CONTENTS

NEWS FEATURES PERSPECTIVES

2 18 48 EDITOR’S NOTE MYALGIC ENCEPHALOMYELITIS: RESEARCH SPOTLIGHT Not crying wolf UNKNOWN CAUSE. A love of teaching and the chemistry of living organisms 3 NO CURE. NEW HOPE NEWS FROM THE HILL 32 50 Appropriations season — FROM A BAVARIAN BACCALAUREATE OUTREACH what we want and how to help TO BACTERIAL BLEACH Sparking the flame of science 4 36 52 NEWS ESSAY Member update 2018 TABOR AWARD WINNERS Leadership: the sock’s-eye view 9 44 WHAT TO WEAR 54 LIPID NEWS WHEN SCIENCE MEETS SICKNESS The state of the lipid research community — AT THE ANNUAL MEETING improving grant review Science prepared me for cancer treatments, but nothing prepared me for surviving 10 JOURNAL NEWS 18 52 10 miRNAs take the wrecking ball to colorectal cancer 12 When HIV drugs don’t cooperate 13 A rare blood disease can teach us about blood clotting 14 Charting the mitochondrial interactome 15 From the journals 12

15 54 WHEN SCIENCE MEETS SICKNESS

MARCH 2018 ASBMB TODAY 1 EDITOR’S NOTE

THE MEMBER MAGAZINE OF THE AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY Not crying wolf By Comfort Dorn OFFICERS COUNCIL MEMBERS Natalie Ahn Squire J. Booker President Victoria J. DeRose Wayne Fairbrother ave you ever felt sick enough ovary syndrome — and the subject of Gerald Hart Rachel Green President Elect Blake Hill that you thought you should this month’s cover story: the almost see a doctor — made an unpronounceable myalgic Jennifer DuBois Susan Marqusee H Secretary Celia A. Shiffer appointment, took time off work, encephalomyelitis. Takita Felder Sumter hired a babysitter, spent an hour As Lily Williams reminds us in her Toni M. Antalis JoAnn Trejo Treasurer thumbing through ancient magazines feature story on page 18, ME used ASBMB TODAY EDITORIAL in the waiting room — only to be to go by the less accurate “chronic EX-OFFICIO MEMBERS ADVISORY BOARD told (implicitly or explicitly) that fatigue syndrome.” For years, it has Jin Zhang Rajini Rao you’re exaggerating, that it’s all in languished, with research that went Wilfred van der Donk Chair Co-chairs, 2018 Annual Charles Brenner your mind? Or the result of your bad, nowhere and patients disrespected. It Meeting Program Past Chair sloppy living habits? Or not really a mostly strikes women (though plenty Committee Ana Maria Barral big deal and it will go away soon? of children and some men get it), and Cheryl Bailey Floyd “Ski” Chilton If you’re nodding along, chances it’s difficult to diagnose and almost Chair, Education and Henrik Dohlman Professional Development Peter J. Kennelly are you’re female. impossible to treat. It’s finally getting Committee Beronda Montgomery There’s plenty of evidence — a bit of attention from the National Daniel Raben A. Maureen Rouhi enough that all those doctors should Institutes of Health, with $7 million Chair, Meetings Committee Melissa Vaught Binks W. Wattenberg be pretty embarrassed by now — that in targeted funding for four research Sonia Flores women are at greater risk for certain centers. Chair, Minority Affairs Committee ASBMB TODAY conditions that cause pain (migraines, I first heard of chronic fatigue Angela Hopp Susannna Greer for starters) and that they are treated in an interview with the author Executive Editor, Chair, Public Outreach [email protected] less aggressively for pain than men. Lauren Hillenbrand, who described Committee Comfort Dorn For the medical profession, I’m researching and writing her bestseller Matthew S. Gentry Managing Editor, sure it’s complicated. With insur- “Seabiscuit” while lying flat on her Chair, Public Affairs [email protected] Advisory Committee ance companies breathing down their back. That stuck in my mind because, John Arnst Amnon Kohen Science Writer, necks, doctors feel pressure to move although words are my job, even on Chair, Publications [email protected] patients in and out quickly. Like the my best day I have trouble stringing Committee Valery Masterson mechanic who can’t find the source them together. And Hillenbrand is no Designer, Lila M. Gierasch of that funny noise your car makes, outlier. A quick internet search shows Editor-in-chief, JBC [email protected] Ed Marklin a doctor might get impatient with that famous sufferers range from Flor- A. L. Burlingame Web Editor, Editor, MCP [email protected] someone who doesn’t have a clear-cut, ence Nightingale to musicians Randy Edward A. Dennis Allison Frick diagnosable and treatable problem. Newman and Cher to U.S. soccer star Editor-in-chief, JLR Media Specialist, So they put it back on the patient Michelle Akers. [email protected] William L. Smith or imply that if they can’t find it, it’s When I think of Lizzie Mooney, Editor-in-chief, JLR Barbara Gordon Executive Director, probably no big thing. the 12-year-old Illinois girl in Wil- [email protected] Part of this is undoubtedly plain liams’ story who has been terribly sick old garden-variety sexism. We’ve with ME for a quarter of her life, it For information on advertising, contact Pharmaceutical made some progress in gender equity, makes me wish doctors were more Media Inc. at 212-904-0374 or [email protected]. but men’s bodies are still regarded willing to listen to and believe their as the norm in many aspects of patients — and to admit they still life, including health. Much about don’t have all the answers. women, including their pain, remains a side note. In addition, the diseases www.asbmb.org/asbmbtoday that are difficult or impossible to Comfort Dorn PRINT ISSN 2372-0409 diagnose — those for which telltale ([email protected]) is managing markers have yet to be found — seem Articles published in ASBMB Today reflect solely the authors’ views and not editor of ASBMB Today. Follow her the official positions of the American Society for Biochemistry and Molecular largely to afflict women. Fibromyal- on Twitter @cdorn56. Biology or the institutions with which the authors are affiliated. Mentions of products or services are not endorsements. gia, autoimmune disorders, polycystic

2 ASBMB TODAY MARCH 2018 NEWS FROM THE HILL Appropriations season — what we want and how to help By Benjamin Corb

s the calendar turns to March, last year. Committee’s March 9 training webi- appropriations season begins on Funding increases at this level are nar on how to write an op-ed piece A Capitol Hill and advocates from not easy to come by. First, legislators (check the policy blog for details). every constituency kick their efforts responsible for determining budget Legislators and their staffs read local into high gear. The American Society levels must account for mandated papers to stay in touch with the issues for Biochemistry and Molecular Biol- caps to federal spending that have important to their constituents back ogy is no different, and we enter this been in place since 2011. These caps home. There is no better way to build spring with an invigorated interest limit the total amount of federal support for investments in your work in increasing the research budgets at spending authorized in a particular than telling the people and politi- the National Institutes of Health, the year for all discretionary funding. cians in your community about the National Science Foundation and The ASBMB has long been a proud impact your research might have on the Department of Energy’s Office of supporter and leader of Nondefense their lives. We urge ASBMB members Science. For fiscal year 2019, we are Discretionary United, a coalition of across the country to draft and pub- calling on Congress to increase federal federal, state and local organizations lish opinion pieces in local newspa- investments in the life sciences by 8 that have called for the raising of caps pers during the month of March. percent at all agencies. Particularly of on nondefense discretionary federal Writing an op-ed letter too much interest to the ASBMB community is spending, where the overwhelming work? Visit asbmb.org/advocacy for that this would mean an increase of majority of federal funds for science sample tweets and letters that you $2.6 billion to the NIH, $600 million come from. The ASBMB, NDD can personalize and share to tell your to the NSF and $430 million to the United and thousands of other groups representatives about the support you DOE’s Office of Science. have been working for years with need. Share your experiences with us The increases we are looking for congressional leaders on both sides of at [email protected]. We’ll fea- extend beyond the annual biomedi- the aisle to #RaiseTheCaps success- ture your tweets, letters and op-eds on cal research and development price fully three times, most recently in index inflationary rate of 2.2 percent. the current budget deal, which has our blog and spread the word about This accounts for inflation and also raised spending caps into fiscal year the important role you play in help- provides new dollars to increase 2019 — and we must continue to ing us to secure these much-needed funding rates across all three agencies. do so to ensure there is room in the funding increases this year. We look These increases are critical not only federal budget for increases in science forward to working with you. to ongoing research efforts but also to investments. create funding opportunities for new Legislators also must understand scientists beginning their careers, a that an increased investment in sci- Benjamin Corb constituency of the research com- ence is vital to their constituents and ([email protected]) is director of munity the NIH has been looking to to the nation. This is where we need public affairs at the ASBMB. Fol- support since the introduction of its your help. We hope you will partici- low him on Twitter @bwcorb. Next Generation Researcher Initiative pate in the Public Affairs Advisory

MARCH 2018 ASBMB TODAY 3 NEWS Member update By Erik Chaulk

NAS honors Doudna placed at No. 53 on Altmetric’s list of nationally televised program “Daniel the most influential scientific papers Foster, M.D.,” a weekly program that for CRISPR work of the year. focused on medical topics. He also Jennifer Doudna Medina-Bolivar’s research focus lies served on the President’s Council on has received the in plant metabolic engineering for the Bioethics. 2018 Award in production and discovery of pharma- Foster is survived by his wife, Dor- Chemical Sci- ceuticals. othy; three sons, Christopher, Daniel ences from the Altmetric is a digital science com- and Michael; and one grandchild. DOUDNA National Academy pany that collects and tracks data on of Sciences for co- scholarly content complementary to Cech named STORM inventing the gene-editing technology traditional citation metrics, includ- CRISPR-Cas9. ing mentions on social media and in science adviser CRISPR-Cas9 allows scientists mainstream media coverage. STORM Thera- efficiently to alter specific parts of peutics has named the genome. It has revolutionized the In memoriam: Thomas Cech as a field of genetics through its simplicity, science adviser. versatility and precision compared to Daniel W. Foster Founded in other gene-editing tools, demonstrat- Daniel W. CECH 2015, STORM ing the potential for a wide range of Foster, former Therapeutics is a applications. chairman of the British-based developer of small-mol- Established in 1978, the NAS department of ecule inhibitors of RNA-modifying Award in Chemical Sciences rec- internal medicine enzymes for the treatment of cancer. ognizes innovative research in the FOSTER at the University of A leading figure in the field of chemical sciences. The award carries a Texas Southwestern RNA research, Cech shared the 1989 $15,000 prize. Medical Center, passed away Jan. 18. Nobel Prize in chemistry for discover- Doudna is a professor of chemistry He was 87. ing the catalytic properties of RNA. and of biochemistry and molecular Foster received his bachelor’s He also received the Albert Lasker biology at the University of California degree from the University of Texas Basic Medical Research Award and at Berkeley. at El Paso in 1951 and obtained his the National Medal of Science. medical degree from UT Southwest- Cech is a distinguished professor Medina-Bolivar article ern in 1955, graduating first in his of chemistry and biochemistry at the class. University of Colorado, Boulder, and in Altmetric top 100 After completing his residency at director of the BioFrontiers Insti- Arkansas State Parkland Memorial Hospital in Dal- tute, an interdisciplinary bioscience University professor las and a research fellowship at the research and education hub with a Fabricio Medina- National Institutes of Health, Foster focus on improving human health. Bolivar’s research returned to UT Southwestern, joining has been recognized the faculty in 1962. He became a full In memoriam: MEDINA-BOLIVAR in Altmetric’s top professor in 1969 and was appointed 100 articles of 2017. chairman of internal medicine in Aloys L. Tappel Medina-Bolivar is among the 1987, a position he held until 2003. Aloys L. Tappel, a professor emeri- authors of a paper on plant tissue Foster contributed significant tus at the University of California, scaffolding titled “Crossing kingdoms: research that led to greater under- Davis, passed away Nov. 25 from Using decellularized plants as perfus- standing of obesity and diseases of the pneumonia. He was 91. able tissue engineering scaffolds.” heart and liver. Born Nov. 21, 1926, in St. Louis, The paper, published in Biomaterials, In 1974, he began hosting the Tappel studied chemical engineering

4 ASBMB TODAY MARCH 2018 American Academy of Microbiology names new fellows

Eight members of the American Society for Biochem- Congratulations to the following ASBMB members: istry and Molecular Biology are among the 96 new fel- • Thomas Dever, National Institutes of Health lows elected to the American Academy of Microbiology. • Borden D. Lacy, Vanderbilt University Medical The American Academy of Microbiology is an honor- Center ary leadership group within the American Society for • Shan-Lu Liu, M.D., Ohio State University Microbiology, which recognizes significant research • Beronda Montgomery, Michigan State University toward and promotion of microbiology. • Jean Patterson, Texas Biomedical Research Institute Over the past 50 years, more than 2,400 distin- • Holger Sondermann, Cornell University guished scientists have been elected as fellows in recog- • Michael Surette, McMaster University nition of their original contributions toward advance- • Hung Ton-That, University of Texas at Houston ment in the microbial sciences. at Iowa State University, where he sons, Steve and Paul; and 13 grand- ment of biochemistry and molecular earned his undergraduate degree. He children. biology at Oklahoma State University, then earned his Ph.D. in biochem- where he stayed for more than 40 istry at the University of Minnesota, In memoriam: years. where he met his future wife, Ardelle His research centered on the isola- Amber Fish. Eldon Carl Nelson tion and identification of metabolites of vitamin A, synthetic analogs and Tappel came to UC Davis in 1951 Oklahoma State related retinoids. as a member of the department of University professor A decorated faculty member, food science and technology. He Eldon Carl Nelson Nelson was recognized by the univer- remained on the faculty for 50 years, passed away at his sity with the outstanding professor, focusing on teaching food biochemis- home Dec. 27. He outstanding adviser and outstanding NELSON try and nutrition. was 82. mentor awards. Among his many accolades, Tap- Nelson was born Dec. 13, 1935, He is survived by his wife, Jo; pel received the 1965 Guggenheim in Dola, Ohio. He attended the Ohio daughters, Laura and Julie; and four Fellowship, the 1973 Borden Award State University, graduating in 1957 grandchildren. from the American Institute of Nutri- with a degree in animal science and tion, and the 1991 Award for the agricultural education. After teach- Advancement of Application of Agri- ing at Belle Center High School for cultural and Food Chemistry from a year, he returned to Ohio State, Erik Chaulk ([email protected]) is a peer-review coordinator and the American Chemical Society. receiving his master’s in 1960 and digital publications web specialist He is survived by his wife, Amber; Ph.D. in 1963. at the ASBMB. daughters, Susan, Mary, Cath and Liz; Nelson then joined the depart-

Send us your news Have you recently been promoted or honored? Do you have good news to share with your fellow ASBMB members? Email it to us at asbmbtoday@ asbmb.org — and don’t forget to include a photo!

MARCH 2018 ASBMB TODAY 5 WELCOME, NEW ASBMB MEMBERS

Emmanuel Adeyemi, University of Lagos Tiffany Brandt, University of Louisville Haoyun Fang, University of Melbourne Gul Afshan, Milwaukee School of Engineering Richard Breyer, Vanderbilt University Elizabeth Feldman, Nova Southeastern University Vinayak Agarwal, Georgia Institute of Technology Amanda Bries, Iowa State University Grace Ferri, Boston University Leopoldo Aguilera–Aguirre, University of Texas Irina Bronova, National Jewish Health Alexander Finnegan, San Francisco State University Medical Branch at Galveston Merissa Brousseau, Boston University Stephen Floor, University of California, San Carolyn Albert, Saint Louis University Francisco Tristan Brunet, Rhodes College Kimberly Alonge, University of Washington Catherine Fox, University of Wisconsin Medical Hoang (Gwen) Bui, Nova Southeastern University School Ana Paula Alonso, University of North Texas Haley Burger, Pitzer College Fred Fregoso, California State University, Northridge Adnan Alrubaye, University of Arkansas Karol Canales, Vanguard University Molly Gaddis, California Polytechnic State University Benjamin Anderson, Purdue University Celso Caruso–Neves, Universidade Federal do Rio Pascal Gagneux, University of California, San Diego Kelsie Anson, University of Colorado Boulder de Janeiro Sehamuddin Galadari, United Arab Emirates Costin Antonescu, Ryerson University Miguel Cervantes–Ramirez, Universidad Autónoma University, College of Medicine de Baja California Mounika Aramandla, Rhodes College Nisarg Gandhi, Montclair State University Alesa Chabbra, Nova Southeastern University Jacob Athoe, Boston University Malcolm Gardner, J. Craig Venter Institute Jean-Philippe Charrier, bioMerieux Brittanie Atkinson, Oklahoma Health Science Center George Gassner, San Francisco State University Christine Chatas, Alexion Monica Awad, Vanguard University Darwin Gawat, San Francisco State University Lin Chen, Boston University Tyler Ball, University of Wisconsin–Stout Anne George, University of Illinois College of Steven Chuh, Juniata College Sushanta Banerjee, University of Kansas Medical Dentistry Center/ Veterans Administration Medical Center Philip Cohen, University of Dundee Matthew George, Rhodes College Meghan Bannow, University of Wisconsin–Stout Carina Collins, Drury University Homa Ghalei, Emory University Allan Barraza, Nova Southeastern University Miguel Colon, Central Connecticut State University Mike Gillette, Broad Institute of the Massachusetts Michal Bassani–Sternberg, Centre Hospitalier Irazu Contreras, Universidad Autonoma del Estado Institute of Technology and Harvard University Universitaire Vaudois/Université de Lausanne de Mexico Laura Glasscock, Winthrop University Shraddha Basu, South Dakota State University John Corbett, University of Texas Southwestern Danea Glover, State University of New York Upstate Arindam Basu Sarkar, University of Findlay, College Victor Corces, Emory University Medical University of Pharmacy Roslyn Crowder, Stetson University Liam Goldman, Rhodes College Jamie Baxter, University of Toronto , Universidad Central del Caribe Krystyna Cwiklinski, Queen's University Belfast Maxine Gonzalez David Bear, University of Arizona College of Medicine Evan Greenawalt, Thomas Jefferson University Katie Dam, Boston University Leticia Beltran, University of Kansas Dionne Griffin Hung Dang, Texas A & M University Isaac Benque, Boston University Wezley Griffin, University of Arkansas for Medical Paige Darrow, Boston University Sciences Alexandra Berkowicz, Milwaukee School of Chandravanu Dash, Meharry Medical College Engineering Laurie Grove, Wentworth Institute of Technology Jose Del Toro–Dominguez, University of Puerto Rico, Mark Betonio, Rhodes College Maxwell Gyamfi, North Carolina Central University Río Piedras Brianna Betton, Rhodes College Tahar Hajri, Hackensack University Medical Center Jason Den Haese, D'Youville College and Roswell Niraj Bhatt, Council of Scientific and Industrial Park Comprehensive Cancer Center Elizabeth Harrington, Brown Medical School/ Research–Institute of Genomics and Integrative Providence Veterans Administration Medical Center Arti Dumbrepatil, University of Michigan Biology Elizabeth Hartland, University of Melbourne Matthew Eckwahl, University of Chicago Judy Birschbach, Milwaukee School of Engineering Vanessa Hayashi, Boston University Center for BioMolecular Modeling Jasmine Edwards, Rochester Institute of Technology Candace Hayes, Rhodes College Emily Bliss, Otterbein University Emily Eggleston, Vanguard University Francesca Healy, Rhodes College Madison Blue, Hendrix College Leon Elcock, University of Delaware Joshua Heazlewood, University of Melbourne Nicholas Eleuteri, Boston University Bryanna Boese, University of Wisconsin–Stevens Håkan Hedman, Umeå University Point Stephanie Esonwune, Boston University Michael Heiges, University of Wisconsin–Stout Alisdair Boraston, University of Victoria Sernah Essien, Boston University Victoria Henderson, Trinity University Eric Bortz, University of Alaska Anchorage Jose Estrada, Universidad Autonoma del Estado de Yasmin Hilmi, Southwest College of Naturopathic James Bottesch, Eastern Florida State College Mexico Medicine

6 ASBMB TODAY MARCH 2018 WELCOME, NEW ASBMB MEMBERS

Megan Hoffman, Boston University Jamie Kuhns, University of Wisconsin–Stout Kinsey McGlasson, Rhodes College Fanghui Hua, State University of New York Upstate Cindy Kyi, University of Missouri Colin McGonagle, University of New Hampshire Medical University Johant Lakey, Instituto de Investigaciones Científicas James McIsaac, Northeastern University Mia Huang, University of California, San Diego y Servicios de Alta Tecnología de Panamá–Asociación Derek McKay, University of Calgary de Interés Público Yongqi Huang, Hubei University of Technology Jonathan Messerschmidt, Boston University Audrey Lamb, University of Kansas Nadia Hyatt, Rhodes College Gero Miesenbock, University of Oxford Noah Langenfeld, University of Wisconsin–Stevens Lauren Iacobelli, Wayne State University School of Point Luis Milburn, Rhodes College Medicine Robert Langer, Massachusetts Institute of Jacob Miller, West Virginia University Dariya Ignatenko, University of California, Santa Technology Barbara Gayan Mirihana Arachchilage, Howard Hughes Jack Lawler, Beth Israel Deaconess Medical Center Medical Institute, Yale University Sozaburo Ihara, Institute for Adult Diseases, Asahi Life Foundation Elizabeth Lawlor, University of Michigan Adeba Mohammad, Western University , Qassim University Archana Iyer, Georgia State University Litza Ledesma Monjaraz, Mount Saint Mary's Abdelmarouf Mohieldein University, Los Angeles Robert Molday, University of British Columbia Ashleigh Jackobel, State University of New York Upstate Medical University Alexandra Lee, Rhodes College Kelsey Moore, Medical University of South Carolina Walter Jacob, Providence College Keren Lee, Rhodes College Julie Morgan, Georgia State University Sajith Jayasinghe, California State University Andrew Lempner, Rhodes College Frans Mulder, Aarhus University Kristen Jew, San Francisco State University Cheng-Han Li, National Tsing Hua University Anoushka Mullasseril, Rhodes College Brittany Johnson, University of Texas Southwestern Fuchuan Li, Shandong University Crystabel Munoz, Mount Saint Mary's University Medical Center Wei Li, Institute of Zoology, Chinese Academy of Emily Murphy, Boston University Courtney Johnson, University of Texas Health Science Sciences Kendall Muzzarelli, Wayne State University School Center at San Antonio Guosheng Liang, University of Texas Southwestern of Medicine Janae Jones, Mount Saint Mary's University Medical Center Reiner Neil, University of British Columbia Nabil Junaidi, University of Wisconsin–Stout Abby Lidoski, Rhodes College Sophia Nguyen, Nova Southeastern University Aron Kamajaya, California Institute of Technology David Liu, Washington State University Nabeel Nissar, Boston University John Kane, University of California, San Francisco Melissa Lodoen, University of California, Irvine Weining Niu, Northwestern Polytechnical University Cardiovascular Research Institute Madison Lopp, Vanguard University Luiza Nogaj, Mount Saint Mary's University Peter Karp, SRI International Molly Loughrin, University of Wisconsin–Stout Cesar Nopo–Olazabal, Eurofins Lancaster Kyle Kaster, Des Moines University Amanda Lowe, Vanguard University Laboratories Inc. Ildiko Kasza, University of Wisconsin–Madison Slawomir Lukomski, West Virginia University School Monika Oberer, University of Graz Scotland Kemper, Rhodes College of Medicine Alexis Osbourne, Vanguard University Fusun Kilic, University of Arkansas College of John Magnani, GlycoMimetics Maggie Palopoli, Rhodes College Medicine Adebayo Makanjuola, Nigerian Society of Pornpen Panomwan, Princess of Naradhiwas Sophia Kisling, University of Nebraska–Lincoln Biochemistry and Molecular Biology University Rachel Klevit, University of Washington Ryan Maki, University of Wisconsin–La Crosse Lisa Parlato, University of Wisconsin–Stevens Point Rochelle Knier, University of Wisconsin–Stout Francesca Manea, Berkeley Lab Carrie Partch, University of California, Santa Cruz Bruce Knutson, State University of New York Upstate John Marino, National Institute of Standards and Ronald Payne, Indianapolis University School of Medical University Technology Medicine Pallavi Kompella, University of Texas at Austin Tanner Martinez, Rhodes College Niharika Pentakota, University of Queensland Sunnie Kong, Boston University Michelle Martinez–Montemayor, Universidad Daniel Pereira, University of Connecticut Central del Caribe School of Medicine Oleg Kovrov, Umea University Patricia Perez, Mount Saint Mary's University Andrew Mason, King's College London David Kranz, University of Illinois Viviana Perez Hernandez, Nova Southeastern Thomas Matthews, Rhodes College University Klaus Kratochwill, Medical University of Vienna Aras Mattis, University of California, San Francisco Sherket Peterson, Johnson & Johnson Michael Krause, University of Wisconsin–Stevens Point Elizabeth May, Harvard University Christopher Petty, Boston University Amanda Krueger, University of Wisconsin–Stevens Matthias Mayer, Zentrum für Molekulare Biologie der Leslie Poole, Wake Forest University School of Point Universität Heidelberg Medicine

MARCH 2018 ASBMB TODAY 7 WELCOME, NEW ASBMB MEMBERS

Rebecca Portugal, American Chemical Society Russell Sands, Rhodes College Jeffery Tessem, Brigham Young University Student Affiliates Marissa Schafer, Mayo Clinic Kourtland Thompson, University of Wisconsin–Stout Jacques Pouyssegur, Centre National de la Michelle Schaffer, Eastern Illinois University Yee Mon Thu, Grinnell College Recherche Scientifique Mike Schaid, University of Wisconsin–Madison Monali Praharaj, Johns Hopkins University Gemma Topaz, Roxbury Community College Stephanie Schroeder, Webster University Joseph Quinlan, University of Delaware Zally Torres, University of Puerto Rico, Rio Piedras Russel Sequeira, Wake Forest Institute of Gersham Rainone, Providence College Dwight Towler, University of Texas Southwestern Regenerative Medicine Medical Center David Ramírez, Worcester Polytechnic Institute Nicholas Seyfried, Emory School of Medicine Sydney Townsend, University of Nebraska–Lincoln Brigette Rankin, Providence College Hunter Shelton, Rensselaer Polytechnic Institute Tran Doan Ngoc Tran, Texas A & M University Itthipoaln Rasasack, Rhodes College Heegwon Shin, Korea Advanced Institute of Science Shailendra Rathore, Cornell University and Technology Samuel Trenner, Rhodes College Jeffrey Ravetch, Rockefeller University Shunichi Shiozawa, Kyushu University Lata Udari, Eastern Illinois University Austin Rawlings, Covenant Academy Varda Shoshan–Barmatz, Ben–Gurion University Haruna Ueda, University of Tsukuba Richard Redfearn, University of Tennessee Health Kausik Si, Stowers Institute for Medical Research Yuri Ueda, National Cancer Center East Japan Science Center Laurence Sibley, Washington University Shalom Umunnakwe Derek Reese, Emporia State University Jeffrey Sigman, St. Mary's College of California Taylor Underwood, Vanguard University Dakota Reinartz, Hampden–Sydney College Amar Singh, Veterans Administration Palo Alto Selena Vanapruks, Colgate University Natalia Reiss, Providence College Health Care System Sonika Vatsa, Boston University Hongmei Ren, Wright State University Garima Sinha, Rutgers Biomedical Health Sciences at Newark Carlos Vera, University of Colorado Boulder Rossellini Renolo, San Francisco State University Mallory Smith, University of Kansas Medical Center Astrid Viera, Vanguard University Nathaniel Reynolds Alan Smrcka, University of Michigan Medical School James Villanueva, International American University Kyu Rhee, Weill Cornell Medical College College of Medicine Ola Söderberg, Uppsala University Victoria Rhodes, Missouri Southern State University , United States Department of Ramiz Somjee, Rhodes College Catherine Vrentas Denis Richard, Quebec Heart and Lung Institute Agriculture Haizhao Song, Tsinghua University Morgan Rickley, Clarion University of Pennsylvania Isha Walawalkar, Boston University Mallory Soska, Otterbein University William Rinaldi, Providence College Jian-Hua Wang, Institute Pasteur of Shanghai, Susan Stapleton, Western Michigan University Samuel Rivero–Hinojosa, Children's National Health Chinese Academy of Sciences System Camilla Stejskal, Boston University Colin Welsh, Rhodes College Everett Roark, William Carey University College of Brittney Stevens, Vanguard University Osteopathic Medicine Kathleen Wendover, Hendrix College Edward Stites, Salk Institute for Biological Studies Alexander Robbins, University of Wisconsin–La Joshua Weseli, University of Wisconsin–La Crosse Omar Stocks, Rhodes College Crosse Connor West, Medical University of South Carolina Brandon Strong, California Polytechnic State Destany Rocha, Vanguard University University, San Luis Obispo H. Steven Wiley, Pacific Northwest National Lab Johnna Roose, Louisiana State University Edward Stuenkel, University of Michigan Lauren Wilson, University of Arizona Rachel Rosencrans, University of Wisconsin–La Dawoud Sulaiman, University of California, Los Christopher Winski, University of the Incarnate Word Crosse Angeles Tiffany Wong, University of Maryland Lauren Rowland, Rhodes College Ewa Swiezewska, Polish Academy of Sciences , Johns Hopkins School of Medicine Rocio Rueda Jie Xiao Julianna Szuwalski, Rhodes College Catherine Ruesch, Princeton University Wuhan Xiao, Institute of Hydrobiology, Chinese Tiffany Tadros, Vanguard University Academy of Sciences Rick Russell, University of Texas at Austin Danyal Tahseen, Trinity University Xuebiao Yao, University of Science and Technology Christopher Ruth, University of Arkansas Tari Tan, Harvard Medical School of China Ratchell Sadovnik, Northeastern University Kaare Teilum, University of Copenhagen Victor Yu, University of Arizona Kamalika Saha, Sanofi Conor Templeton, Medical University of South Jin Zhang, University of California, San Diego Komal Sampat, Texcell–North America Inc. Carolina Feng Zhao, Puer University Mariel Sanchez, University of New Mexico/Central Kaleb Tenhagen, University of Wisconsin–Stevens New Mexico Community College Point Miaoyun Zhao, University of Nebraska–Lincoln

8 ASBMB TODAY MARCH 2018 LIPID NEWS The state of the lipid research community — improving grant review By Binks Wattenberg

have just returned from bership. The SROs’ responses Washington, D.C., where I have been very enthusiastic. I was on a National Institutes Finding qualified reviewers with of Health study section. I am the right expertise is one of their happy to report that the state of most time-consuming chal- the lipid research community is lenges. They definitely will use excellent. But it always can be our results. better, particularly when getting We know there are more our grants reviewed, and that qualified reviewers out there, is a prime focus of the Ameri- and the SROs would love can Society for Biochemistry to have them serve on their and Molecular Biology’s Lipid panels. So rather than the usual Research Division, or LRD. kvetching around the bar about NIH PHOTO the terrible review your lipid The underlying premise of National Institutes of Health study sessions meet at the main NIH grant received, here is how you a new LRD initiative is that campus in Bethesda, Maryland, shown in this aerial photo. can help. First, if you do lipid grants with a lipid focus suffer research and are not an LRD when study sections do not sent out to the LRD membership to member, join us. Go to the have sufficient lipid-centric reviewers. capture the review experience and Lipid Corner under the “About Us” Although the scientific review officers, research expertise of each member. tab at asbmb.org and click the red or SROs, work to get relevant exper- The response? Not bad, but could be “Join the Lipid Research Division” tise on the panels, several have told better. Out of the total membership, button. Second, only a little more me they sometimes struggle to find 348 received the survey. (Why not than half of the LRD membership lipid reviewers. We need individuals all? Explanation below.) Of those, received the survey, because many of on these panels who can put the lipid we received 143 responses — an you have asked not to receive e-mails work into context for the other study outstanding response rate for this from the ASBMB. We have no way to section members. Toward this end, kind of survey request. The survey reach you. Please consider changing we have an ongoing effort to improve identified 46 individuals who have this in your profile so we can get in the review of lipid-related grants by NIH reviewing experience, which is touch. identifying qualified reviewers with the strong preference of the SROs, While the state of our community lipid expertise. This has been a three- and an additional eight U.S.-based is strong in many ways, the fate of phase effort. researchers with non-NIH reviewing lipid grants is in your hands, in more First, early last year we reached experience. Those individuals might ways than one. Help us to help you. out to the ASBMB membership to be recruited by SROs to increase the encourage members involved in lipid ranks of reviewers. research to join the LRD if they had In the third phase, the results of Binks Wattenberg (brian. not done so already. This has swelled [email protected]) is the survey, in spreadsheet form, are an associate professor in the the ranks of the division, and we are now being distributed to SROs of department of biochemistry and now 640 members strong. study sections that historically have molecular biology at Virginia The second phase was a survey handled grants from the LRD mem- Commonwealth University.

MARCH 2018 ASBMB TODAY 9 JOURNAL NEWS miRNAs take the wrecking ball to colorectal cancer By Rachel Evans

Analogies for cancer abound, from The “construction materials” in these miRNAs are the city workers a military-style battle against villain- cancer are often lipids that provide that come in to block shipments and ous cells that mutate and harm the energy for ever-growing cancer cells. stop work on the illegal building. peaceful host to a garden where doc- Many of these cells have altered In their latest project, the group tors pluck out the weedy cancer and lipid metabolism to enable rapid sought to identify miRNAs specific nourish the helpful immune cells. A growth and carcinogenesis in a harsh to the ACSL/SCD network that laboratory in the molecular oncol- tumor microenvironment. IMDEA combat cancer cells. In extensive ogy group at the Madrid Institute researcher Ana Ramirez de Molina bioinformatics assays using miRNA- of Advanced Studies, or IMDEA, and her Ph.D. student, Silvia Cruz detecting algorithms, they identified Research Institute on Food and Gil, explain that the group previ- 31 miRNAs that may bind a region of Health Sciences in Spain sometimes ously identified a key pathway in mRNA, leading to reduced expres- views cancer as an illegal construction altered lipid metabolism, known as sion of the ACSL/SCD network. The project. Researchers who focus on the abnormal acyl-CoA synthetase/ researchers then confirmed the roles the role of lipid metabolism in cancer stearoyl-CoA desaturase, or ACSL/ of miRNAs with RNA and protein describe the disease as an unauthor- SCD, lipid network, which promotes detection techniques. They identified ized building that requires delivery invasion and migration of colorectal three main miRNAs that reduced of construction materials (nutrients) cancer cells. Inhibitors of the ACSL/ both RNA and protein expression: as the structure (tumor) grows. Their SCD network actually reduce cancer miR-544a, miR-142 and miR-19b. goal is to understand how to block cell viability. This network could The expression of miRNA-19b delivery and use of these materials. present a novel colorectal cancer corresponded to disease outcome: In a paper in the Journal of therapy target, so the group wanted to low levels of expression were cor- Lipid Research, these researchers identify inhibitory miRNAs, as these related with increased symptoms and describe how they identified unique have emerged as “potent epigenetic disease progression. The group used microRNA networks that may limit modulators of cellular homeosta- cell invasion assays and biochemical delivery of these resources to cancer- sis,” Ramirez de Molina said. In the techniques to show that miRNA-19b ous cells and help combat the disease. cancer-as-construction metaphor, expression reduces adhesion and inva-

COURTESY OF ANA RAMIREZ DE MOLINA/IMDEA RESEARCH INSTITUTE ON FOOD AND HEALTH SCIENCES In colorectal cancer patients, higher expression of miR-19b is associated with better survival. This can be thought of as having more city workers (miRNAs) to prevent delivery of construction materials for cancer via the ACSL/SCD network.

10 ASBMB TODAY MARCH 2018 sion through direct targeting of the ACSL/SCD network. They also found that miRNA-19b expression reduced lipid storage and respiratory capacity Upcoming ASBMB events — curtailing metaphorical resources for the ever-growing building. Treat- and deadlines ing patients with miRNAs like 19b potentially would provide targeted, tailored reduction of oncogene expres- 6–9: ASBMB–Deuel Conference on Lipids sion to reduce cancer progression. miRNA levels also may indicate MAR 9: Public Affairs Advisory Committee training disease severity and give physicians a webinar on how to write an op-ed clearer understanding of individual 15: Accreditation application deadline patients’ cases. Ramirez de Molina encourages health systems to use miRNA detection especially for 12: Capital Hill Day colorectal cancer, because it often APR 13: IMAGE grant-writing workshop shows minimal symptoms until the nominations deadline disease has spread extensively. She is excited about tools like miRNAs. 16: Outreach Student Chapters grants deadline “The possibility to detect them as 21–25: ASBMB annual meeting early detection biomarkers and to 30: Art of Science Communication Course modulate their action would represent a promising and very advantageous applications open tool against cancer progression,” she said. 2: ASBMB award nominations deadline Further research on therapeutic MAY use of miRNAs is needed, and these findings provide excellent fuel for such studies. The lab now is studying 1: Marion B. Sewer Distinguished Scholarship the ACSL/SCD network in complex JUN for Undergraduates deadline tumor organoids of colorectal cancer as well as tumors in other types of 14–16: IMAGE grant-writing workshop cancer. Their discovery of these net- works and their respective miRNAs could help identify more city workers in the body that will block progress of this illegal construction; future work likely will shed more light on the networks delivering fuel and supplies to harmful cancer cells.

Rachel Evans (revans46@jhmi. edu) is a Ph.D. candidate at the Johns Hopkins Bloomberg School of Public Health. When she is not in the lab studying malaria development and antimalarial resistance, she is baking up a storm in her apartment.

MARCH 2018 ASBMB TODAY 11 JOURNAL NEWS When HIV drugs don’t cooperate By Sasha Mushegian

The term “synergy” has gained a reputation as an overused buzzword, but it has a quantifiable definition in pharmacology. Two drugs are consid- ered synergistic if their effectiveness when used together is greater than the sum of their effects alone. That is, a drug that is synergistic with another doesn’t just perform a beneficial func- tion itself but makes the second drug perform its function better. Researchers at Thomas Jefferson University studying combinations of drugs against HIV have discovered why some drugs sometimes act syner- gistically but sometimes do not. The paper describing their research was Koree Ahn applied various doses of host cells, which can vary significantly Journal of Biologi- published in the maraviroc and enfuvirtide to cells and among patients. “Some (patients) cal Chemistry. viruses with slightly different genetic might have very high levels of (co- Second-line HIV drugs, used sequences. receptors) on their T-lymphocytes, after first-line treatments have failed, “We found that many different and those patients would see robust target several steps in the process factors are important for (determin- synergy between these two classes of by which the virus enters human T ing) whether there’s a synergistic drugs,” Root said. “Another indi- cells. Because of the particular steps interaction between these two classes vidual might have lower levels of and proteins they target, two types of inhibitors or not,” Ahn said. co-receptors on the cell surface, and of these drugs, called co-receptor The first factor was the strength therefore not have as robust synergy, antagonists and fusion inhibitors, of the binding between enfuvirtide or none at all.” are expected to be synergistic. But and gp41, which could vary depend- Together, these results suggest that multiple previous studies have yielded ing on mutations in the viral gene variations in viruses and in patients contradictory results: sometimes these that encodes gp41. If the sequence need to be considered when predict- drug classes were indeed strongly syn- of the gp41 protein was such that ing the efficacy of drug combinations, ergistic, but sometimes they displayed enfuvirtide bound to it very tightly, including newly developed co-recep- no synergy at all. then enfuvirtide and maraviroc acted tor antagonists and fusion inhibitors. Co-receptor antagonists like synergistically. But the weaker the The paper by Ahn and Root suggests maraviroc (marketed under the brand binding, the weaker the synergy mathematical models for doing just name Selzentry) bind to receptors between the two drugs. that. on host cells known as co-receptors. This finding implies that when “You need to use these (drugs) with Fusion inhibitors like enfuvirtide virus proteins evolve to avoid bind- care,” Root said. “Drug resistance can (marketed as Fuzeon) bind to a viral ing drugs, it doesn’t affect only the emerge with either one, and when protein called gp41 when it’s in a efficacy of the drug in question; it resistance emerges you lose that extra particular transitional phase. To also affects how much its effects are benefit of synergy.” understand why these drugs don’t boosted by other drugs. This is bad always synergize as expected — and news for patients, because adding syn- to gain a better understanding of the ergistic drugs to a treatment regimen Sasha Mushegian (amushegian@ steps of the HIV infection process is thought to be a way to combat loss asbmb.org) is scientific communi- — associate professor of biochemis- of drug efficacy. cator for the Journal of Biological try and molecular biology Michael The second factor affecting synergy Chemistry. Root and his then-graduate student was the density of co-receptors on

12 ASBMB TODAY MARCH 2018 JOURNAL NEWS A rare blood disease can teach us about blood clotting By Sasha Mushegian

When a person is thought that the anti- injured, blood clotting thrombin function was is essential. However, mainly focused on one once the danger has domain of the protein. passed, it is equally With this work, we essential to stop the have realized that is not clotting response in true.” order to prevent throm- The researchers’ anal- bosis, or the obstruction yses of the new muta- of blood flow by clots. tions suggested that the A protein called anti- domain of the anti- thrombin is responsible thrombin at the oppo- for stopping coagula- site end of the reactive tion, but about one in center loop helps keep 2,000 people have a the thrombin trapped in hereditary deficiency in its final, distorted form. antithrombin that puts When there were spe- them at much higher cific mutations in this risk of life-threatening region, the thrombin blood clots. was more often able to Researchers in Spain return to its active form have analyzed the muta- and degrade and release tions in the antithrom- COURTESY OF IRENE MARTÍNEZ–MARTÍNEZ/UNIVERSIDAD DE MURCIA the antithrombin. bin proteins of these A ribbon diagram of antithrombin highlights locations of functionally important mutations. Martínez–Martínez patients and discovered hopes that understand- that a section of the thrombin by inserting a loop-shaped ing the importance of protein plays an unexpected role in region, called the reactive center loop, this region of the antithrombin could its function. This insight into how into the active site of the thrombin lead to better drugs for preventing antithrombin works could lead not protein, preventing thrombin from blood clotting by activating anti- only to treatments for patients with catalyzing clot formation by distort- thrombin or preventing bleeding by antithrombin deficiency, but also to ing the shape of the thrombin’s active inhibiting it. She also emphasizes that better-designed drugs for other blood site. Many antithrombin mutations the essential nature of this domain disorders. The research was pub- that cause clotting diseases directly of the protein could not have been lished in the Journal of Biological or indirectly affect the reactive predicted from simply studying the Chemistry. center loop. However, biochemi- sequences of healthy antithrombins. The Centro Regional de Hemo- cal studies led by Irene Martinez– “This work has been possible donacion and Hospital Universitario Martinez discovered that mutations thanks to the characterization of Morales Meseguer of the Universidad in a completely different part of the mutations identified in patients,” de Murcia in Spain is a reference cen- antithrombin also contributed to its Martínez–Martínez said. ter for the diagnosis of antithrombin dysfunction. deficiency. For more than 15 years, “We saw that we (had) mutants researchers at the laboratory have that were affecting the function of the been receiving samples from patients Sasha Mushegian (amushegian@ protein even though they were very asbmb.org) is scientific communi- with diverse mutations that affect far from the main part of the protein cator for the Journal of Biological how their antithrombin works. that is in charge of the inhibition,” Chemistry. Antithrombin normally inhibits Martínez–Martínez said. “People

MARCH 2018 ASBMB TODAY 13 JOURNAL NEWS

Charting the mitochondrial interactome By Saddiq Zahari

As the powerhouses of the mitochondria function are cell, mitochondria host vari- two sides of the same coin,” ous supramolecular protein said co-author Philip Lössl. complexes. Delineating “We believe that our protein the structural basis of these maps will help us understand protein complexes is essential the organization principles to improve our understand- that allow mitochondria to ing of how mitochondria work as molecular power- function and generate houses.” energy. In a study published Chemical cross-linking in Molecular & Cellular and mass spectrometry Proteomics, Albert Heck COURTESY OF PHILIP LÖSSL/UTRECHT UNIVERSITY. allowed the researchers to and a team of investigators A molecular map of the oxidative phosphorylation supercomplexes. probe native architecture of at Utrecht University in the protein assemblies in mito- Netherlands, in collabora- chondria that are still intact and data analysis strategies. “In con- and functioning. Most traditional tion with the National Institutes of trast to earlier work based on similar Health, aimed to discover the organi- biochemical methods for studying strategies, our approach is much more protein–protein interactions involve zation and interactions of proteins in sensitive, allowing us to present a solubilizing the membrane using the mitochondria of mouse hearts. more complete molecular interaction a detergent, which can introduce “We were most curious about map of all proteins within mitochon- artifacts. “In such studies, the forceful the organization of protein mol- dria,” Heck said. breaking of the mitochondria can ecules within mitochondria, because This molecular interaction map, have dramatic effects on the protein proteins are the molecular building or interactome, revealed a dense and organization and important informa- blocks that make the mitochondrial interconnected network of proteins. tion may be lost,” Lössl said. With energy factory work,” Heck said. “It The researchers used the map to study the extensive comparative analyses was already known which proteins are the higher-order organization of pro- and structural validation performed involved in energy generation, but it teins and the architecture of protein in their study, the researchers believe is still not fully understood how these complexes in mitochondria. Among that the supercomplex interactions building blocks come together within these are the oxidative phosphoryla- detected in intact mitochondria intact mitochondria.” tion supercomplexes, a series of five should be considered genuine. To chart the organization of protein complexes cumulatively The researchers believe their proteins within mitochondria, the responsible for generating energy. approach can be used to compare researchers used a kind of molecular In addition to confirming known mitochondrial organization in diseases glue, or cross-linker, small enough to interactions, the researchers found related to mitochondrial dysfunc- enter intact mitochondria and form novel cross-links between individual tion, such as Parkinson’s and autism stable links between any proteins complexes, leading them to suggest spectrum disorders. “Our approach within close proximity of one another. that all five complexes coexist in close can be used to elucidate how the The mitochondria then were broken proximity. molecular landscape of mitochon- apart, and the proteins were digested Going a step further to validate dria is reprogrammed during disease and run on a mass spectrometer to their map, the investigators soaked development,” Heck said, “ultimately identify especially the cross-linked the mitochondria in a high-salt solu- providing targets for future therapies.” peptides. tion to disrupt the protein super- The researchers catalogued the larg- complexes. They showed, using the est set of mitochondrial protein inter- same cross-linking technique, that actions thus far, with 3,322 unique Saddiq Zahari (szahari@asbmb. these “dysfunctional” mitochondria org) is the editor for manuscript cross-links. This unprecedented depth displayed a very different protein integrity at Molecular & Cellular was achieved using optimized mass interaction network. “These data Proteomics. spectrometry fragmentation schemes show that protein organization and

14 ASBMB TODAY MARCH 2018 JOURNAL NEWS From the journals By Sasha Mushegian, Laurel Oldach & Saddiq Zahari

We offer a selection of recent called cerebral organoids, which more Copenhagen discovered that GalNAc- papers on a variety of topics from the closely model fetal brains affected transferase 6, known as GalNAc-T6, Journal of Biological Chemistry, by Sandhoff disease. The researchers, one of 20 polypeptides that initiate the Journal of Lipid Research and led by Richard Proia, compared the GalNAc-type O-glycosylation of Molecular & Cellular Proteomics. affected organoids with tissue from a proteins, was absent in healthy colon deceased patient and with organoids tissue but abundant in colon cancer with the disease mutation cor- tissue. Editing GalNAc-T6 out of ‘Minibrains’ mimic rected by genome editing. As in the a colon cancer cell line changed its childhood disease patient’s brain tissue taken after death, growth form to one more closely Sandhoff disease organoids showed resembling healthy colon tissue. Sandhoff disease is a lysosomal GM2 accumulation and overgrowth; Based on the glycosylation targets of storage disease, one of a group of they also had delays in gene expres- GalNAc-T6 in the cancer cell lines, rare but severe disorders caused by sion. The research establishes a new the authors hypothesized that expres- accumulation of macromolecules that model for studying lysosomal storage sion of the enzyme disrupts epithelial cannot be broken down. The genetic disorders and suggests that GM2 development in the colon by affect- mutations that cause Sandhoff disease accumulation not only causes neu- ing cell-cell adhesion. The study was affect an enzyme that breaks down the rodegeneration but also may disrupt published in the Journal of Biologi- sphingolipid GM2 ganglioside. When neurodevelopment prior to birth. cal Chemistry. the enzyme cannot function, GM2 DOI: 10.1194/jlr.M081323 DOI: 10.1074/jbc.M117.812826 ganglioside accumulates in neurons, causing seizures and cognitive and motor decline that begin at about Colon cancer Comparing protein lives six months of age. Most patients die before age 5. Much of what is and glycosylation across species known about the course of the disease Cancer can develop not just Some proteins in the cell live lon- before symptoms appear is based on because of changes in the types and ger than others. While it is established animal models. In the Journal of amounts of proteins present in a that the turnover rates of different Lipid Research, researchers at the cell but also due to changes in how proteins are highly variable, it is not National Institute of Diabetes and those proteins are modified — for known how conserved the turnover Digestive and Kidney Diseases write example, by attachment of sugars rates of the same proteins across about using patient-derived stem cells (glycosylation). Kirstine Lavrsen species are. Researchers led by Sina to grow simple miniaturized brains, and colleagues at the University of Ghaemmaghami at the University of

Biochemical steps toward accessible vaccines Glycoconjugate vaccines consist of a carrier protein attached to a capsular polysaccharide from the pathogen of interest. Produc- tion of glycoconjugate vaccines, for example against the bacte- rial meningitis agent Neisseria meningitidis, is challenging in resource-limited settings due to the biohazards and industrial-scale processes involved in purifying bacterial capsular polysaccha- rides. Timm Fiebig and colleagues at Hannover Medical School developed chemoenzymatic methods to produce N. meningitidis capsular polysaccharides from recombinant capsule polymerases. The streamlined protocols and optimized enzymes described in the study, published in the Journal of Biological Chemistry, were used to produce targeted carbohydrate antigens in two hours with standard laboratory equipment. DOI: 10.1074/jbc.RA117.000488

MARCH 2018 ASBMB TODAY 15 Babies’ skin inspires eczema lotion Babies are soft and adorable and, as parents know, very delicate. Their skin must be moisturized frequently, because it is still slightly water-permeable. Newborns emerge from the womb covered with a waxy substance called the vernix, which protects their skin from dry- ing. Recently, researchers have begun to realize that the vernix also helps babies adapt to life outside the womb by stimulating cells in the skin to make water-resistant lipid molecules. Scientists at Leiden University in the Netherlands, led by Joke Bouwstra, thought it might be possible to harness the vernix to treat adults with skin problems. They formulated a lotion based on lipids normal. The researchers found changes to the synthesis found in the vernix and tested it on the skin of healthy of lipids that were not included in the lotion, suggest- volunteers. In a recent paper in the Journal of Lipid ing that the lotion could mimic the vernix by changing Research, the researchers showed that disrupting the how the skin makes lipids. The researchers have not yet water barrier on healthy volunteers’ arms using tape determined which ingredient drives the changes. The caused a change in the lipids that make up the bar- lotion, or one similar to it, might someday help treat rier. With the new, shorter-chain lipids, more water itchy skin rashes like eczema that are driven by irritants could escape through the damaged skin. Applying the crossing a broken skin barrier. lotion sped up recovery by returning the lipid profile to DOI: 10.1194/jlr.M079186

Rochester attempted to answer this RAGE in the brain How to IsoTaG a T cell question by systematically measur- Post-translational modifications ing the proteome turnover kinetics after infection of proteins are important for activa- in primary fibroblasts from eight Patients recovering from sepsis tion of T cells during an immune different rodent species, from mouse often have long-term damage to the response. One of these modifica- to naked mole rat. The researchers central nervous system, including cog- tions, O-GlcNAc, is known to used stable isotope labeling and mass nitive impairment and neurodegen- be involved in the activation of T spectrometry to quantify the rate of eration. Juciano Gasparotto from the cells; however, its function on most incorporation of heavy amino acid Universidade Federal do Rio Grande glycoproteins remains unknown isotopes in order to calculate protein do Sul in Brazil and colleagues at the due to difficulty in characterizing degradation rates and half-lives. The and mapping O-GlcNAc sites. In University of Texas examined the role researchers observed two striking a study published in Molecular & of receptor for advanced glycation trends. First, more closely related Cellular Proteomics, investigators end products, or RAGE, a signaling species have higher correlations of at Harvard and Stanford universities protein involved in both inflamma- proteome turnover kinetics. Second, led by Christina Woo employed a tion and amyloid protein function, the higher the maximum lifespan method called IsoTaG to catalogue of the species, the lower the global in brain dysfunction following sepsis and quantify the O-GlcNAc sites in protein turnover rates. To explain the in rats. They found that RAGE- resting and activated human T cells. IsoTaG works by metabolically label- latter unexpected trend, the investi- mediated signaling increased in brains ing O-GlcNAc residues and tagging gators hypothesized that long-lived after sepsis and appeared to increase phosphorylation of Tau protein, them via click chemistry with a probe species may have evolved to reduce to enable enrichment and subsequent a hallmark of neurodegeneration. the energetic demands of continuous identification using mass spectrome- Thus, RAGE may be a key factor in protein turnover, which would lessen try. The investigators identified 2,219 the generation of reactive oxygen the progression of long-term brain O-GlcNAcylated peptides from 1,045 species and the subsequent oxidative disorders after sepsis. The study was glycoproteins, the most comprehen- damage. This study was published in published in the Journal of Biologi- sive characterization of O-GlcNAc Molecular & Cellular Proteomics. cal Chemistry. modification sites so far. Using gel DOI:10.1074/mcp.RA117.000574 DOI: 10.1074/jbc.M117.786756 shift assays, they further confirmed

16 ASBMB TODAY MARCH 2018 the quantitative findings of a number of proteins that showed significant How staph bacteria steal our iron changes during T cell activation. The results provide a valuable resource for Staphylococcus aureus, a wide- future studies aimed at a mechanistic spread opportunistic pathogen, understanding of the function of is able to “steal” heme from the O-GlcNAc on specific proteins dur- hemoglobin in human blood as its ing T cell activation. preferred iron source for growth. In DOI:10.1074/mcp.RA117.000261 the Journal of Biological Chem- istry, Catherine F.M. Bowden and How a kinase binds colleagues at the University of Brit- ish Columbia published a crystal the membrane structure of IsdB, a critical mem- Sphingosine-1-phosphate is a brane protein in the S. aureus iron- scavenging pathway. By crystalliz- phospholipid linked to cancer and COURTESY OF THE UNIVERSITY OF BRITISH COLUMBIA ing an intermediate state in which inflammatory diseases including The crystal structure of the overall multiple sclerosis. The phospholipid heme is being transferred between IsdBN1N2•Hbcomplex. IsdB molecules are colored is generated when sphingosine kinase hemoglobin and IsdB, the authors in shades of blue, alpha Hb molecules are beige were able to propose a model by and beta Hb molecules are dark orange. Heme 1, called SK1 for short, translocates to moieties in the alpha Hb chains are shown as which IsdB unfolds hemoglobin’s the plasma membrane and phosphor- green sticks. ylates sphingosine, but the membrane heme-binding pocket to transfer recruitment step is not well-under- heme to the bacterium. stood. In a new paper in the Journal DOI: 10.1074/jbc.M117.806562 of Lipid Research, Michael Pulkoski- Gross and colleagues at Stony Brook DEB disease progression remains ing wound healing. Andrew P. Sawaya University in New York identify a ill-understood. In a study published and colleagues at the University novel cationic patch near a known in Molecular & Cellular Pro- of Miami published a study in the hydrophobic site on the enzyme, teomics, researchers at the Univer- Journal of Biological Chemistry explaining its preference for anionic sity of Freiburg led by Jorn Dengjel examining the mechanism by which a membrane lipids. Both the cationic performed a global transcriptome topically applied statin improves heal- and hydrophobic features, which and proteome profiling comparing ing of diabetic foot ulcers, a debili- form a single membrane-binding primary DEB keratinocytes to normal tating complication of diabetes. The surface, are required for SK1 to bind human keratinocytes. The researchers mevastatin treatment induced expres- to membranes and drive a cellular found that loss of collagen VII not sion of a long noncoding RNA that invasion phenotype that may be only affected the composition of the blocked c-Myc, a transcription factor linked to cancer metastasis. The find- cellular microenvironment but also associated with nonhealing wounds. ing may offer a new target for drugs led to global changes in cell homeo- The results suggest that statins could that disrupt the interface rather than stasis on mRNA and on protein level. be repurposed as part of a diabetes the kinase active site. They showed that TGF-beta-depen- management regimen. DOI: 10.1194/jlr.M081307 dent inflammatory and proteolytic DOI: 10.1074/jbc.M117.811240 processes were perturbed in DEB cells When collagen is lost both in vitro and in vivo. The study Dystrophic epodermolysis bullosa, provides a global yet detailed picture Sasha Mushegian ([email protected]) is or DEB, is an inherited skin fragility of dysregulated molecular conse- quences of collagen VII deficiency. scientific communicator for the disorder characterized by skin blister- Journal of Biological Chemistry. DOI:10.1074/mcp.RA117.000437 ing, abnormal wound healing and Laurel Oldach (loldach@asbmb. excessive scarring, which often leads org) is a communications intern to aggressive skin cancer. It is caused Statins could help with at the ASBMB. by biallelic loss-of-function muta- tions in the gene COL7A1, which wound healing in diabetes Saddiq Zahari (szahari@asbmb. codes for the extracellular protein Statins, drugs commonly used to org) is the editor for manuscript collagen VII. How the loss of collagen integrity at Molecular & Cellular lower cholesterol, have additional Proteomics. VII in epithelial cells contributes to beneficial effects, including improv-

MARCH 2018 ASBMB TODAY 17 FEATURE MYALGIC ENCEPHALOMYELITIS Unknown cause. No cure. New hope. By Lily Williams

Research on a condition that has befuddled scientists for eight decades receives fresh funding, and more than a million Americans, many confined to dark bedrooms, wait for answers

18 ASBMB TODAY MARCH 2018 izzie Mooney is 12 years old. She is tall for her age with long L blonde hair. She likes to wear Chicago Bears pajama bottoms and a hoodie. She’s funny, making up games and teasing her siblings. Lizzie excels in reading and math. She spends time crafting and watches science shows with her parents at night. But it’s hard for her to make it downstairs to the TV room. She can’t go to school. In fact, she might only leave her house once a week. For the past three years, Lizzie has been sick. The government estimates that as many as 1 million to 2.5 million Americans have the same disease as Lizzie: myalgic encephalomyelitis, or ME. Despite these numbers, you probably haven’t heard of ME. What you might have heard of instead is LILY WILLIAMS Lizzie Mooney has myalgic encephalomyelitis. Her health has decreased over the past three years to the point chronic fatigue syndrome, or CFS. where she can barely leave her house or even eat meals at the table with her family. This euphemism for ME conjures an image of someone who just doesn’t is spent on each of these. In fact, feel like getting out of bed. research funding for ME remains less For many ME patients, getting out than what the government spends on of bed would be the highlight of their headaches or hay fever. Multiple scle- week or month. About 25 percent of rosis funding is 12 times the funding patients are housebound, in rooms for ME, but an estimated 400,000 with the blinds drawn and noises patients in the U.S. have MS, fewer muffled. Patients’ bodies are sensi- than half the number who have ME tive to all kinds of stimulation; they even according to the most conserva- suffer from gastrointestinal problems, tive estimate. inability to sleep, chronic pain and When Lizzie got sick, her mother, the disease’s trademarks: cognitive Amy Mooney, took her to their dysfunction and post-exertional primary care physician, who diag- malaise, or PEM. Many patients nosed Lizzie with a mononucleosis- describe PEM as a crash. Something like illness. Lizzie spent the next four as simple as a short walk can severely months in bed. Mooney took her to worsen a patient’s symptoms, leaving infectious disease doctors, rheuma- them bedridden, unable to recover, tologists, neurologists and gastroen- for weeks or months. There’s no terologists, but no one could make a telling how long the crash will last. diagnosis. Imagine having to decide between “The most painful moment was taking a shower and making yourself when an infectious disease doctor lunch. It could be your only activity took me into the hallway,” Amy for the week. Patients with ME have Mooney said. “He said, ‘Congratula- reported lower quality-of-life scores tions. Her blood work is completely LILY WILLIAMS than patients with terminal cancer normal. Nothing is wrong with her.’ Left: Lizzie Mooney sits just outside the kitchen of her and heart disease. In the patient room, they were asking family’s home in Illinois. Myalgic encephalomyelitis saps her energy, but she was still curious about the Yet federal funding for ME Lizzie if we have a healthy family life: lady with the camera who hung out in her house for research remains at a fraction of what Do we have abusive family situations? a week.

MARCH 2018 ASBMB TODAY 19 LILY WILLIAMS Lizzie makes her way down the stairs for a morning tutoring session. Immediately after these sessions, and sometimes halfway through, she retreats to her dark bed- room, where she sometimes shakes in pain for hours. Are we going through a divorce? $5 million and $8 million a year on “The physician at the pediatric ME research. In 2017, the NIH ear- hospital wrote a note to the school marked $7 million for a first-time ME saying it was safe for her to go to research collaboration of four centers. school,” Mooney said. “‘Get her back But some advocates say the govern- to school. Kids with cancer go to ment should be dedicating more than school.’” 50 times that amount. Lizzie hasn’t been to school since she was nine. She works at home with Steps in the right a private tutor when she can. For decades, the search for patho- direction? genic underpinnings for ME came up Among those advocates is journal- empty, and the disease was attributed ist Hillary Johnson, who says billions to psychological causes. Stigma, of dollars would be an appropriate skepticism and limited funding have figure. fueled what advocates characterize as Johnson spent almost a decade a vicious cycle that’s left a big hole during the 1980s and 1990s research- in ME research. But advances in our ing the befuddling lack of interest understanding of the gut microbiome, in ME by government entities such cell-mediated immunity, mitochon- as the Centers for Disease Control drial dysfunction and dozens of other and Prevention and the NIH. She variables may open the door to new compiled her findings into a book, approaches to understanding and “Osler’s Web.” treating the disease. In her book, Johnson chronicles While ME’s existence is no longer the ’80s as a time when the CDC controversial, within the ME commu- actively buried ME research and fund- nity, federal funding for ME research ing. She also casts Stephen Straus, a is. In recent years, the National senior investigator in the Laboratory Institutes of Health has spent between of Clinical Investigation at the NIH’s

20 ASBMB TODAY MARCH 2018 COURTESY OF LINDSAY FRANCE/CORNELL UNIIVERSITY Professors Maureen Hanson and Andrew Grimson examine a cartridge containing DNA at Cornell University’s high-throughput sequencer, used for ME/CFS research.

National Institute of Allergy and years, signifies a step in official ME Infectious Diseases, or NIAID, from recognition. The new NIH grants will 1991 to 1999, as the chief villain. support three collaborative research Straus published a number of studies centers and a data-management on ME, some of which psychologized coordinating center for ME research. the disease. Straus went on to become One grant is going to researchers at the first director of the National Cen- Cornell University led by principal ter for Complementary and Alterna- investigator and American Society for tive Medicine. When he died in 2007, Biochemistry and Molecular Biology he was warmly remembered by his member Maureen Hanson. A 2016 colleagues and was lauded by the NIH study in Hanson’s lab found that ME for what was then still called chronic patients’ microbiomes have signifi- fatigue research. cantly lower microbial diversity and a Joseph Breen is the current chief higher incidence of pro-inflammatory of the immunoregulation section in species than in healthy controls. the Division of Allergy, Immunology Hanson’s work also branches into and Transplantation at the NIAID. fatty acid and lipid metabolism. Her “Fortunately, perspectives about the lab produced a 2017 paper on a study disease have changed,” Breen said. that found significant disturbances “Researchers now have the tools to in numerous fatty acid and amino explore possible etiologies of ME/CFS acid metabolism pathways. Levels and future studies should be revealing, of energy-related metabolites, such especially those with larger cohorts, as ATP and ADP, were significantly initiated early after disease onset and lower in ME patients. Acetylcarnosine with longitudinal follow-up.” and taurine, important to muscle tis- The NIH announcement in sues, also were less abundant. September of four grants totaling Hanson and her colleagues at more than $7 million for fiscal year Cornell will use the new NIH grant 2017, and continuing for the next five to study post-exertional malaise using

MARCH 2018 ASBMB TODAY 21 LILY WILLIAMS Little is known about how ME affects Lizzie’s bodily systems, but the disease prevents her from interacting with her peers or traveling with her family.

neuroimaging, metabolomics and recover, otherwise we would never do single-cell RNA sequencing. it,” Hanson said of the tests. “In fact, The researchers will take blood some of these patients ask to return to samples before and after the study obtain needed disability documenta- participants ride stationary bicycles tion. It is right now the most objec- on two consecutive days. tive way for someone to demonstrate To determine why ME patients their disability. A lot of them have usually can’t replicate their initial per- a great deal of trouble convincing formances, the researchers will search insurance companies or the social their blood samples for biomarkers. security agency that they are actually Hanson’s specific role in the project disabled.” will be to study extracellular vesicles, U.S. medical record and insur- which transport materials between ance billing codes still classify ME cells. In healthy people, exercise as chronic fatigue — as a symptom induces release of these vesicles, which rather than a disease. Even with a may mediate the beneficial effects of diagnosis, the insurance companies physical activity. would not cover Lizzie’s prescription “This is going to be an important medications or supplements, which study to carry out — at the time we cost the Mooneys upward of $1,000 wrote our proposal, there were no each month. One study estimates published studies about extracellular conservatively that ME patients pay vesicles in ME,” Hanson said. $8,675 per year for treatments, and If patients can fall into severe PEM the direct cost to the U.S. healthcare after even basic activities, how could system for all patients could top $7 Hanson’s team find ME patients will- billion. ing to do two days of exercise testing? Also under the NIH grant, “Even though the exercise will researchers led by Dikoma Shungu at likely induce a relapse, most of the Weill Cornell Medical College will patients don’t report that they never do one of the first neuroimaging tests

22 ASBMB TODAY MARCH 2018 An eight-decade mystery Key moments in myalgic encephalomyelitis history

1934: The earliest case of ME is observed and formally recorded as an outbreak of poliomyelitis among staff at the Los Angeles County General Hospital. 1956: The Lancet recommends the name “benign myalgic encephalomyelitis” to describe an outbreak in London; patients have neurological symptoms, myalgia and a number of other symptoms following an infection. 1969: The World Health Organization classifies the disease for the first time as “benign myalgic encephalomyelitis,” listing it as a neurological disorder. 1970: Two psychiatrists in the U.K. review reports of 15 outbreaks of patients with similar symptoms and deduce that the results are due to hysteria, as they see no physical signs of disease. 1978: An international symposium held at the Royal Society of Medicine drops the term “benign,” as it is not commensurate with symptoms reported by patients. 1984: Recorded instances are sporadic around the U.S. until the Los Angeles Times reports an outbreak on the shore of Lake Tahoe. Before the report, the Centers for Disease Control and Prevention sends two epidemiologists to investigate a severe flu-like illness with persistent symptoms. The epidemiologists return empty-handed just days later. 1988: The CDC names the disease now known as ME a “syndrome of chronic fatigue.” 1989: Two British studies attribute ME to a psychological disorder and a self-perpetuating lack of exercise, representing an investigative trend by psychological and psychiatric researchers. 1990: The CDC receives more than 2,000 calls per month from the public requesting information about a flu that never goes away, according to journalist Hillary Johnson. 1991: Researchers from the Wistar Institute in Philadelphia propose the retrovirus HTLV as a causative agent in a paper published in the Proceedings of the National Academy of Sciences. A blinded follow-up study by the CDC fails to replicate their results. 1991: The National Institutes of Health’s Stephen Straus publishes studies stating ME is a psychological disease and shares his findings at scientific talks and hospital grand rounds around the world. He refuses to comply with Freedom of Information Act requests by reporter Johnson to see his research data. He refuses to release information on how funding for disease research is spent. 1996: Hillary Johnson publishes her book, “Osler’s Web,” about a nine-year investigation into the ME/CFS research community. She alleges that research has been stifled and funds misused. 1996: Congress requests that the General Accounting Office and the Department of Health and Human Services investigate claims made in “Osler’s Web.” Both investigations verify the book’s contents. 1999: The ME/CFS Working Group is established at NIH. 2009: An article published in Science describes a link between murine leukemia virus XMRV and ME/CFS. The study cannot be replicated and is retracted in 2011. 2011: The PACE trial reports in The Lancet that cognitive-behavioral therapy and graded exercise therapy can benefit ME/CFS patients. Patients object to the methodology and results, organizing a petition and FOIA request for release of anonymized data. 2015: David Tuller publishes a lengthy methodological critique of the PACE trial. 2016: Independent analysis of data from the PACE trial by American biostatisticians in collaboration with patients fails to support the study’s conclusions. 2016: Advocates and patients organize across the country under the banner of #MillionsMissing to demand increased funding. Advocates and patients who are well enough to attend speak about how the disease has affected them, hang photos of homebound patients and set out pairs of shoes to represent patients who are too sick to join. Demonstrations expand to 25 cities worldwide in May 2017. 2017: The documentary film “Unrest” is released, chronicling the life of its producer Jennifer Brea, an ME patient. 2017: The NIH announces it will award four grants totaling more than $7 million to establish centers for ME research. 2018: If high estimates of prevalence are accurate, up to 8 in every 1,000 Americans have ME. Hillary Johnson referred to ME in the 1980s and ’90s as an epidemic; she now calls the disease endemic.

MARCH 2018 ASBMB TODAY 23 Advocating for their lives

While researchers funded by the federal National Institutes of Health and the private Open Medicine Foundation embark on studies paid for by new grants, patients and advocates continue the push to make myalgic encephalomyelitis more visible. They spent months organizing dozens of rallies around the world in 2016 and 2017, hoping to raise awareness about ME. Amy Mooney wielded a megaphone in downtown Chicago as part of that COURTESY OF ME ACTION Demonstrations to raise awareness about ME were held in cities around the world in May 2017. Shoes #MillionsMissing campaign, which were used to symbolize the patients too ill to leave their beds and join the action. This photo was taken in laid out a pair of shoes for each ME Birmingham, England. sufferer too sick to attend in person. The ground was a sea of shoes no the state’s commitment to improving quality of care for longer worn by their homebound owners. Another rally ME patients. The House encouraged the media to cover is being organized for this May. the disease and Illinois universities to study ME, recom- The 2017 documentary “Unrest” chronicles the life mending that the NIH proportionately fund research of Jennifer Brea, an ME patient who is also the film’s and that the Centers for Disease Control and Prevention producer. It has won or been nominated for more disseminate proper information. Mooney also hosted a than a dozen awards and recently aired on PBS. Rivka screening of “Unrest” in the Chicago suburb where she Solomon organized a screening of “Unrest” in Novem- lives. ber that attracted an audience of 363 — about 100 of “They’re not promising money or anything at this whom were Boston healthcare professionals — and was point,” Mooney said, “but we want universities to say, the largest community screening of the film to date. This ‘Oh, this is real,’ and it to be something they respond event earned a statement of support for ME patients to and investigate.” Mooney used to be able to work, from the entire Massachusetts congressional delegation. but now her full-time job is advocating on behalf of her “In just the past half-year the film, “Unrest,” is shift- 12-year-old. ing the landscape for us,” Solomon said. “But before Journalist Hillary Johnson continues to report on her that, I would say not much changed for us for 30 years.” website, oslersweb.com. She would know; she has been sick for 28. “By and large, each time I do something for ME Solomon also found a champion in Sen. Ed Markey, advocacy, I pay a price,” Solomon said. “I often end up a Massachusetts Democrat, who held a congressional much sicker than before, and I never know for how long briefing about ME on Capitol Hill in May 2017. I’ll be in the relapse. It’s pretty scary that advocating for In Illinois, Amy Mooney worked to pass a proclama- your own life can cause such a detrimental setback in tion in the state’s House of Representatives, affirming your health. I call this our fundamental conundrum.”

on ME patients experiencing PEM. The Research Triangle Institute in The other two NIH research centers North Carolina will house the data- include a team at Columbia Univer- management center, bringing data sity that will look for microbial agents from the three centers into one data- and evidence for immune responses base for standardization and providing to microbes and a team at the Jackson tools for data processing and analytics. Laboratory in Farmington, Connecti- “This is a very important step by cut, that will study how the body’s the NIH,” Hanson said. “But we need immune system, microbiome and more centers and individual studies metabolism interact. relative to the burden of illness and

24 ASBMB TODAY MARCH 2018 LILY WILLIAMS Lizzie lies on a couch at home. Few ME/CFS patients return to full health, even in remission. Recovery is rare, and symptoms often persist for life. number of people who are ill. The days, my brain does not work well. number of research dollars is really And neither does my body. During a inadequate.” relapse it can take me 45 minutes to Breen said he hopes that research- get up a set of stairs because I have to ers will be encouraged by the NIH’s rest between each step.” increased commitment to ME When Solomon was 21, she and research and will continue to apply her two roommates all got mononu- for more funds. cleosis at the same time. Her friends “The NIH ME/CFS working got better. Solomon stayed sick for a group functions as a team and we’re year. Then she went through a seven- just starting the ME/CFS Collabora- year period of what she calls a relative tive Research Center program,” he remission before falling ill again. She said. “In the next five years, we hope- lives in Massachusetts and works from fully will grow the community with home as a writer and ME advocate, a network of ME/CFS centers and when she has energy. small investigator-initiated research Solomon represents most ME project grants.” patients and advocates when she says that the amount of funding ME Millions missing receives — even with new grants — is Rivka Solomon, 55, has had ME way too low. for 28 years. Journalist Hillary Johnson com- When called for a phone interview, pares ME to AIDS, for which funding she didn’t answer, even though she increased drastically “once they real- had seemed eager to talk during email ized it could be transmitted.” Many exchanges to schedule the interview. clinicians and researchers Johnson She called back 25 minutes late. interviewed for “Osler’s Web” in the “Cognitively … I remembered ’80s and ’90s believed ME had a con- your call, but then I forgot,” she said. tagious, infectious cause. In particular “See, this is what happens. On bad geographic locations around the

MARCH 2018 ASBMB TODAY 25 COURTESY OF RIVKA SOLOMON Rivka Solomon has had ME for 28 years, and she is a vocal advocate for increased research funding. Here she speaks as the host of a screening of “Unrest,” a 2017 documentary about ME.

world, doctors began seeing clusters ME is psychological, not physical, of patients with crippling fatigue and Solomon says. One highly visible neurological problems. study has helped promote the psycho- Now, HIV/AIDS receives about logical theory of ME. $3 billion in NIH funding each year The controversial U.K. study, for biomedical research on treatment, known as the PACE trial, was pub- cure, prevention, and co-morbidities lished in 2011, just seven years ago. and co-infections. An estimated 1.1 The results of the $8 million experi- million Americans have HIV. Ade- ments were similar to ME studies quate funding has led to HIV drug from the 1980s. PACE researchers therapies that allow patients to lead asserted that ME patients had a false semi-normal lives. ME is nowhere illness belief, making them reticent close to having a drug therapy, and its to exercise or lead a normal, healthy patients are crippled by bodies that life, perpetuating feelings of illness. cannot perform even minor tasks. Patients could recover from this In 2018, still no cause — infec- false belief, researchers said, through tious or otherwise — has been found, graded exercise therapy and cognitive even though thousands of papers have behavioral therapy to help them real- found biological abnormalities in ME ize they were not, in fact, ill at all. patients. An eight-week exercise program Although new technologies and worsened Lizzie Mooney to the point funding now exist, Solomon believes that she was bedridden. And Amy the real reason ME hasn’t been eluci- Mooney cites another young patient dated is that the federal government whose goal for her exercise program has failed to fund disease research in was to overcome crippling stomach proportion to ME’s high burden of pain and stop using a wheelchair. The illness. This lack of funding hasn’t exercise made her sicker. incentivized new researchers to study The PACE trial came under fire in ME and has propagated the idea that 2015. David Tuller, a senior fellow in

26 ASBMB TODAY MARCH 2018 COURTESY OF LINDA TANNENBAUM Linda Tannenbaum, CEO and president of Open Medicine Foundation, gives a presentation. Her daughter fell ill in 2006 with sudden-onset ME. Tannenbaum has since raised more than $13 million for research. public health and journalism at the heard of ME. “We were told that she University of California, Berkeley’s had something called chronic fatigue School of Public Health, pointed out syndrome and there was nothing problems with the study that included we could do for her other than pain author ties to disability insurance management,” she said. companies, a baseline scoring system Tannenbaum set out to find a that rated patients as simultaneously cure. By 2012, she had formed Open sick enough for the study yet healthy Medicine Foundation. She has since enough to be recovered, and a news- raised more than $13 million, much letter of patient testimonials released of it from the less-than-affluent midway through the study that patient community. An anonymous claimed benefits of the therapy. bitcoin philanthropist from the Pine- “There could be 17 to 20 million apple Fund gave $5 million to OMF of us or more around the world,” early in February. Solomon said, “and yet they still “This disease is real, as emphasized think we’re making this up.” by the caliber of researchers working together on this,” said Tannenbaum, Millions needed who has helped to gather a global col- laborative cohort of ME researchers. Advocates such as Linda Tan- OMF’s 15-member scientific nenbaum are concerned that some advisory board includes three Nobel qualified ME researchers aren’t laureates and six National Academy of being funded by the NIH. In 2006, Science members. Hanson, from Cor- Tannenbaum’s daughter fell ill with nell, is on the advisory board but her sudden-onset ME. Tannenbaum, ME research is not funded by OMF. who lives in Agoura Hills, California, Stanford University researchers, had worked in clinical lab science already funded by OMF for ME for over 23 years and had her own work, applied for but did not receive medical laboratory, but she’d never any of the new NIH grants. So the

MARCH 2018 ASBMB TODAY 27 Myalgic encephalomyelitis facts • Many ME patients report never recovering from a staff in the U.K. flu-like illness, a virus, a fever or some other infectious • There still is not one diagnostic test specific to ME disease. or one agreed-upon research case definition. • Patients must have symptoms for six months to be • Two-day cardiopulmonary exercise tests, tilt table diagnosed with ME. tests (where one lies on a table slowly tilted upward to • Up to three-quarters of patients spend a full year measure how blood pressure and heart rate respond to seeking a diagnosis; for 29 percent of patients, it takes gravity), and natural killer cell tests (which demonstrate more than five years. reduced cytotoxicity in ME patients) have been used to • ME affects both children and adults; 75 percent of indicate disease presence. adult patients are female. • Cognitive dysfunction is well-documented as • While ME has been observed to persist following neurological impairment in ME patients. One study mononucleosis infection and has been referred to incor- performed PET scans on ME patients and found cogni- rectly as chronic mononucleosis, there is no evidence tive impairment in ME patients correlated with brain that ME is a form of mononucleosis. areas such as the amygdala, thalamus and midbrain. • Children experience some different ME symptoms • The majority of ME studies are done with a tiny from adults, with more frequent reporting of abdominal cohort due to a lack of research funding. pain and rashes. • The 2015 Institute of Medicine Report analyzed • In one study, ME was the leading cause of pro- over 9,000 studies on ME and is a good source for a longed sickness absence from school for children and comprehensive ME literature review.

OMF leaders decided to fund another database where researchers can put ME/CFS research center at Stanford new data to use in concert. University, supplying a grant starting “People think they need to create at $1.2 million and continuing for as their own big data and keep it to long as OMF can raise enough funds. themselves, but this is expensive,” More than 20 scientists will make up Davis said. “The rate-limiting step the OMF-funded center at Stanford, from publishing and getting ME along with a growing working group research done is funding. I wish we of more than 30 researchers from top had a lot more money to give every- U.S. and international universities, one to make this much faster.” who are not funded by OMF. The NIH was reluctant to fund his The Stanford ME center is led by initial ME observational experiments, ASBMB member Ronald W. Davis, Davis said. But observation is needed director of OMF’s scientific advisory before any hypotheses and future board and director of the Stanford research directions can be established, Genome Technology Center. Davis’ he said, especially when so little son is severely ill with ME; he can- observation has been done on ME. not leave his room, eat food or even He hopes data he soon will publish speak. Davis has studied heavy metals will allow specialized researchers to and viruses in ME patients. He has study ME in their own fields, without coordinated a large -omics study on the need to do costly and lengthy severely ill patients, a subgroup never background research beforehand. studied before, analyzing genome Jose Montoya, an ME physician sequences, proteins, metabolites, and professor of medicine at Stan- small RNA molecules and more. ford, published a 2017 paper in the Severely ill patients are those who Proceedings of the National Academy are homebound or bedbound, such of Sciences that analyzed an unusu- as Davis’ son, who lacks the energy ally high number of ME patients and even to look at people. Davis hopes controls as compared to typical ME that his current and future research studies: Serum from 192 patients and will help establish a large and open 392 healthy controls was analyzed for

28 ASBMB TODAY MARCH 2018 LILY WILLIAMS Once two grades above her age in math and reading levels, Lizzie can now complete only 45 minutes of private home tutoring per day due to the severity of her illness. She is pictured with her tutor, Judith Meyer. cytokine differences. Immune cells severe symptoms. The study also cites secrete cytokines, or cell-signaling resistin and another adipokine, leptin, molecules that play a role in inflam- as cytokines secreted by adipose tis- mation. The signature flu-like symp- sue that could be important. Leptin toms and muscle pain led researchers has been found to correlate with to believe ME could be an inflamma- fatigue severity, and levels are higher tory disorder. in females. Adipokines contribute to Montoya and his team found crosstalk between the central nervous that two cytokines were significantly system and adipose tissue and could different in ME patients and healthy contribute to neuroinflammation and controls. TGF-beta, found commonly cognitive dysfunction in ME patients. in the monocytes and macrophages In mice, leptin has demonstrated a of the immune system as well as recruitment of neutrophils to the intestinal epithelial cells, is viewed brain during sepsis, prompted by as an anti-inflammatory cytokine. administration of lipopolysaccharide. TGF-beta was higher in ME patients. The new OMF-funded center at Resistin, produced primarily by Stanford will have three main proj- peripheral blood mononuclear cells, ects. One will explore the immuno- has been shown to increase transcrip- logical basis of ME through analysis tion of pro-inflammatory genes and of T cells, the human immune cells was lower in severe ME patients but that kill their infected own. ME could higher in moderate ME patients. In affect T-cell replication and behavior. total, Montoya’s study found 17 cyto- This study also will investigate the kines, 13 of which are pro-inflamma- way personal variations in human leu- tory, that had an upward linear trend kocyte antigen genes regulate immu- when put into context of ME severity. nity in ME patients. These genes In other words, these cytokines’ levels code for the major histocompatibility were higher in patients who had more complex, the cell-surface proteins that

MARCH 2018 ASBMB TODAY 29 LILY WILLIAMS If you ask Lizzie what she would do if she weren’t sick, she says any number of things, starting with returning to school. Here, she and her father, Don Mooney, share a laugh while studying a map on her bedroom wall.

regulate our immune systems. Far from treatment The second project will expand Mary Dimmock, a 31-year veteran OMF’s current big-data genome study of the pharmaceutical industry, now to patients of varying severities and retired, cites a significant roadblock their families, performing clinical and to a treatment for ME: “Pharma has molecular tests that could provide stayed away from this disease.” insight into genetic factors and During her time working for molecular biomarkers for ME. Right pharmaceutical companies, Dimmock now, it has data from 20 ME patients. did everything from drug metabolism The third project will work toward a studies to clinical data management diagnostic that can distinguish ME to business process improvement blood samples from healthy ones initiatives. She saw the considerations using new technology developed at that go into pharmaceutical com- Stanford. The technology also will be panies’ research funding decisions. used to test Food and Drug Adminis- Before they even will think about tration–approved drugs considered for investing in a particular drug or treat- clinical trials on ME patients. ment, there must be potential patients “We need researchers to share their for clinical trials, Dimmock says. To results openly and collaborate and get a patient into a clinical trial, that look at ME/CFS through many patient must be diagnosed. But with body systems, genetics, infectious ME, according to a 2015 Institute of disease, immunology, metabolomics, Medicine Report, up to 91 percent of microbiome and more,” Tannenbaum patients remain undiagnosed. said. “The urgent need is not only ME has numbers to support a huge research but awareness in the medical market. “You’d think this would be community and teaching new doctors a slam dunk for pharma,” Dimmock in medical schools to be able to iden- said. “But we don’t have agreement on tify and acknowledge this.” a research definition, don’t have doc-

30 ASBMB TODAY MARCH 2018 tors treating patients and don’t have “I understand the NIH’s pre- enough academic researchers.” dicament but I want them to take As someone who has seen what it responsibility for this,” Davis said. “I takes to go from research to a market- know it’s hard. There are a lot of dis- able clinical treatment, Dimmock said eases out there and they’re probably she thinks the NIH has taken critical all underfunded. But the NIH needs steps to attract more researchers and to serve the people of this country to promote collaboration. She also is and that’s where the money is coming encouraged by the work of the dif- from, the people.” ferent centers, particularly Hanson’s Johnson is less forgiving. She focus on understanding the disease remembers ME as a public health pathology after exercise studies. crisis. “In 10 years, a majority of Dimmock’s son has ME. She paid people who came down with ME in $65,000 out of pocket in the first year the 1980s are likely to be dead. The after his diagnosis. He eventually was shared memory of an epidemic begin- able to use the two-day exercise study ning in the 1980s will be forgotten, as a way to demonstrate disability. and the government may never have But Dimmock, Solomon, Mooney to address its failures in the ’80s, ’90s and Johnson all worry that the NIH and this century.” lacks any urgency, either in resolving Strides, albeit small, are being the stigma of ME or in really ramping made by researchers, who now rec- up funding. “Because they are taking ognize the role of the microbiome, one or two baby steps at a time, it will immune and nervous systems, and take more than a decade to get there,” metabolism. The number of ME Dimmock said. researchers is growing, even with Breen at NIH is aware that the limited funding. agency’s decision-making process With at least 17 million to 20 can take time and might seem a bit million estimated patients around obscure. Every research application the globe, a researcher entering the to the NIH must undergo a rigorous field now could “make their mark review by experts in the field, both with minimal effort,” Solomon said. by a scientific review group and by an Dimmock would agree. “While I institute’s advisory council or board. appreciate the risk from a pharmaceu- It typically takes about six months tical perspective, the time is ripe for from the time an investigator submits academics to get interested in ME,” an application, Breen said. she said. “It is a fascinating biological “The hard part for patients is mystery.” that the timeline from research to a “Here is your chance,” Davis tells diagnostic test or therapeutic is never his students at Stanford. acceptable because there are people February marked year three of hurting now,” he said. “It looks very Lizzie’s illness. She hopes ME’s mys- inefficient, but we have an open teries are unraveled soon, so she can scope. We need to do more founda- trade her Chicago Bears pajamas for tional studies for future diagnostics jeans and sneakers, leave her bed- and therapeutics.” room, and go back to school. Stanford’s Davis said understand- ing and urgency of funding for the Lily Williams (Williams.lilybeth@ disease are low because we just don’t gmail.com) has a B.A. in ecology, see ME patients. They’re in their beds evolution and organismal biology or at least at home. Trips to the hos- from Vanderbilt University and an pital make them worse, so they don’t M.S. in science, health and envi- ronmental journalism from Medill go. And although most patients aren’t School of Journalism at Northwestern University. dying from ME, they aren’t really liv- She is a freelance journalist and communications ing either. director based in Asheville, N.C.

MARCH 2018 ASBMB TODAY 31 FEATURE From a Bavarian baccalaureate to bacterial bleach The new Journal of Biological Chemistry associate editor investigates heat-shock proteins and their relation to bacterial defense mechanisms against hypochlorous acid By John Arnst

leach, generally speaking, is Bardwell at the University of Michi- bad news for anything it comes gan, where she is now a professor in B in contact with, whether it’s the molecular, cellular and develop- grime, blue jeans or bacteria waging mental biology department and the war against your intestinal lining. At university’s medical school. In 2014, the University of Michigan, Ursula she was elected to membership in the Jakob’s lab is investigating how to Bavarian Academy of Sciences and make the bacteria bent on colonizing Humanities, one of the oldest learned your gut more sensitive to the bleach, societies in Germany. Since the acad- or hypochlorous acid, that your white emy’s inception in 1759, its members blood cells deploy against them. This have included Johann Wolfgang von form of bleach differs only slightly Goethe, Max Planck, Werner Heisen- from the sodium hypochlorite in berg and Albert Einstein. cleaning solutions that can strip dyes Jakob joined the ranks of associate and burn clumsy hands. editors at the Journal of Biological Jakob, who was born in Germany, Chemistry in September. She spoke received her bachelor’s degree in 1991 with John Arnst, ASBMB Today’s and her Ph.D. in 1995, both from the science writer, about her lab’s work University of Regensburg in Bavaria. exploring molecular chaperones and Throughout her college career, the lab mechanisms of bleach resistance in she was in studied the heat-shock pro- bacterial and human cells. The inter- tein Hsp90 and its effect on protein view has been edited for clarity and folding as a molecular chaperone. Her length. current lab’s work involves the heat- shock protein Hsp33, a molecular What is your group chaperone that helps protect bacte- ria against the dangerous effects of focused on? bleach. One of our most interesting With a fellowship from the Ger- projects involves bleach, which is not man government, Jakob did her only a very effective antimicrobial in postdoctoral research under James household settings but has long been

32 ASBMB TODAY MARCH 2018 From the very beginning of my scientific career, we always tried to be on the forefront. From the very beginning, I learned that science is discovering something new. known to be used in a physiologi- other defense systems bacteria have cal context — our white blood cells to deal with bleach. We found that produce bleach, hypochlorous acid, to bacteria, in response to bleach treat- defend our bodies against infectious ment, convert a large amount of their disease. We were wondering how ATP into a long chain of phosphates, bacteria defend themselves against polyphosphate. This molecule was bleach, and in 2008, we found that the pet project of the late Arthur they produce a protein that gets spe- Kornberg in the last 15 years of his COURTESY OF THE UNIVERSITY OF MICHIGAN cially activated in response to bleach life; he was extremely fascinated by In 2000, Jakob received the Burroughs Wellcome and then protects the bacteria from it. this prebiotic molecule and contrib- Fund Career Award in the Biomedical Sciences, which helped jumpstart her career as an assistant We use bleach in our host defense, uted a huge amount to the literature, professor at the University of Michigan. and it works well most of the time to including the fact that polyphosphate kill invading bacteria. However, some is present in every organism that had of the bacteria do survive and can been studied so far. cause persistent infections, and we In bacteria, polyphosphate plays a still don’t know how they manage this very important part in virulence. So feat. Moreover, under extreme condi- this fits exactly with what we found: tions, like chronic inflammation in When we delete the gene that allows patients that suffer from cystic fibrosis bacteria to make polyphosphate, they or persistent infections, we see a lot become super-sensitive to bleach. of tissue damage. This is attributed to They’re no longer virulent, they no the excess bleach that’s being pro- longer make biofilms as effectively duced by our white blood cells. as wild-type bacteria and they make And so the question then was, many fewer antibiotic-resistant cells. “What does bleach do, and how do So, we thought, this is really cool. If organisms defend themselves against polyphosphate was indeed such an it?” The idea was that if we knew that, essential product in bacteria that they we could possibly make bacteria more make it specifically under conditions sensitive to bleach. This might help of infections, then targeting that with boosting the host defense and synthesis should make them much allowing the host to be more able to more sensitive to the host defense deal with bacterial infections while mechanisms. at the same time potentially mitigat- We recently found a drug already ing the damage in the host. What on the market called mesalamine, we figured out is that bleach works which is widely used to treat colitis. as a really potent protein-denaturing We published a paper in Nature agent, essentially boiling bacterial Microbiology a few months back, proteins at room temperature. In their where we found that we can now tar- defense, bacteria activate a chaperone, get polyphosphate synthesis in bacte- Hsp33, which protects the proteins ria in the intestines with mesalamine. against bleach-induced protein It has basically the same effect as if unfolding and aggregation and helps you delete the enzyme from within bacteria survive. the bacteria, making them sensitive COURTESY OF URSULA JAKOB In the last few years, we took to hypochlorous acid. Our hope now Jakob often rides Agave, a Spanish horse she leases another approach and asked what is that we can use this drug maybe at Rosehill Dressage in Northville, Michigan.

MARCH 2018 ASBMB TODAY 33 alone or in combination with other and JBC was always our go-to journal. antibiotics to treat particular persis- I had six JBC papers during my grad- tent infections. uate career. I’ve been a reviewer for years, and then I was asked whether Did anything occur in a I would like to take on an associate editor position at JBC. milestone sort of way that made you choose science What do you do outside as a career? the lab? Do you have any I was raised in a family that was advice for balancing life very interested in biology and the environment. So it was not surprising outside of the lab with life to anybody when I decided to study inside the lab? biology. During my second year as a biology undergrad, I got hired in I ride horses and I play tennis. I the lab where I ended up doing both love riding horses because riding is my master’s thesis and Ph.D. thesis. a little bit like science — you never We studied refolding of antibody frag- fully know where they will take you. ments. Within about half a year or so And I love tennis because it’s competi- after I started working there, my P.I. tive, and, you know, I’m slightly com- came to me and said, “I just saw this petitive, so I like that aspect. What paper about this heat-shock protein, I tell young assistant professors, in GroEL, being able to support refold- advisory roles, is that they absolutely ing of a protein. Maybe we should put need a balance. I had my first child this into our antibody solution and three days after I started my lab, so see whether this helps in our refolding when I see my daughter, who is now experiment.” 16, I know exactly how long I’ve had The paper that he found in our my lab. And my son was born during library was really the landmark paper my third-year review process. that started the chaperone era. So I I think women in general, and was there when the chaperone field this is very generally speaking, have a was born, and that was absolutely harder time with this balance between fascinating to me, to be part of such career and family, because they have a new discovery. We were really in a tendency to constantly feel guilty. this first wave of chaperone research, We feel guilty about not being in the which involved Hsp90. My first lab enough, about not having enough paper, still as an undergraduate, was a time for our children and of course last-author Nature paper. not spending enough time with our Everything we did was new. We partners, and the easiest thing to let developed the assays … it was just go of is yourself and your friends. So wonderful; we were in this full discov- I encourage young assistant professors ery mode. From the very beginning to get as much help around the house of my scientific career, we always tried as needed so you don’t have to waste to be on the forefront. From the very the little time that you have with beginning, I learned that science is duties that you do not enjoy. discovering something new.

When did you first become John Arnst ([email protected]) is ASBMB Today’s science writer. involved with JBC? Follow him on Twitter at twitter. I was trained in a biophysics and com/arnstjohn. physical biochemistry department,

34 ASBMB TODAY MARCH 2018 MARCH 2018 ASBMB TODAY 35 ANNUAL MEETING Journal names winners of 2018 Tabor awards Young investigators to give short talks at ASBMB annual meeting about JBC papers that won them recognition By Laurel Oldach

he American Society for Bio- The new process highlights this chemistry and Molecular Biology work on a broader stage than was T annual meeting in San Diego in offered by the small, focused meetings April will feature five special Spotlight at which the awards were given in Talks by the winners of the Journal of previous years. “I imagine that these Biological Chemistry/Herbert Tabor talks should be a bit different” than Young Investigator Awards. they might have been at a smaller “These are young, promising sci- conference, DeMartino said. Larger entists who are going to present really conferences require presenters to exciting work and become the plenary give more context for their work and lecturers of tomorrow,” said George expose them to questions from diverse DeMartino of the University of Texas disciplines, he explained. Southwestern Medical Center, the The interdisciplinary audience also JBC associate editor who chaired the brings more attention to the work award selection committee. “This is a COURTESY OF SAHAR FOROUTANNEJAD and more opportunities to collabo- chance to see them early on.” Maria Fe Lanfranco provided this drawing by a col- rate. Presenters at previous ASBMB The awards, founded in 2011, league, which illustrates their prize-winning paper. annual meetings have struck up col- (see p. 39) honor longtime JBC Editor-in-Chief laborations with colleagues working (now Co-Editor) Herbert Tabor. papers published in 2017 from fellow in related fields, heard about new Once given by associate editors for editors and ASBMB members. They assays and approaches, and garnered attention from potential employers in top-notch conference presentations, assessed each article using comments industry and academia. the awards as of this year honor first from reviewers and researchers in the DeMartino can speak to the value authors of outstanding articles pub- field along with quantitative mea- of presenting early for a young inves- lished in JBC. Associate editors found sures of impact, narrowing from a list tigator. “I gave my first scientific talk they were reviewing strong research of hundreds of nominations to five in Chicago, at an ASBMB meeting,” from outside of the specialized areas exceptional articles. he said. “It was a great experience; represented at conferences they These articles span a range of top- in fact, I made the contact at that attended; the new process expands ics: the kinetics and complex synergy meeting that got me my current job eligibility to more young researchers. of HIV entry inhibitor molecules, — which was my first job.” In an editorial in JBC, Editor-in- protein structure for bacterial adhe- Chief Lila Gierasch of the University sion, a negative feedback loop in iron of Massachusetts Amherst emphasized homeostasis, an optical approach to the editors’ desire “to celebrate and visualize neuropathology as it forms, Laurel Oldach (loldach@asbmb. recognize … the deep talent pool of and allostery and cooperativity in org) is a communications intern early investigators who publish their a transcription factor responsive to at the ASBMB. She recently finished her Ph.D. in pharmacol- work in the journal.” cAMP. Diverse in subject matter, ogy at Johns Hopkins University. To choose the 2018 honorees, a the articles share a novel technical or These stories about the five 2018 committee of six associate editors conceptual approach to a standing Tabor Award winners are her first assignment for collected nominations of notable problem that impressed the editors. ASBMB Today.

36 ASBMB TODAY MARCH 2018 Who is Herbert Tabor?

Now 99 years old, Herbert Tabor is a senior investigator at the National Institute of Diabetes and Digestive and Kidney Diseases. From 1971 to 2010, he served as editor- in-chief for the Journal of Biological Chemistry, overseeing its expansion from 1,000 to 4,500 published articles per year and its transition to online publication. Over the years, he also has authored 31 articles published in JBC, including nine co-authored with his wife, the late Celia White Tabor. The JBC/Herbert Tabor Young Investigator Awards were conceived to honor him, said Associate Editor George DeMartino of the University of Texas Southwestern Medical Center. “And there’s probably nothing that would honor him more than hav- ing good papers published in JBC.”

Here’s a brief look at Tabor’s life and accomplishments: 1905: The Journal of Biological Chemistry is founded. 1918: Herbert Tabor is born in New York City. 1937: Tabor graduates from Harvard College. 1940: Tabor meets Celia White on a streetcar in Boston. 1941: Tabor graduates with an M.D. from Harvard Medical School. 1942: Tabor starts an internship at Yale New Haven Hospital, working concurrently in the lab of John Peters. 1943: Tabor joins the war effort as medical officer on a Coast Guard cutter escorting Atlantic convoys. 1943: Tabor is transferred to the National Institutes of Health, joining Sanford Rosenthal’s team to study treatment for burns and traumatic shock. 1943: Tabor’s first article is published in JBC: Tabor and Hastings, “The ionization constant of secondary magnesium phosphate.” 1946: Herb Tabor and Celia White marry. 1949: The Tabors move into commissioned officer housing on the NIH campus, where they raise their children and where Herb Tabor still lives today. 1952: Celia White Tabor joins the Rosenthal lab, starting the Tabors’ shared research. 1961: Tabor joins the editorial board of JBC. 1971: Tabor becomes editor-in-chief of JBC. 1975: The Tabors’ first joint article is published in JBC: H. Tabor and C.W. Tabor, “Isolation, characterization and turnover of glutathionylspermidine from Escherichia coli.” 1995: JBC becomes the first scientific journal to be published online. 2010: Tabor steps down as editor-in-chief, becomes co-editor and continues his bench research. 2011: JBC Editor-in-Chief Marty Fedor announces establishment of the JBC/Herbert Tabor Young Investigator Awards to be presented by journal associate editors to presenters at specialized scientific meetings. 2013: Published in JBC 70 years after Tabor’s first JBC article: Chattopadhyay and Tabor, “Polyamines are critical for the induction of the glutamate decarboxylase dependent acid resistance system in E. coli.” 2017: JBC Editor-in-Chief Lila Gierasch announces the Tabor awards will honor work on top-notch papers published by JBC.

MARCH 2018 ASBMB TODAY 37 Researcher recognized for studies of HIV drug synergy

oree Ahn, a 3-D printing enthu- siast, once brought two compet- Complex interactions K ing proposed structures of the HIV 1 envelope protein with him to between HIV drugs a class discussion. “I was able to pres- HIV enters human cells using ent these physical structures so that an envelope protein that binds people could hold them and physi- to two cell-surface receptors and cally observe” the protein’s features, then pulls the viral membrane he recalled. near the cell membrane. Two The envelope protein allows the drug classes block this process: HIV membrane to fuse with a human coreceptor antagonists block cell’s. Ahn published a Journal of interaction between the envelope Biological Chemistry paper on drugs protein and one receptor, and that block viral entry by inhibiting COURTESY OF KOREE AHN fusion inhibitors block mem- the envelope protein’s interaction with Koree Ahn studied the interaction between coreceptor antagonists and fusion inhibitors in HIV infection. brane juxtaposition. surface receptors. The work earned Because these two drugs act Ahn a 2018 JBC/Herbert Tabor on steps in the same process, they Young Investigator Award. was really laid by previous members might behave synergistically. Syn- Ahn laid a foundation for this of the Root lab who had developed ergy between drugs occurs when kinetic and pharmacological research this super-quantitative model for how the result of treatment with both as a freshman at Hamline University (HIV entry) inhibition works,” he together is more dramatic than in St. Paul, Minnesota. “What I origi- said. He used the lab’s model and a would be expected by adding the nally thought would be a semester- library of entry inhibitors to untangle two effects. But in fact, results of long résumé builder instead became whether two classes of drugs exhibit experiments testing for synergy the four-year-long highlight of my synergy when used in combination. were variable and confusing. undergraduate education,” Ahn said. Reports in the literature had con- Koree Ahn and colleagues at He worked with chemist Olaf flicted; as it turned out, so did results Thomas Jefferson University in Runquist to develop mathematical in the Root lab. Philadelphia used a variety of models of cell differentiation based on Ahn observed synergy that others molecules with slight differences colon cancer samples from collabora- in the lab had not, “and that led us to model a complex mechanism tor Bruce Boman, a professor at the to different questions, like, ‘What for interaction of the two drug University of Delaware. Over sum- type of fusion inhibitors did you use? classes. Ahn concluded that mers, he learned wet lab techniques in Did they bind very tightly to the synergy between the drug classes the Boman lab in Newark. He went fusion inhibitor binding site, or very is possible but dependent on two on to graduate school at Thomas Jef- unexpected factors: the location ferson University in Philadelphia. loosely?’” Understanding these techni- and strength of fusion inhibitor “As a person who was from the cal differences helped guide the team binding to the envelope pro- Midwest, I fell in love with the to the cohesive understanding of the tein and the level of coreceptor diversity and the vibrancy of Philadel- factors permitting synergy that they expressed on the target cell. phia … and I was really interested in published in JBC. The work, published in JBC a lot of the research going on there,” Ahn recently packed up his 3-D in July, has clinical implications: he said of his decision to join the printer and moved to Chicago to It suggests that combining the university’s program in biochemistry continue his HIV research. two drug classes may not be an and molecular pharmacology. He now works as a postdoctoral effective treatment strategy. For Ahn’s doctoral project in Michael fellow in the lab of Thomas Hope at more on this work, see a com- Root’s lab at Thomas Jefferson built Northwestern, studying interactions panion article in JBC by Gregory on models of HIV entry established between HIV and molecules present Melikian of Emory University. by colleagues. “All of the groundwork in mucous membranes.

38 ASBMB TODAY MARCH 2018 Neuropharmacologist selected for engineering novel mutant dimers

aria Fe Lanfranco’s scientific career has crisscrossed the Fusing monomers to M Western Hemisphere. Born in Lima, Peru, she moved to understand allostery the United States after college. “That Maria Fe Lanfranco and col- was a big decision,” she said, “but … leagues investigated how two if I really wanted to pursue a career identical subunits of an allosteri- in science, I needed to do a Ph.D. cally activated protein communi- outside Peru.” In the years since then, cate about ligand binding. she has lived and worked all over the The cyclic AMP receptor pro- United States. tein, or CRP, is a transcription Lanfranco won a 2018 Journal factor activated through allostery, of Biological Chemistry/Herbert when binding of a ligand pro- Tabor Young Investigator Award for COURTESY OF MARIA FE LANFRANCO motes a change in the protein’s her work on allostery in an E. coli Maria Fe Lanfranco studied allostery in a bacterial transcription factor. characteristics at a distant site. transcription factor carried out as a CRP has negligible binding to postdoc at Georgetown University. DNA at first, but in complex With colleagues, she developed an studio every few blocks, Lanfranco with the small molecule cAMP, it approach to understand how com- later began to teach classes herself. binds DNA more strongly. munication across ligand binding sites With her husband, biophysicist Like many allosterically affects this protein. She published the Rodrigo Maillard, Lanfranco moved activated proteins, CRP has two work in JBC in February 2017. to Washington, D.C., to start his lab identical subunits. When one She credits her high school biology at Georgetown. The pair, both origi- binds to cAMP, the other is more teacher with making it “almost a no- nally from Lima, had met in college likely also to bind, a phenom- brainer” to study science in college. and married as postdocs. enon known as cooperativity. “I’ve always been interested in When Maillard started his lab, The team studied the interme- identifying targets for the treatment he pitched an allostery project to diate stage, after one cAMP had of pathological disorders,” she said. Lanfranco. She was interested in bound but before the second. Curiosity about the neuroscience of the neuropharmacology angle. To It was difficult to isolate this addiction drew Lanfranco to gradu- her, allosteric modulators are “a very intermediate because it is short- ate work in the laboratory of Kathryn provocative kind of drug, because lived and mutating the purified Cunningham at the University of it’s more interesting to modulate the protein to disrupt cAMP binding Texas Medical Branch in Galveston, activity of a receptor, rather than results in dimers with the muta- where she studied a serotonin receptor turning it on or off.” tion in both subunits. involved in cocaine addiction. After years of working in parallel, The researchers found a way She followed her passion for under- Lanfranco said, collaborating with to mutate just one subunit by standing disease to a postdoctoral Maillard works because “we comple- cloning a linked pair of mono- position studying signaling ethanol ment each other a lot ... but we mers. By adding asymmetric addiction with Dorit Ron at the Uni- kind of set some rules in which we cAMP binding mutations to this versity of California, San Francisco. wouldn’t talk about work at home, molecule, they could capture the She lived in Berkeley and took because then it would be too much.” transient single-cAMP bound a yoga teacher training course. “I Reflecting on her peripatetic dimer more effectively. Bind- started doing yoga because I was feel- pursuit of science, Lanfranco projects ing of a single cAMP molecule ing stressed out — like every student a yogic satisfaction: “All of those cities was enough to open the DNA in graduate school,” she said with (Lima, Galveston, Berkeley and Wash- binding domain of the transcrip- a chuckle. A compelling teacher in ington) have a lot to offer … each one tion factor, thus forming a stable Texas had gotten her more involved. of them, at that particular time in my DNA–protein complex. In Berkeley, where she passed a yoga life, was the perfect place to be.”

MARCH 2018 ASBMB TODAY 39 Chemist peers into neurons to study seeding of alpha-synuclein

ost home bakers get a brown shine on their pretzels by dip- Watching M ping the dough into a boiling bath of water and baking soda. But the spread of for Richard J. Karpowicz Jr., it’s all neurodegeneration about the base. “I’m a chemist, so I make tradi- A number of neurological tional German lye pretzels with one disorders, including Parkinson’s, molar sodium hydroxide,” he said. “I Alzheimer’s and Lou Gehrig’s wear gloves, and I kick my girlfriend disease (formally known as out of the kitchen.” amyotrophic lateral sclerosis) are Karpowicz, a postdoctoral caused by aggregation of proteins researcher at the University of Penn- within neurons. This process can COURTESY OF RICHARD KARPOWICZ JR. sylvania, received a 2018 Journal of be seeded in cultured neurons Biological Chemistry/Herbert Tabor Richard Karpowicz Jr. developed a tag-and-quench fluorescence imaging approach to study Parkinson’s by introducing clumps originally Young Investigator Award for other proteins. formed in a test tube. pursuits in chemistry. With his col- Richard Karpowicz Jr. and leagues, Karpowicz developed a new continue with synthetic organic approach to image aggregation and colleagues developed a new chemistry but heard about Dali Sames transmission of a protein associated fluorescent approach to track with Parkinson’s disease, work that at Columbia University who develops alpha-synuclein clumps only after appeared in JBC last year. fluorescent neurotransmitter ana- they are internalized by cells. The Raised in Lawrenceville, New logues to track vesicle release. researchers tagged the seeds with Jersey, Karpowicz went to the Univer- “That’s where I got involved in a fluorescent protein but then sity of Delaware as an undergradu- tissue culture, assay development, quenched all fluorescence outside ate intending to major in chemical and biological and biochemical and of the cell. They published the optics-based methodology,” he said. engineering. His father, Richard J. work in June in JBC. After earning his Ph.D., Karpow- Karpowicz Sr., had earned a Ph.D. in The authors confirmed that icz wanted to develop techniques to chemistry at the University of Dela- added alpha-synuclein, the pro- ware and introduced him to scientific tackle unsolved problems. He joined the lab of Virginia Lee at the Cen- tein responsible for Parkinson’s thinking at a young age. disease, is taken up and stored for “I grew up doing a lot of fish- ter for Neurodegenerative Disease days within the cell. By adding a ing with him, and he would explain Research at the University of Penn- second, acid-sensitive fluorescent the tides and sunrise and sunset,” sylvania. the younger Karpowicz said. “He “When I interviewed here, the tag, they showed that protein always took a scientific perspective on most important question was, ‘How clumps are kept in the acidic explaining the natural world in a way can we measure internalization of environment of the lysosome and that was accessible to me as a kid.” (alpha-synuclein seeds) or where they that disrupting lysosomal storage In college, Karpowicz fell in love go inside the cell? How can we shed leads to increased seeding of new with biochemistry and changed his some light on what actually happens clumps. major. His research into catalyst inside a neuron?’” This suggested to the authors design with Joseph Fox won him He pitched a plan that came to that just a few events are enough Pfizer and Howard Hughes Medical fruition in his JBC paper. to seed significant aggregations. Institute funding. And on his cooking hobby, he For more on this paper, see Karpowicz’s interests have repeat- reflected, “It’s fascinating what kind the article in the November issue edly pulled him from pure chemistry of flavors can develop through dif- of ASBMB Today, “Tracing the toward its interface with biology. ferent cooking techniques. It’s all path of Parkinson’s proteins.” In graduate school, he intended to chemistry, right?”

40 ASBMB TODAY MARCH 2018 Nutritional biochemist honored for paper on tuning iron levels

athan B. Johnson compares experimental biology to another Controlling iron uptake N challenging process of opti- mization, fly fishing: “You go to the for cell health stream and see what flies are hatch- Iron levels in a cell need to ing on the surface or what nymphs be just right. Excessive free iron there are under rocks, and then you causes accumulation of reactive try to match the hatch the best you oxygen species; deficiency causes can. Like science, fly fishing success is anemia. Therefore, cells express dependent on accurate observations, a complex system of proteins to predictions, reproducibility, presenta- calibrate iron uptake and storage. tion and luck.” Two iron-response proteins, But, he admits, the analogy can IRP1 and IRP2, respond to break down: “You can sometimes COURTESY OF NATHAN B. JOHNSON a low cytoplasmic iron level catch a fish in a day; it’s hard to com- Nathan B. Johnson studied the complex regulation of the RNA-binding protein IRP1. by binding to RNAs, increas- plete an experiment in a day.” ing translation of iron-uptake Johnson won a 2018 Journal of proteins and reducing translation Biological Chemistry/Herbert Tabor he said, and so he decided to pursue of iron-storage proteins. This Young Investigator Award for his a Ph.D. response increases cellular iron work on iron homeostasis, conducted Johnson joined the program in bio- level. When free iron is adequate, as a graduate student and postdoc at chemical and molecular nutrition at the two proteins are turned off to the University of Wisconsin–Madison the University of Wisconsin-Madison. prevent excessive accumulation. and published last year in JBC. He was drawn to work in the lab of Until recently, the two IRPs It all started with the University of Richard Eisenstein by the opportunity were thought to be inactivated Tennessee Agricultural Extension 4-H to design his own project. by distinct mechanisms: IRP1 by program. “I didn’t plan on being a “He gave us the freedom to think adding an iron-sulfur group and scientist,” Johnson said. “I grew up in critically and to work independently, IRP2 by ubiquitination. Johnson rural east Tennessee and was active in and I thought, ‘That’s what I really and colleagues explored crosstalk a 4-H project, part of the meat prod- need in order to succeed in science,’” between the two downregulation uct evaluation team.” He followed Johnson said. pathways, demonstrating that that track to major in food science Since leaving Eisenstein’s lab, John- nothing in the system is as linear and technology. Almost as soon as son has been a postdoc in Rozalyn as it had seemed. They published he started learning the principles of Anderson’s lab in Madison, studying their work in JBC in August. nutritional biochemistry, he realized a transcriptional coactivator upregu- When the iron sulfer-cluster he would love to teach them. machinery was absent, the Biochemistry coursework for a lated in response to aging and caloric researchers saw that IRP1 could master’s degree in nutritional science restriction. He also has developed be degraded by the ubiquitin introduced him to bench science, curricula and is the instructor for ligase that destroys IRP2. They another activity he found he enjoyed. three online courses on macronutrient also found that impaired iron- To find out whether he liked metabolism, personalized nutrition sulfur assembly increases levels of research as much as teaching, Johnson and micronutrient metabolism for the the ubiquitin ligase, indicating took a job as a lab manager in Debo- new online master’s degree in clinical that the ligase is an important rah Segaloff’s lab at the University nutrition program at Madison. backup mechanism for IRP of Iowa. He managed the lab and “I’m in the process of transitioning turnover. worked on structural characteriza- to a full-time teaching role, which was See related articles in Febru- tion of gonadotropin receptors. “After what initially piqued my interest in ary’s ASBMB Today and the doing that for five years, I sort of felt research,” he said. “It’s sort of neat to Sept. 22 issue of JBC. as though I had reached a plateau,” come full circle.”

MARCH 2018 ASBMB TODAY 41 Researcher honored for studies of oral pathogen that infects heart

hy can a bacterium usually found in the mouth also drive Catching fibronectin W an infection linked to heart failure? How does a nascent bacte- to clamp on tightly rial colony in the heart protect itself from being swept away? Catherine Adhesion proteins are key Back won a 2018 Journal of Biologi- drivers of bacterial colony forma- cal Chemistry/Herbert Tabor Young tion. In the case of S. gordonii, Investigator Award for her work on the protein CshA contributes to the mechanism of adhesion between binding to the human extracellu- a bacterial fibril protein and human lar glycoprotein fibronectin. tissues. Because S. gordonii can enter The protein, which she character- the bloodstream and adhere to ized while she was a postdoctoral fel- COURTESY OF CATHERINE BACK heart valves, the binding mecha- low at the University of Bristol, helps nism may have implications for the oral bacterial species Streptococ- Catherine Back found a novel mechanism for strep- tococcal adhesion to fibronectin. development of heart infections. cus gordonii attach to and colonize Catherine Back and colleagues human tissues and may contribute to bacterial infection of the heart. “I managed to work in both at the University of Bristol Back’s first research experience departments, learning microbiology divided a relatively uncharacter- was as an undergraduate at Bristol, and also structural biology,” Back ized region of the protein into where she worked with microbiologist explained. The collaboration between three domains through bioinfor- Howard Jenkinson on an interaction the groups continues to this day. The matic analyses, publishing their between S. gordonii and another labs now work together to character- work in JBC in December 2016. species of commensal oral bacteria. ize other bacterial adhesins. They analyzed each domain’s She stayed on at Bristol for her Ph.D., After earning her Ph.D., Back interaction with fibronectin, extending her undergraduate studies stayed on in Bristol to finish the work finding that one of the three with a closer and more multidisci- described in her JBC article and then domains did not interact. Of the plinary look at CshA, an adhesion moved to the nearby University of remaining two, dubbed NR1 protein. Bath to study a new type of vaccine and NR2, the on and off rates “I thought it was really interesting for tuberculosis. for NR1 were faster, although to work on a protein that not much Back grew up in Exeter in Devon, NR2 was capable of higher affin- was known about,” she said. England, and said she enjoys getting While Jenkinson remained her outdoors both in Bristol and on visits ity binding. They analyzed the primary supervisor, for her project, home. “I often go back to my parents’ structure of both domains, deter- Back drew on the expertise of three house in Exeter,” she said. “It’s near mining that both are responsible principal investigators from two the sea, and near Dartmoor, which is for fibronectin binding. The dis- departments. Jenkinson and Angela a really nice place to go hiking.” ordered NR1 domain interacts Nobbs were frequent collaborators on Back recently returned to Bristol transiently with fibronectin, the microbiology research in the dental to join the lab of Paul Race for a so-called catch. After NR1 makes school, while biochemist Paul Race new project, studying antimicrobials initial contact, NR2 binds more contributed expertise in protein char- from bacteria that colonize deep-sea tightly — the clamp. acterization. sponges. Back suspects the binding she described may be relevant to other pathogens. A number Put these talks on your itinerary of other streptococci “have Check the ASBMB annual meeting program (www.asbmb.org/ CshA-like proteins, which have meeting2018) for location and timing of the Tabor award winners’ a similar sequence and may have Spotlight Talk session, and don’t miss the chance to hear from these a similar mechanism of interac- promising scientists in their own words. tion,” she said.

42 ASBMB TODAY MARCH 2018 MARCH 2018 ASBMB TODAY 43 ANNUAL MEETING What to wear at the annual meeting A guide for packing light and looking great at scientific conferences By Andrea Hadjikyriacou

s a fashion blogger and scientist, Sometimes the conference itinerary conference hall is chilly. I find the best time to meld my states the dress code, but most do • Use accessories like scarves, fun A two passions is at a scientific not, so as a first-time attendee (or socks and jewelry to your advantage. conference. What better place to even a seasoned veteran), you might This can spice up an outfit without network with others in your field, not know what to wear. My advice: filling your suitcase. learn new things, hear about cutting- It never hurts to dress more formally • You don’t have to go out and buy edge technologies and also present on the first day and see what others expensive dress shoes; sure, they can your work to get great constructive are wearing; then you can adjust your complete a look, but more and more feedback? The best ideas I’ve had were clothes accordingly. No need to wear labels are coming out with dressier at conferences. Different perspectives, a suit and tie every day if others are sneakers and flats. A simple black or opinions and outlooks really can help more business casual. At the same dark gray shoe can match well with advance your project. Why not make time, you don’t want to be the person your outfit. Avoid running shoes or it even better by feeling your best and who shows up in casual clothes while gym sneakers if possible. most confident because of your power everyone else is dressed up. • Do wear comfortable shoes (but outfit? When you feel good, that con- they can still be stylish). Heels can be fidence projects to others. But a huge Tips for conference style great, but bring a pair of flats in your problem for a lot of people is the bag to change in case those heels start • Get a feel for what the confer- question, “What do I actually wear?” to hurt after hours of standing. ence dress code is. It is always better I blogged about style for a previ- • One of my shoe tricks: Wear to be overdressed on the first day than boots under wide-legged pants — ous Experimental Biology/American it is to show up in faded jeans and a Society for Biochemistry and Molecu- comfy and stylish. T-shirt. • Avoid wearing sneakers and lar Biology meeting, and it was really • Mix and match your pieces; ripped or faded jeans. You want to fun to see what kind of outfits I could re-wear the same pants with multiple make a good impression and look come up with for each day of the shirts and tops for instantly different professional, especially when you are conference. As a woman who loves to outfits. No one will notice you wore presenting your poster, giving a talk shop, I had a closet full of clothes that those same black pants yesterday. or meeting other scientists. I never wore, mainly because I was • Simple black or dark gray dress • That being said, you can still wear lazy but also because I wasn’t being pants are my go-to; you can switch nice jeans. I would opt for a darker creative about putting pieces together. out different colored and patterned wash of denim with a nice pair of When I finally realized I could mix shirts, sweaters and blouses. shoes or boots and an ironed button- and match, I was able to put together • Capsule pieces, like a white or up dress shirt or a flattering blouse. multiple outfits without packing too black shirt, simple T-shirt or tank top, It’s a good go-to conference look. many things — especially important can be layered under other pieces to • A blazer can always be added for when you have to travel by plane. create a simple outfit when covered by a touch of professionalism; you can I’ve been to several conferences in a blazer. class up those dark jeans and a top my time as a graduate student, and • A vest can add spice and varia- with a blazer, and voila — an instant each one has its own feel — some are tion to your outfit. You could wear outfit that’s both professional and business attire only, some are business the same (clean) shirt and pants the casual. casual, some are very casual — so it’s next day, add the vest, and you have a • Make sure you iron whatever you hard at first to gauge what to wear. new look. Same with a sweater if the wear. Wrinkles can look messy and

44 ASBMB TODAY MARCH 2018 PHOTOS OF ANDREA COURTESY OF TINA LAWSON, NICOLE BECKERMAN, QAIS AL-HADID AND ANDREA HADJIKYRIACOU PHOTOS OF ASBMB STAFFERS AND SHOES BY EMILY HUFF/ASBMB. It’s always a good idea to dress up on the first day of a conference. Left, ASBMB science policy analyst Andrè Porter wears a blazer and tie with dress pants. Right, fashion blogger Andrea Hadjikyriacou opts for a simple dress and jacket; just remember to pack some flats if you wear high heels like Andrea’s (see below).

You can’t go wrong with a pair of black shoes. Opt for a classic style and comfortable heel. Add a pop of color with your socks.

Casual flats are fine, but avoid running shoes and gym sneakers. These gray suede lace-ups and strappy brown flats strike just the right note.

MARCH 2018 ASBMB TODAY 45 Dark pants and a nice dress shirt or blouse make ASBMB science writer John Arnst, below, and fashion For a more casual way to stay warm in a chilly con- a great go-to look when you’re at a conference, as blogger Andrea Hadjikyriacou, above, show how ference hall, wear a stylish cardigan like MCP editor demonstrated by fashion blogger Andrea Hadjikyri- you can dress up jeans or pants and a simple shirt for manuscript integrity Saddiq Zahari, above, or acou, below, and ASBMB public affairs manager with a classic blazer. A good look for your poster pop on a zippered jacket like fashion blogger Andrea Daniel Pham, above. presentation. Hadjikyriacou, below.

unprofessional. names and so on. The simpler the Andrea Hadjikyriacou (andrea@phdfashionista. • If you’re packing light, make sure better. com) is a postdoctoral scholar in industry/ you have laundry access — and be • If you wear make up, remember biotech by day and a fashion blogger at PhD Fashionista by night. She started her blog in prepared to do some spot cleaning. simple always wins. There’s no need to graduate school to show the world that scientists Pack a stain-remover pen. be super flashy; neutral makeup with can be stylish too. You can find her blog at www. • Avoid T-shirts or other cloth- a pop of color on your lips can go a phdfashionista.com and on Instagram and Twitter ing that display slogans, logos, brand long way. @phd_fashionista.

46 ASBMB TODAY MARCH 2018 MARCH 2018 ASBMB TODAY 47 RESEARCH SPOTLIGHT A love of teaching and the chemistry of living organisms

na Maria Barral is an assis- Everything changed when I learned tant professor at the National about biochemistry; I remember how A University in Costa Mesa, excited I was about a chemistry that California, a member of the American looked at living organisms. Society for Biochemistry and Molecu- lar Biology Public Outreach Com- mittee and a member of the ASBMB Were there times when you Today editorial advisory board. In failed at something critical this month’s Research Spotlight, she discusses her involvement in teaching to your path? How did you research and the experiences that led get back on track? to her career. Many times. I’ve run the gamut Tell us about your current from saying no to opportunities that felt too scary to being overeager about career position. interesting results without double- My university is primarily a teach- COURTESY OF ANA MARIA BARRAL checking everything. How to regroup? ing institution, although the faculty As the child of two doctors, one also a researcher, Well, one has to accept not being has a requirement and support for Ana Maria Barral grew up surrounded by science. perfect and that it is OK to make research also. My research explores mistakes, and be kind to oneself. It is the microbes attaching to plastic in spent a few years working at a biotech human to err. Then, just pick up the coastal waters, and I also am involved company and teaching as an adjunct pieces and keep going. It will all pass. in teaching research, particularly how at different colleges while learning Learn from the experience. Personally, to incorporate research in undergrad- more about the science of teaching. I like to have more than one project uate education and flipped learning, Gaining expertise in innovative teach- going (both in science and in my wherein most lectures are delivered ing approaches helped me to land my personal life) so setbacks in one can outside the classroom and students current position. can dedicate in-class time to problem be balanced with successes in others. solving and more active learning How did you first become What advice would you What experiences and interested in science? give to young persons decisions enabled you My parents were both medical doc- from underrepresented tors, and my mother did physiology to reach your current research, so science has been present backgrounds who want to position? in my life since childhood. I read pursue a career in science many books detailing the lives and Mine was a conventional academic similar to yours? research scientist’s path, but during discoveries of scientists and dreamed grad school I was involved in a lot of about becoming one. However, I Be brave. Be bold. Network as teaching and training. As a postdoc, knew I did not want to be a physi- much as you can, and look for men- I realized I missed the interactions cian, and biology did not attract me, tors. Never say no to an opportunity, with students and the challenges and because I thought it was all about because you don’t know when the joys of teaching, and I decided not animals and plants. Chemistry was next one will come. Be who you are. to become a traditional academic. I interesting, but it felt a bit dry. Be authentic.

48 ASBMB TODAY MARCH 2018 What are your hobbies? Do you have any heroes, better, I have my research projects, in which I can involve students. One I love traveling, particularly going heroines, mentors or role of my greatest joys is to see students off-roading to remote places. Run- models? If so, how have who hadn’t thought about becoming ning. Photography. Backyard work. scientists do and enjoy science. Paddle boarding and the ocean in they influenced you? general. Reading. Music. There are many people I admire for what they have done and achieved About the What was the last book in life. But my role models are those Research Spotlight you read? who live their lives to the fullest, in accordance with their principles, and The American Society for Bio- Assuming this is about nonscience are very accomplished and still hum- chemistry and Molecular Biol- books, I am currently reading Diana ble and kind. I know a few people like ogy’s Research Spotlight high- Gabaldon’s “Outlander series”; the that, and I aspire to be like them. lights distinguished biomolecular latest I finished was “The Fiery and biomedical scientists from Cross.” She has a science background, diverse backgrounds as a way to and I enjoy reading her biology com- What is it that keeps you inspire up-and-coming scientists mentaries through the books. I just working hard every day? to pursue careers in the molecu- discovered Nnedi Okorafor (great sci- lar life sciences. Eligible candi- I am very lucky that I love what ence fiction) and got started on Sheryl dates include Ph.D. students, I do. As a laboratory scientist, my Sandberg’s “Option B.” Science-wise, postdoctoral fellows, and new or impact on the world was minuscule, I am slowly winding my way through established faculty and research- while as an educator, I feel I can Michael Quinn Patton’s book on ers. To nominate a colleague for influence others’ lives in a positive qualitative research. It is eye-opening this feature, contact education@ way. My students tend to be older, and gives me a lot of exciting ideas for asbmb.org. assessing teaching innovations. so I also learn a lot from them. Even

MARCH 2018 ASBMB TODAY 49 OUTREACH Sparking the flame of science Supported by an ASBMB grant, Salisbury University students guide children through activities in biology By Gabrielle Voithofer

ne-fifth of all jobs in the U.S. sciences at SU to hold two outreach from the ASBMB Student Chapter workforce are related to science, events to inspire interest in biology in and the department of biological O technology, engineering or children living in Wicomico County, sciences. math, according to the STEM Educa- a rural area on the eastern shore of The ASBMB Student Chapter tion Coalition, and the STEM career Maryland. executive board also organized a field is predicted to grow as much Patti Erickson, an SU associate student-led event called DNA Discov- as 13 percent in the decade between professor, organized field trips for ery, a day of activities at a branch of 2012 and 2022. students and teachers from the Wic- the Wicomico County Public Library. The American Society for Bio- omico County Thinking and Doing Callista Brown, secretary of chapter, chemistry and Molecular Biology program for fourth graders. More obtained materials and led the event. Student Chapter at Salisbury Uni- than 100 students visited SU’s depart- Erickson and chapter volunteers led versity wanted to explore ways that ment of biological sciences; they ran 10 children ages 6 to 12 through teachers and people in STEM fields gel electrophoresis and DNA extrac- three activities: DNA isolation, could work together to spark chil- tion tests, learned about phenylke- candy and foam DNA structures, dren’s interest in STEM and lifelong tonuria and green fluorescent protein, and a Mystery Code worksheet. learning. With funds from a Student and toured some of the SU facilities. In the DNA isolation activity, the Chapters Outreach Grant, we worked The labs were run by professors and participants used Gatorade, deter- with the department of biological students supported by volunteers gent and alcohol to make DNA from

PHOTOS COURTESY OF LAUREN DELONG Salisbury University students help participants assemble their candy DNA structures during the Wicomico County Library outreach event. Left, Mariah Passwaters- Stamper; center, sitting at the table, Jeremie Barbosa; and right in red, Gabrielle Voithofer.

50 ASBMB TODAY MARCH 2018 Andrea Carmack, ASBMB Student Chapter treasurer, helps a participant complete a nucleotide matching worksheet during the Wicomico County Library outreach event. their own cheek cells visible to the the DNA structure activities to spell ident Jamie Barbosa called the experi- naked eye and then placed the white out a “secret” message. The students ence “mutually enriching for both the threads into microcentrifuge tubes as particularly loved putting their DNA young students as well as myself.” necklaces. The volunteers explained into a necklace and making the DNA I personally enjoyed this experience the structure of DNA and taught candy models, according to a review because it allowed me to participate the children about nucleotide base survey. Most said they were happy to in something that involved two things pairing with foam model and let them learn something new. I am passionate about: science and create their own DNA molecules Andrea Carmack, the Student volunteerism. It was impressive to with candy. For the Mystery Code Chapter’s treasurer, said she was witness young kids just enjoy the worksheet, students used the base “excited to share her love of biology process of learning. pairing rules they had learned from with a younger generation.” Vice Pres- After the activities, Student Chap- ter members decided they needed to improve the feedback process. In The Student Chapters Outreach Grant Program a later outreach program, we asked multiple-choice instead of short- Twice a year, the ASBMB awards grants of up to $500 to help its Stu- answer questions. We also offered dent Chapters bring science activities to their communities. The funds can snacks as an incentive to complete the be used to support existing outreach activities as well as to help pilot new survey. This feedback is important to activities. This grant program is an exciting way to encourage our Student improve future outreach events. As Chapters to be more active in their engagement with the local community. a chapter, we hope to organize more These grants support a variety of programs — everything from the events like these and continue to be University of Arizona’s Blastoff! Summer Science Camp to the Marymount active in our community. Manhattan College organ donation drive to the Salisbury University biol- ogy activities described on this page. The goal is to bring science to the public and encourage participation and partnerships in science outreach. The grant program is sponsored by the ASBMB Student Chapters and Gabrielle Voithofer (gvoithofer1@ Public Outreach Committee. In addition to funding, successful applicants gulls.salisbury.edu) is a biology and economics major in her sec- have exclusive access to the committee’s outreach expertise and resources. ond year at Salisbury University Don’t miss out on this exciting opportunity. The next deadline for and the social media and public applications is April 16. Each chapter may apply once a year. For detailed relations chair of Salisbury’s instructions, sample applications and more information, go to the Out- ASBMB Student Chapter. This article originally appeared on The Substrate, the online newsletter reach section of asbmb.org and click on Funding. for ASBMB Student Chapters.

MARCH 2018 ASBMB TODAY 51 ESSAY Leadership: the sock’s-eye view

Editor’s note: This is the first in an She was so good, it seemed she could The many bleach stains and acid occasional series of essays from a writer walk on any solvent. I took her bioor- holes in his clothes were testaments who has his ear to the ground when it ganic chemistry course, and I suspect to his folly. In fact, we students had a comes to life in the lab. I learned a thing or two about arrow game we liked to play called “Where’s I was standing at the counter of the pushing. The more enduring lesson, the hole?” The first person to find the juice bar in Logan Airport, ordering however, was about confidence and hole in our advisor’s clothing on any my breakfast, when I felt a shadow how to project it, which I learned by given day was the winner. It never fall over me. Behind me towered a observing her. I noticed that several took long. man well over 6 feet tall. His spiked women in the class picked up on this I think of that now when I work hair stood up like a row of fenceposts, too. Whether the change was made with graduate students in the lab. and his smile gleamed. The creases consciously or not, soon there was a Some have terrific qualities to recom- on his pinstriped shirt looked like small flock of Marilyn clones, imitat- mend them; but everyone, without they’d cut a steak. As I moved aside to ing her dress, her diction and even her fail, also has some nagging flaw. wait for my drink, he approached the ticks. Maybe they’re a little bit careless or counter. The man at the cash register It’s said that graduate students lazy. Maybe they give up too fast — said warmly, “What can I get you, often pick up something of their advi- or not fast enough — when an experi- Governor?” sor’s style. It helps if your advisor is ment isn’t working. Perhaps they can’t Then it hit me. The stately blonde someone you can relate to. There are assemble a sentence or make a figure sitting at the table, the one who still very few sock puppets in science, to save their life. Like the Scarecrow, looked like Ann Romney — that and I admit it has been difficult find- the Lion and the Tin Man, every was Ann Romney. And this was Mitt ing an appropriate role model. But one of your ragtag band will have a Romney. It was 2013 and he had when I’m about to give an important problem. And just like the Great Oz, recently lost the presidential election, talk or advocate for myself in front as their leader, it’s your job to find the but, feeling a little thunderstruck, I of my boss, I still put on my best hole and help them fix it. thought he still looked every inch a Marilyn impersonation, and I go out 4. A leader makes s**t sandwiches. president. guns a-blazing. As a young sock, I visited the beaches Primates may be conditioned to 2. “Boss” is a four-letter word; at Normandy, France. Like many visi- look for certain physical traits in an however, “leader” has six letters. tors, I was awestruck, imagining boat alpha. Mitt Romney had those in Research labs, by and large, are not after boat dispensing scared young spades. But what about the rest of us? populated by quarterbacks. Many soldiers onto the shore under a rain of The less than eagle-eyed? The height of us went into science because we bullets and mortar fire. I always won- challenged? (In the interests of full appreciated working independently dered how their commanding officers disclosure, I should tell you — I am or in highly collaborative structures, were able to marshal them up the a sock puppet.) Dare I say the nerdy with big tents and round tables. To beach and into enemy lines. Surely, types? Can we not also be leaders? Of many scientists, the word “boss” may such techniques must be sufficient for course, the answer is yes, we can, and have a highly pejorative connotation. motivating discouraged students to go in some cases we absolutely must step You may prefer the more inspiring back into the lab? up. Here are the top six things I’ve word “leader.” I’m here to tell you A few years back, we had an Air learned about leadership from helping that being a leader is a good thing and Force captain in our graduate pro- to manage a large-ish group of gradu- probably something you should aspire gram. Though he’d not seen warfare ate students for the past dozen years: to, regardless of your actual job title. of the Normandy variety, he had 1. If you don’t feel like a natural- Why? Read on. nonetheless completed a great deal of born leader, try imitation. We’ve all 3. A leader finds the hole. When I officer training. Now was my chance heard versions of this before — for was a graduate student, I worked on a to learn: How does the military teach example, dress for the job you want, collaborative project with an assistant officers to lead? not the one you have. I’d take it a professor who was notoriously dishev- In partial answer to my question, step further. When I was a postdoc, eled. He was at the stage of his career the captain referred me to a chestnut there was a snappy young scientist at where he still worked in the lab, or of a book — Dale Carnegie’s “How our institute — I’ll call her Marilyn tried to, though he probably should to Win Friends and Influence People” Mertozzi — who walked on water. have stayed away. — and a recipe of sorts that his Air

52 ASBMB TODAY MARCH 2018 Force colleagues had derived from a potential tripping hazard? Quitting it. He said that when they needed to time was approaching, and still no About the author Leadership: the sock’s-eye view criticize or correct someone at their one had dared to touch the broken own rank or above, he and his fellow clock. Finally, Professor Lu himself officers would cushion the blow by came with a broom and wastebasket wedging it between two compliments: and took care of the mess. the so-called “s**t sandwich.” When I was a postdoc, there was a Much more direct criticism time when there were 12 of us, each from officer to underling would be more ambitious than the next, all completely acceptable; however, even sharing the same cramped lab space. recruits sometimes had a hard time No one had time for good manners or hearing criticisms when dished out even basic sanitation and — needless too directly. to say — the lab was an incredible And so it goes in the laboratory. mess. One day, my co-worker Mike The student’s shortcomings are only (now a faculty member and father of too clear. He fails to keep an orga- two) rounded us up and said: “We’re nized notebook. As a consequence, no having a lab cleanup. All of us. This one else in the lab can understand let afternoon.” alone repeat his experiments. You’ve Whether he or she has the requisite warned him about this a thousand title or authority, the person with times. You are so frustrated, you want whom the buck stops is, by virtue of COURTESY OF MOHAMMED REFAI to roll up the notebook and whack taking action, the leader. You don’t Sock Puppet, Ph.D., started his career as a him over the head with it. Instead, have to have a fancy title or position teaching assistant. you offer: to exert this kind of quotidian leader- “I notice you’re working very ship; you just need to be responsible. Gamma rays created the Hulk. hard in the lab lately, little Timmy.” And let me tell you, these sorts of The bite of a radioactive spider (BREAD) innate leaders are lab gold. turned Peter Parker into Spider- “You’ve really got to record your 6. Some of the most effective lead- man. When an assistant professor methods much more carefully, how- ers are the least visible. In an episode was asked to teach a large intro- ever.” (S**T) of the cartoon “Futurama,” Bender, ductory biochemistry course, “That way, everyone in the lab will the robot, floats out into deep space. without sufficient funds for a get to see exactly how you work your After many weeks, he drifts toward a teaching assistant, Sock Puppet magic!” (BREAD) mysterious nebula that speaks to him. TA was born. Since then, Sock Sounds like little Timmy has just The entity has been quietly monitor- Puppet has attended many classes been served. ing Bender’s journey through the cos- and earned undergraduate and 5. Sometimes, a leader just has to mos, including a time when Bender Ph.D. degrees in biochemistry. pick up the damn clock. A famous harbored a microscopic civilization Sock Puppet, Ph.D., is employed chemist/biochemist from the Univer- that thought he was God. Bender asks as a research scientist in a Moun- sity of Illinois — let’s call him Yi Lu the entity if it is God. It replies, “Pos- tain West university and has seen — once told me a story. sibly.” Bender tells him, “You know, I a thing or two in his many years A big clock hung on the wall over was God once.” in and around academia. He the door to his students’ group office. “Yes,” says the entity. “You were knows what lurks in the back of One day, someone slammed the door doing well, until everyone died.” the -80 °C freezer as well as the too vigorously, apparently, because The entity then gives some advice bottom of the sock drawer, and the clock fell off the wall onto the on how to do a more effective job as he counts many struggling gradu- floor in the middle of the doorway God. The same advice might as well ate students and young faculty and smashed into several pieces. In apply to those of us in more mundane among his friends. When Sock order to enter or leave the office, the positions of leadership: “If you do too Puppet is not wrangling graduate students had to step over the messy much, then people become dependent students, he enjoys jogging, ski- remains of the clock. Professor Lu on you. If you do too little, they lose ing, macramé and searching for watched them do this all day long hope … When you do things right, his long-lost twin brother in and from his office across the hall. He people won’t be sure you’ve done around the dryer. (Email Sock grew increasingly frustrated. Would anything at all.” Puppet, Ph.D., at no one stop and pick up the clock — Now there’s a meme that you can [email protected].) if not to replace it then just to remove hang your hat on.

MARCH 2018 ASBMB TODAY 53 WHEN SCIENCE MEETS SICKNESS Science prepared me for cancer treatments, but nothing prepared me for surviving By Jennifer L. Gooch

he aftermath of cancer treat- ments is a little like getting your T car back from someone you lent it to only to find a new dent in the bumper, stains on the upholstery and an extra 100,000 miles on the odometer. And then the person you lent it to helpfully points out, “But it still runs!” I am grateful to have completed cancer treatments and gotten my car back, and I’m thrilled that it still runs. As a scientist who did her disserta- tion research on signaling pathways that make breast cancer cells grow, I knew a fair amount about the mecha- nisms and even treatments for breast ALL PHOTOS COURTESY OF JENNIFER L. GOOCH cancer before my own diagnosis. For Left: Jennifer L. Gooch received chemo treatments through a port in her chest; the four drugs took about six example, I knew that by the time a hours to infuse. Right: Six months after finishing chemo, she had regrown enough hair to stop wearing a wig. tumor is palpable, it usually already has spread to the lymph nodes. Mine invasive ductal carcinoma, and a growing cells in my body. So my hair was and it had. I also knew that being positron emission tomography scan fell out, my blood counts dropped positive for human epidermal growth further confirmed that I had node- and the lining of my gastrointestinal factor 2, known as Her2, meant that I positive, clinical stage 2B disease. tract thinned (and I had a lingering was going to be treated with targeted Three weeks after that first-ever metallic taste in my mouth thanks therapies that were the direct results mammogram, I received my initial to the platinum). The side effects of of molecular research from the past few decades. That felt strange and cocktail of neoadjuvant chemotherapy the monoclonal antibodies targeting wonderful. — taxotere, carboplatin, trastuzumab, Her2 were less acute but added upper However, there was an entire phase and pretuzumab, or TCH+P. respiratory irritation and skin changes of cancer treatments that I was wholly During my training, the clinical to the mix. With each cycle, the unprepared for — surviving. fellows and other oncologists in the fatigue was more intense as my body In June of 2014, I was diagnosed department would comment that worked to replace all the cells killed with breast cancer barely 24 hours chemotherapy for breast cancer is by chemotherapy. after my first mammogram. I was 40 “relatively tolerable” compared to Following chemotherapy, my treat- years old. The biopsy results defined regimens for other cancers. ment plan included surgery (a mas- the cancer as triple-positive (the And, in truth, it was manageable. tectomy and axillary node removal) as tumor expressed estrogen receptors, The side effects were predictable: tax- well as radiation. Finally, I completed progesterone receptors and Her2) otere and carboplatin attacked all fast- a full year of trastuzumab infusions

54 ASBMB TODAY MARCH 2018 Gooch worked all through her treatments and recovery; here, she gives an interview about a newly funded grant. and started a five-year course of treat- It wasn’t until I really started prevent the weight gain, hair loss and ment with an aromatase inhibitor. driving that car again that I started memory impairment associated with Clinically, mine is a success story. to appreciate all the things that were hypothyroidism. The combination of My oncologist once told me I was a different. There were changes to my chemotherapy and ongoing treatment “textbook” example of how oncolo- body and mind that weren’t part of with an aromatase inhibitor means gists want chemotherapy to go. I the molecular biology of cancer I had that I also manage daily chronic joint was able to work through most of studied or the focus of most cancer pain. Finally, I struggle with aphasia the treatments, taking a few days research. — most often, the image of the item off when needed during chemo and The cytotoxic drugs damaged, is in my mind, but I simply cannot two weeks following surgery. I had perhaps permanently, the nerves in match a word to it. At other times, no unexpected side effects and no my left foot and hand. In addition the word I choose is simply the wrong cardiac damage. I bought a nice wig to the pins-and-needles sensations one, a particularly unfortunate afflic- that resembled my own hair so closely and the pain with cold temperatures, tion when lecturing to students. These that many people did not know that my coordination is poor and I have are part of my new normal. I was undergoing cancer treatments fallen several times. I have Hashimoto In the longer term, I am at until, months later, I revealed my very thyroiditis, a lesser-known side effect increased risk of heart disease, osteo- short, newly regrown hair. of breast cancer treatments in which porosis, lymphedema and secondary In short, my car was returned your body develops antibodies against cancers due to my treatment regimen. to me (minus cancer) with a flurry your thyroid, preventing the produc- Not to mention recurrence of breast of pink celebratory certificates of tion of thyroid hormones. I take a cancer. completion from my cancer team. daily supplement of levothyroxine to And now we come to the sword

MARCH 2018 ASBMB TODAY 55 my disease or I will die from it. Living with this uncertainty is not something science or medicine can prepare you for. I have had a hard time articulating to my doctors both the physical and the mental toll surviving cancer has taken, even though I am certain that many survivors have similar experi- ences. Complaining might make it seem that I am ungrateful for their life-saving work. After all, the car runs, right? The American Cancer Society estimates that there are now more than 15 million cancer survivors in the United States, a number that, One year and 20 days after she was diagnosed, Gooch’s cancer team presented her with pink certificates to thankfully, is projected to continue mark the completion of her treatment. growing. My hope is that, with that growth, survivorship will become a of Damocles. Statistically, about one disease. Studies have shown that the more integrated part of cancer treat- in three women diagnosed with stage difference in detection by screening ment plans — and an increased focus 1-3 breast cancer will at some point versus a patient experiencing symp- of scientific research. be rediagnosed with stage 4, meta- toms and seeing his/her doctor is only static disease. And unlike other types a matter of months. And the outcome of cancer, for the majority of women is the same — metastatic breast can- Jennifer L. Gooch, Ph.D. (jgooch@ with breast cancer, there are no mark- cer is treatable but not curable. emory.edu), lives in Atlanta, ers to detect with a blood test and no As a scientist, I am familiar with Georgia, with her husband and regular scans (other than mammogra- the statistics around overall survival three teenage children. She is a senior medical writer at a medical phy for local recurrence, if a patient of different types and stages of breast communications company and an still has breasts) once treatments are cancer. But I am an N of 1. My out- adjunct associate professor at Emory University completed that will detect metastatic come is binary. Either I am cured of School of Medicine.

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