I t ’ s N o t T oo Late to Jo in U s in a N a h e i m

March 2010

The Many Roles of the Na,K-ATPase

American Society for Biochemistry and Molecular Biology September 30 – October 4, 2010 Registration and Abstract Submission Deadline: August 1, 2010 Transcriptional Regulation by Chromatin and RNA Polymerase II Granlibakken Resort, Tahoe City, CA

Meeting Organizer: Ali Shilatifard, Stowers Institute for Medical Research Keynote Speaker: Robert E. Kingston, Massachusetts General Hospital Harvard Medical School

Plenary Speakers: Paul Kaufman, University of Massachusetts Yang Shi, Harvard University Medical School Karen Adelman, National Institute of Brian Strahl, University of North Carolina at Environmental Health Sciences Tom Kerppola, University of Michigan School Chapel Hill of Medicine Mark Bedford, MD Anderson Cancer Center Ali Shilatifard, Stowers Institute for Medical Tony Kouzarides, Gurdon Institute Research Shelley Berger, University of Pennsylvania W. Lee Kraus, Cornell University Ramin Shiekhattar, The Wistar Institute Joan Conoway, Stowers Institute for Medical Nevan Krogan, University of California, Research San Francisco David Stillman, University of Utah School of Medicine Jacques Cote, Laval University Cancer Robb Krumlauf, Stowers Institute for Medical Research Center Research Raymond Trievel, University of Michigan Medical School Joaquin Espinosa, HHMI / University of Mike Levine, University of California, Berkeley Colorado at Boulder Dylan Taatjes, University of Colorado Anders Naar, Harvard Medical School Jean-Marc Egly, Inst Genet et Biol Mol et Michael Washburn, Stowers Institute for Cell Danesh Moazed, Harvard University Medical Research

Peggy Farnham, University of California, Barbara Myer, University of California, Johnathan Whetstine, MGH Cancer Center Davis Berkeley and Harvard Medical School

Grace Gill, Tufts University Frank Pugh, University of Pennsylvania Jerry Workman, Stowers Institute for Medical Research Steven Hanes, Wadsworth Center Joe Reese, University of Pennsylvania Julia Zeitlinger, Stowers Institute for Medical Research

www.asbmb.org/TranscriptionalRegulation2010 contents March 2010 On the cover: From neurons to sperm and muscle, Jerry Lingrel society news has characterized Na,K- 2 President’s Message ATPase function. 18 5 Washington Update

6 News from the Hill

10 ASBMB Creates the Stadtman Award Two new 11 ASBMB Introduces publications the DeLano Award from FASEB. 5 12 Member Spotlight

14 Retrospective: Paul C. Zamecnik (1912 – 2009)

16 JBC Thematic Series Breaks Down Proteases

2010 annual meeting 17 Professional Development at the Annual Meeting

feature stories 18 Jerry Lingrel: Pumping Out Great Science

in every issue 22 Education ASBMB introduces two new meeting 24 Minority Affairs awards. 10, 11 26 Meetings

28 BioBits

30 Career Insights asbmb today online Have you seen the new ASBMB Today Web 32 Lipid News site? It has features that allow you to comment on articles, share content on Facebook, Twitter and other social networking sites and access podcasts, videos and more. Check it out at www.asbmb.org/asbmbtoday

March 2010 ASBMB Today 1 president’smessage A monthly publication of The American Society for Biochemistry and Molecular Biology Plus the Secret Officers Gregory A. Petsko President Suzanne R. Pfeffer President-Elect Handshake Mark A. Lemmon Secretary Merle S. Olson Treasurer By Gregory A. Petsko Council Members Dafna Bar-Sagi Ruma V. Banerjee Benjamin F. Cravatt Joan A. Steitz apprentice |ah-pren-tiss|, noun Thomas E. Smith Ann M. Stock a person who is learning a trade from a skilled employer, James A. Wells Adrian Whitty having agreed to work for a fixed period at low wages Ex-Officio Members Ellis Bell postdoc |pohst-dock|, noun Chair, Education and Professional Development Committee a person doing the sam­e thing, only for lower wages Joan W. Conaway Chair, Meetings Committee grad student |gr-add stoo-dent|, noun John D. Scott Chair, Membership Committee a person doing the same thing for almost no wages at all Craig E. Cameron Chair, Minority Affairs Committee Laurie S. Kaguni hen I was a graduate student at Oxford University, 40 years ago, I learned 2010 Annual Meeting Program Coordinator Whow to crystallize proteins, collect X-ray diffraction data, program comput- William C. Merrick Chair, Public Affairs Advisory Committee ers and solve protein crystal structures. When I was a postdoctoral fellow at the Toni M. Antalis Chair, Publications Committee Institut de Biologie Physico-Chimique in Paris, I learned how to stabilize proteins in Herbert Tabor solution at subzero temperatures and perform kinetic analysis of enzyme reactions Editor, JBC Ralph A. Bradshaw under conditions that could trap productive intermediates. A. L. Burlingame Then, I went to Wayne State University School of Medicine in Detroit as an Co-editors, MCP Edward A. Dennis instructor in the biochemistry department— my first independent position. I Joseph L. Witztum taught courses, wrote grant applications, prepared budgets, wrote papers, sat Co-editors, JLR on various committees and advised graduate and medical students. Once I had ASBMB Today Editorial Advisory Board Alex Toker more than two students working with me, I hardly ever collected my own data, Chair set up crystallizations or carried out kinetic analyses with my own hands. Note Greg P. Bertenshaw Craig E. Cameron A. Stephen Dahms Irwin Fridovich the monumental disconnect between what I was trained to do and what I actu- Jonathan Gitlin Richard W. Hanson ally had to do to run a lab. Elizabeth A. Komives Bettie Sue Masters Luke A. O’Neill Duanqing Pei I’ve remarked before that, once I became a practicing scientist, I realized I had Carol C. Shoulders Robert D. Wells taken all of the wrong courses as a student. Although I started out as a classical ASBMB Today literature major, because I was interested in science, I took math, physics, chem- Nicole Kresge Editor [email protected] istry, biology, biochemistry, biophysics and so on. I should have taken business Nick Zagorski Science Writer administration, elocution, basic accounting, creative writing, speed-reading, [email protected] politics, sociology and abnormal psychology. Now that I’m chair of a department, I Nancy J. Rodnan Director of Publications [email protected] really wish I’d taken abnormal psychology. Barbara Gordon Executive Director Getting one’s doctoral degree is a watershed moment in the life of a scientist. It [email protected] indicates that a certain level of training has been successfully attained and that one Magazine design & production: Amy Phifer is qualified to engage the subject at a much more advanced level. In the biochem- For information on advertising, contact istry department at Brandeis University, we have a nice custom: At the mini- Capitol Media Solutions at 800-517-0610 or [email protected] commencement when our graduate students receive their doctoral degrees, after they have come up to the platform and have been handed the degree, they do not return to their seats in the auditorium; rather, they are seated up on the platform with the attending faculty members, symbolically welcoming them as colleagues www.asbmb.org in the profession. It always has reminded me of the ceremony at which a medieval craftsman was admitted into a guild. The guild system began more than 1,000 years ago. It had two functions: to protect the exclusive right of only certain people to make a living in a skilled

2 ASBMB Today March 2010 president’smessage

trade and to pass on those skills to select The problem is that some time during members of the next generation, thereby 1. the past half-century, a disconnect devel- ensuring the survival of the guild. oped between what our apprentices and A guild was made up of experts in their journeymen are learning and the set of craft, so-called master craftsmen. Before skills they actually need to succeed when a new employee could rise to the level of they set out on their own. This disconnect mastery, he— they were always men in the 2. occurred because the old model of the Middle Ages— had to go through a two- individual scientist working with perhaps tier schooling period during which he first one apprentice and a technical assistant, was called an apprentice. After this period, doing much of the work with his or her he could rise to the level of journeyman. 3. own hands, ceased to be valid in academia Apprentices, who worked exclusively under (though it continues, to some extent, in a particular master, typically would not learn industry). We continued to train our stu- more than the most basic techniques until dents in how to carry out good experiments they were trusted by their peers to keep the and interpret data, but we often neglect an guild’s or company’s secrets— which, in equally important skill set: namely, the ability some guilds, included a secret handshake, 4. to write well, to manage people effectively thereby enabling members to identify each and to formulate problems in a way that other. makes them fundable. After being employed by a master for Some mentors, to be sure, make it their several years, and after producing a quali- 5. business to give their students experience fying piece of work, the apprentice was and guidance in these things, and some promoted to the rank of journeyman and graduate programs even include formal was given documents (letters from his mas- instruction in some of them, but the basic ter and/or the guild itself) that certified him attitude often seems to be that one is sup- as a journeyman and entitled him to travel posed to acquire these abilities by osmosis. to other towns and countries to learn more of the art. That works for some people, but not for all. Journeymen were able to work for other masters, unlike One difficulty is that students and postdocs usually don’t apprentices, and generally were paid by the day. After take advantage of opportunities for such instruction when several years of such experience, a journeyman could be they are offered; this is particularly true of postdocs, who received as a master craftsman (although, in some guilds, frequently have no organization to arrange formal tutoring in this step could be made straight from apprenticeship). practical matters, and are so absorbed in their work and the This typically would require the approval of all masters of a business of finding jobs that they rank that sort of help fairly guild and the production of a so-called masterpiece, which low on their priority lists. would illustrate the abilities of the aspiring master crafts- My Brandeis colleague Dagmar Ringe hit upon one way man. of solving this problem a few years ago, and her solution Sound familiar? The apprentice stage is a close analogy is worth general consideration. Every biochemistry depart- to the graduate student period of an aspiring scientist. The ment that receives funding for students from the National qualifying piece of work allowing passage into journeyman Institutes of Health is required to offer— and the students (postdoctoral) status would be, of course, the doctoral the- are required to take— a course in the responsible conduct sis. And, aren’t today’s postdocs almost perfect examples of research. This course, which we refer to around here of journeymen? They frequently spend several years with as “The Ethics Course,” covers such topics as conflict of one master and then several more with another, hoping to interest, fraud, disclosure and so forth. Dagmar added, produce a masterpiece: a high-profile paper (or papers) that at the end of the course, a couple of weeks of practical establishes him or her as a rising star and earns him or her workshops on how to give a talk, how to write a paper, how the modern equivalent of master craftsman status— a good to write a grant, how to manage a group, how to teach job that, ideally, will allow him or her to work on his or her a course and so forth. And, the beauty of this idea is not own ideas. only that there is a captive audience of exactly those who

March 2010 ASBMB Today 3 firstpresident’ssecond messagecontinued continued need this information the most; it’s also that new federal superb way for young people to learn the tools of the regulations are coming that will require all students and trade. I hope teaching those tools— including the practi- postdocs receiving federal funding of any kind— train- cal, maybe even mundane skills needed to function as ing grants, support from individual research grants and a practicing scientist in this highly competitive environ- fellowships, regardless of the agency (National Science ment— become routine in graduate student and post- Foundation, NIH, U.S. Department of Energy, etc.)— to doctoral training in biochemistry at every institution. take the ethics course. This makes that course the per- I sure wish I had received instruction like that, instead fect vehicle for ensuring that all of our trainees receive the of being left to stumble my way along by trial and kind of practical instruction that they will need in almost error— mostly error. Because one thing I am completely any scientific career they undertake. convinced of is that effective communication, people- It shouldn’t be hard to find senior scientists in any management skills and so on, are crafts, not arts, and department who are very good at one of these things and can be learned, like any other crafts. Different people can teach the skills effectively, and a couple of weeks of have different levels of talent for these things, of course, instruction of, say, three to six hours a week should be but the basics are accessible to anyone. As I said, I know enough to impart basic tools, although more elaborate that many places already do something of the kind, at programs certainly could be devised, involving practice least for some topics, but it ought to be as much a part of talks and writing with critical feedback, for example. The any advanced education as the qualifying exam, thesis or emphasis should be less on how it is done than the fact ethics course. that it is done, for everyone. And, if anyone knows what the secret handshake is, You see, we are a guild, actually, and the apprentice/ I would appreciate them telling me, because I never was journeyman system, when properly carried out, is still a taught that either.

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UANhorizhalfAD.indd 1 12/17/2009 11:36:38 AM washington update FASEB Two New Publications from FASEB BY CARRIE D. WOLINETZ

he Federation of American Societ- articles that highlight cutting-edge Ties for Experimental Biology is scientific research on the brink of pleased to announce the release of clinical application and describe the the publication “Magic Bullets and pathways of discovery leading to Monoclonals: An Antibody Tale,” the the current developments. The first latest article in its Breakthroughs in article in the series, “How Biomedi- Bioscience series. The series is a cal Research Provides Fertility Hope collection of illustrated articles that to Cancer Survivors,” discusses the explain recent developments in basic latest findings in oncofertility— the biomedical research and how they are preservation of a woman’s fertility important to society. after cancer treatment— and outlines The antibody article describes the some of the historic scientific achieve- century of fundamental immunology ments in fertility treatment, from in research that led to today’s cutting- vitro fertilization to cryopreservation. edge monoclonal antibody therapies Horizons in Bioscience is intended used to treat millions of patients for several types of to supplement FASEB’s existing Breakthroughs in Bio- cancer, autoimmune and inflammatory disorders and science series. Whereas Breakthroughs in Bioscience infectious disease. After the late 19th-century discov- examines treatments currently in use by millions of ery that mysterious substances in the blood could patients and tells the stories of the science that under- be exploited to provide protection against disease lies those clinical advancements, Horizons in Biosci- through immunization, scientists spent decades piecing ence provides the opportunity to explore exciting areas together the details of antibody structure and function. of science in the very early stages of clinical research All over the world, researchers made breakthrough find- and use. ings in immunology, racing to discover how antibodies developed the exquisite specificity that allows them Carrie D. Wolinetz ([email protected]) is director of to defend the body against a host of diseases. From scientific affairs and public relations for the Office of Public guinea pigs to papaya enzymes to Darwin’s theory of Affairs at FASEB. natural selection, the quest to uncover the secrets of antibodies led down some extraordinary avenues of science. In a surprising twist, it was a failed experi- For more information: ment using myeloma tumor cells and the serendipitous Publication Links: development of cell fusion that ultimately resulted in the • Magic Bullets and Monoclonals: An Antibody Tale: system used to produce monoclonal antibodies—very http://bit.ly/97fLfy pure antibodies that bind to singular, specific targets. Soon, researchers realized that monoclonal antibodies • How Biomedical Research Provides Fertility Hope to opened up new pathways to study and attack specific Cancer Survivors: http://bit.ly/cUyTuM diseases, and there are now more than 20 monoclonal Hard copies may also be requested by contacting the antibody-based drugs on the market, including several FASEB Office of Public Affairs at (301) 634-7650. blockbusters. FASEB welcomes topic idea contributions for both Horizons in Bioscience series. Please send suggestions, with brief descriptions, FASEB also has launched a new series, called Horizons to [email protected]. in Bioscience, which provides educational, one-page

March 2010 ASBMB Today 5 news from the hill President Proposes Decent Budgets for Science Agencies BY PETER FARNHAM

he White House released its 2011 federal budget after his appointment this past Tproposal Feb. 1, and, despite fears of the possible fall. They are: impact of a previously announced freeze on domestic • applying genomics and other discretionary spending, science funding was a clear high-throughput technologies; winner overall, with most research agencies receiving • translating basic science increases. Although most administration-proposed bud- discoveries into new and better gets are modified during congressional consideration, this treatments and diagnostics; budget gets science funding off to a good start. • using science to enable health care-reform; The Numbers • global health and President Obama’s budget for 2011 comes in at $3.8 tril- • reinvigorating and empowering lion, with a $1.2 trillion deficit. This is the largest budget, the biomedical research and the largest deficit, in history. Due largely to growing community. public and congressional concern over the size of the The NIH also will continue deficit, the administration is proposing a three-year freeze to award and oversee the $10.4 billion provided in the in nonsecurity discretionary funding (that is, discretionary American Recovery and Reinvestment Act. In addition, the funding outside of defense, homeland security, veterans NIH Common Fund will invest $562 million, an increase of affairs and international affairs), with funding thereafter $18 million over 2010, to support cross-cutting, trans-NIH increasing roughly with inflation. Over the next 10 years, programs that require participation by at least two NIH the policy is expected to save $250 billion. institutes or centers or that would otherwise benefit from However, this freeze affects only a very small portion strategic planning and coordination. of the federal budget, and it is not an “across-the-board” Although the American Society for Biochemistry and freeze; most science funding, for example, is slated to Molecular Biology would like to see a larger proposed increase. In addition, all the programs that are frozen at increase for NIH, Federation of American Societies for current levels have champions who will be working hard Experimental Biology President Mark Lively noted in a to keep them growing. statement that the president’s proposal for NIH was the The budget calls for $66 billion in nondefense research largest proposed increase in eight years, even though it and development, an increase of $3.7 billion or 5.9 per- only allows NIH to keep up with inflation and little else. cent overall more than 2010. “The president understands It is widely believed that the NIH received this increase that, more than ever before, science holds the key to the due to strenuous internal lobbying efforts by Collins, with prosperity of our nation, the security of our people, the the support of U.S. Department of Health and Human health of our planet and the richness of our lives,” said Services Secretary Kathleen Sebelius. John P. Holdren, adviser to the president for science and Of course, the overriding problem of “the cliff” technology and director of the White House office of sci- remains— that is, what happens when the $10 billion ence and technology policy. in extra funding NIH received under the ARRA is spent. Specific agencies fared well, for the most part. This is slated to occur by the end of 2010, a scant nine The National Institutes of Health received $32.1 months away. Thousands of researchers who applied for billion under the budget proposal, an increase of $1.0 grants under this special program are expected to resub- billion or 3.2 percent more than the 2010-enacted level. mit the same grants through NIH’s usual funding mecha- Investments will focus on five strategic priorities, first nisms. Unless changes are made to greatly increase the described publicly by NIH Director Francis Collins shortly NIH budget in Congress this spring, we are likely to see

6 ASBMB Today March 2010 news from the hill

dramatically reduced success rates. a 6.9 percent increase over the 2010 enacted level, sup- For the National Science Foundation, the admin- ports improvements in facilities and research in areas like istration proposes an increase of almost $500 million, health information technology and cybersecurity. to $7.4 billion in 2011, or 8.0 percent more than the Overall, the administration proposal for NSF, the DOE 2010-enacted level. The budget expands NSF’s efforts in Office of Science and NIST would continue the policy climate and energy research and education, networking of doubling their budgets as mandated by the “America and information technology research and environmental COMPETES Act,” signed into law by President Bush in and economic sustainability. The 2011 budget also pro- 2006. The budget proposes completing the doubling vides funding to triple the number of new NSF graduate funding of these agencies by 2017. research fellowships to 3,000 by 2013. (ASBMB was For other science funding agencies, the budget pro- invited to provide written and oral congressional testi- vides: mony on the NSF budget. You can see excerpts of the • $11 billion to the research and development submitted testimony in the accompanying sidebar.) portfolio of the National Aeronautics and Space The administration has proposed that the Administration— an increase of $1.7 billion, or 18.3 percent, more than 2010; U.S. Department of Energy’s Office of Science receive $5.1 billion in 2011, or 4.6 percent more than • about $1 billion for research and development at the National Oceanic and Atmospheric the 2010-enacted level. The budget would fund more Administration and $2.6 billion— an increase of research on climate science, continue U.S. participa- $439 million, or 21 percent— to the multi-agency U.S. tion in international science and energy experiments and Global Change Research Program; expand federal support for energy frontier research cen- • $1.2 billion (up 1.5 percent) for Department of ters, intended to explore emerging opportunities in new Veterans Affairs research and development; and materials and basic research for energy needs. • $429 million (up 63 percent) for the National Institute The U.S. Department of Commerce’s National of Food and Agriculture’s key competitive research Institute of Standards and Technology invests in program, the Agriculture Food and Research Initiative. technological innovation through research, advanced measurement and standards development. The 2011 Peter Farnham ([email protected]) is director of public budget of $709 million for NIST’s intramural laboratories, affairs at ASBMB.

March 2010 ASBMB Today 7 news from the hill continued

ASBMB Congressional several programs we believe need additional support... Testimony on NSF “…we are pleased that the BIO Directorate goes up almost as much as the agency overall, because certain programs within The American Society for Biochemistry and Molecular Biology BIO are even more underfunded than the agency as a whole. was invited to provide a witness to testify on the administration’s “The chemistry division of the Mathematics & Physical 2011 budget proposal for the National Science Foundation before Sciences Directorate fares somewhat less well, with the presi- the House Appropriations Subcommittee on Commerce, Justice dent proposing less than a 6 percent increase there. We hope and Science earlier this month. ASBMB had arranged for Presi- Congress can make sure that this division gets a bit more money dent Gregory Petsko to testify for the society. While the hearing when the agency budget is finalized. was postponed due to the severe snowstorms that blanketed “…the two areas where we consider it vital that adjustments Washington, D.C., in early February, the testimony was submit- be made are in education and human resources and major ted for inclusion in the hearing record. Here are excerpts. The full research instrumentation. version is available on the ASBMB Web site. “The president is proposing only a 2.2 percent increase for President Petsko: “I am honored to be here to express our education and human resources in 2011. I don’t need to go strong support for the president’s request for the National Sci- into the many reasons why science education is so important; ence Foundation for FY 2011. Because, in the overall budget, so many agencies and programs have received smaller increases these have been amply detailed in reports going back at least than NSF’s— or none at all— we are encouraged that the to the 1980s and “A Nation at Risk;” they have been most lately administration continues to demonstrate that it understands described in “Rising Above the Gathering Storm.” It is sad that how important science is as an underpinning for this country’s the problems so eloquently described in “A Nation at Risk” are continued economic growth and prosperity. Nevertheless, we still with us in large measure today. It is our hope that we, as a hope the Congress will view the president’s request as a floor, not nation, can actually begin to provide a level of funding for science as a ceiling, when considering funding levels for the agency in the education that does justice to the eloquent titles of these reports. coming months. Speaking personally, I love doing research, but training the next “ASBMB considers NSF to be one of the most underfunded generation of scientists is the most important thing I do. agencies in the Federal government…. “A second area where we have concern is the flat fund- “We are, of course, very appreciative that the president has ing for the major research instrumentation program. Funding proposed an almost 8 percent increase, almost $500 million, for advanced instrumentation in most universities is in serious bringing the NSF budget to $7.424 billion. However, in a perfect trouble, as agencies struggle to maintain funding for research world, we would like to see the budget increased to $7.68 billion, programs and cut back in other areas that are, unfortunately, to conform to the recommendation of the Federation of American exceptionally vital to a robust research enterprise. We hope Con- Societies for Experimental Biology. This would allow funding for gress can address this problem as well.”

of information related to the genetics of the model plant TAIRing at Research Arabidopsis thaliana. At www.arabidopsis.org, TAIR users BY KYLE M. BROWN can findArabidopsis genome information ranging from the very basic to the very applied, said Eva Huala, director and olecular biologists around the world have come to principal investigator of TAIR. Mrely on actively curated genome databases of model Like a Web-based library, TAIR’s unique and integrated organisms. But the National Science Foundation has set of resources requires an active curatorial effort. The decided to end its support for The Arabidopsis Informa- database and its 20 staff members have relied upon funding tion Resource, known as TAIR, and Arabidopsis and plant provided by the NSF for more than 10 years. biochemists risk losing a vital resource. If the NSF’s decision The genomic resources of TAIR have helped unlock the sets a precedent, Wormbase, Flybase and other databases research potential of Arabidopsis for an entire community may be similarly at risk. of researchers. TAIR has about 40,000 unique users each month from the Americas, Europe and Asia, and the aver- Plantbase age number of users each month has grown steadily since “TAIR is where you go for plant genome science,” said TAIR’s founding. Rebekah Rogers, a Harvard doctoral candidate and former But those who utilize the database often are interested plant molecular biologist. in more than just Arabidopsis. “It’s what everyone in plant Like many similar databases, TAIR provides a host biology uses, even in crop science,” Rogers said.

8 ASBMB Today March 2010 news from the hill continued

A Community Shrinks duce staggering amounts of raw data, genome databases Having awarded TAIR two, five-year grants, the NSF in May integrate sequence information with gene descriptions and 2009 declined to fully renew TAIR’s funding. Instead, the relevant publications. Some databases also are repositories NSF has granted TAIR an additional four years of steeply for unpublished data and minor comments that would not decreasing funding and encouraged the database to seek otherwise be available. funding from other sources. By 2011, TAIR’s NSF funding Without genome databases, “that kind of information will cease. would be lost,” Rogers said. The potential collapse of TAIR’s funding threatens the field of plant genomics. The Future of Databases “The first people to go will be the computational biolo- Like other National Institutes of Health-funded projects, gists,” Huala said. As these researchers rely upon publically many genomics databases are supported by grants that accessible data, they are unlikely to pursue plant research must be renewed every several years. While the NIH contin- if the information is not readily available. If computational ues to support several databases, the grants for two major biologists leave plant genomics, plant biology may fall databases, Flybase and Saccharomyces Genome Data- behind animal research, Huala said. base, are up for renewal in 2011. Other biologists also may be driven away from plant As for TAIR, Huala has discussed the situation with offi- research. Because it provides graphical, easy-to-use inter- cials at the NIH in hopes that they might fund the database. faces, TAIR gives researchers access to genome-based Although conversations are ongoing, the NIH seems “reluc- data without requiring them to write computer programs, tant to take on another model,” Huala said. Rogers said. For now, TAIR is exploring other funding sources, includ- ing corporate sponsorships. Huala said she believes requir- Innovation vs. Infrastructure ing users or institutions to purchase subscriptions may drive Continuing to fund research infrastructure often runs coun- away many academic researchers. ter to the NSF’s focus on funding innovative research. When a resource or program like TAIR ceases to be innovative, Kyle M. Brown ([email protected]) is an ASBMB science the NSF would like to use its limited budget in other places, policy fellow. Huala said. Indeed, TAIR may have fallen victim to an emphasis on new inno- Highlights from the Blotter vations in sequencing technology. The American Society for Biochemistry and Molecular Biology Policy Blotter posts regular “With the flood of genomic news and commentary about current science policy issues. Below are some recent high- data, it may not be the best expen- lights. You can read them and other posts at http://asbmbpolicy.asbmb.org. diture to put so many resources A Strong Science Budget, but NIH Heading for a Cliff (http://wp.me/pFLHF-3j) into a few species,” said Scott Roy, In his annual budget request to Congress, President Obama recommended strong a postdoctoral fellow at Stanford funding increases for many scientific agencies that support the life sciences. University. A computational biolo- NIH Needs $37 Billion in 2011 (http://wp.me/pFLHF-3g) gist, Roy said model organisms On Jan. 28, the Federation of American Societies for Experimental Biology and its may begin to occupy a smaller member societies, including ASBMB, recommended the National Institutes of Health percentage of genome data that budget be increased to $37 billion during 2011. technological advances have made Collins: Reinvigorate the Research Community (http://wp.me/pFLHF-2W) inexpensive to produce. However, Francis Collins, director of the National Institutes of Health, has given several interviews the direction of the field is still and authored a high-profile “policy forum” piece in the journal Science. In each case, uncertain, Roy said. he continued to encourage robust support for the NIH that he says will bring about But, although financial resources great new societal benefits. may limit their numbers, genomic (http://wp.me/pFLHF-31) databases have “a tremendous What Makes DARPA So Special? utility to inform closely related On Jan. 7, at a meeting of the President’s Council of Advisors on Science and Technology, officials from the Defense Advanced Research Project Agency presented genomes,” Huala said. what they believed were the characteristics of this defense-oriented research agency Additionally, though new that have allowed it to innovate and succeed over its decades-long history. sequencing technology can pro-

March 2010 ASBMB Today 9 asbmbnews ASBMB Creates the Stadtman Award BY NICK ZAGORSKI

rom the moment they first a former director of Merck Fset foot on the National Insti- (P. Roy Vagelos), two Nobel tutes of Health campus in 1950 laureates (Michael S. Brown as a young research couple, Earl and Stanley B. Prusiner) and and Thressa Stadtman set forth countless other scientific on a six decade journey of out- luminaries— who owe their standing biochemical research success to taking in Earl and and discovery. Thressa’s unique approach to Their efforts helped elucidate training, known simply as “The the role of coenzyme A in fatty Stadtman Way.” acid metabolism, provide an So, in honor of this first understanding of reversible inter- family of biochemistry (and in convertible enzyme cascades memory of Earl, who passed in cellular regulation and cell away on Jan. 7, 2008, at signaling via a detailed study of the age of 88), the American The new ASBMB award for “great basic science” honors glutamine synthesis, uncover the the accomplishments of Earl and Thressa Stadtman. Society for Biochemistry and biochemical roles of free radicals Molecular Biology will begin and reactive oxygen species and provide mechanistic presenting the Earl and Thressa Stadtman Award at the insights into vitamin B12 biochemistry and the role of 2011 annual meeting in Washington, D.C. selenoproteins— a body of work that established them This award, which honors outstanding achievement as one of the greatest scientific tandems in history. in basic research in the fields encompassed by the Of all their great achievements at the bench, however, ASBMB, was established by the Stadtmans’ friends and perhaps one of the strongest contributions the Stadt- colleagues as a way to give back some of their generous mans left to the science community is the body of more spirit and preserve their incredible legacies as scientists than 100 trainees they mentored— a group that includes and mentors. First announced during the Stadtman Symposium held in April in Bethesda, the award now has been final- The Award ized, and nominations for the inaugural recipient are The Earl and Thressa Stadtman Award recognizes a scientist ready to be taken. for his or her outstanding achievement in basic research in the Much like the diverse breadth of research that the fields encompassed by the ASBMB. The award will be given Stadtmans carried out in their lab over their long careers, annually and will alternate between an established scientist and this award is open to a broad range of fields, so long a young investigator with 10 years or less of post-postdoctoral as they fall under the category of “great basic science.” experience, including medical residency and fellowship. The Also, a unique feature of the Stadtman award is that the established scientist will be honored as “The Earl and Thressa winner will alternate each year between an established Stadtman Distinguished Scientist,” and the younger investigator researcher and young investigator, reflecting the assis- will be honored as “The Earl and Thressa Stadtman Scholar.” tance and advice the Stadtmans provided not just to Nominations must originate from an ASBMB member, but the their own trainees but to scientific colleagues of all ages. nominee need not be an ASBMB member. The award consists In essence, the Stadtman award is a perfect embodi- of a plaque, a $10,000 cash award and travel expenses for the ment of Earl and Thressa Stadtman. recipient and his or her spouse to the ASBMB annual meeting to present a lecture. Nick Zagorski ([email protected]) is a science writer at ASBMB.

10 ASBMB Today March 2010 asbmbnews ASBMB Introduces the DeLano Award BY NICK ZAGORSKI

lthough the term “maestro” is gener- computers will become ever more criti- A ally confined to the musical arena, cal in both storing and making sense of those who knew and worked with the this data. late Warren L. DeLano would not be shy Importantly, the computational about applying this term to his skills with advance recognized by the award must programming. be readily accessible to the scientific Perhaps most notably exemplified by community; sharing and accessibility PyMOL, an open-source tool for visual- was one of DeLano’s strongest beliefs. izing the three-dimensional structures of DeLano embraced the concept of open- proteins and other biological molecules, source technology, making his programs DeLano, who died Nov. 3 at age 37, had and source code freely available to a rare gift for designing computer pro- The memory of Warren L. DeLano prospective users, enabling researchers grams that were complex yet accessible, will be honored with the ASBMB to build on his developments. DeLano Award for Computational technical yet elegant. Biosciences. This award was established with One of the key innovations of PyMOL, the help of ASBMB members Axel T. for example, was that it made the molecular visualization Brunger, professor of molecular and cellular physiol- of complex biomolecular systems available to the aver- ogy at Stanford University, and James A. Wells, profes- age biologist. DeLano’s program was the first of its type sor and chairman of the department of pharmaceutical to use “click-and-drag” functionality to manipulate struc- chemistry at the University of California, San Francisco. tures, allowing scientists to tinker with protein mutants As DeLano’s undergraduate and graduate advisers, and the configuration or chemical composition of bound respectively, Brunger and Wells experienced both his ligands. talents and bright personality firsthand and wanted some DeLano’s legacy will live on through PyMOL, CNS avenue through which to honor his impact. Together, they (Crystallography and NMR system, a software suite to worked closely with DeLano’s family to bring this ASBMB aid in structural determination), Phenix (Python-based award to fruition. Hierarchical Environment for Integrated Xtallography) and the numerous other computer programs he developed. Nick Zagorski ([email protected]) is a science writer at There are few, if any, researchers in the world who work ASBMB. in the areas of structural or computational biology who do not owe a great deal to DeLano’s advances. The American Society for Biochemistry and Molecular The Award Biology will further perpetuate DeLano’s spirit by introduc- The DeLano Award for Computational Biosciences was estab- ing the DeLano Award for Computational Biosciences lished by family, friends and colleagues to honor the legacy in 2011. The award will be presented each year to an of Warren L. DeLano. The award will be given to a scientist investigator who develops the most innovative compu- for the most accessible and innovative development or applica- tational tool or application that helps advance the field of tion of computer technology to enhance research in the life sci- molecular life sciences. ences at the molecular level. The contribution should include two This award also will serve to recognize the grow- key elements— more productive use of computers to accelerate ing importance of the field of computational biology. As and facilitate research and ready access of those programs biological disciplines continue to produce an abundance by the scientific community. The award consists of a plaque, a of complex information, whether it’s continually higher- $3,000 cash prize and travel expenses for the recipient to attend resolution, three-dimensional structures, real-time movies the ASBMB annual meeting to present a lecture. of cell activity or even whole genomes and proteomes,

March 2010 ASBMB Today 11 asbmb member spotlight Bandarian Honored Penning to Receive NPA Award with Pfizer Award Trevor M. Penning, professor of pharmacol- Vahe Bandarian, assistant professor of ogy, biochemistry and biophysics at the biochemistry and molecular biophysics and University of Pennsylvania School of assistant professor of chemistry at the Medicine, has been selected to receive the University of Arizona, has been named the 2010 Distinguished Service Award from the recipient of the 2010 American Chemical National Postdoctoral Association. The Society Division of Biological Chemistry award is given to an individual or entity that Pfizer Award in Enzyme Chemistry. has demonstrated either a profound, The award recognizes Bandarian’s sustained or leadership contribution to work on various aspects of the biosyn- improving postdoctoral experience. thetic pathways for bacterial secondary Penning, who is also director of the Center of Excellence in metabolites. He and his colleagues undertook these studies to Environmental Toxicology at the University of Pennsylvania, will aid in understanding the pathways and chemical transforma- receive his award at the NPA’s eighth annual meeting in March. tions that underlie the biosynthesis of these natural products, the According to the NPA, Penning is “recognized in the postdoc- mechanisms for the evolution of catalysts in these pathways and toral community as a longtime advocate on behalf of postdoctoral the broader issues involving evolution of secondary metabolic scholars, both on the home and national fronts.” He oversaw pathways in bacteria. the formation of the postdoctoral office at the University of According to the ACS division of biological chemistry, Pennsylvania School of Medicine and served as the director of “Professor Bandarian’s work is a tour de force at the cutting edge the office of postdoctoral programs, associate dean for postdoc- of microbial bioinformatics, natural-product biosynthesis, metabo- toral research training and director of biomedical postdoctoral lomics and the de-orphaning of open reading frames of unknown programs. When the NPA was formed in 2001, Penning served function.” on its first advisory board and played an influential role in guiding Bandarian is especially noted for the identification and charac- the nascent organization toward independence and national terization of the gene cluster responsible for the production of the relevance. deazapurine natural products toyocamycin and sanguvamycin in Streptomyces rimosus. Although this class of compounds was discovered more than four decades ago, the biosynthetic path- Halpert Receives Brodie Award ways that produced them had remained elusive. James Halpert, professor and associate dean for scientific affairs at the Skaggs School of Pharmacy and Pharmaceutical Silhavy Elected to GSA Board Sciences, has been awarded the Bernard Thomas J. Silhavy, Warner-Lambert/ B. Brodie Award in Drug Metabolism for Parke-Davis professor of molecular biology 2010. at Princeton University, was recently The award is presented biennially to elected to the 2010 Genetics Society of recognize outstanding original research America board of directors. He took office contributions in drug metabolism and dis- on Jan. 1 and will remain on the board for position, particularly those having a major three years. impact on future research in the field. Named after the scientist “We have a terrific group of new officers known as “the father of modern drug metabolism,” the award and directors this year, and I am looking is sponsored by the American Society for Pharmacology and forward to working with them as we build Experimental Therapeutics Division for Drug Metabolism. on GSA’s strengths and plan for our future. Their election to the For the past 30 years, Halpert’s research has looked at board is a reflection of the esteem in which they are held by their the structure and function of mammalian cytochromes P450. peers and their commitment to serve the community,” said GSA Heterogeneity in the expression levels and/or activities of these Executive Director Sherry Marts in a statement. important drug-metabolizing enzymes is a major determinant of A bacteriologist, Silhavy is particularly interested in protein tar- individual response to medications and environmental toxicants. geting and signal transduction in bacteria such as E. coli. He was Because many of the failures in investigational drug development the first to identify a component of theE. coli protein secretion result from suboptimal pharmacokinetics, drug interactions and/ machinery and the first to describe a “two-component system”— or toxicity, methods for predicting cytochrome P450-mediated a major family of bacterial regulatory elements that sense a metabolism of new compounds are currently in great demand. variety of environmental signals and transduce the information to Progress in this area is dependent on sophisticated understand- transcriptionally regulate gene expression. ing of the structural determinants and mechanisms of cytochrome P450 function, which Halpert has helped to elucidate.

12 ASBMB Today March 2010 asbmb member spotlight Please submit member-related news to [email protected]. Young Shares Raines Wins Repligen Award Jung Medical Award Ronald T. Raines, Henry Lardy professor of Stephen G. Young, professor of medicine biochemistry and professor of chemistry at at the University of California, Los the University of Wisconsin-Madison, is the Angeles, has been named the recipient of recipient of the 2010 Repligen Award in the 2010 Ernst Jung Medical Award. He is Biological Chemistry. This lifetime achieve- being honored for his pioneering research ment award, given annually by the on the mechanisms of lipid metabolism, American Chemical Society, recognizes particularly the elucidation of genetic outstanding contributions to the under- defects in apolipoproteins, triglyceride- standing of the chemistry of biological transport mechanisms and the role of processes, with particular emphasis on farnesylated prelamin A in causing structure, function and mechanism. Raines is the 25th winner of Hutchinson-Gilford progeria syndrome, a pediatric disease that the Repligen Award. leads to hair loss, heart attacks, strokes and other features of The award honors Raines and his contributions and wide- aging. ranging impact on science at the interface of chemistry and The Ernst Jung Medical Award, initiated in 1967 by Hamburg biology. His efforts have led to both understanding and real-world merchant and ship owner Ernst Jung and awarded since 1976, applications. He has provided fundamental insight on the stability is given for pioneering research in medicine. Young shares the of collagen, leading him to discover a new force— the n→π* award with Peter Carmeliet of the Vesalius Research Center interaction— that contributes to the conformational stability of in Leuven, Belgium. As part of the award, both Young and nearly every protein. Raines discovered how to convert a human Carmeliet will receive $215,000. ribonuclease into a toxin with specificity for cancer cells. His Past recipients of the Ernst Jung Medical Award have ribonuclease is in a human clinical trial as an anti-cancer agent. included Anthony S. Fauci, David D. Ho, Francis V. Chisari, Raines also has provided mechanistic insight on cellular-redox Judah Folkman and Stuart A. Lipton. homeostasis. Finally, he has developed chemical processes to synthesize proteins and convert biomass into useful fuels and chemicals. In Memoriam: Gene A. Homandberg In Memoriam: Gene A. Homandberg, chair of the department of biochemistry and molecular biology at the University of North Dakota School of James B. Peter Medicine and Health Sciences, passed away on Dec. 21, at the James B. Peter, founder of Specialty Laboratories Inc., died on age of 59. Oct. 30. He was 76. An Iowa native, Homandberg pursued his education at the A native of Omaha, Neb., Peter earned his medical degree University of South Dakota, where he earned his Bachelor of from St. Louis University in 1958. He then went to the University Science degree in chemistry and a doctorate in biochemistry. He of Minnesota, where he earned a doctorate in biochemistry in then served as a postdoctoral research associate in the depart- 1963, working with Paul D. Boyer. Peter then joined the faculty ment of chemistry at Purdue University and later at the National of the University of California, Los Angeles, where he served as Institutes of Health National Institute of Arthritis, Metabolic and professor, clinical professor and College of Letters and Sciences Digestive Disorders. advisory board member. In 1984, Homandberg became an assistant professor at the In 1975, Peter founded Clinical Immunologies Inc. with the University of Wisconsin School of Medicine and Public Health and mission to “help doctors help patients.” His hope was to bring was promoted to associate professor in 1986. He then joined modern biochemistry and immunology to the clinical laboratory Abbott Laboratories as a senior biochemist and worked there for marketplace. By the mid-1980s, the company had become two years before becoming a professor of biochemistry at Rush Specialty Laboratories Inc., and Peter had created a unique Medical College. He eventually was promoted to the Dr. Ralph niche in the lab industry. He and his scientific team developed a and Marian C. Falk professor of biochemistry endowed chair. In constant flow of proprietary esoteric tests and assays. In 2006, 2002, Homandberg moved to the University of North Dakota and Specialty Laboratories was acquired by AmeriPath Inc., which became the William Cornatzer chair in biochemistry. was subsequently acquired by Quest Diagnostics in 2007. Homandberg was a highly recognized researcher in osteo- Peter also founded the Specialty Family Foundation in arthritis and cartilage physiology, and, in 1999, he was awarded 2006 with a mission to help ensure a Catholic education for permanent membership in the Frontiers in Bioscience Society demographically disadvantaged children. In addition to its of Scientists, based on his work in the regulation of cartilage focus on education, the foundation is involved in researching metabolism in osteoarthritis. methods to support people with alcohol and substance abuse problems.

March 2010 ASBMB Today 13 asbmbnews Retrospective: Paul C. Zamecnik (1912 – 2009) By Arthur B. Pardee

aul C. Zamecnik, senior scientist at Massa- showed that ATP is necessary for amino acid Pchusetts General Hospital and profes- activation leading to peptide bond formation, sor emeritus of oncologic medicine at which, therefore, is not a reversal of prote- Harvard Medical School, was among olysis. They discovered transfer RNAs the most important biochemical and showed that the linkage of amino scientists of the 20th century. He acids to these small RNAs was the passed away Oct. 27, 2009, at the penultimate step of polypeptide age of 96. synthesis. Paul’s group was also Paul received his undergradu- the first to identify the ribosome as ate degree from Dartmouth Col- the site of protein synthesis. lege in 1933, majoring in chem- After that breakthrough, Paul istry and zoology. He obtained continued to perform outstand- his medical degree from Harvard ing research. His RNA sequencing Medical School in 1936 and revealed that Rous sarcoma virus followed it with internships at Hun- RNA has a 3′-OH tail of poly(A) tington Memorial Hospital in Boston bounded by a sequence that is and Lakeside Hospital in Cleveland, identical to one at the 5′ end, suggest- Ohio. During his Lakeside Hospital ing that a cDNA-mediated circularization internship, Paul was awarded a Finney- might occur during reverse transcription. Howell Fellowship and a Moseley Traveling A 13-mer oligodeoxynucleotide complemen- Fellowship to go to the Carlsberg Laboratory in tary to the terminus of RSV inhibited both the Copenhagen, where he worked with Kaj Linderstrom- translation of viral mRNA in a cell-free system and virus Lang. After he returned to the United States, Paul replication. He showed that inhibition depends on both worked at the Rockefeller Institute for Medical Research the ability of deoxynucleotides to enter intact cells and in New York for two years, studying protein synthesis on Watson-Crick base pairing. His pioneering studies on with Max Bergmann. He returned to Cambridge, Mass., antisense DNA and its inhibitory activity arose from that in 1942 to join the faculty of medicine at Harvard Medical work. Antisense oligonucleotides immediately became School and established his laboratory at Massachusetts important research tools for experimentally silencing General Hospital. gene expression. Those papers launched the era of At Harvard, Paul worked with Fritz Lipmann, and the antisense DNA. He applied those concepts to medicine, pair subsequently shared the Massachusetts General targeting the tuberculosis bacterium and the defective Hospital’s Warren Triennial Prize for their seminal study cystic fibrosis gene. Paul is regarded as the founder of on the mechanism of action of clostridium α-toxin. In the antisense therapy field. 1956, Paul became the Collis P. Huntington professor Paul’s wife of 69 years, Mary Connor, died in 2005. He of oncologic medicine at Harvard Medical School, and leaves daughters Karen Pierson and Elizabeth Coakley, son he remained in that position until his retirement in 1979, John, seven grandchildren and two great-grandchildren. after which he continued at the Worcester Foundation for Paul’s major “side interest” was the company and Biomedical Research. conversation of interesting people. He learned to ski at In the 1950s, Paul elucidated, through the develop- Dartmouth and enjoyed skiing every winter. He was a ment of cell-free systems, the biochemistry of protein good swimmer and tennis player. Later in life, he and synthesis. He and colleagues Philip Siekevitz, Robert Mary went to St. John in the Virgin Islands, where he B. Loftfield, Mahlon Hoagland and Mary Stephenson loved to swim and snorkle. When he no longer partici-

14 ASBMB Today March 2010 asbmbnews

pated in sports, he enjoyed watching football, basketball he developed years earlier. He was using in vitro systems and tennis and knew all the players and their quirks. to repair the genetic mutation in cystic fibrosis, to block On a personal note, my first correspondence with cell wall synthesis in Mycobacterium tuberculosis and to Paul led to his pointing out that I should spell his name target antibiotics to specific ribosome sites. correctly, but he forgave me for that. In recent years, we In some of our conversations, he reflected on the times after he discovered tRNA and lamented that he prob- discussed science and enjoyed evenings dining at his ably should not have taken time off in the early 1960s club, the Somerset, in Boston. A word that characterizes for a sabbatical with Sir Alexander Todd in Cambridge. Paul is devoted: As a scientist, he was devoted to ideas When he returned to Boston, he found that the scientific and his research, and, as a person, he was devoted to floodgates had been opened by many others, including his friends. He was a true gentleman— friendly, sincere Marshall W. Nirenberg, Heinrich Matthaei, Robert W. and straightforward. Holley and Har Gobind Khorana. He told me, “I felt as if I Paul will be sorely missed by friends and colleagues, was left standing on Mont-Saint-Michel while the incom- several of whom have provided reflections below. ing tide roared past me.” I visited with him frequently in his final days and hours. By the 1970s, I had come to know Paul Zamecnik Even as the curtain was falling, his utterings included from various RNA meetings, and, in 1979, I suggested phrases such as “Shine-Delgarno sequences” and we collaborate to use psoralen-mediated nucleic acid “ribosome-binding sites.” Paul Zamecnik was a remark- cross-linking in living cells (which my lab had perfected) ably kind, generous, gracious and humble person whose to prove to skeptics that his antisense oligodeoxy- greatest pleasure was scientific discovery. nucleotides that were inhibiting translation were indeed Kurt J. Isselbacher doing so via hybridization with mRNA. We didn’t do the Distinguished Mallinckrodt experiment and, in retrospect, I suspect he had not been professor of medicine Harvard Medical School as bothered by the “skeptics” as I had been, which says much about his legendary determination and confidence The Massachusetts General Hospital found room for in his results. Paul Zamecnik for more than 20 years in the ’60s and Our years as colleagues at the Worcester Foundation ’70s. In an enclave in a research building, Paul and his (1979–1997) were delightful. In early December each year, group did their diligent work on cell-free protein syn- he would send me a handwritten note with the expressed thesis, on the ribosome and transfer RNA, and on other “hope” that I (the director) would not mind if he and his major insights of the early molecular era. Although their wife took a short holiday vacation. Being Paul’s “boss” laboratories were in a nonclinical area, the scientists was a comical situation that amused us both, but those could only reach it by passing through the Bulfinch notes were so typical of his manner (and manners). He Building, the heart and home of the medical service. This was a persistent fountain of ideas to us all, a caring men- guaranteed interaction and consultation between true tor to young faculty, a delightful lunchtime raconteur and, basic scientists and the clinicians trying to cope with of course, a living history of science textbook. cancer and similarly poorly understood disorders, and Blessed with extraordinary prescience, Paul Zamecnik mutual enlightenment was inevitable. The geographical was an experimentalist of uncommon talent who trans- propinquity correlated with Walter Bauer’s design of formed the modern era of biochemistry. That he was also keeping basic scientists and clinicians working together. a gentleman brought the two strands of his being into And it succeeded because of Zamecnik’s medical train- helical harmony. ing, his prior clinical experience in a cancer hospital, his Thoru Pederson scientific brilliance and his approachability. Vitold Arnett professor of biochemistry and molecular pharmacology Daniel D. Federman University of Massachusetts Carl W. Walter distinguished Medical School professor of medicine Harvard Medical School I knew Paul Zamecnik for most of his scientific career, but my closest interactions with him occurred after he returned to the Massachusetts General Hospital and Arthur B. Pardee ([email protected]) is a professor its cancer center in 1997. We discussed his ongoing emeritus of biological chemistry and molecular pharmacology at research about applying the antisense technology that the Dana-Farber Cancer Institute and Harvard University.

March 2010 ASBMB Today 15 asbmbnews JBC Thematic Series Breaks Down Proteases BY NICK ZAGORSKI

n October 1905, Phoebus Aaron Together, these minireviews, ILevene published an article titled and an introductory article writ- “The Cleavage Products of Prote- ten by Bond and Carlos López- oses” in the very first issue of the Ótin, provide insight into the Journal of Biological Chemistry. world of proteases, including the This set the stage for more than details of their structure, enzy- 100 years of protease-related matic activity and regulation. The research in the journal. articles also provide a look back It is perhaps fitting that prote- at the molecular evolution of pro- ases appeared in the JBC so early teases and a look forward at the on, as proteases are themselves frontiers of protease research, likely one of the earliest enzymes to including studies into the pro- appear in protein evolution, catabo- teolytic regulation of transcrip- lizing other proteins to generate the tion factor activity and protein amino acids necessary for primitive ectodomain shedding. organisms. Among the minireviews Of course, as a century of included in the series are a research appearing in the JBC detailed overview of the 26S and other journals has shown, proteases are more proteasome by Ami Navon and Aaron Ciechanover; a than mere random protein destroyers. These ancient review of our current knowledge of human caspases enzymes, which are found in all organisms, from written by Cristina Pop and Guy S. Salvesen; a look at viruses to humans, catalyze a wide range of highly the exosite requirements of serpin specificity by Peter specific reactions that are responsible for modulating G. W. Gettins and Steven T. Olson; a review of the protein-protein interactions, creating new bioactive structural and mechanistic features of intramembrane- molecules, processing cellular information and regulat- cleaving proteases by Michael S. Wolfe and a discus- ing molecular signals. As a result of their multiple roles, sion of the proteolytic regulation of epithelial sodium proteases are involved in almost every physiological channels by Thomas R. Kleyman and colleagues. process including DNA replication, cell proliferation, The thematic minireview series provides a valuable tissue morphogenesis, fertilization, wound repair and overview of the family of protein sculptors known as inflammation. proteases that decisively influence the rhythms of cell That’s why, in spite of their long history, proteases life and death in all living organisms. remain at the cutting edge of biological research today. And that’s also why the JBC decided to run a com- Nick Zagorski ([email protected]) is a science writer at prehensive minireview series covering these diverse, ASBMB. complex and, ultimately, invaluable proteins. Started in the journal in May 2009, the thematic series “Proteolytic Enzymes,” coordinated by JBC For more information: Associate Editor Judith S. Bond, brings together 10 The JBC minireview series “Proteolytic Enzymes” can be found minireview articles that encompass a broad range of online at www.jbc.org/site/thematics/proteolytic_enzymes, topics and many familiar names in the protease com- where it is also available for print purchase. munity.

16 ASBMB Today March 2010 2010 annual meeting

Professional Development For more information: • Times and locations for at the Annual Meeting annual meeting events: www.asbmb.org/meeting2010 • A podcast interview with he American Society for Graduate/Postdoctoral and Graduate Minority Larry Shapiro, the subject TBiochemistry and Molecular of “Naturally Obsessed”: Travel Award Symposium www.asbmb.org/audio.aspx Biology’s annual meeting in Ana- This event begins at 5 p.m. Friday, April heim, Calif., is only a month away. In 23, with a keynote lecture titled “Adven- addition to a great scientific program, tures in a Scientific Career: Juggling toward getting their doctoral degrees. we’ve planned several events that are Research, Teaching and Real Life” by The film was shot over three years’ time geared toward the professional devel- Graham C. Walker of the Massachusetts at Columbia University Medical Center Institute of Technology. This will be opment of young scientists— under- and also documents how X-ray crystal- followed by a poster session in which lography enables the discovery of the graduate students, graduate students all ASBMB travel award recipients will molecular structure of AMP-activated and postdoctoral fellows. present their work. protein kinase, considered prime for Graduate and Postdoctoral targeted drug development because of its 14th Annual ASBMB Professional Development relevance to diabetes and obesity. Undergraduate Student Program* Poster Competition Research Funding by the Back for a third year, this popular American Cancer Society Now in its 14th year, this poster com- program will be held from 9 a.m. to 4:30 At 12:30 p.m. Monday, April 26, Charles petition provides an opportunity for p.m. Saturday, April 24. It will feature Saxe, American Cancer Society program undergraduate students to showcase a morning panel on such careers as director in cancer cell biology and their research. The event, which will be teaching, patent law and science writing, metastasis, will describe the research held from 1 p.m. to 4:30 p.m. Saturday, a networking luncheon and afternoon grant mechanisms available at the ACS April 24, is a great way to meet fellow workshops that address issues particular and how to best approach the applica- undergraduate attendees and to make to graduate students and postdoctoral tion process. A peer review committee friends and contacts before the meeting fellows. member and a grantee also will be pres- starts. The poster session also will have a Minority Scientists’ ent to provide further insights and to networking break during which students Welcome Reception field questions. can visit with prospective graduate This year, the ASBMB Minority Affairs Talk with the Editors: school representatives. Prizes for the Committee is hosting a welcome recep- New Guidelines for best posters will be awarded Sunday, tion from 6 p.m. to 8 p.m. Sunday, Publishing in the JBC April 25, at the ASBMB Award for April 25, after the afternoon symposia. The Journal of Biological Chemistry Exemplary Contributions to Education Primary investigators, industry profes- is hosting a discussion at 12:30 p.m. lecture. sionals, educators, young professionals Sunday, April 25, for people interested in learning about the Journal of Biologi- Careers in Biochemistry and and students are welcome to attend this Molecular Biology: A World of networking and mentoring event for dis- cal Chemistry review guideline changes Options, a Variety of Skills cussions on various topics such as career and how they affect submissions to the journal. The lectures in these symposia, spon- opportunities, mentoring options and sored by the ASBMB Education and Pro- issues facing minority scientists. Women Scientists’ Panel and Networking Reception fessional Development Committee, will Naturally Obsessed: occur from Saturday, April 24, through The Making of a Scientist Join fellow women biochemists and Tuesday, April 27. The lectures cover a ASBMB will present a special screening molecular biologists at 6:30 p.m. Tues- day, April 27, for a panel discussion on variety of topics, including the skills that of the hit movie, “Naturally Obsessed: the gender gap and its impact in the field employers are looking for and tips for the Making of a Scientist” at 6:30 p.m. of science. A reception will follow for grant writing. The symposia also feature Monday, April 26. The documentary informal discussion and networking. a panel on biochemistry and molecular follows a group of eager students, biology careers and a career workshop mentored by Larry Shapiro, along a for undergraduate students. challenging and uncertain journey *Registration required.

March 2010 ASBMB Today 17 sciencefocus Jerry Lingrel: Pumping Out Great Science BY NICK ZAGORSKI

or Jerry B. Lingrel, a distinguished professor in the By that same token, Lingrel Fdepartment of molecular genetics, biochemistry and figured reticulocytes should contain microbiology at the University of Cincinnati and an asso- a vast amount of α and β globin ciate editor for the Journal of Biological Chemistry, great mRNAs. To isolate these mRNAs, he science is in the blood. thought that using an Escherichia coli Not that Lingrel comes from a strong scientific pedi- cell-free translating system, similar to gree— to the contrary, he was just a small-town Mid- that employed by Marshall Nirenberg western boy whose desire to pursue a career in science to crack the genetic code, would be a was encouraged by his parents— but rather that Lingrel reasonable approach; Lingrel would has made a living studying this vital fluid. From his early add different fractions of total mouse breakthrough in isolating and characterizing globin reticulocyte RNA to extracts of E. messenger RNA to his subsequent work sequencing the coli translation machinery and see sodium-potassium pump (Na,K-ATPase) and studying which ones produced globins. its role in regulating blood pressure to his discovery of Of course, his initial attempts Krüppel-like factor 2, a transcription factor that, among didn’t bear fruit, and he jokes, other things, maintains blood vessel integrity; Lingrel’s “It was not the most ideal way to science revolves around blood. discover that there are significant And, it all began not by design but simply by convenience. differences between bacterial and In 1968, shortly after Lingrel, an Ohio native, had eukaryotic protein synthesis.” returned home to begin a professorship at the Univer- However, when he changed his approach and used a sity of Cincinnati after a postdoctoral fellowship at the cell-free translation system from rabbit reticulocytes, he California Institute of Technology, he decided to focus on achieved success and identified a 9 S RNA that resulted in the messenger RNA that encoded the proteins involved in the synthesis of both α and β globin. In doing this, he iden- protein synthesis. tified and translated the first mammalian messenger RNA. As he recalls, mRNAs were sort of a “black box” at Over the next few years, Lingrel and his lab would fur- that time, about a decade after their initial discovery. ther characterize globin mRNA, uncovering many of the “They had been identified in bacteria,” Lingrel says, “and key features we know about these transcripts, including everyone believed they were present in eukaryotic cells their 5′ CAP structure and 3′ poly-A tail as well as the fact as well. But, it was still a lot of theory because no one had that mature mRNAs in the cytoplasm arose from larger managed to isolate an individual mRNA that coded for a precursor RNA molecules in the nucleus. Through his specific protein.” approach, which he shared with many colleagues, globin Lingrel wasn’t sure if it would be feasible to isolate synthesis became the model in which to study mRNA mRNAs, but he figured, “If I want to give myself a chance, structure and translation. I might as well find a system where mRNA is abundant.” That’s where blood came in to the picture. During his No Tension Here postdoc at Caltech with Henry Borsook, a pioneer in As the 1970s progressed, Lingrel continued his work protein synthesis studies, Lingrel had worked extensively with globins. Having made complementary DNA to his with reticulocytes (immature red blood cells), which were isolated mRNA, he was able to identify and clone globin an ideal model system: As hemoglobin factories, all they genes from a variety of mammalian cells and study both basically do is churn out globin chains all day long. the changes in globin expression during development and

18 ASBMB Today March 2010 sciencefocus

and if this ATPase is as important as Lang believes, then sequencing and characterizing it would be a tremendous advance to science.” Working with membrane proteins would be tricky, but Lingrel always has operated with a simple belief: If you take the time to think about a problem and pick the right system to work on it, there’s no reason a project should not work. So, he picked sheep kidney cells, an abundant source of Na,K-ATPase, and, together with a very tal- ented postdoc, Gary Shull, he managed to isolate ATPase mRNA, make cDNA clones, decipher the amino acid sequence for the α and β subunits and identify important residues for pump activity. “It ended up that we published our ATPase sequence in the exact same issue of Nature that David MacLennan reported his sequence for the calcium ATPase,” Lingrel says. “So, in one day, we managed to open up a whole new era in the study of ion transport proteins.” Lingrel would go on to make countless more discov- eries regarding Na,K-ATPase, including showing that the catalytic α subunit had four separate isoforms which contributed to the numerous functions the pump had throughout the body. For example, the α4 isoform is found exclusively in sperm and helps sperm cells move, whereas the α2 and α3 isoforms are highly expressed Jerry Lingrel’s science revolves around blood. in brain cells and produce learning deficiencies when Photo by Dan Davenport, University of Cincinnati AHC. knocked out in mice. Some of his most valued work, however, involves the the evolution of the globin gene family. central role of the ATPase in sodium transport in hyper- Then, in 1976, the University of Cincinnati’s microbi- tension. ology department hired a new faculty member, Dennis It long had been known that steroid-like compounds Lang, who ended up becoming one of Lingrel’s neigh- like ouabain and digitoxin (both derived from plants) bors. Given their similar destination, the two ended up could block the Na,K-ATPase and, thus, force increased carpooling on numerous occasions. And through this heart contractions, a fact that was used to develop similar ridesharing, Lingrel was introduced to another molecular compounds as treatments for congestive heart failure black box: the Na,K-ATPase, which pumps potassium (though they are no longer widely used, as better drugs into and sodium out of a cell. such as angiotensin-converting enzyme (ACE) inhibitors “Lang had done his graduate studies under Efraim have come along). Racker at Cornell, who was a leading expert on the Na,K- However, some controversy also developed, as evi- ATPase,” Lingrel says, “and, during our rides, he kept dence seemed to suggest that animals produced their own telling me how important this enzyme was in biology. So, ouabain-like steroids to modulate Na,K-ATPase activity one day I asked him what they knew about the ATPase (so-called endogenous ouabains). As Lingrel notes, while structure, and he responded that they didn’t even know several studies had shown the presence of ouabain in the amino acid sequence yet.” normal blood samples, it was extremely difficult to prove That sparked an idea: Lingrel admittedly knew very that they had been synthesized in the body. “And, from little about transport proteins, but what he did know was a logical standpoint, people wondered why the human molecular cloning. body would want to synthesize ouabain, which is a toxic “I thought to myself: Oh, our lab could handle that; molecule,” Lingrel says.

March 2010 ASBMB Today 19 sciencefirstsecond focus continued continued

On the other hand, comparative work done by Lingrel’s team found that the binding site for ouabain and similar drugs in the Na,K-ATPase α sub- unit was heavily conserved from fruit flies to humans, which would support a physiological role, and, by extrapolation, a physi- ological ligand. Jerry Lingrel’s group recently has shown that KLF2 is involved in making blood vessels. Here, stained sagittal “So, we decided to sections of wild type (A) and knock-out (B) mouse aorta highlight the vascular defects that occur when KLF2 work on this mystery, but, is deficient. Wu, J., Bohanan, C. S., Neumann, J. C., and Lingrel, J. B.,J. Biol. Chem. (2008) 283, 3942–3950. rather than focus on the compounds, we decided to focus on the binding site.” His reasoning was based on were resistant to hypertension,” Lingrel says, “whereas the the interesting observation that one of the four mouse α animals that had the altered α1 almost blew up because subunit isoforms (α1) happened to be resistant to ouabain. they became so hypertensive.” That seemed to confirm So, he mutated two amino acids in the α2 isoform (the that the ouabain binding site was physiologically impor- major vascular form), so it resembled α1 in one group of tant in regulating blood pressure, and something in the mice and altered α1 so it resembled α2 in another group. blood was interacting with it. Lingrel is currently collabo- He then induced stress in the mice to see what happened. rating with some colleagues at the University of Cincin- “Sure enough, the mice that contained the mutated α2 nati to try to find that elusive endogenous ligand.

Low-stress Levels In some ways, Lingrel is still the curious, small-town Midwestern boy who was fascinated with science and nature. Some of it may arise from the fact that he never really left Ohio. Except for his two-year postdoc at Caltech and a one-year sabbatical at the MRC laboratory in Cam- bridge, England, Lingrel has been a steady fixture in the Buckeye state, from growing up in Byhalia, to his college years at Otterbein College in Westerville, to his gradu- ate studies at The Ohio State University and finally his Jerry Lingrel recently has discovered a role for Na,K-ATPase in the brain, as highlighted by this in situ long and impressive profes- mRNA hybridization analysis of the ion transporter’s α1 and α2 isoforms in developing mouse brains; A sorship at the University of and B show sections through the hippocampus, with the star highlighting robust expression for 1 but not α Cincinnati. α2 in the choroid plexus, whereas the arrow highlights the more intense α2 presence in the ependymal lining. C and D show sections through the cortex, with the arrow highlighting the strong expression of α2 It’s that continued con- in the pia mater. Moseley, A. E. et al, J. Biol. Chem. (2003) 278, 5317–5324. nection with his youth,

20 ASBMB Today March 2010 sciencefirstsecond focus continued continued

spending countless hours trying proper development of the lung to understand how things work, and other tissues in embryos but that has shaped his research path, also had a role in the forma- be it his globin or Na,K-ATPase tion, maturation and integrity of studies, or even his more recent blood vessels. foray into KLF2 (Krüppel-like The most interesting aspect factor). of KLF2 function, though, was These studies began as an off- that it was induced in endothe- shoot of his research with globin lial cells by fluid shear stress. expression, but, as in the case of “That caught my eye,” Lingrel the Na,K-ATPase, Lingrel notes, says, “because it’s in areas of “I’ve managed to make second low-shear stress, like bifurca- careers out of what I thought tions, where you get plaque would just be side projects.” buildups and atherosclerosis; Other researchers had discov- so KLF2 might be an athero- ered a transcription factor, called protective agent.” His group is the erythroid Krüppel-like factor, currently developing transgenic that was critical in orchestrat- mice that overexpress KLF2 in ing the switch from fetal to adult low-stress areas and testing their hemoglobin expression, and Lin- resistance to plaque buildup One of Jerry Lingrel’s many discoveries regarding grel used some cDNA from EKLF Na,K-ATPase was uncovering the sperm-specificα 4 when fed a high-fat diet. as a clone to screen for other isoform, revealed in A as being localized to the mid- Lingrel is thrilled that his proteins that bound to hemoglo- piece region of the flagellum. B shows a control sperm work has helped so many other with only secondary antibody staining. Woo, A. L., et bin genes. al. J. Biol. Chem. (2000) 275, 20693–20699. scientists. Although he’s focused What he uncovered was not primarily on the vascular just a protein that shared a similar system, both KLF2 and the gene-binding region, but one that closely resembled EKLF, Na,K-ATPase are fairly ubiquitous, and his fundamental ushering in a new Krüppel-like protein family. discoveries are applicable to areas like muscle activity, He named this new transcription factor LKLF (for lung neuroscience and development. And, not surprisingly, he’s Krüppel-like factor, although it was later renamed KLF2) been flooded with requests for advice or one of his many and began pursuing its role. He found that it was vital for transgenic mouse lines, which he’s always happy to oblige. One cannot help but wonder whether it’s perfectly fitting or somewhat ironic that this calm and contented Out of Focus: man is revealing the mechanisms of atherosclerosis and A Little Less Conversation, hypertension. A Little More Science Nick Zagorski ([email protected]) is a science writer at Jerry Lingrel’s sabbatical with John Gurdon at the MRC ASBMB. laboratory was a fantastic experience, although it did

take a while to adjust to local customs. “The scientists References there loved to socialize,” he says. “They talked over Lockard, R. E., and Lingrel, J. B. (1971) Identification of Mouse Haemoglobin Messenger RNA. Nature, 233, 204–206. morning coffee, lunch and afternoon tea.” At first, Lingrel Shull, G. E., Schwartz, A., and Lingrel, J. B. (1985) Amino-acid Sequence of the Catalytic Subunit of the (Na+/K+) ATPase Deduced from a Complementary didn’t join the fun – “I thought I was here to work not DNA. Nature, 316, 691–695. talk”— but he eventually got hooked. “I had so much Anderson, K. P., Kern, C. B., Crable, S. C., and Lingrel, J. B. (1995) Isolation of a Gene Encoding a Functional Zinc Finger Protein Homologous to Erythroid fun talking to all the great scientific minds at the MRC Krüppel-like Factor: Identification of a New Multigene Family. Mol. Cell. Biol. 15, 5957–5965. about ideas and techniques, and soon I understood why Woo, A. L., James, P. F., and Lingrel, J. B. (2000) Sperm Motility Is Dependent experiments never seemed to fail there.” However, Lin- on a Unique Isoform of the Na,K-ATPase. J. Biol. Chem. 275, 20693–20699. Dostanic-Larson, I., Van Huysse, J. W., Lorenz, J. N., and Lingrel, J. B. (2005) grel ended up becoming such the social butterfly during The Highly Conserved Cardiac Glycoside Binding Site of Na,K-ATPase Plays a Role in Blood Pressure Regulation. Proc. Natl. Acad. Sci. U.S.A. 102, the day that he had to come back to lab every night to 15845–15850. do the actual experiments. Huddleson, J. P., Ahmad, N., and Lingrel, J. B. (2006) Up-regulation of the KLF2 Transcription Factor by Fluid Shear Stress Requires Nucleolin. J. Biol. Chem. 281, 15121–15128.

March 2010 ASBMB Today 21 education and training Teaching “From Proposal to Publication” BY J. ELLIS BELL

here is no one way to teach science; what works in useful, neither provided me with much satisfaction. So, Tone setting may not work in another. In the past four I went to PubMed and tried various combinations of or five years, there has been much talk about “teaching the terms I was looking for. I found some information science the way you do science.” In a policy forum article about teaching medical and nursing school, but still no published in the journal Science in 2004 (1), Jo Handels- luck. Finally, I looked at two major education journals in man and co-authors wrote, “There is mounting evidence molecular life sciences— CBE Life Sciences Education that supplementing or replacing lectures with active (http://www.lifescied.org) and Biochemistry and Molecu- learning strategies and engaging students in discovery lar Biology Education (http://bit.ly/9dTntB)— and found and scientific process improves learning and retention of some decent answers. knowledge.” Since then, many scientific societies have Interestingly, during my searches, I was not able to find the Science article referred to at the beginning of this article. Even a PubMed ‘There is mounting evidence that search with the paper’s title turned up supplementing or replacing lectures 54,943 results, which effectively buried the “ with active learning strategies and actual reference I was looking for. The only easy way for me to find the article was with engaging students in discovery and an advanced search using the author’s name and the article’s title. My conclusion: scientific process improves learning It’s not easy to find the answers to the and retention of knowledge.’ questions “How do we do science?” and “What is real research?” if you don’t know where to look. included sessions with similar titles in their annual meet- ings, but little has been written about how to translate” Doing Science this approach into formal courses. For a while now, it has So, how do we do science, and what is a real research been recognized that undergraduate research opportuni- experience? ties play a crucial role in undergraduate education, but only a few colleges and universities give their students 1. The Question. real research experiences by requiring full-time, year long Students need to learn that, to do science, they have to laboratory research and a senior thesis. build on what they already know. Knowledge may come So, how do we “do science,” and what is a “real from an observation or from reading scientific literature. research” experience? And, how can we realistically Either way, this knowledge leads to a question, and one teach science the way we do science in the context of a of the first things that scientists do is find out whether four-year undergraduate education? anyone else has asked (and possibly answered) the question. If the question has been answered satisfacto- Searching for Scientific Teaching rily, the scientist moves on and lets his or her curiosity I recently Googled “How do we do science?” and found loose again. If it hasn’t been answered, then he or she an interesting site (http://bit.ly/bL6DbC) that listed develops a hypothesis and starts thinking of experiments things we can do to teach children about science. I also to investigate the hypothesis. Googled “What is real research?” and found another site (http://bit.ly/94epsx) that explained that research 2. Designing Experiments. begins with questions, not answers. While both Web In designing experiments, it is important that students sites contained some information that was potentially understand the limitations of their approaches and how

22 ASBMB Today March 2010 education and training

to interpret their data. They also should understand that writing a proposal is an integral part of doing science. In For more information: the “real” world of research, the proposal both convinces • The University of Montana’s Integrated people that the scientist knows what he or she is talking Biological Science Courses Organized around about and allows him or her to get the resources neces- Research Experience Project (IBSCORE) sary to do the experiments. If done right, proposal writing (http://ibscore.dbs.umt.edu) involves drafts, feedback and revisions. Most under- graduates, however, never get to do this in a meaningful • Wood, W. B. (2003) Inquiry-based Undergraduate way. Often you hear faculty advisers saying, “I don’t want Teaching in the Life Sciences at Large Research them wasting their time writing a proposal when I need Universities: A Perspective on the Boyer Commission them to be in the lab doing experiments.” Report. Cell. Biol. Educ. 2, 112–116. • Udovic, D., Morris, D., Dickman, A., Postlethwait, 3. Doing Experiments. J., and Wetherwax, P. (2002) Workshop Biology: Doing the experiments is, of course, an important part Demonstrating the Effectiveness of Active Learning of the whole process, and, for undergraduates, it is in an Introductory Biology Course. Bioscience 52, an exciting part of their education which could act as 272–281. motivation for further work in the sciences. A critical part • Wright, R., and Boggs, J. (2002) Learning Cell Biology of this is, of course, analyzing and interpreting the data as a Team: A Project-based Approach to Upper- appropriately. Depending on the experiment, this will Division Cell Biology. Cell. Biol. Educ. 1, 145–153. involve statistical analysis, the use of a variety of com- puter programs and an understanding of the limitations of what the data can tell. Real data are the only type of data that can accomplish this— much of the “data” that want to use “real” research in teaching and also “teach we provide to students in the classroom as problem science the way we do science,” we need to radically sets are not real data; instead, they are often simulated rethink how we involve undergraduates in research data designed to illustrate a point and not let a student activities and how we incorporate research activities into struggle with the analysis and interpretation that is an formal class work. We need to think creatively about how integral part of research. we can meaningfully incorporate primary literature into Once the experiments are finished and the data our courses and how we can engage students in hypoth- analyzed and interpreted, presenting the project is a esis building and testing and proposal writing. Perhaps very important part of the scientific process, and plays we could teach courses with titles like “From Proposal a central role in “doing science.” The time it takes to put to Publication” to our first-year biology and chemistry together a good presentation or report is, in many ways, students and focus on research skills rather than memo- the counterpoint to putting together a good proposal. rizing facts. Or, we could at least downplay memorization The ultimate “presentation” is publication in peer- and introduce the facts in a research environment rather reviewed literature. Increasingly, undergraduate students than classroom context. If we taught courses this way, do put together poster presentations and occasionally our students would have a better chance of acquiring the are invited to give short talks at professional meetings, skills essential to “real” research and a better understand- but this is a privilege reserved for a few students and not ing of how we “do science.” something that is incorporated into everyone’s educa- tional experience. Very few undergraduates even get to J. Ellis Bell ([email protected]) is professor of chemistry write the first drafts of papers that will be submitted to and chair of the biochemistry and molecular biology program peer-reviewed journals, despite the fact that such an at the University of Richmond. He is also chair of the ASBMB activity would provide a tremendous education. Education and Professional Development Committee.

Teaching Real Science References Many of the things that are central to real research are 1. Handelsman, J., Ebert-May, D., Beichner, R., Bruns, P., Chang, A., DeHaan, R., Gentile, J., Lauffer, S., Stewart, J., Tilghman, S. M., and Wood, W. B. not the things we are getting undergraduates to do. If we (2004) Scientific Teaching. Science 304, 521–522.

March 2010 ASBMB Today 23 minorityaffairs Mentoring Is a Primary Responsibility BY PHILLIP ORTIZ

he American Society for Biochemistry and Molecular faculty mentor and ask him or her if that’s the legacy he TBiology’s Minority Affairs Committee has several mis- or she wants to leave. sions. One of them is fostering the development of scien- The graduate education system is also a mess. The tists. We think this is important for a number of reasons. present system is one that allows some graduate schools First, funding often is directed toward research areas to admit far more students than they will matriculate. This where there is “interest.” For too long, too little money tremendous attrition is often ascribed to failure of the has been allotted to topics of interest to women and students, but we all know this is not the case. Graduate people of color— for example, hypertension, breast can- students are among our brightest and hardest working, cer and diabetes. By enhancing education and increas- but their programs are neither “rewarded” for retaining ing the number of women and people of color who are them nor “punished” for losing them. All too common professionals, we hope that these topics will begin to is the faculty mentor who is holed up in his or her office receive the funding they merit. Second, we believe in writing grants and papers while the graduate students are social justice— for too long, too few people controlled farmed off on postdoctoral fellows. Little, if any, training or the gates of higher education. This has led to patterns in supervision of those postdocs is expected, as they too will which only a subset of America has access to education be judged solely by the length of their publication record. and professional employment. I believe that, at too many institutions, too little attention is One of the ways the MAC fosters the development paid to a faculty member’s mentoring skills and expertise, of scientists is by engaging in and encouraging mentor- and institutional resources are not directed at promoting ing. For example, at the ASBMB annual meeting in April, the development of these skills. Mentees and students we will be hosting a symposium on mentoring, during (and the requisite mentoring and teaching) in such settings which four speakers will address such issues as mentor- are an afterthought rather than an essential focus. The stu- ing women and nontraditional students, mentorship from dents who do get to graduation often have learned nothing undergrad until tenure and working with mentees at a more than how to succeed in that type of environment. distance. And, as many of them will ultimately not be academic Along those lines, I’d like to use this column to do researchers, those skill sets may not be useful. some mentoring. In my experience, many graduating So what can we do? It is no secret that the behaviors students will be unprepared for the challenges that lie we reward will be the behaviors we encourage. I suggest ahead. This problem is not new or unknown, but, it is too that we begin rewarding students for taking chances often ignored. and asking insightful questions. The current system is one that rewards students with a degree once they have The Education System completed their research project, and those who finish Science education in the United States is in need of with a minimum of delay are those who have chosen (or repair. From primary through graduate education, there is been given) a “clean” project. Students who chose com- a shortage of excellent science teachers. Is it any wonder plex problems that require massive amounts of develop- that scientific literacy rates are low and that “magical ment may find their degrees delayed, if they are ever thinking” abounds? Try this experiment: Ask a science finished. Sadly, it is exactly these students, the ones who teacher at a local K-12 school to explain evolution by are driven by curiosity and challenge, who are discour- natural selection. I have found that many can’t do this aged by our system. well, but will avow to “believing in it.” Similarly, the stu- This situation is not unique to graduate schools. How dents who matriculate from our graduate programs enter many of your grade school teachers rewarded the stu- the professoriate with little or no training in how to teach. dents who had the right answer, and how many rewarded As an example of this, ask a graduate student to define the students who asked the right questions? We foster “pedagogy.” When he or she can’t, track down his or her this in our own children by asking them to work hard and

24 ASBMB Today March 2010 minorityaffairs

be attentive and doing nothing to encourage their curios- it. The path won’t necessarily be easy, and you are likely ity. In my own case, each night over dinner, I would ask to make mistakes along the way, but, never forget that my daughter to tell me three things that she had learned anything worth achieving is worth working for, and what that day. Now, I ask her to tell me three good ques- you learn on the journey ultimately will inform your under- tions she asked that day. That subtle shift resulted from standing and future decisions. expecting her to be a passive learner to being an active Many colleges and universities have career develop- one. What do you— as a teacher, mentor or parent— ment centers that can help by providing career counsel- do to reward the curiosity of those in your charge? How ing, aptitude analysis and other resources. One of the do you help your students learn and understand the exercises you can undertake is identifying the lifestyle processes of science? Which is more important for a you would like, and working backward from there. graduate student— finishing a simple problem or under- Speaking for myself, although I find my career very standing a complex one? What is more important for satisfying I never have forgotten the sage advice given success— “finishing” one’s education or being a life-long to me by a senior postdoctoral fellow at the National learner? In one form or another, we are all mentors, and Institutes of Health. She said, “You will probably never mentoring well is our responsibility. hear someone utter with their last breath, ‘I should have spent more time in the office.’” Similarly, I realized long What You Can Do ago that no one can ever be paid enough to do a job So, what is my mentoring advice to you? I suggest you they don’t enjoy. For that reason, I have worked to build make a five-year plan: Identify what you want your life to my career around my life— I have made my career one be like in five years, and start working toward that goal. If in which I can serve my passions. In my case, I take you want to teach, identify the skills, knowledge, abili- more personal satisfaction in helping mentees identify ties and experiences necessary to reach that goal. For their goals and then work toward those goals than I ever example, if you want to teach at elementary or second- did preparing a manuscript. And, in my evaluations of my ary school, learn about your state’s teacher certification peers, I emphasize successful mentoring and leadership requirements, determine what gaps exist in your educa- in my justification for their reappointment, tenure and tion and experiences and create a road map to get from promotion. where you are now to where you want to be. For the most part, excellent teachers, scientists, parents and [fill Phillip Ortiz ([email protected]) is an associate professor at in the vocational worker of your choice] are made, not the State University of New York, Empire State College. born. Identify what you want to excel at and work toward

Minority Doctorates: The Numbers The data were compiled from three sources— two National The number of minorities receiving doctoral degrees has Science Foundation reports, which show the breakdown of increased over the past several years. The table below shows degrees by specialty, and the American Society for Biochem- the breakdown of doctoral degrees awarded to U.S. citizens istry and Molecular biology graduation survey, which shows and permanent residents from July 1, 2007 to June 30, 2008. degrees awarded in biochemistry and molecular biology.*

Degrees Awarded: Degrees Awarded: Degrees Degrees Awarded: Biochemistry and Science and Awarded: Biological/Medical Ethnic Classification Molecular Biology1 Engineering2 Non-Science2 Sciences3 Native American 3.5% 0.3% 0.5% 0.4% Asian 20.0% 10.4% 5.2% 11.7% Black 5.0% 4.5% 9.9% 3.7% Hispanic 7.9% 5.9% 5.6% 6.1%

1. American Society for Biochemistry and Molecular biology graduation survey. ASBMB Today, December 2008, p. 25. 2. National Science Foundation (2009) Numbers of U.S. Doctorates Awarded Rise for Sixth Year, But Growth Slower. NSF 10-308, Table 2. (http://bit.ly/cBgmkD) 3. National Science Foundation (2009) Doctorate Recipients from U.S. Universities: Summary Report 2007–08. NSF 10-309, Table 9. (http://bit.ly/cNy16N) *Data courtesy of James Zimmerman.

March 2010 ASBMB Today 25 asbmbmeetings Systems Biology for Biochemists Merging the Experimental and Theoretical BY VALERIE DE CRECY-LAGARD AND ALEXANDRE V. MOROZOV

n October 2009, approximately 60 scientists met for a molecular thermometer, he Ithe first “Systems Biology for Biochemists” American analyzed the melting tem- Society for Biochemistry and Molecular Biology Special perature of specific recon-

Symposium at Granlibakken resort in Lake Tahoe, Calif. As stituted ancestor proteins, De Crecy-Lagard biology is now fully in the post-genomic era, the question which pointed to a possible of how the availability of more than a thousand genome thermophilic origin of life. sequences changes the way biochemists design and The afternoon continued conduct their experiments is a pressing one. with an “origin of life” theme Arcady Mushegian of Stowers Institute for Medical as Armen Mulkidjanian of Research organized the meeting to allow experimental Universitat of Osnabruck and theoretical scientists to come together and see how presented evidence for his biochemistry is now integrated at several levels with many “zinc world hypothesis,” in other fields. This integration was apparent during the first which photosynthesizing evening, when Gregory A. Petsko of Brandeis University ZnS precipitating around presented his work that combined yeast genetics and primeval hot springs in high- three-dimensional structures to rapidly identify drug tar- pressure environments could Morozov gets and drug candidates in Parkinson’s disease. Another have driven the synthesis “big picture” presentation was given by Eugene V. Koonin of organic molecules (3). Other afternoon talks covered of the National Center for Biotechnology Information, who a range of topics: Frederic F. Pio of Simon Fraser Uni- showed that evolutionary principles can be extracted from versity talked about automated long range homology whole genome sequences as evolutionary biology goes algorithms, network analysis and experimental methods from “stamp collecting to physics.” used to identify the “inflammasome,” and Georgy P. Karev The emphasis of the next day’s session was on recon- of the National Institutes of Health presented a modifica- structing ancestral and minimal biochemical pathways. In tion of the Eigen “error catastrophy” model that would the morning, Vadim Gladyshev of Harvard Medical School allow biological systems to evolve. Literature mining was and Valérie de Crécy-Lagard of the University of Florida at the core of the Medscan platform Ilya Mazo of Ariadne emphasized the power of using comparative genomic Inc. designed to infer relationships between genes and/ approaches to discover new pathways and physiologi- or compounds using scattered and non-homogeneous cal trends. Gladyshev presented an impressive analysis literature sources. The afternoon ended with Peter D. Karp of players in metal trace-element metabolism in 700 of SRI International presenting the Pathway Tools platform. genomes (1). De Crécy-Lagard showed that in silico data- The focus of the next day’s morning session was mining approaches can be used to identify many missing the progress of the structural genomics initiative. SG is tRNA modification genes. The field of synthetic biology a large-scale structure determination program with an was represented by Mikkel Algire of the J. Craig Venter emphasis on previously uncharacterized protein families. Institute. He described a general method that eliminates Nick Grishin of the University of Texas Southwestern, ligation steps in gene, operon or plasmid assembly that John-Marc Chandonia of Lawrence Berkeley National was used to assemble a whole Mycoplasma mycoides Laboratory, Aled Edwards of the University of Toronto and genome in yeast and transplant it into Mycoplasma Alexey G. Murzin of the MRC Laboratory of Molecular capricolum (2). Eric Gaucher of the Georgia Institute of Biology described the role of SG in improving protein clas- Technology combined phylogeny reconstruction with gene sification schemes and providing new functional insights. synthesis to express “ancestor proteins.” Using EF-Tu as In particular, Chandonia used bioinformatic analysis

26 ASBMB Today March 2010 asbmbmeetings

based on the SCOP structural classification database (4) California Institute of Technology presented a time-lapse to argue that new SG structures have greatly enhanced microscopy study of the Notch-Delta signaling pathway our knowledge of protein families while at the same time — the canonical pathway for communication between decreasing the average cost of solving a protein structure. neighboring cells during development. He found an ultra- Edwards discussed SG contributions to characterizing sensitive protein-level switch between mutually exclusive structural and chemical biology of human proteins, with sending and receiving signaling states and argued that the a focus on epigenetic targets such as histone methyl biochemical mechanism of the Notch-Delta switch could transferases which have been implicated in various human serve as a new design principle in many other intercellular diseases. Murzin described how structure-guided analysis networks. can be used for protein function prediction. This meeting, hopefully, was the first in a long series of The afternoon session started with a talk by Alexandre V. workshops, as it clearly fills an urgent need of integrating Morozov of Rutgers University on the theoretical principles biochemistry with systems biology. of protein folding and evolution. Morozov argued that many * It is with a great sadness that the meeting participants evolutionary phenomena (such as increased evolvability of and the scientific community learned that on Nov. 3, more stable proteins) can be understood using a simple 2009, Warren Delano, 37, passed away unexpectedly. In model in which organismal fitness is proportional to the honor of his work in bioinformatics, ASBMB has created probability of a protein to be folded and therefore functional. the Delano Award for Computational Biosciences. See The next speaker, Warren DeLano* of DeLano Scientific p. 11 for more information. LLC, provided a brief introduction to the main features of a popular open-source molecular visualization software Valérie de Crécy-Lagard ([email protected]) is an associate professor PyMOL. Other speakers in the session discussed how in the department of microbiology and cell science at the University structural and functional genomics can be used to bench- of Florida. Alexandre V. Morozov ([email protected]) is mark large-scale predictions of protein function (Ambrish an assistant professor in the department of physics and astronomy Roy of the University of Kansas), catalog structurally and the BioMaPS Institute for Quantitative Biology at Rutgers uncharacterized protein families (Mensur Dlakic of Montana University. State University), employ mass spectrometry in proteomics

(Vlad Petyuk of the Pacific Northwest National Laboratory) References and study diversity of polyamine biosynthesis pathways 1. Zhang, Y., and Gladyshev, V. N. (2010) General Trends in Trace Element Utilization Revealed by Comparative Genomic Analyses of Co, Cu, Mo, Ni, and Se. J. Biol. with comparative genomics methods (Anthony J. Michael Chem. 285, 3393–3405. of the Institute of Food Research). 2. Lartigue, C., Vashee, S., Algire, M. A., Chuang, R-Y., Benders, G. A., Ma, L., Noskov, V. N., Denisova, E. A., Gibson, D. G., Assad-Garcia, N., Alperovich, N., On the final day of the meeting, the focus shifted from Thomas, D. W., Merryman, C., Hutchison, C. A., Smith, H. O., Venter, J. C., and large-scale protein structure determination to studies of Glass, J. I. (2009) Creating Bacterial Strains from Genomes That Have Been Cloned and Engineered in Yeast. Science 325, 1693–1696. genetic and protein networks. Frederick Roth of Harvard 3. Mulkidjanian, A. Y., and Galperin, M. Y. (2009) On the Origin of Life in the Zinc University spoke about a systems biology approach to World. 2. Validation of the Hypothesis on the Photosynthesizing Zinc Sulfide eEdifices as Cradles of Life on Earth.Biology Direct 4, 27. deciphering genetic interactions in Saccharomyces cerevi- 4. Murzin, A.G., Brenner, S.E., Hubbard, T., and Chothia, C. (1995) SCOP: A siae— a useful technique for identifying protein complexes, Structural Classification of Proteins Database for the Investigation of Sequences and Structures. J. Mol. Biol. 247, 536−540. ordering genes in pathways and finding synergistic drug combinations. Andrey Rzhetsky of the University of Chi- cago described information overload in modern molecular biology caused by an avalanche of new data and ideas For more information and showed how text-mining techniques could be used to • To see the meeting program and slides from several of extract both active and forgotten knowledge from vast sci- the lectures, go to http://bit.ly/bWzN9o. entific literature. Arcady Mushegian described the state of the art in creating similarity metrics for biological networks • To learn more about systems biology, check out the starting from vectors of experimental data assigned to each Journal of Biological Chemistry thematic minireview gene or protein. Mushegian also introduced a novel iterative series, “Computational Biochemistry: Systems algorithm, PSI-SQUARE, designed to search for similari- Biology,” at http://bit.ly/a6Ij1G. ties between network nodes. Finally, David Sprinzak of the

March 2010 ASBMB Today 27 biobits asbmb journal science

Did You Know? JBCA Novel Title Neurotoxin here Ninety-seven American XxxxxxSnake venoms xxxxxxx contain a Society for Biochemistry xxxrich xxxxxxxxxcocktail of pharma- and Molecular Biology xxxxxxxcologically xxx active pep- members have been the xxxxxxxxtides and proteinsxxx that recipients of Nobel Prizes. xxxhave xxxxx contributed xxxxx greatly • Thirty-five of the prizes xxxxto scientific xxxxx xxx advances, xx were in chemistry, and 62 of the prizes were in xxxxxsuch as xxx understanding xxxx physiology or medicine. xxxxxxxxxxxxxxreceptor activity and xxxxxxxxxdeveloping new thera- • The first ASBMB member to receive the prize was xxxxxxxxxxpeutics. The authors Xxxxxx xxxxx xxxxxxx xxxxxxx xxxx Otto Meyerhof in 1922, xxxxxxxxxof this paper have nowxxxxxxxxxx xxxxxxxx xxx xxxxx for his discovery of the Otto Meyerhof was the first xxxxxxxxxxxxadded another member relationship between the ASBMB Nobel Prize recipient. xxxxto this xxxxx class xxxxxxxxxxxx of valu- xxxxxxxxxxxx consumption of oxygen Haditoxin subunit A (blue) xxxxxxxxxxxxable peptides, xxxxxxxproviding xxxxxxxxxxx superimposed on erabutoxin-a and the metabolism of lactic acid in muscle. xxxxa detailed xxxxxxxxx structural xxxx xxx xxxxx(magenta), xxxx erabutoxin-b (cyan) • In both 1962 and 1972, five ASBMB members xxxxxxxxxand functional xxxxxxxxxxxxxxxxxx char- and toxin- xxxxxxxxxα (green). received Nobel prizes. John C. Kendrew and xxxxxxxxxxxxxxxxxxxacterization of a novel xxxxxxxxxxxx xxxx xxxxx Max Perutz were awarded the 1962 Nobel Prize xxxxxxxxxxxxneurotoxin from xxxxxxxxxxxx the venom of xxxxxxxxxxxx the King cobra. xxxxxxx Their in Chemistry, and Francis H. Crick, James D. xxxxxxxxxxx1.5-Å crystal structurexxxxxxxxxxxxxxxxxxxx revealed that this xxxxx new toxin, Watson and Maurice H. Wilkins shared the 1962 Nobel Prize in Physiology or Medicine. In 1972, xxxxxxxxxxxxxcalled haditoxin, xxxxxxxxxxxxxxxxxx exists as a homodimer, xxxxxxxxx similar to William H. Stein, Christian B. Anfinsen and xxxxxxxxxxxxxxxxxxxthe k-neurotoxin family. xxxxxxxxxxxx Interestingly, xxxxhowever, xxxxx the Stanford Moore were honored with the Nobel xxxxxxxxxxxxmonomeric subunits xxxxxxxxxxxx of haditoxin, xxxxxxxxxxxx which consist of Prize in Chemistry, while Rodney R. Porter and xxxxxxxa three-finger xxxxxxxxxxx protein xxxxxxxxxxxxxxxxxxxxfold, closely resemble short- xxxxx Gerald M. Edelman shared the Nobel Prize in xxxxxxxxxxxxxchain α-neurotoxins, xxxxxxxxxxxxxxxxxx unlike k-neurotoxin xxxxxxxxx monomers, Physiology or Medicine. whichxxxxxxxxxxxxxxxxxxx resemble long-chain xxxxxxxxxxxx α-neurotoxins. xxxx xxxxxPerhaps • Four of the ASBMB laureates were women: morexxxxxxxxxxxx interestingly, while haditoxin could antagonize • Gerty Theresa Cori was awarded the 1947 several classes of nicotinic acetylcholine receptors Nobel Prize in Physiology or Medicine for her discovery of how glycogen is broken down and (nAChRs) in neurons and muscle, its greatest poten- resynthesized in the body to be either used or cy is against α7-nAchRs, which are recognized by stored as a source of energy. neither short-chain α-neurotoxins nor k-neurotoxins. • Dorothy Mary Crowfoot Hodgkin received the Given this diverse and unique pharmacology, ha- 1964 Nobel Prize for Chemistry for determining ditoxin might have many future uses in developing the structures of several biologically important compounds using X-ray crystallography. molecular probes and therapeutic agents. • Gertrude Belle Elion was the recipient of one- third of the Nobel Prize for Physiology or Medicine in 1988 for her development of drugs used to treat Structural and Functional Characterization several major diseases. of a Novel Homodimeric Three-finger NeurotoxinFull title here from xxxxx the xxxxxx Venom xxxxxxxxx of xxx • Carol W. Greider received one-third of the 2009 xxxxxxxx x xx xxxxx xx Nobel Prize in Physiology or Medicine for the Ophiophagus hannah (King cobra) discovery of how chromosomes are protected by AmritaAuthors R namesoy, Xingding here xxxxxxxZhou, Ming xxxxxxxx Zhi Chong, xxxxxxxxx xxxxxxx xxxxxxxxxxxx xxxxxxxxxxxxxx xxxxxxxxxx telomeres and the enzyme telomerase. Dieter D’hoedt, Chun Shin Foo, Nandhakishore JournalRajagopalan, info here Selvanayagam xxxxxxxxxxxxx N irthanan,xxxx xxxxxx Daniel For more information about ASBMB Nobel laureates, xxxxxxxxxxxxxBertrand, J. Sivaraman and R. Manjunatha Kini go to http://bit.ly/bTbwER. J. Biol. Chem., published online Jan. 13, 2010

28 ASBMB Today March 2010 biobits asbmb journal science For more ASBMB journal highlights go to www.asbmb.org

JLA LittleR Title D HAhere MExploringCP Title here GoesXxxxx xxxxxxxx a xxxxxxLong xxxxxx Wxxxxxxxay xx CerebrospinalXxxxx Fluid xxxxx xxx xxx xxxxxx xx xxxxxxxxxxxxxxxxxx xxxxx xxxxxx xxxxxx Endocannabinoids are fatty-acid-derived signal- Cerebrospinal fluid (CSF) contains many proteins of xxxxxxxxxxxxx xxxxxxxxxxxxxxxxxx xxxxxxxxx xxxxxxx xxx xxxxx ing lipids that are physiologically important in many neural origin and is often known as a biochemical xxxxxxxxxxxxxxxxxxx xxxxxxxxxxxx xxxx xxxxx xxx xx xxxxx mammalian systems, particularly the brain. In this window into the brain. Therefore, CSF is an ideal xxxxxxxxxxxx xxxxxxxxxxxx xxxxxxxxxxxx xxxxxxx xxxxxxxxxxxxx xx study, the authors report on how two-week docosa- source in the search for biomarkers of neurological xxxxxxxxxxx xxxxxxxxxxxxxxxxxxxx xxxxx xxx xxx xxxxxxxx hexaenoic acid (DHA) supplementation affects the diseases, if the proteomic challenge of characteriz- xxxxxxxxxxxxx xxxxxxxxxxxxxxxxxx xxxxxxxxx xx xxxxxxxxxxxx physiological state of 15 endocannabinoid-related Xvvvvving a biologicalvvvvvv vvvvvvv fluid vvvvv with vvvvv a veryv wide concentration xxxxxxxxxxxxxxxxxxx xxxxxxxxxxxx xxxx xxxxx vvvvvv vv vvvvvvvv xxxxxx xxxxx metabolites in the plasma and brain of mice. Their range of proteins xxxxxxxxxxxx xxxxxxxxxxxx xxxxxxxxxxxx xxxxxxx xxxx xxxxxxxx lipodomic analysis revealed that a DHA-rich diet can be overcome. xxxxxxxxxxx xxxxxxxxxxxxxxxxxxxx xxxxx xx xxxx xxxxx markedly elevated the DHA, eicosapentaenoic In this study, the xxxxxxxxxxxxx xxxxxxxxxxxxxxxxxx xxxxxxxxx xxxx xxxxxxxx xxxx xxxxx xxxxxxxxxxxx acid (EPA), 2-eicosapentanoylglycerol (EPG) and researchers used xxxxxxxxxxxxxxxxxxx xxxxxxxxxxxx xxxx xxxxx xxxxxxxxxxxx xxxx xxxxxxxx xx xxxxx docosahexanoylethanolamine (DHEA) concentra- a combinato- xxxxxxxxxxxx xxxxxxxxxxxx xxxxxxxxxxxx xxxxxxx xxxxxxxxxxx xxxxxxxxxxxxxxxxxxxx xxxxx tions in both plasma and brain, while regulating rial peptide ligand xxxxxxxxxxx xxxxxxxx xxxxxxxxxxxx xxxxx xxxxxxxxxxxxx xxxxxxxxxxxxxxxxxx xxxxxxxxx other metabolite species in a compartment- and/or library bound to xxxxxx xxxx xxx xxxxxxxxxxxxx xxxxx xxxxxxxxx xxxxxxxxxxxxxxxxxxx xxxxxxxxxxxx xxxx xxxxx metabolite-selective manner; in general, DHA sup- porous beads to xxxx xxxxxxxxxxxxxxx xxxxxxxxxxxx xxxx xxxxx xxxxxxxxxxxx xxxxxxxxxxxx xxxxxxxxxxxx xxxxxxx plementation shifted the balance to favor docosa- reduce the dynam- xxxxxxxxxxxx xxxxxxxxxxxUnique protein groups xxxxxxxxxxxxxxxxxxxx identified xxxxx hexaenoic and eicosapentaenoic species compared in a series of one-dimensional gel ic range of protein xxxxxxxxxxxxx xxxxxxxxxxxxxxxxxx xxxxxxxxx with arachidonoyl and oleoyl derivatives. Overall, the fractions from either crude CSF concentrations in xxxxxxxxxxxxxxxxxxx(dotted line) or the first eluate xxxxxxxxxxxx from xxxx xxxxx endocannabinoid metabolome exhibited greater re- CSF and progres- xxxxxxxxxxxxsamples treated with xxxxxxxxxxxx the NH2 library xxxxxxxxxxxx sponsiveness to DHA in plasma, perhaps reflecting (solid line). sively enrich minor xxxxxxx xxxxxxxxxxx xxxxxxxxxxxxxxxxxxxx xxxxx that the brain maintains its lipid population within protein species. xxxxxxxxxxxxx xxxxxxxxxxxxxxxxxx xxxxxxxxx a more stringent homeostatic range. This analysis With this approach, they managed to uncover a host xxxxxxxxxxxxxxxxxxx xxxxxxxxxxxx xxxx xxxxx suggests that even short-term DHA enhancement of previously hidden CSF proteins; of the 1,212 CSF xxxxxxxxxxxx can affect select constituents of brain and plasma proteins they identified from pooled samples using endocannabinoids. liquid chromatography-tandem mass spectrometry, only 745 were detected after peptide library treat- ment. When the protocol was optimized to work Xvvvvv vvvvvv vvvvvvv vvvvv vvvvv v vvvvvv vv vvvvvvvv with individual low-volume samples, as would be the case in any clinical application, the research- ers found that this miniaturized approach was still reproducible and effective at enriching low concen- tration proteins, making it a feasible strategy for Dietary DHA-supplementation does not affect the concentrations analyzing neurological diseases. of 2-arachidonoylglycerol (AG) or 2-oleoylglycerol (OG) in the brain, but decreases them significantly in plasma. FullIn-depth title here Exploration xxxxx xxxxxx of Cerebrospinal xxxxxxxxx xxxFluid by Dietary Docosahexaenoic Acid Supplementation xxxxxxxxCombining x xxPeptide xxxxx Ligand xx Library Treatment Full title here xxxxx xxxxxx xxxxxxxxx xxx Alters Select Physiological Endocannabinoid- and Label-free Protein Quantification xxxxxxxx x xx xxxxx xx Authors names here xxxxxxx xxxxxxxx xxxxxxxxx xxxxxxx system Metabolites in Brain and Plasma Emmanuellexxxxxxxxxxxx Mouton-Barbosa, xxxxxxxxxxxxxx xxxxxxxxxx Florence Roux-Dalvai, Authors names here xxxxxxx xxxxxxxx xxxxxxxxx JodiAnne T. Wood, John S. Williams, David Bouyssié, François Berger, Eric Schmidt, xxxxxxx xxxxxxxxxxxx xxxxxxxxxxxxxx xxxxxxxxxx Journal info here xxxxxxxxxxxxx xxxx xxxxxx Lakshmipathi Pandarinathan, David R. Janero, Pierxxxxxxxxxxxxx Giorgio Righetti, Luc Guerrier, Egisto CarolJournal J. info Lammi-Keefe here xxxxxxxxxxxxx and Alexandros xxxx xxxxxx Boschetti, Odile Burlet-Schiltz, Bernard Makriyannisxxxxxxxxxxxxx Monsarrat and Anne Gonzalez de Peredo J. Lipid Res., published online Jan. 13, 2010 Mol. Cell. Proteomics, published online Jan. 21, 2010

March 2010 ASBMB Today 29 careerinsights Chance Favors the Prepared Mind How to Shape Your Future as a Science Administrator BY SHAWN R. DREW

ore than a century ago, Louis bilities were similar to the activities I MPasteur said, “Chance favors already was doing. Thus, I decided only the prepared mind.” By this he to leave the lab and focus on science meant that sudden flashes of insight administration, incorporating my love don’t just happen— they are the of science and passion for training products of preparation. Preparation, young scientists. therefore, is the key to a successful Currently, I work as a program Shawn R. Drew earned her and fulfilling scientific career. Whether official in the Minority Opportunities bachelor’s degree from Spelman you take the “traditional” academic in Research Division at the National College in 1991 and her doctor- route and become a professor or the Institute of General Medical Sci- ate in biology from Howard Uni- “non-traditional” route and become a ences. We administer research and versity in 1998. She conducted science writer, policy analyst, venture research-training programs aimed her postdoctoral research at the capitalist, etc., you should identify at increasing the number of under- National Institute of Diabetes, your career niche and prepare for it. represented minority biomedical and Digestive and Kidney Diseases. behavioral scientists. I get enor- In 2003, Drew joined the National My Transition from mous satisfaction when speaking Institute of General Medical Sci- Bench to Desk with students, postdoctoral fellows, ences at the National Institutes of I trained as a graduate student and faculty members and individuals in Health as a program director in postdoctoral fellow at the National leadership positions at academic the Minority Access to Research Institutes of Health, but, at the same institutions across the country about Careers Branch. She also serves time, I did a lot of volunteer work. our programs and their benefits. I as the institute’s program director Because I enjoy doing outreach, often think, “I can’t believe I get paid for the Biostatistics Research especially to underrepresented to do this!” Training Grant program and is the groups, I gave presentations to mid- chairwoman of the Committee dle and high school students, taught An Example: The Health to Maximize Representation for science courses at area colleges, Scientist Administrator research-training grant programs. wrote science curricula for my local A career as a science administrator Prior to her appointment, she church, provided laboratory supplies can take place in academia, industry served as director of the NIH and gave presentations to students or government. The NIH employs in Nigeria and mentored under- numerous science administrators Academy, an intramural post- graduate students in my laboratory. to meet its mission of supporting baccalaureate research training One day, while I was a postdoctoral research and training in the bio- program, and was an adjunct fellow, I read an advertisement for medical and behavioral sciences. professor of biology at the Uni- a science administrator position at The primary responsibility for plan- versity of Maryland and Prince the NIH and realized that many of ning, directing and managing the George’s Community College. the required duties and responsi- evaluation of these activities rests

30 ASBMB Today March 2010 careerinsights

with health scientist administrators Instead, my first-hand knowledge of in science and have proof of what (HSAs). Typically, HSA duties include: the NIH helped me to land the job. you have contributed to your field • organizing and managing peer- However, people coming from out- of study. Other desirable skills that review groups to evaluate research side the NIH with only postdoctoral science administration recruiters proposals on the basis of their research training experience may find seek include the ability to com- scientific merit; it more difficult to transition to a HSA municate effectively, leadership and • managing extramural research and position before establishing a lab. management skills and the ability research-training programs and Furthermore, regardless of the type to work effectively and cooperate identifying gaps in research and research training areas warranting of organization you join, the likelihood with others. Do you have these either increased or decreased of getting a position increases with skills? Well, you may have them and funding emphasis; postdoctoral research training, as simply not realize it. For example, if • developing funding opportunity the experience, in part, is designed you’ve mentored people in the lab, announcements designed to elicit to develop your independence and ordered and organized lab supplies research and research-training leadership skills. and equipment, organized data grant proposals from the scientific clubs, journal clubs or other semi- community; The Skills nars or worked with collaborators • providing technical assistance to The first step to preparing for an on research projects, you probably applicants and grantees; administrative career in science is possess leadership, management • conducting site visits to applicant conducting a self-assessment to and team-player skills. Other ways and grantee institutions to determine the adequacy of determine the activities you enjoy, the to obtain these skills include taking research and research-training skills you possess and the skills you leadership or management classes, facilities; lack. This information can help you teaching science courses, editing • serving as a spokesperson for determine whether a science admin- research papers or grant proposals, agency programs dealing with the istration position is right for you. You attending career advice workshops scientific community, Congress and may want to ask family members, and speaking with science adminis- other federal agencies. friends, colleagues and mentors to trators about their job duties. Typically, HSAs attend graduate describe your strengths and weak- Now that you know what a school, do postdoctoral training, nesses to help facilitate your assess- scientific administrative position obtain faculty positions and create ment. Armed with this information, might entail and you know the well-established laboratories before look at the position descriptions in skills involved, conduct your self- transitioning to science administra- science administration career post- assessment to see if that career is for tion. Thus, they have both an appre- ings. Are the duties and responsi- you. If so, try to acquire the training ciation for and the ability to work bilities appealing? Do you currently and skills you need to transition to a with faculty applying for research and perform or have you performed some science administration position. The training support. However, there are of the required duties? shift in focus from your specialized other means, albeit much less com- You may surprise yourself and research area to guiding decisions mon, of transitioning to an adminis- find that you posses the skills that affect the allocation of research tration job at the NIH. For example, I employers are seeking. First, sci- and research-training support is did not have a faculty position before ence acumen is paramount: You definitely achievable if you prepare entering program administration. must demonstrate competence yourself.

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March 2010 ASBMB Today 31 lipid news The Unmasking of Plasmalogens: Chlorinated Lipids BY DAVID A. FORD

ells of the innate immune system can be compared tin (4, 8). Also, HDL-associated α-chlorofatty aldehyde Cto cannons poised to release a diverse arsenal of inhibits protective and vasoregulatory-important eNOS- oxidants that kill invading organisms but can frequently derived NO production (9). These examples represent the cause collateral damage through the oxidation of host cell beginning of our understanding of the role of these newly molecules, including lipids. One of the oxidants produced discovered lipids. in vivo is bleach. Yes, neutrophils, monocytes and some In addition to the chlorinated lipids derived from the macrophages are enriched with myeloperoxidase, which arsenal of RCS produced by MPO, humans accumulate acts to amplify the oxidant potential of these cells by chlorinated lipids from environmental exposure to RCS converting hydrogen peroxide to hypochlorous acid and (e.g., cleaning with bleach and exposure in swimming its conjugate base, hypochlorite (or bleach). These reac- pools). Eosinophils also fire an “oxidant cannon” filled with tive chlorinating species (RCS) can chlorinate lipids, and hypobromous acid derived from brominated vegetable oil the masked aldehyde of plasmalogens has proved to be found in many soft drinks. Thus, not only do we produce the biggest (most reactive) target for the RCS projectile these halogenated lipids as a result of the cannons of thus far. the innate immune system, but we are likely marching Early studies demonstrated that RCS attack esteri- through this battlefield with self-inflicted daily environ- fied and non-esterified fatty acid alkene groups and mental and nutritional exposure to reactive halogenating the primary amines of phosphatidylethanolamine and species and their halogenated lipid products. phosphatidylserine, leading to the production of lipid chlorohydrins and chloramines (1, 2). My lab focuses on David A. Ford ([email protected]) is a professor in the department RCS-targeting plasmalogens, and we found that RCS of biochemistry and molecular biology and director of the Center target the vinyl ether bond of plasmalogens, releasing for Cardiovascular Research at Saint Louis University.

the masked aldehyde as an α-chlorofatty aldehyde with References a residual lysophospholipid by-product (3, 4). Our recent 1. Spickett, C. M. (2007) Chlorinated Lipids and Fatty Acids: An Emerging Role in Pathology. Pharmacol. Ther. 115, 400–409. studies have shown that chlorinated fatty aldehyde is 2. Messner, M. C., Albert, C. J., McHowat, J., and Ford, D. A. (2008) metabolized, giving rise to other chlorinated lipids, includ- Identification of Lysophosphatidylcholine Chlorohydrin in Human Atherosclerotic Lesions. Lipids 43, 243–249. ing α-chlorofatty acid and α-chlorofatty alcohol (5, 6). 3. Albert, C. J., Crowley, J. R., Hsu, F. F., Thukkani, A. K., and Ford, D.A. (2001) Reactive Chlorinating Species Produced by Myeloperoxidase Target the Vinyl It is likely that these chlorinated lipid building blocks may Ether Bond of Plasmalogens: Identification of 2-Chlorohexadecanal. J. Biol. be incorporated into complex lipids. Thus, through the Chem. 276, 23733–23741. 4. Thukkani, A. K., Hsu, F. F., Crowley, J. R., Wysolmerski, R. B., Albert, C. initial volley of RCS attack on plasmalogens, a chlorinated J., and Ford, D. A. (2002) Reactive Chlorinating Species Produced during Neutrophil Activation Target Tissue Plasmalogens: Production of the lipidome is born! Chemoattractant, 2-Chlorohexadecanal. J. Biol. Chem. 277, 3842–3849. These chlorinated lipids are novel molecules that are 5. Anbukumar, D. S., Shornick, L. P., Albert, C. J., Steward, M. M., Zoeller, R. A., Neumann, W. L., and Ford, D. A. (2009) Chlorinated Lipid Species in produced in response to the chemical arsenal released Activated Human Neutrophils: Lipid Metabolites of 2-Chlorohexadecanal. J. Lipid Res. E-pub ahead of print, 10.1194/jlr.M003673. during inflammation, and it is quite possible that they 6. Wildsmith, K. R., Albert, C. J., Anbukumar, D. S., and Ford, D. A. (2006) Metabolism of Myeloperoxidase-derived 2-Chlorohexadecanal. J. Biol. Chem. may have important mechanistic roles in host tissue 281, 16849–16860. injury. Members of this chlorinated lipidome accumulate 7. Thukkani, A. K., Martinson, B. D., Albert, C. J., Vogler, G. A., and Ford, D. A. (2005) Neutrophil-mediated Accumulation of 2-ClHDA during Myocardial in activated neutrophils and monocytes and in infarcted Infarction: 2-ClHDA-mediated Myocardial Injury. Am. J. Physiol. 288, H2955– myocardium and human atherosclerotic lesions (4, 7, 8). H2964. 8. Thukkani, A. K., McHowat, J., Hsu, F. F., Brennan, M. L., Hazen, S. L., and The primary plasmalogen-derived RCS products, Ford, D.A. (2003) Identification of a-Chloro Fatty Aldehydes and Unsaturated Lysophosphatidylcholine Molecular Species in Human Atherosclerotic α-chlorofatty aldehyde and unsaturated lysophosphatidyl- Lesions. Circulation 108, 3128–3133. 9. Marsche, G., Heller, R., Fauler, G., Kovacevic, A., Nuszkowski, A., Graier, choline, may propagate localized inflammatory responses W., Sattler, W., and Malle, E. (2004) 2-Chlorohexadecanal Derived From because they are chemoattractants and elicit the surface Hypochlorite-Modified High-Density Lipoprotein-Associated Plasmalogen Is a Natural Inhibitor of Endothelial Nitric Oxide Biosynthesis. Arterioscler. Thromb. expression of the phagocyte tethering molecule, P-selec- Vasc. Biol. 24, 2302–2306.

32 ASBMB Today March 2010

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September 30 – October 4, 2010

Transcriptional Regulation by Chromatin and RNA Polymerase II Granlibakken Resort, Tahoe City, CA Organizer: Ali Shilatifard Stowers Institute for Medical Research

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Biochemistry and Cell Biology Of ESCRTs in Health and Disease Snowbird Resort, Snowbird, UT Organizer: James Hurley National Institute of Diabetes and Digestive and Kidney Diseases Phyllis Hanson Washington University School of Medicine

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Detection and Physiological Evaluation Granlibakken Resort, Tahoe City, CA Organizer: Katalin Medzihradszky University of California, San Francisco Gerald Hart Johns Hopkins University School of Medicine

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Secretory and Endocytic Pathways Granlibakken Resort, Tahoe City, CA Organizer: Stanford University School of Medicine Vivek Malhotra Center for Genomic Regulation, Barcelona, Spain www.asbmb.org/meetings