furnari, Marymount Sean MacBride, University of Nebraska–Lincoln Manhattan College of Nebraska–Lincoln Mike Slaza, Stockton Je rey Gabell, University Edelina Marzouk, Wesleyan University of Nebraska–Lincoln University Madison Smith, Purdue Colton Hageman, University Kelly McAleer, e College University of Nebraska–Lincoln of New Jersey Mallory Soska, Otterbein Clark Hamor, University Jovan Mirkovic, St. John’s University of St. omas University Brandon Tran, Manhattan Drew Harrahill, University Mackenzie Mitchell, Wesleyan Marymount College of Nebraska–Lincoln University Caitlyn Turner, Trinity College Spencer Jones, University Kevin Mora, Manhattan Giang Vo, St. John’s University of Nebraska–Lincoln Marymount College Quin Waterbury, Purdue University

10 ASBMB TODAY JUNE/JULY 2019 NEWS FROM THE HILL

Biochem, with a side of advocacy By Elizabeth Stivison

elly McAleer, a rising senior at On the community outreach side the College of New Jersey, has of things, many chapter members K turned her longstanding pas- volunteer at a nearby high school, sion for science and science advocacy acting as tutors and mentors in into action. Last fall, she founded science classes. McAleer knows how an American Society for Biochemis- important mentors and teachers can try and Molecular Biology Student be to future scientists who otherwise Chapter at TCNJ that supports both wouldn’t know a science career is current and potential students as well possible. She describes having no as research in general. connection to any scientists when In the summer of 2018, McAleer she was growing up, no family or participated in the rst session of the friends who were scientists. ASBMB’s Advocacy Training Pro- “My rst real exposure to science gram. Two months into the training, came from the classroom,” she said. she realized that an ASBMB chapter “I had a lot of really great teach-

at TCNJ could provide opportunities McALEER OF KELLY COURTESY ers, and in high school I began to and resources for students to take Kelly McAleer founded become serious about pursuing an action on political issues that aect education in science.” research. In addition, she thought a the ASBMB Student All this planning, coordinating chapter would ll a speci c niche at Chapter at the College of and organizing, in addition to her TCNJ, since the college has biology studies and playing violin in the and chemistry departments but no New Jersey with an eye to college orchestra, doesn’t seem to tire distinct biochemistry department. both advocacy and McAleer out in the least. She nds So, without missing a beat, McAleer it energizing to lead others and see organized a meeting in October to community outreach. her vision become a reality. Her time gauge interest, and the chapter was in college and her work with the ocially founded in December with ASBMB have expanded her idea of McAleer as president. what is possible in her life, she said, McAleer launched the chapter “If people want to advocate at and she has become interested in a with an eye to both advocacy and the federal level, they need to un- wider range of biomedical careers. community outreach. “I think if we derstand those bare basics,” McAleer Becoming a physican–scientist, for don’t advocate for science, there will said. example, is intriguing her now. be no science,” she said. “We need Chapter members also hosted a “It’s always been medicine,” she our government and our represen- Donuts and Policy event where they said of her goals. “It still is — but it’s tatives to realize the importance of talked about the current Congress. not just that now.” federal funding for science.” ey have been brainstorming a

To this end, the new ASBMB trip to Washington, D.C., for a day Elizabeth Stivison chapter held a Government 101 on Capitol Hill (modeled on the (elizabeth.stivison@gmail. com) is a Ph.D. student information session where students ASBMB’s annual Hill Day) when the at Columbia University learned the basics of how govern- students would speak directly with studying mechanisms of ment works, from how budgets are their representatives about govern- DNA repair. made to how a bill becomes a law. ment support of science.

JUNE/JULY 2019 ASBMB TODAY 11 LIPID NEWS

An ever-growing role for a tiny lipid By Nicolas Vitale

ritical signaling functions have Although PA is present at low impaired PA synthesis in neurons been attributed to phosphatidic levels in most cell types, it appears from mice bred not to express C acid, or PA, the smallest build- to be critical for neuronal and glial FMR1, a protein that male fragile X ing block in phospholipid biosyn- cell function. Several neurological patients lack. Silencing DGK-kappa thesis. With a small head group and diseases maybe attributed, at least in in pyramidal neurons from the CA1 a net negative charge ranging from part, to altered PA synthesis and/or region of the hippocampus largely -1 to -2 depending on pH, PA can catabolism. For example, Ricardos reproduced fragile X symptoms. is modulate local membrane geometry Tabet and colleagues proposed in PA/DAG imbalance is thus likely to and recruit a large set of speci c 2016 that an alteration of the PA/ aect DAG and PA downstream sig- proteins to con ned membrane sub- diacylglycerol balance could be a naling required for both maturation domains; a recent review by Emeline main cause of fragile X syndrome, a of dendritic spines and establishment Tanguy and colleagues summarizes genetic cause of intellectual disabil- of correct synaptic plasticity. both of these essential actions for ity. ey showed that diacylglycerol Maria Zeniou–Meyer and PA’s signaling function. PA is versa- kinase-kappa, or DGK-kappa, colleagues in 2008 proposed that tile and challenging because it can be mRNA was the main target of fragile the loss of expression of the kinase produced and metabolized by a large X mental retardation protein and RSK2, which leads to Con–Lowry set of enzymes. that reduced DGK-kappa expression syndrome (a rare syndromic form NICOLAS VITALE

Phosphatidic acid is deﬁned by its shape and charge. This conical lipid generates negative membrane curvature and is negatively charged, thereby recruiting positively charged proteins.

12 ASBMB TODAY JUNE/JULY 2019 of mental retardation), reduced PA functions. e former occurs mainly in localizing and potentially quan- synthesis and distorted neurosecre- through PA’s ability to modulate the tifying changes in PA and perhaps tion. Increased PA synthesis has been activity of small GTPases, including dierent PA species. reported in gliobastoma, the most Rho and Arf members. e latter Despite PA’s low abundance, its frequent and aggressive brain cancer. probably results both from the orig- relative simplicity, and the complex- A link between brain PA levels and inal cone shape structure of PA fa- ity of its metabolic and signaling Alzheimer’s disease also is starting voring negative membrane curvature pathways, improved understanding to emerge, but the exact eects of and from PA’s net negative charge of its multiple functions in brain PA imbalance in neurodegeneration allowing local recruitment of speci c development and function is now and cognitive de cits has not been proteins. One remaining challenge within reach. identi ed. Finally, reduced PA syn- is to de ne precisely sites of PA thesis may contribute to fetal alcohol synthesis within the brain and at the spectrum disorders, as ethanol leads subcellular level in neurons. Recent Nicolas Vitale ([email protected]. to phospholipase D-mediated phos- improvements in lipidomics allow fr) is a group leader at the phatidylethanol production at the for sensitive quanti cation of dozens Institut des Neurosciences expense of PA. of PA species made with dierent Cellulaires et Intégratives at the Centre National de la Many cellular pleiotropic fatty acids. According to a study by Recherche Scienti que & functions of PA rely on its ability to Nawal Kassas and colleagues, the Université de Strasbourg and a member of the Journal of regulate actin cytoskeleton dynamics development of novel genetically en- Biological Chemistry’s editorial board. Follow and to modulate membrane-involved coded PA sensors also will be crucial him on Twitter @Nicolas_INCI.

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JUNE/JULY 2019 ASBMB TODAY 13 JOURNAL NEWS Outﬁ tting T cell receptors for special combat

By Jonathan Gri n

esearchers have engineered struct T cells to destroy the infection. binds to a (CMV-associated) peptide antibodylike T cell receptors For immunocompromised patients, that would normally be recognized R that stick to cells infected with however, this defense mechanism is by a TCR,” said Jennifer Maynard, a cytomegalovirus, or CMV, which can diminished, leaving them vulnerable professor of chemical engineering at be deadly for patients with weakened to the virus. the University of Texas at Austin and immune systems. ese receptors Researchers have used T cells to senior author of the study. “Anti- potentially could be used to monitor treat disease before, but engineering bodies cannot normally access these or destroy the virus and might also be and transplanting whole T cells is molecules, so that’s a big deal.” able to target brain tumors. costly and invasive. In a study pub- Researchers frequently use CMV causes lifelong infection in lished in the Journal of Biological bacterial or yeast cells as miniature more than half of all adults by age 40, Chemistry, a team of researchers took biomolecule factories, but their but the virus lies dormant in most. T an alternative approach, producing nonmammalian molecular machinery cells normally circulate through the CMV-detecting TCRs that oat freely often introduces defects in human body and use their membrane-bound in the body and bind tightly to their TCRs, Maynard said. To provide T cell receptors, or TCRs, to detect diseased targets. a more suitable environment, the disease-associated proteins hiding in- “Right now, we’ve got a molecule authors used hamster ovary cells to side infected cells. TCRs then can in- that looks like an antibody but it produce the receptors.

This new hybrid protein combines the cell targeting properties of a TCR with the tight binding and free-ﬂ oating nature

JENNIFER MAYNARD, ELLEN WAGNER/UNIVERSITY OF TEXAS ELLEN WAGNER/UNIVERSITY JENNIFER MAYNARD, of an antibody to create a new molecule able to tag CMV-infected cells speciﬁ cally.

14 ASBMB TODAY 14 ASBMB TODAY JUNE-JULYJUNE/JULY 2019 Our protein could be used to speciﬁ cally target glioblastoma cells, and it would “provide a very unique marker. —Jennifer Maynard ” TCRs naturally bond loosely inside the TCR and prevented sugars with their targets, but the authors from attaching. wanted theirs to bind and not let go. ese new TCRs could track To strengthen these connections, the disease progression in patients or eval- authors randomly mutated the DNA uate new vaccines. ey also might of the TCR component that detects restore immune response in patients the CMV peptide. ey inserted by instructing their cells to attack many versions of the mutated DNA CMV infections, Maynard said. into the hamster cells, which then is new molecule could be manufactured about a million types of e ective in treating glioblastoma as TCR, Maynard said. well. Although these brain tumors do e researchers measured bonding not produce many distinct markers, strength by exposing those myriad they do suppress the immune system, TCR variations to the CMV peptide. which in CMV-infected patients can “We found one that was our fa- bring the virus back to life in tumors, vorite,” Maynard said. “We improved Maynard said. the binding a nity 50-fold.” “Our protein could be used to

To liberate the TCRs from the T speci cally target glioblastoma cells, Jonathan Grif n cell membrane, the researchers further and it would provide a very unique (jgrif [email protected]) is a edited the DNA so the TCRs would marker,” Maynard said. “We would science communicator for all ASBMB journals. attach to the protein stem of Y-shaped use this to monitor or kill some of Follow him on Twitter antibodies. And to help these proteins those tumor cells.” @spelledjon. hold their shape, they added a bond DOI: 10.1074/jbc.RA118.007187

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JUNE/JULY 2019 ASBMB TODAY 15 JOURNAL NEWS How do protein tangles get so long? By Laurel Oldach

ong before Alzheimer’s disease Ohio State University, worked with this can’t be explained by labeled patients notice any symptoms, Ralf Bundschuh to expand this molecules’ preference for like labels. L neuro brillary tangles com- mathematical model to include After Huseby incorporated this posed of tau protein laments begin other known ways that tau brils new mechanism into the model, to form in their brain cells. How behave. Scientists have observed, for it produced a better description toxic these aggregates are and how example, that sometimes one bril of what puri ed tau proteins were well they spread depend on their fragments into two. Or a new bril doing as they formed aggregates. size — that is, the number of tau can nucleate in the middle of an is study is the rst to show that monomers they contain. However, existing bril. the brils can elongate by more than scientists studying tangle formation e simple model predicted a single tau protein at a time. have not been able to explain why many short brils. But Huseby knew Alzheimer’s disease researchers dierent sizes of tau aggregates ap- that, under a microscope, aggregated still are trying to discern whether pear in disease. tau appears as a smaller number of tau brils are a cause or simply an But now researchers have discov- long brils. at discrepancy suggest- eect of the disease. Transmission of ered that instead of adding just one ed that something was happening brils from one cell to another may protein at a time, brils of various in the real world that hadn’t been contribute to the spread of disease in lengths can join end-to-end to create accounted for in the model. ey the brain. A very long bril, accord- one larger lament. e nding, hypothesized that short brils could ing to Kuret, is unlikely to spread in published in the Journal of Biolog- attach end-to-end to get longer. this way. “But once it’s broken up ical Chemistry, helps explain how To test the hypothesis, Huseby into little pieces, those can diuse,” brils can grow to hundreds of nano- labeled tau proteins with three uo- he said, “facilitating their movement meters. It also could help research- rescent colors and allowed them to from cell to cell.” ers understand mechanisms of an aggregate in separate test tubes. en is study used just one type emerging group of drug candidates she mixed the dierent colored brils of tau. Six isoforms are known, and designed to inhibit tau aggregation. in a fourth test tube. phosphorylation and other changes A common simple model of tau Images taken with a super-res- increase the protein’s complexity. aggregation and bril formation olution uorescence microscope e researchers plan to incorporate includes two steps. First, two tau showed long brils with short sec- these variables in future work and proteins bind slowly; additional tau tions of each color, indicating that - to use the model to understand how molecules latch on quickly. brils from the original test tubes had tau inhibitors change the protein Carol Huseby, then a graduate joined ends to form longer brils. aggregates’ behavior. student in Je Kuret’s lab at the Control experiments established that DOI: 10.1074/jbc.RA118.006943 CAROL HUSEBY/OHIO STATE UNIVERSITY CAROL HUSEBY/OHIO STATE

Tau proteins labeled with three fluorescent dyes were allowed to aggregate in separate test tubes, shown in the three images at left. The dierent colored fibrils were mixed in a fourth test tube, at right, resulting in long fibrils with short sections of each color.

16 ASBMB TODAY JUNE/JULY 2019 JOURNAL NEWS Cascading errors How can a mutation in one lipid-turnover pathway cause problems in others?

By Laurel Oldach

ysosomal storage disorders are be neurologically debilitating and is charge, as is typical in healthy cells, genetic diseases. When any often fatal. GM2AP can extract gangliosides and Lone of a number of enzymes in After undergoing endocytosis as ferry them to the relevant enzyme. If the lysosome loses its function, the part of normal membrane turnover, the quantity of neutral or positively molecule it breaks down accumu- GM2 becomes part of the surface of charged lipids increases, the research- lates, slowly building to levels that a vesicle in the lysosome (see gure). ers observed, then that extraction is are toxic to cells. An article in the e enzyme that breaks down GM2, less e ective, and ganglioside break- Journal of Lipid Research gives which resides in the lysosomal down slows. a clue as to why complex lipids lumen, depends on binding between “GM2 degradation activity known as gangliosides accumulate GM2 and an accessory protein called is regulated by molecules in the even in lysosomal storage disorders GM2AP to nd and break down microenvironment of the reaction,” that don’t a ect ganglioside metab- its substrate. Until now, research- Sandho explained. “If the lipids are olism directly. e work was led by ers didn’t know whether GM2AP changed, you change everything.” Konrad Sandho , who discovered recruits the enzyme to the vesicle In addition to building up in a lysosomal storage disorder (since surface or delivers the lipid to the some disorders as the main storage named after him) in 1968. enzyme in solution. product, gangliosides can accumu- e ganglioside GM2 is found Using surface plasmon reso- late in disorders that primarily a ect mostly in the outer plasma mem- nance, scientists in Sandho ’s lab led other lipids, such as cholesterol or branes of cells in the nervous by postdoctoral fellow Susi Anheuser mucopolysaccharides. Before now, system. In Sandho disease, which showed that GM2AP extracts gan- scientists couldn’t explain why that is caused by mutation of the enzyme gliosides from the membrane of in- secondary buildup occurred. is that cleaves the complex sugar in traluminal vesicles. ey also showed paper suggests that raising the con- GM2’s head group, GM2 quickly that GM2AP activity depends on centration of these other lipids in the accumulates in patients’ neuronal the lipid makeup of those vesicles. lysosomal vesicle disrupts ganglioside lysosomes. is accumulation can If the vesicle has a negative surface degradation by a ecting the interaction between GM2AP and the vesicle surface. Richard Proia was not involved with this JLR paper, but he studies sphingolipids at the National Institutes of Health. “Normally, simple-mindedly, you think of each enzyme carrying out a single reaction and working by itself,” he said, adding that this work complicates that

ADAPTED FROM PRIBASNIG ET AL./JBC 2015 view. “If one lipid is stored, and that has a negative e ect on some other pathway, then the other pathways are now going to store lipids. at After endocytosis, membrane-spanning proteins or lipids that become part of an endosomal vesicle explains a phenomenon that’s been can face into the lumen of the late endosome and the lysosome. This makes parts of the molecule known for a long time.” that were once on the cell surface accessible to enzymes in the lysosome. DOI: 10.1194/jlr.M092551

JUNE/JULY 2019 ASBMB TODAY 17 JOURNAL NEWS Study shows long-term effects of weight loss on the proteome By Laurel Oldach

s hard as weight loss is, long- term maintenance can be A even more of a challenge. But Proteomics researchers research published in the journal found that many plasma Molecular & Cellular Proteomics proteins, such as myoglobin, indicates that the hard work of main- shown at left, increase in taining weight loss can pay previous- nonenzymatic glycation after ly unknown health dividends. patients lose weight. It takes six Using plasma samples from a months to a year of sustained PDB / S.E. PHILLIPS study that followed people as they weight loss for glycation to drop lost weight and worked to keep it below baseline levels. o , researchers at a Swiss proteomics company called Biognosys, in collaboration with a team at Nestlé, studied how weight loss a ected participants’ blood proteome. ey observed that while chronic in ammation subsides immediately after weight loss, it takes some time for lasting drop in in ammatory signal- is positive. added bene cial e ects to kick in. ing linked to atherosclerosis and an In future studies, the researchers e diet, obesity and genetics increase in lipid metabolism soon who own the data hope to move study, or DiOGenes for short, was after weight loss. from looking at the whole cohort’s designed to test the bene t of various Because of the depth of their proteome to correlating each study diets in maintaining weight loss. proteome coverage, the Biognosys re- participant’s outcomes with the Among the 550 participants who lost searchers could add a look at protein composition of that individual’s 8 percent or more of their starting glycation. Nonenzymatic glycation proteome at baseline in search of weight and stayed in the study for occurs when high concentrations of biomarkers that could help predict another six months, researchers re- sugar react with proteins in the plas- how future dieters will fare. Mean- ported in 2010, those who followed ma. Many of the glycated proteins while, the Biognosys team wants a high-protein, low-glycemic-index that changed signi cantly during to use its analytic abilities to power diet were most successful at keeping weight loss, including albumin, myo- high-throughput proteomics for it o . globin and some apolipoproteins, clinical trials. More recently, researchers at were unexpectedly more abundant DOI: 10.1074/mcp.RA118.001288 Biognosys led by Lukas Reiter used a after the study’s initial weight-loss streamlined proteomics approach to phase. It took more than six months analyze patient plasma samples from on the weight-maintenance diet for Laurel Oldach the start of the study, the end of its those glycated proteins to drop back ([email protected]) is a science writer for the eight-week weight-loss phase, and six below their baseline levels. Because ASBMB. Follow her on and 12 months into the maintenance glycated proteins can activate the im- Twitter @LaurelOld. phase. Consistent with other weight- mune system, the researchers wrote, loss studies, the team saw a dramatic, the e ect of longer-term weight loss

18 ASBMB TODAY JUNE/JULY 2019 JOURNAL NEWS From the journals

By Courtney Chandler, Isha Dey & Jonathan Grin

Olive proteins and cells, or Tregs, are de cient. demonstrates an approach to quanti- Parkinson’s disease A recent paper published in the fying parameters that could improve Aggregates of alpha synuclein, or Journal of Lipid Research gives insight the performance of simulation alpha SN, are primary components into the role Tregs play in ALD. Qin models. of Lewy bodies, which are linked to Ning and colleagues from Huazhong DOI: 10.1074/jbc.RA119.007685 the degeneration of dopaminergic University of Science and Technol- neurons in Parkinson’s disease. In ogy in China used mice to model Rethinking a vaccine the search for therapeutic molecules, alcohol-induced fat accumulation in for malaria researchers have found that phenolic the liver. ey found that diseased Caused by parasites belonging compounds from olive fruit protect mice had depleted Tregs as well as to the Plasmodium family, ma- against neurodegeneration and ex- aberrant macrophage activation and laria is transmitted to humans by hibit antioxidant properties. Hossein cytokine production. Treg transfer to female Anopheles mosquitoes. is Mohammad–Beigi and an interna- the diseased mice relieved inam- life-threatening disease is prevalent tional team screened extracts from mation and lipid metabolic disorder in developing countries, and the 15 olive varieties and found that and inhibited macrophage activation only approved vaccine is largely Koroneiki olives had the most potent and cytokine production. ey also ineective, so much recent research eects on alpha SN aggregation. found that the eects of Tregs are has been directed toward developing e authors fractionated the extract dependent partially on the cytokine more potent protection against the and identi ed three compounds that IL-10. eir data show a novel role parasite. Studies have shown that drove alpha SN monomers to form for Tregs in ALD and highlight a some attenuated parasite proteins oligomer chains with reduced toxic- potential therapeutic target. can protect humans, but researchers ity. e study was published in the DOI: 10.1194/jlr.M083568 have been unable to nd malaria Journal of Biological Chemistry. proteins that confer this protection. DOI: 10.1074/jbc.RA118.005723 Counting proteins Using malaria parasite–infected of a single cell mice as models, a study by Anthony Tregs help ﬁght Computer simulations can help Siau and colleagues at Nangyang fatty liver disease scientists understand complex cell Technological University and Consumed by people around the signaling pathways, but, to ensure Singapore Immunology Network world, alcohol is a leading cause of model accuracy, researchers need pa- employed immunomic and proteom- illness and mortality. e liver is the rameters determined by experiments ic techniques to identify a repertoire organ primarily responsible for alco- with live cells. Akira Komatsubra and of parasite proteins associated with hol metabolism and can be damaged colleagues in Japan have established protection against Plasmodium yoe- by excessive or prolonged consump- a way to measure protein concentra- lii, the parasite used in labs to infect tion. is progressive damage leads tion and dissociation constants at the mice. Using such criteria as repro- to alcohol-induced liver disease, or single-cell level. By attaching EGFP ducibility and immunoreactivity, the ALD, which presents as a spectrum and HaloTag genes to the ends of authors categorized these proteins of symptoms and severities. Fatty liv- MAPK1 and RSK2 genes, respective- based on how likely they were to ers are the earliest and most common ly, the authors enabled uorescence protect against blood-stage malar- pathology. Recent studies suggest imaging of proteins encoded by the ial infection — the stage when the that fat accumulation makes the liver two modi ed genes and calculated parasites divide in red blood cells and more vulnerable to inammation, their concentrations and dissociation that is responsible for all clinical ma- which is further exacerbated when constants. e study, published in laria symptoms. eir ndings were immune cells called T regulatory the Journal of Biological Chemistry, published in the journal Molecular &

JUNE/JULY 2019 ASBMB TODAY 19 JOURNAL NEWS

Viral cue sharpens arthritis drug’s aim

Tumor necrosis factor, or TNF, protein coordinates in ammatory responses after binding to immune cells, but defects can occur in regulatory pathways that lead to overproduction of the protein, causing chronic in ammation and autoimmune disorders. The drug etanercept, marketed as Enbrel, a soluble form of a TNF receptor, has been approved to treat autoimmune disorders such as rheumatoid arthritis. However, it also blocks essential molecules, including lymphotoxin alpha, or LT alpha, thus increasing a patient’s vulnerability to infections, lymphoma and heart failure. In a study published in the Journal of Biological Chemistry, Sergio Pontejo and colleagues at the Autonomous University of Madrid introduced a component of a poxvirus into etanercept, producing a variant with less than one-sixtieth of the original LT alpha-blocking activity and a mostly retained ability to inhibit TNF proteins. To evade host immune responses, poxviruses deploy proteins called viral TNF decoy receptors that inhibit native TNF molecules. One of these decoy receptors, CrmD, which is produced by the mousepox-causing ectromelia virus, neutralizes both TNF and LT alpha proteins in mice but does not interfere with LT alpha in humans. The authors of the study sought to understand CrmD’s unique binding ability at a molecular level. PONTEJO ET AL. By analyzing how several mutations in CrmD’s binding region affected its binding to TNF and LT alpha, the researchers zeroed in on a motif of three amino acids that prevents the protein from inhibiting human LT alpha. They then mutated etanercept to include this motif and found that the mutation reduced LT alpha-blocking activity more than sixtyfold while weakening TNF inhibition Overlaid crystallographic structures of CrmD threefold. in yellow and etanercept in blue bound to TNF. This safer form of etanercept might replace the traditional form of the TNF The dashed box surrounds the region of the inhibitor in clinical use. CrmD that is key to preventing inhibition DOI: 10.1074/jbc.RA118.005828 of lymphotoxin alpha. —Jonathan Grif n

Cellular Proteomics. When extended antimicrobial properties that can identi ed CopL from Bacillus to Plasmodium species a ecting hu- block the spread of disease, but some subtilis, a close relative of S. aureus, mans, this extensive data set could be strains of Staphylococcus aureus as a membrane-bound lipoprotein used to help validate and characterize have evolved mechanisms to resist that could bind extracellular new vaccine formulations for better copper’s e ect. Zuelay Rosario–Cruz copper. ese ndings, published in prevention of malaria. of Rutgers University and a team the Journal of Biological Chemistry, DOI:10.1074/mcp.RA118.000997 of researchers identi ed two genes, suggest mechanisms by which copB and copL, that enable S. S. aureus thwarts copper and Staph bacteria’s aureus’ copper resistance. Genetic could aid in the development copper resistance evidence suggested that the CopB of methods to better limit Many hospital surfaces are protein plays a role in copper export, infections. copper because the metal has while nuclear magnetic resonance DOI: 10.1074/jbc.RA118.004723

20 ASBMB TODAY JUNE/JULY 2019 ride, or LPS. Using label-free mass kinetic isotope eect in the bacterial Reversing mutant spectrometric analysis, the authors SPT that was absent in the human accumulation in cancer found that upon LPS stimulation, form. is suggests subtle catalytic e transcription factor p53 these phagosomes recruit fewer dierences between cytoplasmic and functions as a tumor suppressor; in proteins that help them mature and membrane-bound forms of SPT and more than half of cancer patients, more proteins that help them present that the position of isotope label- this protein is mutated and accumu- the antigen to T cells, thus changing ing should be considered carefully lates inside cells. Luciana Rangel and their proteome. e study also iden- during kinetic experiments. colleagues at the Federal University ti ed other proteins previously not DOI: 10.1194/jlr.M089367 of Rio de Janeiro report that the known to participate in phagosome small molecule PRIMA-1, which function. is preliminary nding Molecular bridges help can return mutated p53 to a natural paves the way for better understand- patch up DNA shape, also reverses accumulation of ing of the phagosomal proteome and Double-strand breaks, or DSBs, the protein. eir study, published in its dependence on external stimuli. in DNA can be lethal to cells, but the Journal of Biological Chemistry, DOI:10.1074/mcp.RA119.001316 mechanisms have evolved to correct showed that exposing cancer cells to errors in the genetic code. e PRIMA-1 reduced aggregates of p53, Isotope labeling may protein Ctp1 is key to the initiation initiated programed cell death and affect kinetic studies of DSB repair, but exactly how it in- inhibited the ability of mutant p53 Kinetic reactions and metabolic teracts with DNA was until recently to trigger aggregation of native p53. pathways can be studied using isoto- unknown. To nd out, Sara Andres e authors suggest these results pically labeled substrates. Reactants and colleagues from the National point toward p53 as a valid drug are labeled by replacing speci c Institute of Environmental Health target. atoms with their isotopes and can Sciences and the University of North DOI: 10.1074/jbc.RA118.004671 thus be tracked through time. Serine Carolina performed atomic force palmitoyltransferase, or SPT, is the microscopy imaging of Ctp1-DNA Digging into the rst enzyme in sphingolipid biosyn- complexes. e authors write in phagosomal proteome thesis and often is investigated using the Journal of Biological Chemistry In the process of phagocytosis, isotopically labeled L-serine. that they observed polymerized immune cells eat up foreign patho- In a recent study in the Jour- Ctp1 tetramers on dsDNA, forming gens. e primary phagocytes in the nal of Lipid Research, Dominic bridges between strands; when Ctp1 human immune system are dendritic Campopiano of the University of was mutated, cells were sensitized to cells, or DCs, which break down Edinburgh and an international DNA damage. ese images provide pathogens in dynamic compartments team used SPT from humans and valuable mechanistic insights for called phagosomes and present the the bacteria Sphingomonas paucimo- studying disease-causing DSB repair resulting antigen to T cells to start an bilis to investigate the eect isotope defects. immunogenic response. A phago- labels may have on catalysis. SPT DOI: 10.1074/jbc.RA118.006759 some changes its protein compo- is conserved among all organisms sition during its development and capable of producing sphingolipids, Protons and calcium ions in response to various stimuli, but yet the eukaryotic isoform is mem- shall not pass that phagosomal proteome is poorly brane-bound whereas the bacterial Channelrhodopsins, or ChRs, understood. isoform is soluble and found in are light-activated ion channels used In a collaborative study pub- the cytoplasm. Campopiano and in neuroscience to induce activity lished in Molecular & Cellular colleagues monitored SPT-catalyzed in neurons. But activating ChRs Proteomics, Eik Homann and reactions using a series of L-ser- also can allow passage of protons an international team investigated ine substrates that diered in the and calcium ions, which may changes in the phagosomal proteome position of an isotopic label. While trigger undesirable responses such in DCs derived from resting bone the human and bacterial forms of as glial acidi cation or intracellu- marrow versus those stimulated for SPT showed similar kinetics in lar calcium release. To avoid these immune response by lipopolysaccha- many cases, one substrate revealed a eects, Yong Ku Cho and colleagues

JUNE/JULY 2019 ASBMB TODAY 21 JOURNAL NEWS

Tackling an incurable blood cancer

Multiple myeloma, or MM, is a cancer of the plasma cell, a white blood cell responsible for making antibodies, in bone marrow. It is the second most common blood cancer in the U.S. after non-Hodgkin’s lymphoma. MM starts out as a benign condition called monoclonal gammopathy of undetermined signi cance, or MGUS, and then becomes malignant via an intermediate stage known as smoldering multiple myeloma, or SMM. The lifetime risk of getting MM in the U.S. is less than 1%. The disease’s progression is poorly understood and it has no cure, so recent research has sought to understand the microenvironment that contributes to the pathophysiology of MM. A feature of cancer progression is induction of tumor hypoxia as a result of reduced oxygen and nutrient delivery to the tumor cells. MM cells can adapt to hypoxia, which contributes to disease progression. To understand this process better, Astrid Slany and colleagues in Austria and Germany pro led the proteome of primary human MM cells in response to hypoxia induced as the cancer progresses. They analyzed plasma cells from bone marrow of patients with MGUS, SMM and MM and looked for proteins expressed in myeloma cells that aided in their survival, proliferation, and mechanisms to evade apoptosis and immune response. In comparison to nondiseased plasma cells, myeloma cells showed signi cant changes in the expression of proteins that CLINICAL REVIEWS 2018 regulate metabolic processes leading to cell proliferation under hypoxic stress. Also, pro-apoptotic proteins were downregulated, while proteins involved in escaping cell death and immune This cartoon shows plasma cells in bone marrow response were upregulated in hypoxia-stressed MM cells. Their with and without multiple myeloma. Researchers are studying ndings were published in the journal Molecular & Cellular this incurable cancer’s adaptation to lack of oxygen. Proteomics. These results indicate that myeloma cells’ adaptation to hypoxia plays a key role in disease progression. Unique proteins in advanced-stage myeloma cells could serve as novel targets for development of improved anti-myeloma treatment strategies. DOI:10.1074/mcp.RA119.001390 —Isha Dey

at the Massachusetts Institute of found a combination of mutations reveal new principles of optogenetic Technology engineered ChRs that that produced a ChR variant with protein engineering. e study was permit the passage of only certain tenfold reductions in calcium and published in the Journal of Biological ions. By generating and screening proton ux. eir methods o er a Chemistry. hundreds of ChR2 mutants, they means to customize ChRs and could DOI: 10.1074/jbc.RA118.006996

22 ASBMB TODAY JUNE/JULY 2019 Lipid signaling may help prevent atherosclerosis

Atherosclerosis is caused by the buildup of fatty plaque tion and M2-type macrophages that are associated with deposits in the arteries and can lead to heart attack and tissue repair and healing. When Smyth and colleagues stroke. Lysophosphatidic acid, or LPA, is a lipid that func- used LPA to stimulate macrophages isolated from wild-type tions in signaling in vascular smooth muscle and endo- and Lpar4-knockout mice, they found that macrophages thelial cells. While LPA has been shown to be increased from the knockout mice upregulated a marker associated in atherosclerotic lesions in mice, the speci c roles of LPA with M2-type activation. They also detected higher levels and LPA receptors in blood and vascular disease remain an of markers indicative of M2-type macrophages in the aortic active area of research. and coronary arteries from the knockout mice compared to In a recent study published in the Journal of Lipid the wild-type mice. Research, Susan Smyth of the University of Kentucky and These results suggest that LPAR4 may be involved in colleagues investigated the role of a speci c LPA receptor recruiting speci c immune cell subsets or regulating the called LPAR4 in the development of atherosclerosis in phenotypic switch of macrophages from M1- to M2-type, mice. They found that while cholesterol levels and lipopro- which in turn may promote resolution of plaque inam- tein distribution were similar in wild-type and Lpar4-knock- mation. Furthermore, their research supports the idea out atherosclerotic mice, the knockout mice had overall that therapeutic development to target LPA pathways may less atherosclerosis and the atherosclerotic lesions that provide an anti-inammatory approach to prevent some of were present were smaller in size. the complications associated with atherosclerotic disease. Previous studies have shown that LPA can promote DOI: 10.1194/jlr.M091066 inammatory responses, including the switch between —Courtney Chandler M1-type macrophages that are associated with inamma-

Fatty plaque buildup in the heart’s artery causes atherosclerosis, reducing its surface area and hence its oxygen-carrying capacity. MANU5/WIKIMEDIA COMMONS

Courtney Chandler Isha Dey Jonathan Grif n ([email protected]) ([email protected]) is a (jgrif [email protected]) is a is a graduate student at scientist at Thermo Fisher science communicator for the University of Maryland, Scienti c in India. all ASBMB journals. Baltimore. Follow her on Follow him on Twitter Twitter @CourtneyEChan. @spelledjon.

JUNE/JULY 2019 ASBMB TODAY 23 A YEAR OF (BIO)CHEMICAL ELEMENTS

For June and July, it’s atomic Nos. 6 and 7 By Quira Zeidan

his series of articles on chemical and marble — and coal. elements important for life marks Nitrogen is produced in super- T the International Year of the Pe- massive stars when carbon reacts riodic Table in 2019. To date, we have with hydrogen to produce nitrogen, introduced hydrogen, iron, sodium, po- oxygen and helium in a cycle that tassium, chlorine, copper, calcium and generates light and heat. Nitro- phosphorus. is month, we continue gen is the seventh most abundant the series with carbon and nitrogen. element in the Milky Way and the CARBON AND Carbon, with symbol C and solar system, and it represents about atomic No. 6, and nitrogen, with 78% of the Earth’s atmosphere in NITROGEN symbol N and atomic No. 7, are the form of dinitrogen gas, or N2. reactive nonmetals that generally Nitrogen makes up about 0.002% of General structure of an amino acid (with the share electrons with other atoms by the Earth’s crust, where it is trapped exception of proline). The alpha carbon in the forming several covalent bonds. A from the atmosphere during mineral center is bonded to four groups: an amino group carbon atom has four electrons and formation, and it dissolves in the (NH2), a carboxyl group (COOH), a hydrogen four vacancies in its outermost shell oceans via precipitation or sediment atom (H) and a variable side chain (R group). The and can combine with other atoms runo . R group determines the overall structure, size, via four covalent bonds. Nitrogen Both carbon and nitrogen are electric charge and polarity of the amino acid has ve valence electrons in its out- exchanged continuously in the envi- (in glycine, R is another hydrogen atom). ermost orbitals, three of which are ronment. In the carbon cycle, atmo- high-energy unpaired electrons that spheric carbon dioxide is converted each can form a covalent bond. Ni- to organic carbon via photosynthesis. returned to the soil by excretion and trogen typically connects with other Organisms cycle carbon back into decomposition and cycled back into atoms through these bonds. the atmosphere or soil by respiration, ammonia by bacteria and fungi. Carbon is the fourth most excretion and decomposition. In ad- e chemistry of life is organized abundant element in the observable dition, carbon trapped in fossil fuel around carbon. Carbon atoms can universe and the 15th most common reservoirs during older geological react with each other to form very in the Earth’s crust. Carbon is pro- events is released continuously into stable carbon–carbon bonds. Multi- duced in the core of stars when two the environment by erosion, volcanic ple carbon atoms linked together can helium nuclei collide to form highly emission and human activity, con- exist as linear chains, branched trees unstable beryllium, which fuses with tributing to the present cycle. and cyclic rings. ese structures, another helium particle to produce a Unlike carbon, atmospheric called carbon skeletons or backbones, stable carbon nucleus. When massive nitrogen cannot be used directly combine with various chemical stars explode as supernovae, carbon by plants. Instead, nitrogen gas is groups to make the biomolecules and disperses into space. It accumulates combined with oxygen or hydrogen organic compounds found in living in the Earth’s atmosphere where it by soil bacteria and converted into cells. combines with oxygen as carbon nitrates and ammonia, respectively. In addition to carbon–carbon in- dioxide, or CO2. Carbon is dissolved Plants — and subsequently animals teractions, carbon forms single bonds in all of Earth’s water bodies and — use xed nitrogen to build biolog- with hydrogen atoms and both single is a common constituent of large ical molecules such as proteins and and double bonds with oxygen and carbonate rocks — such as limestone nucleic acids. Organic nitrogen is nitrogen. Carbon skeletons bonded

24 ASBMB TODAY JUNE/JULY 2019 Carbon and nitrogen occur in all known life. Together with hydrogen and oxygen, they form stable compounds … where the four elements combined make up between 96% and 99% of any living organism’s mass.

only to hydrogen are called hydro- include amines and amides. Amines macrophages and neutrophils to kill carbons, and they include the tails contain the amino group R-NH2, microorganisms. of fatty acids, methane and methyl which ionizes to R-NH3+ in aqueous Carbon and nitrogen occur groups. Other biomolecules contain solutions due to its reaction with in all known life. Together with carbon atoms bonded to oxygen in an H+ from water. Amines occur in hydrogen and oxygen, they form several chemical arrangements, in- amino acids and some neurotrans- stable compounds commonly found cluding hydroxyl groups in alcohols mitters. Amides are formed by the in biological molecules, where the such as glycerol, carbonyl groups in combination of an acid and an four elements combined make up aldehydes and ketones represented amine, such as during formation of between 96% and 99% of any living in monosaccharides, and carboxyl peptide bonds that join amino acids organism’s mass. groups in carboxylic acids like in in proteins. Enzymatic deamination amino acids. of the amino acid arginine produces Quira Zeidan Nitrogen combines with carbon, nitric oxide gas that readily diuses ([email protected]) is forming ring con gurations such as across cellular membranes, acting the ASBMB’s education and public outreach coordinator. purines and pyrimidines that consti- as a signaling molecule. In ani- Follow her on Twitter tute nucleic acids. Biomolecules that mals, nitric oxide regulates smooth @quirazeidan. contain carbon and nitrogen also muscle contraction and activates

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• Mass Spectrometry in the Health and Life Sciences registration deadline (Aug. 1) • Emerging Roles in Nucleolus early registration deadline (Aug. 2) • Fungal Disease Awareness Week begins Aug. 13 • Serine Proteases in Pericellular Proteolysis and Signaling poster and registration deadline (Aug. 15) • Mass Spectrometry in the Health and Life Sciences (Aug. 18 – 22)

AUGUST • ASBMB–BSC Symposium on the Interplay Between Epigenetic Regulation and Genome Integrity abstract deadline (Aug. 30) • Emerging Roles in Nucleolus poster abstract deadline (Aug. 30)

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JUNE/JULY 2019 ASBMB TODAY 25 FEATURE PERSONALIZED PROTOCOLS Mental health accommodations can help some succeed in the lab — but rst they have to ask

By John Arnst

itting at her desk in the ditions constitute disability, the ADA While anecdotes suggesting a National Institutes of Health’s considers a person to have a disabil- mental health crisis among graduate S eoretical Molecular Biophys- ity if they have a mental or physical students had been circulating for ics Section, Robyn Stix sometimes impairment that substantially limits years, a number of recent papers reaches down to pet Agnes, her one or more major life activities. helped bring greater attention to the white-gold Labrador retriever. e e protections of the ADA scale of the problem. petting releases oxytocin that helps and the right to request and receive A paper in the journal Psycholo- Stix, a postbaccalaureate fellow, cope accommodations extend to stu- gy Research and Behavior Manage- with her chronic anxiety. dents at the primary, secondary and ment in March found that 23.7% of When Shauna Otto, a Ph.D. postsecondary levels for a gamut of a surveyed 325 doctoral students at candidate at Oregon State University, visible and unseen disabilities, which China Medical University in Shen- is working through a bipolar episode includes the mental illnesses that a yang exhibited signs of depression, and nds herself unable to reach number of recent studies have found and 20% exhibited signs of anxiety. out to others in her lab, her contact graduate students are more likely to In a paper published in November at the university’s Disability Access have than the general population. 2018, researchers at Harvard Uni- Services acts as a buer, relaying While accommodations can versity found that graduate students messages between Otto and her be clear-cut in an undergraduate in economics programs experienced primary investigator until she’s well setting — additional time for tests, moderate or severe symptoms of enough to re-enter the lab. an assignee to help with taking notes depression and anxiety at rates more Both Agnes’ presence and Otto’s or even a student helper to lend an than three times greater than the mediator are considered reasonable additional set of hands in a chemistry general population. accommodations under Title I of the laboratory — the informal nature of Both of those papers came in the Americans with Disabilities Act; they research laboratories may leave gradu- wake of a paper published in March allow individuals with disabilities to ate students and postdoctoral fellows 2018 in Nature Biotechnology, do their work to the same extent as feeling uneasy about disclosing their wherein 41% of a surveyed 2,279 people without disabilities. Rather conditions to their PIs and requesting graduate students were found to than specifying which medical con- the accommodations they need. have moderate to severe anxiety, and

26 ASBMB TODAY JUNE/JULY 2019 around 39% of the students were by trainees who want to see increased found to have moderate to severe support for mental wellness. depression. e authors, Teresa Ev- One of the most prominent ans and Nathan Vanderford, pointed voices — or rather, faces — of the out those rates are much higher than conversation about mental health those in the general population, as among graduate students has reported in other research studies emerged on social media. Susanna and by various health organizations. Harris, a graduate microbiology stu- eir results prompted an unprece- dent, started an Instagram account dented urry of news coverage and called e PhDepression. concern among the higher education Since the rst post — in which community. Harris discussed her own experience “ere’s a lot of evidence show- with depression and anxiety as a ing this paper has been received by graduate student at the University the community in a positive light of North Carolina at Chapel Hill — and that it has catalyzed an ongoing more than 100 early-career scientists discussion,” said Evans, an assis- with mental illnesses including tant professor at the University of PTSD, postpartum depression, Teresa Evans of the University of Texas Health Texas Health Science Center at San bipolar disorder and borderline Science Center at San Antonio and Nathan Antonio. personality disorder have shared their Vanderford of the University of Kentucky, published Over the past year, Evans and stories. e PhDepression, now a so- a study in the journal Nature Biotechnology last Vanderford have spoken at univer- cial media limited liability company, year about mental health among graduate students. sities across the United States about also has accounts on Facebook and The results, Evans said, have “catalyzed an ongoing the results of their survey and the Twitter as well as a blog for longer discussion” about what can be done to improve actions that PIs, students, faculty and stories. graduate students’ well-being. administrative leaders can take to ad- “What’s striking to me is the dress the issue. ey often are invited similarity of stories,” Harris said.

JUNE/JULY 2019 ASBMB TODAY 27 FEATURE

“e general tone is ‘I had a history reasonable accommodation is pro- of a little bit of imbalance, I knew cessed by the university’s Oce for that something was a little o in Students with Disabilities, or OSD. college, then I got to grad school is can be initiated by a student and it was just this pressure cooker or by a referral from the university’s Susanna Harris and her team share photos that precipitated all of these issues. counseling and psychological services across The PhDepression’s social media Instead of having the resources and or student health services. accounts that are a conscious contrast support that I did in undergrad, After a student has provided to the stock photos often used to typify where I had an outside mentor or medical documentation of a func- depression, such as those that ran with a counseling group or an RA or a tional limitation, they meet with a coverage of Evans and Vanderford’s roommate, I don’t have that and I disability specialist from the OSD to Nature Biotechnology paper. “It all was don’t have the nancial resources to review their planned coursework and accompanied by a photo of a woman crying feel comfortable getting them.’” discuss potential accommodations. in a window,” Harris said, “and that was Boval and her sta work with about really the impetus to start PhDepression on Reasonable accommodations 500 students each quarter, more than Instagram — to put that smiling face that At the University of Califor- half of whom receive accommoda- everyone sees in academia and include a nia San Diego, Joanna Boval and tions for psychological disabilities. story that is often not told.” her sta handle accommodations From elementary through high requests for undergraduates and school, a student’s parents and their graduate students, some of whom interactions with teachers usually are navigating the onset of mental drive the accommodations process. illness. Modi cations such as waiving course “I think that if they are experi- requirements might be made to encing these things for the rst time, curriculum in a K-12 setting but are it’s very isolating and scary,” said not an option at a university. Boval, the director of the Oce for Students with Disabilities at UCSD. Adult options Under Section 504 of the Reha- “e responsibility is on the bilitation Act of 1973, which bans student to self-identify (and) to ask discrimination against individuals for what it is he or she feels they with disabilities in any program or need in this particular environment,” activity receiving federal funds, pub- Boval said. “It can be challenging if lic schools at all levels are required to students don’t really understand what make a reasonable eort to accom- their disability is or how it really modate students in these activities. impacts them.” For Boval, accommodations are a If a professor or PI resists making matter of equity. an accommodation for a student, “We talk about leveling the Boval may have to resort to asking playing eld, right?” Boval said. other faculty members for support. “So, a reasonable accommodation “If I have diculty getting usually diers from person to person, through to a tenured faculty person depending upon the impact of the about a situation accommodation … disability and also the particular en- I will call a member of my faculty vironment in which they are working advisory committee and I’ll say, or learning or doing a task.” ‘Hey, look, here’s the situation. is At a postsecondary institution is what we need to have happened. such as UCSD, a request for a Can you talk to your colleague?’” she

28 ASBMB TODAY JUNE/JULY 2019 said. “More often than not, when the “Sometimes, they’ll ask to have my lab mates would like it if she rst faculty has heard from who they marginal functions removed,” said were a little more exploratory.” consider their peer, they are more Melanie Whetzel, the lead consul- When Stix was an undergrad- likely, even if they do it reluctantly, tant on JAN’s cognitive/neurological uate at Skidmore College, she was to acquiesce.” team. “Maybe some little tasks that diagnosed within one year with If those methods fail, students they do that could be given to some- both Crohn’s disease and anxiety. In can seek recourse through the Oce one else, and then they would have addition to the oxytocin released by for the Prevention of Harassment more time to spend on the essential close contact, which helps alleviate and Discrimination and, externally, functions.” anxiety, Agnes also assists Stix with the Oce for Civil Rights, the U.S. If an employee and employer the painful gut are-ups caused Department of Education or private are unable to work out a reasonable by Crohn’s, through deep pressure legal means. accommodation, or an employee therapy. In professional settings, if an em- is denied an accommodation, the While Agnes’ presence beside ployer refuses to provide a reasonable employee can le a complaint. e Stix is considered a reasonable accommodation to an employee with outcome depends on a number accommodation, she may have been a disability, the primary avenue of of factors, Carter said. ese can recourse is the Equal Employment include whether there was a valid Opportunity Commission, the fed- reason for the request, whether eral agency responsible for enforce- the employer determined that the ment of the ADA. employee didn’t need an accommo- According to Linda Carter dation, whether the employer made Batiste, the principal consultant and a good faith eort and whether there legislative specialist at the Job Ac- were any accommodation options or commodation Network, employers any that would not create an undue are responsible for accommodating hardship. an employee’s needs up until making “In general, it’s important that an accommodation would be consid- an employer make and document ered “undue hardship.” that it made a good faith eort to try Undue hardship is “a very, very to accommodate,” Carter said. “If, broad term that encompasses a lot of ultimately, the employer determines things,” Carter said. “ere are some that it cannot make an accommo- speci c things that employers don’t dation, the documentation of eort have to consider doing, and that’s can be critical if the employee les a things like creating new jobs, remov- complaint. ing essential functions, providing “Also, it can be helpful to com- personal need items like medications, municate with an employee about things like that.” why an accommodation is being de- e Job Accommodation Net- nied. Sometimes, if the employee un-

work, which provides free guidance derstands why, the employee might ASBMB on workplace accommodations and not be as likely to le a complaint.” disability employment issues, sug- Robyn Stix, a postbaccalaureate fellow at gests a number of potential accom- Canines and convalescence the National Institutes of Health campus in modations for people with depres- At the NIH, where Robyn Stix Bethesda, Maryland, goes everywhere with a sion, including alternative lighting, simulates the molecular dynamics of small pouch of treats and plastic bags for her exible scheduling, noise-canceling membrane proteins, Agnes often can service dog, Agnes, whose red vest bears the headsets and removing nonessential be found sleeping under the desk. words “Not all disabilities are visible.” Stix has tasks. “She’s a lazy dog,” Stix said. “I think anxiety and Crohn’s disease.

JUNE/JULY 2019 ASBMB TODAY 29 FEATURE

considered undue hardship in a lab she didn’t know accommodations where a dog might cause stress in lab were an option during the years animals. When Stix interviewed with she fought against her anxiety and her PI, José Faraldo-Gómez, she was depression. forthright in requesting Agnes be “We ended up deciding that Shauna Otto didn’t know accommodations allowed with her in the lab. she would just be my contact and were available to her when her she “I like to be upfront, because liaison,” Otto said. “Sort of a safe was grappling with a mood disorder as I want to be sure it’s a good envi- third party who would be able an undergraduate. She was well into ronment. If someone’s going to be to keep in contact with me while her graduate studies at Oregon State dierent because I have a service I’m working through my stu or University when an on-campus psychiatrist dog, I don’t want to end up in a lab bouncing back from an episode. She referred her to the o¡ce for students like that,” Stix said. By her account, would email my PI and anybody else with disabilities. There, she was assigned Faraldo-Gómez was happy to oblige. in the department that needed to get a counselor who helps her stay in touch “When I visited, Jose made sure to ahold of me and sort of be a Shauna with her lab when she suers a debilitating ask where we would t best in the concierge.” episode. room.” Now nearing what will likely be When a mental health issue pre- the nal year of her Ph.D. program, vents someone from physically being Otto said she feels optimistic about able to get into a lab space, the best her ability to manage the depres- option may be to give that person sion-compounding anxiety that left time and space to work through their her temporarily homeless near the depressive or anxiety episodes. end of her senior year of college and “I would say, with individuals with mixed success during a postbac- who have a chronic mental health calaureate program. challenge or who have a chronic “I feel a lot better, even just health issue, one of the reasonable reporting issues immediately to my accommodations may be something adviser,” Otto said. “Just having that like occasional absences, because the crutch, having a safe person to help disability is so impactful that they me manage communication.” physically can’t get into the space,” said UCSD’s Boval. ‘More than a pair of hands’ When Shauna Otto was in the Akshat Sharma was diagnosed depths of a depressive episode last with major depressive disorder in winter, a psychiatrist on campus 2012. His depressive episodes and at Oregon State referred her to the medication seemed a thing of the university’s disability access services past when he left his graduate school at the Oce of the Dean of Student support network at the University of Life. ere, she and a sta member Wisconsin-Madison for a postdoc- were able to work out the details toral fellowship at the University of of a reasonable accommodation in Texas Health San Antonio last year. which the counselor would act as a In Madison, Sharma had been a communications buer when Otto part of the local theater community. found herself unable to reach out to In San Antonio, he was daunted the members of her lab. by the musical-heavy theater scene, Otto, who rst began experienc- which he saw as dicult to break ing bipolar disorder near the end of into. He didn’t know anyone outside her time as an undergraduate, said his lab and felt alienated by his new

30 ASBMB TODAY JUNE/JULY 2019 neighborhood. Two men he’d known ly misinterpreted as being shut out and admired back in the Midwest due to incompetence. died by suicide in quick succession. “I think she just felt like I needed In the San Antonio lab, Sharma a break, but the state of mind that was tasked with wrapping up a de- I was in I was like ‘My god, they’re parting postdoctoral fellow’s project, shutting me out of experiments, which involved dissecting 20 mice because I’m incompetent.’” in a day and processing four tissues When Sharma talked to his PI, from each for ow analysis. he said, she told him she was trying “at was his jam,” Sharma said. to help him by reducing his stress — “It was not mine. My idea of a big though experts might contend that day in lab was when I would bleed an unrequested accommodation is ve people and work with their not the most advisable course. When samples. So this was all really new he told her he was embarrassed that and terrifying.” she had to deal with his problem, he All these factors contributed to said, she responded by asking if he’d a depressive episode that came to a be embarrassed if he broke his leg head after a large experiment failed. and couldn’t work. Although his mistakes were only a “(at) crystallized a lot of small factor, Sharma took the whole things for me,” Sharma said. “It of the blame on himself, he said, showed that she saw me as more which pushed his depression and sui- than a pair of hands; she was willing cidal ideation beyond any past point. to be accommodating to make sure “It’s like the depressive and the that the environment in lab was one suicidal ideation are two guys on where I could grow and feel comfort- Tinder who swiped right on each able.” other but have yet to make a date,” Sharma said. “But this was the one The lab as family unit time that I think was terrifying While Otto, Stix and Sharma because it was the one time that I found themselves with supportive was very seriously planning on — on PIs, not all early-career scientists are Paige Bentley, director of counseling and doing it.” as fortunate. While hard statistics on wellness services at Wake Forest University, When Sharma’s PI realized the graduate students’ relationships with thinks many Ph.D. students struggle in the lab gravity of the situation, she con- their advisors are dicult to come environment. “All of the dynamics that would tacted Sharma’s doctoral adviser at by, accounts of the toxic relation- come up in a family show up in a lab as well,” UW-Madison, who reached out to ships between students and their she said. Sharma. primary investigators or advisers Soon afterward, Sharma began abound on Twitter and various cor- working with a psychiatry resident ners of the web. at the medical school. After an ad- “I think one of the biggest strug- justment period, he resumed taking gles for Ph.D. students is the lab medication for his depression. environment,” said Paige Bentley, the Once the worst of Sharma’s director of counseling and wellness depression had passed and he wanted services at Wake Forest University. to get back to work, his PI removed “It’s a small environment and it has him from larger projects to ease him characteristics of a family unit, so all back into a routine, which he initial- of the dynamics that would come up

JUNE/JULY 2019 ASBMB TODAY 31 FEATURE

in a family show up in a lab as well.” Haas said. “at doesn’t mean you For Beth Haas, an assistant pro- have to tell everybody on the street, fessor of chemistry at Misericordia ‘Hey, hi, I have anxiety! Nice to University, a history of dealing with meet you!’ But having that sense that mental illness has helped inform in- if you had a physical health issue, Peter J. Kennelly, a professor at Virginia teractions with students who might people would be understanding and Polytechnic Institute and State University, be struggling themselves. supportive and sympathetic and all saying having a structured accommodations “I learned in graduate school of that. Mental health doesn’t have to process and sticking to it “saves the student that this terrible monster feeling I be dierent. Right?” from having to repeatedly negotiate with had that would grip me from time to instructors and relieves the instructor of trying time had a name, and that name was Extra instruction to act as an amateur psychologist.” Anxiety, and that Anxiety at times At Virginia Polytechnic Institute led to depression,” said Haas. and State University, Peter J. Ken- During graduate school, Haas nelly, a professor of biochemistry, said, she had a supportive adviser approves accommodations for some who both armed Haas’ decision to of his students almost every semester. seek counseling and asked what else “In general, interacting with she could do to help Haas. students through this structured “I’m kind of also passing that process has gone smoothly. e stu- along, you know, paying it forward dents seem comfortable approaching by telling my students, “It’s OK to instructors to discuss their need for not feel OK sometimes, and you’re accommodations,” Kennelly said. not alone in that,’” Haas said. Most of the accommodations At Misericordia University, a he sees as a lecturer fall under the Each fall, the graduate school at the liberal arts college in Dallas, Pennsyl- umbrella of expanded test-taking University of Georgia oers a brown-bag vania, small class sizes give Haas the options. workshop on mental health for faculty ability to get to know her students “In recent years, faculty at my members and students. “It is our most highly better than when she was a visiting university have been informed that attended oering of the entire year — every professor at Michigan State Universi- we are to refer students to the coun- single year,” said Suzanne Barbour, the dean. ty, she said. seling oce rather than attempting “Because there are a few of them, to assist students with emotional and I get to know them so person- and other issues,” Kennelly said. ally, I noticed things that I couldn’t “My own sense is that placing the notice in a room of 125 (students),” decision — as to whether or not a she said. “So I’m noticing individual student has a legitimate need for an distress. And I’m also able to talk to accommodation — in the hands of that person because they know me a professionals with whom students and I know them.” can interact privately works well. By opening up to her students It saves the student from having to about her own history, Haas has repeatedly negotiate with instructors been able to oer them a safe space and relieves the instructor of trying to share their anxieties and illnesses. to act as an amateur psychologist.” “(A student) told me in my oce According to Nathan Van- hours one day that she had appre- derford, an assistant professor in ciated that I had told the class that the department of toxicology and I am a shy person and can be very cancer biology at the University of anxious about meeting new people,” Kentucky and author on the 2018

32 ASBMB TODAY JUNE/JULY 2019 Nature Biotechnology study, even single year. We get some people who have more instructional assistants if PIs have a successful history of come back every year, but there are on the front line with the students,” mentoring, they sometimes feel ill- always new faces,” Barbour said. “We Boval said. “We’re hoping that by equipped to handle many sensitive give them a sense of what mental having this mandatory training, we topics, including the mental health health resources we have on campus give them tools and skills that they struggles of their trainees. for students … but a lot of times, it’s can start using their rst quarter in “ere’s a great need for more just them asking questions, saying, their roles, and that they will start faculty training in broad areas of ‘is is what’s happening with my educating, in small ways, the faculty mentorship to include mental health students. What should I do?’” that they report to.” and well-being issues, because most At the University of Texas faculty currently receive no training Medical Branch at Galveston, David Disclosure on how to be an eective mentor, Niesel and other faculty members As Stix looks to the future of much less on how to deal with im- work similarly to inform graduate her scienti c career, she’s uncertain portant health and wellness issues,” students about the resources available about how PIs might react to her Vanderford said. “When Teresa and on campus. mental health status. (Author’s note: I speak about our graduate student “One of the things that we For an additional perspective on this mental health work, we make it clear thought would be important was conundrum, see Susanna Harris’ that we’re not healthcare profes- to immunize students very early in essay on page 46, “Mental Illness sionals in this area. PIs or mentors their careers,” said Niesel, senior vice Should Not Disqualify Me.”) shouldn’t feel like they need to president and dean of the graduate “I don’t mind saying that I have be healthcare professionals in this school of biomedical sciences. anxiety or that I’m on SSRIs (selective area either, but we all need to be e faculty sought to do serotonin reuptake inhibitors), but equipped with the basic information this through adding material I know that some people judge you on how to connect trainees and col- about survival skills for burnout dierently because of that,” Stix said. leagues with helpful resources.” and depression to a pre-existing Stix thinks she might stay in her According to Suzanne Barbour, a longitudinal course about ethics, current lab for graduate school but professor and the dean of the gradu- in addition to providing graduate doesn’t know how accepting other ate school at the University of Geor- students in the course with PIs might be about having a dog in gia, faculty members at UGA are information about the oce of the lab, even with the mandatory encouraged to direct students who counseling and psychological protections of the ADA. may be in a crisis to the university’s services. “I don’t want to limit where Student Care and Outreach Center. At UCSD, Boval and colleagues I go,” she said. “But I also know “ey are kind of the nexus to di- work with the Teaching and Learn- that, unfortunately, it’s a big risk rect students to services that can help ing Commons, a section of the to go elsewhere, because even with them get out of crisis, whether it’s an executive vice chancellor’s executive interviewing, I might not know how academic crisis, a nancial crisis, a branch, to increase institutional they’d treat me there, how they’d mental health crisis, a behavioral cri- awareness of the accommodations treat her.” sis,” Barbour said. “It’s a unit to which process. Last summer, the com- Laurel Oldach contributed to faculty can refer their students when a mons mandated that instructional this report. faculty member may say, ‘Well, I just assistants on campus, who lead don’t know how to help.’” small discussion sections of 25 to Additionally, the graduate school 30 students for large lecture cours- John Arnst ([email protected]) is at UGA starts every academic year es, needed to go through an online ASBMB Today’s science with a “lunch and learn” for faculty training program about disability writer. Follow him on Twitter @arnstjohn. and students focused on mental health. and accommodations. “It is our most highly attended “e hope is that as our campus oering of the entire year — every grows, we’re going to continue to

JUNE/JULY 2019 ASBMB TODAY 33 FEATURE

The fast-acting drug t 32, Raquel Bennett was looking for a reason to live. She’d offers a new way to treat struggled with severe depression for more than a decade, trying multiple antidepressants and years of talk therapy. depression and fathom its e treatment helped, but not enough to make it seem origins. Recent approval of worth living with a debilitating mental illness, she says. “I a nasal spray promises to was desperate.” AIn 2002, following a friend’s suggestion, Bennett received an injec- expand access, but much tion of ketamine, an anesthetic and psychedelic party drug also known remains unknown about as Special K. During her rst ketamine trip, Bennett hallucinated that God inserted a giant golden key into her ear, turning on her brain. “It long-term use and the was as if I was living in a dark house and suddenly the lights came on,” potential for abuse. she says. “Suddenly everything seemed illuminated.” e drug lifted Bennett’s depression and dispelled her thoughts of suicide within minutes. e eect lasted for several months, and, she says, the respite saved her life. She was fascinated by the drug’s rapid eects and went on to earn a doctoral degree in psychology, writing her dissertation about ketamine. Today, she works at a clinic in Berkeley, California, that specializes in using ketamine to treat depression. “is medicine works dierently and better than any other medication I’ve tried,” she says.

34 ASBMB TODAY JUNE/JULY 2019 Listening to ketamine

By Emily Underwood, Knowable Magazine

When Bennett experimented with ketamine, the notion of using a psychedelic rave drug for depression was still decidedly fringe. Since the rst clinical trials in the early 2000s, however, dozens of studies have shown that a low dose of ketamine delivered via IV can relieve the symptoms of depression, including thoughts of suicide, within hours.

Even a low dose can have intense side eects, such as the sensation COURTESY OF RAQUEL BENNETT of being outside one’s body, vivid hallucinations, confusion and nausea. e antidepressant eects of ketamine typically don’t last more than a week or two. But the drug appears to work where no others have — in the roughly 30 percent of people with major depression who, like Bennett, don’t respond to other treatments. It also works Raquel Bennett is a postdoctoral fellow in clinical psychology and founder fast, a major advantage for suicidal patients who can’t wait weeks for of KRIYA Institute, which works traditional antidepressants to kick in. with patients seeking psychotherapy, “When you prescribe Prozac, you have to convince people that medication management and ketamine it’s worth taking a medication for several weeks,” says John Krystal, treatment. She received her rst ketamine a psychiatrist and neuroscientist at Yale University in New Haven, treatment in 2002. Connecticut. “With ketamine, patients may feel better that day, or by the next morning.”

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Depression, fast and slow

In 2001, writer Andrew Solomon published a haunting description of the depression that derailed his early 30s: “If one imagines a soul of iron that weathers with grief and rusts with mild depression, then major depression is the startling collapse of a whole structure,” he wrote. When Solomon rst fell ill, in the 1990s, many clinicians and researchers presumed that the pathological brain changes underlying depression were inherently slow to repair. This mind-set was rooted in the modest but controversial success of a class of slow-acting drugs that includes Prozac. Developed in the 1950s, the drugs were rst inspired by the chance observation that a hypertension drug called reserpine — an extract of the plant Rauwol a serpentina, or devil pepper — made people intensely depressed. After discovering that reserpine depletes monoamine neurotransmitters in the brain, including serotonin and norepinephrine, scientists hypothesized that low neurotransmitter levels causedepression. They went on to develop monoaminergic antidepressants, drugs designed to increase circulating levels of these chemicals in the brain. Today, monoaminergic antidepressants include selective serotonin reuptake inhibitors (SSRIs) such as Prozac, Lexapro and Zoloft, as well as the older and less commonly prescribed monoamine oxidase inhibitors (MAOIs) and tricyclic and tetracyclic antidepressants. Scientists have long debated whether the drugs work at all, but the most comprehensive study to date — published in The Lancet in 2018 — suggests that they do lower depression symptoms in about 60 percent of depressed people, albeit only modestly more than taking a placebo. The bene ts start to show up only after several weeks of treatment, however, and roughly a third of people with major depression disorder – called treatment-resistant patients — don’t respond to at least two types of monoaminergic antidepressant. By the early 2000s, the monoamine hypothesis had unraveled. This was partly due to the antidepressants’ mediocre performance in patients, and partly to experiments which showed that depleting neurotransmitter levels in healthy people does not make people depressed. Scientists now believe that drugs like Prozac do not directly treat depression’s root cause. Instead, they think the drugs work via an indirect mechanism to subtly boost the growth of synapses and the birth of new neurons, and that this somehow relieves symptoms. Solomon’s bleak metaphor of corrosion was at least partly grounded in science. Many scientists now agree that depression slowly eats away at the neural pathways underlying our sense of worth and well-being, our desire to go to the movies or get out of bed. But research into ketamine holds out new hope that — unlike rusted iron — the depressed brain can be restored, by repairing and strengthening the neural circuits that regulate mood. —Emily Underwood

Slow-acting antidepressant drugs were inspired by the chance observation that a hypertension drug called reserpine — an extract of the plant Rauwolﬁa serpentina, or devil pepper, pictured here — made

VINAYARAJ/WIKIMEDIA COMMONS VINAYARAJ/WIKIMEDIA people intensely depressed.

36 ASBMB TODAY JUNE/JULY 2019 FEATURE

e buzz around ketamine can drown Central to the controversy out just how little is known about the drug. over how ketamine works in In the April 2017 JAMA Psychiatry, the the brain is the NMDA receptor American Psychiatric Association published (illustrated here), which binds to an analysis of the evidence for ketamine FURUKAWA LAB, CSHL the neurotransmitter glutamate. treatment noting that there are few published Some scientists believe data on the safety of repeated use, although ketamine’s antidepressant studies of ketamine abusers — who typically eects hinge on its ability to use much higher doses — show that the drug block NMDA receptors, but can cause memory loss and bladder damage. others believe the drug works Most clinical trials of the low dose used for via other mechanisms. Resolving depression have looked at only a single dose, that mystery is key to developing following up on patients for just a week or similar drugs with fewer side two, so scientists don’t know if it’s safe to take eects, scientists say. the drug repeatedly over long periods. But that’s exactly what might be necessary to keep depression at bay. e analysis also warned about ketamine’s well-established potential for abuse. Used rec- reationally, large doses of the drug are known companies have been racing to bring the rst There simply to be addictive — there’s some evidence ketamine-based antidepressant to market. In aren’t enough that ketamine can bind to opioid receptors, March, the US Food and Drug Administra- raising alarms that even low doses could lead tion approved a ketamine-derived nasal spray, data to know to dependence. esketamine, developed by Janssen Pharma- what the Bennett has now been receiving regular ceuticals, a subsidiary of Johnson & Johnson. optimal dose ketamine injections for 17 years, with few Only two of Janssen’s ve phase III trials had negative side eects, she says. She doesn’t shown a bene t greater than taking a place- for depression consider herself addicted to ketamine be- bo. Still, in February an independent panel is, who is most cause she feels no desire to take it between recommended FDA approval. at makes scheduled appointments. But she does feel ketamine the rst novel depression drug to likely to beneﬁt dependent on the drug, in the same way hit the market in more than 50 years, notes from ketamine that a person with high blood pressure takes Carlos Zarate Jr, a psychiatrist who studies treatment and medication for hypertension, she says. mood disorder therapies at the National Still, she acknowledges what most Institute of Mental Health. what long-term clinicians and researchers contend: ere ousands of people are already ocking treatment simply aren’t enough data to know what the to private clinics like Bennett’s, which pro- should look like. optimal dose for depression is, who is most vide intravenous ketamine infusions. Because likely to bene t from ketamine treatment the drug was approved in the 1970s as an and what long-term treatment should look anesthetic, physicians can legally provide the like. “ere’s a lot that we don’t know about drug as an “o-label” depression treatment. how to use this tool,” Bennett says. “What’s Many ketamine clinics have long waiting lists the best dose? What’s the best route of or are so swamped that they aren’t accepting administration? How frequently do you give new patients, and Janssen’s nasal spray could ketamine treatment? What does maintenance rapidly expand access to treatment. look like? Is it OK to use this in an ongoing But some researchers worry that the nasal way?” spray won’t solve many of ketamine’s prob- Despite the unknowns, pharmaceutical lems and could create new ones. Although

JUNE/JULY 2019 ASBMB TODAY 37 FEATURE

the FDA is requiring that the nasal spray be few advantages over generic ketamine, which administered only in a certi ed doctor’s oce costs less than a dollar per dose, although or clinic, esketamine is “every bit as habit the IV infusions in private clinics often cost forming as regular ketamine,” and will be hundreds of dollars per visit. Janssen has dicult to keep out of the hands of abusers, indicated that each esketamine treatment will says Scott ompson, a neuroscientist at the range from $590 to $885, not including the University of Maryland and a coauthor with costs of administration and observation. Zarate of a 2019 review on fast-acting anti- Zarate and others are still thrilled to depressants in the Annual Review of Phar- see big pharma investing in ketamine, after macology and Toxicology. A nasal spray can’t decades of stalled eorts to nd new psychi- deliver as precise a dose as an IV infusion, atric drugs. “As esketamine hits the market, ompson notes. “If someone has got a cold, venture capitalists will come up with better they’re not going to get the same dose.” versions and move the eld forward,” Zarate In ompson’s view, esketamine holds says. Several drug companies are now testing

38 ASBMB TODAY JUNE/JULY 2019 other ketamine-like compounds in hopes of ompson and others have found that Some developing drugs that have its potent antide- there are fewer connections, or synapses, researchers pressant potential without its psychedelic and between neurons that communicate reward dissociative side eects. signals in the brain in depressed animals. are also testing Some researchers are also testing wheth- Other labs have found shriveled connections whether er ketamine works for conditions beyond in neuronal circuits key to decision-making, ketamine works depression, such as obsessive-compulsive dis- attention and memory. Brain imaging studies order, as well as in speci c subsets of patients, in people with depression have also revealed for conditions such as severely depressed teenagers. Other abnormal activity in neural circuits that reg- beyond scientists are using ketamine to help untangle ulate emotion, suggesting that the ndings in one of the biggest mysteries in neuroscience: rodents may also apply to humans. depression, such What causes depression? (See Depression If faulty neural connections are to blame as obsessive- treatment by the numbers, page 38.) for depression, the next question is, “How do compulsive we get atrophied neural pathways to regrow?” Seeking answers in neural wiring Krystal says. disorder, as well irty years ago, the prevailing thought as in speciﬁc was that low levels of certain brain chemicals, Circuit training subsets of such as serotonin, caused depression. Boost- e answer, many scientists now believe, ing those could remove symptoms. is the brain’s most abundant neurotransmit- patients, such “I felt that depression needed months ter, glutamate. as severely or weeks of treatment — that the plastic Glutamate is the workhorse of the brain. changes involved in the healing process It relays eeting thoughts and feelings, depressed would require weeks to reset themselves,” says and enables the formation of memories by teenagers. Todd Gould, a neuropharmacologist at the strengthening synaptic connections. Gluta- University of Maryland and a coauthor of the mate is the reason you can still ride a bike recent review paper. But ketamine’s speed of years after you learned, even if you never action casts doubt on that idea. practiced. Newer evidence suggests that depression Not all glutamate activity is good. Too is caused by problems in the neural circuits much can cause the equivalent of an electri- that regulate mood, Gould notes. Much of cal storm in the brain — a seizure — and the evidence for this faulty-wiring hypothesis chronically high levels may lead to dementia. comes from rodents. Starting in the 1990s, Abnormalities in glutamate receptors — spe- scientists began to discover intriguing abnor- cialized proteins on the surface of brain cells malities in the brains of mice and rats that where glutamate can dock and bind — are had been exposed to certain stressors, such as linked to a wide array of psychiatric diseases, bullying by a big, aggressive male. including depression and schizophrenia. Stress and trauma are strong predictors To maintain balance, cells called inhib- of depression in people, but scientists can’t itory interneurons act like brakes, releasing ask rats or mice if they are depressed. Instead, a neurotransmitter called GABA that quiets they use behavioral tests for classic depression brain activity. Most mind-altering drugs work symptoms such as anhedonia, the inability to by changing the balance between GABA and take joy in pleasurable activities, ompson glutamate — amphetamines and PCP en- says. Depressed animals “give up easily” in ex- hance glutamate signaling, for example, while periments that test their willingness to work alcohol inhibits glutamate and boosts GABA. for rewards like sugar water, or their interest By the 1990s, scientists had discovered in the intoxicating scent of a potential mate’s that ketamine triggers a gush of glutamate in urine. “ey can’t be bothered to cross the the brain’s prefrontal cortex. is region gov- cage,” he says. erns attention and plays an important role in

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emotional regulation. e out-of-body sensa- Esketamine also complicates the story. tions that some people experience when they Ketamine is made up of two molecules that take ketamine may occur because this rapid form mirror images of each other, R- and release of glutamate “excites the heck out of S-ketamine. Esketamine is made up of just a whole bunch of neurons” in the prefrontal the S form and binds roughly four times as cortex, says Bita Moghaddam, a neuroscien- eectively as R-ketamine to the NMDA re- tist at Oregon Health & Science University ceptor. Despite acting much more powerfully who discovered the drug’s glutamate-revving on the NMDA receptor, studies in rodents eect on rats while studying schizophrenia. suggest that S-ketamine is a less potent anti- Scientists aren’t sure yet how ketamine depressant than R-ketamine, although it’s not forms stronger neural circuits. But the yet clear whether or not R-ketamine could hypothesis goes roughly like this: When ket- work better in humans. amine enters the brain, it causes a short-term Zarate and others now believe ketamine burst of neuronal activity that triggers a series may work through a dierent receptor that of biochemical reactions that create stronger, binds glutamate, called AMPA. By pinpoint- more plentiful synaptic connections between ing which receptor ketamine acts on, re- brain cells. searchers hope to develop a similar drug with At rst, many researchers thought fewer side eects. One hot lead is a com- ketamine’s antidepressant eects relied on a pound called hydroxynorketamine (HNK) structure located on the surface of neurons, — a metabolic byproduct of ketamine that called the NMDA receptor. Like a key that does not aect NMDA receptors but still ts into dierent locks, ketamine can bind produces rapid antidepressant eects in to several types of NMDA receptor, making rodents. e drug appears to lack ketamine’s neurons release the excitatory glutamate disorienting side eects, and Zarate and neurotransmitter. Gould plan to launch the rst small clinical is hypothesis suered a blow, however, trials to establish HNK’s safety in humans when several drugs designed to bind to the this year, likely in around 70 people. “I think NMDA receptor (as ketamine does) failed in we have a very good drug candidate,” Gould clinical trials for depression. says. (Zarate and Gould, among others, have disclosed that they are listed on patents for HNK, so they stand to share in any future royalties received by their employers.) Plastic synaptic remodelers To alter how the brain processes mood, scientists believe ketamine must ultimately change synapses. In experiments in rodents, Ron Duman of Yale University has shown that both ketamine and HNK can harness one of the brain’s most important tools for synaptic remodeling: brain-derived neuro- R.J. G. AGHAJANIAN LIU, DUMAN & R. trophic factor, or BDNF. BDNF is a protein intimately involved in shaping synapses during brain development Ketamine strengthens connections between brain cells. Compared with a control, and throughout the lifespan. Healthy brain a rat neuron (red) treated with ketamine has grown more dendritic spines function depends on having just the right (shown by yellow arrows). amount of BDNF in the right place at the right time. Many mental illnesses, including

40 ASBMB TODAY JUNE/JULY 2019 depression, are associated with low or abnor- By pinpointing mal amounts of the protein. For example, which receptor samples of brain tissue from people who have died by suicide often contain abnormally low ketamine acts amounts of BDNF. on, researchers Duman and colleagues have found that hope to develop both ketamine and HNK cause a sharp up- tick in the amount of BDNF that is released a similar drug from neurons. is increase is required for NIMH JESSICA GILBERT/ETPP, CARLOS ZARATE, with fewer side the drugs’ antidepressant eects, and for the increase in dendritic spines — the stubby eects. protrusions that form synaptic connections with other neurons. Both ketamine and HNK also seem to reduce inammation, which has been linked repeatedly to the stress-induced loss of synapses. Ketamine is not the only compound that can induce rapid synaptic plasticity: Other psychedelics, such as ecstasy (MDMA), acid (LSD), and DMT also trigger similar structur- Ketamine appears to strengthen connections between al changes in neurons and rapid antidepressant neural networks in people with severe depression. In eects in rodents, researchers at the University a study comparing neural activity prior to a ketamine of California at Davis recently found. e infusion (top) and six to nine hours after an infusion eects don’t hinge on getting high, the team (bottom), a single dose made the brain more responsive to reported in March in ACS Chemical Neuro- a simple sensory stimulus, the light stroking of a ﬁnger. science. Even very small doses — too low to cause perceptual distortions — can increase synapse density and lift depression. people with depression, communication Traditional antidepressants such as Prozac among several key brain networks is disrupt- also increase BDNF levels in the brain, but ed. One network, called the default-mode not nearly as fast as ketamine does, Duman network (DMN), is involved in self-referen- says. at is why most antidepressants take so tial thoughts such as ruminating about one’s long to remodel synapses and relieve depres- problems or aws. is network tends to be sion symptoms, he says. hyperactive in people with depression, and less connected to more outwardly attuned Dissecting depression brain networks such as the salience network, Beyond promising new treatments, which helps the brain notice and respond to Zarate and other researchers see ketamine as a its surroundings. powerful tool for probing depression’s tangled In one recent study, Zarate and his col- neurobiology. Studies in mice and rats are leagues found that after receiving an IV dose a good start, but scientists need to study of ketamine, people with depression had more the drug in people to truly understand how normal activity in the default mode network, ketamine aects the brain. Unlike traditional, and that it was better connected to the salience slower-acting antidepressants, ketamine lends network. At least temporarily, the drug seems itself to short-term lab experiments. to help people get unstuck from patterns of Zarate is using neuroimaging tools brain activity associated with repetitive, neg- such as fMRI to study the human brain on ative thoughts. Zarate does caution that the ketamine. Past studies have shown that in study results need to be replicated.

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e team has also used brain imaging to Ketamine in teens? study how ketamine aects suicidal thoughts. For Krystal, weighing ketamine’s still About four hours after an infusion of ket- largely uncharted risks and potential rewards amine, a chunk of the prefrontal cortex that ultimately comes down to a deeply personal is hyperactive in people with depression had question: “What would we want for our- calmed down, researchers found, which cor- selves? For our families? Do we want them to related with people reporting fewer thoughts have to go through several failed trials over of suicide. several months, or even a year, before taking a Ketamine also seems to tune other brain medication that might make their depression regions that are key to eective treatment. better in 24 hours?” Last year, scientists published a study in Some of the hardest decisions are likely mice showing that ketamine quiets abnor- to involve children and adolescents. Hos- mal activity in the lateral habenula, a small pitalization for youth suicide attempts and nodule wedged deep under the cortex. Some ideation nearly doubled between 2008 and Ketamine has researchers have described the lateral habenu- 2015, leaving many clinicians — and parents been deemed la as the brain’s “disappointment center.” e — desperate for more eective and rapid region is responsible for learning from nega- treatments. Left untreated, depression is “re- safe to use as tive experiences, and is hyperactive in people ally bad for the brain” and can cause serious, an anesthetic with depression, as if “broadcasting negative long-term cognitive and developmental prob- in children, but feelings and thoughts,” ompson says. lems when it starts young, Zarate says. “e Such studies remain exploratory. As to question is, is that going to be better than the there aren’t why ketamine works — and just as important, long-term side eects of ketamine?” yet su¡cient why its eects are transient — scientists are Scientists don’t yet know. Ketamine has still speculating. “I think ketamine is resetting been deemed safe to use as an anesthetic in clinical data neural circuits in a way that improves the children, but there aren’t yet sucient clinical to show how symptoms of depression, but the risk factors data to show how low, repeated doses of low, repeated — whether genetic, environmental or other ketamine used for depression could aect the risk factors — are still present,” Gould says. “It developing brain. doses of seems to help reset things temporarily, but the On a more fundamental level, scientists ketamine used underlying cause is not necessarily resolved.” don’t fully understand the neurobiology of for depression Helen Mayberg, a neurologist at Mount adolescent depression, notes psychiatrist Sinai Hospital in New York who specializes Kathryn Cullen of the University of Minne- could aect in using an experimental procedure called sota. It may involve abnormalities in brain the developing deep brain stimulation to treat depression, development, such as the way the prefrontal suggests that ketamine may be like using a cortex connects to brain regions that process brain. de brillator on someone experiencing cardiac emotion, but “we don’t know if the brain arrhythmia. “I am not addressing the fact connection abnormalities emerge because of that you have underlying heart disease, but toxic stress induced by depression, or if these now that your arrhythmia is gone, I can abnormalities predispose people to develop concentrate on other treatments.” depression, or if depression itself reects It’s important to put the potential risks abnormal development,” Cullen says. “It’s of ketamine into perspective, particularly critical to gure out how to alleviate the bio- for people contemplating suicide, research- logical changes that are associated with [teen] ers emphasize. Most people are willing to depression so that the brain can get back on a tolerate severe side eects for other life-saving healthy trajectory.” treatments, such as cancer drugs, Mayberg Two recent clinical trials — one at Yale points out. “If you can interrupt an extreme and another at Minnesota run by Cullen — suicidal plan and ideation, I’ll take that.” have found that ketamine can lower symp-

42 ASBMB TODAY JUNE/JULY 2019 toms in severely depressed teenagers, but nei- ther study was set up to follow the teenagers long-term, says Cullen. Janssen is currently running a trial of its esketamine nasal spray with 145 youths who are suicidal, but the results of that study have not been published JANSSEN PHARMACEUTICALS, INC. yet. Cullen thinks ketamine has potential for use in teens, particularly to avoid suicide, but “there are still a lot of unknowns.” Not just a quick ﬁx Worldwide, depression aicts more than 300 million people, making it the leading global cause of disability. When contemplating such overwhelming misery, the vision of a world in which depression can be cured with a single injection or squirt of nasal spray holds obvious appeal. Although clinicians are hopeful that Janssen Pharmaceutical’s newly approved esketamine But — despite the hype — that is not nasal spray, Spravato, will expand access to treatment, many also worry about the drug’s what ketamine oers, Bennett says. Based potential for abuse. on her own experience as a patient, and her clinical work, she is troubled by the framing of ketamine as a “rapid” depression treatment the drug’s antidepressant eects. if that precludes the slower, more eortful Unlike some researchers and pharmaceu- process of psychotherapy. Without psycho- tical companies, which consider ketamine’s therapy, she says, “you’re not giving patients and esketamine’s hallucinogenic side eects any tools to help themselves, just making them inherently negative, Bennett thinks that for dependent on a molecule that has temporary some people the visions can be positive — This article is republished eects. When the eect wears o, they have to particularly in the context of therapy. ere’s from Knowable Magazine, go back for more medicine. is is going to be scant scienti c evidence to support the idea an independent lucrative for the pharmaceutical company but that such hallucinations are therapeutic, and journalistic endeavor from probably not in the patient’s best interest.” they can be deeply disturbing for some peo- Annual Reviews. In Bennett’s clinic, ketamine is admin- ple. (If people who experience hallucinations istered only alongside talk therapy, which do better, it may simply be because they have she uses to prepare patients before they take received a higher dose of ketamine, Krystal ketamine, and afterward to help them process points out.) the experience. “I think this is the only ethi- Still, Bennett thinks researchers and cli- cal way” to administer a drug that can trigger nicians need to stay open-minded about why disorienting psychedelic experiences, she ketamine is helping people — and be more says. “is isn’t a ‘take two and call me in the attentive to the settings in which ketamine and morning’ situation.” esketamine are administered. “People consis- Emily Underwood (emily.l.underwood@ ere’s growing scienti c interest in tently report that they experience the presence gmail.com) is a freelance whether ketamine can enhance the eective- of God, or their own sacredness,” she says. science writer and contributing correspondent ness of therapy by increasing the brain’s abil- “When someone comes to my oce wanting for Science magazine. ity to remodel circuits through experience, to kill themselves, ready to die — and then She is based in Coloma, California. Follow Krystal notes. And in 2017 a small Yale study they have a transformational moment where her on Twitter found that providing cognitive behavioral they believe their life is sacred — it’s indescrib- @em_underwood. therapy in tandem with ketamine can extend able how exciting that is as a clinician.”

JUNE/JULY 2019 ASBMB TODAY 43 RESEARCH SPOTLIGHT Understanding the link between metabolism and aging Princeton postdoc aims to motivate younger scientists

By Courtney Chandler

rowing up in rural Mississippi, Now a Howard Hughes Medical “I’d never worked with nema- Melanie McReynolds used Institute Hanna Gray fellow and todes before, and it was fascinating G to watch St. Jude Children’s postdoctoral research assistant at to integrate genetics, metabolism and Research Hospital infomercials that Princeton University, McReynolds biochemistry all together,” she said. focused on scientists and their nd- studies diseases of aging in Joshua She received numerous awards ings; those TV segments sparked her Rabinowitz’s lab. She focuses on how for her work, including the Amer- interest in research. the molecule nicotinamide adenine ican Society for Biochemistry and “At a young age, I didn’t realize dinucleotide, or NAD+, is produced Molecular Biology 2016 Best Poster the in-depth scienti c process I was and used. Because NAD+ can carry Award in the category metabolism, learning, but it was so inspirational electrons between chemical reactions, disease and drug design. She defend- to hear and see the scienti c story it is involved in myriad processes ed her thesis in 2017 and credits unfold and come to life,” she said. within cells. Hanna–Rose with molding her as a “And then in college, I was Previous studies have associated scientist and teaching her to think intrigued by the ability to ask and a decline in NAD+ with aging and outside the box. answer questions of the unknown.” disease, and McReynolds describes “Melanie approached her McReynolds followed in her par- the molecule as a “master regulator” research with con dence from the ents’ footsteps and attended Alcorn of age-dependent pathology. She start,” Hanna–Rose said. “She liked State University in Mississippi for investigates NAD+ metabolic ux in to think creatively about how to her undergraduate studies. After her young and old mice, using isotope approach problems, and it was fun sophomore year, she was one of 10 labeling, mass spectrometry and to see her mature in this creativity top Alcorn students selected for a quantitative modeling to understand to start focusing it in productive research trip to Bangalore, India. how the rates of production and directions.” “is was my rst experience consumption of the NAD+ chemical Inspired in part by a love of with biomedical research,” she said. backbone vary between these groups. teaching and mentoring, McReyn- “It changed my life and promoted “ese are fundamental ques- olds decided to stay in academia, my love for science.” tions the eld needs answered,” leading to her position at Princeton. She also participated in the McReynolds said. “Our initial results She also wants to lead by example. now-defunct Alcorn State/Penn State are exciting and will hopefully be “I want there to be a lot of peo- Bridges to the Doctorate Program, published soon.” ple of color in tenure positions,” she funded by the National Institutes of is type of metabolic ux analy- said. “I want to make sure I can be Health to promote science training sis isn’t new to McReynolds. As a an example for others, or a represen- for underrepresented minorities. At graduate student in Wendy tation for others, who also want to the program’s end, McReynolds had Hanna–Rose’s lab at Penn State, she pursue academic science.” a bachelor’s degree from Alcorn and studied NAD+ biosynthesis. She McReynolds has struggled with a master’s from Penn State, where she pioneered many mass spectrometric doubt and adversity. During her did research in Craig Cameron’s lab. and isotopic labeling techniques second year as a graduate student, e Bridges program triggered her to study the physiological roles of she took a four-part candidacy exam interest in diseases related to metabo- NAD+ in the nematode Caenorhab- that included a paper critique, paper lism and aging. ditis elegans. presentation, research proposal and

44 ASBMB TODAY JUNE/JULY 2019 COURTESY OF MELANIE MCREYNOLDS COURTESY

chalk talk on the proposal. “I bombed my chalk talk,” she said. “I was still getting familiar with the research, was still learning how to approach it, and had to repeat the chalk talk.” McReynolds didn’t let this set her back. She learned NAD+ metabolism and biosynthesis in detail, which was important for her current and future research. When the time came for her second chalk talk, her friends showed up with balloons and cheers to show their support. She passed without issue. “e experience strengthened In addition to her research, Melanie McReynolds does my foundation,” she said. “I could motivational speaking, sharing her insight look at it as something devastating, with grad students and undergrads. but I look at it as something that strengthened me as a researcher and scientist.” new questions. postdoctoral work, McReynolds will McReynolds also does motiva- “e big question and the big continue to analyze NAD+ ux and tional speaking outside the lab, shar- picture of where this research can how it relates to aging and disease. ing her insight with graduate stu- go, that’s what keeps pushing me,” Her HHMI Hana Gray fellowship dents and undergraduates majoring she said. “Plus, the joy of scienti c ensures $1.4 million in funding over in science, technology, engineering discovery.” eight years. She aims someday to and mathematics at various univer- Rabinowitz sees McReynolds’ run her own lab focused on metab- sities. Her go-to advice is useful for positivity in action in his lab. She is a olism-related diseases of aging and scientists and nonscientists alike: methodical and determined scientist, hopes her research will inuence “Trust the process and trust your he said, focused on the greater goal drug discovery to combat these science. Stay the course. Trust your even when challenges arise. diseases. ideas and questions, and believe in “What truly amazes me is her yourself enough to know you can positive attitude during setbacks. I stand behind what you’re produc- see that her success on this challeng- Courtney Chandler ing.” ing road reects a tremendous degree ([email protected]) is a graduate student at ese words keep McReynolds of passion, determination and raw the University of Maryland, motivated. She likes the ever-chang- intelligence — plus her fantastic can- Baltimore. Follow her on Twitter @CourtneyEChan. ing nature of scienti c research and do attitude.” that every day brings new tasks and Now in her second year of

JUNE/JULY 2019 ASBMB TODAY 45 ESSAY Mental illness should not disqualify me By Susanna Harris

m I emotionally stable? is It was a true story of overcoming discussing science. I believe academia old question came crawling obstacles through eort, all in the can be a wonderful place where bril- A back when I saw a screenshot name of science. liant minds come together to help of a university recommendation e professor told me to make it each other. form that asked for an assessment clear that I was not relying on med- But am I emotionally stable? of students’ emotional stability.* ication or therapy; otherwise, the When we believe that we have Nestled between “is applicant application committee might not feel achieved our status by luck or help shows integrity” and “is applicant con dent in my abilities. ough his and that we would be dismissed if is able to give clear, concise oral words come back to annoy me when our true selves were discovered, that’s presentations,” the survey oered a I’m introduced as an advocate for called imposter syndrome. But what multiple-choice response to “is mental health, making me feel afraid if society at large, knowing our truth, applicant is emotionally stable.” or ashamed to speak so publicly to really wouldn’t think we belong? If How would I be scored? How my peers, I believe his advice was value in academia is based on the would I rate myself, and would that crucial in winning the fellowship. ability to think, what happens when rating matter if they knew my full My application might have a person admits their mind is some- background? ended up on the desk of a reviewer times broken? A memory bubbled up from who understood the value of seeking Should we encourage others to nearly four years ago. I was preparing help and of being wise enough to use be open about mental illness in a my application for the National Sci- it. Such amazing people surround space where they might face retribu- ence Foundation’s Graduate Research me now. But maybe my story would tion? It’s a valid question when being Fellowship Program. A professor in have been read by one of the many outed for mental illness really does my program was assigned to help people studies have shown to have threaten professional standing and edit the proposal, and I sat in his of- subconscious, or even conscious, can aect relationships throughout ce. e scienti c research was ne, biases against those of us with mental a career. he said; it was logically sound and illness. Maybe it would have been I am emotionally stable-ish. relevant to the foundation’s goals. read by someone who, like the pro- On medication and with ongoing e personal statement required fessor advising me, couldn’t see that a psychotherapy, I can handle more major improvements. diagnosed and treated mental illness stress and disturbances than ever “How do you show them you’re was not a weakness. before. I became able to do this only not just another little white girl?” In my personal statement, I by acknowledging that something I was shocked, but I now ap- wrote that I had nished treatment was wrong in the pipeline of my preciate his honesty that my bland for mental illness. at was true thoughts and making the terrifying story about loving science as a child when I submitted the proposal. A decision to get help. Without a sup- wouldn’t get me very far. year after I was awarded the NSF port system of doctors and friends, After digging around in my fellowship, my next mental health I operate well below my maximum brain, we examined how my love for crisis occurred. ability; with care and treatment, I am biology not only started when I was Would the NSF have funded me a successful graduate student, skillful young but also forced me to deal if they had known about all of this? researcher and overall way better with the crippling social anxiety that I am tenacious, responsible, reliable human. had been part of me for just as long. and intelligent. I love learning and Reaching out for support is a

46 ASBMB TODAY JUNE/JULY 2019 Should we encourage others to be open about mental illness in a space where they might face retribution?

sign of self-awareness and of our community. Instead of pressuring Susanna Harris strength. Estimates vary, but if a sig- our students and professors to hide (susannalharris@gmail. ni cant minority of graduate students their mental illnesses or disclose com) is a Ph.D. candidate in microbiology at the are struggling with symptoms of “emotional stability” status, let’s University of North Carolina mental illness, excluding anyone who create a system that supports them at Chapel Hill and founder of ThePhDepression, a project may be categorized as “emotionally throughout the relatively unstable to increase visibility of those unstable” will debilitate our academic paths of academia. in academia who struggle community. Enforcing a system of with mental health issues. Follow her on Twitter and Instagram @susannalharris. bias against disclosing mental illness *After I asked the university only pushes people to let their illness about its recommendation form, grow until it overtakes them. the question about emotional By providing support, we can stability was removed immediately. stabilize almost anything and make it It will be a much longer process more resilient — including a person. to remove these same questions We can change the environment from the minds of the application within academia to do just that, and reviewers and the prejudice I believe it will make us better as a that comes along with them.

JUNE/JULY 2019 ASBMB TODAY 47 ESSAY What I wish people understood about studying science at a small college

By Kerri Beth Slaughter

ometimes people ask me why I My professors simply memorizing the material. e chose to attend a small liberal changed science from class interactions also encouraged Sarts college to pursue a basic camaraderie among the students, and science degree. I won’t tell you that words in a textbook we spent many hours helping each attending a small school is the best to something that I other solve problems to prepare for choice for everyone, but it was the could see, touch and exams. right decision for me. imagine. My biology professor was As a kid in public school, I Michael Whitney. In one of our always made good grades, but my cell biology classes, he handed each teachers thought I was shy. I rarely of the building itself but because of student a container of Play-Doh, and spoke up to answer questions. I pre- the professors who invested in me. we spent part of the period molding ferred to listen and observe instead of Richard Lura taught organic actin monomers and tubulin dimers jumping into the discussion. When chemistry and biochemistry, two to learn about assembly of the cyto- I began looking at colleges, I was classes that often inspire a love–hate skeleton. Beyond being a fun activity daunted by the idea of attending a relationship for science students. for the students, Dr. Whitney’s eort large university with freshman classes He never used PowerPoint slides or to help us become visual learners of 100-plus students. tried to integrate technology in the sparked my fascination with the I eventually interviewed for classroom. Rather, he transformed a cytoskeleton, a topic that will be a scholarships at Milligan College, a basic science class into an interactive signi cant focus of my dissertation small Christian school nestled in discussion and learning experience. research. the Appalachian Mountains of East For the rst lecture of each new At Milligan College, I grew close Tennessee. e campus had few- unit in organic chemistry, instead of to the community of science pro- er students than my high school. plowing through the details of the fessors and students as we learned During my interview, I met with next chapter, Dr. Lura gave a broad together in the lab and classroom. three professors and the college pres- overview of the material. He engaged My professors changed science from ident. Although I was a little nervous the class in discussion about where words in a textbook to something that at rst, I started to feel at ease as I we might nd organic compounds I could see, touch and imagine. ey talked with them about my goals and in our daily lives or in industry. helped me learn how to ask thought- interests in science. ey helped me After studying for the previous unit’s ful questions about science instead of feel comfortable in my own skin, and exam, this discussion helped me accepting what I was told as fact. I was impressed by how much they remember the big picture of what I My professors also taught me enjoyed engaging with students. was learning. how studying science could strength- A few months later, I sat down Dr. Lura sometimes asked stu- en my Christian faith, and they at a desk for my rst class in the dents to act out chemical reactions provided a safe space to discuss Milligan science building, built in so we could visualize what happens controversial topics. Over time, I 1972; the funky architecture and at the molecular level. ese comical found myself speaking up in class funky smells were the rst things I demonstrations, such as modeling more often to answer questions and noticed. I didn’t realize how much I nucleophilic substitution reactions, build on class discussions. I was no would learn and grow there during helped me develop a deeper under- longer the shy kid sitting quietly in my four years in college, not because standing of chemistry instead of the corner of the classroom.

48 ASBMB TODAY JUNE/JULY 2019 Scientists can be born in the absence of state-of-the art research facilities and millions of dollars in funding. Sometimes all you need is a creative professor, an eager student and a bit of Play-Doh.

By senior year, I had decided to “coming out of your shell,” perhaps pursue a Ph.D. in biomedical science because I heard it too often as a kid. Kerri Beth Slaughter ([email protected]) so that I could become a science pro- However, I wholeheartedly believe is a graduate student in the fessor like the ones who inuenced that my professors at Milligan College biochemistry department at the University of Kentucky. me at Milligan College. I am now a helped draw me out so that I could Follow her on Twitter doctoral candidate in the biochem- reach my full potential as a scientist. @KB_Slaughter. istry department at the University Scientists can be born in the of Kentucky, and my small-school absence of state-of-the art research background has contributed greatly facilities and millions of dollars in to my success as a graduate student, funding. Sometimes all you need is scientist and communicator. a creative professor, an eager student I’ve never been fond of the phrase and a bit of Play-Doh.

Kerri Beth Slaughter, left, and fellow science club members dressed up as elements from the periodic table to hand out candy at Milligan

COURTESY OF KERRI BETH SLAUGHTER COURTESY College’s Trunk or Treat.

JUNE/JULY 2019 ASBMB TODAY 49 OUTREACH University program aims to serve and inspire future scientists

By Madison Honer & Maura Southwell

hen Edwin Li joined the school teachers and academic re- the desire, ability and opportunity to Saint Joseph’s University searchers. He recruited SJU micro- have a career in these elds.” W biology department in 2010, biologist Brian Forster, SJU science High School LINKS also pro- he noticed the school’s strong culture outreach coordinator Caitlin Fritz vides a unique opportunity for the of community service. As a Jesuit and honors biology teacher Matthew future scientists of SJU. Marly René institution, SJU encourages students Jurkiewicz from Bishop McDevitt works as an undergraduate LINKS and faculty members to work for High School in Wyncote, Pennsylva- fellow in Jurkiewicz’s honors biology social justice and serve others, a nia, to create High School LINKS, class. “is experience strengthened practice described in Latin as “cura modeled on the mentor-based my presentation and leadership personalis,” which translates as “care GeoKids program. ey developed a skills,” she said. “I also learned to for the entire person.” curriculum, “Genes, mutations and communicate better with students Li rst experienced science diseases: Understanding the origins and my peers, which will bene t outreach at SJU with a molecular of genetic disorders through experi- me in interacting with colleagues, biology graduate student, Jessica ential learning.” professors and professionals in the King, who was a GeoKids fellow. In the program, undergraduate future. e students are great and so e GeoKids Learning Integrating LINKS fellows, mentored by Li and eager to learn more. It really made Nature, Kids and Science, or LINKS, Forster, lead a ve-week unit focused me realize how much of an impact fellowship places graduate and on DNA structures and functions, outreach has on the community.” advanced undergraduate fellows into genetic mutation and inheritance, High School LINKS expand- rst- through fth-grade classrooms gene expression, and protein struc- ed in 2017 into Overbrook High in Philadelphia. Mentors from the ture and functions. e high school School, 10 minutes from SJU’s Wagner Free Institute of Science, a students learn techniques such as campus. e SJU faculty and under- museum in the city, work with the polymerase chain reaction, electro- graduates worked with Overbrook SJU fellows who co-teach weekly phoresis, bacterial transformation biology teacher Christina Johnson to hands-on lessons in natural science. and enzyme-linked immunosorbent develop a new curriculum focused “I noticed all of the outreach assay. e unit culminates in a eld on how genetic mutations can lead programs were focused on mac- trip to SJU’s laboratories, where they to biodiversity. During the unit, the ro-level biology — teaching elemen- analyze the phenotype, chromo- Overbrook students visit SJU’s bio- tary students about ecosystems and somes, proteins and DNA of three diversity lab to see sh, reptiles and organisms,” Li said. samples to determine which patients amphibians up close. Li wanted to develop an outreach are diagnosed with sickle cell anemia, e eld trip and the interac- program based in molecular biology, Down syndrome and Cri-du-chat tions with professors and college his area of expertise. He envisioned syndrome. students are priceless, Johnson said. undergraduate biology majors and Jurkiewicz, an SJU alumnus, “e LINKS program allows our high school students learning togeth- now has had LINKS fellows in his students who would normally not er and inspiring each other. classroom for six years. “For many go to a college lab during their high In 2013, Li applied for grants of my students,” he said, “the biggest school careers the opportunity to from the American Society for takeaway from the LINKS program engage and spark an interest. ey Biochemistry and Molecular Biology is to … see young men and women were able to visualize how genetics to fund a partnership between high just a few years older than them with can play a major role in the lives of

50 ASBMB TODAY JUNE/JULY 2019 JUNE/JULY 2019 May. in lab biodiversity University Joseph’s Saint the to trip ﬁeld the during hunt ascavenger completes student School High Overbrook an Below, March. in University Joseph’s Saint to trip ﬁeld their during students School High McDevitt Bishop to technique proper micropipetting demonstrates Li Edwin biologist molecular At right, ASBMB TODAY 51

MAURA SOUTHWELL & ASHLEY BLISS OUTREACH

living things such as an albino red share their passion for cellular and Madison Honer (mh641683@ ear slider turtle.” molecular biology, organismal and sju.edu) recently earned a On a recent eld trip, Overbrook evolutionary biology, or both. We B.S. in biology from Saint Joseph’s University, where High School students discussed how have met the diverse interest of our she led the High School skin color is determined by genetics. undergraduate students while also LINKS program at Overbrook High School. She will pursue eir observation of the animals’ ful lling the educational needs of graduate work in biology at body patterns led them to talk with our high school partners.” Saint Joseph’s and continue SJU students and faculty about how LINKS has served hundreds of her work in science outreach through the GeoKids LINKS fellowship. genetics in uence human skin color. high school students and has provid- One Overbrook student made the ed more than 20 SJU undergraduates Maura Southwell connection that the skin condition with experience in science outreach ([email protected]) is the project coordinator for vitiligo, where patches of skin lose and public engagement. science outreach at Saint pigment over time, may be linked to Alison Kloiber graduated from Joseph’s University, where she earned a B.S. and an an inheritable genetic mutation. SJU last year and is a High School M.S. in biology. Her thesis Li has realized his goal. “ e LINKS alumna. She now works in work focused on the effects of melatonin on adult continuation and expansion of High an internship using the skills she zebra sh behavior. Follow her on School LINKS has allowed us to developed in the program. “While Twitter @SJUscienceout. capture the interest of a wide range three years ago I was clueless about of students,” he said. “ is is one of this eld,” she said, “I am now the few outreach programs to o er considering (science outreach) as a SJU students the opportunity to potential career path.”

LINKS fellow Madison Honer focuses a dissecting scope for Overbrook High School students to see and try to pick a roundworm during their ﬁ eld trip to Saint Joseph’s University in May.

52 ASBMB TODAY JUNE/JULY 2019 MASS_V12.pdf 1 6/28/19 8:11 AM MASS_V12.pdf 1 6/28/19 8:11 AM

13th INTERNATIONAL SYMPOSIUM ON MASS SPECTROMETRY IN THE HEALTH AND LIFE SCIENCES: MOLECULAR AND CELLULAR PROTEOMICS Aug. 18 – 22, 2019 • Hotel Nikko, San Francisco Aug. 18 – 22, 2019 • Hotel Nikko, San Francisco

CHAIRS: A.L.CHAIRS: Burlingame, University of California, San Francisco StevenA.L. Burlingame A. Carr, Broad, University Institute of California,of MIT and San Harvard Francisco BernhardSteven A. Carr,Kuster,BroadTechnical Institute University of MIT ofand Munich Harvard Bernhard Kuster, Technical University of Munich

PROGRAM PARTIAL LISTING OF SPEAKERS PARTIAL LISTING OF SPEAKERS PLENARY SPEAKERS: MichalPLENARY Bassani-Sternberg, SPEAKERS: Ludwig Cancer Center, Switzerland Matthew Ellis, Baylor College of Medicine StevenMichal Bassani-Sternberg,Elledge, Harvard Medical Ludwig School Cancer Center, Switzerland MikeMatthew MacCoss, Ellis, Baylor University College of Washingtonof Medicine Steven Elledge, Harvard Medical School Mike MacCoss, University of Washington Marcus Bantscheff, Anne-Claude Gingras, Matthias Mann, Birgit Schilling, GlaxoSmithKMarcus Bantscheff, Lunenfeld-TanenbaumAnne-Claude Gingras, MaxMatthias Planck Mann, Institute of BuckBirgit Institute Schilling, for Research GlaxoSmithK ResearchLunenfeld-Tanenbaum Institute, Toronto BiochemistryMax Planck Institute of onBuck Aging Institute for Research Maria Barna, Research Institute, Toronto Biochemistry on Aging StanfordMaria Barna, University Sebastian Vaca Jacome, Florian Meier, Adam Sperling, Stanford University BroadSebastian Institute Vaca of Jacome, MIT MaxFlorian Planck Meier, Institute of Dana–FarberAdam Sperling, Cancer Institute Isabell Bludau, andBroad Harvard Institute of MIT BiochemistryMax Planck Institute of Dana–Farber Cancer Institute ETHIsabell Zurich Bludau, and Harvard Biochemistry Pierre Thibault, ETH Zurich Susan Klaeger, Tamara Ouspenskaia, UniversityPierre Thibault, of Montreal Chuna Choudhary, TechnicalSusan Klaeger, University of Munich BroadTamara Institute Ouspenskaia, of MIT University of Montreal UniversityChuna Choudhary, of Copenhagen Technical University of Munich andBroad Harvard Institute of MIT Jeff Twiss, University of Copenhagen Jeroen Krijgsveld, and Harvard UniversityJeff Twiss, of South Carolina Stuart Cordwell, GermanJeroen Krijgsveld, Cancer Research Jeffrey A. Ranish, University of South Carolina UniviersityStuart Cordwell, of Sydney CenterGerman Cancer Research InstituteJeffrey A. for Ranish, Systems Biology Namrata Udeshi, Univiersity of Sydney Center Institute for Systems Biology BroadNamrata Institute Udeshi, of MIT Michel Desjardins, Angus Lamond, Karin Rodland, andBroad Harvard Institute of MIT UniversityMichel Desjardins, of Montreal UniversityAngus Lamond, of Dundee PacificKarin Rodland,Northwest National and Harvard University of Montreal University of Dundee LaboratoryPacific Northwest National Michiel Vermeulen, Robert Gerszten, Janne Lehtiö, Laboratory RadboudMichiel Vermeulen, Institute for BethRobert Israel Gerszten, Deaconess KarolinskaJanne Lehtiö, Institute Hannes Röst, MolecularRadboud Institute Life Sciences for MedicalBeth Israel Center Deaconess Karolinska Institute UniversityHannes Röst, of Toronto Molecular Life Sciences Medical Center Kathryn Lilley, University of Toronto Mathias Wilhelm, Michael Gillette, UniversityKathryn Lilley, of Cambridge Mikhail M. Savitski, TechnicalMathias Wilhelm, University BroadMichael Institute Gillette, of MIT University of Cambridge EuropeanMikhail M. Molecular Savitski, Biology ofTechnical Munich University andBroad Harvard Institute of MIT LaboratoryEuropean Molecular Biology of Munich and Harvard Laboratory The main symposium will be preceded by a one-day minisymposium on the latest The main symposium will be preceded by a one-day minisymposium on the latest methods and applications of data-independent analysis. methods and applications of data-independent analysis. To see full program, register and book housing, visit: ASBMB.ORG/MASSSPECTROMETRY ANNUAL MEETING

Members of the American Society for Biochemistry and Molecular Biology shared their science, learned from others and made connections at the ASBMB annual meeting held April 6–9 at the Orange County Convention Center in Orlando, Florida. To see more photos, go to asbmb.org/asbmbtoday.

54 ASBMB TODAY JUNE/JULY 2019 JUNE/JULY 2019 ASBMB TODAY 55 FAST-TRACK YOUR ABSTRACT

HATE WAITING MONTHS TO HEAR IF YOUR MEETING ABSTRACT HAS BEEN ACCEPTED? The ASBMB’s priority consideration program is for you!

Submit your abstract for the 2020 ASBMB Annual Meeting in San Diego by Oct. 15 — you are guaranteed a decision within two weeks.

International researchers are encouraged to participate and get an early start on the visa process.

The Experimental Biology submission system will open in September.

MARK YOUR CALENDAR: The priority consideration deadline is Oct. 15 All early birds are eligible!

WWW.ASBMB.ORG/MEETING2020

ASBMB_TODAY_June-July2019_AbstractAd_V2.indd 1 7/1/19 11:01 AM CLASSIFIEDS

Texas Tech University Paul Foster Rutgers University - Robert Wood School of Medicine Johnson Medical School

Medical Educator Biochemistry (Assistant Professor or Higher) Tenure-Track Faculty Positions in Biomedical Science

The Texas Tech University Health Sciences Center El Paso - Paul L. Our faculty members drive federally funded research programs in Foster School of Medicine is seeking a highly qualied faculty member broad areas of biomedical science. We seek individuals with research to join our Department of Medical Education with an emphasis on interests that will complement and/or expand our existing strengths, teaching medical biochemistry. The successful candidate will assume a with special emphasis on work related to the human microbiome. Suc- major educational role working with an interdisciplinary team of fac- cessful candidates will be provided with access to high-performance ulty to develop and deliver an integrated clinical presentation-based computing clusters and other core resources, laboratory space at curriculum. The successful candidate will also engage in scholarship CABM, and will be expected to develop and maintain strong, external- and academic service activities aligned with individual interests, cre- ly funded research programs, and participate in collaborative projects dentials and experience.. with other Departments and Institutes on the campus. http://www.asbmb.org/Careers/Jobs/80347/ http://www.asbmb.org/Careers/Jobs/80308/

Gilead Sciences, Inc. The University of Montana Western

Research Scientist, Biophysics Professor of Biology

Gilead is seeking a motivated researcher to work in the Biophysics The successful candidate(s) will teach one section of our science major group within the Research organization. The successful candidate introductory cellular-level biology course, Principles of Living Systems will support discovery projects with development and execution of (BIOB160), two sections of our Biology major General Genetics course biochemical assays to measure protein activity, oligomeric state and (BIOB375) and one section of our Biology major Biochemistry course protein-ligand interactions using techniques such as UV-Visible and (BCH380). Montana Western uses a block schedule where our classes uorescence spectroscopy, analytical ultracentrifugation and calorim- etry. The candidate must be motivated, driven, creative, and able to all meet for at least three hours each day for 17 or 18 instructional work independently, and must display scientic rigor. The candidate days. The Biology Department’s courses are designed to provide will be required to select appropriate experimental approaches to students with authentic experiential learning opportunities that inte- address scientic questions. Responsibilities will include development grate both lecture and lab/eld topics most days of the block. This and troubleshooting of protein activity and protein-ligand binding is an outstanding opportunity for candidates who are trying to gain assays, data analysis and management, writing reports and SOPs, and undergraduate teaching experience, or for candidates who would like presentation to project teams and senior leadership. The successful to experience what teaching on a unique block schedule involves. All candidate will work in a team environment and will need to communi- courses will be capped at 24 students allowing for close interaction cate eectively. with undergraduate students. Candidates interested in teaching indi- http://www.asbmb.org/Careers/Jobs/80342/ vidual courses or all four courses are encouraged to apply. http://www.asbmb.org/Careers/Jobs/80174/ SEE YOU NEXT YEAR

SAN DIEGO | APRIL 4 – 7 20