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September 2007

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ON THE COVER: A delegation of seven representa- tives from ASBMB recently visited society news Beijing, Guangzhou, and Shanghai 2 President’s Message where they met with Chinese sci- entists, students, and members of 6 Washington Update the Society’s counterpart in China. 7 New JBC Minireview 12 Compendium on Interferons 10 Retrospective: Daniel E. Koshland Jr. special interest 12 ASBMB Delegation Tours China 14 Early Medical Research Funding and the Evolution of Modern American Biochemistry 2008 meeting overview 16 Systems Biology: a shared goal with diverse views 18 The Diverse Aspects of Protein Synthesis and Degradation 20 A Renaissance for Metabolism Research compendium. 7 22 RNA: From Atom to Organism 23 ASBMB Taps 8 Scientists and 1 Politician for Top Awards science focus 27 Maurice Swanson: Finding New Cures for Muscular Dystrophy 30 Matthias Mann: Using Proteomics to Understand Protein Interactions departments 4 News from the Hill 8 Member Spotlight 24 Career Insights 26 Education and Training 32 BioBits resources 34 For Your Lab 35 Career Opportunities 36 Scientific Meeting Calendar e transcription cttor two-step. 32

September 2007 ASBMB Today 1 president’smessage

A monthly publication of The American Society for Biochemistry and Molecular Biology Peer Review Front Officers Heidi E. Hamm President and Center Gregory A. Petsko President-Elect BY HEIDI HAMM Mark A. Lemmon Secretary Merle S. Olson Treasurer Council Members Alan Hall Kuan-Teh Jeang Suzanne R. Pfeffer Linda J. Pike John D. Scott Joan A. Steitz Kevin Struhl James A. Wells t’s great to be back from a very Groups (IRGs). (More information is Ex-Officio Members Iproductive and interesting trip to given at cms.csr.nih.gov/AboutCSR/ Ellis Bell China with our ASBMB delegation. We OpenHouses.htm.) The open house on Chair, Education and Professional met our goals of establishing a closer Biomolecular IRGs, which is particu- Development Committee Laurie S. Kaguni relationship with Chinese scientists in larly relevant to ASBMB, will be held on Chair, Meeting Committee biochemistry and molecular biology, December 18. George Hill and we were delighted with the warm The Panel on Scientific Boundaries Chair, Minority Affairs Committee Kendall J. Blumer and enthusiastic welcome we received. for Review, headed by Bruce Alberts, Anna Marie Pyle I am sure you have been hearing undertook the latest reorganization Co-chairs, 2008 Program Committee about the many calls for information of study sections. I have been work- Mary J. C. Hendrix Chair, Public Affairs Advisory Committee from the National Institutes of Health ing closely with Bruce for a couple of Robert E. Rhoads (NIH) on many topics. One which is years on the issue of how to influence Chair, Publications Committee dear to our hearts is peer review. It’s the CSR to have more ongoing input Herbert Tabor Editor, JBC good to see that the NIH is making a from extramural scientists on how study Ralph A. Bradshaw major effort to examine the peer review sections are functioning. This ongoing A. L. Burlingame process. This critical reexamination fo interaction has led to a proposal for the Co-editors, MCP Edward A. Dennis the peer review system has been a high two societies to work together to provide Editor, JLR priority of ASBMB, prompted by the our input to the CSR. Thus, the two

ASBMB Today crisis in funding and resultant doubling societies will jointly analyze the makeup Editorial Advisory Board of NIH grant applications over recent and scope of the study sections that are Alex Toker years. A key reason for this reassessment of most interest to the two societies, Chair is to be sure the system is operating as it determine whether there is sufficient Mike Autry Greg P. Bertenshaw Craig E. Cameron A. Stephen Dahms was meant to after the last major over- breadth, expertise, and balance between Irwin Fridovich Richard W. Hanson haul instigated by the Panel on Scientific basic and clinical investigators, etc. Our Elizabeth A. Komives Bettie Sue Masters Luke A. O’Neill Boundaries for Review almost 7 years analysis will be provided to the CSR at Duanqing Pei Carol C. Shoulders ago. Of course, we hope that completely this open house. If you are willing to be Robert D. Wells new ideas will emerge from this reex- involved in this analysis, please let me ASBMB Today amination to help us overcome the real or Mary Hendrix, chair of the Public Nicole Kresge Editor crisis in peer review that has resulted Affairs Advisory Committee, know of [email protected] from the lack of investment in biomedi- your interest! In particular, we need Pat Pages Science Writer [email protected] cal research over the last 5 years. ASBMB members who have served on Nancy J. Rodnan Director of Publications A number of activities to assess these study sections recently, as they are [email protected] Barbara Gordon Executive Director peer review are underway. Toni Scarpa, the real experts on how well the study [email protected] director of the Center for Scientific sections are working. Magazine design & production: Amy Phifer Review (CSR), announced a series of Additionally, a Working Group of

For information on advertising contact open houses to give the extramural the NIH Advisory Committee to the FASEB AdNet at 800-433-2732 ext. 7157 or community a chance to voice their views Director, focusing on a review of the 301-634-7157, or E-mail [email protected]. on the quality and expertise of various current peer review system at NIH, met study sections and Integrated Review in Washington, D.C. on July 30 to hear www.asbmb.org

September 2007 comments from the scientific com- Working Group co-chairs Lawrence We hope all of you with an inter- munity. ASBMB President-Elect Greg Tabak, director of the National Institute est in the NIH peer review system will Petsko delivered ASBMB’s comments, of Dental and Craniofacial Research, bookmark this site and visit it regularly which covered 4 main points: and Keith Yamamoto, University of to keep abreast of what is going on. Oversight of study sections should California, San Francisco, noted in The Working Group will be accepting be ongoing. The Center for Scientific their July 12 letter to the commu- comments from concerned members Review must monitor the IRGs and nity about the group that “With the of the biomedical research community; study sections to ensure that they are increasing breadth and complexity of the NIH also currently has a request functioning as they should, and make science, along with the rising number for information on the NIH System to changes as appropriate based on feed- of research grant applications, we are Support Biomedical and Behavioral back from both members of the study Research and Peer Review (grants.nih. sections and those whose proposals are gov/grants/guide/notice-files/NOT- reviewed there. Critical OD-07-084.html). Senior researchers should continue reexamination In his opening remarks, Yama- to serve on study sections. ASBMB moto noted that there had been many also recommended that assistant of the peer review changes in peer review since he became professors not serve on study sections. involved in the mid-1980s. In 1987, Petsko recommended that senior system is a high there were only 1,800 people serving researchers be compelled to serve on priority of ASBMB on study sections. Now, that figure has study sections, similar to serving on grown by an order of magnitude— juries when called upon. As he noted, 18,000 scientists are currently serving. “holding a federal grant is a privilege, taking a comprehensive look at our Furthermore, the nature of science is not a right,” and thus those who hold review process to ensure its continued different; the scope of applications is them should be expected to pay back strength for applicants and reviewers much broader than 20 years ago. the system by study section service if alike. We would like you to participate Yamamoto went on to note that called upon. in this discussion.” NIH Director Elias the review process must evolve and Study section membership must fit Zerhouni was in attendance the entire adapt to these changes. For example, the charge of the study section. Care meeting. there is currently too much emphasis should be taken to ensure that indi- NIH formed the Working Group to on preliminary data and experimental viduals with all necessary expertise to gather information from the external detail. One way to deal with this might carry out the reviews the study section community to hear ideas on ways to be to move toward an “editorial board” is charged with are selected to serve. improve the process. The July 30 meet- model of peer review, with permanent Study section size should be ing was the first in a series of meetings panels that evaluate applications as they manageable. Under the reorganization, planned through the end of the year. A come in. The technical details would be many study sections have too many second meeting will be held in Wash- sent to panels of technical experts for areas of science under their purview. ington to hear comments from the vol- review and the editorial board/study ASBMB suggested that some of the untary health community; three more section would look at the proposal as sections should be broken down into meetings will be held in the fall—one a whole. This model would also avoid smaller groups. each in New York, Chicago, and San artificial competition. Petsko also recommended that the Francisco. ASBMB will work to ensure This was only one of a number of application package be redesigned so that a few of our members attend each ideas floated at the meeting; others will that it is only 15 pages long. of these sessions and offer comments fi no doubt emerge in coming months. As The comments were based on a possible. Petsko noted in his closing remarks, the survey conducted in March 2006 of A website has been established to NIH peer review system “is the jewel of ASBMB members on peer review. The keep the biomedical research com- American science,” and if it is going to above points synthesized the major- munity apprised of the activities of the be modified, it must be done deliber- ity of the more than 1,000 comments Working Group. It can be accessed at ately and thoughtfully to maintain its received. enhancing-peer-review.nih.gov/. luster.

September 2007 ASBMB Today 3 news from the hill

The Senate bill, passed in June, provides a $29.9 billion Congress Leaves (3.5%) increase for NIH. However the bill also increases the amount of the transfer from NIH to the Global HIV/ for August Recess AIDS fund from $99 million in FY2007 to $300 million in FY 2008. As a result, the actual increase for NIH programs in with Veto Threats FY 2008 is $799 million (2.8%), compared to $549 million (1.9%) in the House bill. Both the House and Senate bills Looming fall short of the projected 3.7% increase in the Biomedical Research and Development Price Index (BRDPI) for FY 2008. he 2008 appropriations bills currently being debated There may be some interesting discussions in confer- Tin Congress would provide $22 billion more in Federal ence about policy issues. First, the House approved a man- spending than President Bush proposed in his FY 2008 datory public access policy regarding scientific publications budget. On August 2, the President reaffirmed his intentions resulting from NIH-funded research. to veto spending bills if this money remains in them. The current NIH Public Access Policy asks researchers ASBMB Today has learned that Senate Majority Leader to submit their NIH-funded research articles to PubMed Harry Reid (D-NV) met with the Democratic caucus on Central for online availability within 12 months of publica- August 2 and told them he would not be scheduling a tion in a peer-reviewed journal. The House bill makes the floor vote for the Labor/Health and Human Services (HHS) submission mandatory. In recognition of copyright issues, appropriations bill, which funds NIH. With the looming however, a phrase was added requiring NIH to implement veto threat, expectation of another supplemental funding the policy “in a manner consistent with copyright law.” request in September for the Iraq war, and the likely need to Publishers are not happy with this language, however. respond to the report on progress in Iraq due in September, According to a statement by the Association of American Reid did not see an opportunity to devote time to the bill. Publishers, “mandatory submission of the final peer-re- Thus, Hill staff expects the bill to be wrapped into either a viewed manuscript cannot be implemented ‘consistent with giant omnibus appropriations bill or a copyright law’ because of its adverse “minibus” made up of two or three such impact on journal publishers’ copyright bills. This is not likely to occur until the interests in the version of the manu- late fall, if then, thereby necessitating a script published as a journal article.” continuing resolution, if not a series of them until final agreement is reached. NSF Also Under the Gun Therefore, it is very likely that most On July 26, the House voted to pass of the major science agencies, includ- the FY 2008 Commerce, Justice, Sci- ing NIH and NSF, will be on a continu- ence and Related Agencies Appropria- ing resolution once October 1, 2007, tions Act, which funds NSF and other arrives. How long they will remain in this science agencies as well as a host condition is anyone’s guess. of other programs. The $53.8 billion bill provides NSF with $6.51 billion, a NIH Spending and Policy Issues $592 million increase over its FY 2007 On July 19, the House passed the FY budget and $80 million more than the 2008 Labor/HHS Bill by a vote of 276- President proposed. House Com- 140. The bill provides NIH with a $750 merce, Justice and Science Appropria- million increase (2.6%) in FY 2008. How- tions Chairman Alan Mollohan (D-WV) ever, the actual NIH program increase is stated, “this increase would continue $549 million (a 1.9% increase) because the goal of doubling NSF’s funding in the House would require that NIH trans- 10 years.” fer $201 million of its increase to the However, the President has said Global AIDS fund. he will veto this bill as well, mainly

4 ASBMB Today September 2007 because of what the White House terms “an irresponsible The Senate Appropriations Committee approved an and excessive level of spending” as well as “other objec- increase for NSF of $637 million or 10.8%, to $6.55 billion tionable provisions.” These comments were made in a in FY 2008. The full Senate is expected to vote on the bill Statement of Administration Policy issued on July 24. within the next two months, and then a conference commit- Regarding the NSF, the Statement of Administration Pol- tee will be appointed to reach a compromise between the icy says, “the Administration supports neither the additional House and Senate versions of the bill. $72 million above the [President’s budget] request allocated to NSF education programs that lack proven effectiveness, nor [Appropriations Committee] report language that seeks to allocate funds away from the NSF research programs Go Visit Your Congressman that most directly contribute to America’s economic com- Congress left Washington on August 3 for the traditional petitiveness.” August recess. They spend this time taking both vacations This is an apparent reference to report language and the pulse of their constituents. In this latter capacity, instructing NSF to fund Biology, Behavioral, Social and please try to arrange to visit with your member this summer Economic Science, and Geosciences at the agency while he or she is home. Contact the ASBMB Public Affairs at “comparable” levels to those enjoyed by the other Office if you would like assistance. In addition, you might research directorates. ASBMB supported this language consider watching the training DVD the ASBMB Public when we became aware of it. It is highly unusual for the Affairs Advisory Committee produced this spring, called White House to single out such report language as a rea- “Meeting with Your Congressman: A Guide for the Grass son to veto an appropriations bill. Unfortunately, although Roots Advocate.” You can watch this DVD on the ASBMB the House passed the bill by a large majority, the margin of website (the link is on the home page at www.asbmb.org victory was several votes short of the two-thirds number under “What’s New”) needed to override the threatened veto.

Science Policy Fellow to Join Staff Welch Foundation Pre-doctoral Fellowship in July 2005. She has a long record of academic and community service, including a Angela Noel Hvitved, a Ph.D. candidate in biochemistry and cell term as president of the Biochemistry and Cell Biology Graduate biology at Rice University, Houston, Texas, has been selected by Student Association at Rice. the Public Affairs Advisory Committee as ASBMB’s first science “Science literacy for all Americans,” Hvitved says, “is critical policy fellow. Ms. Hvitved, who defended her thesis in August, will for the health of our national science policy. A 2004 National be joining the ASBMB staff no later than October 1 after moving Science Foundation (NSF) report on scientific literacy indicated here from Houston. that almost half of Americans believe that humans coexisted with As Hvitved told ASBMB Today, “Science and scientists should dinosaurs and did not develop from earlier species. Each and exert a much greater influence on our public policy than they every scientist should consider this a serious concern, not only currently do. One of my goals for this fellowship is to learn how because that 50% can elect policy makers with funding and over- career scientists can become actively involved in policy making. sight responsibilities, but also because it contradicts everything I wholeheartedly believe in the concept of the ‘civic scientist’ and we spend our lives trying to accomplish—expanding the pool of hope to help scientists appreciate the civic responsibilities that human knowledge.” accompany scientific training.” During her year-long fellowship, Hvitved wants to work on Hvitved received twin bachelor’s degrees in Biochemistry and lifting the ban on federal funding for most human embryonic stem Philosophy from Iowa State University in 2000 and has been a cell research, restoring funding increases to the National Insti- graduate student at Rice since 2001. She notes that her degree in tutes of Health (NIH), and raising awareness of the critical lack philosophy provided her with an extensive background in political of scientific literacy among Americans. In addition, Hvitved will theory and ethics and helped her cultivate a broader interest in be helping the staff and Public Affairs Advisory Committee with the intersection of science and society. various research projects, writing regularly for ASBMB Today, and She has worked as a teaching and research assistant at Rice generally helping to advance the ASBMB’s policy goals. . and has received two training awards, including a Robert A. —Peter Farnham

September 2007 ASBMB Today 5 washington update FA S E B FASEB Calls on Scientific Community to Endorse Common Guideline for COI, Unveils Toolkit BY CARRIE D. WOLINETZ

ASEB has issued a call to the scientific community Delivering the keynote address, House Energy and Fto adopt more consistent policies and practices for Commerce Committee Vice-Chair Diana DeGette (D-CO), disclosing and managing financial relationships between applauded FASEB’s efforts and stated, “By creating a academia and industry in biomedical research. This sum- more consistent standard to the extent possible we are mer, FASEB unveiled a framework for a national guideline more likely to avoid ambiguity and confusion. Without and held a meeting of more than 75 representatives of such standards, we run the risk of further confusing the scientific societies and other key stakeholders to discuss public about the integrity of research and exacerbating the process of implementation. Participants in the meet- their distrust.” ing included industry leaders like Gail Cassell of Eli Lilly; The FASEB framework is based on three guiding government officials such as Norka Ruiz-Bravo, of the principles: investigators must conduct research activities National Institutes of Health; and institutional groups rang- objectively, operate with transparency, and be account- ing from the Association of American Medical Colleges able to all stakeholders. To promote practices to achieve (AAMC) to the National Association of State Universities these principles, FASEB developed the COI Toolkit and Land Grant Colleges (NASULGC) as well as more website containing recommendations to improve the than two dozen scientific societies. In conjunction with the management of academic-industry relationships and conference, FASEB launched the COI Tookit, a website promote investigator education. Many of the recommen- designed to help researchers, institutions, publications, dations were derived from guidelines FASEB published and industry put into practice FASEB’s recommendations. in 2006 (opa.faseb.org/pdf/FASEB_COI_paper_7x06. Leo T. Furcht, immediate past president of FASEB pdf). The Toolkit provides a platform for the community to and chair of the committee that developed the program, share resources with the goal of moving toward a national described the challenge before the community: “FASEB guideline. is concerned that the lack of clarity and consistency in Participants in the meeting expressed enthusiasm for current conflict-of-interest policies may cause confu- a set of common principles and guidelines that they could sion by investigators and ultimately inhibit their ability to use to help better manage financial relationships between protect the integrity of research.” According to Laura academia and industry. “It is essential that the various Brockway, FASEB’s lead staffer on the project, “FASEB’s stakeholders work together to study the effectiveness of recommendations articulate the issue from the investiga- policies and practices and strive to balance the need for tors’ perspective because they, as a group, determine the more common standards with preserving case by case effectiveness of policies and practices.” analysis and situational driven decision making, when warranted,” said Brockway. “While flexibility is needed, operating under more broadly agreed upon guidelines Your Congress—Your Health will benefit the public and ensure future public support for Research!America, the Albert and Mary Lasker Foundation, biomedical research.” and several other partners recently released the results of a The work was funded by a grant from the Association new Your Congress–Your Health public opinion poll. A similar of American Medical Colleges–Office of Research Integrity poll was sent to all members of Congress. Responses from Responsible Conduct of Research Program for Academic both polls can be found at www.yourcongressyourhealth.org/. Societies. The FASEB COI toolkit may be viewed online at If your members of Congress have not yet submitted their opa.faseb.org/pages/advocacy/coi/toolkit.htm. responses to the Your Congress–Your Health questionnaire, please send them a message asking them to participate. Carrie D. Wolinetz is with the FASEB Office of Public Affairs.

6 ASBMB Today September 2007 firstasbmbsecondnews words New JBC Minireview Compendium on Interferons

nterferon (IFN), the first cytokine discovered, was identi- Montreal, Canada) focuses Ified by the British virologist Alick Isaacs and the Swiss on the centrally important researcher Jean Lindenmann in 1957 during their seminal interferon regulatory factors studies on virus interference. They found that influenza (IRFs) involved in transcrip- virus-infected cells produced a secreted factor that trans- tional activation of the type ferred a virus-resistant state to previously uninfected cells. I interferon gene promoters. The factor was designated interferon because of its ability Next, Sidney Pestka to interfere with virus growth. (Robert Wood Johnson To celebrate the 50th anniversary of the discovery Medical School, Piscat- of interferons, the Journal of Biological Chemistryy (JBC) away, New Jersey) provides an account of the discovery will release a compendium of eight Minirevieww articles of interferons, their purification and molecular cloning, and published in the journal on this topic. The compendium the biologic activities of IFNs. is available for $22.00 on the JBC Web site (www. In the fifth Minireview, Nicole de Weerd, Shamith jbc.org/), and a summary of the compendium is avail- Samarajiwa, and Paul Hertzog (Monash University, able for free at www.asbmb.org/asbmb/site.nsf/main/ Melbourne, Australia) focus on recent developments in publications?opendocument. understanding the biochemical properties and functional The compendium will also be distributed to the attend- activities of the type I IFN receptor proteins. ees of the Annual Meeting of the International Society for The combined biochemical and genetic studies of the Interferon and Cytokine Research, September 16—19, in mechanisms by which interferons induce transcriptional Oxford, United Kingdom. activation of new cellular gene expression led to the “The JBC is pleased to provide this thematic compen- discovery of the Janus tyrosine kinase (JAK)-signal trans- dium of Minireviews on interferon signal transduction and ducers and activators of transcription (STAT) signaling antiviral innate immunity,” says Charles E. Samuel, editor pathway by the Darnell and Stark laboratories. In the sixth of the Minirevieww section and associate editor of the JBC. Minireview, Christian Schindler (Columbia University, New “Much knowledge about interferons has been gained York), David Levy (New York University School of Medi- during the past 50 years, so it is important to assess the cine), and Thomas Decker (University of Vienna, Austria) depth of that knowledge with a focus on recent advances provide an overview of the JAK family of protein kinases and the new questions that yet need to be addressed.” and the STAT family of transcription factors. Seven of the articles highlighted in the compendium Keiko Ozato, Prafullakumar Tailor, and Toru Kubota were published in 2007 and were part of two Minireview (National Institutes of Health, Bethesda, Maryland) then series. The first series consisted of three articles on innate describe the mechanisms by which the IRF family of immunity and was published in the May 25 issue of the transcription factors plays critical roles in both innate and JBC. The second was composed of four articles on signal adaptive immunity, including the induction and action of transduction and was part of the July 13 issue of the the IFNs. JBC. An eighth article from the January 9, 2004, issue of In the final Minireview of the compendium, Samuel the JBC was added to these articles. Wormald and Douglas Hilton (Walter and Eliza Hall The first two Minireviews in the compendium, by Institute of Medical Research and Cooperative Research Mitsutoshi Yoneyama and Takashi Fujita (Kyoto University, Centre for Cellular Growth Factors, Parkville, Australia) Japan) and Satoshi Uematsu and Shizuo Akria (Osaka describe the biochemical properties and mechanisms University, Japan), provide updates on two kinds of of action of three families of proteins that inhibit cytokine nucleic acid sensors and the biochemical pathways by signal transduction, the SH2-containing phosphatases which they signal the production of interferon. (SHP), the protein inhibitors of activated STATS (PIAS), In the third Minireview, John Hiscott (McGill University, and the suppressors of cytokine signaling (SOCS).

September 2007 ASBMB Today 7 asbmbfirstsecond member spotlightwords Please submit news about yourself to [email protected] Caruthers and Fedoroff Awarded Georgiou Is Amgen Biochemical National Medal of Science Engineering Awardee Marvin Caruthers, professor of Chemistry and George Georgiou of The University of Texas Biochemistry at the University of Colorado at (UT) at Austin has been honored with the 2007 Boulder, and Nina V. Fedoroff, the Verne M. Amgen Biochemical Engineering Award for his Willaman Chair in Life Sciences and Evan profound impact on protein therapy and other Pugh Professor at Penn State University and protein research. an external professor of the Santa Fe Institute, Georgiou received the award and delivered are the recipients of the 2006 National Medal a lecture on his research at the Biochemical CARUTHERS of Science, the nation’s highest award for Engineering IV conference in July in Quebec lifetime achievement in scientific research. City, Canada. The bi-annual award was given in recognition of They received their medals at a White House Georgiou’s research excellence and leadership in biomedical ceremony in July. engineering. Caruthers was recognized for his lifetime Georgiou holds the Cockrell Family Reagents Chair at the UT accomplishments as a chemistry professor, Austin, with a primary appointment in the Department of Chemi- researcher, and biotechnology innovator. He pio- cal Engineering and further appointments in the departments of neered research in nucleic acid chemistry result- Biomedical Engineering and Molecular Genetics and Microbiology FEDOROFF ing in new methods that are used worldwide for and in the Institute for Cell and Molecular Biology. the chemical synthesis of DNA and RNA. His research has had a profound impact in protein engi- Fedoroff received the medal for her pioneering work on plant neering, protein-based therapeutics, and on the fundamental molecular biology and for her being the first to clone and charac- understanding of protein biogenesis. His biochemical engineering terize maize transposons. She has also contributed to education contributions include the invention of numerous commercially and public policy pertaining to recombinant DNA and genetic important technologies for facilitating the discovery and manu- modification of plants. U.S. Secretary of State Condoleezza Rice facturing of protein therapeutics, and in particular therapeutic also recently named Fedoroff as her new science and technology antibodies. He has also made seminal discoveries in the areas of adviser. oxidative protein folding and protein secretion.

Jordan Awarded Pincus Medal Raines Receives Rao V. Craig Jordan, Alfred G. Knudson Chair of Makineni Lectureship Cancer Research and vice president of the Ronald T. Raines, Henry Lardy Professor of Medical Sciences Division at the Fox Chase Biochemistry and Professor of Chemistry at the Cancer Center, Philadelphia, is the co-recipient University of Wisconsin-Madison, has won the with Angela Brodie of the 2007 Gregory Pincus 2007 Rao Makineni Lectureship award from the Prize and Medal from the Worcester Founda- American Peptide Society (APS). tion for Biomedical Research at the University The award, one of only three bestowed by of Massachusetts Medical School, Worcester. the APS, is given every other year to recognize The international award recognizes outstanding research “an individual who has made a recent contribu- in endocrinology and honors Gregory Pincus, a co-founder of tion of unusual merit to research in the field of peptide science.” the Worcester Foundation in 1944 and the scientist responsible Raines was honored for his “self-assembly of synthetic collagen for the development of the oral contraceptive. Jordan is being triple helices, which provides new strategies for developing honored for his pioneering research in developing the antiestro- biomaterials for use in medicine and nanotechnology.” His award genic drug tamoxifen for the treatment and prevention of breast address was delivered at the 20th APS symposium in June 2007 cancer as well as the recognition of selective estrogen receptor in Montréal, Canada. modulators that lead to the subsequent development of the drug Raines has made notable contributions to the exploration and raloxifene for the prevention of both osteoporosis and breast exploitation of proteins. He demonstrated that mammalian ribo- cancer. Jordan started his research on tamoxifen at the Worces- nucleases can become potent cytotoxins and potential cancer ter Foundation in the early 1970s. Currently, Jordan is exploiting chemotherapeutics. Raines discovered fundamental attributes of his discovery of the new biology of estrogen action that causes the collagen triple helix, enabling him to assemble triple helices apoptosis in antihormonally resistant breast cancer cells. that are stronger and longer than any found in nature. He and Laura L. Kiessling developed the traceless Staudinger ligation as a means to couple synthetic peptides and thus synthesize proteins.

8 ASBMB Today September 2007 Wells Presented with Borchardt Wins Biomolecular Medal of Friendship Science Award Robert D. Wells, past president of the Ronald Borchardt, Solon E. Summerfield American Society for Biochemistry and Distinguished Professor of Pharmaceutical Molecular Biology and of the Federation of Chemistry at the University of Kansas School of American Societies for Experimental Biology Pharmacy, is the recipient of the PolyPops (FASEB), received the Medal of Friendship Development Foundation Award. He shares the (Universitatis Lodziensis Amico Medal) from award with Ismael J. Hidalgo, chief scientist the Rector (President) Professor Wojciech and cofounder of Absorption Systems. Katner of the University of Lodz, Poland, in The researchers are being recognized for June. This medal is provided to special friends of the university their discovery and development in the late 1980s and early who have made substantial contributions to the education and/ 1990s of Caco-2 cells, a human colon carcinoma cell line that is or well being of the institution. widely used today in in vitro assays to predict the transport rate of Wells has trained a number of postdoctoral research associ- drug candidates across the intestinal epithelial cell barrier. ates at the University of Wisconsin-Madison, the University of The award is presented annually by the Society for Biomo- Alabama at Birmingham, and the Institute of Biosciences and lecular Sciences to members of the scientific community who Technology, Texas A&M University System Health Science Center have shown innovation in the design and application of plastics since 1979. At that time, Wells’ first research associate joined his and polymers in microplate development and design. The prize team to investigate non-B DNA structures in gene expression. includes a $2,500 honorarium. This was quickly followed in 1986 by a second research associ- ate, Adam Jaworski. Jaworski has been instrumental helping IN MEMORIAM: Wells identify young scientists to work in his laboratory as well as new professors to hire at the latter two institutions. Approximately Harry Rudney 1918–2007 20 scientists have been hosted in the U.S. Furthermore, the Harry Rudney, chairman emeritus of the Department of Bio- total number of Polish citizens educated or trained in the U.S. in chemistry and Molecular Biology at the University of Cincinnati technical or scientific pursuits due to the Jaworski-Wells collabo- College of Medicine, died on May 30, 2007. rations is 46. Born in Toronto, Canada, on April 14, 1918, Rudney was a member of a struggling Jewish immigrant family. Although he Lefkowitz Lauded with Shaw Prize couldn’t afford college, he attended public lectures offered by the University of Toronto. Among the lectures he heard was one Robert J. Lefkowitz, Howard Hughes Medical given by Bruno Mendel, who worked at the Banting Institute. Institute investigator at Duke University Medical Rudney wrote to Mendel and suggested an experiment that he Center, has received the Shaw Prize in Life could do. Mendel was so impressed that he offered Rudney a Science and Medicine for 2007 for his research job in his lab, which helped him pay his way through the Univer- into understanding the receptor system that sity of Toronto. controls the body’s response to drugs and Rudney went on to receive a master’s degree from the hormones. Lefkowitz will receive the award, University of Toronto in 1948 and a Ph.D. from Western Reserve which includes a $1 million prize, during a University in Cleveland in 1952. He joined the faculty at Western ceremony in Hong Kong in September. Reserve before being recruited by the University of Cincinnati The annual prize, which was first granted in 2004, was estab- to be the chairman of the Department of Biochemistry and lished by Run Run Shaw, a Chinese native who founded the film Molecular Biology. He was the Andrew Carnegie Professor of company Shaw Brothers Limited in Hong Kong in the 1950s. Biological Chemistry from 1967 until 1989. After his retirement, Shaw also serves as executive chairman of Television Broadcasts he returned to serve as interim chairman of the Department of Limited, also in Hong Kong. Pharmacology for three years. He later served as chairman of Lefkowitz received the award for his “relentless elucidation” the institutional review board. of seven-transmembrane-spanning receptors. These receptors Rudney was elected to the Fellows of the Graduate School are the targets of almost half of the drugs on the market today, at the University of Cincinnati in 1976 and received the George including antihistamines, ulcer medications, and beta blockers for Rieveschl Jr. Award for distinguished research. He served as heart disease. Lefkowitz first cloned the receptors in the 1980s. president of the Association of Medical School Chairmen of “I am so deeply honored to be recognized like this,” Lefkowitz Biochemistry and was on the editorial board of the Journal of said. “I am also proud that all I have accomplished happened Biological Chemistry. while I was here at Duke. It is a very fulfilling feeling to have years of hard work recognized like this.”

September 2007 ASBMB Today 9 asbmbnews

RETROSPECTIVE: Daniel E. Koshland, Jr. (1920-2007)

aniel E. Koshland, Jr., former friends and family. Below, as a tribute, DASBMB president and a tireless we offer thoughts and reflections from booster of the biological sciences, died several of Koshland’s friends and former on July 23 following a massive stroke. colleagues: A long time professor of Molecular and I knew of Koshland’s fame before I came to Cell Biology at the University of Califor- Berkeley, yet he was never intimidating even nia, Berkeley and a resident of Lafayette, as he cast an imposing scientific presence. California, Koshland was 87. He made graduate school a thoughtful, Koshland graduated from the Univer- rewarding and—importantly—enjoyable sity of California, Berkeley in 1941 and experience with his innovative ideas and promptly joined the Manhattan Project, charming wit. I am very proud to have purifying plutonium for the atomic bomb. passed through his lab, and I frequently He received his Ph.D. from the Univer- reflect on his teachings as I develop my own sity of Chicago in 1949. After a two- scientific perspectives. year postdoctoral fellowship at Harvard — Gideon Bollag, vice president, Plexxikon, University, he accepted an appointment former Koshland graduate student at the Brookhaven National Laboratory, where he remained Dan loved to write limericks, and he would always write one for for 14 years. He then joined the faculty of the University of the students/postdocs on the occasion of their departure from the California, Berkeley, where he also served as chair of the lab. He and I communicated in limericks after I left the lab. On Molecular and Cell Biology Department from 1973 to 1978. the occasion of the ASBMB symposium in his honor, I presented him Koshland became editor-in-chief at Science magazine in with the following limerick: 1984. He held the post for 10 years, during which time he There once was a man named Koshland, D. E. was best known for his incisive and witty editorials. This was Who thought about things like enzymes with glee most evident in the character he created, “Dr. Noitall,” who From fits induced was intended to represent the many scientists who took nar- To mechanisms deduced He enraptured us all with his chemistry row, overly simplistic views of important issues. — Alexandra Newton, University of California at San During his lifetime Koshland made major contributions to Diego, former Koshland postdoc the fields of enzyme action, short- and long-term memory, and science education. In the 1950s, he proposed that the With the death of Dan Koshland, biochemistry has lost a giant. then popular lock-and-key theory of enzyme action was inad- He was a brilliant scientist whose research was characterized by equate to explain all forms of enzyme action. To augment that its originality and boldness. As a teacher, he was outstanding— theory, he proposed an induced-fit theory of enzyme action. combining insight, rigor, and wit. He was a superb citizen devoting In the 1970s, his interest turned to the mechanism by which his energy and wisdom to problems in education and public policies cells “remember” situations and events. He demonstrated affecting science. His contributions are inestimable. — Howard K. Schachman, University of California at that bacteria have short-term memory and that purified mam- Berkeley, friend malian cell lines show rudimentary memory.1 An heir to the Levi Strauss fortune, Koshland endowed While working in the Koshland lab, I learned from a great scientist the National Academy of Sciences with a $25 million gift to how to dare. He pushed us to think outside the box, to follow up on establish the Marian Koshland Science Museum, named for wild guesses and hunches and not worry about sticking our neck his late wife, an immunologist who did ground breaking work out with a speculation—as long as we label it as a speculation. This on a cholera vaccine and the behavior of antibodies. advice has guided me well throughout my career. We extend our sympathy and thoughts to Koshland’s — Daria Mochly-Rosen, Stanford University, former Koshland postdoc

10 ASBMB Today September 2007 Dan loved to play with names and puns, both to promote the Dan always said that his ambition was to die young as old as research and to promote his postdocs. This story is one he used to possible. He succeeded: very few people, of any age, have had a tell on the lecture circuit in the early 1970s. A series of experiments younger heart or a more open mind. He went the way we should were published on enzyme mechanisms that he would refer to as the all go: suddenly, while still sharp and having fun. He managed to “Neet-Koshland” experiments that were done in conjunction with combine a gift for theorizing with a talent for clever but rigorous Ken Neet. Shortly later he published studies on receptors (with Pete experiments—a feat that few have done so well. And throughout Lovely) that he referred to as the “Lovely-Koshland” experiments. He it all he gave the impression that he was just a kid playing with his would laugh and say that he had to quit this approach when one day favorite toy. a new postdoc walked into his lab—Phil Strange. — Greg Petsko, Brandeis University and Harvard — Kenneth Neet, Rosalind Franklin University of Medical School, friend Medicine and Science, former Koshland postdoc Dan used to say when we caught him with a Snickers bar that he Dan and I were both past presidents of the American Society for ate as many preservatives as he could so that he could live as long Biochemistry and Molecular Biology. At the most recent meeting in as possible. My favorite Dan joke was about isocitrate dehydroge- Washington, D.C. we had a chance to visit for about half an hour nase crystals—that they were so beautiful that he wanted to make before our past president’s meeting started. I recall thinking to a ring for his wife. She refused when she found out she had to sit in myself as we talked, what a wit he still has and what a sharp mind. AmSO4 every time she wore it. He was an icon when I was a student in the 1960s, so just to see — Susan Tsutakawa, Lawrence Berkeley National him functioning at such a high level at the ASBMB meeting was a Laboratory, former Koshland graduate student real inspiration for an aging biochemist like myself. Dan was a true giant in the field of biochemistry. He will be missed. FOOTNOTES: — Jack E. Dixon, University of California More information on Koshland’s research can be found in his Journal of Biological at San Diego, friend Chemistry Classics article (2007, 37, e29). specialinterest ASBMB Delegation T

12 Tours China

13 specialinterest Early Medical Research Funding and the Evolution of Modern American Biochemistry BY SEYMOUR S. COHEN

he United States did not develop an official national regularly to Warm Springs, Georgia, to attempt to regain T policy of financial support for medical research some muscular strength. In 1934, his legal partner, Basil for almost a decade after World War II. Here I will O’Connor, who led the Warm Springs Foundation since describe how some financial support was developed in 1928, had begun fundraising to generate research funds to that period, i.e. 1946–1956, for what subsequently became find a cure for the disease, and in 1938 President Roosevelt the basis of the now large structure of American medi- and O’Connor announced the formation of the National cal research. To do so it seems desirable to describe some Foundation for Infantile Paralysis. In that year O’Connor personal experiences in developing a career in biochemistry appointed Tom Rivers, a leading virologist at the Rockefeller before, during, and after American entrance into that War. Hospital, to lead a Scientific Research Committee. One of In 1937, I began graduate study in the Department of the first decisions of the research committee was to expand Biochemistry at Columbia University’s College of Physi- knowledge in the field of virology by developing variously cians and Surgeons and worked as a bottle washer for $40 a trained younger scientists, and this decision resulted in the month. My fellowship in the last year of my graduate work announcement in Science to which I had responded. was $800. Salaries for academic positions for new Ph.D.s In 1934 and 1935 Stanley published on the crystallization were about $1,800 per year. of tobacco mosaic virus, and very soon thereafter Bawden The Columbia Department of Biochemistry at that time, and Pirie discovered RNA in the virus. Having read these chaired by Professor Hans T. Clarke, has been described as papers and the book of Bawden on plant viruses, I began one of the best in the country. Many of the faculty had been my work at the Princeton laboratories in the spring of 1941. relatively recent European refugees, some of whom had Early in 1942, shortly after the U. S. entered the war, Stanley obtained positions or consultative connections in clinical and I were able to report on the isolation and existence of a departments. Both postdoctoral fellows and graduate stu- viral RNA much larger than a tetranucleotide. dents were supported on absolutely minimal fellowships. Soon after 1941, Rivers and many members of the After receiving my Ph.D. early in 1941, I sought a Scientific Research Committee of the Polio Foundation postdoctoral position. Offers of a Naval position at Point went off to the armed forces until about 1947. Stanley’s Barrow, Alaska, and one at Peiping Union Medical College laboratory turned to the study of influenza vaccine, and I in China were not appealing. Curiously, pharmaceutical became involved in attempts of the Army and an academic companies were not interested in my information on blood Committee of Medical Research to improve the typhus clotting. However an issue of Science in 1940 had pointed vaccine, whose rickettsial antigens comprised less than to new fellowships in virology for the National Foundation 1% of the total protein in the vaccine. This work led me to for Infantile Paralysis, and I applied for one of these to work the Childrens Hospital of Philadelphia and the University with Wendell Stanley at the Rockefeller Institute in Princ- of Pennsylvania. By the end of the 1940s the rickettsia of eton. I was interviewed by Homer Smith for the adminis- typhus proved to be of bacterial structure and composi- tering National Research Council and by Stanley, who was tion, but the discovery and use of antibiotics had revealed $pleased by the notion of exploring the nature of the nucleic an inability of both penicillin and the known sulfa drugs to acid in tobacco mosaic virus. The awarded fellowship paid control infections by this fastidious microbe or indeed true $2,100 per year, and I was excited at my good fortune. viruses. In 1945 and 1946 the need for chemotherapeutic In 1924 Franklin D. Roosevelt had been hit by disabling agents to control virus infections led me to begin to work poliomyelitis and after a very difficult illness had traveled on the biochemistry of bacteriophage multiplication. 14 ASBMB Today $September 2007 It is important to realize that the National Institutes of well as new useful analytical reagents. Also the application Health (NIH) did not develop a system of funding medical of isotopic techniques had created new techniques of chem- research before 1955. In the period of 1946 to 1949 my work ical discovery in the many microbial systems. The decade on phage was supported by remnants of funds through the was also marked by the extraordinary enzymology in the Office of Naval Research to the Childrens Hospital. After American laboratories of a few European refugees, such my early studies on the biochemistry of phage multiplica- as the Coris, Lipmann, Szent-Gyorgi, and Ochoa, which tion appeared in 1946 to 1948, financial support was devel- revealed that phosphorylated intermediates were important oped through the good offices of the Commonwealth Fund, in the metabolism of cells generally. and this was maintained until 1963, when this fund decided The relevance of these biochemical advances to the not to compete with NIH research funds. growth of knowledge in phage and other virus systems was In 1946 and 1947, the donation of funds through the accepted enthusiastically by the members of the research March of Dimes had been sufficiently successful to encour- committee of the National Foundation for Infantile Paraly- age the Polio Foundation to renew the activities of its sis who wanted to develop these new findings in animal cell research committee, and under the systems. These scientists also contrib- O’Connor and Rivers leadership this uted in major ways to the develop- body reviewed the status of virology. A The National ment of the structural biochemistry key meeting of virologists in Madison, Institutes of Health of the nucleic acids and proteins. The Wisconsin, in 1948 was held under the foundation was particularly active in auspices of the research committee. In (NIH) did not develop encouraging and financing the study these few post-war years it had become a system of funding of the growth, cytology, and composi- clear that the phage systems permit- tion of animal cells that might serve as ted studies of the interaction of viruses medical research hosts for the polio virus and produce and separate host cells, and these had before 1955 enough virus to serve as a vaccine for included my own findings on the exag- poliomyelitis by 1956–57. This devel- gerated synthesis of virus nucleic acids opment had been highlighted in 1953 and proteins in infected bacteria as well as the dependence of by the Cold Spring Harbor Symposium on Viruses, which such synthesis on host cell metabolism. After that meeting, was supported by the National Foundation for Infantile the research committee pointed to the importance of similar Paralysis. A major section on the phages included the first experiments on virus-infected animal cells. The commit- American report of Watson and Crick on DNA structure, tee then attempted to encourage the development of animal while the reports of Wyatt and Cohen described a new DNA tissue culture systems and of establishing virus-infection on pyrimidine whose synthesis required phage infection. The plated tissue cultures as well as the isolation and character- symposium concluded with a section on the multiplication ization of several strains of polio virus from infected tissue of animal viruses in tissue culture, including the detection cultures, etc. In addition to these steps, which became the of phage-like polio virus-induced plaques in monolayers of basis of providing the killed virus in the Salk vaccine used in animal cells by Dulbecco and Vogt. 1957, the research committee encouraged financially much of In a very few years, i.e. the post-war decade from 1947 the work on the cytology, genetics, and composition of ani- through 1956, the work on animal cells, stimulated by the mal cells generally as well as on the structure, isolation, and National Foundation for Infantile Paralysis, had produced enzymatic synthesis of the nucleic acids. It will be clear that new data and directions in the study of their growth, the work and financial support via the Scientific Research behavior, and composition. These studies now pointed to Committee of the Polio Foundation in the decade from 1948 approaches to the curbing of pathological cells, as in the to 1956 functioned as essential anticipants of the NIH. growth of human cancers, and provided major incentives The Cold Spring Harbor International Symposium in to research which might be undertaken by the American 1946 had stimulated the study of the growth, heredity, and Cancer Society and the National Cancer Institute and other metabolism of microbial cells. Those studies then occurred institutes of the NIH. in a decade-long period in which American laboratories had been newly stocked with centrifuges, spectrophotom- REFERENCE 1 Chargaff, E., and Cohen, S. S. (1939) On Lysophosphatides. J. Biol. Chem. 129, eters, and the crude apparatus of paper chromatography as 619–628 $ September$ 2007 ASBMB Today 15 2008 annual meeting Systems Biology: A Shared Goal with Diverse Views BY FREDERICK P. ROTH AND BRENDA ANDREWS

n a well known Indian tale, blind men offer diverse descrip- the most likely hypotheses (e.g. unpublished work by Fred- Itions of the same elephant (“…seizing on the swinging tail erick Roth (Harvard Medical School) and colleagues). that fell within his scope, ‘I see,’ quoth he, “the Elephant is very like a rope!” (1)). Systems biology is the contemporary Global Systems Biology: Relationships elephant in the room, and it is easy to wonder whether the Before we can hope to simulate a global system, we must diverse scientific views operating under this name are of first have a general understanding of how the parts are the same beast. However, systems biologists do share a related to one another. Current challenges include protein common ultimate goal: to produce a dynamic model that networks, genetic networks, gene regulatory networks, and can predict the actions and internal workings of an entire chromatin networks. This area remains even less explored organism. than the parts list. For example, Marc Vidal (Dana-Farber Currently unachievable in any organism, a predictive Cancer Institute/Harvard Medical School) and colleagues dynamic model of an entire organism will require concerted have roughly estimated that only ~1% of all interactions effort on several fronts. Minimally, we must: 1) learn the between human proteins are known (4). We have only “parts list” for organisms of interest; 2) obtain a basic under- begun to learn about genetic interactions (cases in which standing of the relationships between all parts; 3) observe perturbations of two genes together yield a surprising system dynamics across time, space, and individuals; and result that often indicates a functional relationship). For 4) prepare for the global modeling challenge by first model- example, Brenda Andrews (University of Toronto), Charlie ing small subsystems. Boone (University of Toronto), and colleagues are using an automated genetics platform to create a complete map of Global Systems Biology: Parts double-mutant genetic interactions that lead to a significant Ultimate success in systems biology depends on the unfin- fitness defect in budding yeast. These groups have also ished task of defining the parts—genes, gene products, and begun to explore the effects of other genetic perturbations, their basic functional role. Current challenges include gene/ particularly gene overexpression, with the aim of reveal- protein definition, post-translational modifications, pheno- ing unappreciated functional connections in S. cerevisiae typing, epigenomics (e.g. heritable chromatin structure), (5). Furthermore, much of the dynamic control of biological and function annotation. It is clear that the parts list is far systems is affected through transcriptional regulation. Unfor- from complete. For example, recent work by Takashi Ito tunately, we do not yet have a complete map connecting (University of Tokyo) and colleagues has expanded the list transcription factors to their DNA binding elements in any of Saccharomyces cerevisiae (the most extensively studied species. Tim Hughes (University of Toronto), Martha Bulyk eukaryote) by dozens of introns, hundreds of new transcrip- (Harvard Medical School), and colleagues are systematically tion units in regions previously thought to be intergenic, identifying DNA-binding specificity of transcription factors in and hundreds of intragenic alternative transcriptional start mouse (unpublished work). In the meantime, it is clear that sites (2). The connection of genes to basic cellular roles, a comprehensive predictive model of any organism awaits e.g. determination of cell shape, also remains incomplete. a complete understanding of the relationships between In a single whole genome phenotyping screen in Droso- components. phila melanogaster, Amy Kiger (University of California, San Diego) and colleagues expanded the list of genes affecting Global Systems Biology: Dynamics cell shape by one-third (3). It is clear that our most basic We must also learn how the parts of an organism and their understanding of genes and gene functions remains vastly relationships change over time and space within an organ- incomplete. A current challenge is the integration of dispa- ism and between organisms and environmental stimuli. rate sources of data to roughly assign genes to functional Current areas of interest include gene expression, signaling, roles, which can focus limited experimental resources on development, genetic variation, and pathogenic systems.

16 ASBMB Today September 2007 For example, Jason Lieb (University of North Carolina, Cha- riz, G. F., Gibbons, F. D., Dreze, M., Ayivi-Guedehoussou, N., Klitgord, N., Simon, C., Boxem, M., Milstein, S., Rosenberg, J., Goldberg, D. S., Zhang, L. V., Wong, pel Hill) and colleagues are investigating how the occupancy S L., Franklin, G., Li, S., Albala, J. S., Lim, J., Fraughton, C., Llamosas, E., Cevik, S., Bex, C., Lamesch, P., Sikorski, R. S., Vandenhaute, J., Zoghbi, H. Y., Smolyar, and activity of human regulatory elements change in living A., Bosak, S., Sequerra, R., Doucette-Stamm, L., Cusick, M. E., Hill, D. E., Roth, F. P. & Vidal, M. (2005) Towards a proteome-scale map of the human protein- cells (6). One class of circuit that affects dynamics and protein interaction network. Nature 437, 1173-1178 homeostasis in living organisms is feedback, and our knowl- 5 Sopko, R., Huang, D., Preston, N., Chua, G., Papp, B., Kafadar, K., Snyder, M., Oliver, S. G., Cyert, M., Hughes, T. R., Boone, C. & Andrews, B. (2006) Mapping edge of the existence of such circuits is incomplete. Rachel pathways and phenotypes by systematic gene overexpression. Mol. Cell. 21, Brem (University of California, Berkeley) and colleagues are 319-330 6 Giresi, P. G., Kim, J., McDaniell, R. M., Iyer, V. R. & Lieb, J. D. (2007) FAIRE searching systematically for evidence of regulatory feedback (Formaldehyde-Assisted Isolation of Regulatory Elements) isolates active regula- tory elements from human chromatin. Genome Res. 17, 877-885 (unpublished work). A major challenge for systems biol- 7 Bao, Z., Murray, J. I., Boyle, T., Ooi, S. L., Sandel, M. J. & Waterston, R. H. (2006) Automated cell lineage tracing in Caenorhabditis elegans. Proc. Natl. Acad. Sci. ogy will be grappling with complexity and dynamics within U. S. A. 103, 2707-1272 multicellular organisms. As an example of current work in 8 Workman, C. T., Mak, H. C., McCuine, S., Tagne, J. B., Agarwal, M., Ozier, O., Begley, T. J., Samson, L. D. & Ideker, T. (2006) A systems approach to mapping this area, Robert Waterston (University of Washington) and DNA damage response pathways. Science 312, 1054-1059 colleagues have developed technology for tracking the 9 O’Dea, E. L., Barken, D., Peralta, R. Q., Tran, K. T., Werner, S. L., Kearns, J. D., Levchenko, A. & Hoffmann, A. (2007) A homeostatic model of IkappaB metabo- location and lineage of all cells in real time through the early lism to control constitutive NF-kappaB activity. Mol. Syst. Biol. 3, 111 10 Kaufmann, B. B. & van Oudenaarden, A. (2007) Stochastic gene expression: development of the worm Caenorhabditis elegans (7), which from single molecules to the proteome. Curr. Opin. Genet. Dev. 17, 107-112 they are now scaling up.

Local Systems Biology: Systems Biology Thematic Meeting Subsystems and Simulation ORGANIZERS: On the path towards modeling and simulating entire organ- Brenda Andrews, University of Toronto isms, we can begin by modeling and simulating smaller Fritz Roth, Harvard Medical School modules and subsystems. For example, Trey Ideker Symposium: (University of California, San Diego) and colleagues have Global Systems Biology: Parts been assembling knowledge about individual physical and Unexpected complexity of the budding yeast genetic interactions to model cellular responses to DNA transcriptome, Takashi Ito damage (see Ref. 8 for an example). In an example of Functional genomic analysis of morphogenesis, Amy Kiger Systematic function annotation in microbes and mammals, dynamic subsystem modeling, Alexander Hoffmann (Univerr- Fritz Roth sity of California, San Diego) and colleagues are developing temporal models of inflammatory signaling pathways (see Symposium: Global Systems Biology: Relationships Ref. 9 for an example). A major challenge in the modeling Interactome networks and human disease, Marc Vidal of subsystems is that many of our experimental measure- Genetic interaction networks in yeast, Brenda Andrews ments of cellular systems are derived from the study of Cracking the second genetic code, Tim Hughes ensembles of cells rather than individual cells. Alexander Symposium: van Oudenaarden (Massachusetts Institute of Technology) Global Systems Biology: Dynamics and colleagues have been exploring stochastic phenomena, Genome-wide identification of active human regulatory (e.g. Ref. 10), for which measurements on the single cell elements by formaldehyde-assisted isolation of level will be critical. regulatory elements, Jason Lieb In summary, systems biologists have a shared vision for Expression variation and regulatory feedback, Rachel Brem where the field must ultimately go, but the scale of the chal- Title TBD, Robert Waterston lenge is immense and demands a diversity of vision as we Symposium: proceed. Local Systems Biology: Subsystems and Simulation REFERENCES An integrated physical and genetic interaction map of 1 Saxe, J. G. (1873) The POEMS of John Godfrey Saxe, James R. Osgood and Company, Boston, Massachusetts genotoxicity, Trey Ideker 2 Miura, F., Kawaguchi, N., Sese, J., Toyoda, A., Hattori, M., Morishita, S. & Ito, A temporal code to generate specificity in inflammatory T. (2006) A large-scale full-length cDNA analysis to explore the budding yeast signaling, Alexander Hoffmann transcriptome. Proc. Natl. Acad. Sci. U. S. A. 103, 17846-17851 3 Kiger, A., Baum, B., Jones, S., Jones, M., Coulson, A., Echeverri, C. & Perrimon, Dynamics of signal transduction and gene expression N. (2003) A functional genomic analysis of cell morphology using RNA interferr- in single cells: feedback, inheritance and survival, ence. J. Biol. 2, 27 Alexander van Oudenaarden 4 Rual, J. F., Venkatesan, K., Hao, T., Hirozane-Kishikawa, T., Dricot, A., Li, N., Berr-

September 2007 ASBMB Today 17 2008 annual meeting The Diverse Aspects of Protein Synthesis and Degradation BY MARK HOCHSTRASSER AND RACHEL GREEN

iological systems devote considerable effort to the recent biochemical studies focusing Bsynthesis and subsequent folding of the enormous on the termination step of protein Mark Hochstrasser cellular repertoire of proteins. And, like all cellular pro- synthesis. Each talk will broadly focus cesses, protein synthesis and folding are subject to on the theme of protein synthesis many different levels of regulation to allow for the timely being a series of allosteric switches, production of needed functional proteins. An under- dictating the specificity of each standing of the basic molecular mechanisms of protein molecular event. synthesis and folding will be key for deciphering how The Protein-Assisted Folding these systems can be regulated. Just as overall pro- and Misfolding session will focus

tein synthesis is an enormously complicated and highly on discussion of diverse aspects of Rachel Green regulated process, so too is the controlled destruction of protein folding and misfolding. Judith cellular proteins. Many important regulatory proteins are Frydman (Stanford University) will talk about recent stud- subject to rapid degradation as this allows tight control ies on the organization of the chaperone machinery in of their concentrations in the cell. the eukaryotic cytosol and how it In addition, any protein made in the Just as overall protein promotes folding of newly trans- cell can suffer biosynthetic errors or lated polypeptides and clearance post-translational mishaps such as synthesis is an enormously of misfolded proteins. Jeff Kelly incorrect folding or improper assem- complicated and highly (The Scripps Research Institute) will bly. Accumulation of such defective regulated process, so too is discuss how the mechanisms of proteins can be toxic and is linked to the controlled destruction protein folding and misfolding are a variety of degenerative disorders related to normal physiology and such as Alzheimer and prion dis- of cellular proteins. disease. Art Horwich (Yale Univer- eases. Much of this regulatory and sity) will describe the mechanism of quality control proteolysis falls under the province of the a complex ring-shaped folding machine, the chaperonin ubiquitin-proteasome system. Four sessions focusing on GroEL, which together with its detachable lid cofactor diverse aspects of protein synthesis and degradation will GroES uses ATP to bind and fold proteins within its cen- comprise the Protein Synthesis, Folding, and Degradation tral cavity. Theme. In the Protein Turnover and Quality Control ses- In the Mechanisms of Protein Synthesis session, sion, Brenda Schulman (St. Jude’s Children’s Research the speakers will focus on the molecular mechanisms Hospital) will first describe the class of enzymes that of protein synthesis, principally in bacteria. Jamie Cate provide the gateway into the ubiquitin system and closely (University of California, Berkeley) will speak about recent related protein-conjugation systems. These so-called E1 structural advances detailing the interactions of the or E1-like enzymes use ATP to activate the C terminus of 70 S ribosome with ribosome recycling factor. These ubiquitin or ubiquitin-like proteins (Ubls) for amide bond studies will illuminate key interactions that facilitate the formation with target proteins. In the second talk, Randy poorly understood recycling step of protein synthesis Hampton (University of California, San Diego) will detail that follows completion of the polypeptide chain. Scott the fascinating mechanistic link between sterol-regulated Blanchard (Cornell University) will next discuss current degradation of HMG-CoA reductase and protein quality advances in defining the thermodynamic and kinetic control at the endoplasmic reticulum (ER). HMG-CoA is parameters of allosteric movements of the ribosome dur- a polytopic ER membrane protein and is the rate-limiting ing elongation using single molecule approaches. Finally, enzyme in the synthesis of cholesterol and related sterols. Rachel Green (Johns Hopkins University) will describe A specific ubiquitin-protein ligase (E3) functions both in

18 ASBMB Today September 2007 HMG-CoA degradation and quality control of a subset of aberrant ER proteins. Mark Hochstrasser (Yale University) Protein Synthesis and will describe another set of ubiquitin- and Ubl-dependent urnover Thematic Meeting reactions that occur at the ER membrane and inner ORGANIZERS: nuclear membrane. These include ubiquitin ligation to Mark Hochstrasser, Yale University specific abnormal ER membrane proteins and to certain Rachel Green, Johns Hopkins nuclear regulatory proteins. The Ubl known as SUMO is University School of Medicine also subject to attachment and removal at the nuclear Symposium: membrane, and a new link between SUMO dynamics Protein Turnover and Quality Control and RNA quality control will be described. Structural insights into ubiquitin-like protein transfer For the Protein Turnover in Cell Regulation session, cascades, Brenda Schulman Sterol regulation and protein quality control at the ER, a series of diverse regulatory mechanisms subject to Randy Hampton control by protein turnover will be outlined. The first SUMO and ubiquitin at the nuclear envelope and ER, speaker, Michael Rape (University of California, Berkeley), Mark Hochstrasser will describe the intricate control of cell cycle progres- Symposium: sion through mitosis by what is probably the most Protein Turnover in Cell Regulation complex E3 ubiquitin ligase, the anaphase-promoting Ubiquitin ligase machinery: from plant biology to human diseases, Ning Zheng complex (APC). How different substrates are targeted by The multiple roles of ubiquitin in orchestrating mitosis, the APC at defined stages of cell cycle progression will Michael Rape be a central topic. In the next talk, Ning Zheng (Univer- Structure and function of rhomboid intramembrane sity of Washington, Seattle) will lay out the remarkable proteases, Sinisa Urban story of how the simple plant hormone auxin regulates Symposium: plant growth by binding to a specific subunit of another Mechanisms of Protein Synthesis ubiquitin ligase. Crystallographic data from Zheng reveal Ribosome function is modulated by built in switches, Rachel Green an elegant mechanism by which auxin binding stimulates Single-molecule observations of allostery in translation, subsequent substrate binding. In the last talk, Sinisa Scott Blanchard Urban (Johns Hopkins University School of Medicine) will Structures of E. coli ribosome with ribosome recycling discuss the unusual ability of certain proteases to cleave factor, Jamie Cate transmembrane proteins within the plane of the mem- Symposium: Protein-Assisted Folding and Misfolding brane. How hydrolysis reactions can occur in the hydro- Chaperone-mediated protein folding in the eukaryotic phobic interior of lipid bilayers has been a long standing cytosol, Judith Frydman puzzle, but biochemical and structural data from Urban Amyloid diseases, Jeffery W. Kelly and others on the rhomboid proteases have now shed Chaperonin structure and function, Art Horwich considerable light on this problem.

TRAVEL AWARDS Join us for the ASBMB Annual Meeting !PRIL  s3AN$IEGO #! s'RADUATE0OSTDOCTORALs'RADUATE-INORITY s5NDERGRADUATE&ACULTYs5NDERGRADUATE3TUDENT Application Deadline: October 19, 2007 www.asbmb.org/meetings

September 2007 ASBMB Today 19 first2008second annual meetingwords A Renaissance for Metabolism Research BY MARK JOHNSTON

etabolism is pretty much figured out, right? One need tians found that yeasts metabolize Mlook no farther than the remarkably well annotated glucose in the same way, producing metabolic chart taped to the wall in most every the lab to ethanol rather than lactate (which made see that. Most steps in most metabolic pathways of the the Egyptians very happy). I (Mark major experimental organisms, as well as humans, have Johnston) will describe the basis for been characterized. What more is there to know? Less and this lifestyle of yeasts, which provides a less, it might seem, by one (admittedly unscientific) measure: paradigm for understanding the metab- the number of papers in the Journal of Biological Chemis- olism of cancer cells (and continues Mark Johnston try (JBC) with the word “metabolism” in the title declined to provide us with bread and bever- steadily over the last 50 years, from 606 in the 1950s to only ages that make us happy). Contributing to the unorthodox 270 in the 1990s. So why attend sessions on metabolism at metabolism of tumor cells is the increasing hypoxia they the ASBMB meeting? It’s an area that’s all but wrapped up, must endure, which is possible because of the hypoxia-in- isn’t it? ducible factors (HIFs) that mediate the cells’ response to this Certainly not! Important, novel, and often surprising stressful condition. Celeste Simon (University of Pennsylva- discoveries continue to be made about the mechanisms, nia) will provide insight into how HIFs modulate metabolism meaning, and momentousness of metabolism. And because and promote tumor proliferation. of that well annotated metabolic chart, the questions being One of the best known and most prevalent metabolic asked are incisive, and the answers are penetrating. Indeed, diseases is diabetes. It is not a coincidence that the pre- metabolism research is in something of a renaissance: JBC diabetic condition is known as the “metabolic syndrome.” is on a pace to publish in this decade 474 papers with the Despite many years of intensive investigation, diabetes word “metabolism” in the title, the most since the 1950s. remains enigmatic and difficult to treat, so there is a thirst The golden age of metabolism research may be upon us! for new insight into the disease. In the Metabolism and And we’re seeing that discoveries in the field of metabo- Diabetes session, Grahame Hardie (University of Dundee) lism relate more and more directly to human disease. If will describe new findings on a central sensor of cellular the “translational research” that we are increasingly urged energy status: the AMP-activated protein kinase (AMPK). (sometimes badgered) to pursue is to come to fruition, I sus- This “fuel gauge of the cell” is the target of antidiabetic drugs pect that some of the first and most significant successes and a focus of efforts to find new therapies. The endpoint will be won in the arena of metabolism. It seems fitting, then, of the progression towards diabetes is chronic high levels to focus the Metabolism sessions at the ASBMB meeting of glucose in the blood, ultimately caused by failure of the on important human diseases. These sessions promise devices for its disposal. Barbara Kahn (Harvard University) to provide an early window into a field whose impact only will discuss the importance of glucose sensing and transport stands to increase. in the maintenance of metabolic harmony. The other side of The unusual metabolism of many types of tumor cells the diabetic coin is glucose starvation, and Pere Puigserver has been recognized since the early 1930s, when Otto War- (Harvard University) will describe how cells adapt to this burg (and, independently, Herbert Grace Crabtree) discov- condition by increasing fatty acid oxidation. What he has to ered that those cells tend to “ferment” glucose (producing say will prove relevant to obesity and ageing. lactate) rather than oxidize it, even though they harvest less Some surprising connections between altered metabo- energy in doing so. There has been renewed interest in this lism and neurodegeneration that have surfaced recently will phenomenon in recent years. In the Metabolism and Cancer be described in the Metabolism and Neurodegeneration session, Doug Wallace (University of California, Irvine) will session. Who would have thought that defects in glycolysis present his intriguing ideas for the role of the mitochondrion might contribute to Parkinson disease? Barry Ganetzky (Uni- and hexokinase in the “aerobic glycolysis” of cancer cells. versity of Wisconsin, Madison) was as surprised as anyone But long before Warburg and Crabtree, the ancient Egyp- when his studies of a Drosophila mutant with neurological

20 ASBMB Today September 2007 problems led him to that conclusion. A role for metabolic defects in epilepsy should not surprise anyone, however, Metabolism Thematic Meeting because it has long been known that certain forms of epi- lepsy can be controlled with diet. But Avtar Roopra’s (Uni- ORGANIZER: Mark Johnston versity of Wisconsin, Madison) observation that an inhibitor Washington University School of Medicine of glycolysis blocks certain types of epilepsy was a surprise and opens the door for a new class of anticonvulsant drug. Symposium: Jeff Milbrandt (Washington University) will describe his dis- Metabolism and Diabetes covery that increasing the NAD+ level in damaged neurons AMPK: the fuel gauge of the cell, Grahame Hardie delays---and in some cases prevents---axonal degeneration Nutrient control of gluconeogenesis through PGC-1- and death. Maybe there’s some hope for us ageing baby alpha/SIRT1 deacetylase complex, Pere Puigserver boomers after all! Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony, Although that metabolic chart tacked to the wall in the Barbara Kahn lab represents a remarkable scientific accomplishment, we Symposium: must admit that it’s somewhat superficial: it doesn’t really Metabolism and Cancer describe the highly interconnected and dynamic metabolic The Warburg effect in yeast, Mark Johnston network. How do all those pathways coordinate with each Mitochondria and cancer: stochastic genetics and other, and how do they adjust in harmony when the cell’s energetic pathophysiology, Doug Wallace circumstances change? The speakers in the Metabolic Net- Hypoxia-inducible factors: central regulators of the works session will begin to provide some of the answers. tumor phenotype, Celeste Simon Bernhard Palsson (University of California, San Diego) Symposium: will present integrated metabolic and regulatory network Metabolism and Neurodegeneration models that enable predictions of cell growth phenotypes NADH, AMPK, and neurodegeneration, Jeff Milbrandt of mutants missing certain transcription factors. Christina TPI deficiency and neurodegeneration in Drosophila: Smolke (Caltech) will discuss work from her lab integrating an AGE-dependent link to a common mechanism? Barry Ganetzky molecular switches into synthetic and endogenous cel- Glycolysis and epilepsy, Avtar Roopra lular networks. And James Liao (University of California, Los Angeles) will describe his efforts to design intracellular Symposium: oscillators that interface with metabolism with the goal of Metabolic Networks predicting cellular behavior and designing gene metabolic Identification of genome-scale metabolic network circuits for novel functions. models, Bernhard Palsson Even though we have that comprehensive metabolic Integration of molecular switches into synthetic and endogenous cellular networks, Christina D. Smolke chart—indeed because we have it—research on metabo- The design of intracellular oscillators that interact lism is alive and well, and more exciting than ever! Come with metabolism, James Liao see for yourself at the 2008 ASBMB meeting.

#!,,&/20!0%23 Choose from over 200 biochemistry topic categories. Share your research with more than 13,000 Experimental Biology attendees. Short talks will be selected from submitted abstracts. Abstract Submission Deadline: November 7, 2007 www.asbmb.org/meetings

September 2007 ASBMB Today 21 first2008second annual meetingwords RNA: From Atom to Organism BY FRANK SLACK AND ROBERT T. BATEY

he past decade has brought discoveries that have x-ray structures of the metabolite binding domain of ribo- Trevolutionized our thinking about gene regulation and switches and how binding induces conformational changes cell biology. The emergence of a role for RNA in almost all in the RNA that allow it to control gene expression. Julie aspects of biology has resulted in a paradigm shift in how Feigon (University of California, Los Angeles) will focus upon biologists view the subcellular world. In the past, RNA was developing atomic resolution models of RNA using NMR primarily viewed as a messenger shuttling information from spectroscopy to understand how they function in a biologi- DNA to proteins or the structural components of translation. cal context. Nils Walter (University of Michigan) will focus We now understand that RNA plays many more important upon the use of single molecule fluorescence experiments roles in the cell, from gene regulation to catalysis. In this to reveal the mechanisms by which ribozymes are able to ASBMB meeting theme we have tried to capture a few achieve catalytic activity. snapshots of this very exciting scientific frontier in four ses- The Emerging Non-coding RNA World session will be sions that present views of the RNA world that span from chaired by Tom Gingeras (Affymetrix). This session aims to atomic to organismal levels. introduce the audience to the large amount of newly dis- The Riboregulation session will focus upon recent work covered transcription and RNA species present in the cell. uncovering the mechanisms by which RNA regulates gene John Mattick, (University of Queensland, Brisbane, Australia) expression inside the cell. This session will by chaired by will kick off the session with a discussion of the complexity James Goodrich (University of Colorado, Boulder), who will of non-coding RNA species found in eukaryotic cells and present data on how non-coding RNAs that are induced how this might be proportional to species complexity. Tom by heat shock are able to repress transcription by RNA Gingeras (Affymetrix) will describe the recent discovery of polymerase II. Ronald Breaker (Yale University) will describe massive transcriptional output in animal cells. Then, recent how cis-acting regulatory elements in mRNAs called ribo- Nobel laureate Andrew Fire (Stanford University) will discuss switches are able to regulate gene expression through their new aspects of RNA interference. ability to specifically bind a range of small molecule metabo- The Roles for Small Non-coding RNAs session will be lites. Finally, Gisela Storz (National Institute of Child Health chaired by Frank Slack (Yale University). This session will and Human Development, National Institutes of Health) will focus on functions for some of the newly discovered RNA describe the role of small non-coding RNAs in bacteria and species. First Slack will introduce microRNAs and their how they serve to regulate a number of processes. roles in development and cancer. Next, Anastasia Khvorova The session on Dynamic RNA Structures chaired by (Dharmacon/Thermo) will discuss recent advances in small Robert Batey (University of Colorado, Boulder) will center interfering (siRNAs) technology. This will be followed by a upon the atomic level structure of RNA and functional con- discussion on the roles of miRNAs in plants by Marja Tim- formational changes that they undergo. Batey will describe mermans (Cold Spring Harbor Laboratory).

Small RNAs and Dynamic RNA Elements Thematic Meeting Organizers: Frank Slack, Yale University and Robert T. Batey, University of Colorado-Boulder Symposium: Symposium: Dynamic Symposium: The Symposium: Roles for Riboregulation RNA Structures Emerging Non-Coding Small Non-Coding Small Non-coding RNAs in Probing conformational RNA World RNAs bacteria, Gisela Storz changes in riboswitches, New RNA species in animals, MicroRNAs in cancer, Gene regulation by Rob Batey John Mattick Frank Slack riboswitches, Ron Breaker NMR studies of dynamic RNA Massive transcriptional siRNAs, Anastasia Khvorova Role of B2 and Alu RNAs in elements in telomerase, output, Tom Gingeras MicroRNAs in plants, regulation of transcription, Julie Feigon New endogenous siRNAs, Marja Timmermans Jim Goodrich Single molecule studies of Andrew Fire RNA dynamics, Nils Walter

22 ASBMB Today September 2007 ASBMB Taps 8 Scientists and 1 Politician for Top Awards

he American Society for Biochemistry and Molecular the U. S. House of Representa- TBiology (ASBMB) has announced the recipients of its tives, will receive the Howard K. annual awards competition. Eight scientists and one politi- Schachman Public Service Award. cian were singled out for their outstanding achievements The award recognizes an individual and contributions to science. The awards will officially be who best demonstrates dedication to presented at the Experimental Biology 2008 meeting, April public service in support of biomedical sci- 5–9, 2008, in San Diego. ence. Castle was selected in recognition of his I. Robert Lehman of Stanford University will give the repeated efforts to boost the budget of the Herbert Tabor/Journal of Biological Chemistryy Lectureship. National Institutes of Health since 2003 Lehman received the award for his outstanding scholarly and for his efforts to promote a more contributions to the field of DNA metabolism, his admirable rational Federal policy regarding use of track record as a mentor, and his unparalleled service to the human embryonic stem cells. Journal of Biological Chemistry. The Schering-Plough Research Institute Award will be C. David Allis of the Rockefeller University will be hon- presented to Scott A. Strobel, a Howard Hughes Medical ored with the ASBMB Merck Award for his seminal contri- Institute professor at Yale University. The Schering-Plough butions to the field of chromatin biology. The Merck Award Award was established to recognize young investigators for is given to a researcher who makes outstanding contribu- outstanding research at an early stage of their careers. Durr- tions to research in biochemistry and molecular biology. ing his short career, Strobel has become a major leader in Alexandra C. Newton of the University of California, the study of the structure, function, and mechanism of RNA San Diego will be presented with the Avanti Award in Lipids. molecules involved in catalytic processes. Newton has worked for over two decades on molecular John D. Scott a Howard Hughes Medical Institute aspects of lipid signaling and as a result has been able to investigator at Vollum Institute, Oregon Health & Science elucidate the molecular controls that regulate the function of University, will be honored with the William C. Rose Award. protein kinase C. This award honors outstanding scientists The award recognizes outstanding contributions to bio- whose research interests are in the field of lipids. chemical and molecular biological research and a demon- The FASEB Excellence in Science Award will go strated commitment to the training of younger scientists. to Mina J. Bissell of the Lawrence Berkeley National Scott’s work on the AKAP family of scaffold proteins has Laboratory. The award recognizes outstanding achievement transformed the field of intracellular signaling. He has by women in biological science. Bissell is a world renowned also been an exemplary trainer of graduate students and leader in the area of the role of extracellular matrix (ECM) postdoctoral fellows who have gone on to make their own and microenvironment in regulation of tissue-specific func- contributions to the field of signal transduction. tion with special emphasis in breast cancer, where she has The ASBMB Award for Exemplary Contributions to Edu- changed some established paradigms. cation will be presented to Michael F. Summers, a How- S. Walter Englanderr of the University of Pennsylvania ard Hughes Medical Institute investigator at the University of School of Medicine will give the Herbert A. Sober Lecture- Maryland, Baltimore County. Summers has pioneered efforts ship. This lectureship, which is awarded every two years, to recruit and retain students traditionally lost to science and recognizes outstanding biochemical and molecular biologi- aided in broadening the diversity of students engaged in cal research with particular emphasis on development of science. The award, administered annually by the ASBMB methods and techniques to aid in research. Englander has Education & Professional Development Committee, is given been a central figure in the development and application to a scientist who encourages effective teaching and learn- of hydrogen exchange-base methods that revolutionized ing of biochemistry and molecular biology through his or her insight into the biochemistry and biophysics of proteins. own teaching, leadership in education, writing, educational The Honorable Michael N. Castle, (R-DE), member of research, mentoring, or public enlightenment.

September 2007 ASBMB Today 23 firstcareersecondinsights words A Generalist Finally Finds Her Place

BY SYDNEY C. GARY

trong generalist tendencies are feeling more and more like “a fish out Snot that helpful when you are of water,” or “a fish on a bicycle,” or supposed to be attending to one something involving a fish. It wasn’t molecule acting on one specific cell good. type during a tiny window of devel- Like most of us in this growing opment in a mouse brain. “Focus, fraternity of alternative career hold- Sydney Gary Sydney!” my postdoctoral advisor ers, I forced myself to endure a self- Sydney Gary is the assistant direc- would say encouragingly (or was it assessment exercise, which revealed tor of the Banbury Center at Cold frustratedly?). I found it near impos- that my strengths and interests were Spring Harbor Laboratory (CSHL). sible to do this, especially with all the not being maximized as a labora- She received a B.S. in Biology from interesting things going on outside tory scientist. I liked to teach, write, Southwestern University in George- of the cell culture dishes I stared into create graphics and figures, design town, Texas, and received a Ph.D. day after day. websites—even troubleshoot and fix in Pharmacology/Toxicology from I had switched research areas faulty lab equipment or computer the Medical College of Virginia in between graduate school and my problems. Also, I realized I lacked the Richmond. In the 9 years between postdoctoral training, from study- drive and personality evident in those her Ph.D. and her current position at ing gene expression in leukemias at of my peers who were succeeding at CSHL, she was a postdoctoral fellow the Medical College of Virginia to the academic research game. I finally at Yale University, a visiting assis- developmental neurobiology at Yale accepted that I should be doing tant professor at Haverford College University. This was because I found something else that would capitalize in Haverford, Pennsylvania, and a the brain fascinating and wanted to on my strengths. medical editor and writer at Man- learn all I could about neurobiology, So, after four years as a postdoc, isses Communication in Providence, and going into a new field seemed I took that first difficult step away Rhode Island. exciting. from the bench. I applied for and was My first two postdoctoral years offered a one-year visiting assistant were fantastic, full of learning every- professor job at Haverford College, track position advertised in my area thing I could about neurobiology, a small liberal arts college outside of expertise and in my admittedly applying new techniques, and just of Philadelphia. This appeared to be narrow target geographical area. enjoying the opportunity to grow my dream job, and I loved it there. I—along with another 300 dream job scientifically. Around year three, Unfortunately, when the year was seeking hopefuls—applied. One of though, my research project was up, I was back on the job market. those other 300 got it. sputtering, and my publication record But at least I had experience teach- I spent the next two years back at was far from robust. I needed to rein ing undergraduates, so I was ready Yale, in the nether world of the “asso- in my “diverse” interests a bit and to send in my CV and teaching ciate research scientist” (non-tenure follow my advisor’s urging to be more philosophy to all the small, liberal track faculty), which was a strange focused on my research project. art colleges reasonably close to the existence. I was fortunate that my I tried, I really did. But it just northeastern city I had adopted as postdoc advisor was willing to keep wasn’t working for me. I hate to home and watch the next dream job me around while I was looking for resort to tired metaphors, but as my fall into place. That particular aca- the next opportunity to come sweep postdoc years kept accruing, I was demic job cycle, there was one tenure me away, and I enjoyed keeping my

24 ASBMB Today September 2007 research project going. But it did Internet career websites and search scientific meetings and postgraduate seem a bit like treading water. capabilities, it all came down to just courses in the world. As assistant At this point, I decided that rather meeting someone on the basketball director of the Banbury Center at than wait around for the perfect court and having a discussion about Cold Spring Harbor Laboratory, I am small-college position that fulfilled what I wanted to do. I spent two involved in developing new pro- my very restrictive criteria, I would years as an associate editor, learning grams, meetings, and courses, focus- instead focus on applying my gener- how to write for a deadline, conduct ing on the areas of neuroscience and alist tendencies to become a science interviews with researchers, design mental health. Amazingly, I get to writer/medical writer. I started apply- and layout a publication, and manage interact almost every day with highly ing for all sorts of different positions, freelancers. I also learned a lot about respected international scientists from academic journal editor to med- clinical psychiatry, adding a useful who come to Cold Spring Harbor as ical education specialist with meeting participants, course a small biotech firm. Every- lecturers, and sometimes one seemed to be looking for even course students. I also someone with demonstrated am fortunate to get to work writing or editing experience, closely with many of the sci- and my volunteer column for entists here as well as other a quarterly magazine, paltry fellow “generalists” who number of research papers, have made their way to Cold and various grant writing Spring Harbor to contribute exercises just didn’t cut the mustard. It medical slant to my basic science their various skills as directors of was a very frustrating time. training. It was exhausting work but programs, editors of books, etc. We After almost two years of search- also fantastic experience that was can all thrive here in this unique and ing, I finally landed a job as an critical for my next career move. wonderful place. associate editor for a group of clinical This seemingly meandering career When I saw the advertisement for psychiatry publications based in path had provided me with the CV the position at Cold Spring Harbor Providence, Rhode Island. The main of an authentic generalist. People Laboratory, it seemed to be tailored reason I got the job was that I had suddenly took me seriously when I for my patchwork background of met the editor during a pickup bas- applied for non-research jobs, includ- neurobiology, clinical psychiatry, ketball game, and we started talking ing the position I now hold at Cold teaching, and writing. It was the about our jobs and my desire to get Spring Harbor Laboratory—finally easiest cover letter I ever wrote for a into writing/editing—and she took my dream job. Cold Spring Harbor job application, everything just came a chance on me. So after all my high is a high caliber research institu- together. My generalist tendencies tech job searching using the array of tion that also runs some of the top finally paid off.

2008 ASBMB ANNUAL MEETING Preliminary Program Available Online Visit www.asbmb.org/meetings for more information!

September 2007 ASBMB Today 25 firsteducationsecondand trainingwords -ENTORINGOF0OSTDOCTORAL3CHOLARS Attracts National Attention BY KEITH J. MICOLI AND LUCIA MOKRES

he training of current and future scientists in the regarding mentoring and effort reporting, in response TUnited States has been an area of increasing con- to a request by the NPA. The NIH now states that time cern for the past decade as the number of postdoctoral spent mentoring postdoctorates can be counted toward scholars has grown without an increase in the number percent effort reported on a research grant “to the extent of independent academic positions into which they that mentoring activities are not readily separable from may transition. Although there have been tremendous activities related to supervising the participation of stu- advances in technology and in the way in which science dents and postdoctorates in the funded research project” is performed, there has been little change in the train- (see OMB circular A-21 and the NIH clarification at ing of postdoctoral scholars in the past century. As job grants1.nih.gov/training/q&a.htm#post). markets and grant pay-lines have tightened, the aver- In a similar effort to foster appropriate mentorship age first time National Institutes of Health (NIH) R01 of postdoctorates, the U.S. Congress and President Bush recipient is now over 40 years old. Funding agencies, recently approved a new provision on postdoc mentor- universities, and individual mentors are now recogniz- ing as part of the America Competes Act, reauthorizing ing that to maintain a dynamic and creative workforce the National Science Foundation. According to SEC. and to encourage the best and most capable students to 7008, entitled “Postdoctoral Research Fellows:” enter science, there must be more effort ppa lied to mak- B MENTORING‰ćF %JSFDUPS TIBMM SFRVJSF UIBU BMM ing the postdoctoral period more effective as a means of HSBOU BQQMJDBUJPOT UIBU JODMVEF GVOEJOH UP TVQQPSU transitioning to independence. QPTUEPDUPSBM SFTFBSDIFST JODMVEF B EFTDSJQUJPO PG Great strides have been made towards enhancing UIF NFOUPSJOH BDUJWJUJFT UIBU XJMM CF QSPWJEFE GPS postdoctoral training in the last five years with the cre- TVDI JOEJWJEVBMT BOE TIBMM FOTVSF UIBU UIJT QBSU PG ation of the National Postdoctoral Association (NPA), UIF BQQMJDBUJPO JT FWBMVBUFE VOEFS UIF 'PVOEBUJPOT the expansion of institutional Postdoctoral Training CSPBEFS JNQBDUT NFSJU SFWJFX DSJUFSJPO .FOUPSJOH Offices, and the increased attentionp aid to new and BDUJWJUJFT NBZ JODMVEF DBSFFS DPVOTFMJOH USBJOJOH young investigators by the NIH and the National Sci- JO QSFQBSJOH HSBOU BQQMJDBUJPOT HVJEBODF POXBZT ence Foundation (NSF). One major area of focus for UP JNQSPWF UFBDIJOH TLJMMT BOE USBJOJOH JO SFTFBSDI these organizations has been the development and FUIJDT endorsement of effective mentoring policies and pro- C REPORTS‰ćF %JSFDUPS TIBMM SFRVJSF UIBU BOOVBM grams for postdoctoral fellows. Mentorship in labora- SFQPSUT BOE UIF ĕOBM SFQPSU GPSSFTFBSDI HSBOUT UIBU tory management and research skills is crucial for the JODMVEF GVOEJOH UP TVQQPSU QPTUEPDUPSBM SFTFBSDIFST development of young scientists if they are to become JODMVEF B EFTDSJQUJPO PG UIF NFOUPSJOH BDUJWJUJFT competent investigators and managers of indepen- QSPWJEFE UP TVDI SFTFBSDIFST dent laboratories, and principal investigators must be The NIH clarification and the NSF reauthorization encouraged to emphasize this key aspect of postdoctoral represent major steps towards the development of poli- training. cies that will foster more comprehensive and effective Regrettably, for some time there has been debate mentoring practices for postdoctoral fellows. The U.S. whether the time spent mentoring postdoctoral fel- research enterprise will benefit greatly from the addi- lows could be counted towards the percent of effort on tion of young scientists who have received top quality a research grant. By allowing principal investigators to training in all aspects of their investigative careers. bill for time spent mentoring as part of effort report- ASBMB continues to advocate for such improvements in ing, they may be more likely to ensure that appropriate postdoctoral training policies, working in collaboration mentorship is provided during the postdoctoral training with NPA and other scientific organizations to achieve period. To this end, the NIH has clarified its position this goal.

26 ASBMB Today September 2007 sciencefocus Maurice Swanson: Finding New Cures for Muscular Dystrophy BY PAT PAGES enes can go wrong in many a child growing up in Seattle. He Gdifferent ways. Most known remembers particularly enjoying his genetic diseases are directly caused biology and chemistry classes. He by mutations in specific genes, but also remembers being fascinated by in some neuromuscular diseases the a surgical operation that he attended cause is indirect and the mutant gene at a relatively young age. His father, produces an abnormal mRNA that an obstetrician-gynecologist, had Marice S. Swanson attaches itself to proteins essential for allowed Swanson to watch the entire normal adult development. operation—a hysterectomy, or surgi- where his interest in biochemistry Maurice S. Swanson, profes- cal removal of the uterus—that he and molecular biology was fostered. sor of Molecular Genetics and was conducting. The operation gave He worked on mRNA translation in Microbiology at the University of Swanson a first-hand, practical look Euglena, a pear-shaped, one-celled Florida, Gainesville, has spent the at surgery and may have prompted organism that, like a plant, makes past 15 years understanding how him to specialize in the biomedical its own food by photosynthesis, but these RNA-binding proteins work field later in life. when in darkness acts like an animal and finding ways to prevent their Swanson attended Colorado by eating tiny plants and animals. damaging effects. Recently, Swanson College, a liberal arts college in During this period, he also became intrigued by the process of cellular senescence Scientists should now be able to design and aging, and this “ interest prompted drugs that may cure many important him to transfer to the neuromuscular diseases in the near future University of Califor- ” nia, Berkeley, for his doctoral studies. has also tested chemical compounds Colorado Springs, where courses are For his Ph.D. thesis, Swanson that have showed promise in the taken one at a time. Every semester, began working on the free radical treatment of muscular dystrophy, a students would take an average of theory of cell aging, which transi- disease that weakens and ultimately four courses, one after the other. “I tioned to studies on mitochondrial wastes away muscles. really enjoyed this way of learning,” bioenergetics and the regulation “The knowledge that diseases can Swanson says. “In other colleges, of electron transport chain com- be caused by sequestration of RNA- students take concurrent classes in ponents. During this period, he binding proteins is relatively new,” multiple subjects. At Colorado Col- enjoyed being surrounded by a large Swanson says. “But so much research lege, I was able to focus on one topic number of Ph.D. students, postdoc- has been done on this topic that sci- at a time, which was an early taste of toral students, and scientists from entists should now be able to design what it would be like to be a scien- many countries. He notes that “the drugs that may cure many important tific researcher.” lab was quite diverse with biochem- neuromuscular diseases in the near After graduating with a bachelor’s ists, biophysicists, and physiologists future, which is very encouraging.” degree in Biology, Swanson pursued a working closely together—it was a Swanson’s interest in nature master’s degree in Biology at the Uni- wonderful interplay of scientists who and science started when he was versity of California, Santa Barbara, approached problems from different

September 2007 ASBMB Today 27 sciencefocus continued

ability to relax once they contract and affects one of every 8,000 people. “One of the principal manifestations of the disease is muscle hyperexcit- ability,” Swanson says. “When patients with myotonic dystrophy contract one of the muscles in their arm, it’s very difficult for them to release that contraction.” The muscles progressively weaken and eventually waste away. The disease also affects the heart muscle and is associated with irregular heart rhythms that can lead to sudden death. It also can result in cataracts, prema- Fig. 1. Nuclear RNA foci (red) in normal (left) and myotonic dystrophy (right) cells viewed ture hair loss, and mild to moderate in a microscope by fluorescence in situ hybridization. The nucleus is stained blue. mental retardation. These symptoms worsen with each generation as ever perspectives but often came to similar to recognize specific RNA sequences.” increasing copies of a malfunctioning conclusions about which experiments In 1989, Swanson moved to the RNA repeat sequence are produced. needed to be done to answer the rel- University of Florida to set up his Swanson and colleagues discovered evant question.” own laboratory, where he investigated that, after the repeats are transcribed After completing his Ph.D. in 1980, how nuclear RNA processing and into mRNA, the resulting CUG Swanson initially went to Northwest- mRNA export are coordinated in (from the DMPK gene) and CCUG ern University, Evanston, Illinois, to yeast. The scientists found that yeast repeats (from the ZNF9 gene) fold work with Emanuel Margoliash, now also expresses hnRNPs, and one of into an unusual hairpin structure, and emeritus professor of Biochemistry these proteins, Nab2p, is involved in the contorted mRNAs accumulate and Molecular and Cellular Biol- both polyadenylation—the addition in areas of the nucleus called foci. ogy at Northwestern, to continue his of adenine nucleotides to the 3’ end of The hairpin structures then bind to studies on mitochondrial bioenerget- mRNA—and mRNA export from the proteins called muscleblind-like 1 ics. His interest in RNA biology was nucleus to the cytoplasm. (MBNL1), which bind to both CUG later rekindled by his interaction Later, Swanson and colleagues and CCUG repeats. with another Northwestern profes- found a related protein in human “When viewed in the microscope by sor, Gideon Dreyfuss, who is now a cells, which they called CUGBP1 fluorescencein situ hybridization (Fig. Howard Hughes Medical Institute because it prefers to bind to CUG 1), the nuclei of these cells look like investigator and Isaac Norris Profes- repeats in mRNA. This discovery led they have measles,” Swanson says. “You sor of Biochemistry and Biophysics at them to work on myotonic dystrophy, can also see that these CUG repeats the University of Pennsylvania School a neuromuscular disease caused by colocalize with MBNL1 proteins.” of Medicine, and Swanson started the expansion of a CTG repeat in the In people not affected with the working on nuclear RNA processing. Dystrophia Myotonica Protein Kinase disease, CUGBP1 and MBNL1 are “Our work centered on how (DMPK) gene and, in turn, results involved in RNA alternative splicing, RNA is processed in a cell nucleus, in the production of a mutant RNA the process that regulates the removal especially how RNA binds to a very with tandem CUG repeats. Another of introns from pre-RNAs as well as the abundant class of RNA-binding fac- research team then discovered that removal of some exons from coding tors called the heterogeneous nuclear a less common form of the disease, sequences. This splicing is often regu- ribonucleoproteins, or hnRNPs,” called myotonic dystrophy 2, is caused lated according to cell type and devel- Swanson says. “We discovered that by a series of between 80 and 11,000 opmental stage. In the case of muscle these and many other types of RNA- CCTG repeats in the first intron of the cells, some exons that are leftovers binding proteins contain a structural zinc finger protein 9 ZNF9( ) gene. from the fetal developmental stage are motif—now called the RNA recogni- Both forms of myotonic dystro- removed, so that only exons coding for tion motif—that allows these proteins phy cause skeletal muscles to lose the adult muscle proteins are activated.

28 ASBMB Today September 2007 Fig. 2. Schematic representation of the sequestration of MBNL1 (red ovals) in myotonic dystrophy (coding regions, black boxes; untranslated regions, smaller open boxes; fetal alternative exon, gray box; CUG repeat shown as a double-stranded RNA).

In myotonic dystrophy, because a few weeks. mately lead to an effective treatment of MBNL1 is sequestered by the CUG “We simply flooded the muscle myotonic dystrophy and possibly other and CCUG repeats, it cannot remove with extra copies of the muscleblind neuromuscular and neurodegenerative certain fetal exons anymore, and the protein,” Swanson says. “We were able diseases in humans.” resulting mRNAs are then translated to to correct the myotonia as early as four produce fetal muscle proteins, which weeks after injection, and at 23 weeks BIBLIOGRAPHY: Bandziulis, R. J., Swanson, M. S., and Dreyfuss, G. are unable to work in adult muscle tis- it was completely eliminated in the (1989) RNA-binding proteins as developmental regulators. Genes Dev. 3, 431--437 sues (Fig. 2). muscle that was injected with the virus Kanadia, R. N., Johnstone, K. A., Mankodi, A., Lungu, “Newborn muscle is very differ- carrying this muscleblind protein.” C., Thornton, C. A., Esson, D., Timmers, A. M., Hauswirth, W. W., and Swanson, M. S. (2003) A ent than adult muscle; muscle pro- Encouraged by these results, the muscleblind knockout model for myotonic dystro- phy. Science 302, 1978--1980 teins must undergo multiple changes scientists are now planning to inject Miller, J. W., Urbinati, C. R., Teng-umnuay, P., Sten- between the time we are newborns and MBNL1 directly into the bloodstream. berg, M. G., Byrne, B. J., Thornton, C. A., and Swanson, M. S. (2000) Recruitment of human the time we become adults,” Swan- “About 30% of myotonic dystrophy muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy. EMBO J. 19, son says. “But in adult patients with patients succumb to heart problems, so 4439–4448 myotonic dystrophy, the fetal forms theoretically systemic injections might Nykamp, K. R., and Swanson, M. S. (2003) Toxic RNA in the nucleus: Unstable microsatellite expression of proteins that are expressed during also prevent that,” Swanson says. in neuromuscular disease. Progress in Molecular and Subcellular Biology (Jeanteur, P., ed.). RNA embryonic and neonatal life are pres- Swanson and colleagues eventually Trafficking and Nuclear Structure Dynamics, Springer-Verlag, Berlin-Heidelberg ent, and these are incompatible with hope to find out whether correcting Teng-umnuay, P., and Swanson, M. S. (2006) Myo- adult muscle function.” myotonia early by restoring normal tonic dystrophies types 1 and 2. Nucleic Acids and Molecular Biology, Vol. 19 (Fry, M., and Usdin, Because MBNL1 proteins are inac- levels of MBNL1 might prevent at least K., eds.) Human Nucleotide Expansion Disorders, Springer-Verlag, Berlin-Heidelberg tivated in myotonic dystrophy, Swan- some of the muscle loss that character- Kanadia, R. N., Shin, J., Yuan, Y., Beattie, S. G., son and colleagues recently decided izes the adult onset disease. Wheeler, T. M., Thornton, C. A., and Swanson, M. S. (2006) Reversal of RNA missplicing and myo- to inject a surplus of MBNL1 in mice Swanson is very excited about the tonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proc. carrying the genetic flaw underlying therapeutic prospects of his latest Nat. Acad. Sci. U. S. A. 103, 11748–11753 the disease, so that even if some pro- results. “Our work provides proof of Timchenko, L. T., Miller, J. W., Timchenko, N. A., DeV- ore, D. R., Datar, K. V., Lin, L., Roberts, R., Caskey, teins bind to mRNA, others can still principle that the approach is effective, C. T., and Swanson, M. S. (1996) Identification of a (CUG)n triplet repeat RNA-binding protein and its splice out the fetal exons. The experi- at least in mice,” Swanson says. “Our expression in myotonic dystrophy. Nucleic Acids ment worked: the mice recovered after hope is that this strategy will ulti- Res. 24, 4407–4414

September 2007 ASBMB Today 29 sciencefocus Matthias Mann: Using Proteomics to Understand Protein Interactions BY PAT PAGES

nderstanding how all the proteins dimers in the gas phase. Uin a cell work together may soon In 1983, he met with John Fenn, a be a reality, thanks to new technologies professor of chemical engineering at pioneered in part by Matthias Mann, Yale University, New Haven, Connecti- director at the Max Planck Institute cut, who was developing a new tech- for Biochemistry in Martinsried (near nique to identify the chemical com- Munich), Germany. Mann has spent his position of molecules. Until then, the 25-year career developing these tech- most common technique to do so was niques with the hope of better under- by vaporization and “electron impact” standing how drugs work at the cellular mass spectrometry (MS), in which a Matthias Mann level and finding ways to improve molecule was broken down into ions current drugs while minimizing their and the various ions were separated by Unlike traditional mass spectrom- side effects. mass and charge, leading to knowledge etry, electrospray MS does not break “To understand what proteins do in of the molecule’s chemical composition. a molecule into ions and look at the cells, scientists used to study them one But the new technique, called electro- chemical nature of each ion. Instead, at a time, but with current technologies, spray ionization, was easier to use and it ionizes the entire molecule and we can look at thousands of proteins at more accurate than mass spectrometry determines its chemical composition a time,” Mann says. “If you think of a and could be used to analyze larger at once. Then the technique identifies cell as a factory, we used to study every molecules. different molecules present in a sample worker separately, but now we can look Until the early 1980s, physicists and by separating them by charge and mass at the factory in one shot, which is chemists had been the main users of (see figure). During his Ph.D. years, much more interesting.” mass spectrometry, because the mole- Mann showed that electrospray lived This new perspective on proteins, cules they were studying were relatively up to its promise by successfully identi- called proteomics, is generating an small. Biologists, who usually work fying peptides and proteins. increasing amount of research on the with larger molecules—such as organic After receiving his Ph.D. in 1988, inner workings of cells and is being molecules, proteins, and DNA—used Mann became a postdoctoral fellow at used to design new drugs against a another technique called the Edman the University of Southern Denmark in wide variety of diseases, including degradation method. This technique Odense, where he worked on another cancer, diabetes, and neurodegenera- determined the amino acid sequence of technique called matrix-assisted laser tive diseases. Mann, in particular, was a protein by removing the amino acids desorption and ionization (MALDI). among those who created and devel- one by one and then analyzing them, The technique, which worked like oped this field and has trained dozens but this method was very slow and electrospray ionization but was much of scientists in it, both in Denmark and laborious. faster (see figure), had been introduced Germany. Electrospray ionization—for which in 1988 by German scientists Michael Mann’s early interests were in phys- Fenn received the 2002 Nobel Prize in Karas and Franz Hillenkamp. Eager to ics and mathematics. He graduated Chemistry—offered the potential to test this new technique, Mann con- from the University of Gottingen in replace the Edman method. So when verted an existing mass spectrometry 1982 with a major in physics and then Mann heard about it, he quickly became machine into a MALDI machine. pursued a master’s degree in physics. interested. While working with Fenn, In 1992, Mann moved to the Euro- For his master’s thesis, he worked on a Mann was so excited about the electro- pean Molecular Biology Laboratory, device that produced a beam of atoms spray technique that Fenn invited him where he set up his first research team. or molecules to study how they formed to work as a Ph.D. student in his team. At that time, the first DNA-sequencing

30 ASBMB Today September 2007 databases started to become avail- work on proteins that were relevant to the isotope into their proteins, making able, which was an opportunity for a wide range of biomedical problems, them heavier than their counterparts. Mann and his colleagues to match including cancer, aging, and diabetes. The two populations are then combined the information they had collected on There was a lot of pressure, too, because and analyzed together by electrospray, proteins with that of a database’s DNA. we had pledged to show that mass MALDI, or other similar techniques. The scientists were able to study many spectrometry could outperform the old SILAC—which is now a popular proteins at a time, leading to their first chemical methods.” proteomics technology—is being used proteomics studies. The proteins Mann and his team by many scientists to study cell signal- Mann’s team used the DNA infor- identified were mostly regulatory— ing and protein-protein interactions. mation as follows. First, an unknown those switching on other proteins or Mann and the 40 scientists and stu- protein was cleaved into peptides by those interacting with genes to control dents working in his third team at the a protease such as trypsin, and the their transcription, of which there are Max Planck Institute of Biochemistry masses of the peptides were measured about 20 families. These proteins are are now actively pursuing research on a by using either electrospray or MALDI. particularly relevant to medical applica- variety of topics, which include refining Then, a computer program converted tions, Mann says, because they can the current proteomic technologies, the DNA information into proteins cause diseases when they are defective. developing techniques to analyze the and determined the peptides that they In 1998, Mann went back to the protein composition of body fluids-- would produce if cleaved by trypsin. University of Southern Denmark, -including blood, urine, and cerebro- The computer program compared the where he set up his second research spinal fluid---to diagnose the early masses of the peptides of the unknown team and later developed a technique to symptoms of various medical condi- protein to the peptide masses of each detect differences in protein abundance tions, and studying epigenetics, changes protein encoded in the genome, and between two samples. Called stable in genes not caused by mutations but the results were statistically analyzed to isotope labeling with amino acids in by proteins interacting with genes. find the best match. cell culture (SILAC), this technique “I feel privileged to be part of such “By combining the mass spectrom- compares the protein composition of an interesting and growing field of etry techniques with DNA databases, two populations of cultured cells to study,” Mann says. “I couldn’t have we boosted our research considerably,” understand differences between, say, imagined that my original work on Mann says. “We were suddenly able to normal and cancerous cells, or cells that mass spectrometry would have led me respond differently to to such a large number of interesting the same drug. problems. And it’s only the beginning: In this technique, Now that we have developed all these one cell population proteomics technologies, we can expect is fed with a growth a lot of promising results, especially in medium contain- the pharmaceutical area.” ing normal amino acids, while a second BIBLIOGRAPHY population grows on Aebersold, R., and Mann, M. (2003) Mass spectrome- a medium containing try-based proteomics. Nature 422, 198-207 Andersen, J. S., and Mann, M. (2006) Organellar “heavy” amino acids, proteomics: turning inventories into insights. EMBO Rep. 7, 9 which contain a non- Fenn, J. B., Mann, M., Meng, C. K., Wong, S. F., and radioactive isotope, Whitehouse, C. M. (1989) Electrospray ionization for mass spectrometry of large biomolecules. Science such as carbon 13 246, 64-71 Mann, M. (2006) Functional and quantitative proteom- instead of carbon 12 ics using SILAC. Rev. Mol. Cell Biol. 7, 952-959 or nitrogen 15 instead Ong, S. E., and Mann, M. (2005) Mass spectrometry- based proteomics turns quantitative. Nat. Chem. of nitrogen 14. When Biol. 1:5 252-262 Fig. 1. Simplified representations of the electrospray and Steen, H., and Mann, M. (2004) The ABC’s (and MALDI techniques when used to identify various peptides. the cells of the sec- XYZ’s) of peptide sequencing. Rev. Mol. Cell Biol. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews: ond population grow, 5, 699-711 Molecular Biology (Steen, H., Mann, M. (2004) The ABC’s (and XYZ’s) of Peptide Tyers, M., and Mann, M. (2003) From genomics to Sequencing. Nature Reviews: Molecular Cell Biology 5, 699-711), copyright 2004. they incorporate proteomics. Nature 422, 193-197

September 2007 ASBMB Today 31 firstbiobitssecond asbmb words journal science

The Transcription ,OOKING)NSIDE4 "OX &ACTOR4WO STEP T-box (Tbx) genes encode a family of transcription fac- tors that regulate a variety of developmental processes. The interferon regulatory factor 3 (IRF-3) transcrip- Tbx18 and Tbx15 encode a closely related pair of T-box tion factor is a key component of the innate antiviral proteins that, together with Tbx22, form a subgroup of response. It is activated by phosphorylation mediated the Tbx1 subfamily in vertebrates. Functional analyses as part of a signaling cascade by the kinases TBK1 and in mice have shown that Tbx15 is needed for skin and IKK. Phosphorylation results in IRF-3 dimerization and skeletal development, and Tbx18 is required for the removal of an autoinhibitory structure, allowing interac- formation of the vertebral column, the ureter, and the tion with the co-activators CBP/p300. In this JBC pa- posterior pole of the heart. In this JBC paper, the authors per, the authors provide evidence for a two-step model characterize the subcellular localization, DNA binding for the mechanism of IRF-3 activation by phospho- specificities, protein interactions and transcriptional rylation. Using purified proteins they show that TBK1 properties, and the structural prerequisites of the two can directly phosphorylate full-length IRF-3 in vitro. proteins. They show that both proteins homo- and het- Phosphorylation erodimerize, bind to various combinations of T half sites, at residues in and repress transcription by interacting with proteins in site 2 (Ser-396 the Groucho family of corepressors. The authors also to Ser-405) of provide evidence that competition with activating T-box IRF-3 alleviates proteins constitutes a possible mode of regulation of the autoinhibition to promoters for Nppa and Dll1 in vitro and in vivo. allow interac- tion with CBP and facilitates phosphorylation at site 1 (Ser- 385 or Ser-386). Phosphorylation at site 1 is, in turn, required for IRF-3 di- merization.

Overexpression of Tbx18 coincides with downregulation of Dll1 and Hey1. Two-step model of IRF-3 activation. Transcriptional Repression by the T-box Interferon Regulatory Factor 3 Is Regulated by Proteins Tbx18 and Tbx15 Depends on Groucho a Dual Phosphorylation-dependent Corepressors Switch Henner F. Farin, Markus Bussen, Martina K. Schmidt, Manvendra K. Singh, Karin Daniel Panne, Sarah M. McWhirter, Tom Schuster-Gossler, and Andreas Kispert Maniatis, and Stephen C. Harrison J. Biol. Chem. 2007 282, 25748–25759. J. Biol. Chem. 2007 282, 22816–22822

32 ASBMB Today September 2007 firstbiobitssecond asbmb words journal science Lipid Transfer in Trading a Phosphate Prostate Cancer for a Sugar Several studies have shown that a high intake of dietary Many cellular and nuclear proteins add O-GlcNAc fatty acids can increase the risk of prostate cancer. to serine and threonine side chains in response to Moreover, circulating prostate cancer cells metastasize environmental and biological stimuli. Some of the in the bone marrow, which harbors a rich source of lipids known O-GlcNAc sites are the same as or adjacent stored inside adipocytes. Although prostate cancer cells to phosphorylation sites, and it is thought that exhibit higher levels of lipid in the presence of adipo- the addition of the sugar might occur directly in cytes, there has been no data that unequivocally estab- competition with that of the phosphate. In this MCP lish that this increase is the result of adipocyte-to-tumor paper, the authors examined O-GlcNAc perturbations cell lipid transposition. In this JLR paper, the authors in response to inhibition of glycogen synthase use Fourier transform infrared (FTIR) microspectroscopy kinase-3 (GSK-3). Using stable isotope labeling with to demonstrate that human prostate cancer cells do amino acids in cell culture (SILAC)-based quantitative indeed uptake isotopically labeled fatty acids from an mass spectrometry they identified 45 potentially adipocyte. This study is significant not only because it O-GlcNAcylated proteins. Ten of these proteins demonstrates lipid-specific translocation between adi- showed increased O-GlcNAcylation, and 19 showed pocytes and tumor cells but also because it uses FTIR decreased O-GlcNAcylation upon GSK-3 inhibition. microspectroscopy to characterize various biomolecular They also mapped the O-GlcNAc site of vimentin, features of a single adipocyte without the need for cell which showed increased O-GlcNAcylation upon GSK-3 isolation and lipid extraction. inhibition.

Adipocytes transfer lipids to surrounding cancer cells. 45 potentially O-GlcNAcylated proteins were identified

Direct Evidence of Lipid Translocation between Adipocytes and Prostate Cancer Cells Dynamic Interplay between with Imaging FTIR Microspectroscopy O-GlcNAcylation and GSK-3- dependent Phosphorylation Ehsan Gazi, Peter Gardner, Nicholas P. Lockyer, Claire A. Hart, Michael D. Brown, Zihao Wang, Akhilesh Pandey, and and Noel W. Clarke Gerald W. Hart

J. Lipid Res. 2007 48, 1846–1856 Mol. Cell. Proteomics 2007 6, 1365-1379

September 2007 ASBMB Today 33 firstfor yoursecond lab words

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34 ASBMB Today September 2007 career opportunities

collaborations and Burlington is a great Touro University 5NIVERSITYOF0UERTO2ICO place to live. Foreign scientists as well as College of Medicine TRACK FACULTY POSITION US permanent residents and citizens are FACULTYY EDUCATION The Department of Biochemistry at the invited to apply. The University of Vermont POSITION:BIOCHEMISTRY University of Puerto Rico School of Medi- is an equal opportunity, affirmative action AND MOLECULAR BIOLOGY cine wishes to fill a vacant tenure-track employer. Women and minorities are Touro University College of Medicine is a faculty position. newly created allopathic medical school encouraged to apply. Applicants must have a Ph.D. or equiva- located in northern New Jersey, a few Interested candidates should e-mail a lent degree and an active research program minutes from NYC. We are seeking a complete CV and a list of three references in a field of Biochemistry. The research candidate to fill a faculty education posi- to: Dr. Susan S. Wallace, Professor and program should be disease-oriented preferr- Chair, Department of Microbiology and tion in Biochemistry and Molecular Biology. ably in the areas of cancer, neuroscience, Molecular Genetics, The Markey Center This person is responsible for developing, diabetes, or other metabolic disorders. for Molecular Genetics, University of implementing and evaluating our medical Applications to human genomics, proteom- Vermont, 201 Stafford Hall, Burlington, VT education program in Biochemistry and 05405 ics, and “metabolomics” are highly desir- Molecular Biology. Qualifications include a [email protected] able. The candidate must demonstrate a doctoral degree, a passion for teaching and or: successful track record of research funding Dr. Sylvie Doublié, Associate Professor, experience in a medical school environment. with currently active research support. The Department of Microbiology and For more information visit our Web site at successful candidate will be expected to Molecular Genetics, University of Vermont http://touromed.touro.edu mentor graduate students and participate Sylvie.Doublié@uvm.edu Applicants should submit a in team-taught graduate and professional letter of interest and current CV to: [email protected] courses at the School of Medicine. Salary University of Wisconsin– Interest may be expressed confidentially. and rank will be determined according to Madison Touro is an equal opportunity employer. experience. TENURE-TRACK POSITION Advancing health care through science, Applications must include a cover let- IN BIOCHEMISTRY compassion and caring. ter, statement of research interests with The Department of Biochemistry at the 3 representative publications, curriculum University of Wisconsin-Madison (www. 5NIVERSITYOF&LORIDA vitae with recent research support, and biochem.wisc.edu) invites applications for POSTT-DOCTORAL POSITION three letters of recommendation. a position in biochemistry at the Assistant IN BIOCHEMISTRY AND Send your application before October Professor level. Applications in all areas of 31, 2007 to: José R. Rodríguez-Medina, MOLECULAR MICROBIOLOGY biochemistryy will be considered. The Depart- A senior or entry-level Post-Doctoral position Ph.D., Chair, Department of Biochemistry, School of Medicine, University of Puerto ment is particularly interested in candidates is available immediately to study membrane Rico Medical Sciences Campus, PO BOX working with cutting edge technologies biogenesis and protein translocation systems 365067, San Juan, P.R. 00936-5067 (nanotechnology, cellular imaging, proteom- in Streptococcus with particular emphasis The University of Puerto Rico School of Medicine ics/metabolomics/lipidomics) in animal, on the signal recognition particle (SRP) is LCME accredited and is an Equal Opportunity/ plant or model organisms in research areas pathway. Applicants should have a strong Affirmative Action Employer. background in biochemistry and molecu- related to the chemistry of protein or nucleic acid function, regulation of metabolism, or lar microbiology. Experience with cellular University of Vermont fractionations and membrane extractions; neurobiology. The University and Depart- TWO POSTDOCTORAL ment provide an excellent environment for protein chemistry techniques such as density POSITIONS gradient centrifugation, electrophoresis, the development of an outstanding research Highly motivated candidates are invited chromatography and protein purification; program. The successful candidate will be to apply for two postdoctoral positions and techniques to evaluate protein-protein expected to develop a vigorous, extramurally- to study the interactions of DNA repair interactions such as two-hybrid systems, funded, independent research program, glycosylases and DNA polymerases with fluorescence methods, calorimetry, chemi- and to participate in the undergraduate and oxidative DNA damages using biochemi- cal cross-linking, immunoprecipitation and graduate teaching programs of the Depart- cal and structural approaches. Applicants familiarity with mass spectrometry, nuclear must have a strong biochemical/biophysical ment. PDF applications should include a magnetic resonance, circular dichroism and background. Experience in x-ray crystal- curriculum vitae, a list of publications, and surface plasmon resonance will be given lography is highly desirable. Experience in a brief summary of accomplishments and preference. A Ph.D. and English language protein overexpression and purification is directions of future research and be sent proficiency are required. Salary is com- a plus. The successful candidates must to [email protected]. Three mensurate with experience and range be able to work independently as well as letters of reference should be forwarded to follows NIH guidelines. collaboratively. Excellent verbal and written the same address with applicant’s name in E-mail CV and letters of reference to L. communication skills are required. The header. Applications should be completed Jeannine Brady, Ph.D. at The University of Florida, Department of Oral Biology, scientific atmosphere at the University of by October 15, 2007. [email protected]fl.edu Vermont is collegial with many ongoing [email protected].

September 2007 ASBMB Today 35 scientific meeting calendar

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