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2 16 24 EDITOR’S NOTE COMBATING PARASITIC DISEASES ESSAYS 2015’s top 10 Pairing science with the paso doble 20 3 GUARDIANS OF THE GENOME 28 NEWS FROM THE HILL GENERATIONS 2015: The science policy year in review 16 When science runs in the family The science behind 4 this year’s Nobel 31 MEMBER UPDATE Prizes. HOBBIES PHOTO CREDITS: 31 The Chemophilately Museum NATIONAL INSTITUTES OF 5 HEALTH (TOP) AND WORLD 32 The maestro’s weaving art HEALTH ORGANIZATION IN MEMORIAM (BOTTOM) 33 A mock PI works out 7 34 NEWS MINORITY AFFAIRS 7 Glycobiologists expand symbol nomenclature 24 Overcoming impostor syndrome 8 How dangerous are holiday plants to pets? 36 10 EDUCATION JOURNAL NEWS 36 Who the heck is David Baltimore? 10 Bioengineering a microbial workforce 38 Graduation survey results 11 Structural studies of GRK5 14 Engaging with enzymes 15 Racca wins Tabor award 40 OUTREACH 8 Cracking open the lab doors 42 OPEN CHANNELS

10 28

DECEMBER 2015 ASBMB TODAY 1 EDITOR’S NOTE

THE MEMBER MAGAZINE OF THE AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY 2015’s top 10 By Lauren Dockett OFFICERS COUNCIL MEMBERS Steven McKnight Squire J. Booker President Karen G. Fleming Gregory Gatto Jr. t is a heady thing to look back 3. Feature | Science in sign language Natalie Ahn Rachel Green President-Elect Susan Marqusee over a year’s worth of publica- by Maggie Kuo (February) Jared Rutter tions. At ASBMB Today, it means 4. Cover story | Breaking dogma? by Karen Allen I Secretary Brenda Schulman getting to revisit all those in-depth Rajendrani Mukhopadhyay (Febru- Michael Summers Toni Antalis features, moving personal essays, and ary) Treasurer ASBMB TODAY EDITORIAL a glittering parade of prize-winning 5. President’s Message | “Funding ADVISORY BOARD ASBMB members (including four decisions: the NIH method” by Ste- EX-OFFICIO MEMBERS Charles Brenner Nobels and a Breakthrough prize in ven McKnight (April) Squire Booker Chair Wei Yang Michael Bradley just the past two months)! There are 6. Defying Stereotypes | “So, a bio- Co-chairs, 2016 Annual Floyd “Ski” Chilton more than a few issues from the past chemist walks into a comedy Meeting Program Cristy Gelling year that I’ve dog-eared and piled into club …” by Rajendrani Mukhopad- Committee Peter J. Kennelly a safe corner so that we might reread hyay & Geoffrey Hunt (June/July) Peter J. Kennelly Rajini Rao Chair, Education and Yolanda Sanchez coverage of research that we can dig 7. Defying Stereotypes | “Beyond Professional Development Shiladitya Sengupta deeper into one day. And where would the finish line” by Geoffrey Hunt & Committee Carol Shoulders we be without the reader exchanges Rajendrani Mukhopadhyay Daniel Raben touched off by the president’s columns (February) Chair, Meetings Committee ASBMB TODAY Angela Hopp in 2015? Having decidedly duller 8. President’s Message | “The straight- Takita Felder Sumter Executive Editor, Chair, Minority Affairs watercooler talks, that’s where! jacket of hypothesis-driven research” [email protected] Committee Lauren Dockett In 2015, we generated 270 articles by Steven McKnight (June/July) Thomas Baldwin Managing Editor, and 426 pages of content. More than 9. President’s Message | “Welcome Chair, Outreach Committee [email protected] half of those pages were written by aboard!” by Steven McKnight Wes Sundquist Rajendrani Mukhopadhyay Chair, Public Affairs Chief Science Correspondent, ASBMB members, participants in (August) Advisory Committee [email protected] our contributors program, or volun- 10. President’s Message | “Two kinds Blake Hill Valery Masterson teers from the larger biochemistry of grants?” by Steven McKnight Chair, Publications Designer, and molecular biology community, (May) Committee [email protected] Lauri Pantos reminding us that the magazine is an You’ll see one member essay in that F. Peter Guengerich Manager of Publications inclusive space for member voices and top-10 list and if we were to dig just a Interim editor-in-chief, JBC Technology, [email protected] Herbert Tabor Ciarán Finn perspectives from all corners of the little deeper into our reader favorites, Co-editor, JBC Web Publication Assistant, BMB world. we’d find many more. Your stories are [email protected] A. L. Burlingame Late in the year, we use the imper- perennial hits. Editor, MCP Allison Frick Media Specialist, fect metric of website page views Whatever year it is, this remains Edward A. Dennis [email protected] to get a sense of our most popular your magazine. Keep in touch in 2016 Joseph L. Witztum Barbara Gordon articles. It’s unfair to our most recent and be a part of it! Co-editors, JLR Executive Director, [email protected] articles, since they haven’t had as Lauren Dockett (ldockett@asbmb. much time to accrue hits, but it’s still org) is the managing editor of an interesting glimpse at what readers ASBMB Today. For information on advertising, contact Pharmaceutical Media Inc. at 212-904-0374 or [email protected]. have been seeking. The 10 most-read online articles (so far) in 2015 PRESIDENT'S www.asbmb.org/asbmbtoday 1. Cover story | Waiting for the day to PRINT ISSN 2372-0409 come by Rajendrani Mukhopadhyay MESSAGE Articles published in ASBMB Today reflect solely (June/July) the authors’ views and not the official positions of the American Society for Biochemistry and Molecular 2. Essay | The reality that dare not Steven McKnight's column will Biology or the institutions with which the authors are affiliated. Mentions of products or services are speak its name by Andrew D. Hol- resume next month. not endorsements. lenbach (April) ©2015 ASBMB

2 ASBMB TODAY DECEMBER 2015 NEWS FROM THE HILL

Science policy year in review By Chris Pickett

t has been a busy year in sci- #RaiseTheCaps lobbying push led by institutes and centers and sensible ence policy. Congress debated the Nondefense Discretionary United policies that promote research. A draft I major legislation in 2015 that coalition. The push resulted in Con- version of the Senate’s bill is expected could improve research funding, the gress relaxing the spending caps on in mid to late autumn. National Institutes of Health unveiled the federal budget. some long-anticipated projects and Federal agencies the American Society for Biochemis- Congress In June, the NIH unveiled a set of try and Molecular Biology continued In the spring, the U.S. House of long-expected rules for grant applica- to increase its prominence as a leading Representatives proposed $1 billion tions meant to improve rigor and voice on critical policy issues. and the U.S. Senate proposed reproducibility in basic research (2). $2 billion in funding increases to the Some of the new guidelines include The ASBMB NIH budget for fiscal 2016. Nei- requiring grant applications to evalu- In July, members of the ASBMB ther of these increases has come to ate sex as a biological variable, authen- Public Affairs Advisory Committee fruition. However, the success of the tication of cell lines and identification published a paper in the Proceedings #RaiseTheCaps campaign means that of antibodies (3). of the National Academy of Sciences Congress will have some flexibility to The NIH also began work on its that explored the scientific commu- increase the budgets of federal science- next big-science project, the Precision nity’s recommendations for improving funding agencies in the coming year. Medicine Initiative (4). The PMI is the sustainability of the research enter- In nonappropriations news, after meant to sequence the genomes of prise (1). The society now is planning more than a year’s worth of work, one million Americans to make per- a summit that will bring together debates and committee hearings, the sonalized medicine more of a reality. experts to develop implementation House passed the 21st Century Cures However, the federal agency is facing plans for some of the recommenda- Act in June. The bill would increase significant competition from Alpha- tions. funding for the NIH by $8.8 billion bet, the parent company of Google, The ASBMB continued its efforts over five years. While the increased which has begun working on a similar to provide new ways of understanding funding would be welcome, the initiative. research funding and engaging with society still had several concerns about And these were just the highlights! Congress. The society sponsored a funding restrictions and other policy The development of policies around congressional briefing in September riders in the bill and ultimately nei- the use of CRISPR/Cas9 and similar that presented the effects of stag- ther endorsed nor opposed 21st Cen- technologies, the government avoid- nant research budgets on scientists tury Cures. As the Senate works on its ing shutdown and default, and the and encouraged a return to a period own version of the bill, the ASBMB ASBMB’s continuing efforts to engage of budget growth. The society also has been advocating for the Senate to young scientists in advocacy were all played a major role in the recent include increased funding for all NIH major storylines in 2015. We expect 2016 will be just as busy. REFERENCES Chris Pickett (cpickett@asbmb. 1. http://www.pnas.org/content/112/35/10832.full.pdf org) is a policy analyst at the 2. http://www.asbmb.org/asbmbtoday/201509/NFTH/ ASBMB. 3. http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-103.html 4. http://www.asbmb.org/asbmbtoday/201510/NFTH/

Interested in science policy? Follow our blog for news, analysis and commentary on policy issues affecting scientists, research funding and society. Visit policy.asbmb.org.

DECEMBER 2015 ASBMB TODAY 3 MEMBER UPDATE

Hobbs wins that change the levels and distribution in the disease’s progression. of cholesterol and other lipids in the Lobel and Sleat’s treatment method Breakthrough Prize body, leading to the development of is also being recognized with a 2015 Helen Hobbs, a cholesterol-lowering drugs that won biopharmaceutical Edison Patent professor of inter- U.S. Food and Drug Administration Award from the Research and Devel- nal medicine and approval this summer. opment Council of New Jersey. The molecular genetics Among her many accolades, Hobbs award recognizes scientists and inven- HOBBS at the University of has been elected to the National tors who do outstanding research and Texas Southwestern Academy of Sciences, the American development work in the state. Medical Center at Dallas and an Academy of Arts and Sciences, and investigator at the Howard Hughes the National Academy of Medicine. Hanawalt and Pollard Medical Institute, has been awarded receive Wilbur the Breakthrough Prize in Life Sci- Lobel honored with ences for her innovative contributions Cross Medals to the field of genetics. Innovators Award and A set of international awards Edison Patent Award recognizing outstanding achievements Peter Lobel, a in the life sciences, fundamental phys- member of Rutgers ics and mathematics, the $3 million University’s Cen- HANAWALT POLLARD Breakthrough Prizes were founded ter for Advanced by prominent innovators in the fields LOBEL Biotechnology and Yale University alumni Philip C. of science and technology, includ- Medicine and a pro- Hanawalt and Thomas Pollard are ing Google co-founder Sergey Brin, fessor in the department of biochem- being honored by the Yale Gradu- 23andMe founder Anne Wojcicki, istry and molecular biology at Robert ate School of Arts and Sciences with Facebook founder Mark Zuckerberg Wood Johnson Medical School, won Wilbur Cross Medals. Named in and his wife Priscilla Chan, Alibaba a 2015 Innovators Award from the honor of Wilbur Lucius Cross, former founder Jack Ma and his wife, Cathy New Jersey Inventors Hall of Fame. dean of the Yale Graduate School and Zhang, and entrepreneur Yuri Milner Lobel and David Sleat at Rutgers were governor of the state of Connecticut, and his wife, Julia Milner. The prizes recognized for discovering the cause the medal recognizes the outstanding are awarded at a celebrity-hosted, tele- of Batten disease and for providing achievements of alumni in scholar- vised ceremony designed to promote groundwork for treatment of the ship, teaching, academic administra- science and inspire future innovators. disease. Also known as late infantile tion and public service. Hobbs holds the Eugene neuronal ceroid lipofuscinoses, or Hanawalt is the Morris Herzs- McDermott distinguished chair for LINCL, Batten disease is an inherited tein professor in biology at Stanford the study of human growth and disorder of the nervous system that University. A pioneer in the field of development; the Philip O’Bryan usually begins in early childhood and DNA repair, he discovered the process Montgomery Jr., M.D., distinguished can cause loss of vision, recurrent of repair replication in DNA in 1963 chair in developmental biology; and seizures and motor problems. Patients and subsequently helped develop the 1995 Dallas Heart Ball chair in ultimately become physically and novel techniques for studying DNA cardiology research at the University mentally incapacitated before prema- repair. In addition to his research of Texas Southwestern Medical ture death in late childhood. accomplishments, Hanawalt is a cel- Center at Dallas. Since 1999, she has Batten disease is caused by muta- ebrated educator and recipient of the directed the Dallas Heart Study, a tions in the CLN2 gene and protein Excellence in Teaching Award from multiethnic, population-based study tripeptidyl peptidase I, or TPP1. the Northern California Chapter of in Dallas County designed to aid in Lobel and Sleat have developed a Phi Beta Kappa. He is also a member the understanding of cardiovascular treatment method that involves of the National Academy of Sciences disease. administering TPP1 in an amount and a fellow of the American Acad- Hobbs, with her collaborator effective to reduce symptoms. Previ- emy of Arts and Sciences. Jonathan Cohen, helped develop new ously, patients’ symptoms have been Pollard is the Sterling professor of treatments for heart and liver disease managed only by anti-epileptic drugs molecular, dellular and developmental by identifying genes involved in lipid and physical, speech and occupational biology at Yale. An honorary recipient metabolism and fatty liver disease. therapies. Initial clinical evaluation of of the Wilbur Cross Medal, Pollard She identified rare genetic variations a TTP1-based treatment shows a delay is being recognized for his service to

4 ASBMB TODAY DECEMBER 2015 IN MEMORIAM the Yale Graduate School. He served IN MEMORIAM: as dean of the graduate school from Five ASBMB members 2010 to 2014 and is celebrated for his Oscar Touster efforts to develop mentoring strate- elected to National (1921 – 2015) gies and other initiatives for students. Academy of Medicine Oscar Touster, Pollard maintains an active lab group, emeritus professor which explores the molecular basis of Five members of ASBMB were among the 70 new members of molecular biology cellular motility and cytokinesis. He and 10 foreign associates and biochemistry at has pioneered investigations into the elected to the National Acad- Vanderbilt Univer- actin cytoskeleton, which accounts for TOUSTER emy of Medicine. Election to sity, passed away in structure and movement in all cells. the NAM is considered one February. He was 93. Pollard received a Gairdner Interna- of the highest honors in the Touster grew up in New York City tional Award in 2006. fields of health and medicine and obtained a bachelor’s in chemistry and recognizes individuals who from the College of the City of New Schell is a Young Scientist have demonstrated outstanding York. He recieved his master’s from Seminar Series winner professional achievement and Oberlin College in 1942, but World commitment to service. Below War II delayed his doctoral work. John Schell, an Before returning to his studies, M.D./Ph.D. can- are the newly elected members: Touster worked for the TNT-produc- didate in the lab of Evan Dale ing Atlas Powder Company, training Jared Rutter at the Abel, as a lab supervisor. He met his wife University of Utah, SCHELL Carver College Eva, who later became a poet and pro- is one of five winners of Medicine, fessor of English at Peabody College of iBiology’s Young Scientist Seminar University of in Nashville, in a plant in Kentucky. Series. A vehicle for young scientists, ABEL Iowa He subsequently served as a research Ph.D. candidates or postdocs to pro- biochemist at Abbott Laboratories and mote their research to a wider audi- Mario R. worked on penicillin research with ence, the series competition provides University of Illinois’ Herbert Carter. winners an all-expense-paid trip to Capecchi, University of Touster ultimately would obtain a San Francisco, California, where they Ph.D. in biochemistry and continue take part in a science communica- Utah School of CAPECCHI working with Carter after the war. tion workshop and record 30-minute Medicine In 1947, Touster joined Vanderbilt research talks that are posted and University and remained at the school Christopher advertised on the iBiology website. for his entire career. Sixteen years after K. Glass, Supported by the Lasker Founda- joining, he founded and became the University of tion and the Alan Alda Center for first chairman of the department of California, Communicating Science, the Young molecular biology at Vanderbilt’s Col- San Diego Scientist Seminar Series helps young GLASS lege of Arts and Science and graduate biologists hone their message, improve school. He received the Thomas Jeffer- Kenneth S. communication skills and showcase son Award and the Harvie Branscomb Ramos, their work on a larger stage. Award from Vanderbilt for his service. Schell is working on cellular University of Touster also served as president of metabolic homeostasis and, along with Arizona Health the Oak Ridge Associated Universi- Rutter, helped identify the mitochon- RAMOS Sciences Center ties, a consortium aimed at promoting drial pyruvate carrier, a gene that plays and enhancing scientific research and an important role in cellular metabo- Kevin Struhl, education, from 1976 to 1988. lism. In his video for the Young Harvard Preceded in death by his wife of 65 Scientist Seminar Series Medical School years, Touster is survived by a daugh- (www.ibiology.org/ibioseminars/ ter and two grandchildren. john-schell.html), he examined how STRUHL Written by Erik Chaulk. defects of the mitochondria affect Image courtesy of Vanderbilt human metabolic function. Written by Alexandra Taylor University Special Collections and Written by Erik Chaulk University Archives

DECEMBER 2015 ASBMB TODAY 5 6 ASBMB TODAY DECEMBER 2015 NEWS Glycobiologists expand symbol nomenclature By Alexandra Taylor

entirely voluntary. lycans are structur- “The last thing you ally complex and want to do is try and G difficult to represent push a nomenclature on paper. This December, onto other scientists,” editors of a glycobiology he says. textbook introduced an No official interna- extended nomenclature tional body currently system that simplifies governs nomenclature complicated branch- for the symbolic depiction of glycans. ing sugar structures into The new system is easy-to-use symbols. The the product of a col- new nomenclature will laboration between be available for free as an THE CONSORTIUM OF GLYCOBIOLOGY EDITORS, LA JOLLA, CALIFORNIA.ORIGINAL DRAWING BY RICHARD D. CUMMINGS. many leaders in the advance online appendix A new nomenclature system extends to plants, invertebrates, archaea and bacteria. field. The editors of of the third edition of “Essentials of Glycho- lication for the December issue of “Essentials of Glycobiology,” pub- biology” are coordinating with several the journal Glycobiology, the book lished by Cold Spring Harbor Press. databases that may decide to adopt editors said that they hope the new it. The International Union of Pure The system expands on the widely nomenclature will “help students and and Applied Chemistry, for example, adopted nomenclature from the researchers to more easily discover and is considering using the system in its textbook’s second edition (2005). appreciate the relevance and beauty recommendations for carbohydrate That version was limited to glycans in of glycan diversity in living systems, nomenclature. vertebrates. The new system has been and to communicate this exciting After the recent National Research expanded to include common mono- information to others.” Council report on glycosciences, the saccharides in plants, invertebrates, There will be one central website National Institutes of Health Direc- archaea and bacteria. “We’re trying to available through the National Center tor’s Common Fund awarded $10 address the fact that there are many for Biotechnology Information as million toward a glycoscience pro- more monosaccharides in nature than a reference. Each monosaccharide gram for development of new tools the limited list represented in the symbol will be linked to its entry in and approaches. These are promising current version,” says Ajit Varki at the PubChem at NCBI, and pre-drawn signals of the growing importance of University of California, San Diego. symbols will be available to download the field. For glycoscience to make Varki, a member of the American or copy and paste. unhampered progress, a clear, acces- Society for Biochemistry and Molecu- The editors hope that making the sible and ubiquitous nomenclature lar Biology, is executive editor of the system freely available will discourage could provide some much-needed textbook’s third edition. the introduction of minor variations consistency. The goal in developing this system to the nomenclature. These variations was to make it logical, easy to remem- popped up when the second edition’s Alexandra Taylor (ataylor@ system became widely adopted. asbmb.org) is a science writing ber, and easy to use. New symbols intern at ASBMB Today and a have been added, but existing symbols Consistency may help to avoid master’s candidate in science and will remain intact, making the system confusion, but Varki stresses that medical writing at Johns Hopkins easier to adopt. In an invited pub- adoption of this system will be University.

DECEMBER 2015 ASBMB TODAY 7 NEWS How dangerous are holiday plants to pets? By Indumathi Sridharan

oliday decorations aren’t The toxic amounts in a plant will complete without orna- vary with the species and stress H mental plants. But certain the plant was exposed to during seemingly innocuous holiday growth,” says Wismer. “Another plants can be poisonous to pets. If factor is the size of the animal and ingested, these plants can induce the amount of plant ingested — vomiting, diarrhea, abdominal did the cat just nibble a leaf or eat pain and excessive salivation. Sei- the entire plant?” zures, coma or death may occur in In the case of amaryllis, the severe cases. In 2009, the Animal toxicity varies according to plant Poison Control Center at the part; the foliage and flowers are less American Society for Prevention toxic than the bulb. Some plants of Cruelty to Animals received are deadly only to certain pets. For 8,000 calls related to poisonous example, true lilies cause kidney plants during holiday season. failure in cats, while dogs experi- Holly, amaryllis and Christmas ence only mild stomach upset. The rose are some of the most toxic reason for this species difference is holiday plants, according to Tina unknown. Wismer, the medical director Not all holiday plants are of the ASPCA Animal Poison a cause for concern. Contrary Control Center. The toxic effects to popular belief, poinsettias of these plants come from specific (Euphorbia pulcherrima) are not bioactive compounds. toxic to pets. Research indicates “Holly contains triterpenoid that the pulcherrima species lacks FLORA DE FILIPINAS saponins; these are soaplike sub- Flowers of the amaryllis are less toxic than the bulb. diterpenes, a key toxic substance stances that irritate the digestive generally found in the Euphorbia tract and can cause severe vomit- trations of sodium and potassium genus (3). ing and diarrhea, sometimes with ions. Amaryllis contains alkaloid Despite best efforts to keep pets blood. Fortunately, most species of compounds, such as lycorine. Lyco- away from plants, accidental ingestion holly have prickly and leathery leaves rine inhibits peptide bond formation may happen. In preparation for such that are not normally attractive to during protein synthesis by interfering an event, Wismer recommends keep- pets,” says Wismer. with the peptidyl transferase activity ing a list of all plants in the household Cardiac glycosides in the Christmas of ribosomes (1, 2). These toxins can and calling a veterinarian in cases of rose can cause death by affecting heart lead to depression, convulsions and suspected ingestion. rhythm. These compounds affect the tremors. contractility of cardiac muscles by The severity of the toxic effects Indumathi Sridharan (sridharan. binding to Na-K ATPase, an enzyme depends on many factors. “One [email protected]) important factor is the plant itself. earned her bachelor’s degree that modulates intracellular concen- in bioinformatics in India. She holds a Ph.D. in molecular REFERENCES biochemistry from Illinois Institute 1. Wink, M., Mitt. Julius Kuhn-Inst. 421,93 – 112 (2009). of Technology, Chicago. She did her postdoctoral work in bionanotechnology at Northwestern 2. Kukhanova, M., et al. FEBS Lett. 160, 129 – 133 (1983). University. 3. Evens, Z.N. et al., West J. Emerg. Med. 13, 538 – 542 (2012).

8 ASBMB TODAY DECEMBER 2015 Holiday plants dangerous for cats and dogs (except one) “Since many different plants have the same common name, knowing their Latin names can come in handy.” – Tina Wismer, American Society for Prevention of Cruelty to Animals Animal Poison Control Center FLICKR COMMONS USER DREW AVERY THE U.S. DEPARTMENT OF AGRICULTURE THE U.S. DEPARTMENT FLORA VON DEUTSCHLAND, ÖSTERREICH UND DER SCHWEIZ (1885)

Hippeastrum (amaryllis lily, belladonna lily, Ilex opaca (American holly) Ilex aquifolium (English holly) Saint Joseph lily, cape belladonna, naked lady) WIKIMEDIA COMMONS USER TARAGUI THE NATIONAL GEOGRAPHIC MAGAZINE (1917) THE NATIONAL FLORA VON DEUTSCHLAND, ÖSTERREICH UND DER SCHWEIZ (1885)

Helleborus niger (Christmas rose, hellebore, Solanum pseudocapsicu (Jerusalem cherry) Phoradendron flavescens (American lenten rose, Easter rose) mistletoe) SAFE FREEPIXELS.COM WIKIMEDIA COMMONS USER VIZU FLORA VON DEUTSCHLAND, ÖSTERREICH UND DER SCHWEIZ (1885)

Viscum album (European mistletoe) Solanum dulcamara (bittersweet night- Euphorbia pulcherrima (poinsettia) shade)

DECEMBER 2015 ASBMB TODAY 9 JOURNAL NEWS Bioengineering a microbial workforce By Kathleen McCann

hey may not punch timecards, wear protective clothing or gos- T sip around the water cooler, but microorganisms are a vital part of the industrial work force. The metabolic pathways of microorganisms have been harnessed and engineered to produce molecules that are important to the pharmaceutical, food, chemical and alternative-energy industries. In the November issue of the Journal of Lipid Research, investigators from the University of Saskatchewan describe how they engineered one particular yeast, Pichia pastoris, to produce ricinoleic acid, a rare fatty acid commonly used in the manufac- ture of a wide variety of products. Ricinoleic acid is produced natu- rally in high amounts by castor beans. But harvesting the acid from the

beans can be tricky, since castor beans U.S. DEPARTMENT OF AGRICULTURE also produce high levels of the potent Xiao Qiu and colleagues at the University of Saskatchewan engineered a yeast to produce high yields toxin ricin. To circumvent this prob- of ricinoleic acid, which occurs naturally in castor beans. lem, researchers have tried identifying expressed in yeast, the yeast produced in engineered plants. other ways of procuring ricinoleic acid higher levels of ricinoleic acid. While Qiu’s work represents a sub- from plants. Initially, tobacco and the In the article, Qiu and his col- stantial step forward in bioengineering commonly used plant model organ- leagues describe how they took microorganisms for industrial gains, it ism Arabidopsis were engineered to this production process one step does raise some interesting questions. express an enzyme of the ricinoleic further by identifying yet another For instance, why was Pichia a more acid biosynthesis pathway. But both enzyme that plays a critical role in effective organism for ricinoleic acid? plants produced a comparatively small the biosynthesis of ricinoleic acid. Can Pichia be engineered to produce fraction of ricinoleic acid and proved When expressed in yeast, the enzyme high amounts of other important bio- to be poor replacements for the castor CpDGAT1 significantly outper- materials? Furthermore, can we deter- bean. formed CpDGAT2. With this new mine what makes Pichia such a robust Xiao Qiu and his colleagues have a enzymatic ace in hand, they turned organism and then engineer a plant to long-standing interest in lipid biosyn- to the yeast Pichia pastoris, which is have the same capabilities? However thesis and bioengineering, and they known for producing a high yield of these questions are answered, it has turned to microorganisms to tackle biomass and oil. They incorporated become clear that microorganisms the ricinoleic acid problem. Like the CpFAH and CpDGAT1 into the can make powerful contributions to castor bean, the fungus Claviceps pur- genome in such a way that they could modern industry and society. purea is known to produce high levels express these enzymes conditionally. of ricinoleic acid. Qiu previously had After inducing expression for three Kathleen McCann (kathleen. identified two enzymes, CpFAH and days, ricinoleic acid accounted for [email protected]) earned her Ph.D. in genetics from CpDGAT2, that were important for more than half of the total fatty acids, Yale University. She is now a the biosynthesis of ricinoleic acid in representing a significant improve- postdoctoral fellow at the National C. purpurea and had demonstrated ment over the production levels seen Institute of Environmental Health that when these enzymes were Sciences.

10 ASBMB TODAY DECEMBER 2015 JOURNAL NEWS Structural studies of GRK5 A conversation with two JBC Paper of the Week authors By Diedre Ribbens

he Journal of Biological Chemis- try featured two Papers of the Week T in August about structural studies of G-protein-coupled receptor kinase 5, or GRK5. The studies (1, 2) were authored by two groups that conducted their work separately and then later discovered that their structures of GRK5 were in agreement. The JBC’s podcast host, Diedre Rib- bens, interviewed the corresponding authors of the papers, Jeff Benovic of Thomas Jefferson University and John Tesmer at the University of Michigan, to hear more about their work on the GRK5 protein and how these two struc- tures have affected the GRK field. Here, we’ve reprinted some of their conversa- tion. You can listen to the full podcast or read the full transcript at www.jbc.org. Ribbon representation of GRK5·AMP-PNP crystal structure. Full-length GRK5(1–590) was crystallized, and residues 15–543 are clearly resolved (the first and last residues are labeled). Benovic and Tesmer both got their start studying GRKs with Robert PNP or the nucleoside sangivamycin. identify the kinase that phosphory- Lefkowitz, a Howard Hughes Medical The Tesmer group study also solved lates the β₂adrenergic receptor in an Institute investigator at Duke University the GRK5 structure to a 2.4 Å resolu- agonist-dependent manner. And then Medical Center whose group pioneered tion but complexed with an inhibitor this … ultimately led to the cloning the GRK field. (Lefkowitz won the called CCG215022. Importantly, the of cDNAs for what are now called Nobel Prize in chemistry in 2012.) two groups realized that their struc- GRK5 and GRK6. We published that tures captured GRK5 in a strikingly in 1993, and then we really spent, not DIEDRE RIBBENS: similar conformation at its C-terminus full time, but a good portion of our G-protein-coupled receptor kinases, or that was unique to this enzyme and time over the last 20 years trying to GRKs, are a family of protein kinases not found in other GRKs. Ultimately, understand how this kinase func- that have a role in the desensitization these structures will enable future tioned. of G-protein-coupled receptors. In studies probing the function of GRK5 RIBBENS: Tesmer also crossed particular, GRK5, one of the most and possibly lead to the design of paths with the Lefkowitz lab dur- widely expressed proteins in the GRK selective inhibitors. ing his postdoc. As a collaborator, family, has been implicated in several In my interview with Benovic he worked on GRK2, which eventu- diseases, such as cardiovascular disease, and Tesmer, they shared how they ally led him to start his own research cancer, diabetes and Alzheimer’s. became interested in studying GRKs, group focused on GRKs. Although structures have been solved how their work on GRK5 addressed BENOVIC: (GRK5 is) one of the for other GRKs, such as GRK2 and previously unknown questions in their few kinases that John’s group hasn’t GRK6, no structure has been solved field and where each of their research crystallized, but it’s interesting because for the clinically relevant GRK5. The groups would like to go next. it’s been implicated in a number of study by Benovic’s group was able to BENOVIC: Well, for me, it actu- human diseases, including various car- resolve the structure of human GRK5 ally goes back to my graduate work in diovascular diseases, prostate cancer, at a resolution of 1.8 Å in complex the mid-’80s (when) I worked with diabetes and a number of neurological with either the ATP analog AMP- Bob Lefkowitz, and we were trying to CONTINUED ON PAGE 12

DECEMBER 2015 ASBMB TODAY 11 CONTINUED FROM PAGE 11

disorders. So I think it’s an interest- ing enzyme and interesting potential therapeutic target. TESMER: When I started my lab in the late ’90s, my initial proj- ect was to structurally characterize GRK2 … and we were interested in it in principle because it interacted with a lot of G-protein subunits, and that was my specialty as a postdoc. And, since then, I actually collaborated with Jeff to look at other members of the GRK family, and one that we worked together on was GRK6, which we published back in 2006. And GRK5 is a member of that subfamily to which GRK6 also belongs. More recently, we decided to look at these kinases more in a translational sense because we had a good feel for what they looked like structurally; and of course GRK2 was one of them because of its involvement in heart failure; and then we also turned back to GRK5 because, as Jeff pointed out, it’s involved in a host of diseases including cardiac hypertrophy. And so it’s been actually something that we’ve been working on for a number of years and looking for the structure of, which we finally got to be able to publish with Jeff this year. RIBBENS: Tesmer and Benovic crossed paths often, leading to the occasional collaborative study. TESMER: I think the people in sangivamycin complex (PDB entry 3NYN) (13). CCG215022 (spheres with yellowﰁour field, at least I feel, have a habit A, comparison with the GRK6 carbons) binds in the active site of the GRK5 kinase domain. As in most other GRK structures, the AST region of getting together when they need to is disordered (last visible residues denoted by asterisks). The C-terminal region of GRK5 (royal blue) has a sangivamycin (brown), despite the fact they areﰁand going their own ways when they dramatically different conformation than observed for GRK6 feel like they’re able to … Jeff, I think closely related enzymes (see C). Key residues in the C terminus are labeled to emphasize how they contribute we first started working together in to packing in each structure. Side chains shown with beige carbons are from the RH domain of GRK6 (same identity and numbering as in GRK5). GRK6-Pro-547 is analogous to GRK5-Pro-546, which was mutated in 2003 or so … this study. B, close-up view of the interactions between the C-terminal region (royal blue) and the RH domain BENOVIC: Right. Yeah. We had (green). Hydrogen bonds/salt bridges are shown as dashed lines. certainly had our own efforts actu- ally in trying to crystallize GRK2, on the crystallization side of it, and and a lot of that will be collaborative, and they didn’t really go anywhere, then we worked somewhat on GRK6, and some will kind of be trying to do and then that was a major focus of but it was really us just providing some other things and publishing on John’s group. And a former trainee of mine, Rachel Sterne-Marr — I kind of reagents to John to do the work — to our own too, I’m sure. linked her up with John to help with facilitate the work. You know, so we’ve TESMER: Mm hmm. It’s all good. some characterization of GRK2. So collaborated over the years. I think RIBBENS: Benovic admitted that that was kind of our initial interaction we’re trying to do some similar things, his group had never undertaken a solo

12 ASBMB TODAY DECEMBER 2015 effort to solve a GRK crystal structure electro-pharmacologists would like to the case for Tesmer’s group working before, but GRK5 seemed to present know which of these particular kinases with the bovine form of the enzyme. the perfect opportunity to make an are responsible for certain phenotypes TESMER: The truth of the matter attempt at doing so. in cells, and there’s no chemical probes is we’ve been working on GRK5 for BENOVIC: Really, the field, at out there that are very good, in my quite some time, and we had actually least the GRK crystallography field, opinion, that are selected for indi- given up on it. And, of course, kudos which has given tremendous insight vidual members of this family. to Jeff for getting it done with the — in terms of how these proteins … And, of course, there are unre- human enzyme. We’re working with function, how they fold — was almost solved issues … GRK5 is very closely bovine. And as a consequence of our completely driven by John’s work. He related to GRK6, and there’s a bit drug-design efforts, a postdoc in my crystallized GRK2, GRK2 in various of a controversy on what’s going on lab, Kristoff Homan, noticed that one complexes, GRK1 and GRK6 and has with its C-terminal structure, and its of the inhibitors that we had rationally multiple papers and has gained a lot C-terminus is very important for its designed as a GRK2 inhibitor … of insight. membrane targeting in cells. In prior increased the thermostability of GRK5 For us, the challenge was that we structures of GRK6, it appeared to enormously … really had never tried to crystallize be in a conformation that wouldn’t That worked almost instantly after a GRK alone … But we thought permit it to interact with membranes, — I don’t know — four years of try- really one of our goals was to bet- and so that was an unanswered ques- ing to crystallize it otherwise, and so ter understand how GRKs interact tion as to what was really going on in that led us to the structure. And what with GPCRs and how this results in the C-terminus of the subfamily of the structure enabled us to do is look activation of the GRK … GRK5 was GRKs. at how this drug interacts with GRK5. a very well-behaved protein, so we RIBBENS: I asked the two It verified our rational design strate- thought it might be a good model to researchers at what point they became gies. We’re very pleased with that. really pursue that effort. And then aware of their simultaneous efforts to RIBBENS: Ultimately, publishing when … a senior postdoc joined my obtain a GRK5 crystal structure and back-to-back papers allows the work lab a few years ago — Konstantin how they came to publish in the same of both groups to garner equal visibil- Komolov, who had a lot of experience issue of the JBC. ity from the field and draws attention with GRK1 — we decided that he BENOVIC: We certainly discussed to the important similarities between would focus on trying to crystallize it initially at an (American Society for their two structures. GRK5. And this paper for us is the Biochemistry and Molecular Biology) TESMER: The neat thing was that culmination of … his initial efforts in meeting a few years ago. We had had we both resolved the same C-terminal this area. the structure at that point, and I’m structure, and I believe I speak for And it turns out that he actually not sure how far along John had been both of us in that we both believe got crystals almost immediately once on his structure, whether they had that this is the proper confirmation he purified enough protein … Then, their complex or not at that point … of the C-terminus when this enzyme once we had that, we really just used And then we’ve been in a few meet- would be interacting with a mem- John’s GRK6 structure to do molecu- ings together and have talked in more brane. And that’s really the power of lar replacement to solve the structure detail about it. the two papers, I think. So often in of GRK5. TESMER: Yeah, that’s exactly crystal structures, the flexible parts RIBBENS: Tesmer’s group was right. And I have to thank Jeff. I think or the movable parts and frankly the going at the problem from a slightly his structure was done earlier than interesting parts end up trapped in different angle, as they wanted to solve mine, and I think he actually delayed crystal contacts or in weird conforma- the structure of GRK5 so his group his publication so that we could tions, and it’s sometimes hard to figure could focus on the design of specific resolve our structure fully and write out if it’s functional or not. And when inhibitors of the enzyme. the paper and publish them together, you get two independent structures, TESMER: We decided to tackle which I’m very thankful for. completely different crystal forms, it’s the problem of developing selected RIBBENS: Working with the really a powerful confirmation that inhibitors for GRKs, and there’s a human GRK5, Benovic’s group you’re looking at the right thing. need for this in a couple different seemed to solve the GRK5 without Diedre Ribbens (diedre.johnson@ camps, one of which is that a lot of too many roadblocks, but that was not gmail.com) is a science writer, educator and communicator REFERENCES based in Minneapolis. She earned 1. Komolor et al., J. Biol. Chem. 2015 DOI:10.1074/jbc.M115.647297 her Ph.D. at Johns Hopkins School of Medicine. 2. Homan et al., J. Biol. Chem. 2015 DOI:10.1074/jbc.M115.647370

DECEMBER 2015 ASBMB TODAY 13 JOURNAL NEWS Engaging with enzymes Reflections on Ortiz de Montellano’s passion for heme and renewal By Alexandra Pantos

n a recent issue mother who was a pendent researcher in 1972. His most of the Journal teacher from Missouri, notable contributions have been to I of Biological Ortiz de Montellano the study of cytochrome P450, a huge Chemistry, Paul Ortiz grew up with two family of more than 21,000 enzymes de Montellano, a pro- siblings. His younger that have a heme cofactor. That work fessor in the pharma- sister, Ana, went on to has included studying porphyria, a ceutical chemistry and become a writer and rare disease that can cause neurologi- pharmacology depart- professor, and an older cal symptoms and skin problems from ments at the Univer- brother, Bernard, who the buildup of excess porphyrins. sity of California, San studied to be a chem- (In normal quantities, porphyrins Francisco, looked back ist, is now an emeritus are used to produce heme.) Ortiz on a scientific career ORTIZ DE MONTELLANO professor of anthropol- de Montellano also has researched that revolved around ogy. multiple classes of hemoproteins and heme enzymes. Heme enzymes With a bit of help from a biology enzymes found in Mycobacterium perform a wide array of functions and teacher he calls “phenomenal,” Ortiz tuberculosis, the bacterium which are involved in biosynthesis, carrying de Montellano discovered a passion causes most cases of tuberculosis. oxygen in the blood and metaboliz- for science as a high schooler in San Since tuberculosis is a leading cause ing drugs. Ortiz de Montellano is Antonio, Texas, and went on to the of death in HIV/AIDS patients, this best known in scientific circles for his Massachusetts Institute of Technol- research was done as part of a team extensive research on the cytochrome ogy for his undergraduate degree in studying HIV/AIDS. P450 family of enzymes and his work chemistry. He says he always knew Ortiz de Montellano is currently with heme oxygenase and heme-mod- he belonged in science, but it was his considering following in his father’s ifying peroxidases tied to cytochrome brother enrolling in graduate school at footsteps and becoming a writer, per- P450. the same time that Ortiz de Montel- haps of novels. He also enjoys reading Born in Mexico City to the lano started his undergraduate career about history and historical fiction distinguished Mexican poet Bernard that sealed his choice of field. and notes particular interests in the Ortiz de Montellano and an American Ortiz de Montellano went on to do industrial revolution, military history, his graduate work in bioor- and the mid-1600s, during which ganic chemistry at Harvard Louis XIV and Charles II reigned. University under E.J. Corey, Ortiz de Montellano says he who won the 1990 Nobel believes it is “always important to take Prize in Chemistry, and time to renew oneself” and has taken Konrad Bloch, who won the five sabbaticals over the years. His 1964 Nobel Prize in Physi- advice to young scientists is to keep ology. After earning his one foot in the ideal world and one in Ph.D., Ortiz de Montellano the practical world. “One has to keep did a postdoctoral fellow- in mind that one has to eventually ship in bioorganic chem- make a living,” he says. But he stresses istry at the Swiss Federal that once the practicalities are taken Institute of Technology in care of, it is important to do some- Zurich, Switzerland. thing you love. The students and postdoctoral fellows in Paul Ortiz de Montellano’s laboratory when they entered the cytochrome P450 and heme world. Ortiz de Montellano Alexandra Pantos is an editorial Seated from left to right, Kathryn Prickett, Paul Ortiz de Montellano, has studied a wide array of assistant at the ASBMB and a Dianne Jassawalla. Standing from left to right, Wayne Vinson, Kent topics since he joined the senior biology student at the Kunze, Bruce Mico, Gary Yost and Stephen Dinizo. Kunze, Mico, Yost, University of California, University of Maryland. and Dinizo were the founding members of the P450 team. Prickett, Jassawalla and Vinson worked on squalene biogenesis. San Francisco, as an inde-

14 ASBMB TODAY DECEMBER 2015 JOURNAL NEWS Racca wins Tabor Award for lipid research By Erik Maradiaga

na Racca, a postdoctoral 6, and before completing her doctor- researcher at the National Uni- ate, she extended her work on KLF6 A versity of Córdoba in Córdoba, and the placenta in Charles H. Gra- Argentina, received the Journal ham’s laboratory at Queens University of Biological Chemistry/Herbert in Ontario, Canada. Racca returned Tabor Young Investigator Award for to Córdoba to finish her Ph.D. and her research on two members of the then joined Beatriz Caputto’s lab for a Fos transcription family and their postdoctoral fellowship. Caputto’s lab relationship to malignant cell growth specializes in the molecular mecha- in breast tumors. nisms of c-Fos and Fra-1. Racca has shown that c-Fos and Racca says that because c-Fos and Fra-1 work in the cytoplasm inde- Fra-1 are expressed at nearly unde- pendent of their nuclear functions as tectable levels in healthy breast cells, transcription factors. The two mol- therapeutic strategies targeting their ecules interact with and activate key cytoplasmic function shouldn’t do enzymes of the phospholipid synthesis secondary harm. She will continue pathway — particularly CDP-DAG her work on the interactions of c-Fos synthase — by increasing the rate of and Fra-1 and study how negative membrane biogenesis in the endo- Ana Racca received the Tabor award from JBC dominant peptides derived from the Associate Editor George Carman at the 56th plasmic reticulum. This increase helps International Conference on the Bioscience of Lipids proteins they activate can help block sustain the proliferation of malignant in Argentina. phospholipid synthesis and slow breast cells. tumor growth. Raised in the town of Carmen de a Ph.D., joining the lab of Graciela Patagones in southern Argentina, Panzetta and working on trophoblast Erik Maradiaga (em3914a@ Racca moved to Córdoba for a bio- differentiation in normal and diseased student.american.edu) is a biology major at American chemistry degree at the National Uni- human placenta. Her special focus University. versity of Córdoba. She remained for was on the role of Krüppel-like factor

DECEMBER 2015 ASBMB TODAY 15 FEATURE

16 ASBMB TODAY DECEMBER 2015 Combating parasitic diseases Nobel in medicine recognizes work that led to treatment for river blindness and lymphatic filariasis By Alexandra Taylor

fter nearly a decade of digging in regions of sub-Saharan Africa are the dirt, researchers in the 1970s affected most severely by river blind- A unearthed a novel treatment for ness, although the disease also is found parasitic infections. The scientists had in limited areas in South and Central sifted through hundreds of thousands America and Yemen. Lymphatic fila- of soil samples before coming up with riasis, often referred to as elephantiasis, the powerful properties of ivermec- occurs in tropical and subtropical tin. Ivermectin is potent, cheap to regions of Asia, Africa, South America, produce and easy to administer. After the Western Pacific and the Carib- its success as a veterinary antiparasitic, bean. ivermectin won approval in 1987 for River blindness is spread among use in humans, bringing hope to the humans by blackflies. The flies become hundreds of millions of people suffer- infected with microscopic larvae by ing from debilitating, yet neglected, feeding on the blood of an affected tropical diseases. person and then pass the worms from On Dec. 10, Satoshi Ōmura, a host to host. Lymphatic filariasis is member of the American Society for spread in a similar fashion by cer- Biochemistry and Molecular Biology, tain species of mosquitoes. For both will receive part of the Nobel Prize in diseases, a person must be bitten many medicine for his work on ivermectin, times to become infected, so short- which is used to treat river blindness term visitors to these regions typically and lymphatic filariasis. Ōmura will are unaffected. split one half of the prize with William In river blindness (also known as C. Campbell of Drew University, who onchocerciasis), as the worms mature, worked on ivermectin as a member they cause nodules in the skin that of Merck’s natural products team. itch unbearably. Often they permeate (Ōmura and Campbell will receive the cornea, leading to a loss of vision. the Nobel Prize alongside Tu Youyou, Patients with advanced river blind- who is recognized for her discovery of ness often are unable to work and may artemisinin, an antimalarial drug.) exhibit irrational behavior. Their skin begins to look aged. Lesions caused by Origins of disease scratching leave the skin vulnerable to bacterial infection. River blindness and lymphatic The flies that transmit river blind- filariasis both are caused by parasitic ness live near rivers and streams; fertile roundworms and are endemic to some of the world’s poorest areas. Rural CONTINUED ON PAGE 18

DECEMBER 2015 ASBMB TODAY 17 CONTINUED FROM PAGE 17 with the American pharmaceutical industry; upon his return to Japan, he farmland sometimes is abandoned as a established a partnership with Merck result. In addition to being economi- with the aim of developing new veteri- cally crippled by a loss of able-bodied nary drugs. workers, villages afflicted with river Rather than hunting for a cure blindness often are shunned by to a particular disease, researchers neighboring communities for being in Merck’s natural product isolation unclean. unit were tasked with identifying any In lymphatic filariasis, worms compounds that might have activity infiltrate and damage the lymphatic against pathogenic microorganisms. system, sometimes with no exter- At the company’s New Jersey location, nal symptoms. Rarely, a victim will the scientists sifted through samples develop lymphedema, a swelling in from Ōmura and others over the the limbs, breasts or genitals. Dam- course of a decade. age to the lymphatic system leaves The researchers fermented the soil the patient with a decreased ability to sample containing the Streptomyces fight off infection, and the swelling and found that the bacteria were associated with lymphedema can be WORLD HEALTH ORGANIZATION producing avermectins. Avermectins physically impeding. Ivermectin is distributed throughout affected regions are thought to be part of the bacteria’s under the brand name Mectizan According to the World Health Organization, more than 25 million natural self-defense system. Bacteria people have river blindness worldwide. likely produce avermectins to paralyze The Centers for Disease Control and the soil worms who feed on them. Prevention estimates that lymphatic While at Merck, Campbell and his filariasis affects more than 120 million colleagues demonstrated that aver- people. mectins were particularly effective against parasitic worms. Researchers Origins of ivermectin isolated and purified 16 avermectin derivatives. They selected the most In the 1970s, potent one and chemically modified there was a great it to make it less toxic. The result was interest in medicines ivermectin. derived from natural Ivermectin originally was used as ŌMURA products. Conduct- a veterinary antiparasitic therapy. It ing research at the rapidly became the market leader in Kitasato Institute in Japan, Ōmura antiparasitic veterinary treatment and collected thousands of soil samples has generated an average of $1 billion from all over the country in hopes of in annual sales. Ivermectin is perhaps discovering microbes with medici- most recognizable in the U.S. as the nal applications. He isolated strains active ingredient in the heartworm of Streptomyces bacteria from the preventative Heartgard. It also com- samples and cultured them in his bats mites, ticks and insects. laboratory. In 1981, clinical trials of ivermectin In 1974, he found a particular in humans began in Senegal. Before strain of Streptomyces bacteria in ivermectin, the only available treat- a soil sample that he had collected ments for river blindness either caused from a nearby golf course. He sent severe side effects or were impossible it, along with 49 other of the most to administer to patients on a large promising soil samples, for testing scale. at the U.S. pharmaceutical company Merck. Working as a visiting profes- sor at Wesleyan University a few years How ivermectin works prior, Ōmura had made connections Ivermectin is extremely effective at

18 ASBMB TODAY DECEMBER 2015 paralyzing parasitic worms. free for as long as Ching Chung “C.C.” Wang worked necessary to eradi- at Merck in the 1970s and discovered cate river blindness. the mechanism of action for ivermec- Merck partnered with tin. (Every year, the ASBMB issues the World Health the Alice and C.C. Wang Award in Organization, the Molecular Parasitology, which was World Bank and established by Wang and his wife.) several nongovern- Ivermectin works “by opening the mental organizations GABA receptor-controlled chloride to distribute the drug ion channel,” says Wang. “It keeps the to nations where the chloride ion channel open, so there disease was rampant. is no response signal from the central “If you think about nerve to the motor neuron.” public-private part-

With no neurotransmission nerships, this is the CENTERS FOR DISEASE CONTROL AND PREVENTION between the central nervous system model, particularly for neglected trop- A technician in Tanzania tests school-age children and the motor neurons, larval nema- ical diseases, where there isn’t a lot of for lymphatic filariasis. todes are paralyzed, making them market-driven incentive to make these unable to reproduce. Once the adult types of drugs,” says Zachary Mackey, parasites have died off, the population a parasitologist at Virginia Polytechnic within the human host declines. Institute and State University. The Ivermectin is unique in that it does partnership has served as a model for not cross the blood-brain barrier, so it drug donations by other pharmaceuti- does not have the same harmful effect cal companies, such as albendazole by on humans as it does on parasites. GlaxoSmithKline, which is used in Treatment once a year is enough combination with ivermectin to treat to control the river blindness parasite, lymphatic filariasis. but a patient must receive ivermectin The Nobel announcement noted every six months for several years to that ivermectin has “radically lowered be cured. When administered annu- the incidence of river blindness and ally, a combination of ivermectin and lymphatic filariasis.” Ōmura and albendazole, another antiparasitic that Campbell’s discovery has “provided is made by GlaxosmithKline, can pre- humankind with a powerful new vent the spread of lymphatic filariasis. means to combat these debilitating diseases that affect hundreds of mil- Public–private partnership lions of people annually,” it said. Using ivermectin coupled with Executives at Merck in the 1980s an insecticide program, the United were faced with a quandary: Their Nations’ Onchocerciasis Control Pro- scientists had unearthed one of the gramme cured 30 million people of most powerful human antiparasitic river blindness in West Africa between treatments ever discovered. It had the 1974 and 2002. The Carter Center, a potential to cure hundreds of millions nongovernmental organization work- of people suffering from neglected ing to fight river blindness, is cam- tropical diseases. However, they were paigning to increase treatment to two unable to market the drug in the times a year in parts of the world that affected areas without being accused remain affected. It hopes to eliminate of exploitation. What happened next the disease worldwide by 2025. was a humanitarian triumph that has served as a model for drug distribu- Alexandra Taylor (ataylor@ asbmb.org) is a science writing tion in the developing world. intern at ASBMB Today and a In 1987, P. Roy Vagelos, then master’s candidate in science and the chief executive officer of Merck, medical writing at Johns Hopkins decided to give the drug away for University.

DECEMBER 2015 ASBMB TODAY 19 FEATURE Guardians of the genome Nobel Prize in chemistry recognizes three DNA repair mechanisms By Alexandra Taylor

n the very act of being alive, we chemistry of DNA repair. (The JBC is humans expose our DNA to a con- published by the American Society for I stant onslaught of damage. Every Biochemistry and Molecular Biology.) time it replicates, our genetic code On Dec. 10, 2015, Tomas Lindahl, amasses mutations. Ultraviolet rays Paul Modrich and Aziz Sancar will from the sun, oxygen in our lungs, receive the Nobel Prize in chemistry. and exposure to natural and synthetic All three are members of the ASBMB chemicals cause us to accumulate and contributors to a field of DNA about 200 mutations per day. If not repair that dates back to the late for certain repair mechanisms present 1920s. (Scientists were studying the in the human genome, our lives would effects of radiation on the genome be very short. long before comprehending its struc- We now know that more than 100 ture.) And while none of this year’s genes are involved in the efficient laureates discovered DNA repair per correction of DNA damage. Problems se, each has made major contributions with DNA repair mechanisms can to the molecular understanding of have serious consequences, in some how various repair pathways fix differ- cases leading to cancer and other con- ent types of DNA damage. ditions, such as neurological damage Therapeutic applications are begin- and developmental defects. Changes ning to emerge from our understand- to the infamous BRCA1 tumor sup- ing of DNA repair mechanisms. pressor gene, for example, can reduce This year’s Nobel Prize in chemistry the cell’s ability to repair DNA, lead- highlights the value of fundamental ing to breast or ovarian cancer. research done at a time before transla- There was a time when scientists tional applications were on scientists’ assumed DNA was immutable, but radar. Modrich appreciates the Nobel that time has passed. “Damage is all committee underlining the impor- over the genome,” says F. Peter Gueng- tance of basic research. “My personal erich of Vanderbilt University. “Even view is that most major biomedical if you lead a relatively clean life, you’re advances can be directly traced to still going to get certain amounts of advances in basic science,” he says. damage.” Sancar will receive the Bert and Guengerich is the interim editor- Natalie Vallee Award in Biomedical in-chief of the Journal of Biological Science, which recognizes established Chemistry, which has published scientists for outstanding accomplish- papers by the three biochemists who ments in basic biomedical research, at will be awarded Nobel Prizes this the ASBMB 2016 Annual Meeting in month for describing some of the San Diego next April.

20 ASBMB TODAY DECEMBER 2015 Base excision Tomas Lindahl, now at the Clare Hall laboratory of the Francis Crick

LINDAHL Institute in the U.K., carried out his prize- winning research at the Karolinska Institute in Stockholm. In the 1970s, he and his team demonstrated that TOM ELLENBERGER, WASHINGTON UNIVERSITY SCHOOL OF MEDICINE IN ST. LOUIS, AND DAVE GOHARA, SAINT LOUIS UNIVERSITY SCHOOL OF MEDICINE (NATIONAL INSTITUTES OF HEALTH) DNA decays over time. This work An enzyme encircles and repairs a broken DNA strand. eventually led Lindahl to identify the DNA repair mechanism known as cine, has worked base excision repair. extensively on DNA Base excision repair targets routine mismatch repair. The chemical damage that would other- copying mechanism wise cause breaks or mutations in the for DNA is imper- MODRICH DNA — problems that could poten- fect: Each time a tially lead to disease. This pathway cell duplicates its DNA, incorrect seeks out and removes damaged bases bases sneak in, known as mismatches. in DNA strands and then patches the Rather than allow these mistakes to strands with new nucleotides. perpetuate, the mismatch repair path- Patrick Sung, a DNA repair expert way acts as a copyeditor, seeking out at Yale University and a JBC associate the errors and fixing them. Errors are editor, finds the Nobel committee’s 1,000 times less likely with a func- acknowledgement “a major morale tional mismatch repair system. booster for people who study DNA Modrich and colleagues determined repair,” and says, “Lindahl’s work the pathways for mismatch repair in has brought to the forefront of our both E. coli and human cells. They awareness that DNA repair is critically also demonstrated that tumor cells important. He’s been a very powerful from patients with Lynch syndrome, spokesperson for the field over several one of the most common forms of decades.” hereditary cancer, are deficient in Indeed, from 1986 to 2005, Lin- mismatch repair. They showed that dahl served as the director for Clare such cancers have insufficient levels of Hall, the principal research laboratory certain proteins required for the initia- of the Imperial Cancer Research Fund tion of mismatch repair. (now a part of Cancer Research UK). In addition to his work on mis- “My time at Clare Hall has been very match repair’s role in Lynch syndrome stimulating,” he says. “We tried to and related cancers, Modrich is get together a number of people who interested in the expansion of triplet were top-class in the field of DNA repeat sequences, which underlies a repair, which wasn’t as fashionable at number of neurodegenerative diseases. that time as it is now. In that way, the In the case of Huntington’s disease, for Clare Hall laboratory became a world example, the proliferation of a specific leader in this area.” three-base DNA sequence leads to the production of toxic proteins in the Mismatch brain. Work by others in mouse mod- els has shown that triplet expansion Paul Modrich, at the Howard depends upon a functional mismatch Hughes Medical Institute and the repair system. Duke University School of Medi- CONTINUED ON PAGE 22

DECEMBER 2015 ASBMB TODAY 21 CONTINUED FROM PAGE 21 to radiation or chemotherapy. For this About the Nobel reason, fundamental research into the Nucleotide excision various repair pathways is starting to festivities Aziz Sancar, at the make inroads toward clinical applica- The Nobel Prizes are handed University of North tions. Drugs that hinder DNA repair out annually on Dec. 10, the Carolina, Chapel are currently undergoing clinical trials. anniversary of Alfred Nobel’s Hill, started studying However, many aspects of DNA death. In the days leading up repair are highly complex and not yet SANCAR how UV light can to the ceremony, the laureates cause DNA damage fully understood. One example is the deliver lectures about their in 1974. UV exposure causes lesions, role of the circadian clock. In mam- work. The ceremony itself takes such as the thymine dimer, which mals, the circadian clock turns genes place at the Stockholm Con- induce a kink in the DNA. During on and off depending on the time of cert Hall, where the laureates UV light exposure, a photon causes a day. Sancar and his colleagues found are honored with a speech and covalent bond to form between two that DNA repair activity in mice is at endowed with a diploma and bases where none should exist. its highest around 4 p.m. and at its a medal. The celebration then Sancar and colleagues mapped out lowest around 4 a.m. In cases where moves to Stockholm City Hall, a pathway similar to Lindahl’s, known DNA repair can diminish the efficacy where members of the Swedish as nucleotide excision repair. Sancar’s of chemotherapy, this fluctuation royal family join 1,300 guests research was based on the work he was potentially could be exploited to for a Scandinavian-inspired doing with photolyase, an enzyme that time the delivery of anticancer drugs, banquet. On the same day, the repairs UV damage to DNA in certain optimizing their impact with minimal Nobel Peace Prize is awarded organisms. He improved our under- side effects. separately in Oslo, Norway. standing of the nucleotide excision repair pathway, which corrects lesions Stimulating the field resulting from UV light exposure by There are many DNA repair detecting the damage, cutting it from mechanisms beyond the three the DNA, and rejoining the strands. acknowledged by the 2015 Nobel This research has been instrumental Prize in chemistry, such as chromo- to our understanding of skin cancer, somal breakage repair. Many who which can be caused by UV light made important contributions were damage. not recognized due to the interpreta- This year, Sancar and colleagues tion of specific stipulations in Alfred completed a map of the nucleotide Nobel’s will by the prize committee excision repair pathway for the entire (1). For example, Sancar’s mentor human genome. This map can be used Claud Rupert discovered the enzyme to determine the ways in which each photolyase in 1958. Sancar considers specific nucleotide in the genome is him to be the father of the field. repaired. Sancar is gratified to have Nevertheless, experts in DNA finished the project: “I went to Peru to repair are thrilled with the recogni- give a couple lectures. I told my wife tion bestowed by the prize. As Lindahl that if my plane hits the Andes and says, “I hope that it will stimulate the I die, I’ll die a happy man because I field a great deal. My colleagues are have the map.” very positive and enthusiastic about drawing attention to the field.” Cancer and clocks As seen in the work of Modrich Alexandra Taylor (ataylor@ asbmb.org) is a science writing and others over the past 20 years, intern at ASBMB Today and a DNA repair is not always positive. master’s candidate in science and Cancer cells with increased DNA medical writing at Johns Hopkins repair activity can develop resistance University.

REFERENCES 1. http://pubs.acs.org/doi/full/10.1021/ac9018457

22 ASBMB TODAY DECEMBER 2015 Royal Swedish Academy of Sciences’ explains Nobel Prize in chemistry 2015.

FROM THE ROYAL SWEDISH ACADEMY OF SCIENCES NOBEL PRIZE IN CHEMISTRY 2015 POPULAR SCIENCE BACKGROUND, ILLUSTRATIONS BY JOHAN JARNESTAD/THE ROYAL SWEDISH ACADEMY OF SCIENCES

DECEMBER 2015 ASBMB TODAY 23 ESSAYS Pairing science with the paso doble By Natalya Gertsik

he Spanish Gypsy dance resounds aggressively, almost menac- T ingly, at 120 beats per minute from every unattended corner of the polished but visibly beaten space. The sound slices through a sweat-induced dew. Layers of net, stretch satin, chiffon and organza adhere to tiny, curve-embracing bodysuits through which every taut, elegantly sculpted muscle can be seen moving in rhythm with the reverberations. Neons, rhine- stones, cheetah prints and fringe flash swiftly in human whirlpools of sweat and sparkle. Figures appear in many places at once, the changes in speed and direction making it impossible to discern between object and image reflected in floor-to-ceiling, wall-to- wall mirrors and in the reflections of the reflections. Heels click sharply against the floor in step with the flamenco rhythm. Bodies drop or fly with every buildup and crash of the music. Wrists and ankles writhe and The writer’s discarded dance shoes, worn down by hours of practice and competition. whirl. Fingers curl. Pelvises thrust vig- orously toward one another and then Spanish bullfights, marking the bull- to graduate school, lived in three of recoil. The breath surrounds, mounts fighter’s entrance into the ring and the five boroughs of New York City, and and attacks, saturating the music with final kill. Today, paso is performed at traded in bell-bottoms for skinny its greedy inhales and loud, urgent, dance competitions worldwide, most jeans, all the while working on my carnal exhales. These are professional frequently to the song “España Cañi,” chasses cape (a classic figure of the ballroom dancers. This is the paso a piece of music so complex that it paso). Lest you think this is a perspec- doble. must be choreographed bar for bar. In tive on classical dance, allow me to The paso doble, or paso, is one of addition to being the most choreo- add that I was simultaneously pursu- five dances in the international Latin graphically demanding, the paso ing a career in biochemistry and am division of competitive dancesport. also requires a strong dose of acting now finishing my Ph.D. in biomedi- The others are cha-cha, samba, rumba skills, as the man plays the combative cal research at Weill Cornell Graduate and jive. Together with the waltz, fox- matador and the woman his swift, School for Medical Sciences. This is trot, tango, Viennese waltz and quick- sinuous cape. It is the fiercest of the not to list my accomplishments, but step, the Latin dances fall under the five international Latin dances. to explain that in recent years I’ve umbrella term “ballroom dance.” Paso I spent years watching the paso learned quite a bit about learning and is a pair dance set to march music that and decades mastering it. In that time the way in which efficient learning was played at popular and gruesome I went from high school to college differs across disciplines, and to lay

24 ASBMB TODAY DECEMBER 2015 the foundation for the topics I’d like to explore, which are the somewhat unexpected similarities and differences between learning the science of dance and learning the art of science. The talent dupe To begin with, common miscon- ceptions abound about both dance and science. The first is the pervasive and inaccurate idea that dance, along with most other art forms, is primarily an innate, talent-based vocation. In reality, the 10,000-hour rule applies as much to dance as it does to astrophys- ics. This has been demonstrated time after time by ballerinas like Misty Copeland, who was told repeatedly that she did not have the natural form The writer as a young ballroom dance competitor. characteristic of a principal dancer but prevailed despite these alleged genetic 10,000-hour rule that dance does. Studying, memorizing and knowing disadvantages. But the best scientists are not neces- will make a good scientist. Wonder- The importance of the 10,000-hour sarily the ones who can recite every ing, daydreaming and stumbling will rule also has become overwhelm- product and intermediate of the citric make a great one. The best scientists ingly apparent in my own experience, acid cycle and calculate molarities in are just spacey artists in white coats. as many dancers that the industry their heads. Nor are they those who deemed untalented have risen to the can pipette the fastest and perform tail Knowing by trying vein injections with atomic precision. American and world ballroom finals as For better or worse, my own sci- The best scientists are the ones who a result of raw, unadulterated dedica- entific career has been a hodgepodge get curious, creative and emotional. tion. One friend who was deemed of blunders, some of which led to They realize that in order to do average as a young dancer was so discoveries, others to day drinking. something new, you may need to get motivated and exhibited such a vehe- One of my more fortuitous accidents a little chancy, a little uncomfortable, ment work ethic that he landed both occurred when I was trying to purify and deviate from much of what you on the big screen with Jennifer Law- one protein but ended up purifying learned in those 10,000 hours. rence and Bradley Cooper in “Silver another, far more interesting candi- Just as great choreography is often a Linings Playbook” and in the national date. I had been purifying a behemoth result of mistakes and digressions from final, far above many others who were of a transmembrane enzyme (protein considered inherently gifted. the director’s vision, so are some of the A) for six months, and the purifica- Talent may help you get noticed, most pivotal discoveries the offspring tion appeared to be working; that is but hot, sweaty, calloused labor takes of fortuitous accidents. Penicillin was to say, the protein complex and its the prize. discovered when Alexander Fleming’s activity were intact after purification. poor sterile technique resulted in an However, while the purified protein Spacey artists infestation of mold on his Petri dish, exhibited activity, the crude protein leading to the realization that some in white coats did not. Now, even an elementary molecule released by the fungus has understanding of protein purification The reverse stereotype, that the best antibacterial properties. Viagra was is enough to recognize the peculiarity scientists are those who work the hard- discovered as a result of a failed clini- of this observation. After a month of est and study the most, is similarly cal trial meant to alleviate hyperten- titrating every reagent under the sun false, as it masks the equally impor- sion. Accidents are the driving force but still obtaining the same strange tant qualities of creativity and vision, of groundbreaking innovation, and and inexplicable result, I finally pre- words often reserved for artists. I am it takes an open mind to perceive sented the data (or lack thereof) to my not saying that science is an innate fortune in the misfortune of these boss, who chuckled and said I had two talent — it certainly follows the same costly and often demoralizing events. CONTINUED ON PAGE 26

DECEMBER 2015 ASBMB TODAY 25 CONTINUED FROM PAGE 25

left hands and could not do an activity assay to save my life. I, however, had a more optimistic view of the situation — it seemed to me that there was an endogenous inhibitor of protein A in our system. Purification of this inhibi- tor would be a higher-impact project than the one I was pursuing. My boss declared, “I don’t believe it.” In spite of his skepticism, I pro- ceeded to test the hypothesis. Several weeks later, glowing and elated, I presented him with the evidence that confirmed that I do not, in fact, have two left hands. Only then did I become aware of the fact that his earlier challenge had been a clever attempt at reverse psychology. He had wanted me to pursue the unlikely theory. “You never know until you try,” he proclaimed. New thoughts Actually, you often do not know even after you try, and between the trying and the succeeding there will be many hazy detours, discouraging obstacles and cryptic clues. Some would say that the best way to solve such problems of scientific ambiva- lence is to plow forward, work harder and generate more data. I would say that it is to go on vacation and drink a margarita. The endogenous inhibitor idea came to me at a friend’s destina- tion wedding on a beach in Mexico. A colleague of mine solved all her cloning problems while speeding down a slope in Whistler. The key is As a dancer and scientist, the writer has benefited from trusting in technique. to give ourselves time to think in a new way, with a different geographical going after that singular experimental detrimental in dance. Certainly, or psychological perspective aiding in endpoint and cleaning up the stu- daily training requires a great deal the process. Thinking, as it turns out, dent’s wound, we may be overlooking of thought, but a great dancer is one is a difficult commodity to come by some of the most interesting biological who does not need to think when the when the protein column is leaking, phenomena hidden in the data. moment comes to perform. My own the building fire alarm is wailing, meditative breakthrough came when three timers are beeping and the rota- No thoughts I trained with a coach who taught tion student is bleeding after having me to disconnect my ego from my cut himself with a scalpel intended for While analyzing and ruminating body. After two hours with him, I mouse surgery. But in the turmoil of are critical in science, they are often was able to improve more than I had

26 ASBMB TODAY DECEMBER 2015 ROSS DEN PHOTOGRAPHY in the previous two years. Learn- pondering, then the goal for a dancer whether or not it was worth it — ing how to go on autopilot is one of is to train a body so capable that he no practicing the same rumba walks the best things that can happen to a longer needs to ponder. day after day, running the repeti- dancer. On the other hand, prolonged As a student of both science and tive Western blots and PCRs. It was autopilot can be one of the most dance, I discovered that there is one neither noticed nor applauded, neither detrimental qualities for a scientist. necessary but not sufficient prereq- glamorous nor sexy. But it was damn As my yoga teacher likes to say, “We uisite for achieving both hyper- and liberating: The constraint of techni- are so busy as human doings that we hypo-consciousness in these very cal training gave me the freedom of forget to be human beings.” Believe it different disciplines: technique. Sound artistic expression. It is in those hyper- or not, doing too many experiments technical training is the reason a and hypo-conscious, post-10,000 hour at the expense of being a scientist may dancer can trust his body to take over moments of euphoric abandon that actually impede scientific progress. A his mind and a scientist can trust his the real discoveries and the tremen- scientist who gets too comfortable in creativity to surpass his dogma. Tech- dous, hair-raising moves are made. To her techniques and routines risks not nique allows us to execute all the banal learn something until it is instinctual only missing what could have been a tasks like pirouetting and pipetting is to give yourself the ability to forget groundbreaking observation but also so that we can cultivate the creativity, it all consciously and selectively in interpreting ambiguous data in a way energy and artistry essential to moving order to change your view and dis- that supports her desired hypothesis. from the studio to the lead role in a cover something new. professional production or from the Natalya Gertsik (nat.gertsik@ Trusting in technique task-based experiments to the major gmail.com) is a graduate student Thinking makes our science discoveries. Inspiration can happen in at Weill Cornell Medical College interesting and our dancing dull. If an instant, but technique takes 10,000 and is conducting her thesis at hours to learn. Memorial Sloan Kettering Cancer the goal for a scientist is to take a Center. step away from pipetting and toward To this day I cannot tell you

DECEMBER 2015 ASBMB TODAY 27 When science runs in the family By Rajendrani Mukhopadhyay

ome scientists credit certain schoolteachers or graduate- S school and postdoctoral advisers as role models. Henrik Dohlman at the University of North Carolina at Chapel Hill stays within his family. He credits his father. “I really look up to him,” he says of Claes Dohlman. “He’s not only done great things professionally, he’s a very kind man.” “Great things professionally” is a succinct way to put it. Claes Dohl- man, who has been affiliated with Harvard University since 1958, is a well-known figure in vision research. Inducted into the American Society of Cataract and Refractive Surgery’s Hall of Fame in 2004 and the recipient in 2007 of the American Academy of Ophthalmology’s highest honor, the Laureate’s Award, the elder Dohlman is considered the founder of modern corneal science. His research into corneal physiology established the Henrik Dohlman and his parents after a ceremony at the University of North Carolina at Chapel Hill. basis for current clinical practice with dry eye disease, corneal burns, wound being the chair of Harvard’s oph- U.S. Food and Drug Administration healing and corneal transplantation. thalmology department, director of in 1992. To date, over 10,000 patients Although he retired from university an ophthalmology laboratory, and a have had the device inserted in their administration in 1989, Claes Dohl- chief at Massachusetts Eye and Ear. eyes. man has stayed on as a scientist. He is At a time when most retirees take life The younger Dohlman says of the director of Boston Keratoprosthe- easier, Claes Dohlman has been in the his 93-year-old father with a hint sis Research and Development, which laboratory, perfecting the device. “It’s of understatement: “He has a lot of is part of Massachusetts Eye and Ear, work that really blossomed in his 70s energy.” where he has created a device he’s and 80s,” says his son. most famous for: an artificial cornea The artificial cornea can be used From Sweden to the U.S. known as the “Boston keratoprosthe- on patients who can’t rely on standard sis.” human corneal transplants, such as Science and medicine surrounded Claes Dohlman first conceptual- chemical-burn victims.The prosthetic, Claes Dohlman as he grew up in ized the device in the 1960s. But he which resembles a collar button and Sweden. His father was the chairman turned his full attention to the device is made of medical-grade plastic and of the ear-nose-throat department at in the 1990s, once he retired from titanium, won clearance from the the University of Lund. “It was hinted

28 ASBMB TODAY DECEMBER 2015 Claes and Henrik Dohlman that there was only one worthwhile a Ph.D. in biochemistry from the curious, always eager to lecture people profession to consider and that was Karolinska Institute. on how things really are and copiously academic medicine,” remembers His work caught the attention of read all kinds of literature.” Dohlman. “All my friends were head- Charles Schepens, who was a famous He also had a willingness to ing for medicine so I followed the retina surgeon at The Retina Institute experiment. Claes Dohlman describes path of least resistance.” of Boston. Schepens offered Dohlman a moment in 1968 when he and After completing an obligatory a fellowship at Harvard University. Carin opened the front door of their yearlong stint with the Swedish navy Having been in the U.S. for the home to a sales representative from a (“To be a naval officer was out of the Hopkins fellowship, Dohlman says, hearing-aid company. All of the adults question. I’m a weakling”), Dohlman he knew that “the possibilities, profes- were confused. The sales representa- got an M.D. and finished a residency sionally, were so much greater.” tive insisted that a Henrik Dohlman in ophthalmology at the University of So in 1958, Dohlman and his wife, had contacted the company. The par- Lund’s Eye Clinic. Carin, moved to the U.S. with three ents couldn’t figure out why a hearing- The chemistry of proteoglycans, children. Two years later, Henrik aid sales representative wanted to see which are proteins bound to glycos- became their fourth child and the an 8-year-old boy. aminoglycans and plentiful in the first to be born in the U.S. Two more The confusion cleared when the cornea, intrigued him. Jonas Frieden- children followed. child admitted to finding an adver- wald was working at Johns Hopkins tisement that offered free testing of University on the histochemistry and The little professor a hearing aid. “I had this image that biochemistry of corneal wound heal- it would give me super powers, and I ing. Drawn by his work, Dohlman Henrik Dohlman displayed traits would hear what people were saying did a fellowship with Friedenwald in of an academic at a young age. “He at great distances,” says Henrik Dohl- the early 1950s in Baltimore, Md., was a little professor from the start,” man, still sounding sheepish almost and then returned to Sweden to get says his father. “He was always very CONTINUED ON PAGE 30

DECEMBER 2015 ASBMB TODAY 29 CONTINUED FROM PAGE 29 who laid the foundations for modern ful experience for both of us,” recalls species nomenclature and ecology. Henrik Dohlman. “The talk that came five decades after the incident. “So I Carin Dohlman shared her love and out in the end bore no resemblance filled out the card, and then the sales- wonder of nature with Henrik. to what I’d prepared. It was the first man showed up. When he discovered and last time I’ve given a scientific that the person he was about to try to Identity of his own presentation with my father in the sell a hearing aid to was an 8-year-old audience.” Like his father, Henrik Dohlman boy with perfect hearing, he stomped But Henrik Dohlman acknowl- earned a Ph.D. in biochemistry. But off.” edges that the pain of having his father he is quick to point out that he always The younger Dohlman recalls redo his first public presentation for his childhood home in Arlington, was intent on making his way through him was well worth it. “I’m a much Mass., as filled with joyful chaos of science as independently as possible. better public speaker because of it!” he a large and close-knit family. “When His research portfolio at UNC focuses says with a laugh. my father came from work, we all on understanding the fundamental swarmed to greet him and he would properties of yeast G protein-coupled ‘Just shrug it off’ be tackled by his kids,” he says. “Din- receptors, a far cry from clinical cor- nertime was masses of spaghetti and neal research. Besides teaching his son the value conversation.” But the first project Henrik Dohl- of a good talk, Claes Dohlman has But Henrik Dohlman got hints man was involved in as a graduate influenced Henrik in two other critical from a young age that his father was a student dropped him into his father’s ways. “Probably the most important well-known figure in the community. territory. The younger Dohlman was one was that I saw from an early age “Every time I would pass the principal in the laboratory of Robert Lefkowitz that he really loved his work,” says of my elementary school, he’d tousle at Duke University in the 1980s. At his son. “That’s not a bad way to go my hair and say, ‘How’s the son of the the time, the laboratory was focused through life.” famous Dr. Dohlman?’ I figured if my on cloning the ß-adrenergic receptor, The other way Claes Dohlman has principal knew who he was, then my the first hormone-based G protein- helped Henrik is to be a model for a father must be prominent.” coupled receptor identified and good laboratory manager: “He’s always Education was critical in the cloned. The work later led to Lefkow- had a positive outlook. He rarely loses Dohlman family. Among the six, two itz’s Nobel Prize in chemistry in 2012 his temper. He tries to be generous are M.D.s and the rest are Ph.D.s. along with Brian Kobilka at Stanford in assigning credit. He does not get “My father is very proud of the fact” University. distracted by office politics or idle that all his children hold advanced “I thought I was working in an area gossip.” degrees, says Henrik Dohlman. “If I that had nothing to do with vision When it comes to research, Claes can say one thing about my parents, research,” says Henrik Dohlman. “But Dohlman knows how to roll with the is that they were exceedingly generous the first thing we noticed about this punches. That’s something his son financially. They put six kids through receptor was it was clearly homolo- says he’s still working on. “There are college and then graduate or medi- gous to rhodopsin, the light receptor.” many failures in this business. There cal school. It’s something I took for Because of the striking similari- are a lot of setbacks, and there’s no granted when I was growing up. But ties between the two systems, Henrik escaping that. You can drive yourself once I got to college and grad school, Dohlman’s first scientific confer- crazy if you let it get under your skin. I realized what a gift that was, to have ence was the annual meeting of the The best that you can do is brush it off no financial barriers to completing my Association for Research in Vision and and move onto the next challenge,” education. That’s my inheritance.” Ophthalmology. “It was not only one says Henrik Dohlman, who is also Henrik Dohlman was the only one of my first public presentations, but it an associate editor for the Journal of to go into the life sciences. His other was a public presentation in front of Biological Chemistry. “I hear my Ph.D.-toting siblings are economists. about 500 of my father’s friends and father’s voice in my head saying, ‘Just He credits his mother for turning him colleagues, with my father in the front shrug it off.’” onto biology even though she holds row,” recounts the younger Dohlman. a degree in political science. Carin Perhaps realizing how unprepared Rajendrani Mukhopadhyay Dohlman also grew up in Sweden, his son was for his first presentation at ([email protected]) is the chief science correspondent where, as her son notes, all schoolchil- a national scientific meeting, the older for the American Society for dren are taught to appreciate the natu- Dohlman pulled him aside and asked Biochemistry and Molecular ral world and revere the 18th-century to see the slides and hear the talk Biology. Follow her on Twitter at botanist and zoologist Carl Linnaes before the event. “It was a very pain- twitter.com/rajmukhop.

30 ASBMB TODAY DECEMBER 2015 The Chemophilately Museum By Aditi Dubey

hen letters were still the only Gu-Gang Chang, form of long-distance com- professor emeritus at W munication, the stamps that National Yang-Ming carried them to their destinations University in Taiwan, were miniature works of art with is a biochemist and CHANG special meanings and identities. The a passionate stamp collecting of stamps became a popular collector. Chang owns a comprehen- hobby soon after the first stamps were sive set of chemistry-themed stamps issued in the mid-19th century. that has taken 30 years to amass. Originally the purview of children Chang’s collection revolves around and teenagers, stamp collecting was “chemophilately” and features an array elevated when a French stamp enthu- of chemistry-themed subjects, such as GU-GANG CHANG siast who was president of the first chemical concepts, chemical history Sample stamps from The Chemophilately Museum. stamp collectors’ society coined the and notable chemists. device to protect against pilferage. term “philately.” It connoted not only Chang has made his set available Perfins are historical philatelic materi- collecting but the serious study of online through a website called the als.” Chang says perfins are seldom stamps and postal history. The Ameri- Chemophilately Museum used today, as postage meters have can Philatelic Society estimates that (chemophil.blogspot.com). This vir- replaced them. The perfins in the around 5 million people in the U.S. tual museum features his collection in exhibition contain symbols or abbre- alone collect stamps. Several famous both English and Taiwanese, indexed viations for elements, compounds personalities including Franklin D. by topics such as atomic energy and including methane, and biological Roosevelt and Charlie Chaplin were X-ray crystallography. Some stamps molecules like hemoglobin. “It is fun enthusiastic stamp collectors. date back to as early as 1888, and oth- to find out that so many biological Stamps have long celebrated a wide ers refer to current events. Chang says terms are embedded in perfins,” says range of subjects including science the crystallography section of stamps Chang. and scientists like Americans Barbara was added to the exhibition when the With this site, Chang hopes to McClintock, Linus Pauling, Melvin United Nations proclaimed 2014 the bring themed stamp collecting to a Calvin, Edwin Hubble, Josiah Willard International Year of Crystallography. wider and newer audience — one Gibbs, Czech-American nobelists There are several sections in the that’s not deterred by the drop-off Carl and Gerty Cori, and Spanish- Chemophilately Museum on DNA- in stamped mail. He says, “In this American biochemist Severo Ochoa. themed stamps and famous scientists, electronic era, it is increasingly less Several scientific events of importance such as Charles Darwin and the common to receive stamped mail. have found their place on postage. Nobel laureate Marie Curie. Unusual However, stamp collecting remains Mercury Project and Messenger Mis- aspects of the collection include items one of the most common hobbies in sion stamps were released in 2011 at like Philippine Science Tax Stamps, many societies.” the Kennedy Space Center in Florida which served as documentary revenue to commemorate NASA’s Mercury stamps from 1969 to 1978. In addi- Aditi Dubey (dubeyad@ exploration efforts. More recently, a tion to stamps, the site also features scarletmail.rutgers.edu) is a stamp depicting global sea-surface antique advertising cards, collectible graduate student studying the mechanism of selenocysteine temperatures based on NASA’s satel- revenue labels and perfins. incorporation at Rutgers lite images was released in 2014 in Chang describes perfins as stamps University Robert Wood Johnson Washington, D.C. that have “punched holes as a security Medical School.

DECEMBER 2015 ASBMB TODAY 31 The maestro’s weaving art By Emir Avilés-Pagán

Break time The maestro, the professor — For coffee and paper, One into another turned. Saw my professor Surrounded now With keyboard in hand, By the concert hall, Her eyes in synchrony, The maestro, the grand pianist, The melody to start. Weaving his art. Swift movements, rapid beats. Such music, such magic, Sounds of rising harmony, No comparison, Gazing at the screen, None alike. Emir Avilés-Pagán (emir.aviles@ gmail.com) is a Ph.D. student at Grazing the keys, No more a draft the Massachusetts Institute of Clear the air, But now Technology studying fly develop- Calm all down. A finished grant. mental genetics.

32 ASBMB TODAY DECEMBER 2015 A mock PI works out By Vivian Tang

A major task that’s ever so grueling, Science is great but addictive and sedentary. The endeavor of completing my Ph.D. May also bring harm insidiously — Perhaps a new hobby to make it more interesting, Bad postures, aches and pains are cautionary; One that I came upon through my own study. I need to be humbled constantly.

When there’s a published article to be read, A second hobby I’ve cultivated, I’ll dive straight into the introduction. A need to counter my sedentary lifestyle. Then, there’s a challenge to be met, Before my academic pursuit is vindicated Although in a hypothetical situation. I just need to go the extra mile.

With just the introduction and nothing else covered A hobby that kills two birds with one stone But the aims of the published study clear in mind, To destress and slim down with benefits I’ll always With the scientific knowledge and skills I’ve acquired, emphasize, What methods would I have used that are fine? A rigorous workout regime of my own — Nothing will ever beat regular physical exercise. Assuming the role as a principal investigator, Obtaining novel data is what I’m geared toward. Confronted with stressful and demanding commitment, Techniques and strategies that make me a prolific researcher, With a constant need for high brain power and mental Published results needed to put my best foot forward. agility, Our physical health and fitness always an essential To have the gene encoding it amplified and identified, requirement, Its catalytic mechanism unraveled by structural biology, Although it’s too easy for us to see exercise as frivolity. Site-directed mutagenesis to get its active site verified. I think I have got a good grasp of enzymology. When the stress of my Ph.D. takes a toll on me, Just taking a walk helps me put things into perspective, The composition of the microbiota be subject to analysis, But a full rigorous workout is better than one can see. The bronchoalveolar lavage fluid be collected for proteomic It’s a fountain of youth that keeps my mind productive. profiling, Assays be performed to detect changes in lipid synthesis. Is the thought of adding to my regime something new Getting it all right is a confidence booster so overwhelming. Or becoming a part-time certified personal trainer plausible? Rock climbing, scuba diving, fencing, just to name a few, Flow cytometry to investigate possible T-cell polarization, Either way will render my life as a scientist even more RNA silencing experiments to elucidate the cell signaling sustainable. pathway, Immunohistochemistry to visualize the cellular localization. If only my efforts to complete my Ph.D. My reasoning is all sound, but I won’t be carried away. Endure as well as running on a treadmill. The need to listen to my mind and body — Getting the techniques and approaches right They’re set to push me uphill. Does not mean that I would be experimentally productive. Therefore, let’s turn to my mentors for their insight The world of academia is relentless. That has enabled me to thrive and be innovative. With the two hobbies, I hope to stay resourceful. Despite my faith, I’m not entirely fearless — Vivian Tang (victoriousvivian@ Time and opportunities are not plentiful. hotmail.com) is a graduate student at the School of Pathology and Laboratory Medicine at the University of Western Australia.

DECEMBER 2015 ASBMB TODAY 33 MINORITY AFFAIRS Overcoming impostor syndrome By Marion Sewer

friend and col- league shared with A me a recent experi- ence she had at a faculty awards ceremony. Her institution was awarding one of its highest hon- ors, and while the cita- tion was being read and the accomplishments of the winner listed, my friend’s colleagues were pointing at her and whispering, “This has got to be you.” Despite their reassurances and the plain facts of her extensive academic and service activities being read aloud, she refused to believe the award was for her. Later, she would reveal that not only did she feel that the award couldn’t have been for her but, perhaps more troubling, she felt that she didn’t deserve it. This sense of not being worthy plagues many, particularly high achievers with CVs that tell a clear story of exceptional qualifica- tions and accomplish- ments. The sense of unworthiness has a name — impostor syn- drome — and is defined as a complex array of feelings characterized by suffer from impostor syndrome in feel like an outsider. a belief that one is incompetent and high proportions, the syndrome is per- Since a seminal paper on impos- any achievements are in fact unde- vasive and can affect anyone whose life tor syndrome was first published by served strokes of luck or other external experiences, including socioeconomic Pauline Rose Clance and Suzanne factors. Although members of under- status, sexual orientation, religious Imes (1) in 1978, many books and represented minorities and women beliefs, or other factors, make them articles have chronicled the struggles

34 ASBMB TODAY DECEMBER 2015 of successful, high-achieving individu- planted by seemingly well-meaning which describes the instrumental role als from professional spheres. Joyce individuals. I often reflect back on a support group can play in career Roché described her struggles with a graduate school interview during trajectories. imposter syndrome in her book The which a faculty member told me that Speak about your fears with a Empress Has No Clothes: Conquering despite my strong academic record mentor, partner or therapist or in a Self-Doubt to Embrace Success (2). I would have to work twice as hard journal. Voicing your fears, doubts Roché shared her journey as an Afri- as other students because “all of the and concerns with a trusted individual can-American woman growing up in other black students” have to work may provide objective clarity. New Orleans who went on to become harder. Similarly, after being awarded Share your achievements and vice president of Avon and CEO of a Howard Hughes Medical Institute accomplishments — celebrate publica- Girls Inc. In the book, she describes predoctoral fellowship, I was told by tions, funded grants, defenses and the deep-seated fear that she would a mentor that “they always pick one awards. fail and be revealed as undeserving black student,” so I should feel lucky Accept compliments and accolades. of her achievements. Eventually, she to have been picked. Statements like Don’t diminish the impact of well- developed coping strategies to dampen these can trigger periods of self-doubt wishes from friends and colleagues by the inner voice that undermined her and isolation, particularly during dismissing them as luck. confidence, and she finally accepted challenging times like preparing for Don’t give power to assumptions that she had earned a seat at the table. a qualifying examination, revising a others make about you. Stereotypes Roché’s story resonates with many grant application, reviewing student are pervasive and applied to every minority professionals in STEM, evaluations, or navigating the promo- population. Try not to let the opinions particularly those in academia. While tion and tenure process. of others undermine your goals. there have been gains in the number All of this can be compounded Seek out low-risk opportunities of underrepresented minorities that further by stereotype threat, a to act like you are more confident pursue undergraduate and doctoral phenomenon studied extensively by than you feel — a course lecture or degrees in STEM disciplines, the Claude M. Steele, profesor of psychol- departmental research seminar can be number of these graduates that ogy and executive vice chancellor and the motivational spark needed to allay matriculate into tenure-track faculty provost at the University of California, self-doubt. positions has not changed significantly Berkeley. Steel found people feel at Give yourself the right to make in decades. The proportion of tenured risk of confirming negative stereotypes mistakes and to say no. Avoid saying full professors from underrepresented about their social groups, such as the yes to committee service merely to minorities still hovers around 5 stereotypes that women are bad at diversify the group. percent (3). Similarly, while female math and that African-Americans are Keep a healthy sense of humor and graduate students outnumber their less intelligent (4). perspective. Sometimes the hoop you male counterparts in the biological sci- So how does one develop mecha- have to jump through is moving … ences, their numbers lag behind when nisms to cope with the feelings of and on fire. it comes to tenured professorships. impostor syndrome? There is no one- Assess your strengths and challenges For underrepresented minorities, size-fits-all answer, but the following holistically. Ponder the source of your impostor syndrome can complicate strategies may help (3, 5): feelings of inadequacy. Perhaps they an already challenging career path in Develop a network of colleagues are rooted in a need for a more fulfill- which isolation and the pressure of and friends — take a page out of the ing existence. representing an entire race or gender book Every Other Thursday: Sto- Reframe failures as opportuni- are already in play. ries and Strategies from Successful ties for growth — “unscored” simply Further seeds of doubt can be Women Scientists by Ellen Daniell, means that the leap to “funded” will be greater. Don’t lose touch with your authen- REFERENCES tic self — regularly reflect on your 1. Clance, P.R. and Imes, S.A., Psychotherapy: Theory, Research and Practice. 15, 241 – 247 (1978). personal definition of success and seize 2. Roché, Joyce M., The Empress Has No Clothes: Conquering Self-Doubt to Embrace Success,Oakland: opportunities to change your path. Berrett-Koehler Publishers, 2013. 3. National Science Foundation, National Center for Science and Engineering Statistics, Women, Marion Sewer (msewer@ucsd. Minorities, and Persons with Disabilities in Science and Engineering: 2015, 15 – 311, 2015. edu) is a professor at the Skaggs School of Pharmacy and 4. Steele, Claude M., Whistling Vivaldi: And Other Clues to How Stereotypes Affect Us,New York: Pharmaceutical Sciences at the WW Norton and Company, 2010. University of California, San 5. Young, Valerie, The Secrets of Successful Women: Why Capable People Suffer from the Imposter Diego. Syndrome and How to Thrive in Spite of It,New York: Crown Business, 2011.

DECEMBER 2015 ASBMB TODAY 35 EDUCATION Who the heck

is David Baltimore? By Eleftherios P. Diamandis

y research lab consists of 12 silence. Ph.D. students and 12 post- Perhaps when you are M doctoral fellows and associates. starting out these days, At a weekly lab meeting last spring, reciting the names of someone asked, “Who is Vladimir distinguished predecessors Ilyich Lenin?” I was rather astonished in your field can seem like to discover that other than me, no one a trivial exercise in view of in the room recognized Lenin’s name. the mountains of mate- Perhaps being able to name the first rial you need to learn for leader of the Soviet Union is of little a competitive specialty. concern to today’s young scientists. When I ask younger scien- After all, the man was not in their tists why they don’t recog- field. But it is also the case that nize the greats, the answers several of my own and other graduate I receive range from “How students and postdocs are not familiar would I ever know?” to with many of the giants of modern “I really know a lot about science. my specialty, but I am not For instance, a student of mine good with names.” once complained about an unfair But it’s not only the question that was asked during the names that concern me. final examination of a Ph.D. thesis This generation, encour- containing a series of reverse tran- aged to focus on current Vladimir Ilyich Lenin scription-polymerase chain reaction technologies, is also not experiments. The unfair question trained, as previous genera- During a lab meeting, I asked my was simply, “Who discovered reverse tions were, in essential math and mea- students, “Which measured signal is transcriptase?” At another lab meet- surement techniques. Many students larger: 99 or 100?” and they thought ing, a guest speaker showed a quote are unable to prepare a buffer unless it was a bad joke. But they appreci- attributed to David Baltimore, leaving following a recipe, do not understand ated it when I explained that if the my staff to ponder, “Who the heck is basic measurement principles — uncertainty of the two numbers is David Baltimore?” (See box.) Not too such as those of pH, absorbance and 2 percent or higher, then the two sig- long ago, at a final Ph.D. examination fluorescence — and cannot define the nals are the same (or, more accurately, on regenerative medicine, I asked who difference between a molar con- not statistically different). Finally, discovered inducible pluripotent stem centration and an absolute amount some of my students can explain how cells. The candidate responded that (i.e., 1 pmol/L vs. 1 pmol). When a mass spectrometer works, an instru- the discovery was made by a Japanese performing simple calculations, such ment that is used daily in my lab, but group but he failed to name the Nobel as verifying the ratio of 99/10, they are generally stuck when you ask them Prize winner. often turn to a computer or calcula- the difference between a C-8 and a These kinds of knowledge gaps are tor. And when it comes to statistics, C-18 column used for the up-front not limited to North America. When they sometimes do not understand chromatography step. I presented to a group of medical the difference between a t-test and a Why is this happening? Although students in Spain recently, I asked Mann-Whitney U-test or ANOVA. there might not be one particular rea- if anybody knew of Spaniards who They can, however, use a computer to son, it appears that the dissemination had won Nobels, and again there was calculate them. of ready-made reagents and purchased

36 ASBMB TODAY DECEMBER 2015 services is exacerbating the issue. In will matter for young students who two Nobel Prize winners from decades my opinion, these allow for a faster aspire to true relevance in their field. ago, you may get an interview for a research pace at the expense of the In a global, competitive world, the job at one of your invitees’ institu- educational component of in-depth people most likely to succeed are those tions. technical knowledge. with both deep and broad knowledge Regarding names of Nobel laure- A related observation is that our and good communication skills. ates, here are my suggestions: wet lab, which was very crowded 15 Let us go back to Lenin for a We have 20-plus freezers in the years ago, is now usually empty. I find minute. Imagine sitting at a table lab, and I propose naming each after most of my graduate students sitting with another five or ten speakers at a a Nobel laureate. It’s tough to miss at their desks performing complicated conference you organized, and each the name when you are opening the bioinformatics analyses of their own speaker is specialized in one thing. freezer! or using publicly available databases to How will you ever sustain a discus- When Nobels are awarded in early delineate mechanisms of disease and sion for two or three hours if the only October each year, we could hold a hunt for new biomarkers. thing you know (even if perfectly) is special lab meeting with three presen- I suspect that not knowing the very narrow? tations: one on the new winners and old folks, the old math, and the old Scientists are expected to have two on previous ones, starting, let’s techniques is common in many other knowledge and opinions about other say, in 1950. research labs. But beyond an old guy peoples’ work — especially timely We could also have a hall of fame like myself getting worked up about it, topics like climate change, pollution, in the corridor or lab displaying some is it really a bad or worrisome develop- renewable energy, stem cells, new can- Nobel winners and their work. ment? cer therapies, epidemics, animal and Regarding analytical knowledge, Scientific knowledge is expanding human cloning, and so forth. Even we senior scientists and mentors at an exponential pace, and our new politics, sports, music and movies have should advise, remind and expect scientists in training have little time a place for discussion in such settings. our students to know the principles to learn the fundamentals of basic But how can we remain generally of fundamental techniques and their techniques or to remember names of informed while pursuing our more limitations so that data are interpreted legends. Most likely, this situation will narrow questions? properly. After all, we bear respon- get worse with time. One way to sustain a well-rounded sibility for the validity of such data, Don’t get me wrong — the younger phenotype is by reading broadly, especially when published. generation is not only brilliant at including leading general and specialty Eleftherios P. Diamandis using and adapting to newer technolo- journals, magazines, and newspapers, ([email protected]) is a gies but also very resourceful and well even if you seem to have no free time. professor and head of the clinical equipped to solve meaningful scien- You likely will be a far more memora- biochemistry division at the University of Toronto and holds an tific questions in the years to come. ble individual if you show off multiple endowed chair in prostate cancer Still, I strongly believe that having interests beyond your specialty. And if, biomarkers at Mount Sinai Hospital and University a solid foundation in basic principles during a discussion, you name one or Health Network.

David Baltimore • An American biologist, university administrator, and 1975 Nobel laureate in physiology or medi- cine for discovering the enzyme reverse transcrip- tase • Served as president of the California Institute of Technology (Caltech) from 1997 to 2006 • Currently president emeritus and professor of biology at Caltech • Served as president of The Rockefeller University from 1990 to 1991 • Served as president of the American Association for the Advancement of Science in 2007

CALIFORNIA INSTITUTE OF TECHNOLOGY • Won the U.S. National Medal of Science in 1999

DECEMBER 2015 ASBMB TODAY 37 EDUCATION Results of the 2015 ASBMB annual graduation survey By Erica Siebrasse

he American Society for Bio- U.S., and 158 institutions submitted dents were from primarily under- chemistry and Molecular Biology complete surveys, for a response rate graduate institutions. Very few degrees T has surveyed programs in bio- of 18.3 percent. This was a significant of any type were awarded to students chemistry and molecular biology since improvement over the 2014 response from under-represented races and eth- 1999. Several changes were made to rate of 13.8 percent. nicities. This trend was also observed this year’s survey, including revised Of note, the 2015 respondents in the percentages of biochemistry questions to improve accuracy and represented a greater variety of insti- and molecular biology faculty, over the addition of new questions about faculty demographics. The 2015 tutional types (No. 4 below) than in half of whom were reported to be survey went to departments across the 2014, when the majority of respon- white men.

38 ASBMB TODAY DECEMBER 2015 DECEMBER 2015 ASBMB TODAY 39 OUTREACH Cracking open the lab doors Do-it-yourself biologists band together in Baltimore By Lisa Z. Scheifele

or most Americans, exposure ance that made open-ended science allow them to work in a community, to science laboratories ended in experiments a reality for everyone? develop project ideas, share expertise F high school or college. In those and make unexpected interdisciplin- early science classes, students were led Access and community ary connections. through standard, cookbook protocols Baltimore UnderGround Science and arrived at expected outcomes. Do-it-yourself biology is a move- Space, or BUGSS, is a place for just Few were able to perform authentic ment of citizen and professional this kind of creative biology. We research or pursue open-ended ques- scientists who believe everyone should are a community laboratory with a tions. The joy of actual discovery was have an opportunity to engage in the mission: to enable those interested in reserved for those who went to gradu- scientific process. While the phrase biotechnology to learn and do science ate school and gained professional- might call to mind nefarious hackers in a fun, safe and socially responsible level laboratory access. But what if toiling alone in garages, the real- manner. BUGGS offers community there were a venue that allowed the ity is that most DIY biologists work lectures, lab classes, workshops and public to engage in the scientific pro- openly and collectively. Many have meet-ups for member projects in a cess, encouraged nonscientists to ask banded together to create community newly revitalized neighborhood of questions that professional scientists labs where members can share space, east Baltimore. We want the public ask, and offered equipment and guid- material and equipment. These spaces to engage in science at a variety of levels, so for novices we offer highly mentored courses and instruction; for those who want to learn about the latest technologies and discover- ies we offer lectures from eminent local scientists; and for those who want to engage fully and use biologi- cal technology we offer access to the technology and guidance to bring their research ideas to fruition.

Authentic research Citizen scientists who seek out community labs often are highly educated and keep up with the latest scientific developments. With an Out- reach Seed Grant from the American Society for Biochemistry and Molecu- lar Biology, BUGSS has been able to offer these citizen scientists a Build- a-Gene course. For the past three summers, the course has brought together patent attorneys, librarians, computer programmers, high school LISA Z. SCHEIFELE students and artists who have spent Marissa Sumathipala, shown setting up PCR reactions, mentored other high school students in the 2015 Build-a-Gene course. their Saturday mornings in the lab

40 ASBMB TODAY DECEMBER 2015 learning gene-synthesis protocols. Since gene synthesis uses polymerase chain reaction and molecular cloning to assemble a gene from oligonucle- otides, teaching the protocols allows us to expose learners to cutting-edge concepts of synthetic biology while helping them master fundamental skills in molecular biology. Offering the class as a five-week series allows students to repeat fundamental techniques, such as micropipetting, PCR and gel electrophoresis; this allows enough independence to build proficiency with enough instruction to complete the tasks accurately. Over the past three years, partici- pants have synthesized genes for fluo- rescent proteins, yeast chromosome fragments and bacteriophages. While the protocol is standardized, each gene may differ in how well it assembles, allowing students to experience the various outcomes of real research — including failure. John Torcivia- Rodriguez, a Ph.D. candidate in bioinformatics at George Washington University, says, “The course helped reaffirm in my mind that biology Build-a-Gene participant and BUGSS board member Ryan Hoover selecting bacterial colonies for PCR screening. doesn’t have 100 percent success, but I was surprised by the level of success An inclusive and ethical Hopkins Berman Institute of Bioeth- we did have!” ics who led a discussion about gene Students often take the class to scientific enterprise editing technology. get hands-on training with current BUGSS sees its role as one of creat- Opening the doors of the lab to materials and methods and as a way ing informed citizens who are engaged citizen scientists offers unprecedented to spark future research ideas. Krystal with research science, increasing opportunities for engagement and Dodd, a recipient of an Outreach Seed knowledge of cutting-edge tech- invites broader participation in the sci- Grant scholarship, came to BUGSS niques in biochemistry and molecular entific enterprise. These new research- as a student recently out of school biology, and promoting discussion ers bring diverse perspectives and who was looking for “lab space and between scientists and the voting engage in exciting interdisciplinary peers interested in pursuing their own public. Synthetic biology, including dialogue. The work of citizen scientists does not seek to compete in depth or projects. I find this refreshing and a the Build-a-Gene course, has yet to rigor with that of professional scien- much needed outlet for my biologi- enter the broad public consciousness, tists but instead can stimulate new cal passion,” she says. Build-a-Gene and we hope to dispel the myths, insights into how science can address participants have gone on to design fears and concerns about this promis- the needs and visions of our commu- their own projects. A group of high ing technology. We also assume the nities. school students engineered yeast responsibility of introducing this technology to the broader public by cells to degrade excess starch, solv- Lisa Z. Scheifele lzcheifele@ requiring safety training and engaging ing a real-world industrial problem, loyola.edu is an associate actively in ethical discussions. In con- professor of biology at Loyola which won them a silver medal in the junction with our course, we held a University Maryland and a International Genetically Engineered member of the board of directors public lecture in bioethics with Debra Machines competition. of BUGSS. Matthews, a researcher from the Johns

DECEMBER 2015 ASBMB TODAY 41 OPEN CHANNELS Reader comments Below are two threads of reader comments about the November President’s Message

What nuggets of information can we learn from this story? Well for one, this sentence is rather worrying: “Koshland was so impressed with the application that she and her colleagues recruited Allison from Texas to the University of Cali- fornia, Berkeley.” What we can learn is that 30 years ago it was perfectly OK for a reviewer to break confidentiality and headhunt a grant applicant on the basis of exciting (presumably unpublished) data in a proposal. Thankfully today’s NIH guidelines forbidding contact between reviewers and grantees, even post hoc, ensure that such unethical practices are rare. – BamaSS

I think your inability to see past Steve’s provocative prose and point out a “breach of protocol” is unfor- tunate. You seem to have missed the whole point of this article. Science has turned into a game today where First thread First people try and sell trendy ideas rather than try to undertake rigorous, unbiased scientific inquiry. There isn’t any room for bold science today — just timid, safe and mediocre work coming from scientists desperately trying to preserve their research programs. So many papers, so little impact. It is no wonder that the public is losing faith in science. I wager even scientists are losing faith in the scientific enterprise. – Shaq Jones

Dr. McKnight, I hope you actually read this message and consider what the community has to say, since we as scientists should be will- ing to listen to debate and adjust our hypothesis if stronger arguments are presented. As a working biomedical researcher, I hope that you would use your position and this forum to address the real issues in the biomedical research enterprise rather than constantly castigating reviewers who are doing a tough job for little credit. Some of the real issues are 1) flat NIH budgets allocated by Congress for the last 12 years that have not tracked with inflation, decreasing the pur- chasing power of each grant dollar and increasing the need for more grants to get research done; 2) public and private academic research institutions that have viewed NIH funding as revenue and have consistently increased indirect costs, reducing the amounts of direct cost dollars available for research; 3) academic institutions that have required their faculty/staff to recover some or most of their salaries from extramural funding rather than putting more skin in the game and paying faculty/staff for their work through base dollars; 4) reduced public support for research that helps the entire community due to the politicization of the biomedical research enterprise and caricature of scientists and the scientific process; 5) loss of early- and midcareer scientists that have struggled to establish and maintain their research programs in the worst funding environment in memory. All of these things are very real issues that affect most if not all of biomedical scientists and are the root of the problem, not merely a symptom like reviewer behavior.

Second thread Second Dr. McKnight, you said in one of your first messages as president of ASBMB that you wanted to have a serious debate (President’s Message: “Wow!” November, 2014), but we have not seen any such debate yet. What we’ve seen is a superficial treatment of the problem by attacking some of our own (i.e., reviewers) and using anecdotes rather than data instead of trying to address the real problems. Please use this forum and what remains of your time in this position to try to tackle real problems that can help the entire ASBMB membership (and all other scientists as well), rather than beating up the people in the trenches. If you cannot do this, I implore (incoming president Natalie) Ahn to start to addressing these issues in a real, constructive way when she takes over as ASBMB president. This is what we saw when (Jeremy) Berg was presi- dent of ASBMB and is what we would hope to see from future leaders of this organization. – Philapodia

My contention is that more money won’t solve the problem. Higher quality scientists are the solution. This requires that the great scientists of today take their responsibility of training young scientists more seriously. In other words, they need to invest in the training of their students beyond just offering cursory/high-level

42 ASBMB TODAY DECEMBER 2015 scientific feedback. We need to bring back the master-apprentice relationship that once pervaded science. Feeding more money to a system of scientific training that turns out poorly trained, ill-equipped scientists won’t improve anything. I suspect Steve McKnight trained in an era where the biomedical research enterprise was much smaller, and students had much more meaningful mentoring relationships. This is largely lost now, and this may account for the supposed mediocrity that is plaguing science. Nowadays, most top PIs are more interested in selling their science and attaining visibility rather than actually doing science. How can you honestly claim to run a world-class lab when you travel 25 weeks of the year? When scientists quit being scientists to become administrators and figureheads, it is a loss for trainees and ultimately a loss for science. Stop pumping more money and feeding universities an endless supply of cheap graduate student and postdoc labor. Ask established scientists to take a more active role in driving scientific projects and increase the effi- ciency of their research groups rather than simply throwing more money at them. Demand high-quality sci- entific training to be the norm rather than the exception. This is the adrenaline shot that science needs. Once we get this right, then we can talk about more money. But as it stands, we as scientists are failing the public. – Shaq Jones

I strongly disagree. I think this idea that scientists today are substandard compared to past scientists (aka McKnight’s riffraff) is a red herring distracting from the real issues listed above and has little basis in actual fact. Just because you want to understand a system in more than superficial detail does not mean you are a low-quality scientist; it means that you think that the system is important enough to spend a significant proportion of your life (which we each only have one) studying and is a sign of intense focus and scientific curiosity. Try to develop a new therapeutic approach with CRISPR/Cas9 without doing the detail work to understand how the system actually works and what potential pitfalls may occur, and you risk causing great harm to patients and their families. There is a place for both grand innovation and detail work in modern science, and both need to be funded. In terms of publications, there is limited space in

Second thread Second the glamour journals that everyone wants to get into (Science/Cell/Nature), and using publica- tion in those type of journals as a surrogate for actually critically analyzing the quality of data in so-called lower tier journals has become a lazy way of looking at the quality of science. We’re supposed to critically review data — not only our own but also data of others. Doing research takes money. You can’t do research without money, and control and distribu- tion of money is unfortunately at the heart of how science functions these days. Those with money (i.e., those “great scientists”) can come up with innovative ideas because they have the luxury of time to think and try new things without putting their careers in jeopardy. Those sup- posed substandard scientists who don’t have much or any money (probably 85-plus percent of working scientists these days) can’t support staff or afford to do experiments to get money to do more experiments unless they constantly submit grants and hope to get lucky. Just like with rich people, money begets money, and those who don’t have money have a much harder time achiev- ing the same level of success than those who have it. Merit only plays a part in who gets NIH money; there is a significant role of who you are and what you have done in the past. The constant attack on young scientists (riffraff) by certain “elite” older scientists is analogous to every other societal situation where a privileged population is threatened by a new popula- tion and does what it can to retain control. Women getting the vote, civil rights, gay rights, etc. Perhaps it’s human nature, but this type of discrimination is not healthy and generally fails in the long run. – Philapodia

Correction In “Eyes everywhere! Funny illustrations bring biology to life” (Hobbies, November) we reported about how Giek Far Chan, a lecturer at the School of Applied Science at Temasek Polytechnic in Singapore, uses drawings to enliven the classroom. Chan is a woman. We regret the error.

DECEMBER 2015 ASBMB TODAY 43 44 ASBMB TODAY DECEMBER 2015 Upcoming ASBMB events and deadlines 5 – 8: ASBMB Special Symposium Kinases and Pseudokinases: Spines, Scaffolds and Molecular Switches, San Diego DEC .

9: ASBMB workshop Developing and Sharing Best Practices: From Concept to Classroom, Melbourne, Fla.

JAN. 23: ASBMB workshop Developing and Sharing Best Practices: From Concept to Classroom, Hattiesburg, Miss. 23: ASBMB workshop Developing and Sharing Best Practices: From Concept to Classroom, New York City 28: Late-breaking abstract deadline for the ASBMB 2016 Annual Meeting, San Diego

Feb. 23: Discounted housing closes for the ASBMB 2016 Annual Meeting, San Diego Feb. 27: FEB. ASBMB workshop Developing and Sharing Best Practices: From Concept to Classroom, Westerville, Ohio

March 1: Early discounted registration closes for the ASBMB 2016 Annual Meeting, San Diego MAR .

DECEMBER 2015 ASBMB TODAY 45