ASBMB Launches New Web Site—www.ASBMB.org
July 2008
Gregory Petsko takes charge of ASBMB
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ORG-027-ORFSketchV7.indd 1 1/24/08 4:45:45 PM contents July 2008 On the Cover: Brandeis structural society news biologist Gregory Petsko 2 From the Editor takes over as ASBMB President this month. 3 President’s Message Learn more about him 5 Washington Update on pages 3 and 12. 7 ASBMB Launches New Website 10 A Report on Women in Science 17 New Visa Rules for Travel special interest 12 Presidential Profile: Gregory Petsko 14 Picture Perfect! 2009 meeting Thematic Overviews: Signaling & Cell Systems ASBMB Homepage gets a renovation. 7 16 Membrane Dynamics & Organelle Biogenesis 18 Principles of Receptor Signaling Assay 20 withMetabolism and Disease Acetylation, sirtuins, Mechanisms and the histone 22 Lipid Signaling code. 30 Code Readerand Metabolism 1) Select hits science focus 30 John Denu: The Importance of Reversible Protein Acetylation departments 2) MS/MS 6 News from the Hill 8 Member Spotlight m/z Histone H4 24 Minority Affairs 26 Career Insights 28 BioBits Tail PTM Library podcast summary resources Download the June ASBMB AudioPhiles JLR 34 Career Opportunities News Podcast to hear about some papers that look into the function of PCSK9, a protein that is 34 For Your Lab rapidly gaining more research interest due to its role in regulating LDL cholesterol in the blood. 36 Scientific Meeting Calendar This and other podcasts are available at: SGRGKGGKGLGKGGAKRHR(http://www.faseb.org/asbmb/media/media.aspMe3K)V Histone Sequence July 2008 ASBMB Today 1 (pS)G(MeR)GKGGKGLGKGGAKRHR(Me3K)V Code? SGRGKGG(AcK)GLGKGGA(AcK)RHR(Me2K)V Etc. firstsecond from words the editor A monthly publication of The American Society for Biochemistry and Molecular Biology ASBMB Today Welcomes Officers Gregory A. Petsko President New President Heidi E. Hamm Past President Mark A. Lemmon Secretary By Nicole Kresge Merle S. Olson Treasurer Council Members We at ASBMB Today would like to welcome new ASBMB President Gregory Dafna Bar-Sagi Alan Hall John D. Scott Joan A. Steitz Ann M. Stock Petsko of Brandeis University, who officially took office on July 1 follow- Kevin Struhl James A. Wells ing a one-year term as president-elect. This issue contains Petsko’s inaugural Ex-Officio Members President’s Message, as well as a short profile introducing the man taking over Ellis Bell the reins of ASBMB for the next two years. We wish him all the best in his Chair, Education and Professional Development Committee new role, and we look forward to working with him in the future on both his Laurie S. Kaguni monthly columns and other ideas for the magazine. Chair, Meeting Committee ASBMB Today would also like to thank outgoing President Heidi Hamm for George Hill Chair, Minority Affairs Committee all her contributions to the magazine and, of course, the society, over the past Kendall J. Blumer two years. We know that in her role as past president she will continue to help Anna Marie Pyle Co-chairs, 2008 Program Committee ASBMB grow and become a major voice for basic biological Mary J. C. Hendrix scientists, students, and educators everywhere. Chair, Public Affairs Advisory Committee This issue of the magazine also marks the Toni M. Antalis Chair, Publications Committee first of our three thematic previews for the Herbert Tabor upcoming 2009 ASBMB annual meeting in Editor, JBC New Orleans. As we may have said a few times Ralph A. Bradshaw A. L. Burlingame before, it’s never too early to start thinking Co-editors, MCP ahead, so be sure to read our previews Edward A. Dennis to find out about the exciting topics Joseph L. Witztum Co-editors, JLR being covered and the speakers who will be presenting research at the meeting ASBMB Today Editorial Advisory Board next year. This month features overviews Alex Toker of two of the five thematic groups: “Cell Chair Greg P. Bertenshaw Craig E. Cameron Systems” and “Metabolism and Signaling.” A. Stephen Dahms Irwin Fridovich Over the next two issues we will cover the Richard W. Hanson Elizabeth A. Komives remaining themes of “Nuclear Transac- Bettie Sue Masters Luke A. O’Neill Duanqing Pei Carol C. Shoulders tions,” “Molecular Structure and Dynam- Robert D. Wells ics,” and “Protein Synthesis, Folding, ASBMB Today and Turnover.” In addition, as part of Nicole Kresge Editor our efforts to expand into other media, [email protected] ASBMB will feature podcasts with the Nick Zagorski Science Writer [email protected] organizers of these thematic sessions Nancy J. Rodnan Director of Publications that will provide more insight into these [email protected] upcoming symposia. Be sure to go to the Barbara Gordon Executive Director [email protected] ASBMB multimedia section on our newly revamped web site to hear more. Magazine design & production: Amy Phifer For information on advertising contact FASEB AdNet at 800-433-2732 ext. 7157 or 301-634-7157, or E-mail [email protected]. www.asbmb.org 2 ASBMB Today July 2008 president’smessage First Things First BY GREGORY A. PETSKO want to begin my two-year sentence—I mean, term— tougher; that peer review is in peril; I as President of ASBMB by saying to all those who and that research priorities are not voted for me: “I’ll get you for this if it’s the last thing I being set the way they should be. ever do.” I mean, I was president-elect for a year, now I’ll These and other problems are so be president for two years, and then past president for a severe that they threaten the entire year. That’s four years! Convicted felons get paroled in magnificent edifice that is American science, an edifice three! that I believe has also been the foundation for much of But seriously (and for those of you who don’t know the prosperity that this country has enjoyed in the last 60 me, let me say up front that I take years. I intend to try to do some- as few things seriously as possible), thing about this, using both the thank you for expressing your con- Although bully pulpit of the ASBMB presi- fidence that I can lead this organi- dency and the human resources of zation. I would be a lot less confi- ASBMB is in the society—by which I mean you. dent myself were it not for the fact I need your advice and support as that Heidi Hamm and the other fine shape, we try to put things right. past presidents have bequeathed In future columns, I’ll try to me a Society that is in superb shape the same address these and other prob- on all fronts: financially, adminis- cannot be lems. It’s the nature of essays to tratively, and in terms of its mis- focus on the difficulties we face sion. I’ll try very hard not to mess said for and what we ought to do about it up. That should be easier than them. But that focus can give you might think, because they have American a strident, negative tone to the also bequeathed me a superb staff dialogue, and that’s not the way that I’m just getting to know and science. I want this to begin. So in this on whom I intend to rely heavily. letter I want to step back from So please join me in congratulating These are the things that are wrong with Heidi on a magnificent two years American science and talk about as president, in which she showed the toughest the many things that are right. that this job can be an activist posi- It’s easy to forget just how tion. I intend to continue that to times I’ve fortunate we are. We live and the best of my abilities. seen in my 35 work in a country where freedom Although ASBMB is in fine of inquiry is protected by law, shape, the same cannot be said for years doing and where the public has a high American science. These are the degree of respect for what we toughest times I’ve seen in my 35 independent do. We are part of a great tradi- years doing independent research. tion that stretches back literally I don’t have to tell you that the research. thousands of years, to before funding situation is historically bad; Euclid and Archimedes, and that the influence of science on government has become that is responsible for nearly all human progress. To virtually non-existent under the Bush Administration; put it another way, the reason I’m writing this column that young people face enormous difficulties starting their at a nice desk in a room lit by an electric light while careers; that mid-career scientists face equally enormous sitting on a comfortable chair in a cozy house instead ones staying in their field or moving to a new one; that of sitting in a tree wondering where my next banana is competition at home and from abroad has never been coming from is entirely due to people like you, who for July 2008 ASBMB Today 3 president’smessage continued centuries have dared to ask questions and pursue ideas. whom we can talk about things of mutual interest. We Even those of us who never make that earth-shattering are truly citizens of the world. discovery will have contributed some brick or mortar Moreover, our friends and colleagues can come from of consequence to the enormous wall that is human every age group. That’s almost unique in this world. knowledge. In nearly every other line of work there is a hierarchy Ours is a noble and honorable profession, and it is that is based in large part on age and experience. Upper a profession in the original sense of the word: a service management tends to be middle-aged and doesn’t performed for the public good. We live by our wits, to socialize or even work with much younger junior execu- be sure, but we do so for the benefit of mankind. We tives. We can and do both without regard for such artifi- never have to question the value of what we do; we need cial barriers. For those of us who teach or train graduate no justification for getting up in the morning and going students and postdocs, we have the added pleasure of to work. Indeed, most of us work way beyond the tradi- working daily with extraordinarily bright, dedicated, tional 40-hour week, with no overtime pay, because we interesting young people. Just imagine: these smart kids love what we do and recognize its worth. Most people do what we tell them to—and if they are really smart, in the world have jobs; we have a vocation. Sometimes they do stuff we’d never have thought to tell them. The we forget just how lucky we are in that regard. There are pleasure of training our successors and watching them aspects of what I do that I could cheerfully do without, grow is something I wouldn’t give up for all the gold in but I can honestly say that I would scrub floors if I had Ireland. to in order to do science. So let’s work together to try to fix the things that are And most of us don’t do it alone. We are fortunate wrong, but let’s also remember to celebrate the things to have colleagues and collaborators and to have them, that are right. Science is a great life. We get to explore potentially, in almost every country on earth. Think of and discover and at the same time know that what we do it: we can go anywhere and the odds are there will be is worthwhile. Yes, there are problems, but it sure beats people who will be interested in what we do and with working for a living. JBC Online now features Paper of the Week author profiles! www.jbc.org 4 ASBMB Today July 2008 washington update FASEB Hearing on Stem Cells Foreshadows New Legislative Effort for Ethical Guidelines BY CARRIE D. WOLINETZ recent hearing on “Stem Cell Science: The Founda- they could fully replace hESC. They both referred to embry- Ation for Future Cures,” held by the Health subcom- onic stem cells as the “gold standard” against which other mittee of the House Energy and Commerce committee, cell lines must measure up. proved to be popular among members of Congress, with Although no further details of the upcoming DeGette- more than a dozen in attendance to hear testimony on the Castle legislation were forthcoming, there were a number current status of stem cell research. Witnesses included of questions about the current lack of regulatory frame- National Institutes of Health (NIH) Director Elias Zerhouni work for ethical oversight of stem cell research. Zerhouni and embryonic stem cell scientists George Daley and enthusiastically supported the enactment of “harmonized John Gearhardt, as well as adult stem cell researchers and and cohesive oversight” that would apply to all stem cell patient advocates. The hearing was held at the request of research being conducted in the U.S., stating “I wish com- Representative Diana DeGette (D-CO), who announced mon ground could be found…” as well as his belief that plans to introduce new legislation with Representative Mike NIH is the entity best able to administer such as system. Castle (R-DE) that would not only expand the number Witness statements and an archived webcast of the hear- of human embryonic stem cell (hESC) lines available for ing may be found at: http://energycommerce.house.gov/ federal funding, but would “construct a framework for cmte_mtgs/110-he-hrg.050808.StemCell.shtml. ethical oversight for all cell-based research.” A similar The general sense in Washington is that it is unlikely any DeGette-Castle bill, the Stem Cell Research Enhancement legislation to overcome the presidential policy restricting Act, has passed both houses of Congress multiple times, federal funding of hESC will move forward in this Congress. but has been unable to garner sufficient votes to override a However, presidential candidates Barack Obama and John presidential veto. McCain have expressed support for hESC research and Topics at the hearing ranged from details about the have voted to support passage of the Stem Cell Research state of the science to current NIH funding levels of stem Enhancement Act. Therefore, it seems highly probable that cell research to the feasibility of NIH serving as a regula- a new administration would alter the current policy. What tory body to ensure ethical oversight of stem cell research. remains to be seen is the shape of regulations that would Comments from the members of Congress present gener- be put into place following removal of the funding restric- ally fell along partisan lines, with the Democrats on the tion. With the Guidelines for Human Embryonic Stem Cell subcommittee supporting all types of stem cell research, Research from the National Academies and the Guidelines including embryonic, and the Republican members empha- for the Conduct of Human Embryonic Stem Cell Research sizing the importance of adult stem cell research and the from the International Society for Stem Cell Research newer induced pluripotent stem (iPS) cells. Zerhouni testi- already being used on a voluntary basis by research uni- fied that from the scientific standpoint, hESC, adult stem versities, it will be interesting to see if the federal govern- cell, and iPS cell research were all “faces of the same coin.” ment chooses to adopt one of these existing models for its In response to questions about the clinical merit of adult regulatory framework. (For FASEB comments on these two versus embryonic stem cells, Zerhouni pointed out that sets of guidelines, please visit: http://opa.faseb.org/pages/ there is an average of 17 years between a basic science PolicyIssues/stemcellscnt_pi.htm) The proposed DeGette- idea and clinical trials, and that hESC technologies were Castle bill could potentially impose a different regulatory far younger than their adult stem cell counterparts. He later scheme and may expand beyond hESC research based added, “If we had more resources, we could accelerate the on Representative DeGette’s assertion that the ethical research…” Daley and Gearhardt talked at length about framework would apply to “all cell-based research.” If the the impact iPS cells would have on the future of stem cell bill is introduced, it will likely be referred back to the House research, describing the exciting potential of this new tech- Energy and Commerce committee of which Representative nology while cautioning that it was too soon to tell whether DeGette is vice chair. July 2008 ASBMB Today 5 news from the hill Some Science Funding Survives in Supplemental Bill By Peter Farnham n June 19 the House overwhelmingly approved two Subcommittee approved a $1.2B increase for NIH—4.1% Ospending measures—one a $162 billion war fund- over 2008. While we have a long way to go, this is a very ing measure, the other a $95.5 billion measure funding good start. Of course, there is a standing presidential a major veterans education program, unemployment veto threat in place for any spending bill that exceeds his benefits, and, in a small but significant victory for science, requests; however, as in the maneuvering surrounding the about $337 million in new science funding. supplemental bill discussed above, it is possible that as The science funding includes $150 million for NIH, we enter the last months of the Bush presidency, his abil- $62.5 million for NSF, $62.5 million for DOE science pro- ity to sustain vetoes will continue to diminish. grams, and $62.5 million for NASA. The NIH funding is to be spread on a “pro rata basis” Everyone Likes NSF, but Will it across all NIH institutes and centers, with at least some of Suffer from Other Funding Battles? it going to the Director’s Common Fund. The NSF money Finally, in continued good news for science, the 2009 is divided between Research & Related Activities ($22.5 NSF appropriations bill was marked up on June 12, M) and Education and Human Resources ($40 M). The and the relevant subcommittee gave the agency a Office of Science receives the $62.5 M in money slated $6.9 billion budget for next year, up about $500 million for DOE, and the NASA money is to support the Science, from the president’s request (which was itself a 13% Aeronautics and Exploration program. increase over 2008). The vote in the House for the The NSF is a rare point of agree- domestic spending component of the ment between the Congress and the supplemental bill was overwhelming, President; all players support more 416 – 12. Majority Leader Harry Reid money for NSF under the America (D-NV) indicated that he thinks the bill Competes Act, which passed with will pass the Senate by the end of June, great fanfare two years ago and which and the President, bowing to political the President signed. However, the reality, has indicated he will sign the bill. agency got caught up in a budget Although the increases for NIH fight last year having to do with issues pale in comparison to the need at this beyond its control, and thus last year’s agency, the funding in the supplemental generous increase got vetoed. The does represent some progress and is proposed increase this year is designed the first break in the impasse over fed- to make up for the veto last year. eral domestic spending that has been It remains to be seen whether Con- going on for months now. gress and the President can restrain The reasons for the impasse are themselves from election-year postur- basically tied to the political situation. ing enough to let NSF and NIH enjoy This being an election year, everything desperately needed funding increases is contentious. And, up until this bill, this year. the President had had enough political support in the House to enforce vetoes. In other good news, the House Peter Farnham CAE is public affairs officer began to mark up the Labor/HHS of the Society, a position he has held since appropriations bill in mid-June, and 1985. He can be reached at pfarnham@ the NIH fared well. The Labor/HHS asbmb.org. 6 ASBMB Today July 2008 asbmb news A Renovation for www.ASBMB.org ver the past couple of months we have been work- sharing, whether through blogging, or other Web 2.0 Oing hard to combine some new technology and a technology. fresh new face for the society’s webpage! As the last As an ASBMB member, you’ll also have access to redesign was about 3 years ago, we decided it was restricted member-only areas of the website. Your time for a functional overhaul and an updated look. unique member-only space will include personal profile ASBMB is proud to announce the unveiling of the information, the ability to update your contact infor- brand new www.ASBMB.org. The entire site has been mation online, to monitor event registration, exclusive redesigned. Not only has site naviga- tion been improved, we’ve added a few new sections to our site including interactive areas and a special members only section. ASBMB has always posted society news, but the new version of the site will have a dedicated space for hot news stories, (whether they be journal or society related), enhanced search functionality, and an archive for news stories with a powerful search engine allowing you to easily find that old article you read a couple months back, but can’t remember exactly when. access to the digital edition of our monthly member The interactive area of the new site will include magazine, ASBMB Today, and a number of other monthly summaries of top research from each of the member-only privileges. Also, take advantage of the ASBMB journals, our Audiophiles podcasts, video opportunity to give us your feedback and thoughts on excerpts, members in the news, supplementary ASBMB articles through comment posting. research footage, and other media of interest. This is We’re excited about the new design look and func- also the place to come if you want to hear proprietary tionality, and we hope you enjoy the fresh new face of interviews with leading scientist and journal editors. www.ASBMB.org! If you have comments, or feedback We are also developing a concept for an “ASBMB as we proceed through the website launch, please Online Lounge” that will include social network- feel free to email Jessica Homa, Marketing Manager at ing functionality and provide a forum for knowledge ASBMB at [email protected]. July 2008 ASBMB Today 7 asbmb member spotlight Glimcher Recipient Katzenellenbogen of Mentoring Award Given Esselen Award Laurie H. Glimcher, Irene Heinz Given John A. Katzenellenbogen, Swanlund Chair Professor of Immunology at the Harvard in Chemistry at the University of Illinois, School of Public Health and Professor of Urbana-Champaign, has received the 2008 Medicine at the Broad Institute, received Gustavus John Esselen Award for Chemistry the American Association of Immunologists in the Public Interest. Excellence in Mentoring Award. The award, The award, which is presented annually given in recognition of her exemplary by the Northeastern Section of the American contributions to a future generation of Chemical Society, is one of the section’s scientists, was presented to Glimcher this most prestigious honors. It recognizes a past April at the 95th Annual Meeting of the American chemist whose scientific and technical work has contributed to the Association of Immunologists. public well being, and has thereby communicated positive values According to the American Association of Immunologists, “In of the chemical profession. The award was established in 1987 addition to a distinguished academic career and major scientific to honor the memory of Gustavus John Esselen, past-chair of the contributions to the field of immunology, Dr. Glimcher has had a Northeastern Section and founder of Esselen Research. career-long commitment to the development of scientist trainees Katzenellenbogen received the award for his work in understand- and mentoring. Her dedication to trainees’ success has resulted in ing estrogen receptor structure, function, and dynamics. He devel- a cadre of successful scientists across the spectrum of the science oped an extensive series of steroid receptor-based agents labeled enterprise and the establishment of lifelong friendships.” with fluorine-18 and technetium-99m for imaging receptor-positive Glimcher’s laboratory uses biochemical and genetic approaches breast and prostate tumors by positron emission tomography. His to elucidate the molecular pathways that regulate CD4 T helper cell more recent work involves studies of the estrogen receptor protein development and activation. Specifically, she studies the transcrip- and the coregulator proteins of steroid hormone receptors. tional pathways involved in the regulation of Thelper1/Thelper2 (TH1/TH2) responses by interleukin-4 and interferon cytokines. Robinson Receives Christian B. Anfinsen Award Kelleher Granted Pittcon Carol Robinson, of the University of Achievement Award Cambridge, has been selected to receive the Neil Kelleher, Professor at the University of 2008 Christian B. Anfinsen Award from the Illinois, received the 2008 Pittsburgh Protein Society. The award, which is Conference Achievement Award. The award, sponsored by The Aviv Family Foundation, sponsored jointly by The Pittsburgh recognizes significant technical achievements Conference and the Society for Analytical in the field of protein science. Chemists of Pittsburgh (SACP), recognizes Robinson, who is being recognized for individuals for outstanding scientific her outstanding pioneering scientific contri- achievements within 10 years following butions in the fields of mass spectrometry and structural biology, completion of their Ph.D. has driven the continual development of novel mass spectrometry Kelleher has three main areas of research: custom instrumen- approaches and instrumentation that are used in laboratories tation for Fourier Transform Mass Spectrometry (FTMS), Nuclear around the world. Signaling, and Natural Products. More specifically, his interests lie After contributing to the development of a prototype electro- in the enzymology of natural product biosynthesis, mass spec- spray time-of-flight mass spectrometer that substantially extended trometric based studies of the histone code, and development the mass/charge range, Robinson designed a more sophisticated of FTMS for top down proteomics (i.e. analyzing intact proteins machine, a high mass quadrupole time-of-flight mass spectrom- directly; no proteases). eter. Using this technology, she demonstrated that macromolecular He has received several awards for his research, including the particles with masses in excess of 2 MDa can transverse the mass Pfizer Award in Enzyme Chemistry from the American Chemical spectrometer in an intact state, permitting the recording of their Society Division of Biological Chemistry, a Presidential Early Career mass spectra. In her exploration of the extent to which solution Award, a National Science Foundation CAREER Award, and the phase complexes resemble those studied in the gas phase of the Lilly Analytical Chemistry Award. Kelleher is also an Alfred P. Sloan mass spectrometer, Robinson used ion mobility measurements of Fellow, a Packard Fellow, a Burroughs Wellcome Fund Young protein complexes to show that the 11-mer protein rings formed Investigator, a Searle Scholar, and a Fulbright Scholar. by the RNA-binding protein TRAP could not only be retained in the gas phase but their stability could be altered by the addition of cofactors. 8 ASBMB Today July 2008 asbmb member spotlight Please submit news about yourself to [email protected] Jordan Honored with Mobashery Honored Karnofsky Award Lecture with Astellas Award V. Craig Jordan, Vice President and Research Shahriar Mobashery, Navari Family Professor Director for Medical Sciences and the Alfred in Life Sciences at the University of Notre G. Knudson Chair of Cancer Research at the Dame, is the 2008 recipient of an Astellas Fox Chase Cancer Center, is the 38th USA Foundation Award by the American recipient of the highest award from the Chemical Society. Mobashery received the American Society of Clinical Oncology, the award for his work on antibiotic resistance David A. Karnofsky Award and Lecture. The and his contributions to the understanding of award recognizes clinical research that has the bacterial cell wall. changed the way clinicians treat cancer. The Astellas Awards were established Jordan is the first Ph.D. to receive this award that recognizes by the American Chemical Society to recognize individuals or his seminal laboratory work on the pharmacology of the drugs teams who have significantly contributed to scientific research tamoxifen and raloxifene. He was the first to recognize that that improves public health through their contributions in the these drugs are selective estrogen receptor modulators, i.e. they chemical and related sciences. The award carries a $30,000 stimulated or blocked estrogen target tissues around the body. He prize. Mobashery and the other award recipients will be honored took these laboratory data and collaborated with the clinical com- in August at the 236th American Chemical Society national meet- munity to complete the appropriate clinical testing. For 20 years, ing in Philadelphia. tamoxifen was the gold standard for the treatment and prevention The Mobashery lab has been seeking new approaches to of breast cancer, and raloxifene is used to prevent osteoporosis understand the antibiotic-resistant superbacterium MRSA (meth- and breast cancer. icillin-resistant Staphylococcus aureus). This variant of S. aureus surfaced in the early 1960s and has recently emerged as a serious health problem. By figuring out how MRSA lives and thrives, the I n M emoriam : Mobashery group has enabled the development of strategies for Richard Abrams killing this difficult organism. Richard Abrams, a distinguished biochemist, died in Pittsburgh in January at age 90. In Memoriam: Abrams was born in Chicago, obtaining his B.S. (1938) and Ph.D. (1941) degrees in chemistry from the University of Chicago. Graham Jamieson He was a Research Instructor in the Department of Chemistry at Graham A. Jamieson died in Bethesda, Maryland, this past March the University of Chicago from 1941 to 1942 and then became at the age of 78. He was a leader and distinguished scientist at the a Group Leader in the Biology Division of the Manhattan Project American Red Cross for 38 years. (1942 to 1946). From 1946 to 1951 he held the position of Assistant Born in 1929 in Wellington, New Zealand, Jamieson obtained Professor in the Institute of Radiobiology and Biophysics at Chicago. both his B.S. (1949) and M.S. (1951) degrees from New Zealand’s In 1951, he moved to Pittsburgh, remaining there for the rest of his University of Otago. He received his Ph.D. degree in organic life. His first appointment was as Associate Director (1951 to 1958) chemistry from the University of London, Lister Institute of of the Montefiore Hospital Institute of Research, becoming Director Preventive Medicine, in 1954. from 1958 to 1965. At the same time, he held professorial appoint- After doing several research fellowships, Jamieson joined the ments in the Department of Biochemistry and Nutrition, Graduate American Red Cross Blood Services in 1961 as a biochemist in its School of Public Health (GSPH), University of Pittsburgh. Terminating transfusion blood research and development (R & D) program, and his work at Montefiore, he became Professor and Chairman of in 1964, he became a senior scientist and the assistant research the GSPH Department of Biochemistry and Nutrition in 1965. This director. Named research director in 1969, Jamieson oversaw department was renamed the Department of Biochemistry in the major growth of the program and expanded the effort into new sci- Faculty of Arts and Science in 1968; he continued as Chairman until entific and technical fields. Under his guidance, the R & D program 1972. He retired in 1984 with the title of Professor Emeritus. achieved national and international recognition and respect. His research focused on nucleic acid metabolism, and in While developing this program, Jamieson also conducted a 1955, with Marian Bentley, he isolated inosine 5´-monophosphate significant research program in platelet biology. His department’s dehydrogenase, the enzyme responsible for converting IMP to research addressed many topics, including the role of platelet XMP, from rabbit bone marrow extracts and demonstrated a glycoproteins in platelet function, identification and characteriza- requirement for glutamine for the further conversion of XMP to tion of platelet receptors, and the interaction of platelets with GMP. Moreover, in a collaboration with Mary Edmonds beginning tumor cells and extracellular matrix proteins. After 15 years in 1957, he examined animal cell extracts for RNA synthesis lead- guiding the R & D program, Jamieson resigned his position as ing to the isolation of poly(A) and poly(A) polymerase. director in 1984 to return his full attention to research. He retired in April 1999. July 2008 ASBMB Today 9 asbmb news Legislation on Supporting Women in Academic Science BY ANGELA HVITVED arlier this spring, the House Science and Technology implemented by the proposed bill. The May hearing was ESubcommittee on Research and Science Education a follow up to one held in October 2007, during which held a hearing to receive comments on draft legisla- the NAS report was reviewed and participants discussed tion titled “Fulfilling the Potential of Women in Academic how potential legislation could be constructed to address Science and Engineering Act of 2008.” The legislation, the concerns identified (see ASBMB Today, December sponsored by Representative Eddie Bernice Johnson 2007). (D-TX), was crafted in response to a 2007 National Acad- The hearing charter posed several questions of the emies report “Beyond Bias and Barriers: Fulfilling the witnesses relevant to their fields of expertise, but there Potential of Women in Academic Science and Engineer- was a general focus on two major issues: ing.” The report discussed obstacles facing women in 1. Describe the key elements of effective training and academic science and engineering careers and provided education programs addressing gender bias (and a list of recommendations addressing these concerns. their metrics for success) and Several of the report recommendations, including 2. What demographic data can or should be collected workshops to increase awareness of gender bias and to assess gender disparities in academic science and better tracking of federal funding information, would be engineering. What Women (Scientists) Want: The National Institutes of Health Announces RFA on Initiatives to Support Women in Science BY ANGELA HVITVED Few dispute the numbers on retention rates for women in such as underrepresented minority women and socio- science and engineering, but there is less consensus about economically disadvantaged women what should be done and, more importantly, what works. To • the efficacy of programs designed to support the careers address these questions, the National Institute of General of women in science Medical Sciences (www.nigms.nih.gov) issued a notice of Investigators are strongly encouraged to collaborate with intent for a Request for Applications (RFA) on “Research on colleagues in the natural, behavioral, and social sciences, Causal Factors and Interventions that Promote and Sup- and other fields as needed. The RFA was developed in a port the Careers of Women in Biomedical and Behavioral subcommittee of the National Institutes of Health Working Research (NOT-GM-08-126).” The RFA will be published in Group on Women in Biomedical Careers, which was created July 2008 with a receipt date of October 2008; they antici- to consider the recommendations of the National Academies pate funding up to eight R01 awards after September 2009. report on women in academic science, “Beyond Bias and The aims of the RFA, as described in the notice of intent, are Barriers.” The purpose of this group is to develop innovative to support research on: strategies and tangible actions that promote the advance- • the causal factors, such as individual characteristics, ment of women in research careers in both the National institutional/departmental environment, organizational Institutes of Health intramural and extramural research structure, and disciplinary culture or practices, explaining communities. This RFA is one of several initiatives that have the current patterns observed in the careers of women come out of the Working Group. More information can be in science and variation across different subgroups, found on their web site, womeninscience.nih.gov. 10 ASBMB Today July 2008 asbmb news The hearing featured testimony by Lynda Carlson, director of the National Science Foundation (NSF) Divi- sion of Science Resources Statistics; Linda Blevins, Evolution Watch: senior technical advisor in the Department of Energy Academic Freedom Office of Science; and Donna Ginther, associate profes- sor of economics at the University of Kansas and director Legislation: of the Center for Economic and Business Analysis. One Step Forward, The three witnesses weighed in with their thoughts on the proposed legislation and suggestions for possible One Step Back… improvements. There was a spate of “Academic Freedom” legislation this With respect to improved collection of demographic spring but fortunately for science education, little progress data for federal funding, most agree that it should be a goal. However, it is clear that current mechanisms could has been made in these efforts. For those not familiar with not meet the proposed requirements. Carlson, who is this type of legislation, these bills purport to protect the the director of the NSF division that is responsible for rights of teachers and students to discuss the controversies collecting demographic data on proposals and awards, and weaknesses of evolution in the science classroom but plainly stated that this legislation would exceed its cur- are generally considered an indirect method of introducing rent data collection capabilities and that it does not intelligent design. In many states, the language was mod- have the authority to require other agencies to maintain eled on draft legislation provided by the Discovery Institute, a such records. Additional obstacles include the fact that pro-intelligent design creationist organization, as part of their principal investigators cannot be required to provide “Teach the Controversy” campaign. In the past few months, demographic information (due to privacy laws), and the “Academic Freedom” Acts were introduced in the Florida, proportion of PIs voluntarily reporting their gender has Louisiana, Alabama, Missouri, South Carolina, and Michigan continually declined over the last 10 years. Despite state legislatures. There is a bit of good news, though. As these difficulties, all three witnesses seemed to agree state legislative sessions close, many of these initiatives that better data collection is necessary for better under- standing the underlying causes of the disparities. are dying in the process, although proponents promise to The topic of workshops received slightly more mixed revive them next session. As of this writing, time has run out support. Blevins, who helped coordinate the “chemistry for initiatives in Florida, Alabama, and Missouri but action workshop” on gender bias, discussed what she believes continues in South Carolina, Michigan, and Louisiana. The are important components of a successful program. For National Center for Science Education is closely monitoring those not familiar with this concept, in 2006 the chemis- these bills and regular updates can be found on their web try community organized a workshop addressing issues site, www.ncseweb.org. of gender bias targeted to the chairs of the top 50 uni- versity chemistry departments. This workshop inspired a similar effort by the physics community and serves as a model for proposed programming in the legislation under evaluation of outcomes from the proposed workshops. discussion. Ginther, who studies the issue as an econo- Although changing attitudes is important, the key test of mist, pointed out that with admittedly imperfect data, success is whether those changes affect concrete out- one cannot conclude that gender bias alone accounts comes, and this aspect should be analyzed more rigor- for the gender gap in academic success. Her research ously. She went on to conclude that an additional action suggests that issues of productivity, resulting from mar- the federal government could take would be childcare riage and child rearing, may also explain the discrepancy, support though direct and indirect funding. Details of at least in part. However, until better data on home and witness recommendations can be found in their testi- family commitments can be merged with productivity mony on the subcommittee web site, science.house. and funding success, it will be difficult to make definitive gov/subcommittee/research.aspx. Watch for updates on conclusions on the role played by gender bias. the progress of the proposed legislation in the months to Ginther expressed concern about appropriate come. July 2008 ASBMB Today 11 special interest Presidential Primer: Gregory Petsko Brandeis professor takes over ASBMB leadership on July 1 regory Petsko, the Gyula and Katica Tauber Professor His lab work of Biochemistry & Chemistry at Brandeis Univer- helped renew his sity, offers a simple explanation when asked why he childhood sci- Gdecided to run for president of ASBMB. “Because I’m stupid,” entific interests, he says. “Heidi Hamm and Susan Taylor approached me and he eventually about the presidency and suggested I run, but they told me graduated Princ- not to worry, because I would lose. And I fell for it.” eton having studied With a little more prodding, Petsko does offer other, more both chemistry and serious, motivations for taking up the mantle of presidency. classical literature. Considering the divergent nature of these “Frankly, I don’t like what I see: the decreased funding, politi- two disciplines, it may be no surprise that Petsko was unsure cization of science, lack of science education, and the general which direction to take as graduation neared. “I applied to growth of a society that is replacing ‘reason’ with irrational- law, medical, and graduate schools, to give you some idea ity. Not many jobs can give you the bully pulpit you need to of my confused mindset,” he says. One thing he was fairly try to do something about this decay, but ASBMB president certain of was that he would like to spend some time studying could be one.” abroad, and that led him in 1970 to apply for and win a Rho- And judging by his first answer to the question, we des scholarship, which seemed to present him with a golden probably already have a good idea of what kind of president opportunity. “Oxford was king when it came to the classics,” Petsko will be: direct, unabashed, and forthright. He pro- Petsko says, “so I set sail to get an advanced degree in classical vides some more of that honesty when discussing his hopes literature and buy time while I sorted things out.” for improvement during his two-year tenure. “I have no real And set sail he literally did, as back then Rhodes recipi- expectations of change,” he says, “and I’m pretty sure I won’t ents were transported to Great Britain onboard the Queen succeed in many of my efforts, but at the same time, it would Elizabeth II. However, during that eight-day voyage across be irresponsible not to try. After all, we cannot be afraid of the North Atlantic, Petsko’s would-be mentor at Oxford, uncertainty or failure.” noted classical scholar Maurice Bowra, unexpectedly died; This brave front comes from Petsko’s unusual career track Petsko arrived at the university to find himself with nobody in his younger days. While he certainly displayed a strong to work for. interest in modern science growing up—“I loved watching “I decided to call Bob [Langridge] and see if he had any Mr. Wizard on television, and blew up my parents’ basement advice, since he had studied in England, and he told me to go with my first chemistry set like everyone else”—he had an and see David Phillips, the crystallographer,” Petsko says. “Of even stronger passion for the ancient world. A devout reader course, when I went to talk with David, he looked at me as of ancient Greek and Roman authors, he enrolled in Princ- if I had two heads. ‘Why should I take you in?’ he asked me, eton University in 1966 to major in classical literature. To at which point I replied, ‘Because I won’t cost you anything.’” make some extra money, he started working in labs part time, Taken under Phillips’ wing, Petsko spent the next three years first with inorganic chemist Bill Horrocks then later with learning more about X-ray crystallography, during which Robert Langridge, a structural biologist who had worked in time he helped solve one of the earliest protein structures: England with Maurice Wilkins, the sometimes overlooked triose phosphate isomerase. Thus was a future biochemist third scientist who helped discover the double helix. and structural biologist born. 12 ASBMB Today July 2008 special interest But while he has been building an impressive resume as And while he may jokingly complain about taking this posi- a research scientist over the past 35 years by using structural tion, he is ready to stop just writing and start doing. analyses to tease out the functional aspects of enzymes, “I’ll definitely need a little time to test the waters,” he says, Petsko has always striven to broaden his horizons. This “because at this point I don’t know enough about the ‘power’ includes work at the lab bench (he recently ventured into of the office versus the ‘powers’ of the office. Fortunately, the realm of yeast genetics to look at cell cycle control) and ASBMB has a first-rate staff, and I will lean on them for beyond. That was, in fact, a big reason why he took a posi- assistance.” tion at Brandeis in 1990 following 13 years on the faculty at However, once he’s comfortable, he does have a few ideas research powerhouse MIT. “I had wanted to work at a smaller for his agenda. institution where both students and faculty were immersed One is to continue Heidi Hamm’s efforts at improving in a more diverse environment.” Brandeis also gave Petsko National Institutes of Health (NIH) policy, especially the drift the opportunity to put his humanities knowledge to use, and away from funding individual investigator-initiated projects, over the years he has taught courses such as “Chemistry and and he plans to meet with policymakers at both NIH and on Art” (using science to find forgeries), “Scientists in Films and Capitol Hill. Petsko will also try to mobilize ASBMB mem- Plays,” and even “The History of Detective Novels.” bership to make local differences where possible, as well as Another reason for choosing Brandeis was that they coordinate larger efforts with other scientific societies “so offered Dagmar Ringe, Petsko’s co-principal investigator, a that we can speak with one voice.” Petsko hopes to address professorship, whereas at MIT she was only in charge of the other topical issues like the splintering of big societies into teaching labs. “Dagmar is one of the best scientists I have ever smaller ones and the direction of open access in publishing as known, and I’m fortunate to have had her running a joint well. Still, he wants to leave open a good deal of space for the research program with me for the past 30 years,” he says. “It unexpected, be it new policies or new trends. “There is a lot was important that she get some recognition, and she did: her of reaction involved in this work,” he says. first faculty appointment anywhere was with tenure in the One point that Petsko stresses, however, is that the sci- Brandeis University biochemistry department, one of the best entific community needs to take many of its problems, like in the world.” funding deficiencies, on its own shoulders. “I know we have The combination of these qualities—blunt honesty, another new U.S. president taking office soon,” he says, “and valuing a diverse education, recognizing the importance of while I believe whoever takes over will be more receptive working with others, and daring to wade into new territory— to scientists, it will be foolhardy to believe that a change in taken along with Petsko’s history of vocal contributions to the Washington will produce any immediate changes in funding. cause of science (he has written a monthly opinion column No one is coming on a white horse to save us.” on science and society for Genome Biology for the past eight And while it may not be a popular thought, Petsko years) make him a fitting candidate for ASBMB’s top post. believes the first step to improving funding for science is to acknowledge that scientists have to share some of the blame as well. “We had a period when NIH fund- ing doubled, but we screwed up our priorities and didn’t spend the money the best way possible, such as infusing our R01 pool, so when funds tightened we developed shortages. Once we recognize that, we can begin to correct it.” As is his nature, Petsko is not afraid to include himself in any blame. “We’ve all made mistakes we need to acknowledge; look at me, I got tricked into running for ASBMB president.” July 2008 ASBMB Today 13 publishing series Picture Perfect (PPI). When resized, raster images If a figure is constructed entirely of This article is fifth in a series on must readjust to the fixed grid so text, lines, or charts (in other words, publishing your research in the image quality suffers as some dots (or vector elements), the best option Journal of Biological Chemistry. pixels) must straddle an opening in is to copy images from PowerPoint The series will address a variety of the grid. In addition, a raster image and paste them into a program like issues that authors may have when with low DPI appears very jagged Adobe Illustrator. This copy-and- writing and submitting articles to when output at the high resolution of paste method will actually give more the JBC. The articles are written by commercial printing. Photoshop is predictable results without all the the primary program for editing ras- resolution, font, color and quality Cadmus Communications, a Cenveo ter images, to be saved in TIF format. issues found when submitting native company, which is responsible The difference may not be vis- PowerPoint files. The full instructions for the editing, production, and ible on a 72 DPI computer monitor, are available by following the Power- printing of JBC articles. but the enlarged illustration gives a Point link at the Digital Art Support comparison. web site. Fortunately, there are additional user-friendly options and we will Many authors need some guidance share one of the best ones in this to create artwork that is aesthetically article. First, there is one important pleasing and relevant to the message rule to remember about working of the report or paper. Included in this with PowerPoint files: NEVER use article are some suggestions for prepar- the PowerPoint “Save As…” option ing print-ready artwork that will pro- to create a TIF file — in fact, do duce high-quality images in the JBC. not “save as” any other format from within PowerPoint. Image Editing Tips & Tricks Graphic images processed by a PowerPoint computer can be divided into two By far, the most common question distinct categories: vector and raster. from authors is how to take Microsoft Vector images lend themselves to well PowerPoint source files and convert defined elements composed of lines them into usable digital art files for and curves of specific colors. They publication. Because of quality issues, are created in programs like Illustra- many journals do not accept Pow- tor, FreeHand, and CorelDRAW and erPoint files for print production. saved as EPS files. Vector graphics are PowerPoint is an application designed “resolution independent” and can be to create on-screen computer presen- sized without any loss of quality. tations at 72 DPI resolution. In addi- Raster (or halftone) images are tion, PowerPoint lacks the capacity In addition to the aforementioned more suitable for photos requiring for failsafe management of fonts and “cut-and-paste” option, another complex color variation mapped to for seamless cross-platform (Mac/PC) method is to separate the series of a non-flexible grid. The grid density file usage. As a result, PowerPoint PowerPoint slides into individual sets the resolution and is expressed in images may not reproduce with suf- PowerPoint files. Each of these files dots per inch (DPI) or pixels per inch ficient accuracy or quality. can then be converted into an Acro- 14 ASBMB Today July 2008 publishing series bat PDF file. To create a PDF file from ber when using Illustrator to work on Rule (line) weight: A common PowerPoint, the system must have your figure. issue with PowerPoint files is that the appropriate version of Adobe Sizing: Go to the “Window” pull rules are often set to “Hairline”; this Acrobat installed. Depending on the down menu, click “Transform” to produces a rule that is too thin for configuration, it may be as simple as display the Transform palette if not print production. clicking the Acrobat PDF button on already visible. Go to “Select” and Under the “Window” pull down the toolbar. click on “All” to highlight the entire menu, click on “Stroke” to display the figure. The small chain-link image Stroke palette if not already visible. at the far right of the palette should Using the direct selection tool, click have lines connecting the height to select one of the thin lines. Under and width dimensions. Clicking the the “Select” pull down, scroll to chain-link will toggle the lines off and “Same” and select “Stroke Weight.” on. This is important because it keeps If there is no button on the toolbar, the height proportional as the width it should be available as a choice in is adjusted. Enter the appropriate the “print” dialog window. width for the figure. With all strokes with the same weight selected, increase the stroke To confirm the figure size is value. As a general rule, thin rules acceptable, check the size of the should not be less than 0.5 pt. smallest type. To do this, use the direct selection tool (the white arrow) Once a PDF file is created, it to select the smallest type in the fig- should be inspected to ensure that ure. Under the “Window” pull down none of the notorious PowerPoint menu, click on “Type” and select “glitches” occurred during the trans- “Character” from the fly out menu to formation. These glitches can include display the Character palette if not the disappearance of special charac- already visible. The smallest type is ters (e.g., Greek and math symbols) often ~6 pt (subject to each journal’s or rotated text becoming un-rotated. standard). Next, the PDF file can be opened for final editing and refinement in Illus- Finish trator or Photoshop, as appropriate. Finish by converting type to Illustrator outlines, then save as an EPS file. Generally, Illustrator is the best Converting the PDF to Photoshop option for editing figures. Among 600 DPI TIF files is another option. other things, Illustrator retains all the Detailed instructions are on the vector information in the final EPS web site: http://art.cadmus.com/da/ file. There are a few things to remem- instructions/ps80_win.jsp. July 2008 ASBMB Today 15 2009 annual meeting Membrane Dynamics and Organelle Biogenesis BY FRANCES BRODSKY AND DAVID LAMBRIGHT ow functionally distinct yet highly dynamic membrane- geting by endosomal Rab Hbound compartments form, mature, interact, divide, GTPases and phosphoinositi- and exchange endogenous or foreign material remains one des. Suzanne Pfeffer (Stanford Brodsky of the most challenging problems in eukaryotic cell biology. University School of Medicine) Our understanding of the mechanisms that control these will present analyses of vesicle fundamental cellular processes continues to expand at a tethering at the Golgi that high- rapid rate and is the subject of the talks in the “Membrane light the importance of syner- Dynamics and Organelle Biogenesis” theme. The talks gism between small GTPase will highlight new insights into the underlying molecular families for localization of GRIP machinery from a variety of perspectives including functional domain golgins. Juan Bonifacino genomic and molecular biological approaches, structural (NICHD, National Institutes of investigations of trafficking complexes, three-dimensional Health) will describe studies on cryoelectron microscopy reconstructions of membrane the molecular mechanisms of remodeling intermediates, phylogenetic analyses of evolu- coat protein, adaptor and scaf- tionary relationships, and studies of pathogen subversion. folding complexes involved in Lambright A major function of intracellular membrane traffic is to cargo recognition, and sorting generate and maintain organelle integrity in eukaryotic to and from endosomes. cells and to regulate organelle inheritance upon cell divi- Membrane traffic pathways are subverted by numer- sion. The session “Organelle Biogenesis and Evolution” ous pathogens for infection, propagation and intracellular will address conservation and diversity in the pathways for survival. The “Trafficking Mechanisms and Pathogen organelle biogenesis and inheritance and include strong Subversion” session will cover membrane traffic pathways consideration of eukaryotic membrane trafficking. Fran- that are subverted by virus, bacteria and intracellular para- ces Brodsky (University of California-San Francisco) will sites. James Hurley (NIDDK, National Institutes of Health) describe how gene duplication in the vertebrate lineage will describe structural studies of the ESCRT (Endosomal expanded clathrin function in tissue specific pathways Sorting Complex Required for Transport) components of the while maintaining critical properties that are required for endosomal pathway that are exploited by the human immu- control of membrane traffic by clathrin. Mark Field (Uni- nodeficiency virus for virus budding. Mark Marsh (Medical versity of Cambridge) will discuss phylogenetic analysis of Research Council Laboratory for Molecular Cell Biology) will proteins in the endocytic system and comparative insights discuss cellular locations of human immunodeficiency virus from studying endocytosis in protozoa. Janet Shaw assembly and release in macrophages. Norma Andrews (University of Utah) will focus on mitochondria and the (Yale University) will describe how studying pathogens that mechanisms of membrane remodeling and movement that take advantage of these mechanisms for intracellular sur- control their distribution and inheritance. vival has elucidated mechanisms of membrane repair. Dynamic networks of protein-protein and protein-lipid The “Membrane Dynamics and Transport” session will interactions mediate and confer specificity to vesicular traf- combine mechanistic investigations of membrane dynam- ficking processes. The session “Cargo Sorting and Vesicle ics during budding and tubulation with functional genomic Targeting” deals with the molecular mechanisms underly- analyses of the molecular machinery controlling forma- ing selective incorporation of cargo molecules into budding tion and maturation of transport carriers. Jenny Hinshaw vesicles and subsequent targeting of vesicles preceding (NIDDK, National Institutes of Health) will discuss the role fusion. David Lambright (University of Massachusetts of dynamins in membrane remodeling, highlighting the Medical School) will discuss regulation of vesicle tar- application of x-ray crystallography in conjunction with 16 ASBMB Today July 2008 2009 annual meeting Membrane Dynamics & Organelle Biogenesis Organizers: Frances Brodsky, University of California-San Francisco, and David Lambright, University of Massachusetts Medical School Symposium: Organelle Symposium: Trafficking Mechanisms Biogenesis and Evolution and Pathogen Subversion • Evolution and function of a novel clathrin isoform, Frances Brodsky • The ESCRT complexes: From lysosome biogenesis to viral budding, • Origins of the endocytic system: Insights from protozoa, Mark Field James Hurley • Mechanisms of membrane remodeling and movement: Lessons • HIV assembly and release in macrophages, Mark Marsh from the mitochondrion, Janet Shaw • Cellular responses to injury: New insights from the study of host- pathogen interactions, Norma Andrews Symposium: Cargo Sorting and Vesicle Targeting Symposium: Membrane Dynamics and Transport • Mechanisms for regulation of vesicle targeting, David Lambright • The role of dynamins in membrane remodeling, Jenny Hinshaw • Molecular analysis of vesicle tethering at the Golgi, Suzanne Pfeffer • Caught in the act: Membrane remodeling as seen by electron • Protein coats involved in sorting to and from endosomes, cryomicroscopy, Vinzenz Unger Juan Bonifacino • Global analysis of endocytic recycling in yeast, Elizabeth Conibear cryoelectron microscopy to examine constricted and brane binding and bending modalities. Finally, Elizabeth non-constricted intermediate states. Vinzenz Unger (Yale Conibear (University of British Columbia) will describe University) will present three-dimensional reconstruc- new transport complexes identified through genome- tions of FBAR domains on membrane tubules visualized wide analysis of endocytic recycling in yeast using an by cryoelectron microscopy. These reconstructions approach that features automated phenotypic recogni- reveal polymeric assemblies with distinguishable mem- tion and novel computational algorithms. All New www.ASBMB.org More Science More Society News More Interaction Come See What’s New! July 2008 ASBMB Today 17 2009annualmeeting continued Principles of Receptor Signaling BY MARK LEMMON AND ALEX TOKER ells can only respond to their environment or commu- affinity” receptors and describe Cnicate with one another because of the existence of an studies about EGF binding array of receptors for nutrients, hormones, and other cues. to the cell surface that allow Many of these receptors function at the cell surface, trans- translation of structural data to mitting information across the limiting membrane, whereas what happens to the recep- Lemmon others in the cytoplasm or nucleus respond to signaling tor in living cells. Finally, Phil molecules that freely enter the cell and are critical players in Cole (Johns Hopkins University orchestrating cellular responses. The wide range of patho- School of Medicine) will illu- logical conditions, such as cancers, diabetes, and immune minate intracellular aspects of disorders, in which specific receptor proteins are either RTKs, discussing some surpris- mutated or otherwise altered highlights the central impor- ing mechanisms of tyrosine tance of receptor signaling in biology. Recent advances in kinase activation against the understanding the mechanisms used by different receptor backdrop of important disease- classes and the relay pathways that transduce these signals related mutations. will be highlighted during the four sessions in the “Principles The session titled “Trans- of Receptor Signaling” theme at the ASBMB 2009 annual membrane Signaling by meeting. GPCRs” moves to heptahelical Toker The first session will be chaired by Zena Werb, receptors, in which a much (University of California San Francisco) and will feature a larger portion of the receptor is embedded in the mem- strong emphasis on mechanisms by which cellular recep- brane. Heidi Hamm (Vanderbilt University Medical Center) tors impact disease progression. Alex Toker (Beth Israel will chair this session. William Weis (Stanford University Deaconess Medical Center, Harvard Medical School) School of Medicine) will begin by describing the first will discuss the family of matrix proteinases collectively structural views of how G protein-coupled receptors known as ADAMs, and how they modulate breast cancer (GPCRs) such as the β2-adrenergic receptor transmit cell invasive migration. Next, Werb will discuss the large signals across the membrane, a tour de force that pre- family of conventional matrix metalloproteinases and how pares the field for more major breakthroughs. Heterotri- they regulate tumorigenesis. Thus, the first two presenta- meric G proteins play a crucial role as molecular switches tions will focus on matrix degradation and ligand release in GPCR signal transduction pathways, and these will be as mechanisms that promote tumor progression. The the topic of the second talk by Hamm, who will describe session will end with a presentation from Bert O’Malley how GPCR activation is communicated to the G protein (Baylor College of Medicine) who will discuss proteolysis switch. In the final talk, Lakshmi Devi (Mount Sinai School in the context of nuclear receptors, including recent find- of Medicine) will discuss two other important aspects of ings on steroid nuclear receptor coregulators. GPCR control, intracellular trafficking and GPCR het- The second session will examine mechanisms of erodimerization, with a particular focus on opioid recep- signaling through cell-surface receptor tyrosine kinases tors. (RTKs), particularly the epidermal growth factor (EGF) The final session will be chaired by Fred Hughson receptor, and will be chaired by Mark Lemmon (University (Princeton University) and will focus largely on receptor of Pennsylvania School of Medicine). Kathryn Fergu- signaling in unicellular organisms. Hughson will describe son (University of Pennsylvania) will discuss structural his work on mechanisms of signaling in quorum sensing, aspects of how EGF binding promotes dimerization of in which bacterial cells communicate with one another to the extracellular part of the EGF receptor as well as how synchronize certain activities across a population. Mark therapeutic antibodies that bind the EGF receptor exert Goulian (University of Pennsylvania) will then discuss their inhibitory effects. Linda Pike (Washington Univer- how bacterial cells maintain insulation of distinct signal- sity School of Medicine) will then provide answers to the ing pathways, thereby preventing promiscuous cross- long-standing question about the nature of the “high- talk, while also taking advantage of certain opportunities 18 ASBMB Today July 2008 2009annualmeeting continued Principles of Receptor Signaling Organizers: Mark Lemmon, University of Pennsylvania School of Medicine, and Alex Toker, Beth Israel Deaconess Medical Center, Harvard Medical School. Proteolysis and Receptor Signaling Transmembrane Signaling by GPCRs • ADAM proteases and cancer invasion, Alex Toker • Structure of GPCRs, Bill Weis • How matrix metalloproteinases regulate signaling in cancer, • How GPCRs activate G proteins, Heidi Hamm Zena Werb • Opioid receptor dimerization/signaling, Lakshmi Devi • Proteolysis and nuclear receptor coregulator function, Bert O’Malley Signaling in Bacterial Receptor Systems Tyrosine Kinases in Cancer • Bacterial quorum sensing, Fred Hughson • Tyrosine kinase mechanisms and pathways, Phil Cole • Insulation and specificity in bacterial two-component signaling • Negative cooperativity in EGFR signaling, Linda Pike systems, Mark Goulian • Structural aspects of extracellular EGFR signaling, • Design principles of receptor signaling networks, Naama Barkai Kathryn Ferguson to integrate the signals from multiple pathways. Finally, signaling networks becomes more sophisticated, it is Naama Barkai (Weizmann Institute of Science) will discuss increasingly clear that they are typically robust systems new perspectives in a fascinating frontier in cell signal- defined by their organization and system properties rather ing: biological networks. As our understanding of cellular than the nature of their components. Inflam_half_JBC.qxd:Layout 1 5/19/08 3:35 PM Page 1 An AACR Special Conference in Cancer Research Chemical and Biological Aspects of Inflammation and Cancer October 14-17, 2008 JW Marriott Ihilani Resort and Spa at Ko Olina • Ko Olina, Oahu, Hawaii Conference Chairpersons: Michael Karin Lisa M. Coussens Moores UCSD Cancer Center, La Jolla, CA UCSF Comprehensive Cancer Center and Cancer Lawrence J. Marnett Research Institute, San Francisco, CA Vanderbilt University Medical Center, Nashville, TN Abstract Submission, Award Application, and Early Registration Deadline: August 10, 2008 www.aacr.org July 2008 ASBMB Today 19 2009annualmeeting continued Metabolism and Disease Mechanisms BY JÜRGEN WESS AND SEAN OLDHAM he coordinated activity of central and peripheral indicating that carbonic anhy- Tmetabolic processes plays a key role in the proper drase II-expressing pancreatic function of virtually every cell type. Improper signaling cells give rise to both new Oldham through distinct metabolic pathways has been impli- islets and acini after birth and cated in a variety of disorders including obesity and type injury (ductal ligation), which 2 diabetes (T2D). Altered metabolism is also known to has implications for a poten- lead to impaired physiological function associated with tial expandable source of new senescence and aging. Interestingly, recent studies have islets for diabetes replenish- led to the identification of many novel metabolic path- ment therapy. ways and signaling molecules that play critical roles in The “Metabolic Signaling health and disease. and Obesity/Metabolic Syn- In the “Metabolic Signaling in Senescence and Aging” drome” session will highlight session, the speakers will focus on molecular mecha- several metabolic pathways nisms that modulate aging and age-related diseases and signaling molecules that including T2D. Several laboratories have shown that are of significant pathophysi- Wess aging is tightly coupled to nutrient availability and that ological relevance. Sean Old- dietary restriction increases life span. Brian Kennedy ham (The Burnham Institute (University of Washington) will present studies designed for Medical Research) will discuss how altered TOR to identify the molecular pathways that underlie the (target of rapamycin) signaling regulates metabolism longevity effects of dietary restriction. Nir Barzilai (Albert and contributes to obesity, diabetes, and aging. Laurie Einstein College of Medicine) will discuss the physiologi- Goodyear (Harvard Medical School) will discuss some cal actions of a novel mitochondrial peptide, humanin, of the metabolic roles of AMP-activated protein kinase including its ability to prevent neurotoxicity and its (AMPK) and its upstream kinase LKB1, two serine/ peripheral insulin-sensitizing effects. Peter Elliott (Sirtris threonine kinases that have been proposed to function Pharmaceuticals, Inc.) will focus on the role of sirtuins as master regulators for a diverse array of metabolic in diseases of aging, specifically the consequences of processes, particularly examining the putative roles of mitochondrial biogenesis in animal models of disease AMPK and LKB1 in regulating skeletal muscle metabo- and clinical trials with T2D patients. lism. Heidi Tissenbaum (University of Massachusetts) will T2D is emerging as a major threat to human health focus on studies aimed at identifying the molecular con- worldwide, and the “Signaling Pathways Involved in Dia- nections between lifespan, diabetes, and obesity, using betes” session will focus on various factors that regulate as a model the nematode C. elegans, which is endowed insulin action and glucose homeostasis. Morris White with an insulin/IGF-1 signaling pathway that modulates (Howard Hughes Medical Institute/Children’s Hospital) both longevity and fat storage. will talk about molecular mechanisms of insulin signaling The “Metabolism and Nutritional Signaling” session in the central nervous system, pancreatic β cells, and will focus on metabolic/nutritional factors and path- liver that play important roles in nutrient homeostasis ways that might serve as therapeutic targets in various and growth. G protein-coupled receptors are known to metabolic disorders. Gen-Sheng Feng (The Burnham regulate the activity of many cell types involved in glu- Institute for Medical Research) will discuss the functions cose homeostasis, and Jürgen Wess (NIDDK, National of Shp2 tyrosine phosphatase in orchestrating signal- Institutes of Health) will discuss new strategies aimed ing events downstream of insulin and leptin receptors at understanding the in vivo roles of distinct G protein in glucose homeostasis and energy balance. Laura pathways in modulating β cell function. Susan Bonner- Bordone (Novartis Institute for Biomedical Research) will Weir (Harvard Medical School) will describe studies talk about a mouse model overexpressing SIRT1 that 20 ASBMB Today July 2008 2009annualmeeting continued shows phenotypes resembling calorie restriction. Her 2008 Interactive talk will also deal with the role of SIRT1 in regulating insulin secretion. Cristina Rondinone (Hoffmann-La Roche Inc.) will describe strategies, such as the use of Annual Meeting different enzymatic regulators of triglyceride synthesis that are aimed at reducing the exaggerated plasma- Award Lectures free fatty acid and triglyceride levels usually associated with obesity for obesity therapy, insulin resistance, and other components of metabolic syndrome. Now Live! These incorporated sessions will highlight many important advances in the field of metabolism, bring- ing together researchers who are using a wide range of experimental approaches. The increasing integra- tion of biochemistry and molecular biology with cellular and organismal physiology promises exciting times ahead for metabolic research. Metabolism and Disease Mechanisms Organizers: Jürgen Wess, NIDDK, National Institutes of Health, and Sean Oldham, The Burnham Institute for Medical Research Metabolic Signaling in Senescence and Aging • Conserved links between nutrient signaling, translation, and aging, Brian Kennedy • Central regulation of peripheral glucose metabolism: Target therapy for aging, Nir Barzilai • Sirtuins: Novel metabolic targets for disease of aging, Peter Elliott Signaling Pathways Involved in Diabetes • IRS signaling and diabetes, Morris F. White • GPCR signaling pathways in β cells, Jürgen Wess • Pancreatic regeneration: Role of pancreatic progenitors, Susan Bonner-Weir Metabolic Signaling and Obesity/ Metabolic Syndrome • TOR in metabolism and aging, Sean Oldham • AMPK: A critical metabolic signal, Laurie Goodyear • Regulation of lifespan and fat storage by C. elegans tubby, Heidi Tissenbaum Metabolism and Nutritional Signaling • Shp2 and molecular signaling in obesity/diabetes, Gen-Sheng Feng • SIRT1, calorie restriction, and metabolism, Laura Bordone • Targets affecting lipid metabolism to treat metabolic diseases, Cristina Rondinone www.asbmb.org/ 08Awards.aspx 2009annualmeeting continued Lipid Signaling and Metabolism BY SUZANNE SCARLATA & RUSSELL DEBOSE-BOYD he lipid field has been established as one of the most dynamics of internal vesicles. Tprominent in biochemistry and cell biology, and new Bertil Hille (University of Wash- concepts and mechanisms continue to emerge. The ington School of Medicine) will “Lipid Signaling and Metabolism” theme at ASBMB 2009 discuss the affect of PI lipids will encompass the ways in which lipids are maintained on the properties of certain ion Debose-Boyd and stored in the cell, the role they play in cell signaling, channels, and Peter Dev- their ability to organize protein complexes and mediate reotes (Johns Hopkins University School of Medicine) will protein signals, and the ability of a specific family of lipids, describe how PI lipids regulate the dynamics of chemot- inositol phospholipids, to regulate key events in the cell. axis and cytokinesis. The first session will be devoted to the role of mem- In the third session, the mechanism for lipid storage brane domains in lipid signaling. Although the existence and transport will be discussed. Storage and transport of protein and lipid domains in the plasma membrane is of lipids play important roles in metabolism, membrane well known, the ability of these domains to affect cellular synthesis (cholesterol and phospholipids), and steroid functions through their composition and organization is synthesis. Abnormalities in these processes are associ- just beginning to be uncovered. Presentations will focus ated with obesity, fatty liver, cardiovascular disease, and on the effect of domains on functions such as G protein neurological disorders. Karen Reue (UCLA) will talk about signaling, membrane-cytoskeletal adhesion, and phago- lipin proteins, which participate in triglyceride and phos- cytosis. Speakers in this session will be Suzanne Scarlata pholipid biosynthesis as phosphatidate phosphatases (Stony Brook University), Michael Sheetz (Columbia Uni- and also act as inducible transcriptional coactivators versity), and Sergio Grinstein (Hospital for Sick Children, in conjunction with peroxisome proliferator-activated Toronto, Canada). receptor-γ coactivator-1a and peroxisome proliferator- The second session will explore signaling through activated receptor-a. Dawn Brasaemle (Rutgers Univer- phosphatidyl inositol (PI) lipids. It is known that PI lipids sity) will discuss the importance of lipid droplets in lipid are coupled to both growth factor and G protein ago- metabolism and disease. John Dietschy (University of nists to raise intracellular calcium levels that can gener- Texas Southwestern Medical Center) will discuss choles- ate a host of intracellular responses. Additionally, these terol metabolism in the brain. lipids appear to be involved in other cellular processes. The final session will look at the various lipid-mediated Shamshad Cockcroft (University College London) will talk signaling events. Some of these signaling cascades control about the role of these lipids and their transporters in the feedback regulation of lipid synthesis and guard against Lipid Signaling and Metabolism Symposium: Role of Membrane Symposium: Phosphatidylinositol Domains in Cell Signaling Signaling and Metabolism • Regulation of G protein Signals by Membrane Domains, • Co-ordination of vesicle delivery and signaling by Suzanne Scarlata phosphatidylinositol transfer proteins, Shamshad Cockcroft • Membrane-Cytoskeleton Adhesion; Mechanical Controls and PIP2 • Dynamics of PIP2 regulation of Kv7 (KCNQ)K channels, Bertil Hille Dynamics, Michael Sheetz • Signaling Networks in Chemotaxis and Cytokinesis, Peter Devreotes • Lipids dictate surface charge and direct signaling during phagocytosis, Sergio Grinstein Symposium: Mechanisms for Lipid Storage and Transport Symposium: Novel Lipid-Mediated Signaling Events • The Role of Lipin Proteins in Lipid Storage and Metabolism, • Sterol-accelerated ubiquitination and degradation of HMG CoA Karen Reue reductase, Russell DeBose-Boyd • Control of Triacylglycerol Metabolism by Lipid Droplet Proteins, • New insights from lysophospholipid receptor-null mice, Jerold Chun Dawn Brasaemle • The Role of Phospholipid Synthesis in Lipid-Mediated Signaling and • Mutations in NPC1 and cholesterol metabolism in the brain, Regulation in Yeast, Susan A. Henry John M. Dietschy 22 ASBMB Today July 2008 2009annualmeeting continued lipid overaccumulation, whereas others mediate cell-cell lipid synthesis in lipid-mediated signaling events in yeast. communications. Russell DeBose-Boyd (University of Texas These primary presentations will be complemented Southwestern Medical Center) will discuss feedback regula- by short talks selected from abstracts submitted within tion of the cholesterol biosynthetic enzyme, 3-hydroxy-3- these areas. The organizers encourage students, post- methylglutaryl CoA reductase. Jerold Chun (The Scripps doctoral fellows, and young investigators to submit Research Institute) will present the latest findings on abstracts for these sessions. We look forward to fruitful lysophospholipid-mediated signaling pathways. Susan discussions in the ever-expanding field of lipid cell and Henry (Cornell University) will describe the role of phospho- molecular biology. US Alters Conditions this rule in August 2008 and it will be mandatory by January 12, 2009. This online registration, however, need only be com- on Visa-Free Travel pleted once every two years, and not during every trip. The ASBMB Annual Meeting is an international event, and our In addition, our U.S. members should also take note as travel foreign members and guests planning on attending next year’s agreements are typically made on a reciprocity basis; therefore, meeting should take note of an important travel change: U.S. visitors to visa-free countries, such as those in western The U.S. State Department, in an effort to boost security, has Europe, will likely have to start registering in advance of travel as announced that visitors traveling to the U.S. from visa waiver well. countries (such as Great Britain, Australia, and Japan) will soon For the official announcement about the new system, called have to register online 3 days in advance of travel. Currently, the Electronic System for Travel Authorization (ESTA), as well as such visitors fill out paper forms on route and are screened by a full list of visa waiver countries, please go to: http://travel.state. customs agents upon entry. The U.S. will begin implementing gov/visa/temp/without/without_1990.html W146 THE NEW SELECTIVE ANTAGONIST W146 [S1P1 Antagonist] W140 [S1P1 Control Molecule] Avanti Number 857390 Avanti Number 857391 Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Sphingosine 1-phosphate (S1P1) regulates vascular barrier and lymphoid development, as well as lymphocyte egress from lymphoid organs, by activating high-affinity S1P1 receptors. We used reversible chemical probes (i) to gain mechanistic insights into S1P systems organization not accessible through genetic manipulations and (ii) to investigate their potential for therapeutic modulation. Vascular (but not airway) administration of the preferred R enantiomer of an in vivo–active chiral S1P1 receptor antagonist [W146] induced loss of capillary integrity in mouse skin and lung. In contrast, the antagonist did not affect the num- ber of constitutive blood lymphocytes. Instead, alteration of lymphocyte trafficking and phenotype required supraphysiological elevation of S1P1 tone and was reversed by the antagonist. In vivo two-photon imaging of lymph nodes confirmed requirements for obligate agonism, and the data were consistent with the presence of a stromal barrier mechanism for gating lymphocyte egress. Thus, chemical modulation reveals differences in S1P-S1P1 ‘set points’ among tissues and highlights both mechanistic advantages (lymphocyte sequestration) and risks (pulmonary edema) of therapeutic intervention. M Germana Sanna, Sheng-Kai Wang, Pedro J Gonzalez-Cabrera, Anthony Don, David Marsolais, Melanie P Matheu, Sindy H Wei, Ian Parker, Euijung Jo, Wei-Chieh Cheng, Michael D Cahalan, Chi-Huey Wong & Hugh Rosen. Copyright Nature Publishing Group. Published online at http://www.nature.com/naturechemicalbiology Phone 800-227-0651 (205-663-2494 International) or Email [email protected] for details of Avanti’s selection of lipids of unparalleled purity visit www.avantilipids.com FROM RESEARCH TO CGMP PRODUCTION - AVANTI’S HERE FOR YOU firstminoritysecond affairs words Where Is the Equity in Education and Can ASBMB Help? BY Thomas D. Landefeld t has been decades since Brown v. Board of Education and and Proposition 2 in Michigan, has been devastating. Ever Ithe Civil Rights Movement. Where are we now relative since Proposition 209 passed in California in 1996, minor- to those efforts made to achieve equality in education and ity enrollment in professional schools, particularly in the elsewhere so many years ago? Unfortunately, not very far. health professions, has fallen and never recovered. As a Historically, W. E. B. Du Bois stated: “The problem of result, fewer minorities are attaining professional degrees, the 20th century is the problem of the color line.” We are severely thwarting efforts to address health disparities. It is now almost a decade into the 21st century and the color expected that similar declines will soon be seen in Michi- line is still a major problem, as illustrated by the chang- gan and other states that are considering such propositions. ing demographics of our country and the not-so-changing The efforts by groups that support these propositions, demographics of education. For example, the percentage such as the Center for Equal Opportunity and Center for of black and Hispanic faculty has hovered around 4-5% for Individual Rights, have also had deleterious effects on the past few decades. Similarly, under-represented minor- programs targeting under-served individuals in the educa- ity students receiving graduate and professional degrees tional system, e.g. summer research programs for minori- has increased ever so slowly. For example, in 2006 the total ties. The playing field when these groups started their number of black, Hispanic, and Native American students attack was far from level, and since then it has become even who obtained a Ph.D. in the sciences represented only 10% more unequal. of the total Ph.D.s awarded. Similarly, under-represented A major obstacle in fighting these groups has been the minorities comprise less than 10% of health professionals fact that they have received government support all the (M.D.s, nurses, pharmacists, dentists, etc.), a distressing way to the top levels, including from the Department of number when one considers that this group comprises Justice and the Office of Civil Rights. For this to change, almost 30% of the population! government priorities have to change. This certainly could The significance of these low numbers is exacerbated begin with a new administration that is responsive to these by the impact that minority health disparities is having needs, much like the Clinton administration and the then- and will continue to have on our country. For example, the Office of the Surgeon General under David Satcher. Change incidence of diabetes is 1.5 times greater in Hispanics than also requires legislature at both the local and national in whites and two times greater in blacks than in whites, level with similar commitments. Certainly we as scientists, whereas the prevalence of diabetes in Pima Indians has ASBMB members, and citizens can assist by supporting been reported to be as high as 80%. In addition to diabetes, candidates that stress equality in their platform. Also, as a a plethora of other disorders affect minority populations professional society of over 10,000 scientists, we can work disproportionately, e.g. obesity, hypertension, prostate to inform and educate legislators about the importance of cancer, glaucoma, and cardiovascular disease. Considering this issue, not only to science but to society as well. This these disparities in combination with the leaky pipeline can be done as individuals, but more importantly it can of minorities to the graduate and professional levels and be done through ASBMB groups such as the public affairs the lack of attention that these areas have received in the group. past, the health status of our future society is at great risk. Are we doing that? If one examines the important issues Professional scientific societies such as ASBMB can help that have been taken to Congress by the ASBMB public make a difference; however, things must change for this to affairs group (referenced in President Hamm’s column happen. in the June issue of ASBMB Today) one does not see the So what needs to change? I will focus on just a few of issue of under-represented minorities in science. Why is the many problems. First, the anti-affirmative action move- that? One only has to look at graduate programs across the ment, as demonstrated by Proposition 209 in California country, national scientific conferences, and committee 24 ASBMB Today July 2008 firstminoritysecond affairs words and board meetings everywhere to see that this should be Some may even question whether someone who is not high on the list of issues to be addressed by societies like of color can truly be effective in making progress for those ASBMB. Along these lines, the May issue of ASBMB Today of color. To answer that, one simply has to read Carter G. featured an article by Minority Affairs Committee (MAC) Woodson’s The Mis-education of the Negro, first published member Jerome Nwachukwu and reported on a meeting in 1933, in which he states: “It is alright to have a white on diversity cosponsored by FASEB. In fact, that meeting man as a head of a Negro college or a red man at the head focused specifically on the role of professional societies in of a yellow one, if in each case the incumbent has taken enhancing diversity, and it included society executives and out his naturalization papers and has identified himself as representatives with an interest in diversity. Who repre- one of the group which he is trying to serve. It seems that sented ASBMB at this retreat? Were any members of the the white educators of this day are unwilling to do this, MAC involved? If not, why not? To make strides in this and for that reason, they can never contribute to the actual area we need to do it as a well informed and committed development of the Negro from within. You cannot serve group. If not, how can we expect the message to be relayed people by giving them orders as to what to do. The real with the compassion and experience necessary? servant of the people must live among them, think with Another major problem, in fact the one I consider most them, feel for them, and die for them.” significant, is “white privilege,” defined as the social inheri- And how does this relate to ASBMB? Simple: how many tance of rights, advantages, power, and opportunities by white scientists within ASBMB are willing to do what those who are white. Interestingly, despite this being the Woodson states? Very few, I would guess. So until such source of most of these problems, this issue is talked about a time when more individuals are willing to make this least because those who have white privilege do not want to sacrifice, we will continue to make efforts piecemeal that acknowledge it, and those that do not have it are extremely cannot ultimately make a difference at an organizational, vulnerable when talking about it. Moreover, those that have institutional, or society level. This should not be surprising it seem constantly threatened by the fact that they may lose because as Frederick Douglass stated, “there is no progress it, whereas those that do not have it seem to think they can without struggle.” Why would one expect changes of this never really obtain it. The presence of white privilege is seen magnitude to occur without a major effort or significant in essentially every poll regarding color, i.e. whites see no sacrifices, especially if status quo is really not that bad, at problem, people of color do. Does this mean the problem least from the “privileged” perspective? doesn’t exist? To the contrary, it exists but individuals who So what’s the bottom line? Can ASBMB make a real are in positions to address it simply choose not to because difference in this area? Certainly applying pressure and of their privilege. An excellent example in academia is the providing information to governmental representatives approval of legacy admissions, which are almost always for including state or national congresspersons, governors, and those white and privileged, versus affirmative action pro- mayors is critical. And although individuals can do this, grams, which almost always target people of color. doing it as a 10,000+-member society is even more effec- This problem is harder to address because folks who tive. But when will ASBMB choose to make this an issue? are part of the white privilege group have to be willing to As for actually choosing to give up some of the white speak out and take action against it, even though it would privilege to embrace the cause, this has to be an individual mean sacrificing some of that privilege. Few are willing to decision. But if the person making such a decision is an do that, and that is exactly why so much of the talk about ASBMB president or a council member, then who knows? diversifying an organization or an institution is just talk. It ASBMB could truly make a difference in changing the face is stated or written because that is the “right thing to do,” of science and academia so as to parallel the face of the but those in the power positions see the possibility of los- Society in this century and, in doing so, help to ensure the ing some of that power, and subsequently, many diversity color line is no longer a problem in the 22nd century! programs never leave the paper they are written on. Will these programs only materialize if the person in charge is not someone who enjoys white privilege and therefore not Thomas D. Landefeld is Professor of Biology and Pre-health at risk for losing it? Not necessarily; however, that person Advisor at California State University Dominguez Hills. He is a in charge has to be willing to make sacrifices that many in member of the ASBMB Minority Affairs Committee and can be those positions are not prepared to make. reached at [email protected]. July 2008 ASBMB Today 25 firstcareersecond insights words Scientists and Lawyers: More in Common Than Meets the Eye BY JOHN J. EMANUELE am an attorney and concentrate highest regard; after all, how many Imy practice on prosecuting pat- among us have the courage to try to ents, providing legal opinions on the prove ourselves wrong every time we value of U.S. patents, and supporting go to work? Moreover, while many Emanuele litigation involving patents. Although attorneys are paid to tell one side of a trained as a scientist, I decided to story best (i.e. their client’s), it is nec- in both technical and legal terms helps enter law after I became interested essary to know as much as possible scientists who practice law to stand out in patents while I was working as a about both sides of the story to do the from their peers. research scientist. Reasons that people most effective job. In the practice of with science backgrounds give for law, as in science, diligence matters. Writing Is Essential becoming attorneys are as varied as In the practice of law, as in science, to Both Professions the people themselves. To make this you may not lie. One of the great- Most attorneys spend most of their article of interest to a wider audience, est misconceptions about lawyers is billable time writing. You cannot draft I decided to write about what I see as that they lie. In reality, a lie can get strong patents, persuasive briefs, or similarities between the two profes- an attorney fired and cost them their even memos or letters explaining the sions. Many, if not most, people think license. Again, like scientists who law to senior attorneys or to your clients that scientists and attorneys are worlds publish results that they know to be unless you develop good writing skills. apart; however, in my opinion this is false, deliberately telling tall tales to A very big part of the practice of law, not necessarily the case. For example, a court or to opponents can result in like science, is communicating in writ- both scientists and lawyers believe in the loss of reputation and professional ing with your peers and, increasingly, the existence of objective reality and standing. with the uninitiated. Explaining patent that we can uncover it if we work hard law to a scientist who is a novice inven- enough. In addition to this fundamen- Law School and tor or an invention to a judge with a BS tal similarity, there are many other Graduate School: degree in English present opposite sides qualitative parallels as well. Learning a New Language of the same coin. Similarly, a major Lawyers, like scientists, speak in their component of being a successful (i.e. Honesty own language, and a big part of gaining well funded) research scientist is being Both scientists and lawyers value admittance to either group is learning a good writer. Journal articles, like legal diligent information gathering and the jargon. If you don’t believe this is briefs and memos, are only as good as a dispassionate analysis of the facts. true, think back to the first time that their endnotes. No judge cares what Whether testing a hypothesis in the you tried explaining your research an attorney thinks. Each statement in laboratory or the validity of some- project to your non-scientist friends or a legal brief or motion, just like each one’s story told under oath, the facts family members. On the flip side, read statement in a peer reviewed journal and how they can best be interpreted the fine print on the agreement that article, must be supported by proper are of primary interest to people in you have with your credit card com- references or pinpoint cites to data. both professions. pany and then tell the rest of us what Both the style and frustrations of scien- I have always held scientists in the it means. The ability to communicate tific writing provide excellent training 26 ASBMB Today July 2008 firstcareersecond insights words for law school and the practice of law. film prints and journal articles to MP3 to examine patent applications and If you are considering attending law files. Trademarks are actually about determine which applications warrant school, my best advice is to learn how protecting consumers; someone asking patent protection. The rationale for to write effectively, especially under a for a Coke® has the right to receive a patents is that they promote economic tight deadline. Grades in law school Coke® and not a Pepsi®. Any licensed growth by allowing investors that fund depend directly upon how well you attorney may practice copyright, trade- the development of an invention the write under pressure, and your success mark, and trade secret law and litigate right to monopolize the invention and happiness as a practicing attorney patents. But only a registered patent long enough to allow the investors are very likely to be tied closely to how agent or patent attorney may represent to recoup their investments plus an well you write and how much you enjoy clients before the United States Patent incentivizing profit. Patents also serve writing. and Trademark Office (PTO). the common good by encouraging To become a registered agent you inventors to share their knowledge Uses of a Science Degree must pass the patent bar exam, a test with the general public. In order to in the Practice of the Law administered by the PTO. To take the qualify for a patent, inventors must Like many attorneys with a technical exam you must have studied either describe their inventions and teach background, I have concentrated my science or engineering. In practice, (enable) their competitors how to use practice in the area of patent law. Great most patent attorneys and agents have them as well. When the patent term potential exists in many areas of the degrees in either engineering or one expires, anyone may freely use the invention. If you are considering attending Currently, there is considerable “ debate among economists and law law school, my best advice is to school professors as to how well this system works. Most experts agree that learn how to write effectively, patents are essential to the pharma- especially under a tight deadline. ceutical industry. This fact means that ” people with degrees in both the life sciences and the law still have decent law for people who possess a technical of the natural sciences. As a marketing job prospects, although the number of background, including environmental tool, an advanced degree in some tech- opportunities varies by region. Jobs are law, regulatory affairs such as represent- nical field is very helpful, but it does more plentiful in areas of the country ing clients before the Food and Drug not guarantee success as an attorney. A with large investments in the pharma- Administration or the Environmental registered patent attorney (in contrast ceutical and biotech industries. Protection Agency, medical malprac- to a registered patent agent) is someone tice, toxic tort liability, product liability, who is admitted to at least one state bar Closing and transactional work involving the and who has also passed the patent bar For me, the practice of law has been possession or use of intellectual prop- exam. In most states, you must gradu- a great experience because I am paid erty such as patents and technical trade ate from an accredited three-year law to learn something new almost every secrets. school and then pass the bar exam of day. If you are interested in becom- that state to be admitted to bar. ing an attorney, I urge you to seek out Intellectual Property: The U.S. Constitution gives Con- someone in the profession and offer to Technical Writing gress the authority to create copyrights take that person to lunch. Lawyers love and the Law and patents: “Congress shall have to talk about their work and themselves For most technical people, intellectual power . . . To promote the progress of like most folks do, so you will likely get property means patents. To lawyers, science and useful arts, by securing for some great insight into both the field intellectual property includes patents, limited times to authors and inventors and the job market in your region. If trade secrets, copyrights, and trade- the exclusive right to their respective you look like a prospective client, the marks. Copyrights govern the right to writings and discoveries” (U.S. Const. attorney will very likely pay for your reproduce and distribute materials from Art. 1 § 8). Congress created the PTO lunch! July 2008 ASBMB Today 27 biobits asbmb journal science Silencing Superoxide ABL Bodied Dismutase Structures The use of small interfering RNA (siRNA) to silence The ABL protein kinase is mutant genes that possess unwanted functions an important drug target holds promise for treating disorders such as Parkin- in the treatment of chronic son disease or amyotrophic lateral sclerosis. One myelogenous leukemia (in big roadblock, however, is developing stable siRNA the form of the BCR-ABL molecules that can effectively treat such chronic fusion protein). However, degenerative conditions. In this article, the authors current structural under- designed and tested a chemically stabilized siRNA standing of ABL is largely (modified on the 2’-hydroxyl position of the nucle- based on x-ray crystal- otide) for human Cu,Zn superoxide dismutase (SOD1) lography of the solid state in a mouse model of ALS, infusing the siRNA through that may not capture the an osmotic pump implanted near the spinal cord. The full ensemble of available molecule demonstrated remarkable stability, lasting conformations. Now, the for at least one month at Ribbon diagram of ABL kinase NMR structures of the bound with the inhibitor body temperature. The ABL kinase in complex nilotinib (in green). authors also showed that with three clinically used their approach met many drugs (imatinib, nilotinib, and dasatinib) have been other criteria for therapeu- solved, providing the first detailed solution structures of tic effectiveness, includ- a kinase-inhibitor complex. These structures provide in- ing widespread siRNA sights into the dynamics of ABL protein kinase and help distribution, intracellular clarify its physiologically relevant binding modes. For uptake, and most impor- example, residual dipolar coupling data on the imatinib tantly the ability to knock and nilotinib complexes show that the ABL activation down SOD1 and slow loop adopts the inactive conformation, whereas the disease progression with- dasatinib complex preserves the active conformation, out adverse side effects. contrary to the predictions based upon molecular mod- Although clinical trials are eling. These structures should enhance our understand- still far in the future, this ing of multiple inactive conformations observed in some Fluorescence microscopy study does bring siRNA kinases and may also shed light on how point muta- revealing wide distribution therapy one step closer to tions in BCR-ABL lead to drug resistance, enabling the of modified OS D1 siRNA in mouse spinal cord. that goal. rational design of more potent inhibitors. Therapeutic Gene Silencing Delivered by a Solution Conformations and Dynamics of ABL Chemically Modified Small Interfering RNA Kinase Inhibitor Complexes Determined by NMR against Mutant SOD1 Slows Amyotrophic Substantiate the Different Binding Modes of Lateral Sclerosis Progression Imatinib/Nilotinib and Dasatinib Hongyan Wang, Animesh Ghosh, Navratna Vajpai, André Strauss, Huricha Baigude, Chao-shun Yang, Gabriele Fendrich, Sandra W. Cowan-Jacob, Linghua Qiu, Xugang Xia, Hongxia Zhou, Paul W. Manley, Stephan Grzesiek, and Tariq M. Rana, and Zuoshang Xu Wolfgang Jahnke J. Biol. Chem. 2008, 283, 15845–15852 J. Biol. Chem. 2008, 283, 18292–18302 28 ASBMB Today July 2008 biobits asbmb journal science For podcasts of more ASBMB journal highlights go to www.asbmb.org/media PCSK9 Reduces Comparing CFTR LDL Receptors Repair Strategies Proprotein convertase subtilisin/kexin type 9 (PCSK9) Cystic fibrosis has been gaining attention as a regulator of the low is a reces- density lipoprotein receptor (LDL-R) protein; gain- sive disorder of-function mutations in PCSK9 cause hypercholes- caused by terolemia, whereas loss-of-function mutations result mutations in lower plasma LDL and reduced risk of coronary in the cystic disease. Several studies have been teasing out the fibrosis trans- therapeutic potential of PCSK9, but so far treatments membrane require doses over 100-fold higher than normal circu- conductance lating levels to be effective. In this article, the authors regulator successfully reduced LDL-R levels in mouse liver with (CFTR) that Functional connectivity map of the CFTR- normal plasma concentrations of PCSK9 (0.05–0.60 disrupt protein interacting proteins during chemical µg/ml). They obtained large quantities of purified folding and traf- rescue or genetic repair (red ovals). recombinant human PCSK9 from stably transfected ficking, causing HEK293S cells and directly injected the protein into degradation, and that also provoke an inflamma- mice. A single injection could reduce liver LDL-R tory response in the lungs. Two approaches to by ~90% in less than an hour, and receptor levels alleviate CFTR degradation are chemical rescue returned to normal after six hours. Treatment with a with agents like sodium 4-phenylbutyrate or gene gain-of-function PCSK9 mutant (D374Y) accelerated transfer therapy. In this study, the authors looked the process, whereas a catalytically inactive form of for CFTR-interacting proteins that act in com- PCSK9 (S386A) also proved effective, suggesting the mon during chemical rescue or genetic repair mode of action of this protein is not dependent on its of cultured ∆F508-CFTR bronchial epithelia to catalytic activity. identify therapeutic networks. Their CFTR interac- tome revealed that both repair avenues produced changes in a subset of HSP70 chaperones associ- ated with endoplasmic reticulum-associated degra- dation; these regulatory changes occurred at both the cell surface and in subcellular compartments. These HSP70 system proteins could not only mark therapeutic interactions, but may themselves be useful targets to correct CFTR ion transport and Immunoblot analysis of LDL-R levels in liver membranes of wild-type mice 5–480 minutes after the injection of 32 mg of restrain the inflammatory phenotype. recombinant human PCSK9. Plasma PCSK9 Preferentially Chemical Rescue of ∆F508-CFTR Reduces Liver LDL Receptors Mimics Genetic Repair in Cystic in Mice Fibrosis Bronchial Epithelial Cells Aldo Grefhorst, Markey C. McNutt, Om V. Singh, Harvey B. Pollard, Thomas A. Lagace, and Jay D. Horton and Pamela L. Zeitlin J. Lipid Res. 2008 49, 1303–1311 Mol. Cell. Proteomics 2008 7, 1099–1110 July 2008 ASBMB Today 29 sciencefocus John Denu: The Importance of Reversible Protein Acetylation BY NICK ZAGORSKI rotein phosphorylation is appreciation stems Punquestionably a critical cel- from the work of lular process, but the focus given Denu, who switched to the attachment and removal of over from the bus- Denu phosphate groups from proteins tling phosphorylation sometimes leaves the impression that field to work on this it’s the be-all and end-all method “other” modification. of regulating proteins. However, an Through his studies, we’ve found In high school and later col- abundance of reversible chemical that proteins throughout a cell— lege at Wisconsin, that reasoning modifications for proteins exist, each nucleus, cytoplasm, even mitochon- would lead Denu toward biochemistry, serving their own purpose in care- dria—can be modified by acetylation and particularly enzymology. “I fig- fully controlling the countless activi- and learned more about the sirtuins, ured, to really satisfy my desire about ties occurring inside cells. proteins whose deacetylation of how biology works at the molecular One such emerging modifica- metabolic enzymes might hold the level, why not try and understand the tion might be reversible acetylation key to a longer life span. He’s also enzymes that carry out biology. To this (not to be confused with irreversible begun to branch out to other modi- day the minute details about enzy- N-terminal acetylation that caps many fications, examining how all of them matic processes still fascinate me.” proteins during translation). True, come together to form the enigmatic After completing his undergradu- most researchers consider acetylation “histone code.” ate biochemistry degree in 1988, an important event, but typically only Denu moved on to Texas A&M in relation to histones, the protein Here’s Looking University for his doctorate. And if spools that compact our DNA thread at You, Kid you’re wondering what convinced a into form-fitting chromatin. Alter- Denu has always been interested small town Wisconsin boy to relocate ing the pattern of acetyl groups can in the living world; a large part of to Texas, he quotes one of his all-time change which portions of chroma- that stemmed from his upbringing favorite movies, Casablanca: “I went tin are exposed to DNA-binding in the southern Wisconsin town of there for the waters,” Denu says in an proteins, making them essential for Beloit. His house backed along a impressive Bogart tone. “I was misin- proper gene expression, replication, wooded creek, which, better than any for m e d .” and repair. large screen TV, gave Denu a first- In all seriousness, Denu sought “But there’s so much more to hand glimpse into the wonders of to take advantage of his Ph.D. years. acetylation than one protein class,” nature. “I spent a lot of time as a kid “This was a prime opportunity for says John Denu, Professor of Biomo- in my backyard, just observing the me to get away, find a warm place to lecular Chemistry at the University creatures and other natural events.” study, and experience life in a differ- of Wisconsin-Madison School of As he grew a bit older, he shifted ent culture. And Texas certainly fit Medicine and Public Health. “And his wonder to a deeper level, trying that bill.” He notes that Texas A&M only recently have we gained a greater to understand what elements were also contained a large and strong appreciation for this modification.” A behind all these natural things he had biochemistry department, giving him goodly amount of credit for this new been enamored by in his youth. plenty of options for his graduate 30 ASBMB Today July 2008 sciencefocus studies; he ended up joining the lab family known as dual specificity removal of acetyl groups. “Going to of Paul Fitzpatrick, where he stud- phosphatases. Phosphatases gener- acetylation didn’t seem like a major ied the mechanisms of flavoproteins ally act on one of two amino acid intellectual jump,” he says. “It gave (enzymes that use the riboflavin groups, with most recognizing ser- me a way to explore an exciting new derivative FAD and/or FMN as a ines/threonines, whereas a minority area but remain within the confines of cofactor). recognizes tyrosine. The dual specific- reversible modifications.” After completing his disserta- ity phosphatases, first identified by The excitement of acetylation had tion, Denu moved on to a post-doc Dixon in 1991, could recognize both sprung from David Allis’ discover- with Jack Dixon at the University groups equally. Not much was known ies in the mid-90s of the first histone of Michigan, a position that would about them, except they were regu- acetyltransferase (HAT) enzymes let him apply the enzymology skills lated by mitogens and thus central in Tetrahymena, “a discovery that he learned as a student to the field players in cell growth and cancer, opened the floodgates of chroma- of reversible protein modifications. but Denu helped uncover both the tin research,” Denu says. Scientists “It had become such a fascinating structure and catalytic mechanism of soon discovered that many of the concept to me,” he says. “Add just one these enzymes before venturing off co-activators for the transcription tiny chemical group to a protein, and to start his own lab at Oregon Health factors they studied were in fact that can completely change its struc- Sciences University (OHSU) in 1996. histone acetyltransferases, revealing ture or function.” Denu specifically the importance of these enzymes in chose that lab because Dixon was one The Beginning of a gene expression. Not long after, it of the leaders in protein phosphoryla- Beautiful Friendship was discovered that several transcrip- tion, specializing in the phosphatase Denu initially continued his phos- tion factors themselves, proteins like enzymes that remove phosphate phatase studies at OHSU but p53, were also targets of acetylation. groups. soon decided to take a slight detour Denu, though, believed that these For his project, Denu got to and pursue a different type of revers- findings still represented just the tip work on an unusual subset of this ible modification: the addition and of the iceberg. After all, the side chain target of acetylation Poly(ADPr) or ADPr NAD+ Salvage is a positively charged Pathway Nicotinamide TRPM2 Channel Gating lysine (although some & other functions? NADases AMP Nucleus recent studies suggest PARPs PP NMN i NAD+ Nicotinamide + OAADPr NAD+ Nicotinamide + OAADPr that serine and threo- NADH ATP NMNAT Nucleus nine can also be acety- Other protein Acetate ATP Other protein targets SIRT1 targets SIRT1 Gene Silencing lated by pathogenic CoA & other functions? bacterial proteins), a O inactive active + common residue in O N H N + H 3 N AceCS1 H N AceCS1 H 3 PPARG Fatty Acid Metabolism many enzyme catalytic PGC1A Gluconeogenesis/Glycolysis p53 Apoptosis sites. Converting that Protein Acetyltransferase FOXO Survival Under Stress positive charge into a Acetate Global Transcription Cytoplasm AMP p300 Histones neutral group would PPi Ac Ac CoA Acetyl CoA be a logical way to HDACs shut an active site Other protein Ac Ac SIRT3 down. targets Mitochondria Chromatin Acetate ? In 2006, Denu, inactive active ATP after following many O + CoA AceCS2 H N AceCS2 TCA cycle & N 3 Fatty Acid Synthesis & leads, found an H other pathways AMP other Acetyl CoA functions example, the meta- PPi Protein Acetyltransferase Acetyl CoA bolic enzyme acetyl- CoA synthetase, More than just chromatin: sirtuin deacetylases regulate many important pathways throughout a cell. which joins acetate July 2008 ASBMB Today 31 science focus continued and coenzyme A. His study, dem- that played a role in life span (at least novel metabolite of largely unknown onstrating that an acetyl group on in lower organisms), these proteins— function. “Maybe some of the phe- a key lysine (the one that binds officially named the SIR2 (silent notypes associated with sirtuins are ATP) needed to be removed for information regulator 2) family— because of the actions of this ADP- proper function, provided the first could deacetylate histones, but appar- ribose molecule and not protein evidence of a mammalian enzyme ently they required the NAD+ cofactor. deacetylation.” being controlled by reversible acetyla- “And this was just too bizarre,” To find out if his idea might be tion. “I knew it could only be a matter Denu says, “as all other known correct, Denu has been further explor- of time before we saw other proteins, deacetylases only needed water to ing this unusual metabolite. “We not just those involved in gene expres- remove the acetyl group. So I decided don’t know what OAADP ribose sion, with acetylation modifications,” I had to characterize this reaction; does, so our best approach to under- Denu says. “And now that we’ve from my background as an enzymolo- standing this chemical is to go after escaped the nucleus (acetyl-CoA syn- gist, this was too interesting not to the proteins or enzymes that bind thetase has two isoforms, one in the pursue further.” Denu found that it, metabolize it, or degrade it,” he cytoplasm and the other in the mito- in the case of SIR2, the NAD was says. Along with Andrew Scharenberg chondria), I think we’ll find many actually a substrate in the deacetyla- at the University of Washington, he more.” Denu points out that a recent tion reaction; following removal, the showed that TRPM2, an ion channel proteomics study suggests that over acetyl group was transferred onto that is involved in cell death, is one 200 proteins can be acetylated in the ribose ring of NAD, generating potential target (and, interestingly, mammals. an acetylated ADP-ribose molecule TRPM2 can bind both the acetylated (O-acetyl-ADP-ribose (OAADP)). and non-acetylated ADP-ribose). For Old Times’ Sake “Of course, this begs the ques- Other researchers have found that The search for a non-histone-related tion of why Mother Nature would OAADP ribose can bind to a histone acetylation took a while as Denu go through the trouble of consum- H2A variant known as macro-H2A, as found himself transported to a strange ing NAD to perform a reaction that well as a complex in yeast responsible new world a little over 8 years ago. can easily be done by other means.” for silencing certain regions of the He had begun his studies characteriz- Although several researchers proposed genome, thus working in synergy with ing the structure and function of HATs that sirtuin activity might be closely sirtuins. “There are definitely some when he read about some unusual linked to the NAD concentration in interesting targets out there.” proteins called sirtuins. Originally cells, Denu wondered if at least part of In addition to the metabolite, identified as transcription silencers the reason might be to generate this the sirtuins themselves have some Assay with Code Reader 1) Select hits 2) MS/MS Histone H4 m/z Tail PTM Library SGRGKGGKGLGKGGAKRHR(Me K)V Histone Sequence 3 (pS)G(MeR)GKGGKGLGKGGAKRHR(Me3K)V Code? SGRGKGG(AcK)GLGKGGA(AcK)RHR(Me2K)V Etc. Cracking the histone code: a chromatin-binding protein (the “code reader”) is passed over a peptide library containing the ~800 possible modification states of the H4 tail; positive interactions are then analyzed by mass spectrometry, revealing the modification sequences that promote binding for each protein. 32 ASBMB Today July 2008 science focus continued interesting targets, as Denu notes they are an enzyme class that’s been found Out of Focus: to act on non-histone proteins. In fact, SIRT1 and SIRT3 are enzymes Love and Basketball that deacetylate the cytoplasmic and Next to science and family, one thing that John Denu loves is basketball. He’s mitochondrial acetyl-CoA syn- been playing it since his youth, and one of his big childhood dreams was making thetases, respectively. This connection it to the professional ranks. “But of course, this was not reality,” he says. Today, he is especially promising because it ties settles for his twice weekly pick-up basketball group with other faculty and staff in to that most tantalizing of sirtuin from the University–but lest you think biochemistry professors have no skills, Denu properties, aging. “SIRT1 has gotten a notes it’s a fairly competitive affair. “It’s been a real love of mine, and I use many fair amount of press as a protein that basketball analogies to help describe science and life: leadership, competition, promotes increased life span through excellence, teamwork, and camaraderie. Not everybody understands my analo- caloric restriction or resveratrol, the gies, but I use them anyway.” chemical in red wine that harbors many health benefits,” he says. It’s pos- sible that sirtuins may extend life span modification that they don’t like; “My HATs were on hold for a little through their direct regulation of met- besides phosphorylation and acetyla- bit after all the sirtuin studies took abolic and mitochondrial enzymes, tion, methylation and citrullination off,” he says, “but now I’ve managed and one of Denu’s major initiatives (removing a side chain nitrogen from to get the resources to pursue both is finding more direct links between arginine) also occur on histones—just with equal fortitude.” HATs typically deacetylation to metabolism. to name a few. occur as multisubunit complexes, Denu’s aspirations to unlock “Even the short tail of histone and Denu is trying to figure out what the mysteries of sirtuins eventually H4, which is about 22 amino acids job the other proteins in the complex brought him back to his home state in long, has over 800 possible modi- have. “Do they enhance catalysis? Do 2003. “OHSU was a wonderful place, fication permutations,” says Denu, they restrict substrate access? Or, is but as a smaller medical institute with “although the tail of histone H3 ranges it even some other function we’re not a limited number of departments, it in the millions.” considering?” would have been difficult to continue No histone is too big for a modifi- He doesn’t know the ending yet, but our research, which was going down a cation buff like Denu, though, who has as someone once said: “Maybe one will chemistry road,” he says. As it hap- decided to take on this challenge. His come to you as you go along.” pened, the University of Wisconsin approach is to develop a combinatorial Nick Zagorski, Ph.D., a graduate of Johns had the opportunities and the open- peptide library that contains all 800 Hopkins and Cornell Universities, is a ing. It also gave him new collaborators possible states of the histone H4 tail. science writer for ASBMB. He can be like Richard Weindruch and Tomas By passing a specific protein over the reached at [email protected]. Prolla, who have been studying aging library, he can see which peptides elicit and calorie restriction in mice; the the strongest binding. “In essence, three of them have recently begun we’re asking chromatin proteins what Bibliography Denu, J. M., Zhou, G., Wu, L., Zhao, R., some new “metabolomics” studies modifications they prefer.” Denu has Yuvaniyama, J., Saper, M. A., and Dixon, J. E. (1995) The purification and characterization with sirtuin knock-out mice. tested his library with human JMJD2A of a human dual-specific protein-tyrosine histone demethylase and found that phosphatase. J. Biol. Chem. 270, 3796-3803. Tanner, K. G., Landry, J., Sternglanz, R., and Denu, Go Ahead, Tell It... binding affinity could range over J. M. (2000) Silent information regulator 2 family of NAD-dependent histone/protein deacetylases The “genetic code” may have been 1000-fold depending on the modifica- generates a unique product 1-O-acetyl-ADP ribose. Proc. Natl. Acad. Sci. U. S. A. 97, a tough nut to crack, but it pales in tions, demonstrating that this strategy 14178-14182. comparison with the “histone code,” should be useful to decode the optimal Borra, M. T., Smith, B. C., and Denu, J. M. (2005) Mechanism of human SIRT1 activation by the arrangement of modifications on patterns for histone-binding proteins. resveratrol. J. Biol. Chem. 280, 17187-17195. Garske, A. L., and Denu, J. M. (2006) SIRT1 top histone proteins that dictates how And much like Bogart and Berg- 40 hits: Use of one-bead, one-compound acetyl- they interact with the DNA wrapped man from his favorite film, Denu peptide libraries and quantum dots to probe deacetylase specificity. Biochemistry 45, 94-101. around them as well as other proteins. has also been reunited with an old Hallows, W. C., Lee, S., and Denu, J. M. (2006) Sirtuins deacetylate and activate mammalian The complexity arises because histones flame, the HAT enzymes he began acetyl-CoA synthetases. Proc. Natl. Acad. Sci. U. apparently have yet to meet a protein characterizing nearly a decade ago. S. A. 103, 10230-10235. July 2008 ASBMB Today 33 career opportunities Visit www.asbmb.org for more listings Tulane University and the latest career opportunities tenure track position The Department of Biochemistry, Tulane University Health Sciences Center, School of Medicine invites applications for a tenure track posi- tion at the Assistant or Associate Professor level. The successful candi- date will be a highly interactive scientist with a strong record of research Case Western University accomplishments and a demonstrated ability to utilize interdisciplin- Dept. of Periodontics ary approaches for solving important problems in the biomedical sci- ences. Candidates with research strengths in the following areas are Postdoctoral position encouraged to apply: genetic/genomic approaches to the mechanistic Postdoctoral position available to study host-pathogen interac- basis of disease; structural/functional studies of human proteins; and tions (J. Biol. Chem. 2007, 282:25000-25009; J. Immunol 2007, the molecular biology and protein biochemistry of model organisms 179:2501-2508). Experience in biochemistry and molecular and for the study of cancer and infectious disease. The candidate will be cell biology is required. expected to establish a vigorous, well-funded research program and Please contact: Dr. Yiping Han, Associate Professor, Dept. of to participate in medical and graduate education. Periodontics, Case Western Reserve University, Cleveland, OH Applicants should send a CV and a statement describing 44106, Phone: (216) 368-1995, Email: [email protected] research interests and career goals to the Biochemistry Search Committee, TUHSC SL43, 1430 Tulane Ave., New Orleans, LA 70112-2699 or by email to [email protected] University of Minnesota Tulane University is an Affirmative Action/Equal Opportunity Employer and encourages Molecular Biologists applications from minorities, women, and other qualified persons. and Biochemists Research Associate, Research Assistant Professor and Postdoc- toral Associate positions are available in the Department of Phar- University of Cincinnati macology, University of Minnesota. We are using multi-disciplinary Postdoctoral Fellow (28UC3548) approaches, including transgenic, biochemical, molecular, cellu- The University of Cincinnati’s College of Medicine is currently seeking lar, imaging and biophysical methods to address a wide range of a candidate for a post-doctoral position within a well-funded labora- biological and pharmacological questions related to opioid recep- tory at the Center for Lipid and Atherosclerosis Studies (CLAS) at the tors as well as hormone nuclear receptors and their coregulators University of Cincinnati Genome Research Institute. The successful in gene regulation. We are focused on the regulatory mechanisms candidate will be involved in proteomic and lipidomic analyses of high that control the expression of opioid receptors and other neuronal density lipoproteins (HDL). The position will involve the development genes, signaling pathways of opioid receptors, and the mecha- of techniques for identifying and quantifying the protein and lipid con- nism of action of nuclear receptors and their coregulators in gene tent of HDL. transcription. A Ph.D. and evidence indicating research success is Min. Quals.: PhD. in a biological science, excellent command of required. Previous training in molecular biology, biochemistry, neu- the English language. roscience or biophysics is preferred. The ideal candidate will have previous experience in protein chem- For research and department details, see the following istry, immunoprecipitation of proteins, proteomics, gel electrophoresis, University of Minnesota websites: http://www.pharmacology.med.umn.edu and and especially mass spectrometry is an advantage. Ability to work well http://mcbda.ahc.umn.edu with others both in and outside the laboratory. Interested applicants should email a curriculum vitae, For more information see our website at: [email protected] statement of research interests and names of three references To apply for position (28UC3548), please see www.jobsatuc.com to Dr. Horace H. Loh, Head, Department of Pharmacology, The University of Cincinnati is an affirmative action/equal opportunity employer. University of Minnesota at [email protected] UC is a smoke-free work environment. 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