A NEW ANGLE Discovery of a Mutation in a Rare Pediatric Brain Tumor Gives Researchers New Targets to Go After for a Cure Submit Your Next Paper to an ASBMB Journal!

Vol. 14 / No. 6 / June/July 2015

A NEW ANGLE Discovery of a mutation in a rare pediatric brain tumor gives researchers new targets to go after for a cure Submit Your Next Paper to an ASBMB Journal!

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NEWS FEATURES PERSPECTIVES

2 18 29 PRESIDENT’S MESSAGE A NEW ANGLE GENERATIONS The straight-jacket 29 Temptation of hypothesis-driven research 24 30 The truth goes only so far MEET SVETLANA LUTSENKO 5 32 NEWS FROM THE HILL 27 HOBBIES Young scientists advocate Something is fishy in the dean’s office! for research funding on the Hill DEFYING STEREOTYPES “So, a biochemist walks 6 into a comedy club …” 33 MEMBER UPDATE EDUCATION 18 33 Playing games to learn Chief science 35 Empty bench syndrome 7 correspondent Rajendrani RETROSPECTIVE Mukhopadhyay reports on an important advance 36 Richard Nelson Perham in the study of a pediatric OPEN CHANNELS (1937 − 2015) brain cancer that has always been unbeatable. 8 29 LIPID NEWS Development of lipids and lipid 16 analogues as potential drugs 11 TOOLKIT All about ELISA 32 12 NEWS 12 Let’s talk about aphasia 27 13 JOURNAL NEWS 13 A look at the Tat system 14 Study outlines how inadequate vitamin E can cause brain damage 15 The promise of personalized nutrition 16 An unexpected finding in prehistoric bison bones

JUNE/JULY 2015 ASBMB TODAY 1 PRESIDENT’S MESSAGE

THE MEMBER MAGAZINE OF THE AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY The straight-jacket

OFFICERS COUNCIL MEMBERS Steven McKnight Natalie Ahn of hypothesis-driven President Squire J. Booker Karen G. Fleming Jeremy M. Berg Gregory Gatto Jr. Past President Daniel Leahy Anjana Rao research Karen Allen Secretary Jared Rutter Brenda Schulman By Steven McKnight Toni Antalis Michael Summers Treasurer ASBMB TODAY EDITORIAL EX-OFFICIO MEMBERS ADVISORY BOARD he advancement of biomedical this latter kind of research follows the Dorothy Beckett Charles Brenner research requires both leaps of concepts of inductive inquiry (I2). Mary Roberts Chair discovery and the steady progress Central to the utility of the I2 form Co-chairs, 2015 Annual Michael Bradley T Meeting Program Floyd “Ski” Chilton that separates one leap from another. of biomedical research is the defini- Committee Cristy Gelling Leaps are universally unanticipated; tion of a phenomenon. Here is an Peter J. Kennelly Peter J. Kennelly no one ever wrote them as specific example of a phenomenon of interest. Chair, Education and Rajini Rao Professional Development Yolanda Sanchez aims in National Institutes of Health During hibernation, the core body Committee Shiladitya Sengupta grant applications. Gradual transitions temperature of ground squirrels goes Daniel Raben Carol Shoulders are the opposite. They are the essence from 37°C down to 4 – 5°C. Perplex- Chair, Meetings Committee ASBMB TODAY of what we write as the specific aims ingly, with robust periodicity, hiber- Takita Felder Sumter of our grant proposals. Gradual transi- nating ground squirrels warm back up Chair, Minority Affairs Angela Hopp Committee Executive Editor, tions fit hand-in-glove with hypothe- to 37°C around once every 10 days [email protected] Thomas Baldwin sis-driven research. (2). These brief periods of warming Lauren Dockett Chair, Outreach Committee Managing Editor, I lament that, as presently con- are called interbout arousals. What is Bob Matthews [email protected] structed, the NIH system of funding the utility to the hibernating ground Chair, Public Affairs Rajendrani Mukhopadhyay science is locked into the straight- squirrel to periodically warm up for Advisory Committee Chief Science Correspondent, jacket of hypothesis-driven research. about a day? Kathleen Collins [email protected] Chair, Publications Valery Masterson It is understandable that things have To me, this is a cool phenom- Committee Designer, evolved in this manner. In times of enon. Interbout arousals are almost [email protected] Martha J. Fedor Lauri Pantos tight funding, grant reviewers find it perfectly periodic, and they entail Editor-in-chief, JBC Manager of Publications easier to evaluate hypothesis-driven re- profound changes in body tem- Herbert Tabor Technology, [email protected] search plans than blue-sky proposals. perature. Instincts tell me something Co-editor, JBC Ciarán Finn The manner in which the system has quite important is taking place when A. L. Burlingame Web Publication Assistant, Editor, MCP [email protected] evolved has forced scientists to per- hibernating animals warm up briefly Barbara Gordon Edward A. Dennis form contractlike research that grant like clockwork. As cool as this science Executive Director, Joseph L. Witztum [email protected] reviewers judge to be highly likely to is, it is hard to distill it down to a set Co-editors, JLR Allison Frick succeed. In financially difficult times, of measurable, specific aims. Sure, Media Specialist, more risky scientific endeavors with one can say that it would be useful [email protected] no safely charted pathway to success to do some cataloging — measuring For information on advertising, contact Pharmaceutical often get squeezed out. metabolite fluctuation as a function of Media Inc. at 212-904-0374 or [email protected]. We all recognize the formula and hibernation and entry and exit from nature of hypothesis-driven research; interbout arousals. Sure, one might we describe it over and over in the hope then to garner some clues that thousands of grant applications we might lead the way out of the woods www.asbmb.org/asbmbtoday PRINT ISSN 2372-0409 write and submit for review by the But it is hard to say exactly how the Articles published in ASBMB Today reflect solely NIH each year. But how should we science would unfold in the context of the authors’ views and not the official positions of describe the riskier blue-sky research the hypothesis-driven form of research the American Society for Biochemistry and Molecular Biology or the institutions with which the authors that our granting agencies tend not to we are now forced to perform. As are affiliated. Mentions of products or services are favor? I have written about this topic nebulous as it might seem, my predic- not endorsements. before (1), and I have suggested that ©2015 ASBMB

2 ASBMB TODAY JUNE/JULY 2015 tion is that a talented and dedicated ES cells divide more rapidly than any is neuron death enacted? scientist would have a good chance of cancer cell – almost as fast as micro- I can think of hypotheses with making cool discoveries if offered the bial organisms, such as yeast. Why do which to begin investigation of these chance to pursue this research for the ES cells divide so rapidly, and how is phenomena, but most such hypoth- duration of a typical R01 grant from hypermitotic drive facilitated? I also eses would be highly biased owing to the NIH. find it fascinating that prototrophic the extreme limitations of my knowl- Were it up to me, and it is clearly strains of yeast (AKA wild type, native edge of ES cell growth, yeast metabo- not, I would demand that NIH grant or nondomesticated), when grown lism or hippocampal neurogenesis. applications start with the descrip- under nutrient-limiting conditions in This being the case, it would be folly tion of a unique phenomenon. When a chemostat, enter into an incredibly to submit NIH grant applications in I say unique, I mean unique to the robust and periodic metabolic cycle. search of funding to support research applicant. The phenomenon may have What is the physiologic utility of on these topics. As mentioned above, come from the prior research of the this metabolic cycle, and what is the it is not up to me to guide the NIH applicant. Alternatively, the phenom- underlying regulatory logic control- on how to spend its funds. On the enon may have come from the ap- ling it? Finally, the vast majority of other hand, we live in a country that plicant’s unique observation of nature, newly formed neurons born daily is highly protective of freedom of medicine or the expansive literature. in the adult mouse brain die along speech. With that in mind, I happily Phenomena abound. One of the pathway toward differentiation offer the thesis outlined in this essay several that have intrigued me over and ultimate wiring into the central and close with Albert Einstein’s iconic the past decade is the speed of mouse nervous system. Why do so many of quote: “If we knew what we are doing, embryonic cell duplication. Mouse the cells die, and by what mechanism it would not be called research.”

Steven McKnight (steven. REFERENCES [email protected]) 1. McKnight, S.L. Cell 138, 817 - 819 (2009). is president of the American 2. Carey, H.V. et al. Physiol. Rev. 4, 1153 - 1181 (2003). Society for Biochemistry and Molecular Biology and chairman of the biochemistry department at the University of Texas-Southwestern Medical Center at Dallas.

JUNE/JULY 2015 ASBMB TODAY 3 SAVE the DATE

Over 26% of attendees in 2014 made a scheduled spoken presentation. Submit an abstract by August 4 to be considered for a speaking spot:

• Minisymposium Standard Talk (15-minute talk, 5-minute Q&A) • Minisymposium Lightning Talk (5 minute talk, 1-2-minute Q&A) • Microsymposium Talk (5-minute talks with electronic posters)

The meeting’s arc will follow the integration of cell biology across diverse fields, scales, and structures into newly relevant scientific disciplines. It’s about connecting traditional cell biology questions to new sequencing-based and super high-resolution imaging methods enabled by big data collection and analysis. Present your best and boldest science at this forward-thinking meeting! ascb.org/2015meeting /ascbiology @ascbiology ascb #ascb15

4 ASBMB TODAY JUNE/JULY 2015 NEWS FROM THE HILL

Young scientists Participants:

Melanie Alvarado, a graduate student advocate on the Hill at the University of Alaska Anchorage Taylor Fuselier, a graduate student at the Tulane University School of Medi- By Allison Frick cine in New Orleans

Tara Gonzalez, a graduate student at the University of Delaware oung scientists from colleges and Amy Hawkins, universities across the United a postdoctoral fellow at the University of Utah Y States arrived on Capitol Hill in June to talk with senators and repre- Aminul Islam, a postdoctoral fellow at sentatives about the value of biomedi- Uniformed Services University of the Health Sciences in Maryland cal research. For a seventh year, the American Society for Biochemistry Ryan Kelley, a graduate student at the and Molecular Biology’s Hill Day gave University of Oklahoma Health Sci- ences Center researchers the chance to meet with lawmakers and congressional staffers Kelli Lytle, a graduate student at about the work they are doing. Oregon State University Torrey Truszkowski, a graduate student at Brown Joshua Mieher The undergraduates, graduate University originally from Providence, R.I., visits with , a graduate student at students and postdoctoral scholars U.S. Sen. Sheldon Whitehouse, D-R.I. the University of Alabama at Birming- collaborated with the ASBMB’s ham Public Affairs Advisory Committee to Jeannette Osterloh, a postdoctoral highlight the critical role that federal fellow at the Gladstone Institutes in investments play in supporting the San Francisco nation’s scientific enterprise and how Dakota Pouncey, an undergraduate those investments will lead to im- student at Hendrix College in Arkansas provements in the quality of life and Jarod Rollins, a postdoctoral fellow well-being of Americans. at Mount Desert Island Biological Laboratory in Maine Allison Frick ([email protected]) is the ASBMB’s Kimberly Sauls, a graduate student print and digital media specialist. at the Medical University of South Carolina Megan Sheridan, a graduate student at Lynn Ulatowski, a postdoctoral fellow at Case West- the University of Missouri–Columbia ern Reserve University originally from South Euclid, Tyler Stanage, a graduate student at Ohio, visited with U.S. Sen. Sherrod Brown, D-Ohio. the University of Wisconsin–Madison Jackie Thompson, a graduate student at the University of Kansas Medical Kelli Lytle, Jeanette Osterloh and Sharona Gordon at Center the office of U.S. Sen. Ron Wyden, D-Ore. Torrey Truszkowski, a graduate student at Brown University Kristeena Wright, a graduate student at Marshall University Lynn Ulatowski, a postdoctoral fellow at Case Western Reserve University Chistopher Yarosh, a graduate student Preston Hensley, Jarod Rollins, Torrey Truszkowski, at the University of Pennsylvania congressional staffer Todd Adams and ASBMB policy Melanie Alvarado, Amy Hawkins and Wes Sundquist fellow Sarah Martin visit the office of U.S. Rep. Jim meet with a staff member in the office of U.S. Sen. Langevin, D-R.I. Lisa Murkowski, R-Alaska

JUNE/JULY 2015 ASBMB TODAY 5 MEMBER UPDATE

6 members named HHMI investigators 10 members The Howard Hughes Medical Institute named 26 researchers HHMI investiga- elected to the tors in late May. Six members of the American Society for Biochemistry and National Academy Molecular Biology were among them. They were: of Sciences The National Academy of Sci- ences in late April elected 84 new members and 21 new foreign associates. Ten ASBMB members were among those elected. SQUIRE J. JARED RUTTER XINZHONG REUBEN S. KIM ORTH TOBIAS C. BOOKER University of DONG HARRIS University of WALTHER They were: Pennsylvania Utah School of Johns Hopkins University of Texas Harvard State University, Medicine University Minnesota, Twin Southwestern University University Park Cities Medical Center

BRENDA BASS ALFRED University of GOLDBERG Utah School of Harvard Medical Gairdner fund and Sharp wins Chemical Medicine School AACR recognize Heritage Foundation’s Cantley Othmer medal Lewis Cantley is be- The Chemical Heritage ing honored with the Foundation is present- ALAN NANCY IP 2015 Canada Gairdner ing the 2015 Othmer HINNEBUSCH Hong Kong International Award Gold Medal to Phil National University for his groundbreaking Sharp. The Othmer Institutes LEWIS PHIL SHARP of Health CANTLEY work in the field of Gold Medal was cancer research. The Canada Gairdner established in 1997 to recognize the International Awards, which come achievements of individuals who have with a 100,000 Canadian dollar prize, made significant contributions to recognize biomedical scientists who chemical and scientific heritage in a present novel research toward under- number of key areas, such as research, JEANNIE LEE JOHN LIS standing human biology and disease. legislation or entrepreneurship. Harvard Cornell University Medical School The Gairdner Foundation is recogniz- Sharp’s innovative research in the field ing Cantley for his discovery of the of genetics has dealt with the molecu- enzyme phosphoinositide 3-kinase, lar biology of gene expression relevant or PI3K, which has proven vital in to cancer and the mechanisms of understanding cancer. Additionally, RNA splicing. Sharp, who serves both the American Association for Cancer as Institute Professor at the Massa- SHIGEKAZU RAFAEL RADI Research is recognizing Cantley’s chusetts Institute of Technology and NAGATA University of outstanding work with the Princess member of the department of biology Kyoto the Republic in University Uruguay Takamatsu Memorial Lectureship. and the Koch Institute for Integrative This award, started in 2007, is given Cancer Research, also has founded out annually to a scientist whose work several biotech companies including makes a profound impact toward Biogen and Alnylam Pharmaceuticals. understanding and treating cancer. Sharp is one of three scientists who His lecture, entitled “Targeting PI3K will get an Othmer Gold Medal at the NAHUM JEREMY for Cancer Therapy,” was in April. Heritage Day Awards, the CHF’s an- SONENBERG THORNER McGill University University Cantley is director of the Sandra and nual celebration of scientific and tech- of California, Edward Meyer Cancer Center at nological achievement, this month. Berkeley Weill Cornell Medical College. Written by Eric Chaulk

6 ASBMB TODAY JUNE/JULY 2015 RETROSPECTIVE Richard Nelson Perham (1937 − 2015) By Sheena E. Radford and Nigel S. Scrutton

he world lost one of its most protein activity and went on to hold gifted biochemists Feb. 14 with the world record in the mid-1960s for T the death of Richard Nelson determining the longest amino acid Perham at the age of 77. An active, sequence (more than 330 residues) of renowned member of the academic a protein. This work merited Perham’s science community until the very end, first major article in Nature, which Perham was distinguished for his work was published in 1968. on the chemistry of proteins and the In 1965, Perham became demon- assembly of giant protein complexes strator in the University of Cambridge and was a leader in bringing the pow- Biochemistry department. At the er of protein-engineering approaches same time, he was awarded a Helen to problems of protein structure and Hay Whitney Fellowship to study at function. Yale University with Frederic Rich- Perham pioneered the development ards. There he met (over a shared of chemical tools to understand pro- electron microscope) gifted biologist tein structure and function, revealing Nancy Lane. The couple returned to how enzymes generate energy from Cambridge and married in 1969. glucose (via the remarkable, massive Perham made many significant 2-oxoacid dehydrogenase multien- contributions in his 50 years at zyme complexes) and how viruses Richard Nelson Perham Cambridge. In the late 1960s, he assemble capsid coats. Using protein uncovered the importance of charge- redesign, he was the first to switch the ding scientist. In 1955, Perham took charge interaction between protein co-enzyme requirement of an enzyme the entrance exam for the University subunits in the self-assembly of (altering glutathione reductase from of Cambridge. The first of his family tobacco mosaic virus capsids, and later using NADPH to NADH for catalysis to go to university, he was awarded a he elucidated the novel mechanism of and lipoamide dehydrogenase from place at St. John’s College. protein–DNA charge interaction that NAD+ to NADP+). He also made At the time, the field of biochem- governs the assembly of filamentous outstanding contributions to our istry was a hothouse of discovery bacteriophage virions. He introduced knowledge of the structure and as- and achievement. The structure of a number of important techniques in sembly of filamentous bacteriophages DNA had been solved in 1953. The chemical modification of proteins, in and was among the first to use these first sequence of a protein (insulin) particular based on reversible amidi- phages to display foreign peptides was determined in 1955. And the nation and trifluoroacetylation of on their surface, opening the door to first three-dimensional structure of lysine residues. their use for the production of novel a protein (myoglobin/haemoglobin) After some 30 years of effort, Per- vaccines. was established in 1956. A whole new ham and his team produced the first Perham was born April 27, 1937, world was opening up. complete description of the structure in the London borough of Houn- A Ph.D. with double Nobel Laure- and assembly pathway of the pyruvate slow West. He went on scholarship ate Fred Sanger was Perham’s next dehydrogenase multienzyme complex to Latymer Upper School, whose step. He worked on the structure (whose molecular mass is 10 MDa). liberal outlook and broad curriculum and mechanism of glyceraldehyde He also uncovered a new mechanism including the arts and sport (both of 3-phosphate dehydrogenase under J. of active-site cooperativity distinct which remained passions of his for Ieuan Harris. Those two identified life) inspired and nurtured the bud- a key cysteine residue required for CONTINUED ON PAGE 9

JUNE/JULY 2015 ASBMB TODAY 7 LIPID NEWS Development of lipids and lipid analogues as potential drugs By Michael Murray

he biological activities of lipids moieties that readily are degraded groups, replacement of the β-carbon underscore their potential for (1). Important deactivation pathways with heteroatoms such as oxygen T development as novel therapeu- in prostanoids include oxidation at or sulfur, and inclusion of aromatic tics. To date, the alkyl phospholipids hydroxyl groups at the ω-end of the systems at the ω-end of the fatty- probably have been the most inten- molecules or at carbon atoms β to the acid chain has produced stabilized sively studied lipid-based therapeu- fatty acid carboxyl group (1). prostaglandin analogues suitable for tics, with miltefosine having value Incorporation of bulky substitu- therapy. in the treatment of skin cancers and ents adjacent to susceptible hydroxyl For example, stabilization of the leishmaniasis and perifosine in certain lymphomas. However, the broad roles of many lipids in diverse cellular processes also could detract from their clinical value because of undesired side reactions. In contrast, certain lipid biotransformation products have narrower spectrums of activities that could produce better-targeted drugs. The 20-carbon ω-6 polyun- saturated fatty acid arachidonic acid undergoes biotransformation mediated by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes to prostaglandins, leukotrienes, epoxides and more complex prostanoids. The analogous biotransformation of ω-3 PUFA, such as eicosapentaenoic acid and docosahexaenoic acid, generates structurally similar but function- ally quite different eicosanoids. In cells, these endogenously produced ω-6 and ω-3 PUFA metabolites are extremely potent molecules whose properties could be adapted in novel therapeutics. A significant problem to overcome in the development of prostanoid- based drugs is their low in vivo stability due to rapid secondary metabolism. Several clinically useful agents that have been developed are A) Structures of the ω-6 arachidonic acid-derived prostaglandin F2α (PGF2α) and prostaglandin E2 prostaglandins that have been modi- (PGE2) and the ω-3 eicosapentaenoic acid-derived prostaglandin E3 (PGE3). Arrows indicate sites at which fied structurally to stabilize chemical biotransformation may occur. B) Structures of the clinically useful prostaglandin analogues sulprostone and bimatoprost.

8 ASBMB TODAY JUNE/JULY 2015 ω -end of PGE2 and replacement of — has been shown to possess anti- related systems has enabled the reten- the carboxylate with a substituted sul- angiogenic properties that could be tion of the pharmacological activity fonamide produced sulprostone (see adapted to cancer chemotherapy (4). of the endogenous lipid metabolite figure) that has utility in postpartum P450-mediated epoxides also have precursor (8, 9). hemorrhage after childbirth (2). The considerable potential as novel thera- Recently, the in vivo antihyperten- ω ω PGF2α analogue bimatoprost, which peutics. -6 PUFA epoxides regulate sive actions of -6 PUFA epoxides carries an N-ethylamide substituent vasoactivity, while the ω-3-17,18- were replicated in an orally active in place of the carboxylate and a phe- epoxide of EPA, but not its regioiso- bioisosteric analogue (10). It may nyl ring at the ω-end (see figure), is mers, kills tumor cells (5) and DHA be possible to capture the anticancer favored in primary glaucoma, because epoxides suppress angiogenesis and activities of EPA and DHA epoxides it effectively decreases intraocular metastasis (6). Some of these proper- and other prostanoid metabolites, pressure and has a low incidence of ties have been reproduced in synthetic such as PGE3, using suitable chemical side effects (3). Recently, PGE3 (see analogues (7 − 10). Thus, bioisosteric modifications that inhibit metabolic figure) — the cyclooxygenase-derived replacement of the epoxide moi- degradation to facilitate the develop- metabolite of the ω-3 PUFA EPA ety with urea, carbamate, amide or ment of novel anticancer agents.

Michael Murray (michael. REFERENCES [email protected]) is a 1. Collins, P.W. & Djuric, S.W. Chem. Rev. 93, 1533 – 1564 (1993). professor of pharmacology at the 2. Schmitz, T. et al. Obstet. Gynecol. 118, 257 − 265 (2011). Sydney Medical School. The work 3. Dams, I. et al. Prostagl. Other Lipid Mediat. 104 − 105: 109−121 (2013). described has been supported by grants from the Australian National Health and 4. Szymczak, M. et al. Blood 111, 3514 − 3521 (2008). Medical Research Council. 5. Cui, P.H. et al. Brit. J. Pharmacol. 162, 1143 − 1155 (2011). 6. G Zhang, G. et al. Proc. Natl. Acad. Sci. USA 110, 6530 − 6535 (2013). 7. Dyari, H.R. E. et al. J. Med. Chem. 57, 7459 − 7464 (2014). 8. Falck, J.R. et al. J. Med. Chem. 52, 5069 − 5075 (2009). 9. Imig, J.D. et al. Front. Physiol. 1, 157 (2010). 10. Khan, M.A.H. et al. Clin. Sci. 127, 463 – 474 (2014).

RETROSPECTIVE CONTINUED

CONTINUED FROM PAGE 7 the European Journal of Biochemistry, edge of art, literature, history, sport from allostery in enzyme activity and reinventing it into what is now FEBS and all types of music. He was an elucidated unexpected mechanisms J, and served as editor until 2013. inspired teacher and mentor, loyal to of active-site coupling in his multi- Perham won election to the Euro- his students, and passionate about enzyme complexes based on motile pean Molecular Biology Organisation the University of Cambridge and St. protein domains. (1983) and the Academia Europaea John’s College. He leaves a legacy of Perham was a servant to the (1992). He was a fellow of the Royal more than 350 scientific papers; an scientific community. He served as a Society (1984) and the Academy of array of well-trained graduate bio- councilor and trustee for the Novartis Medical Sciences (2005). He won the chemists; and family, friends and the (formerly CIBA) Foundation, chaired Max Planck Prize (1993), the Novartis scientific community proud of such a the scientific advisory board of the Medal of the Biochemical Society brilliant man. Lister Institute of Preventive Medi- (1998) and the Diplôme d’Honneur Sheena E. Radford ([email protected]) is cine, and sat on the advisory commit- from the Federation of European a professor at the University of Leeds. Nigel S. tee and was vice-president of the Fon- Biochemical Societies (2011). Scrutton ([email protected]) is a professor at the University of Manchester. A longer dation Louis-Jeantet de Médicine in Perham was a truly exceptional version of this article appeared in The Biochemist Geneva. In 1998, he took the helm of scientist with an impressive knowl- magazine.

JUNE/JULY 2015 ASBMB TODAY 9 NEWS Renaming Institute of Medicine By Erik Maradiaga

he Institute of Medicine has been issues concerning medicine, biomedi- everywhere.” renamed the National Academy cine and health. Likewise, NAS President Ralph T of Medicine. The name change Victor J. Dzau, who was presi- J. Cicerone said the name change is comes as part of an internal reorga- dent of the IOM and is now the first “an acknowledgement of the impor- nization at the National Academies. president of the National Academy of tance of medicine and related health The new academy will continue as an Medicine, said: “This change recog- sciences to today’s global research honorific society and will contribute nizes the important achievements of enterprise.” He said: “It will also bet- to and complement the work of the medicine and health researchers, clini- ter align us to take a more integrated, National Academy of Science and the cians and policymakers in improving multidisciplinary approach to our National Academy of Engineering by medicine both nationally and globally. work, reflecting how science is best advising on health matters. We look forward to expanding our done today.” The IOM was founded in 1970 work together with the other acad- Erik Maradiaga (em3914a@ under the congressional charter of the emies, and I am confident that this student.american.edu) is an National Academy of Science, which development will enhance our ability undergraduate at American was established in 1863. It is respon- to provide evidence-based advice University. sible for providing unbiased advice on aimed at improving the lives of people

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10 ASBMB TODAY JUNE/JULY 2015 TOOLKIT All about ELISA Enzyme-linked immunosorbent assays have widespread use By Aditi S. Iyengar

What is it? ans Administration Medical Center Antibodies recognize and bind to described an immunoassay they devel- specific antigens, such as peptides, oped to measure insulin in human proteins and hormones. The enzyme- blood plasma. That assay used ra- linked immunosorbent assay, better dioactively labeled antibodies. Yalow known as ELISA, exploits this anti- went on to win the 1977 Nobel Prize gen–antibody specificity to detect and in medicine for the work (Berson died measure, with the help of enzymes, in 1972 and couldn’t be awarded the the presence of proteins in samples of prize posthumously). unknown composition and concen- The technique garnered much trations. attention, but it was accompanied by concern over the long-term effects of using radiation. The idea of replac- How does it work? ing radiation with less hazardous In a plate-based ELISA, researchers substances was born out of a need to immobilize an antigen in a microwell maximize safety while minimizing MOUNT SINAI ARCHIVES plate. Next, they add antibodies that costs. Though initially met with im- Rosalyn Yalow won the 1977 Nobel prize for work that recognize the antigen at sites called mense skepticism, the concept of us- laid the groundwork for ELISA. epitopes. These antibodies are special ing enzymes as a reporter label started in that they are coupled to specific to gain popularity. used routinely to measure serum an- enzymes. The researchers then treat In 1971, three groups indepen- tibody concentrations against various the antigen–antibody complex with dently and simultaneously published toxins and pathogens, such as celiac appropriate chromogenic substrates their work proving the feasibility disease, mycobacterium tuberculosis that are catalyzed by the antibody- of ELISA as an alternative to ra- and the influenza virus. conjugated enzyme, resulting in dioactively labeled immunoassays: In 1976, Dennis Bidwell and Ali- a color change. Finally, this color Eva Engvall and Peter Perlmann ster Voller from the Institute of Zool- change is read and analyzed by a in Stockholm University measured ogy in London introduced the first microplate reader. immunoglobulins in rabbit serum, sensitive microplate assay to screen Researchers have tinkered with this Anton Schuurs and Bauke van Wee- for viral infections, including malaria. basic principle of ELISA to develop man from the Organon Pharmaceuti- This microplate format since has been more sensitive variants. The sandwich cal laboratories in the Netherlands adapted to detect other viruses — ELISA, for example, uses of a pair of quantified human gonadotropin with its best-known application being antibodies — a capture antibody and hormone in urine samples, and Stratis the screening test for human immu- an enzyme-linked detector antibody Avrameas and Guilbert at the Pasteur nodeficiency virus titers in patients. — to recognize two separate epitopes Institute in France measured serum ELISA also has affected our daily on the same antigen. The antibody immunoglobulin levels. lives in the form of home pregnancy pairs in a sandwich ELISA signifi- tests, ovulation tests, over-the-counter cantly reduce background signals and What are its applications? bacterial infection kits and drug tests. make antigen detection a lot more In the 1970s, the American phar- Aditi S. Iyengar (iyengarsaditi@ specific than a conventional ELISA. gmail.com) earned her Ph.D. in maceutical company Abbot Laborato- cancer biology from Louisiana ries first developed solid-phase radio- State University Health Sciences How did it come about? immunoassay kits to detect hepatitis Center at New Orleans and In 1960, Solomon Berson and B. Since then, ELISA has become a completed her postdoctoral research at Mas- sachusetts General Hospital, Boston. Rosalyn Yalow at the Bronx Veter- powerful diagnostic tool and now is

JUNE/JULY 2015 ASBMB TODAY 11 NEWS Let’s talk about aphasia By Indumathi Sridharan

magine life without language. or injury.” Some studies show that the For people living with aphasia, undamaged parts of the left hemi- I that’s their reality. Aphasia, which sphere take over language function is caused by damage in the language (1). This ability of the brain to regain centers of the brain, affects the ability function by forming new neural to speak, understand speech, and read connections is called neural plasticity. or write. There are currently one mil- The formation of new connections lion Americans with aphasia; 80,000 is controlled tightly by positive and new cases occur in the U.S. every negative regulators (2). For example, year. As stroke is the leading cause growth-associated protein 43 helps of aphasia, the American Stroke As- form cellular projections called neu- sociation designates June as National rites that connect one neuron with Aphasia Awareness Month to increase others. Neurite outgrowth inhibitor access to information and support for A, or Nogo-A, inhibits neural connec- aphasia patients. tivity by blocking neurite outgrowth (3). What causes aphasia? Aphasia occurs when blockage Are there biochemical or rupture of a blood vessel cuts off interventions available blood supply to the language centers located in the brain’s left hemisphere. to improve recovery? Without oxygen and nutrients, the Pharmacological agents, when neurons die. Neuronal death and used along with speech therapy, can missing neural connections result in improve language recovery in aphasia impaired language abilities. Head patients. Piracetam, a γ-aminobutyric acid derivative, is a drug that acts on injuries, tumors and degenerative sentences, albeit with meaningless or neurotransmitters like acetylcholine diseases also can cause aphasia by empty words. They also have difficul- and glutamate. Patients using pirace- damaging the left hemisphere. ty comprehending spoken language. tam have improved comprehension, Global aphasia affects both speech reading and writing because the drug What are the types and comprehension. stimulates cholinergic and gluta- Most aphasia patients retain good of aphasia? matergic neurotransmitter systems. memory, attention and perception. Broca’s aphasia affects the ability Preclinical studies indicate that ad- “A lot of them improve with targeted to fluently speak in grammatically ministering an anti-Nogo-A antibody speech therapy,” says Yasmeen Faroqi- accurate sentences. Comprehension or transplanting stem cells at the site Shah at the University of Maryland. may be mildly impaired. People with of damage to replace dying neurons She adds, “An important question is Wernicke’s aphasia can construct can boost neural plasticity and help in how the brain recovers after a stroke recovery (4).

REFERENCES Indumathi Sridharan (sridharan. [email protected]) earned 1. www.sciencedirect.com/science/article/pii/S1053811911014595 her bachelor’s degree in bioin- 2. www.medscape.com/viewarticle/763955_4 formatics in India. She holds a 3. www.clinicaltrials.gov/ct2/show/NCT02416856 Ph.D. in molecular biochemistry 4. www.ncbi.nlm.nih.gov/pmc/articles/PMC3405725/ from Illinois Institute of Technology, Chicago. She did her postdoctoral work in bionanotechnology at Northwestern University.

12 ASBMB TODAY JUNE/JULY 2015 JOURNAL NEWS

A look at the Tat system By Alexandra Pantos

n order for most proteins to relocate across membranes, they I must unfold, take their journey and then refold upon reaching their destinations. However, in some situ- ations, a protein needs to be translo- cated while remaining folded. This is the job of the Tat system. In a recent minireview in the Journal of Biological Chemistry, Kenneth Cline of the University of Florida explores the mechanism of the Tat system. Tat, which stands for Cyclical mechanism for Tat protein transport. The TatBC receptor complex binds the substrate signal peptide twin-arginine translocase, transports in an energy-independent step. The receptor complex is depicted in the figure as a TatBC heterodimer, but it is a variety of substrates of different actually a multimer estimated to contain up to 8 TatBC units. Signal peptide binding triggers PMF-dependent sizes and types. The Tat system exists assembly and oligomerization of TatA. The resulting complex is the translocase. Changes in the TatA oligomer in various organisms and is present are thought to facilitate protein transport, after which the translocase dissociates. in some archaea and some mito- (also known as RR) motif. This motif translocation and notes which model chondria. Cline, however, focuses his is not the entire consensus sequence, he thinks is best. He includes details review on research of the system in but the rest of the sequence varies about how the oligomeric TatBC the thylakoid membranes of plant among organisms and appears to be structure may enable gated TatA chloroplasts and in the cytoplasmic less important than the RR motif. assembly to form the translocase. He membrane of the E. coli bacterium. Once the signal peptide targets the says mechanisms for how the proton- Cline notes that the system substrate, a cycle of substrate binding, motive force and signal peptide bind- has three components in both the translocase assembly and transloca- ing act as triggers are still speculative. thylakoid and in E. coli: TatA, TatB tion occurs. The author explains that In fact, Cline emphasizes that and TatC. The thylakoid orthologs of TatB and TatC are first present in much of the information presented bacterial TatA and TatB are known equal amounts as a receptor complex. in the minireview is preliminary and as Tha4 and Hcf106 based on their TatA is separate until the substrate is based on a single study. He believes genetic isolation, but the author indi- signal peptide binds to the receptor that additional approaches will be cates that the functions of these com- complex, which then “triggers TatA necessary to create a detailed map of ponents are similar enough that this assembly and oligomerization at the the subunit organization of TatABC distinction is not necessary. He refers substrate-TatBC interface,” Cline and substrate as well as to gain an to them as TatA and TatB throughout writes. This complex is known as the understanding of the interactions that the review. He also points out that translocase. Curiously, the order of regulate assembly of the translocase. the system’s presence in prokaryotes the next steps is not known, but the The author reminds readers that this and prokaryote-derived organelles author says they include transporta- research is still at a relatively early suggests that Tat has been around for tion of the substrate, cleavage of stage. He goes on to propose some quite some time. signal peptide and disassembly of the potential approaches for learning The author highlights important TatA oligomer. more, especially about how TatA steps and players in the mechanism of In the rest of the minireview, Cline assemblies enable passage of the sub- Tat. He notes that the signal peptide delves deeper into the roles of TatA, strate across the membrane, which he has three parts: an amino proximal TatB and TatC, and he offers details views as the core issue. N domain, a hydrophobic H domain about how substrates bind and what and a polar C domain that contains Alexandra Pantos (apantos@ that binding triggers. The author also the signal peptidase cleavage site. At asbmb.org) Alexandra Pantos goes into some aspects of the research the N−H junction, however, lies the is an intern at the ASBMB and that are not 100 percent certain. He a senior biology student at the most important feature: the Arg-Arg discusses models for TatA-facilitated University of Maryland.

JUNE/JULY 2015 ASBMB TODAY 13 JOURNAL NEWS Study outlines how inadequate vitamin E can cause brain damage By David Stauth

itamin-E deficiency, it appears, findings about the role of lyso PLs may cause neurological damage also come after other recent studies In the United States, 96 V by interrupting a supply line of showed that low levels of DHA-PC specific nutrients, robbing the brain in the blood plasma of humans are a percent of adult women of the building blocks it needs to biomarker than can predict a higher maintain the function and integrity risk of developing Alzheimer’s disease. and 90 percent of men of the neural membrane. “This research showed that vitamin New findings on this role of this E is needed to prevent a dramatic do not receive adequate micronutrient, in National Institutes loss of a critically important molecule levels of vitamin E in of Health-supported work done with in the brain and helps explain why zebrafish, were published in the Jour- vitamin E is needed for brain health,” their diets. nal of Lipid Research by scientists said Maret Traber in the College of from Oregon State University. Public Health and Human Sciences the necessary materials,” Traber said. The research showed that zebraf- at OSU, and lead author on this “In a sense, if vitamin E is inade- ish fed a diet deficient in vitamin E research. quate, we’re cutting by more than half throughout their lives had about 30 “Human brains are very enriched the amount of materials with which percent lower levels of docosahexae- in DHA but they can’t make it – they we can build and maintain the brain.” noic acid-containing phosphatidyl- get it from the liver,” said Traber, Some other research, Traber said, cholines, or DHA-PC. This major who also is a principal investigator in has shown that the progression of membrane phospholipid species is the Linus Pauling Institute at OSU. Alzheimer’s disease can be slowed by part of the cellular membrane of “The particular molecules that help increased intake of vitamin E, includ- every neuron. carry it there are these lyso PLs, and ing one study published last year in In searching for a mechanism of the amount of those compounds is the Journal of the American Medical action, scientists examined the level of being greatly reduced when vitamin Association. But that disease is prob- lysophospholipids, or lyso PLs, that E intake is insufficient. This sets the ably a reflection of years of neuro- serve as substrates for phospholipid stage for cellular membrane damage logical damage that already has been synthesis and as transporters for get- and neuron death.” done, she said. The zebrafish diet used ting DHA from the plasma into the DHA, an omega-3 polyunsatu- in this study was deficient in vitamin brain. Once inside, these lyso PLs be- rated fatty acid, has been increasingly E for the whole life of the fish — as is come the building blocks for neural- recognized as one of the most impor- the diet of some humans. membrane maintenance and repair. tant fatty acids for brain health. It’s Vitamin E most often is provided It was found that brain lyso PL levels found in certain omega-3 rich foods, by oils, such as olive oil. But the high- are an average of 60 percent lower primarily cold-water fish like salmon est levels are often found in foods that in fish maintained on the vitamin–E and mackerel. don’t make the highlight list of an deficient diet. DHA is the needed nutrient, Tra- average American diet — almonds, Why is this important? Because the ber said, but it’s the lyso PLs that help sunflower seeds or avocados. year-old zebrafish used in this study, get it into the brain and ultimately act “There’s increasingly clear evidence and the deficient levels of vitamin E as the building blocks for maintaining that vitamin E is associated with they were given, are equivalent to hu- the neural membrane. brain protection, and now we’re start- mans that have eaten a low vitamin E This membrane is highly dynamic ing to better understand some of the diet for a lifetime. And unfortunately, and is in a constant state of turnover, underlying mechanisms,” Traber said. that’s pretty common. so an adequate supply of lyso PLs is In the United States, 96 percent needed at all times to facilitate nor- David Stauth (david.stauth@ of adult women and 90 percent of mal membrane — and, subsequently, oregonstate.edu) is a science writer at Oregon State University. men do not receive adequate levels of neuron activity. vitamin E in their diets. And the new “You can’t build a house without

14 ASBMB TODAY JUNE/JULY 2015 The promise of personalized nutrition Studies find that a high-fat, low-carb diet improves cholesterol levels in people with a particular gene variant By Vivian Tang

n international team of research- evidence for the notion of a personal- and provide the replication that had ers led by Lu Qi at the Har- ized dietary intervention based on been lacking. A vard School of Public Health genetic background.” Qi and co-authors emphasize that recently reported in the Journal of To understand these results, you they administered the diets under Lipid Research that a high-fat, low- have to know a bit about the cho- conveniently managed conditions, carbohydrate diet appears to improve lesteryl ester transfer protein — the which facilitated adherence to the cholesterol levels in obese people with CETP in the genotype name. regimen by more than 80 percent of a particular gene variant. CETP is a glycoprotein that the participants throughout the dura- The researchers studied the effects regulates blood lipids by facilitating tion of both trials. Also, they noted of this diet in a two-year randomized the transfer of cholesteryl ester and that study participants either highly trial called Preventing Overweight triglycerides between HDL and other restricted their saturated-fat intake or Using Novel Dietary Strategies, or lipoproteins. Mutations in the CETP were counseled to avoid foods high in POUNDS LOST, involving more gene affect CETP expression or activ- saturated fats. than 700 obese individuals. Weight loss in individuals They observed that individu- with the CETP rs3764261 als with a certain variant of CC genotype was insig- the CETP gene ended up nificant during the first few with increased levels of high- months, with most of them density lipoprotein (known regaining weight six months as HDL or good choles- into the trials. The research- terol) and decreased levels of ers say this indicates that triglyceride six months into weight loss is only partially the trial. dependent on restoration of The researchers then HDL and triglyceride levels. did a second independent, Also, they affirmed that two-year randomized trial even after adjusting for called the Dietary Interven- changes in body weight, the tion Randomized Controlled Trial, or ity, which affects HDL cholesterol restoration of lipid levels remained DIRECT, with 171 obese individuals. levels. The variant CETP rs3764261 significant, with the elevated HDL Again, only those with the specific CC is a HDL cholesterol-decreasing levels persisting throughout the two- CETP variant on the high-fat, low- mutation. year duration of the trials – an indica- carb diet showed significant improve- Previous genomewide-association tion of the continuous beneficial ment in HDL and triglyceride levels. studies had established that the effect of the high-fat, low-carb dietary The results from these trials CETP genetic variant rs3764261 intervention even after weight regain. “indicate that individuals with the has a stronger association with HDL The team now will explore whether CETP rs3764261 CC genotype cholesterol levels than other loci other genetic variants or mechanisms might be more responsive to low- across the human genome. However, interact with dietary intervention carbohydrate, high-fat weight-loss investigations exploring the relation- and affect not just lipid levels but diets in raising HDL cholesterol and ship between the CETP genetic also other physiological traits, such as lowering triglyceride levels compared variants and dietary fat intake thus far glucose, body fat and blood pressure. with those without this genotype,” have been mostly short-term studies the researchers wrote. “Our findings that detected either no association Vivian Tang (victoriousvivian@ provide novel information to the or associations that could not be hotmail.com) is a graduate student at the School of Pathology development of effective strategies for replicated. The findings reported in and Laboratory Medicine at the dietary interventions and supportive the JLR paper confirm the association University of Western Australia.

JUNE/JULY 2015 ASBMB TODAY 15 JOURNAL NEWS An unexpected finding in prehistoric bison bones By Rajendrani Mukhopadhyay

n Oct. 14, 2010, construction work- O ers excavating a site for a reservoir dam near Snowmass Village, Colo., stumbled across bones. The bones belonged to a woolly mammoth. More careful digging revealed close to 5,000 bones from different Ice Age animals. Camels, mastodons and bison were among them. In a recent paper from the journal Molecular & Cellular Proteomics, researchers reported the analysis of proteins found in the bones of an extinct species of giant bison from the site. From their analysis, they described an unexpected feature of ancient collagen. The bones at the Snowmass Village fossil site (which also is known JAMES ST. JOHNS UNDER CREATIVE COMMONS LICENSING as the Ziegler reservoir Skeletons of the extinct Bison latifrons. site) were remarkably well-preserved. The high tion of the bones, to see if he could mass Village site when, he says, “one altitude of the site, which was a help with analyzing samples. of the scientists described the smell of lake in the Ice Age, kept it at rela- Hansen’s laboratory carries out the bone fossils as ‘very organic.’” tively cool temperatures over the past mass-spectrometry analyses, and Mindful of the issue of contami- 130,000 to 150,000 years. The cooler he was aware of existing mass-spec- nation, Hansen and colleagues were temperatures probably contributed to trometry work on fossilized proteins. careful with the samples given to the preservation of the buried materi- Some studies have suggested that red them by the museum. The samples als; even some of the ancient plant blood cells can be preserved in an- were skull bones from an extinct spe- material buried at the site was still cient bones, but the validity of these cies of giant-horned bison from the green at the time of the discovery. interpretations has been questioned. Pleistocene era called Bison latifrons. Kirk Hansen at the University Skeptics also have wondered about “We took extra precautions by using of Colorado, Denver, heard of the inadvertent contamination of ancient new chromatography columns and Snowmass Village discovery in 2010 samples with modern proteins. ensuring the samples were placed in “while listening to public radio on my However, Hansen says, “I thought only new vials,” he says. way into work.” Hansen is a protein that the methods we were develop- The investigators carried out mass biochemist whose expertise is in the ing to improve characterization of spectrometry on the proteins left in extracellular matrix. He called the proteins from the extracellular matrix the bison bones. The biggest chal- Denver Museum of Nature & Sci- could be used on these well-preserved lenge was in the data analysis. Some ence, which was directing the excava- samples.” Hansen knew he would get of the proteins had degraded as good-quality samples from the Snow- expected of old proteins, producing a

16 ASBMB TODAY JUNE/JULY 2015 “laddering” effect in the peptides, and ies of ancient collagen, such as proline gen, crosslinking chains together to numerous peptides were changed by hydroxylation. stablilize its ropelike structure. But post-translational modifications. But one modification was new and it was assumed the seemingly labile But the investigators sorted unexpected — hydroxylysine gluco- glycosylated residues would not with- through the data and identified sylgalactosylation. “This was the first stand the test of time. extracellular matrix proteins and discovery of a preserved glycan, to the “You’d imagine, over this period of plasma proteins. Thirty-three of the best of my knowledge,” says Hansen. time, you would have lost the sugars. ancient bison proteins mapped over “Finding it in a sample that is over That’s one of the reasons why we to modern bovine proteins, showing 100,000 years old was surprising.” never bothered to look for them: We the evolutionary kinship. Bioarcheologist Matthew Collins didn’t expect to find them. This work In particular, Hansen and col- at the University of York in the U.K., elegantly shows that I was wrong!” leagues sequenced in detail the who specializes in studying ancient says Collins. “We’re now going back collagen from the bison samples. The collagen, is most impressed with the and looking at our samples for glyco- extracellular matrix protein, which finding of the hydroxylysine glucosyl- sylated residues.” forms a fibrous, ropelike structure, galactosylated residue. Glycosylation As Hansen and colleagues were bore modifications seen in other stud- is a key structural feature of colla- working on the bison samples, data came from a young Siberian woolly mammoth called Lyuba. Her proteins bore similar modifications to those of the bison. “Finding these modifications in modern tissue samples usually requires some form of enrich- ment,” says Hansen. But with these two fossils, “the modifications were relatively easy to find.” He says the discoveries suggest that collagen with hydroxylysine glucosylgalactosylation might be enriched over time because it creates a stable complex. Hansen and his team’s next aim is to study the relationships between collagen modifications and collagen fiber architecture. The ramifica- tions of the work will go beyond the study of ancient proteins. As Hansen explains, “Once we make progress in this area, we will have a better understanding of the microenviron- ment’s role in tumor progression and the ability to rationally design biomaterials for tissue engineering applications.”

Rajendrani Mukhopadhyay ([email protected]) is the chief science correspondent for ASBMB. Follow her on Twitter KIRK HANSEN at twitter.com/rajmukhop, and Cranial bone sample from Bison latifrons that shows connective tissue. read her blog at wildtypes.asbmb.org.

JUNE/JULY 2015 ASBMB TODAY 17 FEATURE A NEW ANGLE Discovery of a mutation in a rare pediatric brain tumor gives researchers new targets to investigate for a cure

By Rajendrani Mukhopadhyay

18 ASBMB TODAY JUNE/JULMAY 2015 “Some of these cancers affect thousands of people. Others affect few. But, regardless of magnitude, the lessons we may learn may cure us all” – BROOKE AND KEITH DESSERICH IN “NOTES LEFT BEHIND.” enise Downing remembers feel- billions of dollars to send satellites ing incredulous and frightened into space, and we don’t even get D as she sat with her husband, upset when they get lost!” she says. Jeff, in a doctor’s office on a January “But 250 children die every year from day in 2012. They just had heard a a brain tumor, and we allow that to pediatric neuro-oncologist tell them go on.” that their daughter, 4-year-old Cait- But the tide is turning. Shortly lin, had a rare brain tumor. after Caitlin was diagnosed, two sci- The doctor had diagnosed Caitlin entific papers described the sequences with diffuse intrinsic pontine glioma, of DNA from DIPG and other or DIPG. Denise Downing asked the pediatric brain tumors. Researchers specialist how many children had sur- found mutations in the most unlikely vived the disease and Caitlin’s chances location: histone genes. of beating it. Misregulation of proteins such as The doctor said, “Zero.” Bewil- kinases and cell-cycle regulators is dered, Downing remembers asking, known to promote tumor growth.

“Zero what?” But not histones. “No one, absolutely DENISE DOWNING The doctor clarified: There were no no one, in their wildest dreams would In 2012, Caitlin Downing died at age 5 from a rare survivors of DIPG. have expected this,” says C. David Al- pediatric tumor. Caitlin Downing died on Novem- lis of The Rockefeller University, who ber 11, 2012, nine months after her studies these proteins around which a diagnosis. She was 5 years old. cell’s DNA winds like thread. Each year in North America, Since this unexpected finding, DIPG kills between 250 and 300 says Souweidane, the nearly non- children. Knowledge of the tumor existent field of DIPG research has stretches back a century, but a treat- “exploded.” Molecular biologists like ment, much less a cure, has been Allis suddenly are discovering that elusive. “There’s not a single approved their curiosity-driven explorations of drug,” says pediatric oncologist Oren the genome’s packaging material have Becher at Duke University. clinical implications. Historically, many clinicians shied away from studying DIPG. “There ‘We are going to help you was a huge disincentive for focusing on the disease. It’s rare. Funding was enjoy your child’ nonexistent. The outcome is dismal. The disease affects both girls and Your chances of succeeding were boys, usually between the ages of 4 horribly low,” says pediatric neuro- and 11. Children with DIPG typi- surgeon Mark Souweidane of Weill cally die within 12 months of their Cornell Medical College. diagnosis. That’s what the Downings discov- The tumor sprouts out of a struc- ered: Because DIPG is a rare disease, ture in the brainstem known as the not much was known about it. Not pons. The pons is involved in eye much funding had gone toward movement, balance, hearing, facial studying it. There wasn’t much to do expressions and other functions. about it. Caitlin’s first symptom was uncoor-

The pain and anger of having no dinated eye movement. It was the WEILL CORNELL MEDICAL COLLEGE recourse still ring in Downing’s voice. Photo on opposite page shows an image of a child's “We live in an age where we spend CONTINUED ON PAGE 20 brain with a tumor.

JUNE/JULY 2015 ASBMB TODAY 19 FEATURE

CONTINUED FROM PAGE 19 was standing. Some foundations Sunday after Christmas 2011. The Downing’s unease turned into dedicated to Downing family had gathered around panic. When her husband got home the dining table. Denise Downing late that night, she told him that, DIPG research looked at her third child, whom she without a doubt, something was describes as a “girly-girl” who loved wrong with their daughter. They took cheerleading, dancing, gymnastics Caitlin to the pediatrician first thing Fly a Kite Foundation and dolls all heavily doused in pink. on Friday morning. The pediatri- (flyakitefoundation.org), in The iris of the preschooler’s eye was cian sent them to the Arnold Palmer memory of Zachary Bernstein, drifting toward her nose. Children’s Hospital in Orlando, Fla., age 11 Downing has relatives with lazy where Caitlin got an MRI scan. The eye, so she offhandedly asked her hus- Downings got the DIPG diagnosis on Hope for Caroline Foundation band Jeff, a family practice physician, Friday, January 13, 2012. (hopeforcaroline.org), in memory if lazy eye is genetic. He said it was, Caitlin’s symptoms were typical. of Caroline Cronk, age 5 and Downing thought no more of Parents of DIPG patients report un- it. The next day, she noticed Caitlin’s coordinated eye movement, uncharac- eyes cross several times and that the teristic clumsiness, inexplicable mood Jeffrey Thomas Hayden Foun- child was holding her head oddly. swings and muscle weakness. The dation (jthf.org), in memory of Sure she was making something out change from a healthy, vibrant child Jeffrey Hayden, age 12 of nothing, Downing carried on. to one stricken with these symptoms By Wednesday, it was clear to both happens in a matter of days. Julian Boivin Courage Downing and Caitlin’s preschool “They progressively lose their for Cures Foundation teacher that the little girl was hold- ability to move, swallow, smile, talk,” (courageforcures.org), in memory ing her head almost to the side. Still says pediatric neuro-oncologist Mi- of Julian Boivin, age 5 thinking lazy eye, Downing made an chelle Monje at Stanford University. appointment with an ophthalmologist “But kids stay very cognitively alert for the next day. The ophthalmologist throughout the course of the disease. The Cristian Rivera Foundation assured Downing there was nothing They are aware of everything happen- (cristianriverafoundation.org), in wrong with Caitlin. ing to them.” memory of Cristian Rivera, age 6 But something gnawed at Down- She pauses. Then she says, with a ing, and she decided to keep Caitlin catch in her voice, “It’s awful.” The Cure Starts Now with her that Thursday. Her daughter Downing, a certified bereavement (thecurestartsnow.org), in memory begged to go back to preschool, but counselor, says, “There is nothing that of Elena Desserich, age 6 Downing told her that she was going can prepare you for when a doctor sits to have a fun day with Mommy with across from you and says, ‘Your child’s a trip to the mall and a McDonalds’ got a brain tumor.’ Then the second The McKenna Claire Happy Meal. “I watched her,” says blow comes when I ask, ‘How do Foundation Downing. “Every hour, she seemed to we treat that?’ She says, ‘There is no (mckennaclairefoundation.org), be getting worse.” treatment, Mrs. Downing. You have a in memory of McKenna Claire Later in the day, Downing was maximum of 15 months. We are go- Wetzel, age 7 home with her four children and ing to help you enjoy your child.’” talking to her oldest daughter, Reflections of Grace Founda- Courtney. Caitlin got up from in No progress tion (reflectionsofgrace.org), in front of the television and tried to In DIPG, the cancerous tissue is memory of Grace Elizabeth Ekis, walk toward Downing. But she ran rooted so intricately into the bed of age 6 smack into Courtney and fell down. healthy tissue that it’s impossible to As she picked herself up, Caitlin, who know how far the tumor spreads and Downing describes as sweet-tem- Children’s Brain Tumor Family where it ends. Surgeons have attempt- pered, yelled in anger at her sister for Foundation (cbtff.org), a consor- ed to biopsy and cut out the tumor, deliberately getting in her way. Both tium of families brought together but because of its vise-like grip on Courtney and Downing stared at her by pediatric brain tumors healthy tissue, they never have been in shock. Courtney hadn’t budged. able to remove the tumor safely. Caitlin couldn’t tell where Courtney With the advent of MRI scanners

20 ASBMB TODAY JUNE/JULY 2015 in the 1980s, radiologists found they The most could diagnose the tumor noninva- sively. “There was a kind of morato- unexpected finding rium, where it felt inappropriate to In 2007, a group of French neu- biopsy the tumors,” explains pediatric rosurgeons safely performed biopsies neuro-oncologist Mark Kieran of of 24 children with DIPG. Kieran, Dana-Farber/Boston Children’s Can- who had been arguing unsuccessfully cer and Blood Disorders Center. “The for the need to biopsy DIPG patients only thing worse than dying of DIPG to advance the field, says the French was to be damaged by the biopsy demonstration provided perfect lever- before you got to die of the DIPG.” age: “We had to argue that either the Without biopsies, there weren’t French neurosurgeons were infinitely any DIPG tissue samples to study. more capable than American neuro- Clinicians tried to make do with surgeons or it was time to allow us to another cancer, adult glioblastoma start to move forward.” multiforme. That brain tumor strikes Getting actual DIPG samples was adults and is thought to be similar a major step forward for the field. An- to DIPG because the two tumors other was that the parents of patients seem to resemble each other under an with pediatric brain tumors were optical microscope. Any clinical trial growing increasingly vocal in advocat- MICHELLE MONJE to test potential therapies for DIPG ing for more research and allowing Fluorescent images of cells taken from a DIPG was based on what was known about their children to be autopsied. sample. adult glioblastoma. “We’ve done that Indeed, it was with autopsy now for 30 to 40 years and unfortu- samples that researchers took an nately made no progress in the disease important step in understanding the whatsoever,” states Kieran. molecular biology of pediatric brain All doctors can offer to DIPG tumors. In 2012, two groups of re- patients is radiation treatment. searchers, one led by pediatric oncolo- Downing and another mother of a gist Nada Jabado at McGill Univer- DIPG patient, Kristine Wetzel, both sity and the other by developmental mention Neil Armstrong’s family. neurobiologist Suzanne Baker at St. The first man to walk on the moon Jude’s Children’s Hospital, published had a daughter with DIPG. Karen data from autopsied pediatric brain Armstrong died when she was 3 years tumors. Independently, the groups old in January 1962. Her treatment had sequenced the DNA extracted of cobalt-based radiation wasn’t from the tumors, including DIPG, drastically different from the radiation and discovered mutations in histones. treatment offered to children with In the cell’s nucleus, histone DIPG today. In James R. Hansen’s proteins form a series of complexes authorized biography of the astro- around which DNA wraps. Histone naut, “First Man: The Life of Neil A. complexes undergo a slew of post- Armstrong,” sources speculate that translational modifications — meth- Armstrong channeled his profound ylation, acetylation, ubiquitination — grief over his daughter’s death into to dictate how tightly or loosely DNA becoming an astronaut. wraps around them. The complicated Radiation temporarily shrinks the pattern of post-translational modifica- tumor and gives the children a tem- tions influences whether or not genes porary reprieve, known as the honey- around the histones are transcribed. moon period, when they can resume Four types of proteins make up their normal activities. But the tumor a histone complex. One is called comes back within months, more ag- histone H3. It is one of the most con- gressive than before, after which there served and fundamental components is nothing left to be done. CONTINUED ON PAGE 22

JUNE/JULY 2015 ASBMB TODAY 21 FEATURE

CONTINUED FROM PAGE 21 Not only does K27M prevent of the histone complexes, and it has methylation, says histone-expert Allis, three variants, H3.1, H3.2 and H3.3. but it also looks like the mutation In the non-DIPG tumors in the poisons the enzymes that add on the brain’s cerebral cortex, investiga- methyl groups, causing methylation tors found a mutation in H3.1 that to go awry across the genome. changed the code for a glycine residue A year after the Jadabo and Baker called G34 into the code for a valine groups published their results, histone or arginine residue. This mutation mutations were implicated in other had a ripple effect: A lysine two pediatric diseases. Researchers found residues down from G34, called K36, that H3 gene mutations now are pres- became improperly methylated. ent in more than 90 percent of two In about 80 percent of the DIPG types of pediatric bone cancers. tumors, investigators discovered a Histone mutations are some of the different mutation in histones. This hottest targets in oncologic drug de- mutation took place in the genetic velopment. Earlier, scientists had tar- code for a specific lysine residue called geted enzymes that modified histone K27. The mutation changed the proteins, and several phase I clinical lysine to a methionine. The mutation trials are under way to test small is known as K27M. Three-quarters of molecules against those histone-modi- the DIPG tumors with histone gene fying enzymes. But until the muta- mutations had the K27M mutation tions were found in DIPG and other in H3.3; the remaining quarter had pediatric cancers, no one thought to the glycine mutation in H3.1. target the histones themselves. The genome contains multiple Researchers have found additional copies of H3.1 and H3.3. But these mutations that may affect the progress mutations turned up only once in a of DIPG. Last year, investigators single copy of each gene. Other copies found mutations in a gene called of the genes were normal. The genes ACVR1 that accompany the muta- “are so redundant that it was unex- tions in H3.1. Unlike the histone- pected a single one of those genes gene mutations, the ACVR1 gene would be a hotspot” for mutations, has been implicated in fibrodysplasia says Baker. ossificans progressiva, another rare

life to have meaning, and I wanted But with the discoveries com- Deciding to donate her death to have meaning as well.” ing out of the DIPG field, Wetzel The decision to allow a child’s tis- When McKenna died, Roberts has come to see the power of tissue sues to be used for research stirs up made the arrangements to have donation. She also finds comfort in conflicting emotions. Kristine Wet- McKenna’s organs sent to Michelle the idea that even in a laboratory zel and her husband, Dave, decided Monje’s laboratory at Stanford. setting, McKenna lives on as the to donate their daughter McKenna’s Since then, the Monje lab has estab- name of the cell line. brain and spinal cord when she died lished a cell line from her tumor. from DIPG four years ago. A friend But the decision brought up and neighbor of the Wetzels, Lisa pain. Wetzel, a high-school history Roberts, was the one to suggest tis- and English teacher, says that the sue donation. first time she held a Petri dish of Wetzel says the decision to DIPG cells in the Monje lab was the donate came easily as McKenna worst moment of her life after losing reached her final hours on July 21, McKenna. All she could think was, 2011, two weeks shy of her eighth “This is what is left of my daugh- birthday. “It was our way of fighting ter – the thing that killed her is the back,” says Wetzel. “I wanted her only thing that is still alive.”

22 ASBMB TODAY JUNE/JULY 2015 disease. In that disease, patients slow- research (see “Deciding to donate”). ly accumulate abnormal bony tissue; With these resources in hand, the illness sometimes is referred to as researchers are developing appropri- ‘stone man disease.’ Connective tissue ate cell lines and animal models that starts to turn to bone, and patients more accurately reflect DIPG as well soon can’t breathe. as carrying out better-informed clini- While these breakthroughs are ex- cal trials. Today, there are 37 ongoing citing, they have left researchers with clinical trials targeting DIPG. many questions. How can a mutation Parents of DIPG patients talk in a single copy of a histone gene be about balancing making sure their so potent as to cause cancer? How children live full lives in their last few do these mutations promote tumor months and going all-out to fight growth? And why do these mutations for more time. The Downings, after cause only pediatric forms of brain spending hours combing through the and bone tumors? There are hints that scientific literature, decided to enroll the spatiotemporal expression of these Caitlin in a clinical trial headed up by genes explains why DIPG happens in Souweidane in New York City. children only in a certain time frame. Caitlin was the first child to be What is obvious, says Becher, is enrolled in the trial, which is still WEILL-CORNELL MEDICAL COLLEGE MRI of a DIPG tumor. The tumor is the diffuse white that pediatric cancers are distinctly ongoing. It is exploring the targeted mass at the top of the spiral cord. different from adult cancers. Pediatric delivery of a radioactive monoclonal cancers are products of developmental antibody directly into the tumor pathways gone awry. Adult cancers through a catheter. The Downings are manifestations of misregulation of had to make several trips between the cell cycle. New York City and Orlando, with The fresh research into what causes Caitlin eager to see her beloved “Dr. pediatric brain cancers is exactly what Mark.” Two weeks after she under- Keith Desserich, a founder of The went surgery to embed the catheter Cure Starts Now, wants to see. His into the tumor, Caitlin celebrated her 6-year-old daughter Elena, whom fifth birthday dressed in a resplen- Desserich describes as a perfect little dently pink Hello Kitty outfit ac- lady, died from DIPG in 2007. In cented with fake pink hair. Desserich’s view, cancer research has When Caitlin died six months been far too dependent on the trifecta later, the Downings donated Caitlin’s of surgery, radiation and standard brain and spinal cord to Souweidane’s chemotherapy. research group. Denise Downing, like “For the last 80 years, we focused every other parent of a child stricken on the same three tenets and tweaked with DIPG, has become a vocal advo- our way to treatments,” says Des- cate and supporter of more research: serich. “You can’t make monumental “I hope the outcome of doing the advances through incremental sci- science is that someday, that pediatric ence. You need to change the way you neuro-oncologist is going to sit across think about everything if you’re going from a set of parents and she’s going to try to find a cure.” to hand them that first blow. She’s going to say, ‘Your child has a brain No more double blows tumor.’ Those parents are going to panic,” says Downing. “But she’s not Researchers are unanimous when going to deliver the second blow, be- they say that the parents of patients cause she’s not going to say, ‘We don’t have changed the landscape of Rajendrani Mukhopadhyay know how to treat that.’ Instead, she DIPG research in the past decade by ([email protected]) is will say, ‘We know how to cure that.’” the chief science correspondent allowing biopsies and autopsies of With her voice breaking, Downing for ASBMB. Follow her on Twitter their children and raising money for says, “I know that the day will come.” at twitter.com/rajmukhop, and read her blog at wildtypes.asbmb.org.

JUNE/JULY 2015 ASBMB TODAY 23 FEATURE Meet Svetlana Lutsenko An associate editor of the Journal of Biological Chemistry By Mollie Rappe

Svetlana Lutsenko at The Johns Hopkins University joined the ranks of the associate editors at the Journal of Biological Chemistry in February 2014. Her laboratory focuses on copper homeostasis. The interview has been edited for length and clarity.

Would you briefly explain per delivery in the brain. The other disease is Wilson’s disease, which is a what your research group disease of copper overload. is studying? In the past two decades, copper We work on human copper me- research has progressed significantly. tabolism. We are very interested in it, Starting from having only cDNAs of because copper is an essential metal genes and no experimental informa- for human growth and development, tion about copper transport across and disruption of copper homeostasis various membranes, we and others causes a wide spectrum of patholo- have gained a lot of insights into how gies. As an essential enzyme cofactor, transporters work and how they are copper is important for respiration, regulated in a cell. for formation of vascular tissue and Using genetically engineered mice for brain development. Enzymes that to study Wilson’s disease helped us to require copper as a cofactor produce uncover new metabolic links between catecholamines, so whether we are copper homeostasis and lipid metabo- happy, sad or depressed very much lism. We have characterized a mouse depends on whether we have suffi- model for Wilson’s disease that is now cient copper. used by a lot of people. My mice, I There are two well-described hu- tell people, are better traveled than man diseases that have been known I am. Right now, we are trying to for almost a hundred years that are generate a comprehensive picture of caused by copper imbalance. Menkes how transporters work in human cells disease is an X-linked chromosomal and how they are regulated — and disorder affecting boys. They invari- also what happens in disease. ably die because they are deficient in The more I learn, the more inter- copper absorption in the gut and cop- esting it becomes, because we now

24 ASBMB TODAY JUNE/JULY 2015 know that copper intersects with to look at the functional role of the many metabolic pathways. We have beta subunit of the Na+/K+-ATPase discovered there is a very tight con- and conformational changes associ- nection with lipid metabolism, and ated with the transport cycle. right now we are really very excited While I was at Penn, I became about learning more about the role interested in copper. Then I moved to of copper in adipocyte maturation. Oregon Health & Sciences Univer- Also, we are very interested in neu- sity. I was hired there as an assistant ronal degeneration and how copper professor. I went through the ranks at contributes to CNS development and OHSU and established my indepen- function. dent lab, and then I came to Hopkins in 2009 as a full professor. Tell us about your Hopkins is really great because people are so interested in science academic background and here and we can work with clini- research training. cians. We have very good collabora- I received my undergraduate tors in the department of medicine, degree at Moscow State University; I so we can actually start translating was born in Moscow. I was really torn our findings. We are still in the early initially between chemistry and biol- stages, but we have started treating ogy, because I really like chemistry; animals with drugs and we have had but I also like furry and fuzzy things, certain small successes at improving and biology seemed appealing. liver function in the Wilson’s disease I was always interested in mem- animal model. brane transporters. I’m just really fascinated. What’s going on in the Did anything occur, membrane? How do cells talk to each in a milestone sort of way, other? How do they get stuff in? Out? When I was an undergraduate stu- that made you choose dent, I decided to do my undergradu- science as a career? ate research working on the Na+/K+- + I have always wanted to investigate ATPase and the Ca2 ATPase. something. As an 8-year-old girl — I I did my Ph.D. in membrane biol- + + think this was unusual — I wanted to ogy working on the Na /K -ATPase, be a detective. trying again to understand how this My parents are both scientists. My transporter works. The institute where mom spent most of her time teach- I did my Ph.D. is the Shemyakin- ing, and my father was a scientist. I Ovchinnikov Institute of Bioorganic just wanted to learn how everything Chemistry. Their strength is in mem- works. brane biology, so it was very good for membrane biology and biochemistry of membranes. What does it mean to you, After that, I realized it would be on a personal level, to be really nice to have advanced post- an associate editor for doctoral training, and fortunately or unfortunately the Soviet Union was JBC? What was starting to fall apart … so I had an your reaction when you opportunity to go abroad and do a were asked to be postdoc. I did my postdoctoral studies at the University of Pennsylvania an associate editor? in the physiology department. I con- Oh, I was delighted! I was really tinued to be interested in membrane transporters and expanded my studies CONTINUED ON PAGE 26

JUNE/JULY 2015 ASBMB TODAY 25 FEATURE

CONTINUED FROM PAGE 25 real biology. delighted, because I remember JBC Now, we have this synergy where being my favorite journal as a gradu- there are great technologies that are ate student. finally coming to the stage where I was in Russia. At that time — it we can apply technology and really is funny how things change — we address, mechanistically, fascinating couldn’t check magazines out of the questions about development, about library without permission. Every- cell programming, about regulation. thing was so controlled, all the infor- The most fascinating aspect of sci- mation. We could make a Xerox copy ence right now is that it is easier to only after filing a request and getting study fascinating biological questions signed permission for every page. mechanistically. Like for real, with So I was carrying this big green JBC tools, and technology, and resolution, magazine back and forth, and because and numbers. I wanted to read quite a few of them and they were very thick at the time, For scientists in training, it was a lot of exercise just to carry the do you have any words JBC to the Xerox copier and back. Scientific journals were the only of wisdom or a favorite way you could get knowledge of what motto? was going on (in the West). The first What I tell people in my lab is this: time I came to the United States in As long as you’re interested in what ’89 and saw all these people who pub- you do, things will fall the right way. I lished these papers, it was wonderful. believe it is very important to do not Then becoming an associate editor of necessarily what is fashionable today the journal that I used to go and get but what you feel excited about, permission to copy from the library because fashions change. Of course — it was really very nice. there are ups and downs, and there always are, and things are sometimes What do you think is the harder, sometimes easier. Some fields most exciting thing about are sexier than others, and they are somewhat easier, maybe, in terms of science these days? funding, but there’s also more compe- I remember I would go to a cell tition. I think the way to have a good biology meeting and many studies time is actually to like what you do. were fascinating but rather descrip- Mollie Rappe (mrappe@asbmb. tive, and I would go to biophysical org) is a Ph.D. candidate in meetings and though that technology biophysics at Johns Hopkins is great, the questions were far from University and a former intern at ASBMB Today.

Observing Father’s Day Visit the online version of this issue Visit our chief science corre- to see snapshots of ASBMB spondent’s blog, Wild Types, to members with their dads and kids: read about Journal of Biological asbmb.org/asbmbtoday Chemistry Associate Editor Henrik Dohlman (right) and his father, prominent vision researcher Claes Dohlman: wildtypes.asbmb.org

26 ASBMB TODAY JUNE/JULY 2015 DEFYING STEREOTYPES: “So, a biochemist walks into a comedy club …” Stand-up comedian Joe Wong traded in his lab tools for a microphone By Rajendrani Mukhopadhyay & Geoffrey Hunt

any people have poked fun at and if things didn’t work out, they get Vice President Joe Biden. But really frustrated. They give up.” M at the 2010 Radio and Televi- That’s the other commonality be- sion Correspondents Association Din- tween science and comedy — perse- ner in Washington, D.C., there was verance. “In science, you don’t always something decidedly unique about make great discoveries. There’s a lot the person roasting Biden. of frustration. You just have to keep “I actually read your autobiogra- doing it,” notes Wong. “It’s the same phy,” comedian Joe Wong told Biden. with comedy. Nobody can guarantee “Today, I see you. I think the book is you’re going to write a great joke much better.” tomorrow, but you just have to keep It wasn’t the jokes or the straitlaced trying.” delivery that stood out but rather Wong readily acknowledges that the fact that Wong isn’t your typical the transition from biochemist to co- comedian. He has an advanced degree median is “not very direct.” Growing in biochemistry, something that none up in mainland China, Wong says, of the previous hosts of the swanky “I grasped American humor early for black-tie event, including Wayne some reason.” He counted Woody Brady and Don Imus, can lay Allen and George Carlin among his claim to. comedy idols. How did a Chinese immigrant While in college in China, Wong who once studied neurotransmitters says, “Some of my classmates were in fruit flies wind up on stage telling trying to read jokes off Reader’s Di- jokes at the expense of the second- gest. They understood every word in highest ranking U.S. official? Accord- the jokes. But they didn’t understand ing to Wong, delivering jokes and why it was so funny. I had to explain getting data have more in common to them why this joke was funny.” than one would think. Though his adeptness at American “In science, you have to fail so humor may have set him apart from many times,” he says. “I’ve learned to his Chinese peers, Wong stuck to a deal with failure. That’s very impor- more traditional career path at first. tant. A lot of people try stand-up IMAGES PRODVIDED BY JOE WONG CONTINUED ON PAGE 28 Former biochemist Joe Wong is now a comedy. They do a bunch of jokes, larger-than-life comedian.

JUNE/JULY 2015 ASBMB TODAY 27 FEATURE

CONTINUED FROM PAGE 27 tant for Wong, because audiences in He enrolled at the Chinese Academy the U.S. and China latch onto differ- of Sciences to study molecular biol- ent things as funny. “Every country ogy and in 1994 moved to the U.S. as has different rules,” he says. “You a graduate student at Rice University. have to know how people live.” In After earning his Ph.D. in 2000, the U.S., Wong stays away from jokes Wong joined a startup company that about public transportation, because didn’t survive long, so he next moved most people drive their own cars. But to Boston for a job at Sanofi Aventis. in China, “jokes about the subway are The change of scenery gave Wong really popular,” he says. the chance to “explore different things Wong keeps his scientific train- and hobbies,” as he puts it. “I played ing hidden during his routines and a little golf. Then I took a stand-up sticks to more general topics. “As comedy class.” With that class, a soon as people know I have a degree change in careers began. Wong fine- in biochemistry, they tune out,” he tuned his routines in clubs around says. But Wong notes with some Boston, struggling to get noticed. satisfaction that he once managed to “After you do this for about seven or get a joke about nitric oxide out on eight years, gradually, you know your Letterman. JOE WONG Nowadays, Wong is busy doing Wong has performed on American talk shows and own style, and at that point, it’s a hosts his own TV show in China. little bit easier,” he says. gigs around Beijing and hosting his His perseverance paid off in 2010 own show on Chinese television when Wong was named Boston Co- called “Is It True?” Watched by 5 median of the Year and won recogni- million to 7 million viewers each tion at the Great American Comedy week, the show offers a smorgasbord Festival. of comedy and investigative report- Catapulted to stardom, Wong has ing and is, according to Wong, the made numerous memorable appear- highest rated one for the network that ances, including ones on “The Ellen carries it. He also makes guest appear- DeGeneres Show” and “The Late ances in plays or other TV shows and Show with David Letterman,” along does comedy routines at corporate with his gig at the correspondents’ events, schools and comedy clubs. dinner, which he considers a career His wife, who used to be a financial highlight. manager at Fidelity Investments in “Growing up, I could never the U.S., now manages his career. imagine comedy could be used to talk Having left a relatively tame scien- about so many different topics, from tific career for the roller-coaster life of philosophy to politics,” says Wong. a comedian, Wong emphasizes that “In China, you can’t joke about po- “it’s important for people who want litical leaders, that’s for sure.” to do something slightly different The ability Wong showed in in science” not to be afraid to take a adroitly tweaking Biden that night is chance. For once, he isn’t joking. a good example of how engrained he Rajendrani Mukhopadhyay has become in American culture and ([email protected]) is society, something he chalks up to the chief science correspondent effort. Even as a graduate student, he for ASBMB. Follow her on Twitter at twitter.com/rajmukhop, and says, he worked hard to be plugged read her blog at wildtypes.asbmb. into mainstream America, reading org. Geoffrey Hunt (ghunt@ novels while experiments ran “to get asbmb.org) is the ASBMB’s public to know the American society a little outreach coordinator. Follow him on Twitter at twitter.com/the- bit better.” geoffhunt. Both writers contribute Such in-depth knowledge of how equally in creating and developing the profiles for America functions has been impor- the “Defying Stereotypes” series.

28 ASBMB TODAY JUNE/JULY 2015 Temptation By Najla Arshad

December 7, 2004 December 17, 2014

It’s three in the afternoon, In the lab close to midnight, full stomach, the lack of sleep shaded, cool bedroom, is blurring my sight the soft teddy bears call, One more wash to go the bed looks inviting — to develop my blot — It’s siesta time, after all ten minutes more

Cool pillow to lay my head, Then I’ve stayed so late the gentle whirr of the fan — to know this result Oh, to snuggle up in bed! Nervously, I wait

Across the room, a stark reminder — The film emerges — my cluttered table — a failed experiment! of exams round the corner My heart submerges

The fingers bleed from paper cuts, Around every corner, failure lurks, from sifting through notes but our tenacity tells us, stuck in that student’s rut … “Next time, it will work!” of inky hands, notes awry, Indeed there is still hope and joy, and books piled for the other has repeated (thrice!) precariously high and serves as my heart’s buoy

As sleep with sweet dreams tries to We’ve uncovered another piece lure, of Nature’s puzzle, my wake-up call so tonight I sleep in peace is my Lehninger crashing to the floor Research may seem Wearily, I try to study, Now a nightmare, to stay awake but I’m living my dream. and make my dreams a reality!

Najla Arshad ([email protected]) graduated from the Indian Institute of Science in Bangalore, India. She is currently a postdoc at Yale University School of Medicine. Photos courtersy of Arshad.

JUNE/JULY 2015 ASBMB TODAY 29 The truth goes only so far Scientists need to do more to increase scientific literacy in their communities By Leonardo Valdivieso–Torres

cience impacts all of us, and icsreview.org) intended to demystify departments often have booths for knowledge of it should not be controversial science, why he thought performing DNA extractions and S exclusive to scientists. I think sound science isn’t necessarily the other science activities. Local families this is the perfect time to build prime driver of public attitudes. and members of the Rutgers com- more and stronger bridges between “There’s plenty of good information munity enjoy these activities while scientists and their communities. We out there for someone who cares to learning key science concepts and scientists must reach out and help our dig for it and can understand it,” about the university. It would be great neighbors understand the facts, the he said. if we could add seminars on science scientific process, and the risks and Scientists often think that the truth misconceptions on the evening of rewards of technologies. We must talk will gain the public’s trust, but this is this event. This is one example of to our family members and friends not always the case. Unfortunately, an existing activity that we can take about the everyday discoveries that a lot of misinformation is published advantage of. lead to improvements to our quality on the Internet and broadcast on of life and that should not be taken TV, two of the public’s major sources Join an outreach program for granted. of information. And with scientists Formal science-outreach programs making up less than 1 percent of the also can clear up misconceptions world’s population, it is very unlikely Why do I say this? among the public. There are many that a member of the public will meet The volume of scientific knowl- scientific societies through which you a scientist in his or her life. edge is growing to the point that can get involved in outreach. Some- I worry we scientists are not sometimes even scientists within the times you can even get paid for it. doing enough to clarify misconcep- same discipline need to fill big gaps At Rutgers, we have the Rutgers tions among the general population. of knowledge to understand each Science Explorer Bus, which is an Herein, I offer three ways to do more. other. How many of us have gone to a ambulatory science laboratory that presentation that we cannot get much travels to K − 12 schools. Student out of (sometimes nothing) — not Hold informational participants perform basic experi- because it is hard to understand but seminars ments and learn science concepts because we are not familiar with the Organize short seminars for faculty while being supervised by scientists. techniques or vocabulary? members and students from other I volunteer with the Rutgers The same thing happens with the university departments and invite the University and Robert Wood Johnson public and our politicians. Despite an public to attend. Universities often Bio Links program. It pairs a postdoc overwhelming amount of research by have conferences on different topics, or graduate student with a teacher in the scientific community confirming but the great majority, if not all, are a public school to assist with teaching the safety of drugs, vaccines, antibiot- designed to be understood by scien- science once a week. I have had the ics and genetically modified organ- tists and not the general public. opportunity and flexibility to come isms, many people have doubts about At Rutgers University, we have up with my own ideas and imple- these advancements. Rutgers Day, at which time the ment them in the classroom. I have I asked Bruce M. Chassy, a profes- university is open to the public and touched upon science misconceptions sor emeritus at the University of many activities are performed for and taught with hands-on experi- Illinois who runs a website (academ- kids and adults. Science clubs and ments how science positively affects

30 ASBMB TODAY JUNE/JULY 2015 have gotten to meet a scientist, something that otherwise probably would not have happened. Donate to nonprofits to support science outreach Donations to scientific nonprofits are often tax deductible, and this is perhaps the easiest way for us to contribute. As Donna Kridelbaugh noted in her article “The giving list: supporting science with annual donations” for ASBMB Today, we all can make a giving list to support science with annual donations and promote a phil- SHANNON ALBERS anthropic culture. There are plenty The author, Leonardo Valdivieso–Torres, talks to David Tribe (left), a professor at the Melbourne University, of nonprofits that promote science during the 2015 Biotechnology Literacy Project Boot Camp at the University of California, Davis, in June. At the three-day event, undergraduate students, graduate students and postdoctoral fellows learned more about and literacy for adults, put scientists in K practiced engaging the public in discussions about biotechnology, nutrition and agriculture. – 12 classrooms and perform hands- on activities in public places. These our everyday lives. I know it might started Bio-Tech in Focus, a website organizations often need money. sound like a lot of work, and it’s defi- that publishes, twice a month, a Finally, I know it is easy to get lost nitely not easy, but the smiles of those bulletin addressing biotechnology in the details of the everyday work of kids when they learn and enjoy the concerns. We need outreach activities a scientist – troubleshooting, writing, activity easily can make it seem like a like these that focus on vaccines and reading and even taking a little time hobby instead of a burden. global warming, for example, with to think and dream. However, we The University of Hawaii at support from experts in those fields. always should keep in mind the big Manoa offers another good example The benefits of doing formal picture and the great advances we all of formal science outreach. The science outreach far outweigh the have achieved as a community. Let’s GENE-ius Day Program exposes burdens. Scientists and science stu- share these goodies through science students in first grade through eighth dents who get involved gain teaching outreach. grade to hands-on biotechnology experience that can enhance their rep- experiments, organizes field trips, ertoire of skills. I personally have had Leonardo Valdivieso–Torres ([email protected]) and holds talks on the relationship to become more creative to engage is a Ph.D. candidate in biochemis- between science and the food we eat. kids and make sure I do not lose their try and molecular biology at GENE-ius leader Ania Wieczorek also focus. And to my satisfaction, 10 kids Robert Wood Johnson Medical School at Rutgers University.

Donate your time and money

Check out these resources: Connect with local venues: American Society for Biochemistry and Molecular Biol- Nature centers and gardens ogy (asbmb.org/Outreach) Museums Genetic Literacy Project (geneticliteracyproject.org) Science centers Academics Review (academicsreview.org) Park authorities Science Cafes (sciencecafes.org) Science and engineering fairs Community centers Find a program that’s right for you: Fitness centers Volunteer Match (volunteermatch.org) Science and engineering clubs All for Good (allforgood.org) Association for Science-Technology Centers (astc.org)

JUNE/JULY 2015 ASBMB TODAY 31 Something is fishy in the dean’s office! By Samarpita Sengupta

ark Schmitt is the dean of the and a hippo tang (think Dory from violet sterilizer, a protein skimmer, a College of Graduate Studies at Disney), a pair of clownfish (Nemo), sump filter, a bioreactor and special M Upstate Medical University in a coral beauty, a royal gramma and lights, has a calming effect when the the State University of New York. His a very shy Mandarin that is rarely stress of grant deadlines and paper passions in life include the endoribo- seen.” submissions begins to take its toll. nuclease RNase MRP and a 120-gal- Schmitt says: “There’s a lot of Schmitt has been an American So- lon saltwater reef fish tank containing science involved in maintaining the ciety for Biochemistry and Molecular a variety of fish and coral. whole reef tank, so, being a scientist, I Biology member for 21 years. A blog post by his institution de- find it to be very fascinating.” Samarpita Sengupta (samarpita. scribed the biochemistry and molecu- Schmitt feeds the fish three times [email protected]) lar biology professor’s tank as “home a week and says the tank, which is is a postdoctoral fellow in the to more than 30 kinds of live coral an ecosystem on its own, containing pharmacology and neuroscience and seven colorful fish – a purple tang fancy equipment such as an ultra- departments at the University of Texas-Southwestern Medical Center at Dallas.

WILLIAM MUELLER/UPSTATE MEDICAL UNIVERSITY

32 ASBMB TODAY JUNE/JULY 2015 EDUCATION Playing games to learn By Paul Sirajuddin

cute yet determined blue Science Foundation, to allow its team unlock more components of the im- monster hobbles across an alien, of scientists, game developers and mune system to use to combat enemy A planetlike surface toward a green engineers to bring the product to ma- bacteria and viruses. Knowing which haystack of pulsating rods, gobbling turity. Other developers have created components of the immune system them up with an audible and satisfac- games in which players fold proteins work best for each enemy scenario is tory “Mmmm.” With a jovial grin on and even build RNA chains. essential to completing each mission. his face, the monster pats his stomach Windows pop up on the screen with in glee, having finished his feast. Public engagement text explaining the science behind the You might think this is a scene cute characters that fight pathogens Each year, upwards of 350,000 from the newest Pixar animated in the body, teaching users how the children, students and curious partici- short. In fact, it’s the college-level, immune system works as the game pants attend the Science and Engi- science-themed video game Im- moves along. neering Festival in Washington, D.C., muneQuest, in which users direct the Players get upgrades based on how a multiday exhibition and celebration movements of a macrophage seeking well they understand the material and of science, technology, engineering out and eating up harmful bacteria answer questions correctly in a quiz- and mathematics, collectively known colonies infecting a host (1). like format. The playing and learning as STEM. Though this seems like a The Electronic Software Asso- are integrated seamlessly so that it great number of attendees, sustained ciation estimates that in 2014, 59 never feels like the science is being public interest in STEM has been dif- percent of Americans played video force fed, something that has been a ficult to garner. A constant challenge games on their smartphones, per- peril of past so-called edutainment for scientists is broadly communi- sonal computers or game consoles. As products. cating their ideas and engaging the technology and gadgets extend their public in a manner that enables them reach into nearly every aspect of so- to take a more active role in science. The collective power ciety, educators increasingly are using At the D.C. science festival in these new mediums to teach complex of gamers 2014, it was clear that scientists concepts. Multiplayer games harness the have to move beyond using static Syandus Inc., the maker of Im- power of pulling individuals together textbooks to engage the public, as muneQuest, is just one of several for a common cause. When news of evidenced by flashy projection screens developers that are aiming to take the Ebola outbreak in West Africa and interactive demos on tablets. As this opportunity to the next level and gripped the public this past sum- an attendee at this conference, I was partnering with scientists. In Im- mer, there was a real fear of a global struck by how the interactive games muneQuest, players take control of pandemic but also an urgency to about science were a hit. the immune system by directing an develop a vaccine to treat Ebola, one arsenal of colorful 3-D animations of of the deadliest diseases in recent macrophages and neutrophils, among No force-feeding times, for which no cure exists. A others, to fight off infections. It is a Using science-themed video games group of scientists from the Univer- strategy combat game akin to block- as an outreach medium is starting sity of Washington joined the fight buster videogames like Starcraft and to pay off. Many of these games are against Ebola with their collaborative Civilization. It even stars the voice ac- now pilot testing in high-school and massively multiplayer protein-folding tors in those high-profile videogames. college-level classrooms. puzzle game, Foldit (2). While the idea of such games may As important as it is to make an In Foldit, players bend, pull and have seemed far-fetched years ago, attractive and engaging game, devel- fold squiggly green lines that repre- there is now considerable support opers are careful not to overwhelm sent amino acids and assemble them for them. Syandus, for example, players with science all at once. Take into proteins in a 3-D space based has received several funding awards, ImmuneQuest as an example: As stu- on the rules of physics and molecular dents progress through the game, they including a grant from the National CONTINUED ON PAGE 34

JUNE/JULY 2015 ASBMB TODAY 33 EDUCATION

CONTINUED FROM PAGE 33 The real power in this game, cal researchers as co-authors of the charges, all while competing with one however, is what happens after play- papers. another to find the highest-scoring ers complete the challenges and put Given the success of these ex- protein structures. Though solving down their keyboards and mice. Find- amples, it’s clear that videogames 3-D structures of proteins histori- ings from the game can be extrapo- and science have a synergistic future cally has been done using powerful lated to a wet lab and tested in the ahead of them. Science outreach is computers and complex computer real world, which has the potential changing: It’s becoming digital and algorithms, the scientists found that to translate into new cures that never interactive. It may not be uncom- human players often were more re- would have been found otherwise or mon to see more classrooms use these sourceful and, in some cases, quicker would have taken years longer to find. products as teaching tools. Instead of at solving protein structures than Similar to Foldit is Stanford killing zombies late at night, the next computers. University and Carnegie Mellon’s generation of students might stay up This crowdsourcing of brain power RNA-building, browser-based game late killing virtual pathogens to give made headlines in 2011 when Foldit EteRNA (3). In that game, which them a leg up on their homework. gamers, in just three weeks, solved the is supported by a National Science Foundation grant, players build RNA REFERENCES structure of an enzyme that dictates 1. http://immunequest.com/ how HIV replicates, a puzzle that had sequences that self-assemble and fold into functional biological models. 2. https://fold.it/portal/ baffled scientists for more than a de- 3. http://eterna.cmu.edu/web/ cade. More recently, Foldit program- EteRNA’s puzzles have drawn tens of thousands of users. Results from mers released an Ebola challenge that Paul Sirajuddin (psiraju1@jhmi. tasked its 200,000 users worldwide EteRNA have been published in the edu) is a radiation oncology to discover protein conformations Proceedings of the National Academy postdoctoral fellow at The Johns that essentially can gum up the Ebola of Science, where the gamers were Hopkins School of Medicine. virus and halt it from propagating. acknowledged alongside the medi-

Science? There’s an app for that! and diameter), to detect the warning signs that a mole might be turning malignant. But now people can take Immune Defense the doctor with them to the beach in the form of an In each and every person, a war has been raging far app called Doctor Mole. A user can take a photo of his longer than any in the history of civilization: the war or her moles, and this app will analyze it using the clas- of the immune system. The game Immune Defense is sic ABCD signs that physicians use. It then rates each the brainchild of Melanie Stegman of Molecular Jig category on a scale and even gives the user photos of Games. It blends a classic tower-defense strategy with examples to educate him or her on what is normal and the dynamic world of immunology by teaching players abnormal. how to use neutrophils and macrophages to destroy bac- Website: doctormole.com teria, not unlike what is happening inside the players’ Platforms: iOS, Android bodies at all times. Stegman has said she aims to use the game to increase awareness and interest in science. The 3D Brain result is an entertaining and educational experience for This app puts the whole brain in the palm of your hand. students from middle school to college. Cold Spring Harbor Laboratory created this simple Website: molecularjig.com/immune-defense-game yet informative app for medical students, neuroscience Platforms: PC, iOS majors or anyone with an interest in the brain. Users can touch a smartphone or tablet to rotate, zoom and Doctor Mole see details and names of 28 structures of the brain. Summer is a time for having fun, relaxing and going Touching the different sections reveals more detailed to the beach. However, warnings are plentiful urg- information including functions, disorders, case studies ing people to apply ample sunscreen to avoid get- and links to recent research. ting melanoma, a skin cancer that originates in the Website: itunes.apple.com/us/app/3d-brain/ pigment-producing melanocytes on the skin in the form id331399332?mt=8 of moles. Doctors have devised a system, the ABCD Platforms: iOS, Android system (which stands for asymmetry, borders, color

34 ASBMB TODAY JUNE/JULY 2015 Empty bench syndrome Here’s to all the undergrad research mentors who said goodbye to great students and felt that little pang of sadness as they cleared the bench for a new researcher By P. H. Grey

n May, an undergrad who spent three years in our lab finished her I last experiment and made the last update in her lab notebook. It was a bittersweet day. Madi joined the lab the summer after her first year of college. Like most undergrads I work with, she was unfamiliar with the concepts and inexperienced with the skills of molecular research. In her first summer, Madi put in 30 hours a week at the bench learning how to pipette, pour agarose gels, perform cloning reactions, safely run the autoclave, P. H. GREY keep a proper notebook, troubleshoot When the bench is empty, a mentor should feel proud for giving an undergrad the tools and confidence to thrive in the research world. techniques and interpret results. She learned, practiced and refined core at the University of Florida, I think not just because of poster presenta- techniques that she would use for her it’s important to get to know my tions, fellowships or research awards. projects over the next three years. undergrads so that I can help them It’s also the little things, such as when Throughout her time in the lab, reach both their personal and profes- an undergrad finds the self-discipline Madi, a microbiology major and sional goals. It’s also important so I to master a difficult technique or says premed student, worked hard. She can direct them to specific opportuni- to me, “Of my two options for the optimized protein expression of sev- ties that will help them get the most next research step, I think I should eral clones, completed actin assays on out of their college experiences. choose No. 1 because …” or when an the confocal microscope and analyzed For example, I encouraged Madi undergrad analyzes a result and, be- the data using the statistical program- to apply to the Frost Scholarship fore I’ve even weighed in, realizes the ming language known as R. She Programme, which funds science, next question that should be asked. used her expertise to help train other technology, engineering and math What I want students to know is undergrads and always stepped up to students to pursue a master’s degree this: As an undergrad in the lab, the take on extra responsibility. at the University of Oxford. Because impact you make might be more than The Monday after she left, when I had taken the time to get to know the results and data you contribute. I glanced at the empty bench across Madi, I knew she was a perfect fit. The bigger the impact your research from me, I felt a pang of sadness. When she was accepted to Oxford mentor makes on you, well, the Training, advising and mentoring on a full scholarship, the entire lab bigger the impact you’re probably Madi hadn’t been my job as much as celebrated. making on her. it had been my privilege – as is often By the time any undergrad’s P. H. Grey ([email protected]) works the case. research experience comes to an end, as a molecular biologist and is As a full-time research scientist and I’ve been proud of his or her accom- co-creator of mentor in David Oppenheimer’s lab plishments many times over – and undergradinthelab.com

JUNE/JULY 2015 ASBMB TODAY 35 OPEN CHANNELS

Re: “Funding decisions: science, in the end, this is a stochas- $3 billion each day beyond its bud- tic (good or bad luck) approach. get. Someday, our exploding national the HHMI method,” – Eleftherios P. Diamandis, Mount debt, soon to reach $20 trillion, must President’s Message Sinai Hospital, University Health be curtailed by serious budgetary cuts by Steven McKnight, Network, University of Toronto (and/or massively increased taxes); when this happens, one can only May issue Re: “The reality that dare hope that scientific research funds In the March issue of ASBMB not speak its name,” will not be severely slashed. Today, Steve McKnight explained the Hollenbach described having had Howard Hughes Medical Institute essay by Andrew a small lab, trying to be an outstand- method for funding decisions and Hollenbach, April issue ing mentor and failing to acquire provided some explanations for its additional research funding after I completely agree with Andrew great success. But he did not mention having co-authored fewer than two Hollenbach about the fairness of that the task of the HHMI selection dozen papers. An even more impres- being able to obtain a research grant committee (i.e., to select and retain sive example came from my own these days. Only a fraction of applica- individuals who have the potential to lab: a senior postdoc who became a tions are now getting funded, and it make significant contributions to sci- research assistant and then tenure- depends on whom you know rather ence) is just about the easiest job on track assistant professor. In the third than the degree of creativity and ex- Earth. This committee could not go year of his five-year R01, he saw the citement of your hypothesis. Funding wrong since it is already dealing with writing on the wall and chose to leave now depends on buzz words, hype, a highly selected pool of overachievers academia to become a house-husband "study-section think," confirmation who are destined to succeed anyway. — caring for his two kids, brewing of previously published boring data, It is the same as asking somebody his own beer, volunteer-teaching sci- and fundability — rather than the to predict who is going to win a ence and music at local middle and possibility of taking a risk that might Wimbledon tennis tournament in five high schools. Now he’s sleeping better make an important breakthrough years. The answer is likely those who at night. He left academia with more contribution to advance a field of won the junior title the past five years than six dozen publications. – Daniel study. or the last year’s winner. McKnight W. Nebert, professor emeritus at the Study-section issues and discrep- also did not speculate as to whom University of Cincinnati College of ancies notwithstanding, another big from the list of the Nobel laureates Medicine and Cincinnati Children’s problem is the fact that the amount was going to win the prize anyway, Hospital of federal funding for basic research irrespective of HHMI support. I is dwindling compared with the suspect most of them. expanding number of aspiring young Clarification The job of picking future stars in principal investigators. Also, more Further analysis of the 2014 ASBMB science is not difficult, if you know National Institutes of Health money graduation survey revealed that four their accomplishments as indepen- is being moved from the pot of fund- schools may have reported incorrect dent juniors. The daunting task is ing R01 and R21 grants to that of numbers of American Indian or to select among 100,000 applicants funding large centers, consortiums Alaskan Native graduates. As ASBMB (old and new) those 5 percent to 10 and infrastructure, which leaves out Today has no means of independently percent who have the so-called “best” the PI who wishes to maintain a small validating their self-reported answers, projects. Most winners and losers are lab and do hands-on, wet-bench it is possible that fewer American separated by very few points. I wish research combined with proper men- Indian or Alaskan Native students I had a solution, and I speculate that toring. Another very serious problem received biochemistry and/or the HHMI selection committee does cannot be ignored: The federal gov- molecular biology degrees in 2014 not have one either. As we say in ernment currently spends about than was reported. Award lectures online If you missed one of the 2015 award lectures in Boston,

visit www.asbmb.org/asbmbtoday to catch up.

36 ASBMB TODAY JUNE/JULY 2015 ANNUAL REVIEWS SPARK A CONNECTION

Annual Review of Biochemistry biochem.annualreviews.org • Volume 84 • July 2015

Editor: Roger D. Kornberg, Stanford University School of Medicine

The Annual Review of Biochemistry, in publication since 1932, sets the standard for review articles in biological chemistry and molecular biology. Since its inception, this journal has served as an indispensable resource for both practicing biochemists and students of biochemistry.

TABLE OF CONTENTS: • It Seems Like Only Yesterday, Charles C. Richardson • Natural Photoreceptors as a Source of Fluorescent Proteins, • Veritas per structuram, Stephen C. Harrison Biosensors, and Optogenetic Tools, Daria M. Shcherbakova, Anton A. Shemetov, Andrii A. Kaberniuk, Vladislav V. Verkhusha • Nuclear Organization, Yosef Gruenbaum • Structure, Dynamics, Assembly, and Evolution of Protein • The Balbiani Ring Story: Synthesis, Assembly, Processing, Complexes, Joseph A. Marsh, Sarah A. Teichmann and Transport of Specific Messenger RNA—Protein Complexes, Petra Björk, Lars Wieslander • Mechanisms of Methicillin Resistance in Staphylococcus aureus, Sharon J. Peacock, Gavin K. Paterson • Functions of Ribosomal Proteins in Assembly of Eukaryotic Ribosomes In Vivo, Jesús de la Cruz, Katrin Karbstein, • Structural Biology of Bacterial Type IV Secretion Systems, John L. Woolford Jr. Vidya Chandran Darbari, Gabriel Waksman • Lamins: Nuclear Intermediate Filament Proteins with Fundamental • ATP Synthase, Wolfgang Junge, Nathan Nelson Functions in Nuclear Mechanics and Genome Regulation, • Structure and Energy Transfer in Photosystems of Oxygenic Yosef Gruenbaum, Roland Foisner Photosynthesis, Nathan Nelson, Wolfgang Junge • Regulation of Alternative Splicing Through Coupling with • Gating Mechanisms of Voltage-Gated Proton Channels, Transcription and Chromatin Structure, Shiran Naftelberg, Yasushi Okamura, Yuichiro Fujiwara, Souhei Sakata Ignacio E. Schor, Gil Ast, Alberto R. Kornblihtt • Mechanisms of ATM Activation, Tanya T. Paull • DNA Triplet Repeat Expansion and Mismatch Repair, Ravi R. Iyer, • A Structural Perspective on the Regulation of the Epidermal Growth Anna Pluciennik, Marek Napierala, Robert D. Wells Factor Receptor, Erika Kovacs, Julie Anne Zorn, Yongjian Huang, • Nuclear ADP-Ribosylation and Its Role in Chromatin Plasticity, Tiago Barros, John Kuriyan Cell Differentiation, and Epigenetics, Michael O. Hottiger • Chemical Approaches to Discovery and Study of Sources and • Application of the Protein Semisynthesis Strategy to the Generation Targets of Hydrogen Peroxide Redox Signaling Through NADPH of Modified Chromatin,Matthew Holt, Tom Muir Oxidase Proteins, Thomas F. Brewer, Francisco J. Garcia, • Mechanisms and Regulation of Alternative Pre-mRNA Splicing, Carl S. Onak, Kate S. Carroll, Christopher J. Chang Yeon Lee, Donald C. Rio • Form Follows Function: The Importance of Endoplasmic Reticulum • The Clothes Make the mRNA: Past and Present Trends Shape, L.M. Westrate, J.E. Lee, W.A. Prinz, G.K. Voeltz in mRNP Fashion, Guramrit Singh, Gabriel Pratt, Gene W. Yeo, • Protein Export into Malaria Parasite—Infected Erythrocytes: Melissa J. Moore Mechanisms and Functional Consequences, Natalie J. Spillman, • Biochemical Properties and Biological Functions of FET Proteins, Josh R. Beck, Daniel E. Goldberg Jacob C. Schwartz, Thomas R. Cech, Roy R. Parker • The Twin-Arginine Protein Translocation Pathway, Ben C. Berks • Termination of Transcription of Short Noncoding RNAs by RNA • Transport of Sugars, Li-Qing Chen, Lily S. Cheung, Liang Feng, Polymerase II, Karen M. Arndt, Daniel Reines Widmar Tanner, Wolf B. Frommer • PIWI-Interacting RNA: Its Biogenesis and Functions, • A Molecular Description of Cellulose Biosynthesis, Yuka W. Iwasaki, Mikiko C. Siomi, Haruhiko Siomi Joshua T. McNamara, Jacob L.W. Morgan, Jochen Zimmer • The Biology of Proteostasis in Aging and Disease, • Cellulose Degradation by Polysaccharide Monooxygenases, Johnathan Labbadia, Richard I. Morimoto William T. Beeson, Van V. Vu, Elise A. Span, Christopher M. Phillips, • Magic Angle Spinning NMR of Proteins: High-Frequency Dynamic Michael A. Marletta Nuclear Polarization and 1H Detection, Yongchao Su, Loren Andreas, • Physiology, Biomechanics, and Biomimetics Robert G. Griffin of Hagfish Slime,Douglas S. Fudge, • Cryogenic Electron Microscopy and Single-Particle Analysis, Sarah Schorno, Shannon Ferraro Dominika Elmlund, Hans Elmlund

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