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The Member Magazine of the American Society for Biochemistry and Molecular Biology Vol. 14 / No. 1 / January 2015 THE MEMBER MAGAZINE OF THE AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY CONTENTS NEWS FEATURES PERSPECTIVES 2 18 24 PRESIDENT’S MESSAGE THE HOLLYWOOD EXPERIMENT CAREER INSIGHTS Anatomy of a discovery Commit 20 4 A QUANTUM LEAP 26 NEWS FROM THE HILL OUTREACH New year. New focus. New opportunities! 22 Best analogies for stem cells for public outreach 5 MEET DENNIS VOELKER MEMBER UPDATE 18 27 HOBBIES 6 Confessions, in verse RETROSPECTIVE Robert Bittman, 1942 – 2014 28 GENERATIONS 28 Generating the NIH 3T3 cell line, the 8 oncogene hypothesis and horses JOURNAL NEWS 29 The making of a man 8 JBC: New Tabor Young Investigator Award winner 8 JBC: Why the bad taste? 32 9 JBC: Myron Goodman reflects on SOS OPEN CHANNELS error-prone DNA repair The 10 most-read online articles in 2014 10 JBC: Exploring muscular disease in 20 humans and cattle 27 11 JBC: From country girl to author on most cited paper: Nira Rosebrough Roberts 12 MCP: Super microbes for biofuel production 13 JLR: Isoform-specific function of Akt in atherosclerosis 14 NEWS 14 National Academies’ report on postdocs 15 Thyroid awareness month 28 18 16 Our “Defying stereotypes” LIPID NEWS series continues Enrichment of acyl chains in the with profiles of lipids of the phosphatidylinositol cycle two Hollywood figures who were trained in science. JANUARY 2015 ASBMB TODAY 1 PRESIDENT’S MESSAGE THE MEMBER MAGAZINE OF THE AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY Anatomy OFFICERS COUNCIL MEMBERS Steven McKnight Natalie Ahn of a discovery President Squire J. Booker Jeremy M. Berg Karen G. Fleming By Steven McKnight Past President Gregory Gatto Jr. Daniel Leahy Karen Allen Secretary Anjana Rao Jared Rutter Toni Antalis Brenda Schulman or hundreds of millions of down the mechanism by which cyto- Treasurer Michael Summers years, plants and animals have plasmic DNA stimulates the innate been engaged in constant immune system? They, of course, EX-OFFICIO MEMBERS F ASBMB TODAY EDITORIAL battle against microbial and viral started by standing on the shoulders Dorothy Beckett ADVISORY BOARD Mary Roberts pathogens. For higher metazoan of others who already had discov- Charles Brenner Co-chairs, 2015 Annual Chair organisms, the adaptive and innate ered that cytoplasmic DNA triggers Meeting Program Committee Michael Bradley arms of the immune system represent activation of an endoplasmic reticu- Floyd “Ski” Chilton Peter J. Kennelly our dual lines of defense against an lum protein designated as STING, Cristy Gelling Chair, Education and Peter J. Kennelly extensive and rapidly evolving bastion MITA, MPYS or ERIS. The STING Professional Development Rajini Rao Committee of enemies. Gerald Edelman and protein, when magically activated by Yolanda Sanchez Susumu Tonegawa won Nobel prizes cytoplasmic DNA, recruits the IKK Daniel Raben Shiladitya Sengupta Chair, Meetings Committee in successive generations decades and TBK1 kinase enzymes, which Carol Shoulders Takita Felder Sumter ago for their discoveries showing the respectively activate the NF-κB and Chair, Minority Affairs ASBMB TODAY nature of antibodies and the elaborate IRF3 transcription factors. Activa- Committee Angela Hopp means by which they are put together tion of NF-κB and IRF3 already was Thomas Baldwin Editor, [email protected] Chair, Outreach Committee to facilitate adaptive immunity. More understood to trigger cells to acti- Rajendrani Mukhopadhyay recently, Bruce Beutler and Jules Hoff- vate the expression of genes vital for Bob Matthews Sr. Science Writer, Chair, Public Affairs [email protected] mann won the Nobel prize for their stimulation of the immune response. Advisory Committee Marnay Meyer groundbreaking work on Toll-like To find out what might happen Kathleen Collins Designer, [email protected] Chair, Publications receptors as the operational nuts and upstream of STING activation, Lauri Pantos Committee bolts of the innate immune system. Chen’s team crafted a cell line miss- Publications Technology Martha J. Fedor Manager, [email protected] Despite being blessed with these ing the STING protein. They could Editor-in-chief, JBC Ciarán Finn gorgeous pinnacles of scientific then expose the cells to cytoplasmic Herbert Tabor Web Assistant, [email protected] achievement, plenty of mysteries DNA and prepare extracts in search Co-editor, JBC Karen Schools Colson remain. Over the past several years, of molecules responsible for propa- A. L. Burlingame Director of Publications, Editor, MCP [email protected] Zhijian “James” Chen and his col- gating the pro-immune stimulatory Edward A. Dennis Barbara Gordon leagues here at the University of Texas signal. Vital to this game plan, Chen’s Joseph L. Witztum Executive Director, Southwestern Medical Center have team used permeabilized macrophage Co-editors, JLR [email protected] cracked open a new set of discoveries cells blessed with an intact STING further clarifying our understanding pathway. By applying extracts from For information on advertising, contact Fox Associates Inc. of how innate immunity works. STING-deficient cells exposed to at 800-440-0231 or [email protected]. Certain pathogens expose their cytoplasmic DNA to the permeabi- genetic blueprint, sometimes in the lized macrophage cells, they could form of duplex DNA, to the cytoplas- monitor IRF3 activation. This was mic compartment of host cells. Our their assay. No matter how arduous, www.asbmb.org/asbmbtoday own DNA belongs within either the biochemists always need a reliable PRINT ISSN 2372-0409 nucleus or the mitochondrion – not assay. Articles published in ASBMB Today reflect solely the in the cytoplasm. Indeed, DNA was The substance produced by authors’ views and not the official positions of the American Society for Biochemistry and Molecular found as an immune-response stimu- STING-deficient cells that activated Biology or the institutions with which the authors are lant even before it was found to carry STING in the recipient macrophage affiliated. Endorsement by ASBMB Today or ASBMB of products or services mentioned is not implied. the genetic blueprint (1). cells turned out to be heat-stable and How did Chen and his team track small – a metabolite, not a protein. 2 ASBMB TODAY JANUARY 2015 By use of an arduous combination the cGAMP synthase enzyme (now of biochemistry. Once Chen’s team of purification, analytical chemistry designated cGAS). threaded the needle in the discov- and synthetic chemistry, Chen and These breakthrough studies ery of cGAMP and the enzyme his team discovered the activating revealed the precise identity of that makes it, other scientists could substance to be cyclic GMP-AMP, the cGAS enzyme and its selective contribute rapidly. Crystallization of abbreviated as cGAMP (2). The activation by DNA (5). Subsequent the cGAS enzyme was accomplished precise nature of the phosphodiester X-ray crystallographic experiments within months of the Chen team’s linkages subsequently was found showed mechanistically how DNA discoveries, and nearly any molecular to be mixed – one was between the binds and activates cGAS and offered biologist could have made knockout 2’-OH of GMP and the 5’-phosphate a compelling understanding of how mice lacking the enzyme for studies of AMP, and the other was between the enzyme converts ATP and GTP of its role in innate immunity. the 3’-OH of AMP and the 5’-phos- into its cGAMP product (3, 6). Those What could not have been phate of GMP (3, 4). That cGAMP is studies positioned the Chen team to achieved without hardcore biochem- the STING activator has since been generate mice selectively missing a istry were the rate-limiting discover- nailed unequivocally, including reso- functional gene encoding the cGAS ies of the cGAMP metabolite as a lution of the X-ray crystal structure of enzyme. These cGAS-deficient mice second message produced in response metabolite-bound STING (4). are considerably more susceptible to to cytoplasmic DNA as well as the Having discovered the cGAMP lethal infection by herpes simplex enzyme that synthesizes cGAMP in metabolite as the signaling message, virus than wild-type littermates, and response to exposure to cytoplasmic the Chen team turned to its mode of studies of immune adjuvant effects of DNA. As members of the Ameri- synthesis. They incubated cytoplasmic cGAMP have yielded vivid evidence can Society for Biochemistry and material from cultured cells with ATP of the importance of the cGAS Molecular Biology, we should take and GTP in the presence of DNA. pathway for proper deployment of pride in the dominance of our scien- By applying these reactions prod- the immune system (7). For-profit tific discipline: Textbooks are filled ucts to permeabilized macrophages biotechnology companies, large and with the fruits of our field. Future (after DNAase digestion and heat small, now are pursuing cGAS inhibi- textbooks covering disciplines rang- treatment), Chen’s team could track tors as potential treatments for auto- ing from immunology to cell biology fractions capable of producing the immune diseases and cGAMP-related to biochemistry undoubtedly will cGAMP stimulant of STING activity. molecules for immunotherapies and feature the contributions of Chen and Again, by use of a sophisticated array vaccines. his team briefly summarized in this of chromatographic steps, the team I recount this story as a celebra- essay. Boy, should we be proud of our was able to isolate, purify and identify tion of our discipline – the discipline field, including its illustrious past, vibrant present and promising future. REFERENCES Biochemistry rules! 1. O’Neill, L.A. Cell 3, 428 – 430 (2009). Steven McKnight (steven. 2. Wu, J. et al. Science 339, 826 – 830 (2013). [email protected]) 3. Gao, P. et al. Cell 5, 1094 – 1107 (2013). is president of the American 4. Zhang, X. et al. Mol Cell 2, 226 – 235 (2013). Society for Biochemistry and 5. Sun, L. et al. Science 339, 786 – 791 (2013). Molecular Biology and chairman 6. Zhang, X. et al. Cell Reports 6, 421 – 430 (2014).
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