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January 2010 Taking NMR to New Heights

American Society for Biochemistry and Molecular Biology ASBMB2 SPECIAL 0 SYMPOSIA 1 1 CALL FOR PROPOSALS

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ATodayFullPageAd_2011_Proposal Submission2.indd 1 11/23/2009 10:50:10 AM contents JANUARY 2010 On the Cover: Anne-Francis Miller is exploring ways to society news improve the sensitivity 2 New Eye Lipids Thematic of NMR spectroscopy. Review Series in JLR 20 3 President’s Message 6 News from the Hill 9 Washington Update 10 JBC: A Call for Papers and a Modest Course Adjustment 11 JBC Wishes PEPCK a Happy Anniversary! 12 Retrospective: Mildred Cohn (1913–2009) 14 Retrospective: Richard I. Gumport (1937–2009) A special JBC PEPCK compendium. 2010 annual meeting 11 17 Russell Wins the Avanti Award in Lipids 18 Wells Receives ASBMB-Merck Award 19 Keller Garners Avanti Proteomic studies Young Investigator Award of hibernation. 33 special interest 20 Anne-Frances Miller: Spinning Toward Success 24 Brian Malow: A Stand-Up Man of Science 26 University of Oregon’s Institute of Molecular Biology Celebrates 50 Years departments 28 Minority Affairs 31 Education podcast summary 32 BioBits Learn more about science comedian Brian 34 Career Insights Malow, featured in this month’s issue, in our latest ASBMB podcast. 36 Lipid News To hear this and other podcasts, go to www.asbmb.org/Interactive.aspx.

January 2010 ASBMB Today 1 firstsecond asbmb wordsnews A monthly publication of The American Society for Biochemistry and Molecular Biology New Eye Lipids Thematic Officers Gregory A. Petsko President Suzanne R. Pfeffer President-Elect Review Series in JLR Mark A. Lemmon Secretary Merle S. Olson Treasurer BY MARY CHANG Council Members Dafna Bar-Sagi Ruma V. Banerjee n January 2010, the Journal of Benjamin F. Cravatt Joan A. Steitz Thomas E. Smith Ann M. Stock ILipid Research begins a thematic James A. Wells Adrian Whitty review series that gives a closer Ex-Officio Members look at the lipids and lipid-soluble Ellis Bell Chair, Education and Professional compounds in the cells and tissues Development Committee of the vertebrate eye. The series, Joan W. Conaway Chair, Meetings Committee “Lipids and Lipid Metabolism in the John D. Scott Chair, Membership Committee Eye,” will contain five articles pub- Craig E. Cameron lished from January to May. Chair, Minority Affairs Committee Laurie S. Kaguni The series begins with an article 2010 Annual Meeting Program Coordinator by Raju V. S. Rajala of the University William C. Merrick Chair, Public Affairs Advisory Committee of Oklahoma Health Sciences Cen- Toni M. Antalis Chair, Publications Committee ter. Rajala discusses phosphoinosit- Herbert Tabor ide 3-kinase (PI3K) signaling in Editor, JBC Ralph A. Bradshaw the vertebrate retina. He and his A. L. Burlingame co-workers were the first to show Co-editors, MCP Edward A. Dennis that light in retinal rod receptors export by RPE cells, which is similar Joseph L. Witztum regulates the PI3K-dependent path- to the more intensively studied Co-editors, JLR way in the retina. Improper regula- process of atherosclerotic lesion ASBMB Today Editorial Advisory Board Alex Toker tion of PI3K has been implicated formation. Chair in diabetic retinopathy, a common Norma Giusto at Universidad Greg P. Bertenshaw Craig E. Cameron A. Stephen Dahms Irwin Fridovich blinding disorder, and, as such, Nacional del Sur, Bahia Blanca, in Jonathan Gitlin Richard W. Hanson research on the PI3K pathway may Argentina, will examine retinal rod Elizabeth A. Komives Bettie Sue Masters Luke A. O’Neill Duanqing Pei lead to therapeutic applications. outer segments. The review will Carol C. Shoulders Robert D. Wells Bis-retinoids have been linked discuss the possible relationship ASBMB Today to cell death of the retinal pigment between lipid-dependent signaling Nicole Kresge Editor [email protected] epithelium (RPE) and retinal degen- events, translocation of important Nick Zagorski Science Writer erative diseases, including age- molecules and association/disasso- [email protected] related macular degeneration (AMD), ciation of membrane proteins. Nancy J. Rodnan Director of Publications [email protected] a major cause of visual impairment in In the final review, Haydee E. P. Barbara Gordon Executive Director older adults. In February, Janet Spar- Bazan and Sachidananda Kench- [email protected] row of Columbia University will pub- gowda of the Louisiana State Magazine design & production: Amy Phifer lish a look at the formation, physical University Health Sciences Center For information on advertising, contact attributes and possible functions of School of Medicine will look at the Capitol Media Solutions at 800-517-0610 or [email protected] bis-retinoids in the retina. lipids involved in corneal injury and In her review for March, Chris- repair mechanisms and how that tine A. Curcio of the University of knowledge may lead to treatments Alabama at Birmingham will look for corneal wound healing. www.asbmb.org at extracellular lipid deposits that are tell-tale signs of AMD. Evidence Mary L. Chang ([email protected]) is indicates that those deposits result managing editor of the Journal of Lipid from lipoprotein formation and Research.

2 ASBMB Today January 2010 president’smessage Ring in the New BY GREGORY A. PETSKO

ere’s to the new year: May it be a damn sight bet- I still have six months to go as Hter than the old one. ASBMB president. It started out with such promise. We had a new I thought it might be a good president— one who promised to restore science to time to take stock of the state its rightful place in the councils of government (and, to of science in general, and the state of the ASBMB in our joy, he has). We had $10 billion in stimulus money particular, as we get ready to welcome in the first year for the National Institutes of Health to spend. Health- of the second decade of the 21st century. I have to care reform looked imminent. The war in Iraq was say that I think the state of science is good, though winding down. I had only another one-and-a-half years still threatened from the usual sources. And, I think as American Society for Biochemistry and Molecular the ASBMB is healthy but would be healthier if we had Biology president. All was well. more young members. But as 2009 winds down, that feeling of optimism Let me start with the ASBMB. Online is where has given way to one of anxiety— almost of impending it’s at. Last fall, we launched a new Web site for the doom. Delight over the stimulus has become frustra- Journal of Biological Chemistry, and now the editorial tion with the NIH Challenge Grants in Health and Sci- side is making adjustments (see article on p. 10). Our ence Research and the fear that the 2011 NIH budget two other journals, the Journal of Lipid Research and will be disastrously small. Health-care reform is being Molecular and Cellular Proteomics, also will be getting held hostage by a small group of senators who either similar Web sites in the coming year. MCP is going wish to use it as way of restricting abortion rights or, online-only in 2010, and JBC and JLR will follow when one is forced to conclude, who may be in the pock- the time is right for our users. Along with that, we soon ets of the insurance industry. As the war in Iraq winds will have a new Web site for ASBMB Today, replacing down, the war in Afghanistan is growing larger. And the old online pseudo-journal format. We think that

January 2010 ASBMB Today 3 president’sfirstsecond messagecontinued continued these represent real improvements in how we deliver tion budget. While the latter is on target with President content to our members over the World Wide Web. Obama’s stated intent to double the NSF budget, the The sites are meant to be easier to navigate, easier to former is below the expected level of scientific inflation. It browse and packed with more opportunities to find more would put the 2010 NIH budget at just under $31 billion. information. Our publications are intended to serve you, My Federation of American Societies for Experimental our members, first and foremost. So, write to us and let Biology counterparts and I have calculated that we need us know what you think of the new Web sites. And, if a 2011 appropriation for NIH of about $37 billion to avoid you have suggestions, please let us hear from you. We a catastrophic shrinkage of the NIH Research Project will listen. Grant Program (R01) pool when the stimulus winds As I said, I am still concerned with the demographics down. of our membership. I know this is also a major concern Of course, everything will depend on the state of the of my successor, Suzanne Pfeffer (and while I’m at it, economy around this time next year, and, if you can let me offer her my condol— er, my congratulations on becoming president-elect) and that she already has a number of exciting ideas for getting more young people …Italy’s foremost to join the society and for improving the ways in which we serve our younger members. But we still need your science agency actually help. Please, urge your best postdoctoral fellows to “ funded the publication of a take advantage of our free-for-the-first-year membership offer. We believe that once they experience the benefits creationist book authored by of membership, they will want to continue. They’re our its own vice president. lifeblood, and we are anemic at the moment. Otherwise, the health of the society is good. Thanks to prudent fiscal management (which is to say I had no predict that, you don’t need me to tell you anything. My input into it whatsoever), our finances are in relatively guess is that we will see the gross domestic product,” good shape, and we have been able, despite the reces- which I regard as a nearly useless statistic, grow by sion, to launch a few interesting new initiatives. One around 3 percent next year, which means the recession you will be reading more about in the coming months will be “officially” over. But I am also guessing that this is a series of joint conferences in Latin America, spon- will be a jobless recovery, by which I mean that unem- sored by ASBMB and our sister society in Brazil. My ployment will still be between 8 and 10 percent by the counterpart in that society, Debora Foguel, and ASBMB end of next year. If I’m right, a big boost for NIH will be past-President Bettie Sue Masters have taken the lead in very difficult to obtain— though not impossible— as the getting this cooperation off the ground, for which I would multiplier for NIH funds (the return to the economy for like to convey my deepest thanks. The first meeting will every dollar invested) is about $2.20. take the form of an advanced school on the subject of Speaking of NIH, kudos to Jeremy M. Berg, the head biofuels, an area of biochemistry in which Brazil already of the National Institute of General Medical Sciences, is among the world’s leaders. Watch ASBMB Today for for managing to keep the payline at NIGMS for compet- more details. ing R01 applications at right around the 30th percentile, Finally, our annual meeting, to be held in Anaheim, even when the stimulus money is not added in. I’m not Calif., in April 2010, is looking to be very popular. going to ask him how he managed that particular feat of Advance registration is running hot and heavy, so be sure legerdemain when so many other NIH institute directors to get yours in to secure your place at the Woodstock seemed to have had trouble doing so, but I suspect hav- of biochemistry. (OK, I admit that Jimi Hendrix and Janis ing fewer big science initiatives to fund didn’t hurt. Joplin won’t be there, but it will still be a great party.) Health-care reform is turning out to have more cliff- But, if the state of ASBMB is largely good, the same hangers than the last Indiana Jones film. Without getting cannot be said of the state of science in general. As into the politics of it, let me simply say that it’s going to I write this, the U.S. Senate— the same Senate that be a very tough battle to get this passed. That’s noth- seems to be using health-care reform as a football— ing new: Seven previous U.S. presidents have tried, and has just passed an appropriations bill that calls for about failed, to reform the health-care system in this country a 2.3 percent increase in the NIH budget and about a (beginning with Woodrow Wilson, who almost suc- 6.7 percent increase in the National Science Founda- ceeded in 1916 but was interrupted by a little something

4 ASBMB Today January 2010 president’sfirstsecond messagecontinued continued called World War I, and ending with Bill Clinton, whose fossil-dating methods are wrong and that dinosaurs have failure still rankles), so, if Obama succeeds, it will be a been extinct for only 40,000 years. Now, you might think, monumental accomplishment no matter what the bill Italy being a Catholic country, that the Roman Catholic looks like. But, make no mistake about it, this present Church was behind this somehow, but you’d be wrong. reform is not about controlling costs— it’s about getting The fascinating thing about this is that physicist Nicola everybody covered. There is no possibility that health- Cabibbo, president of the Pontifical Academy of Sci- care costs will go down, for the long term, unless we ences, the group of scientists who advise the Pope, has address the soaring cost of end-of-life care and shift expressed strong disapproval of CNR funding such a our mindset more toward prevention rather than treat- book. “The Catholic Church has accepted the thesis of ment. All of this makes biomedical research an essential evolutionism,” he points out. All of which suggests to me part of any real effort to get costs under control, which that we are shooting ourselves in the foot if we make the is another reason why I wouldn’t give up just yet on that strident voices of the Richard Dawkinses of the world our $37 billion NIH budget for 2011. spokespeople. We have more in common with sensible Looking back on 2009, though, the most ominous people of faith than we sometimes realize, and we need sign I see that all is not right with the world of science to build bridges to them so we can join against the is the continued efforts on the part of religious funda- forces of ignorance. mentalists to inject religious doctrine into the teaching of So, here’s to the new year— may it be a damn sight science in our public schools. Their latest ploy masquer- better than the old one. And may we all be healthier, ades as “critical thinking” or “freedom of expression” and happier and living in a more peaceful, more rational world takes the form of laws prohibiting someone from being when it’s over. dismissed from his or her job for teaching the alleged controversy about evolution, by which they mean that it’s perfectly OK for a so-called science teacher to present creationism, intelligent design and other Bible- in-science-clothing religious doctrines as legitimate alternatives to evolution, even though anyone who does so ought to be fired for incompetence. Don’t be fooled: Come work with us! Fundamentalists have no interest in critical thinking. They do not want debates about the truth. Their inten- Faculty Position in Biological Technologies tion is to replace science with religious doctrine, and I Department of Biological Engineering don’t mean a choice of religions either. This is all about The MIT Department of Biological Engineering invites applications for a very narrow, fundamentalist Christian point of view, a tenure-track faculty position at the assistant professor level, to begin July 2010 or thereafter. Applicants should hold a Ph.D. in a science or one that seeks to replace evidence-based thinking with engineering discipline related to biological engineering. A more senior faculty appointment may be considered in special cases. The candidate a blind faith in authority. It is very dangerous, it is not is expected to direct a pioneering research program that develops and going away and it has to be fought. applies transformative biological technologies in critical areas such as energy, the environment, nutrition, or novel materials. Faculty duties And, for those of you in more secular Europe con- also include teaching at the graduate and undergraduate levels, and supervision of student research. gratulating yourselves on not having this problem, let We especially encourage individuals from underrepresented groups to me point out to you that the American Association for apply, because of MIT’s strong commitment to diversity in engineering the Advancement of Science ScienceInsider reported education, research and practice. Interested candidates should send application materials to the Biological on Dec. 9 that Italy’s foremost science agency actually Engineering Faculty Search Committee at: [email protected]. Each application should include: a curriculum vitae; the names and funded the publication of a creationist book authored addresses of three or more references; a strategic statement of by its own vice president (http://bit.ly/8NADZF). Entitled research interests; and a statement of teaching interests specifically in the context of the Biological Engineering graduate and undergraduate “Evolutionism: The Decline of an Hypothesis,” the book educational programs at MIT (http://web.mit.edu/be/education/ and http://web.mit.edu/be/education/ugrad.htm). We request that each was funded by the Italian National Research Council candidate arrange for the reference letters to be sent directly to (CNR) and authored by Roberto de Mattei, a profes- [email protected]. Questions may be directed to: Prof. Douglas Lauffenburger, Head, sor of the history of Christianity and Catholicism at Department of Biological Engineering, MIT 16-343, 77 Massachusetts the European University of Rome and, as I said, a vice Avenue, Cambridge, MA 02139 or [email protected]. president of the council. The book is based on the pro- Responses by 1 February 2010 will be given priority. MIT is an Equal Opportunity/Affirmative Action employer. ceedings of a conference on the same topic that was, believe it or not, sponsored by the council in February. http://web.mit.edu Among its creationist claims, the book asserts that

January 2010 ASBMB Today 5

PUBLICATION ASBMB Today SIZE 3.375” x 4.875” SCREEN 85 lpi WO # 123435 IO # 581143 NOTES news from the hill More Bang for the Buck BY KYLE M. BROWN

ven as the president and Congress make overtures culture adverse to the risk-taking necessary for innovative Eabout the importance of greater investment in research. science, federal agencies are under increasing pressure In response, federal agencies recently have re-evalu- to make the most efficient use of the funds they are ated their grant-review procedures to make the process given. Bruce Alberts, editor-in-chief of Science Magazine, more innovation-friendly. For example, the National and others say that traditional funding mechanisms have Institutes of Health recently changed its grant application created a peer-review culture that funds conservative and form, reducing its length and requiring less preliminary incremental science (1). In response, federal agencies, data and fewer specific research methods (2). Further, nonprofits and private enterprises are developing new the National Science Foundation has adopted the lan- ways to fund creative, innovative and breakthrough- guage of innovation into every grant review it facilitates. oriented science. But will they create more scientific Since 2008, the NSF has used a definition of so-called “bang” for our buck? “transformative” research to instruct reviewers in identify- ing research on the scientific cutting edge (3). Identifying Innovative Projects But, the NIH and the NSF have gone even further and Traditional science funding is project oriented. Proposals created project-based funding mechanisms that attempt historically have required detailed descriptions of spe- to specifically fund innovative research. For example, the cific methods and preliminary data. Peer-review panels NIH’s Exceptional, Unconventional Research Enabling traditionally have chosen proposals that may be the best Knowledge Acceleration (EUREKA) Awards “target science but are also most likely to succeed. Many poli- investigators who are testing novel, unconventional cymakers and scientists say that approach has created a hypotheses or are pursuing major methodological and

6 ASBMB Today January 2010 news from the hill

technical challenges” (4). Demonstrating that it, too, will fund yet-untested ideas, the NSF has created the Early- House and Senate Negotiators concept Grants for Exploratory Research (EAGER) to Agree on 2010 Science Budgets support potentially transformative ideas or approaches in the absence of preliminary data (5). U.S. House and Senate negotiators have agreed on Other agencies in the U.S. defense and energy the 2010 budgets for several large scientific agen- departments are specifically tasked with funding innova- cies, including the National Institutes of Health and the tive research projects. The Defense Advanced Research National Science Foundation. While traditionally passed Projects Agency is famous for supporting efforts that in separate appropriations bills, the NIH and NSF budgets led to the development of the stealth fighter and the will become part of a large omnibus bill, combining six Internet (6). The Department of Energy’s Advanced appropriations bills into one piece of legislation. Research Projects Agency-Energy, ARPA-E, is mod- While Congress and the president previously had eled after DARPA and aims to fund “nimble, creative passed five of the 12 bills that traditionally fund the inventive approaches to transform the global energy federal government for 2010, the budgets for the NIH and landscape” (7). the NSF and 85 percent of federally funded life science research had yet to be finalized. With the publication of “People, Not Projects” the conference committee’s report, the House and Sen- While federal agencies rely on project-based grants to ate have paved to way for final passage by both houses fund the vast majority of research, some private founda- of Congress. tions have developed different philosophies. By funding According the report, the NIH will be funded at $30.72 “people, not projects,” Howard Hughes Medical Insti- tute believes that scientists will be able to “capitalize on billion for 2010. Adding an additional $692 million to the a flash of insight that occurs at three in the morning,” NIH budget, this 2.3 percent funding increase from the Gerald M. Rubin, vice president of the institute, said in previous year is a compromise between the 3.14 percent recent testimony before the U.S. House of Representa- and 1.47 percent proposed by the House and Senate, tives’ Committee on Science and Technology (8). The respectively. institute’s investigator program provides multiyear fund- The NSF will receive a larger relative boost. Negotia- ing to individuals who will creatively push the boundaries tors have agreed to increase the NSF budget by 6.7 of science, working at the frontiers of their chosen fields. percent to more than $6.9 billion. The bill’s summary also With funding that is not tied to any specific project or supports the president’s initiative to double the funding proposal, the institute hopes to give investigators the for basic research at “key agencies,” such as the NSF, in “ability to move quickly to take advantage of unforeseen 10 years. targets of opportunity,” Rubin said. Perhaps the most dramatic increase was given to the Following that model, the Pew Scholars Program in U.S. Department of Veterans Affairs Medical and Pros- the Biomedical Sciences provides funding for early-stage thetics Research program. This program’s budget will investigators. Each year, between 15 and 20 early-career grow by 13 percent in 2010 to a total of $581 million. faculty members are chosen to receive the four-year UPDATE: The House and Senate have passed the awards. While freed from the constraints of present- ing extensive amounts of preliminary data, investigators Consolidated Appropriations Act of 2010, the large must demonstrate creative, innovative, risky approaches omnibus spending bill that includes budgets for the NIH, and ideas (9). NSF and U.S. Department of Veterans Affairs Medical and Even the NIH is experimenting with this approach. Prosthetics Research program. The final budgets reflect In 2010, it awarded seven Pioneer Awards to investi- the agreements reached by House and Senate negotia- gators who proposed pioneering and transformative tors in early December. The House passed the appro- approaches that could have an unusually high impact on priations act on Dec. 10 and the Senate passed the bill a broad range of biomedicine (10). Additionally, the NIH on Dec. 13. President Obama signed the science funding Director’s New Innovator Award is tasked with “stimulat- bills in mid-December. ing highly innovative research and supporting promising

January 2010 ASBMB Today 7 newsfirstsecond from thecontinued hill continued new investigators” by funding early-career faculty who may lack preliminary data (11). Highlights from the Policy Blotter Innovation Prizes The American Society for Biochemistry and Molecular Popular in the private sector, innovation prizes soon Biology Policy Blotter blog posts regular news and may fund federal science research. These competi- commentary about current science policy issues. Below tions award large cash prizes to teams that success- are some recent highlights. You can read them and fully complete predefined tasks. Previously, awards other posts at http://asbmbpolicy.asbmb.org. have inspired scientists and engineers to measure a ship’s latitude accurately, fly across the Atlantic Ocean • A Lesson From Nobel Laureates: Basic Science Requires Federal Dollars and even develop better algorithms for predicting how (http://wp.me/pFLHF-27) much someone is going to enjoy a movie based on President Obama’s recent visit with the 11 American their Netflix movie preferences (12, 13). Now, the U.S. 2009 Nobel Prize laureates underscores the House of Representatives is encouraging the NSF to importance of federal funding for basic science. explore innovation prizes as a possible catalyst for • An Ongoing Conversation: scientific innovation (14). Women In Science (http://wp.me/pFLHF-2c) Impact Uncertain Several nonprofits, blogs and federal agencies recently have released publications about women With so many new mechanisms for funding innovative in science, and some have surprising takes on the research, it is difficult to determine which will prove the issue. best. More time and more research will be needed to • NIH, Collins Announce assess whether these novel mechanisms are fostering Approval of Stem-Cell Lines high rates of breakthrough science. But, by care- (http://wp.me/pFLHF-23) fully comparing them and other programs, we should The National Institutes of Health has approved the soon know the outcome of our nation’s innovation use of 13 lines of stem cells under a new policy that will expand dramatically the resources available for experiment. regenerative biomedical research. • “Growing Pains” for Evolution Kyle M. Brown ([email protected]) is an ASBMB science (http://wp.me/pFLHF-1W) policy fellow. Actor Kirk Cameron has teamed up with a creationist group to promote a version of Footnotes 1. Alberts, B. (2009) On Incentives for Innovation. Science, 326, 1163. Darwin’s “Origin of the Species” with a creationist 2. NIH Web site. Restructured Application Forms and Instructions for introduction. Application Due Dates on or after Jan. 25, 2010. http://bit.ly/6QAL8v. 3. Testimony of James P. Collins, assistant director, Directorate for Biological Sciences, National Science Foundation, before the U.S. House of Representatives, Committee on Science and Technology, Subcommittee 8. Testimony of Gerald M. Rubin before the Subcommittee on Research and on Research and Science Education. Oct. 8, 2009. Investing in High Risk, Science Education of the Committee on Science and Technology, United High Reward Research. http://bit.ly/7kdy9v. States House of Representatives. Oct. 8, 2009. http://bit.ly/5rsUJ6. 4. NIH Web site. Exceptional, Unconventional Research Enabling Knowledge 9. Pew Charitable Trusts Web site. Pew Scholars Program in the Biomedical Acceleration (EUREKA) (R01). http://bit.ly/6eULHx. Sciences. http://bit.ly/54QhQd. 5. NSF Web site. Chapter II -- Proposal Preparation Instructions. Early- 10. NIH Web site. Pioneer Award. http://nihroadmap.nih.gov/pioneer. concept Grants for Exploratory Research Grant Proposal Guide. http://bit. 11. NIH Web site. NIH Director’s New Innovator Award. http://bit.ly/4XQBfd. ly/7T2r5g. 12. King, R. (2009) Innovation prizes through history. Business Week. 6. Defense Advanced Research Project Agency Web site. www.darpa.mil/ http://bit.ly/6M59xc. history.html. 13. Netflix Web site. Netflix Prize. www.netflixprize.com. 7. U.S. Department of Energy Web site. Advanced Research Projects 14. House Report 111-149.Commerce, Justice, Science, and Related Agency-Energy. http://arpa-e.energy.gov. Agencies Appropriations Bill, 2010. http://bit.ly/6edHEc.

submission fee free.

8 ASBMB Today January 2010 washingtonfirstsecond updatewords FASEB FASEB Opposes Great Ape Protection Act BY CARRIE D. WOLINETZ

he Federation of American Societies for Experi- The Great Ape Protection Act has a broad defini- Tmental Biology is leading opposition to the Great tion of “invasive research,” including “any research Ape Protection Act (H.R. 1326), a bill that would end that may cause death, bodily injury, pain, distress, fear, all invasive research on great apes, including chim- injury or trauma.” This includes testing of any drug or panzees, gorillas, bonobos, orangutans and gibbons. other substances, research that would involve restrain- (Note: Gibbons are not technically great apes, but they ing, tranquilizing or anesthetizing the animal, removal are defined as such in the legislation.) of the animal from its social group or taking tissue In a letter sent to all members of the U.S. House samples, including blood, outside of necessary veteri- of Representatives, FASEB, along with other scientific nary care. FASEB is concerned that this broad defini- organizations, patient-advocacy groups and research tion could not only have a negative impact on biomedi- institutions, expressed concern that the bill would cal research on human diseases but also research “harm medical research that helps both humans and that is designed to benefit the great apes themselves, great apes.” The legislation was reintroduced in the such as the development of an Ebola virus vaccine for 111th Congress after failing to gain support in the pre- wild chimps or the treatment of heart disease in cap- vious Congress and has rapidly gained more than 100 tive gorillas. This also could limit relatively noninvasive co-sponsors. Passage of the legislation is considered work, such as genomic or cell culture studies, which a high priority by a number of animal-rights groups, require tissue collection. including the Humane Society of the United States and In addition to the joint letter, FASEB has been work- the Physicians Committee for Responsible Medicine. ing with its member societies and scientists to educate The joint letter of opposition emphasizes “that the policymakers about the potential consequences for research community is strongly committed to ensur- research under the bill, as well as raising awareness ing that the highest quality of humane care is main- about the multiple legal and regulatory protections that tained for all animals used in research, that animals are exist for animals used in research, particularly nonhu- housed and maintained under conditions appropriate man primates. The Great Ape Protection Act has been to their species and that research involves only the referred to the House Energy and Commerce Commit- minimum number of animals required to obtain valid tee, which has not held hearings on the subject and results.” is currently quite busy dealing with health-care reform Unfortunately, if the Great Ape Protection Act is legislation. A companion bill has not yet been intro- passed, it could halt a number of ongoing biomedical duced in the Senate. research studies, particularly on hepatitis C, for which chimpanzees are currently the only existing animal Carrie D. Wolinetz ([email protected]) is director of model. “Chimpanzees are a unique and invaluable scientific affairs and public relations for the Office of Public resource for ethically conducted biomedical research, Affairs at FASEB. particularly translational research through which sci- entific discoveries are advanced into treatments and cures,” the letter continues. Chimpanzees serve as For more information: models in studies investigating malaria, human cyto- • FASEB’s joint letter to the House of Representatives megalovirus, rotavirus, norovirus, respiratory syncytial concerning the Great Ape Protection Act can be virus, prion diseases and monoclonal antibody devel- found at http://bit.ly/6aPRSc. opment, among others. Under the existing research • If you would like more information on this legislation system, chimpanzees no longer used in research are and its status, contact Carrie D. Wolinetz at not euthanized; rather, they are humanely maintained [email protected] or 301-634-7650. in retirement facilities until their natural deaths.

January 2010 ASBMB Today 9 asbmbnews JBC: A Call for Papers and a Modest Course Adjustment BY ROBERT D. SIMONI

he Journal of Biological Chemistry was founded in is judged to be novel, important, of broad interest and T1905 with the principle that the journal would publish technically sound, it will be accepted and published in work on the “chemical side” of any biomedical discipline. the JBC, an icon among scientific journals. The time from While the fields have evolved over the past 100 years, acceptance to publication is one day! this guiding principle applies as well today as it did when In our ongoing effort to improve our service to the the journal was founded. research community, changes recently have been made The co-founders of the JBC, the first editor, John with respect to how papers are submitted, reviewed and Abel, and chief financial supporter Christian Herter, published: wrote to many prominent “biochemists” announcing the • The Table of Contents headings now reflect all areas purpose of the new journal: “We are willing to publish of biology that can be studied at molecular and cellular anything of a chemical nature in the whole field of biology levels to emphasize that we welcome submissions whether this touches the plant or animal kingdom.” This from the entire range of modern biological research. broad statement of purpose has evolved into the recently • Articles now may be listed under more than one Table recast JBC mission statement: “The Journal of Biological of Contents heading, in keeping with the increasingly Chemistry publishes papers based on original research interdisciplinary nature of biological research. that make novel and important contributions to under- • The submission fee for articles has been discontinued standing the molecular and cellular basis of biological to hold down costs to authors and simplify the submission process. processes.” The JBC has defined “anything of a chemical nature” • The JBC Web site, www.jbc.org, has been updated as work that provides clear “mechanistic insight” into any with many new features to better serve readers and authors. biological process. In this age of expanding interdisci- plinary research, a great number We thank you for mak- of exciting molecular and cellular ing the Journal of Biological biology studies are being carried Chemistry one of the most out in neuroscience, developmen- highly cited journals in the tal biology, cell biology, medical world. With your support, science, biophysics, immunology, JBC will continue to publish microbiology, physiology, etc. original research articles that We wish to emphasize that we make “novel and important consider “mechanism” to mean contributions to under- “the molecular process through standing the molecular and which biological processes are cellular basis of biological carried out” and that much of the processes” for the next 100 research in these areas would be years. This is our mission of very welcome in the JBC. service. Upon submission to the JBC, an author’s work receives broad, Robert D. Simoni is a professor fair consideration with timely and at the department of biology at constructive reviews. JBC has one Stanford University. He is also of the fastest turnaround times deputy editor of the Journal of from submission to first deci- Biological Chemistry. He can be sion: 22 days. And, if the work reached [email protected].

10 ASBMB Today January 2010 asbmbnews JBC Wishes PEPCK a Happy Anniversary! Thematic collection honors 55 years of PEPCK research BY NICK ZAGORSKI

ver the past 55 years, many important studies on the thought, PEPCK Oenzymology, genetics and metabolic role of phospho- plays a broader enolpyruvate carboxykinase (GTP) (also known as PEPCK) role in cataplero- have graced the pages of the Journal of Biological Chem- sis, the process of istry. Whether it’s the original trilogy of articles from 1954 removing anions by Merton F. Utter describing the purification and prelimi- from the citric acid nary characterization of the mitochondrial form of PEPCK cycle. Thus, PEPCK (then referred to as oxalacetic carboxylase) or Richard W. has a role in four Hanson’s widely read 2007 article detailing the metabolic metabolic pathways: gluconeogenesis, glyceroneogenesis, effects of overexpressing the cytosolic form of PEPCK in serine synthesis and the conversion of amino acid carbon mouse skeletal muscle, JBC always has published cutting- skeletons to pyruvate for subsequent oxidation in the citric edge research on the important enzyme. acid cycle. Perhaps fittingly, then, the journal has decided to mark The third minireview, by Jianqi Yang, Lea Reshef, the 55th anniversary of the publication of Utter’s articles Hanoch Cassuto, Gabriela Aleman and Hanson, discusses with a special PEPCK compendium that combines both transcription control of the gene for the cytosolic form of research and review articles. PEPCK. The authors note the emerging importance of On the research side, the collection features the semi- histone modification as a key regulator of tissue-specific nal article by Utter and Kiyoshi Kurahashi describing the PEPCK-C transcription and also highlight the insights that purified enzyme, along with 10 other articles that have may be gained from a critical analysis of the PEPCK-C appeared in the JBC in the past decade. gene promoter across an evolutionary range of species. The recent articles cover a variety of biological areas, Hanson, who in addition to contributing to the minireview including the regulation of PEPCK transcription by factors series helped coordinate the JBC compendium, notes that, such as glucocorticoids, functional insights gained from despite 55 years of research on the mechanisms, metabo- recent structural analysis and the evolving story of the lism and molecular biology of PEPCK, many gaps in our enzyme’s metabolic role in vertebrates. knowledge still remain. However, he said he is confident The compendium also contains three minireview articles that research on the fascinating enzyme shows no signs of published in the JBC in October. The first, by Gerald M. slowing down, and he’s looking forward to celebrating many Carlson and Todd Holyoak, provides insight into the reac- more PEPCK anniversaries in the future. tion mechanism of PEPCK. Despite the efforts of many dedicated researchers, the mechanism of PEPCK has Nick Zagorski ([email protected]) is a science writer at remained elusive over the years, but recent high-resolution ASBMB. structures of the enzyme from a variety of organisms have revealed details about the reaction’s reversibility and nucleotide specificity. For more information: That new information has clarified the metabolic role The PEPCK 55th anniversary collection can be found at of PEPCK, a topic covered in the second minireview by www.jbc.org/site/thematics/pepck, where it is also available Jianqi Yang, Satish C. Kalhan and Hanson. Rather than for print purchase. being involved exclusively in gluconeogenesis as originally

January 2010 ASBMB Today 11 firstasbmbsecond news words Retrospective: Mildred Cohn (1913–2009)

ildred Cohn, the first female president of members of the chemistry department at Penn. Mthe American Society for Biochem- But it is not the honors that stand out. istry and Molecular Biology and the first Mostly, I recall the extreme pleasure of woman appointed to the Journal of spending hours in her long, narrow and windowless office bouncing Biological Chemistry editorial board, around ideas about methods and passed away on Oct. 12 at age 96. mechanisms. Mildred’s questions Information on Cohn’s life and pio- were piercing, and it was quite an neering work in nuclear magnetic education to learn to expect them. resonance can be found in an She was a fabulous mentor. By article, titled “Mildred Cohn: Isoto- example, she taught both scientific pic and Spectroscopic Trailblazer,” integrity and generosity. Mildred in the September 2009 issue of also insisted that I earn first author- ASBMB Today. Below are reflec- ship on our papers by writing them tions by her friends and colleagues. myself. Later, in my role as a student, I Mildred Cohn was one of the great also got the pleasure of house-sitting figures of 20th century biochemistry/ for Mildred and Henry in Penn Valley. biophysics. She influenced several gen- There, I came to appreciate that in her erations of scientists with her brilliant use professional life she was Mildred Cohn, but of physical methods to probe the structures in her personal life was Mildred Primakoff. In and functions of proteins. She was also one fact, when editing our papers, she would some- of my scientific heroes. She wasn’t very tall, but if, as times call my writing girlish, meaning not succinct, Robert Browning said, the best way to measure someone and sign her comments “MCP.” It was an era when “male is by the length of the shadow that his or her mind casts, chauvinist pig” was a common phrase, and Mrs. Primakoff then Mildred Cohn was a giant. enjoyed the irony of her initials! When I was no longer a student, Mildred became a Gregory A. Petsko Gyula and Katica Tauber professor friend. After Henry’s death, I remember helping her hang of biochemistry and chemistry pictures after she moved into her apartment overlooking Brandeis University Rittenhouse Square. Before Henry got sick, Mildred used to occasionally talk about what they would do together in Mildred didn’t have very many graduate students, and their retirement. In recent years, Mildred became a theater I was her last. It was 1976. Mildred distinctly told me that buddy. We enjoyed countless hours in the theater, and the I could do a rotation but that she was no longer taking meals before or after were always filled with rich conversa- students. A fellowship allowed me to persist, and, one or tion— sometimes science, often personal. two papers later, she officially accepted me as her student. I will miss Mildred. I will miss seeing the family photo- At first, I was intimidated and couldn’t bring myself to call graphs grow in size. I will miss hearing about the accom- her “Mildred” like everyone else did. She was only slightly plishments of children and grandchildren and the arrival younger than my grandmother, and it just didn’t seem right of great-grandchildren. I was fortunate to have become to call someone of her generation by his or her first name! Mildred’s student when I was young and to have had her When Mildred was elected the first female president as part of my life for so many decades. I knew Mildred as of the American Society of Biological Chemists (now a great woman, a great scientist, a great mentor and as a ASBMB), I don’t recall there being any great fuss about great friend. that honor in the lab. She did, however, include me in the Eileen K. Jaffe presidential festivities at the annual meeting. While I was Professor a student, Mildred also was honored in a fete thrown by Fox Chase Cancer Center

12 ASBMB Today January 2010 firstasbmbsecond news words

As Mildred Cohn’s first postdoctoral fellow, I was deeply saddened by her death. Mildred was a perfect In Memory of Mildred mentor, inspiring by example, and was understanding and Mildred Cohn’s children have set up a Gmail account supportive of my ventures into mechanistic chemistry, tolerant of my idiosyncrasies and corrective of my errors. where friends and colleagues can post their memories As an independent investigator, I long continued to rely on for Mildred’s family to collect. To contribute, send your Mildred for sound scientific and administrative advice. recollections to [email protected]. I am consoled by the fact that Mildred led a long, Donations can be made to the Mildred Cohn Fund at productive and mostly healthy life, reaching 96 years. I The American Committee for The Weizmann Institute of take great pride in my association with Mildred and by the Science, 633 Third Avenue, New York, NY 10017. fact that, as a medical doctor, I continued to annoy her about her smoking until she stopped at age 50, which may well have contributed to her long life. problems. At one of the conference lunches, I serendipi- Albert S. Mildvan tously ended up sitting next to Mildred and her husband, Professor emeritus of biological Henry Primakoff. During the lunch, I sought Mildred’s chemistry and chemistry advice about my desire to apply NMR expertise to biologi- Johns Hopkins University cal problems, considering my unfamiliarity with biology. School of Medicine She said that it is possible to overcome the barrier with some effort and stressed the importance of collaborating It is a pleasure to remember Mildred Cohn as a friend with biochemists who can identify significant questions to and scientist. Her pioneering use of oxygen-18 for probing answer. She mentioned that she knew of physicists who enzymatic reactions of phosphate compounds served as used sophisticated methods to study trivial biological a basis for my later investigations. She cordially shared problems. This discussion was at the back of my mind her knowledge of methodology and readily participated when I wrote to her in 1972 about coming to her lab to in discussions of mutual interest. Much of what I and my explore my goal. She arranged a visiting scientist position colleagues were able to accomplish was made possible by for me, and, thus, a pivotal turn in my professional career her contributions. occurred. Paul D. Boyer I started working in her group in December 1973. During Emeritus professor of chemistry University of California, Los Angeles the first six months, I was clueless as to how I could carve a niche for myself in this new field. Fortunately, Mildred Mildred Cohn was a brilliant, nationally and internation- knew how to communicate with and utilize the strengths ally respected scientist who was a wonderful role model of a physicist, and before long some significant results emerged. for her fellow scientists, especially for women. In her I developed a warm personal relationship with Mildred. quiet way, she broke glass ceilings and was an innovative Her rich experience in science, and her marriage to leader in her field. She was one of a handful of scientists Henry, an illustrious physicist, made Mildred a source of who attended the ASBMB 50th anniversary celebration fascinating and entertaining anecdotes about science and in 1956 and the 100th anniversary celebration in 2006. scientists. She also had an excellent memory and was At the centennial celebration, at the age of 93, she gave a most interesting raconteur. I enjoyed listening to, and a priceless presentation, highlighting her career at the being inspired by, many stories during my stay at Penn. I female scientists’ reception. The presentation captured had the distinct pleasure of visiting Mildred at her home in her resilience and clarity. Philadelphia this past August. We spent an hour and a half Judith S. Bond chatting about many matters of mutual interest. She was in Professor and chair biochemistry and molecular biology fine fettle, and it was a joy to see every bit of the raconteur The Pennsylvania State University I admired and loved so much. Her passing away leaves an irreplaceable void for me. I first met Mildred Cohn at the International Society of B. D. Nageswara Rao Magnetic Resonance meeting in Israel in 1971. I was an Professor of physics associate professor of physics at the Indian Institute of Indiana University-Purdue University Indianapolis Technology in Kanpur. My expertise was in nuclear spin relaxation in liquids. I was fascinated by the possibility of applying this technique to investigate some biological Continued at the bottom of page 16

January 2010 ASBMB Today 13 firstasbmbsecond news words Retrospective: Richard I. Gumport (1937–2009) BY ROBERT L. SWITZER

he international biochemical community has much energy to the biochemical education Tlost a valued colleague with the death of of medical students and to administrative Richard I. (Dick) Gumport in Chicago on service to the medical school. At Illinois, Oct. 13. Gumport devoted his research Dick’s research initially centered on career to the study of enzymes that phage T4 RNA ligase. In collaboration act on nucleic acid substrates and with Olke C. Uhlenbeck, he demon- to the characterization of biologi- strated that RNA ligase could be cally important protein-nucleic acid used to join oligoribonucleotides, interactions. Moreover, he contrib- and he developed this method as a uted generously to his profession valuable tool for synthesis of RNA through his service as a journal oligomers of defined sequence. editor, as an educator and adminis- Subsequently, Dick extended the trator and through his commitment use of RNA ligase to the join- to the promotion of international ing of oligodeoxyribonucleotides, scientific cooperation. which was widely adopted in DNA Born in Pocatello, Idaho, on June synthetic chemistry. Recognizing the 23, 1937, Dick Gumport worked his extraordinary value of DNA oligomers of way through the University of Chicago known sequence as research tools, Dick with a variety of jobs and received a Bach- became one of the pioneers in adapting elor of Science in general biology in 1960. newly developing methods of chemical synthe- His lifelong commitment to nucleic acids and the sis of DNA oligomers, which could then be joined to enzymes that catalyze their reactions can be traced to his form larger oligomers using RNA ligase. DNA oligomers doctoral studies on RNA polymerase, completed in 1968 prepared in Dick’s lab were used in pioneering studies with at the University of Chicago with Samuel B. Weiss. The techniques that are now universally used: site-directed commitment was strengthened and broadened by Dick’s mutagenesis, primers for sequencing, templates for in vitro subsequent research as a National Institutes of Health synthesis of RNA and mapping the specificity of protein- postdoctoral fellow with I. Robert Lehman at Stanford nucleic acid interactions. Often, Dick gave his oligomers to University from 1968 to 1971. With Lehman, he identi- other researchers with no expectation of co-authorship. fied a covalent intermediate in the DNA ligase reaction, Dick and Jeffrey Gardner, his colleague in Illinois’ micro- namely an adenylyl moiety derived from the NAD+ (or ATP, biology department, conducted a productive collaboration depending on the source of the enzyme) substrate linked for more than 20 years. They investigated the mechanism to an active site lysine residue as a phosphoramide. Dick of site-specific recombination in bacteriophage lambda often cited his experiences in the Stanford biochemistry via characterization of integrase, integration host factor department as inspiration for his ideal of an academic (IHF) and Xis and FIS interactions with DNA and the roles department as a close-knit community of collaborating of these interactions in the regulation of the directionality scholars. of recombination and in forming nucleoprotein complexes. Dick joined the faculty of the biochemistry department They also collaborated on research on the mechanism of at the University of Illinois at Urbana-Champaign in 1971 transcription attenuation in regulation of the Escherichia and spent his entire career there. He was the first full-time coli threonine biosynthetic operon. faculty member in the fledging Urbana campus of the Dick’s interest in DNA synthesis led him to develop University of Illinois College of Medicine, and he devoted methods for the incorporation of base analogues into syn-

14 ASBMB Today January 2010 firstasbmbsecond news words

thetic oligomers for use in detailed characterization of DNA made Mark Twain envious. He was a mentor to many and recognition by proteins, both in collaboration with others showed us all how to live according to strong and honest values. He leaves an incredible void, and we miss him and in his own laboratory. He conducted an extensive pro- profoundly. gram of research into DNA recognition by the EcoRI and Bradford Schwartz RsrI restriction endonucleases and methyltransferases, Dean of the Urbana campus a group of four proteins chosen because they all bind to University of Illinois College of Medicine the same DNA sequence but catalyze different reactions and have little amino acid sequence homology. His studies Knowing Dick for more than 30 years both as a col- provided valuable insight into the details of DNA recogni- league in the restriction enzyme field and as an executive tion by these enzymes. editor of Nucleic Acids Research, I grew to respect and As is clear from this description, Dick Gumport believed admire him greatly. He combined the professionalism of a journal editor and scientist with the fun-loving exuberance strongly in research collaboration rather than competi- of a committed researcher. I cannot remember a dull tion. He was devoted to the highest standards of research moment when Dick and his wife, Bobbie, were around. integrity and effective education, and he gave abundantly Laughter and friendship (plus a little alcohol) were the of his time in support of those ideals. He served as associ- order of the day. He was very much a scientist’s scientist, ate head of the department of biochemistry at Illinois for who set a marvelous example of how to live and love life 12 years and as acting head for one year, and he was both in and out of the laboratory. I miss him greatly. associate dean of the University of Illinois College of Medi- Richard J. Roberts cine, Urbana campus, from 2002 to 2007. Dick generously New England Biolabs devoted his efforts to the work of several American Society for Biochemistry and Molecular Biology committees and Dick and I arrived as rookie assistant professors from West Coast postdocs in the fall of 1971. Since we shared served for 10 years on the Journal of Biological Chemis- long hair, an abhorrence of neckties and an interest in try editorial board. An avid traveler, Dick enthusiastically nucleic acids, it was perhaps inevitable that we became supported international cooperation in biochemistry. He firm friends and collaborators. Dick first suggested that the was among the American biochemists who traveled to newly discovered T4 RNA ligase could solve my difficulties China after the end of the Cultural Revolution as part in making RNAs of defined sequence and then took the of the China-United States Biochemistry and Molecular lead in making T4 infected cells, purifying and assaying Biology Examination Administration (CUSBEA) program in the enzyme. By the summer of 1973, we had successfully 1984 and in many subsequent years. He formed scientific shown that the enzyme could join two RNA fragments, collaborations with biochemists in Russia, Finland and and the resulting paper got us tenure and launched our Turkey. Dick was honored by the award of a Guggenheim careers. Dick was a joy to collaborate with— optimistic, Fellowship in1979 and election as a fellow of the American careful, funny, hard working and thoughtful. Above all, you could trust Dick. Looking back, Dick not only taught me Academy of Arts and Sciences in 2001. how to work with enzymes, but he provided an environ- No retrospective of Dick Gumport’s life and career ment that made doing science fun. would be complete without remembering his wonderful Olke C. Uhlenbeck sense of humor. It provided a sense of perspective and Professor and chairman made him a delightful colleague. “Academic politics are so Department of biochemistry, vicious,” he’d say, “because the stakes are so small.” His molecular biology and cell biology Northwestern University e-mail messages closed with a quote from Mark Twain: “There is something fascinating about science. One gets Dick and I had a wonderful scientific collaboration that such wholesale returns of conjecture out of such trifling lasted 25 years. I was trained as a geneticist, but Dick’s investments of fact.” knowledge and background in nucleic acid-binding Below are reflections from his friends and colleagues. proteins gave me an appreciation for the power of bio- chemical approaches to problems. Dick embodied the ideals of the true intellectual uni- Two of Dick’s most prominent characteristics were versity professor. He was a citizen of the world with an his wit and wonderful sense of humor. I remember a insatiable curiosity, rock-solid integrity and a clear eye particularly long group meeting, where it seemed that no for reality filtered by a sense of humor that would have progress had been made in one of our projects. Dick took

January 2010 ASBMB Today 15 firstasbmbsecondnews continued continued out the fountain pen he always carried and wrote me a was that this rigor was coupled with an unusually kind note. I thought he was going to suggest that we end the and generous spirit. He considered every scientist, meeting. When I read the note it said: “This is why the from undergraduate student to seasoned primary university pays us these fantastic salaries.” investigator, to be a colleague. I feel exceptionally Jeffrey F. Gardner privileged to have had him as my thesis mentor. Professor of microbiology Deborah Hinton University of Illinois at Chief, gene expression Urbana-Champaign and regulation section Laboratory of molecular Dick had a wonderful, quirky sense of humor, and and cellular biology he peppered the lab with absurd pictures and sayings. National Institute of Diabetes Over the sink was a drawing of a snail, titled “The and Digestive and Kidney Diseases Pace of Research.” As a graduate student in his lab, National Institutes of Health I thought that it was just a funny cartoon. However, I came to understand that it represented what made Dick such an outstanding scientist and effective men- Robert L. Switzer ([email protected]) is professor emeritus of tor. He taught us that, to do science right, you must be biochemistry at the University of Illinois at Urbana-Champaign. careful and methodical— in technique, of course, but He gratefully acknowledges Jeffrey F. Gardner for assistance especially in your reading of the literature and design with this article.

of the experiment. However, what made Dick so special Photograph: Copyright Richard B. Hallick, all rights reserved. Reprinted with permission.

Mildred Cohn Retrospective ordered around by my mother in the kitchen at all. Both Mildred and my mom are now gone, and I can continued from page 13 only smile broadly when I think about this moment. I am deeply saddened by the loss of Mildred. She My interactions with Mildred date back to the was truly a grand lady— in every way. 1970s when I became a postdoc in the laboratory Judith Klinman of Ernie Rose at Fox Chase Cancer Center. She was Professor of molecular and cell biology very cordial, intellectually stimulating and already a University of California, Berkeley legend, making her a bit intimidating for me at the beginning of my career. Our interactions became In 1960, when Mildred Cohn and Henry Primakoff much more personal when I found myself on the were contemplating moving to the University of verge of divorcing and becoming a single parent. Pennsylvania because Henry had been offered a Mildred stepped in, had me to dinner at her home, great professorship in physics, Mildred approached and more or less took me under her wing. This friend- Lucile Smith and I (we were the only two female ship/mentorship was to endure for many decades, faculty members in what was then the Johnson through Mildred’s sabbatical to Berkeley and the Foundation for Medical Physics) to ask how we felt decades that followed. women were treated at Penn. Lucile had moved to Our interests in stable isotopes and their use in Dartmouth Medical School and had not been happy reaction mechanisms and enzymology were one with her experiences at Penn. However, I responded thing that drew us together. A second was the that, although the director, Britton Chance, was a never-easily-answered question of how to raise a tough taskmaster, he was equally fair to both women family and be active in science. Mildred will always and men. When the chairman of the department of be my heroine in this regard. Lastly, there was biochemistry (Samuel Gurin) indicated he did not the bond of two women who became friends and want a female faculty member in his department, Brit cared about each other. I have one particularly fond was delighted to welcome Mildred to his faculty. memory of introducing Mildred, who was visiting her Helen C. Davies family in California, to my mother who had moved to Professor of microbiology California. My mother insisted that we make cook- University of Pennsylvania ies together, and I don’t think Mildred liked being School of Medicine

16 ASBMB Today January 2010 first2010second annual meetingwords Russell Wins the Avanti Award in Lipids BY ANGELA HOPP AND NICK ZAGORSKI

he 2010 Avanti Award in Lipids, which recognizes ized by abnormal Toutstanding research contributions in the area of cholesterol and lipid research, has been awarded to David W. Russell, lipid metabolism. the Eugene McDermott distinguished chair of molecu- And, he identified lar genetics at the University of Texas Southwestern 24-hydroxylase Medical Center at Dallas. as the enzyme Russell will present an award lecture, titled “Oxys- responsible for terols: Cholesterol Metabolites of Diverse Function in most choles- Mice and Men,” at 2:15 p.m. Sunday, April 25, at the terol turnover in the brain and recently demonstrated 2010 annual meeting in Anaheim, Calif. that 24-hydroxylase deficiency is linked to defects in Russell received his bachelor’s degree in biology memory and learning. The biochemical underpinnings from the University of Texas at Austin in 1975 and a of this connection are currently a strong focus of his doctorate in chemistry from the University of North lab’s efforts. Carolina in 1980, where he studied in the laboratory of “David has an uncanny insight into biochemical Linda Spremulli. He then moved on to the University of processes and seems always able to come up with a British Columbia as a Damon Runyon Cancer Research critical experiment to test a novel finding,” says col- Foundation postdoctoral fellow, working with Nobel league Edward A. Dennis, distinguished professor laureate Michael Smith before joining the faculty at of chemistry, biochemistry and pharmacology at the UT-Southwestern in 1982. University of California, San Diego. “His current work Shortly after arriving at UT-Southwestern, Russell on the metabolic role of oxysterols will clearly lead to began a collaborative effort with another pair of Nobel new science.” laureates, Michael S. Brown and Joseph L. Goldstein. “In addition, as part of the LIPID MAPS Consor- Together, the trio successfully cloned the gene for the tium, I have had an opportunity to work closely with recently-purified low-density lipoprotein receptor and David and watch firsthand as he developed a complex characterized the receptor’s functional domains, which lipidomics analysis of the sterol category of lipids,” helped them elucidate the molecular basis of familial Dennis adds. “From carefully designed systems biology hypercholesterolemia, one of the most common human approaches, he made insightful conclusions and knew genetic disorders. exactly how to follow up with imaginative experiments After that, Russell decided to move away from the to probe the depths of what underlie his observations.” cholesterol receptor and focus more on the cholesterol The 2010 Avanti Award in Lipids will add to a long itself. Over the next several years, Russell emerged as a and impressive list of honors Russell has received for his scientific leader in elucidating the enzymatic pathways studies on lipid metabolism and cholesterol breakdown. responsible for the metabolic breakdown of choles- He has been awarded the American Heart Associa- terol into other components, such as sterol hormones, tion Louis N. Katz Award, the Texas Instruments Kirby vitamins and bile acids. Through a combination of basic Science Place Award, the Endocrine Society Ernst biochemical studies and genetic analyses knocking out Oppenheimer Award and the Falk Foundation Adolph individual genes involved in cholesterol metabolism, Windaus Prize, among others. He also was elected to Russell’s laboratory has determined the precise role of the National Academy of Sciences in 2006. each enzyme in the cholesterol degradation pathway. Russell also has revealed important aspects of the Angela Hopp ([email protected]) is managing editor for regulation of this cholesterol breakdown and identified special projects at ASBMB. Nick Zagorski (nzagorski@ the genes responsible for several diseases character- asbmb.org) is a science writer at ASBMB.

January 2010 ASBMB Today 17 2010firstsecond annual continued meeting continued Wells Receives ASBMB-Merck Award BY ANGELA HOPP AND NICK ZAGORSKI

ames A. Wells, professor and chairman of the depart- tifically improving Jment of pharmaceutical chemistry at the University upon evolution of California, San Francisco, and director of UCSF’s small and nature, as they molecule discovery center, has been named the winner of designed a sub- the 2010 American Society for Biochemistry and Molecu- tilisin enzyme that lar Biology-Merck Award for his pioneering studies in the was more stable to field of protein engineering. oxidation, heat and Wells, who also serves on the ASBMB Council, will alkali (paving the present an award lecture, titled “Probing and Control- way for its industrial use in laundry detergents and other ling Cellular Remodeling Enzymes,” at 2:15 p.m. Monday, household products). April 26, at the 2010 annual meeting in Anaheim, Calif. Later, in 1998, Wells founded and served as president Wells integrates multiple disciplines, including bio- and chief scientific officer of Sunesis Pharmaceuticals physics, cell biology, chemical biology, molecular biology, and helped invent a novel drug-discovery platform called enzymology and proteomics, to design small molecules Tethering, which efficiently screens molecules to identify and proteins that can selectively activate or inhibit cellular the most potent compounds that block specific protein processes, such as differentiation and apoptosis. Through action. those efforts, Wells hopes to better understand how Prior to that, Wells received his bachelor’s degree in signaling events drive responses, such as cell growth and biochemistry from the University of California, Berkeley, death, and perhaps discover new drugs to treat diseases in 1973 and his doctorate in biochemistry from Washing- like cancer. ton State University in 1979 (working with Ralph Yount). Along the way, Wells has developed numerous inno- He also took on postdoctoral fellowships at both Wash- vative methodologies to improve protein engineering, ington State University and the Stanford University School molecular screening and pharmaceutical chemistry, of Medicine before joining Genentech in 1982. including a disulfide-based protein-trapping technology, “Over his career, Wells has made enormous contri- substrate-assisted catalysis and N-terminomics. butions to our understanding of enzyme mechanisms, “[Wells] is an exciting and highly creative scientist,” allostery, protein plasticity, protein-protein interfaces, noted Ian A. Wilson, professor of structural biology at The small molecule discovery, hormone receptor signaling, Scripps Research Institute, “and these methods that he has molecular recognition, protease signaling and apoptosis,” pioneered have been invaluable to countless researchers in said Molecular and Cellular Proteomics co-editor Alma a multitude of fields.” Burlingame, who is also a professor of chemistry and “His unbridled enthusiasm is infectious and ensures pharmaceutical chemistry at UCSF. “Not only has his sci- his lab is fully regaled with a plethora of ideas,” Wilson ence led to fundamental discoveries, it also produced new continued, “so they can unleash their individual talents to products in both the industrial enzyme and pharmaceuti- further progress drug discovery, biochemical mechanisms, cal sectors.” protein function and understanding of key cellular events The ASBMB-Merck Award, presented annually, recog- that impact human health.” nizes outstanding research contributions in the fields of Wells’ impressive expertise in protein engineering biochemistry and molecular biology. stems from a long and renowned career in the pharma- See the December 2008 issue of ASBMB Today to read ceutical industry. Before joining UCSF, Wells spent nearly an ASBMB Roundtable discussion with Wells on improving two decades at Genentech Inc., where he was a founding the global health system. scientist of its protein engineering department. Dur- ing his time there, Wells produced several key scientific Angela Hopp ([email protected]) is managing editor for special breakthroughs. For example, his group’s work with the projects at ASBMB. Nick Zagorski ([email protected]) is a protease subtilisin was one of the first instances of scien- science writer at ASBMB.

18 ASBMB Today January 2010 firstsecond continued Keller Garners Avanti Young Investigator Award BY ANGELA HOPP AND NICK ZAGORSKI

arah L. Keller, a professor of chemistry and adjunct tougher the better,” Sprofessor of physics at the University of Wash- noted Keller’s post- ington, has been named the winner of the 2010 Avanti doctoral adviser, Young Investigator Award in Lipid Research for her Joseph Zasadzin- innovative and cutting-edge studies on membrane lipids. ski, a professor in As part of this award, established by American the department of Society for Biochemistry and Molecular Biology’s Lipid chemical engineer- Research Division, Keller will present a lecture, titled ing and engineering “Dynamic Domains in Lipid Membranes near a Miscibil- materials at UCSB. “She instills a magic sense of confi- ity Critical Point,” at 11:45 a.m. Monday, April 26, at the dence in her graduate students that it will all work out in 2010 annual meeting in Anaheim, Calif. the end. She lets them take credit for the successes, and Keller’s interdisciplinary research has been instru- she will take the blame for the failures. And she does it mental in revealing how lipid composition affects the calmly and with grace.” physical parameters of cell membranes and how that She presented the first results demonstrating how can lead to changes in membrane protein activity and micron-scale domain formation in membranes varied aggregation. Some of her early studies directly inspired with cholesterol content and temperature. Later, she models of protein aggregation within membranes and showed that lipid domains can be induced from one provided an experimental basis for the theory of mem- membrane leaflet to another— a study that counter- brane lateral pressure. acted the prevailing hypothesis— and that alterations Keller’s interest in this field began with her graduate in the composition of one leaflet could annihilate all education at Princeton University, where she studied the domains in the membrane, even when one leaflet would interactions between ion channels and lipid membranes. have made domains on its own. Given the fact that the Working with Sol M. Gruner, Keller showed that the molecular details of how lipids in one leaflet of a mem- conductance state of alamethicin channels changes dra- brane could affect lipids in the opposing leaflet were matically when the channels are present in dioleoylphos- unknown, those exciting findings have opened a brand phatidylethanolamine compared with dioleoylphospha- new area of study. tidylcholine membranes. Those results had far-reaching Many of her colleagues have noted that Keller’s thor- implications, for at that time there was little evidence for ough analyses and phase diagrams of lipid domains with the idea that lipid composition could affect membrane respect to the surrounding membrane have become the protein activity in the absence of charged lipids, a large gold standard in the field of membrane research. change in membrane thickness, a transition to the gel They also point out that Keller’s excellence extends state or direct binding between lipids and proteins. beyond the laboratory. “Her student evaluations are off Since arriving at the University of Washington in the charts, and she has won every teaching award on 2000, after postdoctoral positions at the University of offer at UW,” noted Michael H. Gelb, Harry and Cath- California, Santa Barbara, and Stanford University, erine Jaynne Boand endowed professor of chemistry at Keller has combined her in-depth knowledge of chem- the University of Washington. “I am confident that, as a istry and physics to tackle even more daring and ambi- result of her inspiring teaching, many of these students tious projects related to membrane lipids. will pursue advanced and creative research in the future.” In just a few years, Keller already has provided He added, “I have already told her that I want to sit in numerous insights into the formation and diffusion of on her course and see how she does it.” lipid domains and how lipid composition can alter the activities of lipid domains and membrane proteins in Angela Hopp ([email protected]) is managing editor for both an intra- and inter-leaflet manner. special projects at ASBMB. Nick Zagorski (nzagorski@asbmb. “Sarah is fearless in her choice of projects — the org) is a science writer at ASBMB.

January 2010 ASBMB Today 19 firstsciencesecond focus words Anne-Frances Miller: Spinning Toward Success BY NICK ZAGORSKI

nne-Frances Miller believes enzyme catalysis, particularly Aenzymes are catalysts oxidation-reduction reactions. extraordinaire. Consider the And, by answering ques- following: The industrial process tions about, for example, how used to make the vast quanti- proteins guide the specificity ties of fertilizer necessary to of broadly reactive cofactors support agriculture worldwide like metal ions or how a flavin’s involves exposing nitrogen gas chemical properties change

(N2) to temperatures in excess when it becomes associated of 400 degrees Celsius at 200 with a protein, Miller hopes atmospheres of pressure. This to figure out one of the most illustrates the difficulty of break- enduring mysteries in enzymol- ing the triple bond in dinitrogen ogy: how proteins can both acti- (second in strength only to that vate and control such powerful of carbon monoxide). Mean- chemical reactions. while, in the roots of leguminous “Take dioxygen, for exam- Anne-Frances Miller in front of one of her NMR machines. plants, bacterial enzymes are ple,” Miller says. “Molecular carrying out the same chemical oxygen is an extremely reactive conversion at room temperature under standard pressure. molecule thermodynamically, but it also has a large kinetic This is the reason that Miller will never cease to be fasci- barrier for activation. This is why it has accumulated to nated by enzymes. “Their ability to speed up chemical reac- about 20 percent of our atmosphere. Because of that bar- tions by factors of millions, billions or more gives biology rier, dioxygen holds a huge reservoir of potential energy.” access to chemistry that would be useless at uncatalyzed “Then, look at proteins,” she adds. “As reagents, they’re rates,” she says. pretty mild-mannered— we even eat them for breakfast. However, Miller, an associate professor of chemistry at How can proteins catalyze reactions with oxygen and not the Uni­versity of Kentucky and director of the university’s get burned up?” nuclear magnetic resonance spectroscopy facility, is quick to point out that proteins should not get all of the glory. Across the Border “Many of the most marvelous enzymes subcontract out Such a sense of wonder about the natural world has been a the dirty work,” she says. “The most difficult chemistry is staple of Miller’s mindset since her youth in Toronto. She actually being executed by metal ions or organic cofactors. recalls that her scientific awakening occurred around the What the protein does is help select the proper substrate, time she was 13 years old, when her family took her and a focus the reactivity on the desired reaction and coordinate friend for a weekend naturalist program on Ontario’s Bruce the reaction with other aspects of metabolism.” Peninsula. During their hikes, Miller was fascinated by how That partnership between the protein and its cofactor much information the guides knew about every moss, plant forms the basis of Miller’s research interests. Using spectro- and liverwort they passed, including tidbits such as the scopic tools like NMR and electron paramagnetic reso- plant’s habitat range, what chemicals were inside it and how nance, which can reveal the details of the molecular interac- the indigenous people used it. tions occurring at the interface of the protein and cofactor, “I remember one foggy morning walk in particular,” she Miller seeks to understand the mechanistic basis behind says. “We had heard a squawk in the distance above us, and

20 ASBMB Today January 2010 firstsciencesecond focus words

one of our guides immediately told us that was a goshawk. position with William Orme-Johnson at the Massachusetts That weekend revealed for me just how much information Institute of Technology and a second postdoctoral fellow- surrounds us, but we don’t notice, and so it passes us by. ship with Al Redfield at Brandeis University, conducting And I keep thinking how much richer our whole experi- NMR studies on the conformation changes in the p21-Ras ence could be if we paid attention more.” protein that contribute to tumor development. Her first That weekend getaway eventually led to a vigorous pur- independent appointment was at the Johns Hopkins Uni- suit of science projects, both for science fairs and personal versity in 1992. curiosity; Miller even dabbled in some plant breeding, Her professional journey was far from a series of seam- which led her to pursue a degree in molecular genetics at less transitions. For example, Miller considers her time the University of Guelph in Ontario, Canada. in graduate school to have been quite rewarding but not Along the way, Miller also began taking physics courses, entirely successful. “I had two projects that either didn’t because she found that most of the biology courses were prove interesting to anyone other than me, or, by the time too descriptive and she was eager to understand science at they worked, someone else had published the result,” she a deeper level; in fact, by the time she graduated in 1982, admits, adding that she learned valuable lessons about Miller was just one course short of a physics major. what constitutes good science, and that helped her career At Guelph, Miller also got her first taste of NMR and immensely later on. “I am enormously grateful to Gary EPR spectroscopy. “The notion that we could observe Brudvig for giving me independence so I could learn these signals from single atoms or electrons was just amazing,” important lessons before it was my career on the line. This she says, “and it was a technology I wanted to learn more was especially courageous of him considering that, at the about.” time, his was.” To do that, Miller crossed the border into the United Other events were unforeseen, however, such as Miller States, following a career trajectory that included graduate having to leave her first postdoctoral position at MIT studies at Yale University with Gary Brudvig, analyzing the because her lab ran out of funding, forcing her to scramble assembly and mechanism of photosystem II, a postdoctoral to find a new lab to work in. This situation was made more difficult by the facts that her husband had just got- ten a job in the Boston area and that Miller wasn’t a U.S. citizen and would have to leave the country if she didn’t find a U.S. Immigration and Natural- ization Service-acceptable position very quickly. And, while Miller did secure a position at Brandeis, two years later the “two-body problem” became an issue again. After many unsuccessful attempts at finding a suitable destination with her husband, Miller eventually received a job offer she simply could not refuse: assistant professor in the Johns Hopkins University chemistry department. Although her long-distance “e-marriage” was trying, Miller had a fantastic time at Hopkins. “I had a chance to launch some very exciting studies and to work with fabulous colleagues; I would have loved to have been able to stay permanently.” Despite the best efforts by her colleagues, the uni- versity couldn’t find a way to open up a spot in the physics department for her husband. “After eight years, our family had reached a point where our Overlay of heteronuclear single-quantum coherence spectra of uniformly 15N-labeled nitroreductase, collected at 37 C (red) and 4 C (black) showing a first child was ready to start school, and we just striking loss of dispersion attributable to conformational averaging. had to be in the same city.”

January 2010 ASBMB Today 21 science focus continued

That led Miller to a difficult professional decision— relocating her lab to the Univer- sity of Kentucky in 1999 so her family could be together.

Heading into Orbit While the nature of the projects in Miller’s group at the University of Kentucky varies to exploit the composition and interests of her lab members, she maintains an overall theme of combining principles of biophysics and spectroscopy to examine protein control over cofactor reactivity. The lab focuses on two enzyme types: superoxide dismutases and enzymes that use flavins as cofactors. Superoxide dismutases, which metabolize toxic superoxide ions

(O2-), regulate the reactivity of potentially reactive chemical species and are fairly well studied, providing a firm foundation for detailed studies of fundamental questions. “That is not to say superoxide dismutase has no more new stories to tell, because it certainly has,” Miller says, noting some exciting work in which her lab provided the first mechanistic explanation as to why iron- or manganese-containing superoxide dismutases become inactive if their cofactor is exchanged with the opposing ion, even though the three-dimensional structures of the two enzyme types are basically superim- posable. Other recent spectroscopic analysis has 2D PASS solid-state 15-NMR spectrum (bottom) and cross-polarization magic revealed insights into how superoxide dis- angle spinning 15N solid-state NMR spectrum of tetracetyl riboflavin labeled with mutase controls the movement of the elec- 15N at positions N1, N3 and N5. For details, see Koder et al. 2006. trons between the active site metal ion and substrate. “Proteins do not have good means of controlling examines samples that are solids or frozen solutions, can electrons directly,” Miller says. “But we found that the big prevent the molecules under study from moving or reori- bridge by which superoxide dismutases regulate the sources enting. This allows orientation-dependent properties to and destinations of the transferred electrons is the protein’s be observed in the spectra, and, in Miller’s case, allows the exceptional control over protons, because the protons have three orientationally distinct components of the chemical a very big influence over where the electrons go.” shift to be resolved. Miller chose enzymes that use flavins as cofactors as her Miller has looked at the carbon and nitrogen atoms of second interest, because these cofactors, which resemble the flavin ring system to complement solution NMR studies nucleotides, hearken back to the ancient RNA world and of the surrounding amino acids of the protein. Most impor- are likely the remnants of the evolutionary ancestors to tantly, the solid-state NMR results often can distinguish enzymes. And, as organic molecules, not inorganic metal between effects on different orbitals of the flavin, result- ions, they have different spectroscopic properties that ing from different interactions between the flavin and the enable Miller to ask a different set of questions. protein. With that information, she hopes to understand Solid-state NMR, which, as implied by the name, how different protein environments cause the bound flavin

22 ASBMB Today January 2010 science focus continued

to emphasize different reactivities out of its inherently broad repertoire. Meanwhile, solution NMR studies of the Out of Focus: Language Barrier surrounding protein address issues such as how some fla- While you won’t catch more than a hint of a Canadian voenzymes like nitroreductase have such a broad substrate accent in speaking with Miller these days, she admits to specificity range. having had occasional communication “challenges” when Beyond these studies, though, Miller is also busy trying she first moved from Guelph to New Haven, Conn. This led to improve on the existing NMR and EPR technologies, so to one of her more bizarre graduate school experiences. as to give them a broader and more cost-effective appeal. One day, while returning from school, she was approached In discussing her drive to do this, Miller reflects back on and accosted by a pair of youths who demanded her when she first came to the U.S. for graduate school. “At the bicycle. “Their accent was so strong and foreign to me that time I left Guelph, there were very few positions available I could barely understand them,” she says. Add in the fact in Canada, as funding for universities was very tight,” she that she came from a small, quiet college town, and she says. “My professors not only repaired laboratory equip- was not prepared for such a situation. “So rather than run ment themselves, because they couldn’t afford to get it away immediately (and lose my bike), I responded with a serviced, they built the equipment themselves as well.” polite, if scared, refusal. Then they had trouble compre- Considering the perilous nature of today’s economy, hending me. After several back-and-forth exchanges in such memories resurface. “In a time of tightening budgets, which I can remember thinking I was completely crazy to there will be questions about the need to continue to run be insisting on retaining my bicycle and repeating ‘I beg expensive NMR facilities,” she says, adding that the cost not your pardon’ (because I still could not understand their only reflects the machines but the cryogens and reagents English), instead of fleeing back up the street, one of them (like heavy isotopes of carbon and nitrogen) required to cracked a smile.” She says, “This whole conversation was produce NMR-quality samples. While NMR holds many probably the last thing they expected and in retrospect, advantages as a tool for structure determination, it is weak it really was humorous. Once it had become a joke, they when it comes to sensitivity because the magnetic moments waved me on and I rode off. I would, nonetheless, not of nuclei are quite small, thus, requiring large amounts of recommend this as a general strategy.” pure protein in each sample. Some research groups have begun trying to alleviate the sensitivity problem by combining elements of NMR and EPR technology in a new application known as dynamic can take a shortcut and focus your measurements just on nuclear polarization. Rather than directly polarizing (or the active site,” she continues. This “smart” DNP, as Miller exciting) nuclear magnetic moments, DNP polarizes elec- refers to it, should make the technique more applicable trons first, as they have magnetic moments about 660 times than ever, as a researcher won’t need large quantities of that of the 1H magnetic moment. DNP then transfers that protein or even a pure sample. Only protein molecules polarization to nearby nuclei. “So in theory,” says Miller, containing the flavin would be evident in a DNP-NMR “you could have an NMR signal that’s 660 times more pow- spectrum. erful than usual, which is mind-boggling.” Thanks to a sabbatical she took, Miller, in collabora- Nick Zagorski ([email protected]) is a science writer at tion with Thorsten Maly and Robert G. Griffin at MIT’s ASBMB. magnet lab, has tried to take DNP one step further. “Cur- rently, DNP relies on added free radicals as bearers of the References Miller, A.-F. (2008) Redox Tuning Over Almost 1 V in a Structurally-conserved unpaired electrons,” she says, “but I realized that biology Active Site: Lessons from Superoxide Dismutase. Acc. Chem. Res. 41, 501- provides built-in radicals whose unpaired electrons can be 510. Koder, R. L.,Walsh, J. D., Pometun, M. S., Dutton, P. L., Wittebort, R. J., and used as sources of polarization. Many flavoproteins can be Miller, A.-F. (2006) 15N Solid-state NMR Provides a Sensitive Probe of prepared with the flavin in a radical state, and the flavin Oxidized Flavin Reactive Sites. J. Am. Chem. Soc. 128, 15200–15208. Vance, C. K. and Miller, A.-F. (1998) A Simple Proposal that can Explain the molecule is bound in exactly the same way in each mol- Inactivity of Metal-substituted Superoxide Dismutases. J. Am. Chem. Soc. ecule. So we know where the polarization starts in every 120, 461-467. Miller, A.-F., Halkides, C. J., and Redfield, A. G. (1993) An NMR Comparison of instance, in contrast with the random and uncontrolled the Changes Produced by Different Guanosine 5’-Triphosphate Analogs in locations of exogenous radicals.” Moreover, the flavin radi- Wild-type and Oncogenic Mutant p21ras. Biochemistry 32, 7367–7376. Miller, A.-F. and Brudvig, G. W. (1989) Manganese and Calcium Requirements cal is often located in the enzyme’s active site. for Reconstitution of Oxygen-Evolution Activity in Manganese-Depleted “So, instead of having to analyze an entire protein, you Photosystem II Membranes. Biochemistry 28, 8181–8190.

January 2010 ASBMB Today 23 specialinterest Brian Malow: A Stand-Up Man for Science BY NICK ZAGORSKI

airly or unfairly, the public’s perception of science Fseems to include a series of less-than-flattering words that begin with “S”: stodgy, stuffy and serious. But it doesn’t have to be that way; science also can be silly. Brian Malow would wholeheartedly agree with that assessment; in fact, he believes in science’s humor potential so much that he’s made an unusual career out of it, perform- ing across the country as a “science comedian” for the past decade. y

Whether he’s giving quick one-liners like “I just started be il reading ‘The Origin of Species;’ don’t tell me how it ends!” G or longer musings about how the constant weight fluctua- o: John tions between his parents— whenever his mom lost weight, t Pho his dad gained weight— was a prime example of the first law of thermodynamics, Malow seamlessly intersperses Arthur C. Clarke, who could write both types of material scientific terminology into jokes about everyday topics, like with equal skill. parents and relationships, that are the staples of comedic Today, he continues to immerse himself in the latest routines. print and online scientific stories daily, turning his brain And that little extra science kick, which has given Malow into a giant scientific database. Physics and astronomy the kind of distinctive niche that every comedian seeks, remain his favorite subjects, but he touches on all types of might be a valuable tool in making the average person more science in his comedy. knowledgeable about science. Malow’s foray into stand-up was not premeditated. “After listening to some of my new material, a friend “It’s certainly not a career I planned,” he says. “My friends once told me, ‘Your jokes contain more information than thought I was pretty funny, but I was never labeled the class other comedian’s jokes,’” Malow says. This inspired him clown in school or anything like that.” to begin adding more educational content to his routines While living in Austin, Texas, he was encouraged to par- – wrapping education in a bit of laughter is a great way to ticipate in a “funniest person in Austin” contest. Although teach people without them knowing it. he didn’t win, the positive feedback he received convinced At the very least, Malow hopes to inspire more enthusi- him to try comedy. asm about science during his routines, which have run the Over the years, as Malow progressed from working the gamut from intimate shows at places like Washington, D.C.’s local comedy-club circuit to becoming a nationally known Marian Koshland Science Museum of the National Acad- comedian, he began incorporating more science into his emies to a nationally televised appearance on the “Late Late routine. “It proceeded through a natural evolution,” he says. Show” with Craig Ferguson. “I had all this scientific information in my head, and, as I Although Malow has no professional scientific back- worked out some comedic material, some weird little fact ground, he embraced science early on. Growing up, he would pop out that would fit in so well with the joke.” loved reading both science fiction and nonfiction, and he Even so, Malow never really considered himself a “sci- was especially influenced by authors like Isaac Asimov and ence comedian” until recently, after he started doing more

24 ASBMB Today January 2010 specialinterest

shows for scientifically savvy audiences. While he tries So, beyond laughter, Malow likes to scan his scientific to keep most of his science content at a level anyone can audiences to see if anyone is nodding along in with the joke, understand, he found occasional jokes based on obscure signaling that the scientific reasoning behind it is sound. scientific references just didn’t work for a general audi- On the plus side, Malow reads about new scientific ence. However, those same jokes would get big laughs from discoveries every day, so he holds a distinct advantage over scientists, giving him a new outlet for his less traditional other stand-up comedians who talk about their foibles, material. annoying parents and spouses or other types of observa- A nice example is his one-liner: “I’m so spontaneous, I tional humor: He never runs out of material. have a negative delta G.” Malow notes that joke would pass over the head of most people, but it’s a riot among chemists. Nick Zagorski ([email protected]) is a science writer at Malow really enjoys performing in front of scientific ASBMB. audiences, whether at universities, museums or companies like Apple or Dell. “Nothing is more fun than making sci- entists laugh. I feel that, if I can bring some levity into their For more information: science world, using their science terms, then I’ve done a • Go to www.asbmb.org/audio.aspx to learn more about great job.” Brian Malow in a podcast in which he further discusses “Now, it does add a layer of difficulty,” he notes, “since, what it’s like telling jokes to scientists and details some unlike other comics, I have to not only be funny but also of his recent efforts to improve science awareness and scientifically accurate. We’ve probably all heard jokes that engender enthusiasm. make no sense, but, among scientists, if your joke is based • You can visit Malow’s Web site at on a false premise, then it may fall flat, no matter how funny http://www.sciencecomedian.com the punch line is.”

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January 2010 UANhorizhalfAD.indd 1 12/17/2009 ASBMB 11:36:38 AM Today 25 firstspecialsecond interest words University of Oregon’s Institute of Molecular Biology Celebrates 50 Years BY CHRIS TACHIBANA

n 1959, the University of Oregon began a daring experi- founded on three principles: No one would be called Iment. Just six years after James Watson and Francis “professor” or “doctor,” facilities would be shared and new Crick published their paper on the structure of DNA, hires would recruit new members. the university founded its Institute of Molecular Biology, bringing scientists from chemistry, biology and physics Oregon Makes a Splash with Zebrafish together in a common space to work in a new field that In keeping with the last principle, in 1960, Stahl recruited combined all three areas. phage biologist George Streisinger, whose work illus- Fifty years later, the risk-takers who founded and nur- trates the collaborative, multidisciplinary philosophy of tured the enterprise have a lot to be proud of, including the IMB: Streisinger generated a series of T4 lysozyme generations of scientists who were shaped at and inspired mutants that were used by protein biochemists like the by IMB. Schellmans and Rick Dahlquist and biophysicists like Brian W. Matthews, S. James Remington and Joan Woz- The Early Years under Aaron Novick niak for studies on protein structure and thermostability. At an anniversary celebration this fall, institute Director In the 1970s, Streisinger used his knowledge of aquar- Bruce Bowerman recalled how chemist Terrell L. Hill con- ium fish to develop the zebrafish as a research model. ceived the institute in 1957 and recruited its first director, Zebrafish are small, hardy and easily bred, developing biophysicist Aaron Novick. from transparent egg to fish in 24 hours. Streisinger real- Hill met Novick when they were both working on the ized that zebrafish could be used as a vertebrate model for Manhattan Project, and Novick’s time there influenced studies on development and behavior that had previously his career and the institute. Carol Gross, a professor at used fruit flies. So, he developed techniques for breeding, the University of California, San Francisco, and keynote mutagenizing and screening zebrafish, including generat- speaker at the 50th anniversary symposium, was a gradu- ing haploid fish for easy phenotypic analysis. The Univer- ate student with Novick. She said that, because of Novick, sity of Oregon continues to be internationally recognized “the institute was very political. Having worked on the for zebrafish research. atom bomb and knowing its aftermath, Aaron was very Gross pointed out that this project illustrates the value antinuclear and antiwar.” She added that Novick’s open, placed on maximizing every individual at the IMB. She egalitarian attitude set the tone of the institute: “He always described the long process Streisinger went through to ate lunch in the lunchroom so he could participate in find and develop a new model organism and said “He discussions [on topics] like: Given rate of protein synthe- finally hit on zebrafish, and what stuck with me was the sis, could a spider make silk de novo or did it have to be time he was given to really think through this transition. premade?” All the while, he had the support of everyone around Novick created the nucleus of the IMB by hiring its first him.” members with the help of biochemists John and Charlotte Another major discovery that came from the institute Schellman, who were known for advancing the study of was the first three-dimensional structure of a DNA-bind- protein structure, folding and stability through techniques ing protein, published in 1982 by Matthews. Steve Kowal- such as circular dichroism spectroscopy. Their first hire czykowski, now a professor at the University of California, was Frank W. Stahl, who had just shown, with Matthew Davis, was a postdoctoral fellow with Peter von Hippel. He Meselson, that DNA is replicated by a semiconservative still remembers the day he saw preliminary data for the mechanism. Stahl, now emeritus, continues to focus on Cro repressor structure: “One of Brian Matthews’ post- the mechanisms of meiotic recombination. In a recent docs showed me how its spacing was perfect to fit into the biology department newsletter, he said the institute was major groove of the DNA. It was stunning.”

26 ASBMB Today January 2010 firstspecialsecond interest words

Von Hippel Reinvents A three-tiered cake marks the 50th anniversary the Institute of the University of Oregon’s Institute of Molecular Biology. Credit: Jack Liu. In 1967, the institute hired von Hippel, who Bowerman called “the heart and soul of the institute.” Von Hippel, a pio- structures, we do a lot of biology, and I neer in the biophysical analysis of think that goes all the way back to DNA transcription and replication my graduate training.” complexes, was institute director Today, the institute has 23 active from 1969 to 1980. Gross did a faculty members, housed in con- postdoctoral fellowship with him tiguous facilities in the university’s and said, “[Novick] invented the science complex. Everyone has institute, but Pete reinvented it, access to proteomics, genomics, bringing a big-science energy and DNA sequencing and histology perspective, with more graduate laboratories; electron and confo- students and bigger labs. He kept all the cal microscopes; facilities for biophysi- great things but brought the institute into the next phase.” cal studies, including x-ray crystallography and nuclear At the anniversary symposium, Bowerman announced magnetic resonance and on-site production of monoclonal the creation of the Peter von Hippel graduate student antibodies and transgenic mice. endowment, seeded with donations from faculty and alumni Looking ahead to the next 50 years, and perhaps trend- (see sidebar). In his spontaneous response, von Hippel spotting for molecular biology in general, Matthews, an praised the IMB for its ability to “evolve with the times and institute faculty member since 1969 and a former director, grow,” saying, “I’m impressed to look around and see people said, “At the time that I joined the institute, a major empha- who have done extremely well, spread out all over the world sis was on the ‘molecular’ part of ‘molecular biology,’ i.e. on and are having an impact.” the basic structure and function of biomolecules. To some degree, the physics drove the biology. Now the emphasis is An Interdisciplinary Institute more on the ‘biology’ aspect. I expect this trend to continue. A primary goal of the IMB is fostering collaboration In the future, it will be the biology that will drive the identi- between scientists with different expertise, and interaction fication of important questions, but techniques from physics is encouraged in many ways. Kowalczykowski recalls, “We will still be a key in solving many of these problems.” didn’t really separate the social and the scientific. Everyone was so accessible. It was such an easygoing place, but that Chris Tachibana ([email protected]) is a science writer belied the scientific intensity.” He remembers having easy based in Seattle and Copenhagen. She acknowledges Bruce access to people like Streisinger, Sidney Bernhard, Stahl, Bowerman and Sarah Cheesman for assistance with the article. Dahlquist, and the Schellmans. “When the institute was formed,” he says, “everyone was all on the same floor and complimented each other fantastically. Decades later, [insti- tutes] were trying to implement programs that were already A Tribute to Peter von Hippel in place at the IMB. That was the genius of the founders, to Unveiled at the 50th anniversary celebration for the Institute fuse biology, chemistry and physics to solve long-standing of Molecular Biology, the Peter von Hippel graduate student problems. It’s a place that was way ahead of its time.” endowment fund is “a tribute to von Hippel’s generosity and The institute’s multidisciplinary approach inspired Rhett magnanimity, and his many and longstanding contributions to Kovall of the University of Cincinnati, who recalls the open- the university and the institute.” The endowment will support ness and community and said that playing on softball teams one graduate student a year, contributing to his or her stipend and interacting with other graduate students definitely influ- and tuition expenses beginning in 2010. enced his career. Although he was solving protein structures If you are interested in making a tax-deductible con- in the Matthews lab, his roommate was studying Caenorhab- tribution to the endowment, contact Sarah Cheesman at ditis elegans genetics in the Bowerman lab. Now the head [email protected] or 541-346-0044. of his own research group, Kovall says, “We don’t just solve

January 2010 ASBMB Today 27 firstminoritysecond affairs words Promoting Diversity in Research Championing an Inclusive Scientific Work Force BY SHAWN R. DREW

hat is diversity? In the sciences, it’s the variety of shows that diverse teams are better at solving complex Winterdisciplinary fields that we often combine to problems (1). On homogeneous teams, unquestioned solve complex biomedical problems; it’s the mathemati- assumptions remain unquestioned, and everyone gets cian, biologist, neurologist and physicist working together. stuck in the same place. If we only listen to people who Diversity is also an array of human characteristics that agree with us, we cease to grow. In the words of writer differ among us and shape our experiences. Walter Lippmann, “Where all men think alike, no one thinks very much.” The Problem Representation does not mean mere numbers or even A current problem in today’s biomedical work force is the a quota. It means having qualified individuals from various underrepresentation of certain groups— namely minori- backgrounds, perspectives and influences to strengthen ties (such as African-Americans, American Indians, Alaska our ability to solve complex scientific problems. In doing Natives, Hispanic/Latino Americans and U.S. Pacific this, diversity is not just a feel-good issue or simply the Islanders) and individuals with disabilities. right thing to do; it benefits everyone through improved Figure 1 shows that there is a disparity in the proportion outcomes. of underrepresented minorities (URMs) versus Caucasians Additionally, scientific researchers are better able to in the sciences. While URMs represent approximately 29 relate to the general public when the scientific work force percent of the U.S. demo- graphic, they represent only approximately 4 percent Disparity of Biomedical Science Representation of the National Institutes of Health R01 biomedical research grant holders. This URM NIH R01 grant holders same downward trajectory URM Science Ph.D. degree holders ~Percentages is not seen with Caucasians, whose representation is at URM Science B.S. degree holders or greater than parity at the URM National Demographic noted levels. The underrep- resentation in the sciences we see for URMs also holds Caucasian NIH R01 grant holders true for individuals with disabilities: They represent Caucasian Science Ph.D. degree holders 11 percent of the Bachelor Caucasian Science B.S. degree holders of Science holders but only 1 percent of the popula- Caucasian National Demographic tion with scientific doctoral 0 10 20 30 40 50 60 70 80 degrees. You might wonder Sources: U.S. Census Bureau; NIH Office of the Director; National Science Foundation “Women, Minorities and Persons with whether it really matters who Disabilities in Science and Engineering Report.” is doing science as long as Note: Underrepresented minorities (URMs) in the biomedical sciences are African Americans, American Indians and Alaska Natives, Hispanic/Latino Americans and U.S. Pacific Islanders. good science is being done. Note: While Asian Americans make up 4 percent of the U.S. population, they account for close to 14 percent of the scientific work It does matter; research force and are not considered underrepresented in the biomedical sciences in the U.S.

28 ASBMB Today January 2010 firstminoritysecond affairs words

has adequate minority representation. Remember the Tuskegee syphilis experiment and the 40 years of unethi- Online Resources cal treatment of African-American men that left a lasting legacy of distrust of the medical/research community? Information on NIH/NIGMS diversity programs: It’s that distrust that is an underlying reason why many • NIH T32 training program: http://bit.ly/4GxEUQ African-Americans are not organ donors and do not • Frequently asked questions about NIH T32 required participate in clinical trials. Furthermore, for the majority recruitment and retention plan to enhance diversity: of this country, the autonomy of the individual in agree- http://bit.ly/7AF80m ing or disagreeing to participate as a research subject is • NIGMS Research Supplements to Promote Diversity in paramount. But for some communities, especially some Health-Related Research: http://bit.ly/6PGZCe American Indian tribes, autonomy of the group outweighs that of an individual. When scientists do not reflect various • NIGMS Minority Opportunities in Research Division communities they intend to study, there can be rampant programs: www.nigms.nih.gov/Minority mistrust and/or an underappreciation of certain cultural Minority-oriented science student conferences: value systems. • Annual Biomedical Research Conference for Minority What the NIH Is Doing Students: www.abrcms.org To increase the diversity of the scientific work force, the • Society for the Advancement of Chicanos and Native NIH requires all applicants for its predoctoral and post- Americans in Science: www.sacnas.org doctoral institutional research training (T32) grants to Academic institutions with a high concentration submit a plan to recruit and retain individuals from under- of underrepresented students: represented groups. At the National Institute of General Medical Sciences, we take a very serious look at these • Department of Education: For details on historically plans and their outcomes. The plans to enhance diversity black colleges and universities, Hispanic-serving are first considered by the initial review group, then by the institutions and tribal colleges: www.ed.gov/index.jhtml National Advisory General Medical Sciences Council and • Appalachian College Association: www.acaweb.org finally by an administrative staff committee. Applications • Gallaudet University (for deaf and hearing impaired with unacceptable diversity plans are barred from funding undergraduates): www.gallaudet.edu until an updated plan is acceptable, regardless of the priority score. NIH also provides research supplements to promote 10 Things You Can Do diversity in health-related research. Those “diversity There are several ways you can help increase diversity in supplements” provide funds to an existing NIH research the biomedical sciences: grant to support an underrepresented student or postdoc- toral fellow to work in a grantee’s lab. Each NIH institute 1. Take on a leadership role in the diversity debate. You can “lead from below” until the “tone at the top” of your or center, much like academic departments, has differ- institution is as committed as you are to increasing ent policies or practices for program implementation. At diversity in the sciences. Organize campuswide NIGMS, we allow more than one student or postdoctoral discussions on diversity issues. fellow per NIGMS grantee for this program. This encour- 2. Participate in the NIH diversity supplement program ages principal investigators to bring multiple underrepre- and other underrepresented-student development sented participants into their labs. Also unique to NIGMS programs supported by the NIGMS Minority is that, beyond the college level, we expect PIs to indicate Opportunities in Research Division. how they will foster the transition of their underrepresented 3. Attend national minority-oriented science student graduate student or postdoctoral fellow over to traditional conferences, such as the Annual Biomedical Research funds. We think of the diversity supplement program as a Conference for Minority Students and the Society for hand up, not a handout or entitlement, and we expect our the Advancement of Chicanos and Native Americans in mentors to aid in transitioning their trainees to mainstream Science meeting, to recruit underrepresented students. training mechanisms. More than 2,000 URM students attend each conference

January 2010 ASBMB Today 29 minorityaffairs continued annually to present scientific research. A good way to interact with students is as a judge. 4. Establish partnerships with academic institutions that have high concentrations of underrepresented students. The partnerships can September 30 – October 4, 2009 be used to both recruit students to your program

Transcriptional Regulation by and better prepare students for your programs. Chromatin and RNA Polymerase II For example, talk to students and faculty at Granlibakken Resort, Tahoe City, CA minority-serving institutions about what it takes to be competitive enough to enter your graduate Organizer: Ali Shilatifard program. Stowers Institute for Medical Research 5. Establish partnerships with local organizations that hold health and science fairs where underrepresented groups are prevalent. These October 14 – October 17, 2010 efforts go a long way to help establish trust of the

Biochemistry and Cell Biology medical research community. of ESCRTs in Health and Disease 6. Contact the office of disability services on your Snowbird Resort, Snowbird, UT campus or at your company and ask officials for Organizer: James Hurley advice on how to make science more accessible. National Institute of Diabetes and 7. Google “recruit student disabilities,” and tons of Digestive and Kidney Diseases useful information will come up to help you reach out to these individuals. Phyllis Hanson Washington University 8. Ensure that your Web sites, brochures and other School of Medicine marketing materials have welcoming and inclusive language. Do you include images of people from diverse backgrounds? Instead of saying October 21 – October 24, 2010 “Persons with disabilities are welcome to apply,” try “People with disabilities are valued members Post Translational Modifications: Detection and Physiological Evaluation of our institution.” In order to reach out to others, look inward and ask questions like: What is our Granlibakken Resort, Tahoe City, CA message? Is our program/institution welcoming Organizer: Katalin Medzihradszky and accommodating? What is our track record? University of California, Who is delivering our message? San Francisco 9. Update your business cards to include Braille; Gerald Hart this is a great way to showcase an inclusionary Johns Hopkins University spirit. School of Medicine 10. Publish your findings on diversity issues. Describe your approaches and conclusions regarding issues of diversity. Web sites like Diverse Issues October 28 – October 31, 2010 in Higher Education (http://diverseeducation. Biochemistry of Memberane Traffic: com/home.html) or Inside Higher Ed (www. Secretory and Endocrytic Pathways insidehighered.com) are useful sources to accomplish this. Granlibakken Resort, Tahoe City, CA Organizer: Suzanne Pfeffer Shawn R. Drew ([email protected]) is the Minority Stanford University Access to Research Careers program director of the School of Medicine Division of Minority Opportunities in Research, program Vivek Malhotra director of the biostatistics training grant program Center for Genomic Regulation, and chairwoman of the Committee to Maximize Barcelona, Spain Representation at NIGMS.

www.asbmb.org/meetings Reference 1. Scott E. Page (2007) The Difference: How the Power of Diversity Creates Better Groups, Firms, Schools and Societies. Princeton, NJ and Oxford: Princeton University Press, , pp. 448.

30 ASBMB Today January 2010

2010HalfPageNature (JHOMA v1).indd 1 12/16/2009 4:28:39 PM education and training An Opportunity to Make a Difference BY J. ELLIS BELL

n a recent speech to the National Academy of Sci- Take the “Science on the Mall Challenge” Iences, President Obama said, “So I want to per- ASBMB is also urging everyone to get involved with suade you to spend time in the classroom, talking— the festival through the “ASBMB Science on the Mall and showing— young people what it is that your work Challenge.” We are asking anyone interested in sci- can mean and what it means to you. Encourage your ence, science education or science outreach to design university to participate in programs to allow students a fun, interactive biochemistry- and/or molecular to get a degree in scientific fields and a teaching cer- biology-themed activity to take to the festival. tificate at the same time. Think about new and creative Entries will be accepted through June 30 and can ways to engage young people in science and engi- be submitted by posting them to the ASBMB Face- neering, like science festivals, robotics competitions book fan page (http://bit.ly/4ynmfn) or e-mailing them and fairs that encourage young people to create, build to [email protected] or [email protected]. and invent— to be makers of things.” The submissions will be judged by the ASBMB Undergraduate Affiliate Network Committee, and the The USA Science best entries will be taken to the USA Science and and Engineering Festival Engineering Festival. Top finalists who are undergradu- The USA Science and Engineering Festival offers ates or high school students will receive travel stipends scientists a great opportunity to answer this clarion to come to Washington, D.C., to attend the expo. call. According to the organizers, “the festival promises to be the ultimate multicultural, multigenerational and Get Involved in Outreach multidisciplinary celebration of science in the United If each ASBMB member agreed to spend just two hours States.” It will take place between Oct. 10 and Oct. a month in meaningful outreach activities, we could have 24, culminating in a two-day expo on the National Mall a major impact on science literacy and the pipeline of in Washington, D.C.. The expo will give more than 500 future scientists. science and engineering organizations from all over So, the challenge to all ASBMB members is this: the United States the opportunity to present hands-on, Find two hours a month and get involved in outreach fun science activities to inspire the next generation of activities. Over the next six to eight months, we will scientists and engineers. track member outreach activities and post updates on Festival founder Larry Bock is encouraging the par- our Web site. Send an e-mail to [email protected] to ticipation of universities, colleges, professional organi- tell us about your outreach activities. zations and industry, and, as discussed in the Novem- ber issue of ASBMB Today, the American Society for J. Ellis Bell ([email protected]) is professor of chemistry Biochemistry and Molecular Biology is committed to and chair of the biochemistry and molecular biology participating. program at the University of Richmond. He is also chairman The festival organizers also are inviting scientists of the ASBMB Education and Professional Development and engineers around the nation to host satellite Committee. events that can be tied in to the festival’s themes. In a time when the scientific community is increas- ingly being asked to justify the nation’s investment in For more information: research, and when there is much talk of the U.S. fall- • To learn more about the USA Science & Engineering ing behind the world in science education, it behooves Festival, go to http://usasciencefestival.org. each of us to think creatively about how we can effec- tively educate the general public about science and its • For more information on the ASBMB Science on the benefits and also encourage a diverse section of our Mall Challenge, go to http://bit.ly/5RD7Jg. K-12 population to get interested in science.

January 2010 ASBMB Today 31 biobits asbmb journal science

For Talin, It’s Avidity Don’t Sleep Not Affinity on This Structure The protein talin can bind to the cytoplasmic tail Current treatments for regions of β3 integrins and regulate the activity of trypanosome diseases like αIIbβ3 integrins. Talin itself is autoregulated – its sleeping sickness often integrin-binding globular head region can be inhib- lack specificity and have ited by binding to the talin C-terminal tail. Interest- severe side effects. Thus, ingly, while overexpression of the talin head domain newer, better drug targets increases integrin activity in mammalian cells, are needed. Trypanosomal such effects are not seen in Drosophila, suggest- sterol 14α-demethylase Ligand-free trypanosomal ing talin-integrin interactions may be different in (14DM), an essential 14α-demethylase (salmon) superposed with the related those organisms. However, in this paper, the author enzyme in the produc- mycobacterial CYP51 (green). shows that the discrepancies are due to differences tion of membrane sterols, in methodologies. Using a Drosophila-based assay is a highly promising lead, as its fungal counterpart that employs only monovalent ligands (where one is a major drug target for treating fungal infections ligand binds to one integrin receptor), the author in humans. In this study, the authors solved 1.9 Å found that talin had no effect on the affinity of αIIbβ3 resolution crystal structures of 14DM from Trypano- integrins for ligand in Chinese hamster ovary (CHO) soma brucei in both a native state and in a complex cells or human platelets. Talin did increase the ability with the inhibitor VN1. Together, they provide the of integrins to bind to multivalent ligands that can first structural insights into a eukaryotic microsomal interact with more than one receptor, but this was 14DM. The structures show that the organization of due to increased integrin clustering and not affinity. the active site cavity and the location of the substrate This study helps reconcile the experimental differ- access channel differ profoundly in 14DM compared ences and also suggests a new model by which talin with water-soluble members of the CYP51 family. regulates integrin activity. VN1 binding does not cause large-scale confor- mational rearrangements, but it does induce local changes in the active site, including the formation of a hydrogen bond network connecting VN1 and two distant and functionally essential protein seg- ments. The structural details of VN1 binding provides a possible explanation for both its selectivity toward trypanosomal 14DM and its potency, and it should provide an excellent template for designing novel parasite-specific drugs.

PAC-1 IgM binding to CHO cells is clustered. Crystal Structures of Trypanosoma brucei Sterol 14 alpha-demethylase and Implications for Selective Treatment of Human Infections Integrin αIIbβ3 Activation in CHO Galina I. Lepesheva, Hee-Won Park, Tatiana Y. Cells and Platelets Increases Hargrove, Benoit Vanhollebeke, Zdzislaw Wawrzak, Clustering Not Affinity Joel M. Harp, Munirathinam Sundaramoorthy, W. David Nes, Etienne Pays, Minu Chaudhuri, Thomas A. Bunch Fernando Villalta and Michael R. Waterman J. Biol. Chem., published online Nov. 16, 2009 J. Biol. Chem., published online Nov. 18, 2009

32 ASBMB Today January 2010 biobits asbmb journal science For more ASBMB journal highlights go to www.asbmb.org

Enhancing Hibernation Wound Healing Is Quite Active Successful wound healing involves the coordina- Mammalian hiberna- tion of multiple physiological processes, such as tion is a complex inflammation, cell migration, angiogenesis, forma- process involving tion of granulation tissue and tissue remodeling. A large-scale reorgani- better understanding of the molecular mechanisms zation of metabolic behind these processes may provide insight into and other pathways. developing improved wound healing therapies. In In this study, the this study, the researchers found that cutaneous researchers con- wounds induced the formation of novel endogenous structed a database dihydroxy-docosahexaenoic acid species (14S,21S- of more than 3,000 Heat map of the 25 most diHDHA,14R,21R-diHDHA, 14S,21R-diHDHA and/or differentially expressed proteins liver proteins from 14R,21S-diHDHA). Using mass-spectrometry analy- during the hibernation cycle; EA, arctic ground squir- early arousal; LT, late torpor; PR, sis, they detailed the structures of those novel com- post-reproduction. rels (Urocitellus par- pounds and the pathways of their formation from ryii) and then used DHA by 12-lipoxygenase and cytochrome P450, label-free shotgun proteomics to analyze changes enzymes found in in protein expression throughout the torpor/arousal both the skin and hibernation cycle. Consistent with previous stud- macrophages. ies measuring mRNA changes, proteins involved in Importantly, glycolysis and fatty-acid synthesis were significantly administration of underexpressed in both late-torpid and early- 14S,21-diHDHA aroused squirrels compared with nonhibernating and 14R,21-diH- animals, while proteins involved in fatty acid ca- DHA to induced tabolism were significantly overexpressed. However, wounds in mice in other cases, the protein and mRNA data did not enhanced wound entirely mesh; for example, proteins involved in closure, growth Representative photographs highlighting translation, protein degradation, mRNA processing how 14,21-diHDHA treatment can and oxidative phosphorylation were overexpressed of granulation tis- accelerate wound closure. sue growth and in early-aroused animals compared with late-torpid vascular formation. These newly identified 14,21-di- animals, whereas no significant changes in mRNA HDHA stereoisomers may represent the molecular levels between those stages had been observed. basis for the healing properties of macrophages The discrepancies suggest substantial post- and, given their abundance in the skin, may provide transcriptional regulation of proteins occurs during an ideal target for developing novel wound-healing hibernation. therapeutic modalities. Shotgun Proteomic Analysis of Hibernating Arctic Ground Squirrels Novel 14,21-dihydroxy-docosahexaenoic Acids: Chunxuan Shao, Yuting Liu, Hongqiang Ruan, Ying Structures, Formation Pathways, and Li, Haifang Wang, Franziska Kohl, Anna V. Enhancement of Wound Healing Goropashnaya, Vadim B. Fedorov, Rong Zeng, Yan Lu, Haibin Tian and Song Hong Brian M. Barnes and Jun Yan J. Lipid Res., published online Nov. 5, 2009 Mol. Cell. Proteomics, published online Nov. 20, 2009

January 2010 ASBMB Today 33 firstcareersecond insights words Taking the Path Less Traveled BY CLIFFORD MINTZ

always have liked science, and, at Wisconsin, I decided to eschew I by the age of 10, I decided that a career as a science educator in I wanted to be a veterinarian. favor of becoming a tenure-track However, after seeing the film “Ben faculty member at a prestigious Hur”— in which two characters who research institution. have leprosy are miraculously cured I received my doctoral degree in – at age 11, I fantasized about what 1981and chose to do a postdoc- it would be like to discover cures toral fellowship with Stephen Morse for infectious diseases. As corny as in the department of microbiology at it may sound, the movie convinced Oregon Health and Science Univer- me that my true calling in life wasn’t sity. There, I investigated the patho- veterinary medicine but microbiol- genesis of Neisseria gonorrhoeae. Clifford S. Mintz has held a variety of ogy. Nonetheless, I enrolled at After two years in Morse’s lab, I positions, including stints as a medi- Cornell University as a preveterinary realized that the field of molecular cal school professor, professional medicine undergraduate with a biology finally had taken off and that recruiter, management consultant dual major in animal science and I would need to develop molecu- and medical/science writer. He is microbiology. During my senior year lar biological skills to compete for the founder of BioInsights (www. at Cornell, Brooks Naylor, my food my coveted tenure-track faculty bioinsights.com), a biopharmaceuti- microbiology professor, invited me position. With this in mind, I joined cal education and training organiza- to do a senior research project in Howard Shuman’s laboratory in tion, co-founder of BioCrowd (www. his laboratory. After several weeks 1984 as a postdoctoral fellow in the biocrowd.com), a social networking in the laboratory, I was hooked, and department of microbiology at the and career development Web site I knew that graduate school, not College of Physicians and Surgeons for bioprofessionals, and the author veterinary school, was in my future. at Columbia University. My work in of BioJobBlog (www.biojobblog. I entered graduate school in Shuman’s laboratory looked at the com). He teaches product devel- 1974 and did my thesis research molecular pathogenesis of Legio- opment and regulatory affairs in in Robert Deibel’s laboratory in the nella pneumophila, the causative several biotechnology training pro- department of bacteriology at the agent of Legionnaires’ disease. grams and is an adjunct professor in University of Wisconsin-Madison. I In 1987, my newly acquired the department of biochemistry and studied the pathogenesis of Salmo- molecular biology training and molecular biology at the George- nella gastroenteritis. Because Deibel respectable publication record town University School of Medicine. was chairman of the department helped me to land a tenure-track and a food microbiology consultant, faculty position in the department he wasn’t around much. This forced of microbiology at the Leonard M. program on the role of lipopolysac- me to become a self-reliant inde- Miller School of Medicine at the charide in the molecular pathogene- pendent investigator very early in University of Miami. I spent the next sis of L. pneumophila. While I was a my scientific career. When I started seven years feverishly doing labora- productive researcher who regularly graduate school, my goal was to tory research, teaching medical published work and was recognized earn a doctoral degree and teach and graduate students, publish- on several occasions for teaching microbiology at a small liberal arts ing papers and writing grants to excellence, I failed to consistently college. However, after three years establish an independent research win grant support to run my labora-

34 ASBMB Today January 2010 firstcareersecond insights words

tory. Consequently, in 1994, I was After three years as a successful medical writing, but I quickly learned denied tenure and forced to leave professional recruiter, an Australian that it pays well and that medical academia— an emotionally dev- biotechnology company hired me writers are always in demand. I astating event that that ended a as a science and business consul- took her advice and landed my first lifelong dream of becoming a world- tant to help guide its antibacterial medical writing job in 2005. Since class research scientist. drug-discovery program. The new then, I have worked at a variety of Luckily, at that time, the U.S. job led to an almost four-year stint medical communications agencies biotechnology industry finally had as an independent management and pharmaceutical companies pre- hit its stride, and I landed a job as consultant advising private and paring manuscripts, posters, slide a scientist at a New Jersey-based publicly traded biotechnology com- presentations and other documents. biotechnology company managing panies on business, scientific and Currently, I am a freelance science an antibacterial drug-discovery pro- financial matters. Also around this and medical writer, a blogger at gram. My two years in industry pro- time, I decided to indulge my own biojobblog.com and a social media vided me with a firm understanding entrepreneurial fantasies: In 2001, enthusiast who, along with Vincent of the business side of science and, perhaps more importantly, con- vinced me that industrial research I was denied tenure and forced wasn’t for me. This, coupled with a desire to teach again, prompted to leave academia— an emotionally me to successfully apply for a job “ devastating event that ended as chairman of biology at a local a lifelong dream of becoming a community college. It was a good idea at the time, but I quickly real- world-class research scientist. ized that, while I still loved to teach, administration wasn’t my strong suit. I left the community college job I founded a bioscience education Racaniello, started an ”online social after a year. and training company called BioIn- network site for bio-scientists called Unfortunately, by 1998 I effec- sights Inc. Two years later, Abraham BioCrowd (www.biocrowd.com). tively had exhausted most tradi- Abuchowski and I founded Prolong Unlike many scientists, my career tional career options for scientists Pharmaceuticals— a drug-delivery path has taken several unexpected with doctoral degrees, and I company with two drugs in early twists and turns. I never intended desperately needed a job— mainly stage clinical development. Unfor- it to be as eclectic or convoluted because I had a wife and three tunately, the rigorous demands of as it has been. Nevertheless, I young children to support. Fortu- running BioInsights and starting believe that my unusual career nately, while working at the com- Prolong ultimately led to the demise trajectory has made me a better- munity college, I helped several of my consulting practice, and, rounded scientist than I would have professional recruiters place new by 2004 I was forced to consider been if I had been able to pursue hires into jobs at biotechnology and another career move. my intended academic career. In pharmaceutical companies; this Luckily, a few years earlier, I had retrospect, I attribute my career prompted me to seriously consider started writing for several biotech- successes to solid problem-solving professional recruiting as a career nology industry trade publications. skills, an unrelenting desire to con- option. In early 1999, I landed a job Although I wasn’t getting paid to tinue to learn and an unwavering as a recruiter at a local recruiting write, the job enabled me to hone ability to take risks. firm. As a new hire, I had to attend and polish my writing skills. In late Finally, and perhaps most impor- recruiter school for six weeks. 2004, a medical communications tantly, I learned that there is no Surprisingly, this training played a expert whom I knew suggested that right or wrong career path in the life pivotal role in subsequent decisions I take a stab at medical writing. At sciences— only the path that you that helped shape my career. the time, I didn’t know much about choose for yourself!

January 2010 ASBMB Today 35 firstlipidsecond news words Enzyme Aliases and Acronyms: What’s in a Name?* BY GEORGE M. CARMAN AND DANIEL M. RABEN

t’s not unusual to be listening to a seminar or reading implies the enzyme desaturates stearoyl (C18)-CoA. Ior reviewing a paper or grant and feeling overwhelmed However, actually, the enzyme desaturates all acyl-CoA and confused by the aliases and acronyms used for substrates from C14 to C20. enzymes. These enzyme identifiers seem to be increas- So how can we effectively and efficiently resolve this ing almost as rapidly as the number of papers published issue? Simply retaining the initial names of enzymes each year. Confusion often results from the fact that these after their catalytic function is identified only perpetu- names frequently bear no relationship to the actual activ- ates confusion in the literature. On the other hand, it is ity or function of their enzyme. For example, how many difficult to rename enzymes without upsetting the people people know the names of the enzymes represented by who coined the aliases and acronyms, especially when the aliases autotaxin, desnutrin, lipin, neuropathy target esterase, PatA/VipD, PTEN, SHIP2 and wunen? It’s pretty common to find a lipid scientist who doesn’t know If lipid scientists don’t that the common enzyme names for these aliases are know what these aliases lysophospholipase D, triacylglycerol lipase, phosphatidic “ refer to, then how do acid phosphatase, phospholipase B, lysophospholi- pase A, phosphatidylinositol-3-phosphate phosphatase, we expect the general phosphatidylinositol-3,4,5-trisphosphate phosphatase reader who is not a lipid and lipid phosphate phosphatase, respectively. If lipid scientists don’t know what these aliases refer to, then aficionado to know? how do we expect the general reader who is not a lipid aficionado to know? those identifiers were established before the enzymatic There are a number of reasons why this practice got functions of the proteins were known. For aliases,” one started. In many cases, the molecular function of a protein solution is to refer to the enzyme activity followed by the is unknown when it is discovered, and an alias is given alias in parenthesis or vice versa. The enzyme activ- based on a mutant phenotype or disease. In other cases, ity could be named according to standards set by the an investigator chooses a name, often with the admirable International Union of Biochemistry with emphasis on the goal of making it easy to remember. No matter what the thermodynamically favored reaction catalyzed. Similarly, cause, rectifying this would go a long way to enhancing acronyms should always be defined, especially when they our ability to stimulate the enthusiasm and imagination of are used in titles and abstracts. Whatever the solution, our colleagues. this may help to make lipid research more easily read and Perhaps it would reduce confusion and increase clarity digested. In doing so, we will go a long way in conveying in the field at large if we changed the names of these the excitement of lipid research. enzymes to ones that reflect their activities. This, however, may not be straightforward. The names of most enzymes George M. Carman ([email protected]) is a professor are derived from their substrates, products and the reac- in the department of food science at Rutgers University. Daniel tions they catalyze. Thus, many enzymes have a variety of M. Raben ([email protected]) is a professor of biological names. For example, phosphatidate phosphatase 2, dia- chemistry at the Johns Hopkins University School of Medicine. cylglycerol pyrophosphate phosphatase and lipid phos-

phate phosphatase all refer to the same enzyme. Another Footnote problem is when an enzyme is more promiscuous than * This article was written in response to a discussion in the forum on the Web site for the American Society for Biochemistry and Molecular Biology’s Lipid its name implies. For example, stearoyl-CoA desaturase Research Division (www.asbmb.org/lipidcorner).

36 ASBMB Today January 2010 2010 ASBMB Annual Meeting

Get Ready to Meet in California!

Anaheim Awaits DEADLINES APPROACHING

Early Registration: February 24, 2010 April 24–28, 2010 Late Breaking Abstracts: February 24, 2010 www.asbmb.org/meeting2010 SPECIAL EVENTS

ASBMB 5K Fun Run, early registration required Minority Scientists Welcome Reception How to Publish in the JBC Workshop Opening Reception and Dance

For the complete list of special events visit www.asbmb.org/meeting2010

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