SEE INSIDE FOR 2008 ANNUAL MEETING SESSION OVERVIEWS

July 2007

Protein Kinase Activation

American Society for Biochemistry and Molecular Biology POSTDOCTORAL FELLOWSHIP Department of Dermatology, OHSU, Portland, Oregon Training Program in Molecular Basis of Skin Pathobiology Promoting Understanding Position for recent PhD, MD/PhD or MD (US citizen or Permanent Resident) in NIH-funded program for training highly of the Molecular Nature qualifi ed candidates for academic careers in basic & translational research in skin diseases, including cancer & psoriasis. OHSU Dermatology has a strong history of clinical & scientifi c of Life Processes research & a 40-year record in training dermatology residents including physician scientists & postdoctoral scientists on the path to independence. Features of this training program are a core of Dermatology faculty & a multidisciplinary network of scientists with international recognition in areas highly relevant to epithelial cell fate, development & diseases. The training program includes seminars in mentors’ departments, Dermatology Research Division meetings & symposia, research forums tailored to postdoctoral students, & national/international meetings in cutaneous biology. Successful candidates desiring an academic career in basic or translational research in cancer The Society’s purpose is to or investigative dermatology using surface epithelial models can advance the science of bio- expect to receive training toward independence in research with chemistry & molecular biology a strong clinical translational component. OHSU is an equal through publication of scientific & opportunity employer; we encourage applicants from diverse educational journals, organization backgrounds that may be underrepresented in academics & of scientific meetings, advocacy science. Applicants must be US Citizens/Permanent Residents. for funding of basic research & For more information & application instructions see: education, support of science http://www.ohsu.edu/dermatology/research/training.php education at all levels, & promot- ing the diversity of individuals entering the scientific workforce.

www.asbmb.org contents JULY 2007

ON THE COVER: society news Activity levels of protein kinase C (high levels in blue; low levels 2 President’s Message in red). Activity is highest near 4 From the Editor the cell membrane where PKC is activated by diacylglycerol. 7 Washington Update (Photo courtesy of Alexandra C. Newton, UCSD.) 27 22 ASBMB Journal News 24 Hendrix and Bradshaw Assume New Posts

2008 overview 8 Biomolecular Catalysis 10 Genome Dynamics: Replication, Recombination, and Damage Response 12 Dynamic Chromatin—Chromosomes in Action 14 Chemical Biology special interest 16 Impact Factor Page Rankled A comparison of journal ranking methods. 16 science focus 27 Alexandra Newton: Understanding the Inner Workings of Cells 30 Jack Griffi th: Seeing What No One Has Seen Before departments 5 News from the Hill

20 ASBMB Member Spotlight Looking at DNA and protein 23 Career Insights interactions. 30 25 Professional Development 26 Education

32 BioBits BY NICOLE KRESGE Science from ASBMB Journals 36 Meeting Calendar resources 34 For Your Lab 35 Career Opportunities Assembling the 20 S proteasome. 32

July 2007 ASBMB Today 1 president’smess age

A monthly publication of The American Society for A Critical Year—Please Biochemistry and Molecular Biology Offi cers Volunteer! Make Your Heidi E. Hamm President Gregory A. Petsko President-elect Voices Heard Mark A. Lemmon Secretary Merle S. Olson Treasurer HEIDI HAMM, PRESIDENT Council Members Alan Hall Kuan-Teh Jeang Suzanne R. Pfeffer Linda J. Pike John D. Scott Joan A. Steitz Kevin Struhl James A. Wells Ex-Offi cio Members s reported in the article on A 6.7% increase for each of the next Ellis Bell Chair, Education and Professional Apage 5 of this issue, the situa- three years is needed to erase infl a- Development Committee tion is not looking very good for the tionary losses NIH has suff ered since Laurie S. Kaguni National Institutes of Health (NIH), 2003. If this level of funding stands, it Chair, Meeting Committee George Hill although things are looking very good would be the fi ft h year in a row that Chair, Minority Affairs Committee for the National Science Founda- NIH has received a subinfl ationary Kendall J. Blumer tion (NSF), which is expecting a 10% increase, and the erosion of the dou- Anna Marie Pyle Co-chairs, 2008 Program Committee increase this year. Th ose of you who bling will thus continue apace. Mary J. C. Hendrix receive grant support from NSF would Flat funding will further discourage Chair, Public Affairs Advisory Committee do well to drop a note to your mem- the best and brightest young scientists Robert E. Rhoads Chair, Publications Committee bers of Congress applauding this from pursuing a research career in the Herbert Tabor fi ne increase and urging them to United States. Another year of failure Editor, JBC support it when the bill comes to the to provide sustained, strong growth Ralph A. Bradshaw A. L. Burlingame House fl oor. in federal support for medical and Co-editors, MCP NIH, however, is experiencing a health research also exacerbates the Edward A. Dennis Editor, JLR very diff erent situation. Th e House fl ight of innovation overseas, leaving appropriations subcommittee on this country far more vulnerable to ASBMB Today Editorial Labor/Heath and Human Services global competition. Advisory Board (HHS) and Education, which funds Your voice is needed! I realize that Alex Toker Chair Mike Autry NIH, provided the agency with a I risk sounding like a broken record, Greg P. Bertenshaw Craig E. Cameron $750 million increase in FY2008, but scientists must take the responsi- Irwin Fridovich Richard W. Hanson to $29.65 billion (a 2.6% increase). bility to educate their community and Elizabeth A. Komives Bettie Sue Masters Luke A. O’Neill Duanqing Pei However, because the House has their Congressperson how important Carol C. Shoulders Robert D. Wells agreed with the President’s proposal to biomedical research is for the future ASBMB Today increase the amount (by $201 million) health of the nation. One way you can Nicole Kresge Editor that NIH is required to transfer to the assist in eff orts to turn this situation [email protected] Global HIV/AIDS program, the House around is to contact your member Pat Pages Science Writer [email protected] subcommittee actually is propos- of Congress and urge him or her to Nancy J. Rodnan Director of Publications ing that NIH receive an increase in support a larger increase in the bill for [email protected] FY 2008 of only $549 million, which the NIH. You can do this in several Barbara Gordon Executive Director [email protected] translates to a 1.9% increase, barely ways. A phone call to the congressional half the 3.7% rate of infl ation for bio- offi ce in Washington is one way. All For information on advertising call FASEB AdNet at 800-433-2732 ext. 7157 or medical research. Th us, the proposed members of Congress can be reached 301-634-7157, or E-mail [email protected]. increase falls signifi cantly short of through the Capitol switchboard at the 6.7% increase recommended by 202-224-3121. You can also write to ASBMB, FASEB, and the broader your member of Congress through the medical research community. House Web site. Go to www.house.gov

www.asbmb.org July 2007 and click on the “Write your represent- of that time at home is spent meet- issue). It should be up on the ASBMB ative” link at the top left of the screen. ing with constituents at one of their Web site by the time you receive this You can also reach your member of district offi ces. Members of Congress issue of ASBMB Today, and you can Congress through the ASBMB Web are home from Th ursday evening to either watch it on the site or down- site (www.asbmb.org); go to the public Monday morning, pretty much every load it from the Web site to a DVD aff airs page and click on the “Write week. Congress usually takes August and watch it later. We will also have a your Member of Congress” link toward off and so your representatives will limited number of copies available to the top of the page. be in their districts a good bit of the send you if you would like to pursue Another way that you can get month. August might be a good time this option. involved more permanently, however, to try to meet with them. Why not To become a member of the Local is through ASBMB’s growing Local consider arranging to meet with your Advocates Network, send an e-mail Advocates Network. Th is group, now representative the next time he or she to me ([email protected]) or to over 300 strong, is comprised of is home? Th is can be easily arranged, ASBMB’s director of public aff airs, ASBMB members who have vol- and our public aff airs staff can help Pete Farnham ([email protected]), unteered to become active in their you with these appointments if you and volunteer to join. Th e critical piece congressional districts as advocates need advice. Students also make of information Pete needs to get you for biomedical and scientifi c research excellent ambassadors for biomedi- involved is your 9-digit home Zip code funding issues. It is not necessary to cal research. Th ey tend to be young, (i.e. the Zip code of where you live, have a great deal of political experi- enthusiastic, and idealistic, and this and thus, vote). Th is will allow us to ence to participate in this group; all attitude is usually catching. If you make sure you get placed in the cor- you need to do is agree to contact your don’t want to go to a meeting with rect congressional district. Of course, member of Congress and Senators your member along, bring a student if you already know who your member occasionally. You will be most eff ective or two along as guests. Th ey’ll fi nd it a of Congress is, provide that piece of if you personally meet with your Con- very valuable experience. information as well. gressperson and get to know him/her. Another option is to invite your In short, this is a very diffi cult We will notify you when particularly member of Congress to visit your lab time for biomedical research, and the important issues come up in Con- or institution and show him or her NIH in particular. Th e agency needs gress, but you should not feel limited the great work you do on behalf of the your help, and anything you can do to responding only to our occasional American people. Th ese are usually to assist us in keeping the pressure on messages. Taking the initiative to con- very nice events, and they pay off big the Congress to begin to restore NIH tact your Representative or Senators is time in the long term. At a minimum, funding levels to what they were in important as well. off er the invitation; they surely won’t 2003 would be most helpful. In addition, don’t limit yourself to come if they are not invited! only phone calls or e-mails. A per- ASBMB has prepared a training sonal visit is a very important tool, DVD on how to conduct a meeting particularly if it is done at home in the with a member of Congress (see the Congressional district. A large portion article about the DVD, also in this

July 2007 ASBMB Today 3 fr om the editor ASBMB Today Welcomes New Editorial Board Members

As part of an ongoing eff ort to make ASBMB Today the • ASBMB Past President Bettie Sue Masters of the Uni- highest quality magazine for our members in the U.S. and versity of Texas Health Science Center at San Antonio. around the world, we have recently expanded the mag- • JBC Associate Editor Luke A. O’Neill of Trinity azine’s Editorial Advisory Board to more closely refl ect College, Dublin. the Society’s members and interests. Th ese new members • JBC Editorial Board member Duanqing Pei, professor include representatives from Europe and Asia, the biotech and deputy director general at the Guangzhou Institute community, and the National Postdoctoral Association. of Biomedicine and Health. We have also added editors from ASBMB’s three jour- • JLR Associate Editor Carol C. Shoulders of the Medical nals–the Journal of Biological Chemistry (JBC), Molecular Research Council Clinical Sciences Centre, London, England. & Cellular Proteomics (MCP), and the Journal of Lipid • ASBMB Past President Robert D. Wells, Robert A. Welch Research (JLR). Endowed Chair in Chemistry at Texas A&M University. Th is newly-expanded ASBMB Today Editorial Advi- Th e Editorial Advisory Board will be chaired by ASBMB sory Board is comprised of: Today Consulting Editor Alex Toker of Harvard Medical • Mike Autry, postdoctoral fellow at the University of School. Th ese board members will act as Minnesota, president of the University of Minnesota a primary source of material for Science Postdoctoral Association, and member of the National Focus articles and will also be involved in Postdoctoral Association Policy Committee. generating other types of articles of interest • ASBMB Education and Professional Development to ASBMB members. Committee member Greg P. Bertenshaw of Correlogic Th is issue of the magazine also marks Systems, Inc. the launch of a new format for our Sci- • Craig E. Cameron, Paul Berg Professor ence Focus articles. Th ese articles will Robert D. Wells of Biochemistry and Molecular Biology now feature high profi le scientists, with at Pennsylvania State University, JBC Edi- in-depth interviews about their work and torial Board member and member of the their contributions to the fi eld. Some of A SBMB Minority Aff airs Committee. these featured scientists will be prominent • Irwin Fridovich , Emeritus James B. researchers, whereas others will be new Duke Professor of Biochemistry at the and emerging “hot” junior scientists who Duke University Medical Center. will shape biomedical research and emerge Mike Autry Carol C. Shoulders • ASBMB Past President and current as the leaders of tomorrow. From time to JBC Associate Editor Rich ard Hanson time we will also feature articles based on of Case Western Reserve University recent journal articles as we have in past School of Medicine. issues of ASBMB Today. • MCP Editorial Board member Elizabeth A. Komives, professor of Chemistry and Biochemistry at the University of

Greg P. Bertenshaw California, San Diego. Nicole Kresge, Editor Duanquing Pei

Craig E. Cameron Irwin Fridovich Richard Hanson Elizabeth A. Komives Bettie Sue Masters Luke A. O’Neill

4 ASBMB Today July 2007 news from the hill 2008 Appropriations Bills Begin to Move BY PETER FARNHAM

arly June found several appropriations bills starting The full House Eto move in the House, and, in marked contrast to Appropriations previous years, the Labor/Health and Human Services Committee was (L/HHS) bill, which covers the National Institutes of tentatively sched- Health (NIH), was one of the fi rst out of the gate. In uled to consider recent Congresses, the L/HHS bill was always one of the bill on June 14, the last. Unfortunately, the news for NIH—at least so with House fl oor far—is not as good as we had hoped. action planned for late June. In NIH Appropriations Fall the past, the bill Short of Infl ation—Again has been conten- The relevant appropriations subcommittee marked up tious because it the L/HHS bill on June 7 and was able to provide only presents an oppor- an additional $750 million for NIH, translating to a 2.6% tunity for both increase over the fi scal year (FY) 2007 level. This was parties to highlight not related to any displeasure with NIH among subcom- their differences mittee members; rather, under the budget resolution, the over social issues, subcommittee received an allocation that, while better complicating debate. Obey has tried to steer clear of than last year’s, still did not allow for overly generous those issues so far, so there is a chance that debate funding increases for the agencies under its jurisdiction. on the bill will move smoothly, allowing the ambitious Under the bill, NIH received $29.65 billion, which schedule of completing work on all appropriations bills is about $750 million above the 2007 level. However, by the end of July to be met. the bill also increases the amount of the transfer from Speaking on behalf of FASEB, President Leo Furcht NIH to the Global HIV/AIDS fund from the $99 million in said “This is the fourth year we’ve seen a proposal for FY 2007 to $300 million in FY 2008, which means the NIH funding that fails to keep pace with infl ation. The net increase in the NIH budget is $549 million (1.9%) proposal is signifi cantly lower than the 6.7% increase over FY 2007. Subcommittee Chairman Dave Obey recommended by FASEB and the broader biomedi- (D-WI) claimed—somewhat debatably—that the cal research community. The fl at funding we have $750 million increase is the largest NIH increase in four experienced over the past several years has had a dev- years, although it is signifi cantly below the ASBMB’s astating effect on the scientifi c enterprise. Our best and request of $1.9 billion, or a 6.7% increase. The alloca- brightest young scientists are being discouraged from tion is also below biomedical infl ation (usually in the pursuing research careers, the pace of discovery has 3–4% range). You may remember that 6.7% increases slowed, and we have eroded our ability to take advan- for each of the next three years are needed to erase tage of the wealth of scientifi c opportunities produced NIH’s losses since the doubling was completed in 2003 by our investment in NIH.” and NIH began to suffer infl ation-fueled cuts. Furcht explained that the scientifi c community Obey noted that the bill falls short of the FY 2005 fund- ultimately would like a sustainable model for research ing levels, adjusted for infl ation and population growth. funding. “To continue our astonishing progress in science He pointed out that the programs funded by the L/HHS and medicine, we need to recoup the losses caused by appropriations bill are “the last best hope for people infl ation during the period of fl at funding,” he said. “Our without means and without advantage” and cited several message is simple: a 6.7% increase each year for the “defi cits” in health, education, and labor programs, admit- next three years would get NIH back on track to restoring ting, “We can’t erase those defi cits in a single year.” the erosion due to infl ationary losses. FASEB feels

July 2007 ASBMB Today 5 news from the hill continued

strongly that the best messengers to explain the value of Senate number for NIH as a way to provide additional biomedical research and why it is so necessary to provide funds to the agency. sustainable funding are the scientists working in labs, It is important to keep in mind that we are only at the making breakthrough discoveries.” start of the appropriations process for FY 2008, and we Several reasons have been offered as to why the hope that we can improve the House number as the increase for NIH is less than we had expected. First, Presi- summer continues. dent Bush recommended signifi cant increases for two pro- grams that are very important to Democrats–a $2.5 billion NSF Numbers Looking Good increase for Pell Grants in FY 2008 and a $1 billion In sharp contrast to the early outlook for NIH, the National increase for the No Child Left Behind program. The House Science Foundation (NSF) has done quite well at the put signifi cant money into these programs in order not to subcommittee level. Markup in the Commerce, Justice, be outdone by the President’s spending proposals— Science, and Related Agencies subcommittee occurred $2 billion more for Pell Grants in FY 2008 and $2 billion on June 11, and NSF was treated very well. The over- more for the No Child Left Behind program in FY 2008. all total for the agency is $6.509 billion, an increase of Therefore, essentially the fi rst $4 billion of the new money $80 million over President Bush’s request and close to the subcommittee received under the budget resolution $600 million over FY 2007 (about 10%). The Research and over FY 2007 levels was taken up by those two programs. Related Activities account, which funds most of the core Second, House appropriators expect Sens. Tom research at the agency, received $5.139 billion, 7.9% over Harkin (D-IA) and Arlen Specter (R-PA) to provide a last year. The Education and Human Resources account signifi cant increase for NIH when the L/HHS bill is taken received $822.6 million, an increase of $124.6 million up in the Senate. If the Senate does so, it is not likely to over FY 2007. The other major accounts at NSF—Major provide comparable increases for many of the programs Research Equipment and Facilities Construction, Agency the House regards as priorities. Thus, during conference Operations, the National Science Board, and the Offi ce negotiations, the House will be able to advocate for of Inspector General—were all funded at the President’s those programs for which it recommended higher fund- requested level. Full Committee markup is scheduled for ing levels (when compared to the Senate) as well as (we mid-June. hope) support the expected higher Senate number for NIH. During conference negotiations in previous years, the House has been willing to accede to the higher Peter Farnham, CAE, is ASBMB’s public affairs offi cer.

Training DVD on Meeting scientists make just about every common mistake that a group can make, including showing up late, failing to introduce them- with Members of Congress selves, behaving discourteously, not having a specifi c request, The ASBMB Public Affairs Advisory Committee (PAAC) has and arguing. Following this meeting, a narrator walks the viewer produced a training DVD called “Meeting with Your Congress- through a critique of the many mistakes made. Then, a second man: A Guide for the Grass Roots Advocate.” The DVD, less meeting is shown where everything goes much more smoothly. than 20 minutes long, was fi lmed in March and debuted at the Again, the narrator critiques the second meeting, pointing out ASBMB annual meeting in Washington, D.C., in early May. what was done properly. The PAAC decided to produce the DVD because of feed- The DVD was fi lmed on location at ASBMB headquarters back it had received from many ASBMB members, who said and features actors from the ASBMB and FASEB public that while they were interested in helping advocate for ASBMB affairs staffs, as well as PAAC members Robert Palazzo interests as well as those of biomedical research, they had and Robert D. Wells. The DVD was produced by Bayou City no idea how to go about meeting with a member of Congress Productions in Houston, Texas. It is available for viewing and and needed some guidance. The committee thus decided that downloading on the ASBMB Web site under the “What’s New” a DVD showing how a meeting with a member of Congress column. A limited number of copies of the DVD are also avail- should go would be useful. able; please let us know if you would like to receive one. The DVD shows two meetings between a fi ctional member We hope all of you will take 20 minutes to view the of Congress and a delegation of biochemists from the fi ctional DVD, particularly if you are planning on getting involved in Eastern Virginia State University. In the fi rst meeting, the visiting advocacy issues.

6 ASBMB Today July 2007 washington update House Version of Farm Bill Proposes Major Changes for USDA Research BY CARRIE D. WOLINETZ

he House Agriculture Subcommittee on • An eighth institute or a sneaky way to fund T Conservation, Credit, Energy, and Research IFAFS? It’s unclear whether the section authorizing the marked up four titles of the 2007 Farm Bill, including “Institute for Future Food and Agricultural Systems” the research title. Oddly, the House bill appeared to be is simply a mistype of “Initiative for Future Agricultural a hybrid of several proposals to restructure agricultural and Food Systems” (IFAFS), which currently exists, research at the U.S. Department of Agriculture (USDA) or a new entity. Although IFAFS has been authorized that had been put before Congress. Although this pro- for a long time, it has essentially never been funded posal itself is likely to undergo tremendous modifi cation, because it is not supported by appropriators. This it does illustrate the potential for increasing, changing, section takes 30% of appropriated funds from National or improving the competitive research portfolio at the Research Initiative (NRI) and uses it to fund IFAFS USDA. FASEB is working with society members to activities while taking the authorized money for IFAFS develop a position on the Farm Bill and to keep the and giving it to NRI. Essentially, this would result in real research community apprised of changes. Some of the money being lost from competitive research at NRI details of the House bill are included below: and replaced with non-existent dollars. What’s espe- • Requires President Bush to submit a single cially odd about this is that transfer is not refl ected in line item in the annual budget for all agriculture the reauthorization level for NRI listed in the staff sum- research, extension, and related activities: It is mary as the same $500 million (although no number is unclear whether this is government-wide, agriculture- cited in the actual bill). related research or only at USDA; would nutrition • Confusing authorization levels: The research title research at the National Institutes of Health (NIH) count, is striking in its lack of authorization levels, despite for example? Also uncertain is the motive behind this; creating a host of new entities and programs. There is this an attempt to gather diffi cult information or an is either no funding level mentioned or odd language effort to hide programs behind one large item? such as “shall fund each research institute through • Restructuring of USDA research: This bill would appropriations available to the various agencies within create a new Agriculture Research Institute, which the mission area.” Only earmarks for targeted pro- is actually a collective of six topic-specifi c institutes grams, reauthorized programs, or what appears to be whose staff is limited to 30 positions total (not per an inserted stand-alone bill on viruses (see next bullet) institute) including six high profi le institute directors. list authorization levels. Although tasked with coordinating and directing all • Live virus bill: Based on its structure, it seems that research activities of the USDA in an “integrated, mul- this section is a non-introduced stand-alone bill that tidisciplinary, interdisciplinary, interagency, and inter- has been inserted. It gives the Secretary of Agricul- institutional manner,” apparently this doesn’t include ture the authority to create a list of viruses that could extramural, competitive, earmarked, or new research cause harm to livestock and prohibit their transporta- programs because the bill also creates a National tion, storage, importation, use, etc. without special Institute for Food and Agriculture (NIFA), an initiative permission. Although there is language to prevent supported in other venues by FASEB. Although the this bill from applying to viruses on the USDA’s select bill says NIFA shall administer “all competitive grants,” agent list, it does make one wonder: If we already it also reauthorizes the National Research Initiative have a select agent law and list that does this, why Competitive Grants Program and earmarks quite do we need another? a few separate competitive research programs (bioenergy, specialty crops, etc.). Carrie D. Wolinetz is with the FASEB Offi ce of Public Affairs.

July 2007 ASBMB Today 7 2008 annual meet ing Biomolecular Catalysis BY VERN SCHRAMM AND SUSAN MARQUSEE

rotein-protein interactions, macromolecular dynam- Research Institute, will share his studies on glycoproteomic Pics, protein and nucleic acid folding patterns, and mapping for drug discovery. Synthesis of DNA in all organ- dynamics in catalysis are the leading edge of the broadly isms requires a balanced supply of deoxyribonucleotides, defi ned fi eld of biomolecular catalysis, one of the 15 ses- and Joanne Stubbe, Massachusetts Institute of Tech- sion themes to be featured at the 2008 ASBMB Meeting nology, will emphasize a new paradigm for inhibition of in San Diego, April 5-9. Molecular dynamics occur at all ribonucleotide reductases by altering subunit interactions. size and time scales in the atomic organization of biologi- Computational chemistry, mutational analysis, and applica- cal molecules. Functional macromolecules have evolved to tions of transition state theory to enzymatic catalysis lead harness this dynamic at both macro- and microscales to to the inescapable conclusion that both global and local optimize biological organization and function. dynamic motions of proteins are essential in enzymatic Organizers Susan Marqusee, catalysis. Schramm will describe an intersection of dynam- professor of Molecular & Cell Biol- ics and thermodynamics in transition state formation and ogy, University of California, Berkeley, inhibitor design. Several of the transition state analogues and Vern L. Schramm, professor of from this research program are in clinical trials for cancer Biochemistry at the Albert Einstein and autoimmune diseases. College of Medicine, have assembled Perhaps no fi eld has matured more in the past decade leaders in diverse areas of this funda- than that of signal transduction. The realization that mentally critical aspect of biochemis- protein-protein transient interactions dominate most of

Susan Marqusee try and molecular biology. the interactions controlling cell division, development, Protein-protein interactions and differentiation, and growth has generated intense interest multifunctional proteins have arisen in exploring protein interfaces. In the session “Energetics from the biological need to cross and Design,” Tanja Kortemme, University of California, water-insoluble barriers, protect reac- San Francisco, will discuss the novel design features tive metabolic intermediates, eliminate of protein-protein interface contacts. Vincent J. Hilser, toxins, and regulate protein function. University of Texas Medical Branch, will describe the In the session “Protein Interactions in design implications for an ensemble-based view of pro- Catalysis,” Ruma Banerjee, University teins. Susan Marqusee, University of California, Berkeley, of Michigan, will describe “protein will explain how to manipulate and detect the protein Vern Schramm

escorts” for vitamin B12 assimila- energy landscape as a protein folds to stable or not so tion, an essential dietary cofactor. stable states. Susan M. Miller, University of California, San Francisco, Protein and nucleic acid folding trajectories are prob- will describe the unusual reactions catalyzed by mercuric lems of near infi nite complexity, yet folding occurs along reductase, essential for converting toxic oxidation states specifi c energetic landscapes controlling the specifi c of mercury to less toxic forms. Protein-protein interactions ensembles and their dynamics. These topics are explored are essential in the pathway of purine de novo synthesis, in the fourth session of this meeting theme with a focus and new advances in understanding the function of these on “Macromolecular Folding and Fluctuations.” A. Joshua multifunctional proteins will be described by Steven J. Wand from the University of Pennsylvania will discuss Benkovic of the Pennsylvania State University. the surprising role for conformational entropy in molecular The essential role of protein catalysts in disease states recognition by proteins. Dynamics and folding in nucleic has made enzymes essential targets both for academic acids have been probed with ever increasing molecular research and the pharmaceutical industry. In the session resolution, and Michael Brenowitz from the Albert “Enzymes as Drug Targets,” Chi-Huey Wong, Scripps Einstein College of Medicine will describe rapid footprint

8 ASBMB Today July 2007 technology as a step towards single nucleotide resolution It will not escape the prudent reader that the meeting in the RNA folding problem. Our perspective on protein theme of Biomolecular Catalysis is tightly interconnected folding is often clouded by the differences in using defi ned with other themes of the meeting. Chemical Biology, RNA, experimental conditions compared to those in the cell. Metabolism, Signaling, and Molecular Dynamics are all rep- Lila M. Gierasch from the University of Massachusetts, resented here as well as being the focus of other themes Amherst, will explore her fi ndings with us in her studies on for the 2008 ASBMB Meeting. This structure provides high the infl uence of the cellular environment on protein folding quality scientifi c sessions throughout the meeting. We look and stability. forward to seeing you in San Diego.

Biomolecular Catalysis, • Targeting Purine Salvage in Cancer and Malaria, Folding, and Design Vern L. Schramm Thematic Meeting Symposium: Energetics and Design • Design of Selective and Multispecifi c Protein Interfaces, Organizers: Susan Marqusee, University of California, Berkeley, Tanja Kortemme and Vern Schramm, Albert Einstein College of Medicine • Design Implications for an Ensemble-based View of Proteins, Symposium: Protein Interactions in Catalysis Vincent J. Hilser • Enzyme and Escort Service in B12 Assimilation, Ruma Banerjee • Manipulating and Detecting a Protein’s Energy Landscape, • The Mercuric Reductase System, Susan M. Miller Susan Marqusee • Protein Interactions in de novo Purine Synthesis,

Steven J. Benkovic Symposium: Macromolecular Folding and Fluctuations Symposium: Enzymes as Drug Targets • A Surprising Role for Conformational Entropy in Molecular • Glycosyltransfer Enzymes as Targets for Glycoproteomic Recognition by Proteins, A. Joshua Wand Mapping and Drug Discovery, Chi-Huey Wong • A Step Toward Solution of the RNA Folding Problem, • A New Paradigm for Inhibition of Ribonucleotide Reductases: Michael Brenowitz Enhanced Subunit Interactions with Substoichiometric amounts • The Infl uence of the Cellular Environment on Protein Folding of Gemzar 5'- diphosphate, Joanne Stubbe and Stability, Lila M. Gierasch

July 2007 ASBMB Today 9 2008 annual meet ing Genome Dynamics: Replication, Recombination, and Damage Response BY PETER BURGERS AND TOM ELLENBERGER

utational drift of the genome is held in check by eukaryotic cells that alter the functionality of the replication Maccurate replication and DNA repair mechanisms. fork or cause a temporary inhibition of cell cycle progres- These essential functions are in turn regulated by cell cycle sion for repair of DNA damage to be completed before checkpoints and other DNA damage responses that mobi- advancing to the next phase in the cell cycle. David Orren lize repair enzymes or trigger programmed cell death when (University of Kentucky) is interested in the function of irreparable damage ensues. Although DNA damage can the WRN and BLM DNA helicases. Patients with Werner result from exposure to environmental toxins, reactions with or Bloom syndrome are defective for helicase function, endogenous metabolites and the stalling of replication forks show defects in genome stability, and are cancer-prone. can cause more pervasive problems, resulting in covalent He will discuss the roles of these DNA helicases in the modifi cations and DNA strand stabilization of stalled replica- breaks. The genome dynamics tion forks, in the resolution of theme of the 2008 ASBMB Meet- replication blockage, and in the ing will feature a rich menu of talks maintenance of telomeres. Two covering structures, enzymatic talks in this session will discuss mechanisms, and regulation of the biochemical function of DNA replication and repair proteins, checkpoint proteins that link DNA complexes, and pathways. damage to progression of the cell The “DNA Replication Mecha- Tom Ellenberger (left) and Peter Burgers. cycle. Peter Burgers (Washington nisms” session will focus on factors University) will discuss how the that function in the regulation of initiation and termination PCNA-like checkpoint clamp recognizes DNA structures of DNA replication. Anja Bielinsky (University of Minnesota) that are formed during DNA repair. Loading of the check- will discuss how the eukaryotic replication initiation protein point clamp onto these DNA structures causes activation Mcm10 is switched from an initiation mode into an elongation of the ATR kinase that propagates the signal downstream mode by ubiquitination. While unmodifi ed Mcm10 binds DNA leading to inhibition of the CDK kinases that drive the cell polymerase ␣ and promotes initial primer formation, its ubiq- cycle. Karlene Cimprich (Stanford University) has studied uitinated form binds proliferating cell nuclear antigen (PCNA), checkpoint function in Xenopus extracts. Such extracts and this form may recruit PCNA to the primer terminus during faithfully reproduce DNA replication and its control and are lagging strand DNA replication. Nicholas Dixon (Wollongong amenable to biochemical analysis. She will present studies University) has determined how the polarity of binding of the elucidating the DNA structures that link damaged replica- Escherichia coli replication termination protein Tus to its ter tion forks to cell cycle checkpoints. sequence allows it to block a replication fork traveling in one The “DNA Repair Mechanisms” session will feature direction but not in the opposite direction. Polar binding of the biochemical mechanisms of DNA repair reactions in a Tus makes it operate as a “molecular mousetrap” captur- broad variety of damage-specifi c responses. Tom Ellen- ing single-stranded DNA as it is being unwound during fork berger (Washington University, St. Louis) will describe movement. Laurie Kaguni (Michigan State University) will several protein-protein interactions in the nucleotide describe a close-up view of the mitochondrial DNA replication excision repair (NER) pathway that are essential for the fork, including the interactions that govern high fi delity mito- removal of helix distorting lesions. Small molecule inhibi- chondrial DNA replication and molecular defects associated tors of these interactions are being developed to dissect with dysfunction of the mitochondrial replication apparatus. alternative repair pathways that share components of the The “DNA Damage Response and the Cell Cycle” ses- NER pathway. Repair proteins that participate in multiple sion will focus on DNA damage response mechanisms in pathways of excision repair may represent control nodes

10 ASBMB Today July 2007 for differential regulation of alternative pathways. Manju of California, Davis) will describe studies of the transition Hingorani (Wesleyan University) is examining how muta- between the central reaction of recombination—the search tions resulting from replication errors are corrected in for homology search and DNA strand invasion—and the E. coli and Saccharomyces cerevisiae by mismatch repair priming of DNA synthesis by the invading DNA 3'-end. The (MSH) proteins. The MSH proteins recognize defects in Snf2 family motor protein Rad54 promotes DNA strand DNA base pairs and bind to MLH proteins that signal invasion and the subsequent turnover of the Rad51 recom- downstream events ultimately resulting in DNA repair. binase, exposing the end of the invading DNA strand for Steady-state and presteady-state kinetic studies of DNA synthesis. This transition to DNA synthesis is critical DNA damage recognition and processing events will be and should only occur when the strand invasion occurred described, addressing the dynamics of binding and signal- at the correct site, increasing the fi delity of DNA repair by ing during the repair of mismatched base pairs. John Hunt homology-dependent recombination pathways. (Columbia University) will describe crystallographic and These principal talks will be complemented with short biochemical studies of E. coli AlkB, which was recently talks selected from submitted abstracts in these areas. shown to remove aberrant methyl groups from DNA in a We look forward to many fruitful discussions in the ever multistep reaction coupled to the oxidation of 2-oxoglutar- developing fi eld of genome dynamics. ate. His work has demonstrated a structural plasticity of the enzyme that accommodates a diverse group of meth- ylated bases as substrates. The functions of eight mam- Genome Dynamics: malian paralogues of AlkB (ABH1-8) are being explored. Replication, Recombination, In the “Double-stranded Breaks and DNA Recombi- nation” session, Michael Cox (University of Wisconsin) and Damage Response will describe the mutational spectra of E. coli strains that Thematic Meeting were selected for extreme resistance to ionizing radiation Organizers: Peter Burgers, Washington University, and (enough to introduce more than 100 double strand breaks Tom Ellenberger, Washington University per genome). The full genomics sequences of independent Symposium: DNA Replication Mechanisms strains exhibiting 2,000- to 10,000-fold resistance reveal • Dynamics of the Mitochondrial Replication Fork, Laurie Kaguni a surprising diversity of independent mutations, some of • Termination of DNA Replication in E. coli, Nick Dixon which are likely to enhance the processing of double-strand • Role of Mcm10 in Yeast DNA Replication, Anja Bielinsky DNA breaks. In collaboration with John Battista (Louisiana Symposium: DNA Damage Response and the Cell Cycle State University), the functionally important genes are being • Clamp-ATR Kinase Interactions in Checkpoint Function, identifi ed, which should reveal the complexity of cellular Peter Burgers responses to this potentially lethal form of DNA dam- • Role for the Werner Syndrome Protein (WRN) in Replication age. Tanya Paull (University of Texas, Austin) is studying Fork Regression, David Orren the mechanisms of DNA double-strand break repair and • DNA Damage Checkpoints in Xenopus Extracts, Karlene break induced signaling pathways in eukaryotic cells. Her Cimprich talk will focus on the Mre11/Rad50/Nbs1 (MRN) complex, Symposium: Double-Stranded Breaks which plays a central role in recognizing and repairing DNA and DNA Recombination breaks. The MRN complex also recruits and activates • Rapid Evolution of Radiation Resistance in Escherichia coli, ATM, the protein kinase that activates a damage-induced Michael Cox cell cycle checkpoint that leads to apoptosis. Biochemical • Mechanism of Recombination in Eukaryotes: Some studies that reveal the molecular basis of MRN and ATM Remodeling Required, Wolf-Dietrich Heyer functions and their interactions will be related to obser- • MRE11-RAD50-NBS1 Complex and Double Strand Break vations of DNA repair and signaling in eukaryotic cells. Repair, Tanya Paull Homologous recombination is a high fi delity strategy for the Symposium: DNA Repair Mechanisms templated repair of complex forms of DNA damage, includ- • Structural Insights in Nucleotide Excision Repair, Tom Ellenberger ing double-stranded DNA breaks and interstrand cross- • Mopping Up after Messy Polymerases, Manju Hingorani links. Moreover, recombination supports DNA replication • Oxidative DNA Repair by AlkB Family Metalloenzymes, in the recovery of broken replication forks and the repair of John Hunt gaps caused by fork stalling. Wolf-Dietrich Heyer (University

July 2007 ASBMB Today 11 2008 annual meet ing Dynamic Chromatin—Chromosomes in Action BY BRAD CAIRNS AND DANESH MOAZED

n recent years, remarkable progress has been made in alternative chromatin states. The chromatin dynamics Iour understanding of chromatin dynamics–the con- theme addresses these areas and will be divided into struction and remodeling of specialized chromosomal four sessions: 1) “Chromatin Regulation of DNA Repair, domains to regulate diverse chromosomal processes. Recombination, and Genome Stability” (chair: Xuetong Researchers leading this progress will be featured during Shen, University of Texas M. D. Anderson Cancer Center); the “Dynamic Chromatin and Gene Expression” theme at 2) “Chromatin Structure in Gene Activation” (chair: Yang the 2008 ASBMB Meeting. Shi, Harvard Medical School); 3) “Chromatin Changes Chromosomes are complex and dynamic and are in Development” (chair: Brad Cairns, University of Utah/ partitioned into domains of differing chromatin charac- Howard Hughes Medical Institute); 4) “Non-coding RNAs ter through multiple mechanisms. First, in addition to in Gene Regulation and Chromosome Structure” (chair: canonical nucleosomes, histone variant nucleosomes are Danesh Moazed, Harvard Medical School). placed at particular locations such The session “Chromatin Regulation of DNA Repair, as centromeres to confer specialized Recombination, and Genome Stability” will address how functions. Second, covalent modifi ca- DNA repair systems fi nd sites of DNA damage within tions (such as acetylation or methyla- repressive chromatin, alter chromatin to facilitate repair, tion) on nucleosomes attract proteins and halt the cell cycle to enable repair. Shen will discuss important for establishing the compo- how nucleosome remodeling factors alter chromatin struc- sition and character (silent or active) ture during DNA repair. Jim Haber (Brandeis University) will of the gene or region. Third, nucleo- discuss how the cell cycle and the DNA repair process are Brad Cairns somes are mobilized and/or ejected coordinated through checkpoint pathways. Jennifer Ger- by complexes termed “remodelers” ton (Stowers Institute for Medical Research) will discuss to assume the correct positions machinery that helps chromosomes associate to facilitate and density on the DNA, which can recombination and DNA repair. facilitate or impede processes such as How genes transition between repressed and active transcription. Additionally, the proc- states will be addresses in the session “Chromatin Struc- ess of transcription itself, as well as ture in Gene Activation.” An important part of this transi- noncoding RNA molecules derived tion involves the methylation and demethylation of histone from transcription, can directly affect proteins, which guides the binding of transcriptional Danesh Moazed the chromatin structure in a region. regulatory factors. Shi will discuss the identifi cation and These four processes work together characterization of histone demethylases and their roles to both build and alter particular chromatin domains: to in transcriptional regulation. Nucleosomes are assembled help form centromeres/kinetochores, to protect DNA at at gene promoters to facilitate repression and ejected to chromosome ends (telomeres), to facilitate recombination, facilitate activation. Jessica Tyler (Colorado State Univer- to regulate transcription, and to localize and assist DNA sity) will describe new insights on the factors that regulate repair machinery. the dynamic nucleosome assembly and disassembly at Current research in chromatin dynamics is focused genes. A key question in transcriptional regulation is how on understanding how chromatin regulatory factors work chromatin modifi cations help guide transcriptional states. together (or antagonistically) to establish and maintain Richard Young (Massachusetts Institute of Technology) will chromatin domains, to form boundaries between chro- discuss new data on how particular chromatin modifi ca- matin domains, and to coordinate transitions between tions help poise genes for different future transcriptional

12 ASBMB Today July 2007 states, a process of particular importance in embryonic Talks in the session “Non-coding RNA in Gene Regula- stem cells, which are pluripotent. tion and Chromosome Structure” will focus on the roles How chromatin structures help guide development is of both large and small noncoding RNAs in regulation of featured in the session “Chromatin Changes in Develop- gene expression and chromatin structure. In fi ssion yeast, ment.” One of the most fascinating examples of chro- components of the RNA interference (RNAi) are required matin specialization during development involves the for the assembly of large heterochromatic domains at establishment and maintenance of the X chromosome repetitive DNA regions that surround centromeres. Moazed inactivation in female mammals. Jeannie Lee (Massachu- will present data on biochemical analysis of RNAi and het- setts General Hospital) will report new information on the erochromatin complexes that work together to assemble function of noncoding RNAs and chromatin regulators in and maintain heterochromatin. Plants have perhaps the the X inactivation process. During meiosis, homologous most remarkable and extensive noncoding RNA regulatory chromosomes must be intimately paired to ensure proper system with well established roles for small RNAs (sRNAs) chromosome segregation. Abby Dernburg (University of in regulation of both DNA and histone methylation. Craig California, Berkeley) will discuss recent breakthroughs Pikaard (Washington University) will speak about the role of involving the identifi cation of pairing sequences and sRNAs in silencing of large chromosome domains involved associate proteins that orchestrate meiotic chromosome in nucleolar dominance in Arabidopsis. The reverse tran- dynamics. Other key questions at the chromatin devel- scriptase telomerase adds simple repetitive DNA elements opment interface include the chromatin packaging and to chromosome ends using a non-coding RNA cofactor as DNA methylation status of germ cells (sperm and eggs) the template to compensate for DNA loss during replica- and how these states change during fertilization and early tion. Kathleen Collins (University of California, Berkeley) will development. Cairns will discuss recent progress in this report new progress on understanding how the telomerase area using zebrafi sh as a model system. ribonucleoprotein complex is assembled and regulated.

Dynamic Chromatin and • Transcriptional Regulation by Chromatin Assembly and Disassembly, Jessica Tyler Gene Expression • ES Cell Pluripotency and Chromatin, Richard Young Thematic Meeting Symposium: Chromatin Changes in Development Organizers: Brad Cairns, Howard Hughes Medical Institute/ • Chromosome Pairing during Meiosis, Abby Dernburg University of Utah School of Medicine, and Danesh Moazed, • Chromosome Marking and Modifi cation during Zebrafi sh Harvard Medical School Development, Brad Cairns Symposium: Chromatin Regulation of DNA Repair, Recom- • X Chromosome Inactivation, Jeannie Lee bination, and Genome Stability Symposium: Non-coding RNAs in Gene Regulation and • Chromatin Responses in DNA Repair, Xuetong Shen Chromosome Structure • Chromatin and DNA Damage Checkpoints, Jim Haber • Non-coding RNAs in S. pombe, Danesh Moazed • Chromatin Cohesion and Recombination, Jennifer Gerton • siRNA Involvement in Multi-megabase Chromosomal Symposium: Chromatin Structure in Gene Activation Silencing in Nucleolar Dominance, Craig Pikaard • Histone Methylation and Demethylation in Gene Regulation, • Telomerase Ribonucleoprotein Assembly and Activity, Yang Shi Kathleen Collins

July 2007 ASBMB Today 13 2008 annual meet ing Chemical Biology BY ANNA MAPP AND LAURA KIESSLING

efi ning the rapidly evolving fi eld of chemical biology California, Berkeley) is focused on combining imaging and Dis challenging. Perhaps the diffi culty arises because nanoscience methods to explore how the spatial arrange- of the prevalence of interdisciplinary research that inter- ment of signaling receptors controls output responses. He weaves ideas and methods from biology and chemistry. uses nanopatterned substrates to organize the signaling Therefore it is appropriate that the chemical biology theme molecules inside living cells into defi ned geometries. With of the 2008 ASBMB session focuses on neither a general new developments in surface science, he can control the research topic nor the application of a key method—rather, number of receptors in a signaling cluster, which makes it it showcases a broad array of research at the interface of possible dissect mechanisms of signal amplifi cation. chemistry and biology. The topics of the individual sessions A forefront area of biology is understanding the molecular range from imaging to neuroscience details underlying nervous system function. Chemical biol- to small molecule control of cellu- ogy approaches to the problem can address fundamental lar processes. The common thread questions in this area from a new perspective. The second linking these areas and the individual session, “Chemical Perspectives in Neurobiology,” highlights presentations is the ability to explore the benefi ts of this approach. Baldomero Olivera (University biological questions using molecules of Utah) takes advantage of the potent and selective venom (and assemblies) not found in nature. peptides from cone snails that show remarkable selectiv- The contributions of chemical ity for individual neuroreceptor classes. These peptides biology to imaging cellular proc- are then used to decipher the physiological roles of the Anna Mapp esses have been dramatic and wide receptors in signaling and, ultimately, to develop novel drug ranging. Since the introduction of candidates. Rather than using peptides or proteins from the fl uorescent calcium ion sensors, nature, Dennis Dougherty (Caltech) incorporates unnatural appreciation of the value of using amino acid residues into specifi c neuroreceptors to probe designed compound to visualize the structures and mechanisms of ion channels. In con- key signaling pathways has grown. trast, Ehud Isacoff (University of California, Berkeley) uses Chemical biology continues to make environmentally sensitive fl uorescent dyes attached in a critical contributions to this area, and site-directed manner to membrane proteins to report local the chemical biology session, entitled protein motion during functional rearrangements. He applies Laura Kiessling “New Strategies for Imaging Protein this method to ion channels to understand the mechanism Localization and Dynamics,” highlights by which they sense physiological signals and gate. some recent developments. One challenge is the ability to The use of bioactive small molecules to study protein selectively illuminate proteins based upon their conforma- structure and function has a long and storied history in tion and/or functional state. Jin Zhang (Johns Hopkins chemical biology, and the third session, “Small Molecule University) has developed a novel approach to visualizing Control of Protein Folding and Assembly,” spotlights new kinase activity in living cells. Her method combines protein directions in this arena. Two of the speakers, Aseem Z. engineering and Forster Resonance Energy Transfer to Ansari (University of Wisconsin-Madison) and Anna Mapp report on the activity of those enzymes. Ron Raines (Uni- (University of Michigan), use small molecules to control the versity of Wisconsin, Madison) has developed another type assembly of multiprotein complexes. Ansari has identifi ed of probe for imaging; his group has designed a new class minimal interaction motifs from developmentally important of “latent” fl uorophores that are unmasked upon cellular transcription factors that can be used to nucleate and stabi- uptake. These can be used to follow internalization, as lize transcription factor complexes at gene promoters. Mapp illustrated by his studies exploring the cellular toxicity of has developed small organic molecules that mimic natural ribonucleases. The research of Jay Groves (University of transcriptional activators and, depending upon the context,

14 ASBMB Today July 2007 can be used to up- or down-regulate targeted genes in cellular systems by affecting transcriptional machinery Chemical Biology assembly. The fi nal speaker, Tom Muir (Rockefeller Univer- sity), has developed a general strategy for controlling the tim- Thematic Meeting ing of protein production within cells. His approach triggers Organizers: Laura L. Kiessling, University of Wisconsin- rapid production of the protein of interest because it relies on Madison, and Anna K. Mapp, University of Michigan small molecule responsive protein splicing. Symposium: New Strategies for Imaging Protein The fi nal session, “Chemical Probes and Their Use in Localization and Dynamics Identifying New Therapeutic Targets,” is focused on the types • Dynamic Visualization of Kinase Activity in Living Cells, of studies that are identifi ed with chemical biology—the use Jin Zhang of small molecule probes to explore biological systems. The • Latent Fluorophores for Biomolecular Imaging, speakers in this session will discuss how small molecule Ron Raines probes can illuminate and validate pathways with potential • Spatial Organization and the Mechanics of Cellular Signal therapeutic value. Randy Peterson (Harvard Medical School) Transduction, Jay Groves takes advantage of high throughput small molecule screens in zebrafi sh to identify modifi ers of organismal processes, Symposium: Chemical Perspectives in Neurobiology ranging from those in developmental biology to adult dis- • Using Conus Venom Peptides to Understand Nervous ease. Such screens have been used to identify novel small Systems and Discover Drugs, Baldomero Olivera molecules that modify the in vivo development of blood and • Neuroreceptors of the Nicotinic Class: Structure to the blood vessels and that serve as powerful tools to explore Rescue?, Dennis Dougherty the biology of blood and vascular diseases. Helen Blackwell • Optical Probing of Neuronal Membrane Proteins, (University of Wisconsin, Madison) also studies signaling, Ehud Isacoff but she focuses on bacteria. She is investigating quorum Symposium: Small Molecule Control of Protein Folding sensing (the process by which bacteria sense their popula- and Assembly tion density) by creating her own language of small molecule modulators. Compounds that interfere with bacterial com- • Cutting and Pasting Proteins in Vitro and in Vivo, Tom Muir munication could lead to the development of new classes of • Regulated Assembly of Transcriptional Complexes by antibiotics. Laura Kiessling (University of Wisconsin-Madison) Engineered Synthetic Ligands, Aseem Ansari is using synthetic molecules to elucidate and inhibit key steps • Dissecting Protein Complexes with Small Molecules, in the biosynthesis of the mycobacterial cell wall. Her studies Anna Mapp are providing insight into the synthesis of biological polymers Symposium: Chemical Probes and Their Use in in the absence of a template. They also suggest new targets Identifying New Therapeutic Targets for treatment of tuberculosis. • Zebrafi sh Chemical Biology–Discovering Modifi ers of The strategies and interdisciplinary approaches that will Development and Disease, Randall Peterson be described in the chemical biology sessions are applica- • Synthetic Ligands That Attenuate Bacterial Quorum ble to diverse systems. We anticipate that these sessions Sensing and Outcomes, Helen Blackwell will stimulate lively discussions and even new collabora- • Small Molecule Probes of Mycobacterial Cell Wall tions. We are looking forward to the meeting and hope to Assembly, Laura Kiessling. see you there.

July 2007 ASBMB Today 15 specialinteres t Impact Factor Page Rankled

BY VINCENT C. HASCALL‡1, JOHAN BOLLEN§, AND RICHARD W. HANSON¶1

a curiosity for authors interested in determining who is “Everything in life should be as simple as possible, reading their work. In many institutions around the world, but no simpler.” the perceived quality of the journals in which the research Albert Einstein is published is being used as a key indicator of the sci- entifi c quality of the research itself. Promotion within an Prologue organization is often based not only on the number of an Those of us who have used Google to search for items individual’s publications but also on the impact that these of interest cannot help but be amazed at its speed and publications have on research in their respective fi eld of accuracy. Somehow, it is able to list items of interest in biomedical science. Different methods are used to estab- an order ranging from the most important to the least lish impact, including letters and discussions with scien- important, and to do so for hundreds of thousands of tists in the fi eld. One presumption in the review process entries! The brilliance of Google lies a good deal in its is that the higher the impact of the journal in which the search algorithm, PageRank, named after one of its origi- research is published, the better the research, and that a nators, Larry Page. PageRank is based on the Perron- journal’s impact may be evaluated objectively in relation Frobenius Theorem (Google lists 96,000 entries for this to other journals. Thus it is of importance to evaluate the theorem), which is used extensively in algebraic graph current methods by which the relative status of journals, theory, to establish the importance of a specifi c site on and presumably the quality of the published research in the Web, thus “bringing order to the Web.” Since schol- these journals, is established. arly journals are now almost exclusively published on the The Impact Factor (IF), developed by Eugene Garfi eld Web, PageRank provides a potentially unique algorithm of the Institute for Scientifi c Information (ISI), has been to evaluate both the relative importance of journals and virtually the only method used to determine the rela- the individual papers published in these journals. In this tive impact of a scientifi c research publication. The IF article, we review the recent use of PageRank to evaluate is defi ned as the number of citations a journal receives 5,709 scholarly journals that are currently published on- over a two-year period divided by the number of line and compare the results to those found using the cur- research papers and reviews published in that journal. rently popular method for ranking journals, Impact Factor. A number of articles and commentaries have noted The Journal of Biological Chemistry (JBC) was ranked fi rst inherent problems with the IF. These include: 1) the by PageRank but 180th by Impact Factor. The possible inclusion of review articles; 2) the inclusion of citations in reason for this dramatic difference in journal ranking, and commentaries, errata, and letters in the numerator, but its potential signifi cance in ranking scholarly journals pub- not in the denominator of the equation used to calculate lished on the Web, is the subject of this article. the IF; 3) the highly skewed, non-Gaussian distribution of citations for the articles; and 4) the lack of considera- Impact Factor Versus PageRank tion of the size of the different fi elds of science repre- Evaluating the relative impact of a paper published in sented in different journals. It is of interest that 7 of the the biomedical science literature has become more than top 10 journals with the highest IF publish only reviews and are often cited by authors to broadly cover an ‡ From the Department of Biomedical Engineering, the area of research on a specifi c subject (Annual Reviews Cleveland Clinic, Cleveland, Ohio 44195, §Digital Library Research & Prototyping Team, Los Alamos National of Immunology is number one on the list, and Annual Laboratory, Los Alamos, New Mexico 87545, and the Reviews of Biochemistry is number two) (Table I). While ¶Department of Biochemistry, Case Western Reserve University no single factor can address all of these issues fairly, the School of Medicine, Cleveland, Ohio 44106-4935 question remains whether there is a method to evalu- 1Associate editors of the Journal of Biological Chemistry. ate the status of a journal that provides a different, more

16 ASBMB Today July 2007 TABLE I The highest ranking journals according to the 2003 ISI IF, Weighted PageRank, and Y-factor, reproduced from Ref. 3

3 2 ISI IF PRw 3 10 Y-factor 3 10 rank value Journal value Journal value Journal

1 52.28 ANNU REV IMMUNOL 17.46 J BIOL CHEM 51.15 NATURE 2 37.65 ANNU REV BIOCHEM 16.51 NATURE 47.72 SCIENCE 3 36.83 PHYSIOL REV 16.02 SCIENCE 19.92 NEW ENGL J MED 4 35.04 NAT REV MOL CELL BIO 13.77 PNAS 14.36 CELL 5 34.83 NEW ENGL J MED 8.90 PHYS REV LETT 14.14 PNAS 6 33.95 NAT REV CANCER 5.93 PHYS REV B 11.32 J BIOL CHEM 7 33.06 CANCER J CLIN 5.72 NEW ENG J MED 8.73 JAMA 8 30.98 NATURE 5.40 ASTROPHYS J 7.83 LANCET 9 30.55 NAT MED 5.39 CELL 7.22 NAT GENET 10 30.17 ANNU REV NEUROSCI 4.90 J AM CHEM SOC 6.26 PHYS REV LETT

balanced approach for specifi cally assessing research to citation data and calculate journal PageRank (PR) values contributions. In this regard, it is interesting that Eugene for the same journal citation network data now used to Garfi eld commented in a September 2005 speech in calculate the ISI IF? Chicago (1) that “In 1955, it did not occur to me that ‘impact’ would one day become so controversial. Like Using PageRank to Rank Journals nuclear energy, the impact factor is a mixed blessing, I What would happen if one were to rank all published sci- expected it to be used constructively while recognizing entifi c journals by their ISI IF and PR values calculated on that in the wrong hands it might be abused.” the basis of the same citation data? Bollen et al. (3) have The PageRank algorithm, which was developed by Brin answered this question by comparing the Impact Factor and and Page (2), forms the basis of the Google search engine PageRank methods using the ISI 2003 citation database now widely in use. A recent article by Johan Bollen and for 5,709 scientifi c journals (Fig, 1, Table I). Interestingly, the colleagues (3) describes the use of this algorithm to obtain a Journal of Biological Chemistry ranks fi rst of all scientifi c jour- metric that refl ects the prestige of a journal. They point out nals in the PageRank method (Fig. 1, horizontal green bar); that IF is in reality an indicator of the popularity of a journal it is in a class with Nature, Science, and the Proceedings since it refl ects the number of citations per article published of the National Academy of Sciences U.S.A., which publish over a two-year period, but it does not consider the relative articles in many different fi elds and serve other functions as prestige of the journals that cite the article. As noted by well. In contrast to its high score in the PageRank assess- Bollen et al. (3), “Google’s PageRank algorithm…computes ment, the Journal of Biological Chemistry ranks ~180th over- the status of a web page based on a combination of the all among the 5,709 journals in its IF (Fig. 1, vertical green number of hyperlinks that point to the page and the status bar). For comparison, the Annual Reviews of Biochemistry of the pages that the hyperlinks originate from. By taking ranks in second place on the IF scale but much lower than into account both the popularity and the prestige factors of JBC on the PageRank scale (Fig. 1, red bars). In an inter- status, Google has been able to avoid assigning high ranks esting extension of the concept of prestige and popularity, to popular but otherwise irrelevant web pages.” The term Bollen et al. (3) proposed a new metric for the evaluation of “popular but otherwise irrelevant” as used in this context scientifi c journals that takes into account both IF and refers to publications that review, but do not themselves PageRank, which they term the Y-factor. Thus, journals contain, the original scientifi c information being cited. that score highly on the basis of their Y-factor will be highly The Google PageRank algorithm is not limited to the ranked by either or both the IF and PageRank. As shown in Web; it can be applied to any network. If PageRank works Table I, the Journal of Biological Chemistry ranks number six so well for the Web hyperlink network, why not translate it among all journals in its Y-factor score.

July 2007 ASBMB Today 17 impact factor continued

Fig. 1. Scatter plot of 2003 ISI IF versus the Weighted PageRank (PRw).

cited the JBC 500 times and REV2 100 times. During the cicitationstations test period, the JBC published 1,000 papers, and REV2 10001000 published 100 papers. These ratios of citations of the JBC IF(JBC)=IF(JBC)= 1.51.5 500500 JBCJBC to a review journal (REV2) are reasonably realistic, as are PREJPREJ PR(JBC)=PR(JBC)= 12.512.5 the relative number of articles in the two journals. The IF PR=12PR=12 N=1000N=1000 divides the total citations for a journal by the number of articles published during the test period. This gives IF val- ues of 1,500/1,000 = 1.5 for the JBC and 300/100 = 3 for 200200 REV1 REV2 IF(REV2)=IF(REV2)= 3 REV2. Therefore the IF method in this model gives a higher PR(REV2)=PR(REV2)= 2.5 number to the review journal. 100 PR=3PR=3 N=100N=100 The PageRank method gives each journal the same PR value at the beginning of the calculation and then Fig. 2. IF and PR lead to different rankings. follows the citations back and forth between pairs of all the journals in an iterative process in which the PR values How do the methods for ISI Impact Factor and the are redistributed between journals as determined by the PageRank actually compare? Fig. 2 provides a model with citations that point to each, compared with citations that four journals that demonstrates how IF and PR compare. point from each of the respective journals. The iteration is In the model, two journals, PREJ and REV1, have cited continued until the PR values converge to stable values as two other journals, the JBC and REV2, during the test guaranteed by the Perron-Frobenius theorem. To illustrate period. PREJ, a prestigious journal such as Science, cited this with the model in Fig. 2, assume that in this iteration the JBC 1,000 times and REV2 200 times, while REV1 the PR values of the two citing journals are 12 for PREJ

18 ASBMB Today July 2007 and 3 for REV1, which are also realistic relative values all journals (i.e. the lemming cloud across journals takes a for a “prestige” journal such as Science and a “popular” stable shape) and then counted the number of lemmings review journal. The PR values of these two journals are at each journal, one would arrive at an approximation of its then shared by the cited journals, JBC and REV2, on the PageRank. In informal terms, the importance or “prestige” basis of the PR of the respective citing journal multiplied of a journal is judged according to how the journal’s cita- by the proportions of citations in that journal for the recipi- tion graph directs simulated readers, i.e. our lemmings, to ent journal. Thus, PREJ gives values of 12(1,000/ its publications. For more details see Refs. 3 and 5. 1,200) = 10 for the JBC and 12(200/1,200) = 2 for REV2, whereas REV1 gives values of 3(500/600) = 2.5 for the Conclusions JBC and 3(100/600) = 0.5 for REV2. This results in a total It is important to note that the currently available methods PR value for the JBC of 12.5 and for REV2 of 2.5. The for the evaluation of the quality of scientifi c papers and iteration would also distribute PR values back to PREJ the status of the journals that publish these papers are and REV1 based upon how many citations JBC and themselves undergoing a period of profound re-evaluation. REV2 cite for PREJ and REV1, and the process, which in No metric of scholarly impact represents a fi nal, perfect reality involves the entire journal citation network, would solution, and it is useful to think of scholarly impact as an continue until the PR values of all the journals abstract, multifaceted notion that can be meas- stabilize. The values of the PageRank ured in many different ways, some more calculation for the ISI IF 2003 cita- What would appropriate and accurate in certain tion database are displayed on happen if one were to circumstances than others (6). the x-axis of Fig. 1. The use of PageRank repre- The notion of the conver- rank all published scientifi c sents an improvement of the gence of propagated PR val- journals by their ISI IF and ISI IF when one is interested ues is instrumental in under- PR values calculated on less in the general popular- standing why review journals ity of a journal and more in its can have higher IF values than the basis of the same expert appeal. Furthermore, as the JBC but lower PR values. In citation data? noted by Bollen et al. (3), “as an essence, REV2 is a more “popular“ ever growing collection of scholarly journal, i.e. its articles have a greater average materials becomes available on the web, and citation rate and therefore a higher IF, whereas the JBC is hence becomes searchable through Google and Google a more “prestige” journal, i.e. its articles receive citations Scholar, our perception of article status (and hence of from more prestigious journals, and it is therefore ranked journal status) will change as a result of the PageRank- higher by Google’s PageRank algorithm. In addition to this driven manner by which Google lists its search results. In effect, the JBC further receives PR due to REV1’s function the future, PageRank, not the ISI’s IF, may very well start as a portal that points to the articles in the JBC that contain representing our perception of article and journal status.” the detailed information needed to understand the results A compromise, of course, would be the use of Y-factor, outlined in the reviews. which rates journals by using an equal measure of both IF It is diffi cult to explain PageRank in purely practical and PageRank. terms on the basis of small-example networks. The main problem is the concept of “convergence.” Whereas the IF REFERENCES 1. Garfi eld, E., at the International Congress on Peer Review and Biomedical Publica- is calculated simply on the basis of static citation rates and tion, Chicago, IL, September 16, 2005 publication numbers, PageRank is an iterative algorithm (4) 2. Brin, S., and Page, L. (1998). The anatomy of large-scale hypertextual web search engine. Computer Networks and ISDN Systems 30, 107-117 that converges upon what is termed a “stationary probabil- 3. Bollen, J., Rodriguez, M. A., and Van de Sompel, H. (2006). Journal status. Scien- ity distribution.” As an example, consider a very large and tometrics, 69, (arxiv.org:cs.DL/0601030) 4. Pillai, S. U., Suel, T., and Cha, S. H. (2005). The Perron-Frobenius theorem: some dense cloud of little lemmings, jumping from one journal to of its applications. IEEE Signal Processing 22, 62–75 5. Page, L., Brin, S. Motwani, R. and Weinograd, T (1998). The PageRank citation the other using citation links (and randomly in a minority of ranking: Bringing order to the web. Stanford Digital Library Technologies Project cases) so that every journal has a chance of being visited. 6. Bollen, J., Rodriguez, M. A., and Van de Sompel, H. MESUR: usage-based met- rics of scholarly impact (poster). In Proceedings of the Joint Conference on Digital If one waited until the numbers of lemmings stabilized over Libraries, Vancouver, June 2007 (www.mesur.org/)

July 2007 ASBMB Today 19 asbmb member spotlight Please submit news about yourself to [email protected]

Baum Receives contributions to the fi eld of oral medicine and oral pathology. He IADR Award has conducted sustained cutting-edge research focused on the pathogenesis and management of salivary gland and related oral Bruce J. Baum, chief of the Gene Therapy medical disorders.” and Therapeutics Branch of the National The IADR Oral Medicine & Pathology Research Award is Institute of Dental and Craniofacial Research supported by Sunstar Americas, Inc., and consists of a cash (National Institutes of Health), received the prize and a plaque. It is one of the Distinguished Scientist 2007 Oral Medicine & Pathology Research Award from the Interna- Awards given annually by the IADR, representing the highest tional Association for Dental Research (IADR). honor the IADR can bestow. Baum received his award in March According to the IADR, “Dr. Baum is an outstanding scientist, during the opening ceremonies of the IADR’s 85th General scholar, and mentor who has made highly visible and signifi cant Session.

Bissell Recognized This year marks the 10th anniversary of the award, which recog- by AACR nizes an individual who has made a major scientifi c discovery in basic or translational cancer research. Bissell gave an award lecture at the Mina J. Bissell received the 2007 Pezcoller AACR Annual Meeting in April 2007. In Bissell’s honor, the Pezcoller Foundation-American Association for Foundation held an award ceremony in early May in Trento, Italy, Cancer Research (AACR) International where she received a cash award of €75,000 and a medallion. Award for Cancer Research for her pio- Bissell’s studies have revealed that the critical unit of biological neering work on the relationship between cancer genetics and function is the integrated signaling circuit provided by the tissue the three-dimensional structure of cells and tissues. Bissell is (organ) architecture. She was honored for systematically looking Distinguished Scientist in the Life Sciences Division at Lawrence beyond the single cell, showing that the interaction of cells with each Berkeley National Laboratory and a recognized leader in the study other and with the extracellular matrix and the rest of the microenvi- of the extracellular matrix and how it regulates genes in both nor- ronment infl uence cell proliferation, survival, morphogenesis, differen- mal organs and malignant tumors. tiation, and cell fate, all processes that go awry in cancer.

Goldstein and Brown Brown and Goldstein shared the 1985 Receive National Nobel Prize for their discovery of the underly- Award for Research ing mechanisms of cholesterol metabolism. Their fi ndings led to the development of statin Joseph Goldstein and Michael Brown and drugs, the cholesterol lowering compounds received Research!America’s inaugural that are now among the most important Builders of Science Award for their achieve- widely prescribed medications in the world. Joseph Goldstein Michael Brown ments in developing the University of Texas Goldstein, a graduate of UT South- (UT) Southwestern Medical Center into one of the world’s premier western Medical School, is chairman of molecular genetics at UT research institutions. Southwestern and regental professor of the UT system. He also Goldstein and Brown, along with their mentor, Donald Seldin, holds both the Julie and Louis A. Beecherl Jr. Distinguished Chair in were honored in March at the 11th annual Research!America Biomedical Science and the Paul J. Thomas Chair in Medicine. Advocacy Awards gala in Washington, D.C. Brown is regental professor of the UT system and at UT South- Research!America is the nation’s largest not-for-profi t public western directs the Erik Jonsson Center for Research in Molecular education and advocacy alliance. Its mission is to make health Genetics and Human Disease. He holds the W.A. (Monty) Moncrief research a higher national priority, and its awards are given to Distinguished Chair in Cholesterol and Arteriosclerosis Research individuals and organizations that advance that mission. and the Paul J. Thomas Chair in Medicine.

20 ASBMB Today July 2007 Mestecky Receives Mestecky is a mucosal immunologist who discovered the Honorary IADR J chain, founded the international Society for Mucosal Immunology, Membership and was the fi rst to show in humans that the oral cavity was part of the mucosal immune system by demonstrating that ingestion of Jiri F. Mestecky of the University of antigen led to antibodies in saliva. Alabama, Birmingham, was recently The award recognizes not only Mestecky numerous scientifi c selected as an honorary member of the contributions to, but also his support of, oral and dental research, International Association for Dental Research (IADR). Each year, the illustrated by his departmental leadership at the University of three most recent living IADR past presidents select an honorary Alabama, which has led to the mentorship of numerous dental member who has made signifi cant contributions to and/or supports scientists who have, in their turn, produced high quality science that dental research. has made an enormous impact on dental research.

Serhan Honored honored for leading a worldwide effort to discover new chemical by NYU signals that control infl ammation and its resolution. Shortly after obtaining his Ph.D. from the NYU School of Medi- In March, Charles N. Serhan, Simon Gelman cine, Serhan identifi ed novel lipid structures formed in the course Professor at Harvard Medical School of cell/cell interactions. Studying infl ammation and its resolution, and director of the Center for Experimen- he identifi ed, characterized, and worked out the modes of action tal Therapeutics and Reperfusion Injury of compounds he himself named lipoxins, aspirin-triggered epimers at Brigham and Women’s Hospital, of lipoxins, resolvins, protectins, etc. The receptors for these agents received the New York University (NYU) Alumnus Achievement turned out to recognize both endogenous ligands and novel deriva- Award from the Biotechnology Study Center of the NYU School tives that hold great pharmaceutical promise. Most recently he has of Medicine. found that some of these lipid intermediates function in the nervous The award recognizes the role of pure science in the develop- system as regulators of neurogenesis. His laboratory leads a world- ment of pharmaceuticals and particularly honors those scientists wide effort to discover new chemical signals that control infl amma- whose work has led to major advances at the bedside. Serhan was tion and its resolution.

Stillman Receives Stillman’s research on cell division has formed the building Curtin Medal blocks for understanding illness, particularly cancer. His work focuses on DNA replication in cells, a process that ensures accurate Bruce Stillman, Cold Spring Harbor inheritance of genetic material from one generation to the next. Laboratory (CSHL) president and Cancer His work has also contributed to knowledge of the mechanisms Center director, received the 2006 Curtin that control DNA replication of human viruses as well as the pro- Medal for Excellence in Medical Research cesses that ensure accurate replication of the human genome and from The John Curtin School of Medical Research (JCSMR) this its associated protein structures, or nucleosomes. past March. The Curtin Medal is an internationally recognized award given “Professor Stillman’s work brings us a step closer to understand- annually to a person who has made an outstanding contribution ing and developing tools to defeat the diseases of our time,” said to medical science and is an Australian citizen, an Australian Professor Judith Whitworth, director of the John Curtin School of resident, or a person whose work has a signifi cant Australian Medical Research at the Australian National University, who pre- relevance. The award may be made for either a major discovery sented the Curtin Medal for Excellence in Medical Research. or for a lifetime achievement in medical research.

July 2007 ASBMB Today 21 asbmbnews ASBMB Journal News BY NICOLE KRESGE

JBC Gets New TOC to ensure that published studies of all macromolecules On June 22, subscribers to the Journal of Biological have the mechanistic slant appropriate for the JBC. Chemistry (JBC) noticed something a little different For more information on these changes, see the about the journal’s Table of Contents. To keep pace with editorial “JBC Calls for Papers in RNA Biochemistry and biological chemistry’s rapidly changing research land- Systems Biology” and the “Guidelines for Editorial Deci- scape, the JBC underwent an overhaul of its Table of sions” on the JBC Web site (www.jbc.org). Contents, resulting in the addition of some new head- ings and the elimination of others. MCP Endorsed as HUPO Journal At the JBC, a group of associate editors, known as the Recently, Molecular & Cellular Proteomics (MCP) MAGIQ committee (MAnaging Growth-Improving Quality), became the fi rst publication to be endorsed as an offi cial is charged with making sure that the Journal continues to journal of the Human Proteome Organization (HUPO). As evolve as the fi eld evolves. This committee part of the agreement between the journal was behind the recent changes in the Table and the organization, MCP will contain a of Contents headings. special section devoted to HUPO news. As the committee explains, “The new This section, which is marked by the headings are meant to better refl ect the HUPO logo, premiered in the June issue types of papers we currently publish and to of the journal with an overview of the encourage submission of manuscripts that HUPO 2006 World Congress. report signifi cant insights into mechanisms In an editorial in the June issue, MCP of biological processes in emerging areas.” Co-editors Ralph A. Bradshaw and Alma For example, the former heading L. Burlingame remarked, “We feel that “Genes: Structure and Regulation” became this is a real addition to MCP and are “Transcription, Chromatin, and Epigenet- pleased to be able to offer it to our read- ics,” and “DNA Replication, Repair and ership. We encourage all individuals inter- Recombination” was expanded to include ested in proteomics to regularly peruse “DNA Replication, Repair, Recombination this section because it will undoubtedly and Chromosome Dynamics.” contain important and interesting infor- Changes were also made to accom- mation and announcements.” modate the new roles for RNA in biology HUPO is an international scientifi c and mechanistic studies of RNA-mediated organization representing and promoting processes. The former “RNA: Structure, proteomics through international coopera- Metabolism and Catalysis” was divided into tion and collaborations by fostering the two new headings: “RNA Processing and development of new technologies, tech- Catalysis” and “RNA-mediated Regulation niques, and training. The organization was and Noncoding RNAs.” launched in February 2001. Another new Table of Contents head- The relationship between MCP and ing, “Biomolecular Networks,” was added HUPO dates back to 2002 when the to cover papers dealing with integration of information journal published the abstracts for the fi rst HUPO World from genomics, proteomics, and metabolomics studies Congress in Versailles. MCP has continued to publish from the perspective of biological mechanisms. the abstracts for every HUPO congress since then. Corresponding changes have also been made to the HUPO members will also receive 50% off the annual JBC Editorial Guidelines to broaden their scope and ASBMB Regular membership rate.

22 ASBMB Today July 2007 careerinsights ANDREW D. ROBERTSON: Creating a Vision

few years ago, while I was still not made the jump from professor to A a biochemistry professor at the medical writer in 2004. University of Iowa, my wife and I Th e transition in 2004 from a were having one of our “kitchen table” tenured full professor in an academic chats, and we sketched out the perfect research-intensive position to one job for me, life science broker: I would where clinical research and writ- track the latest advances in life sci- ing ruled the work day was pretty ence, identify potential but heretofore dramatic. As a medical writer, I co- unrecognized overlapping interests authored manuscripts summarizing Andrew D. Robertson in diff erent fi elds, and then help the results of clinical trials involving scientists working on complementary vaccines. I was even able to off er Andy Robertson received a B.A. in problems to connect and collaborate input into trial design—although I Biochemistry and Cell Biology from with one another. At that time, neither am not sure that my suggestions ever the University of California, San of us could point to a real job with ended up in any trial protocols. Up to Diego, and a Ph.D. in Biochemistry these qualities, but having the ideal that point in my career, biochemical from the University of Wisconsin- job description in mind subsequently research had dominated my profes- Madison. He was a Damon Runyon- proved to be very handy. sional life for over 20 years. Graduate Walter Winchell Cancer Research I have now held three jobs over school and postdoctoral training Fund postdoctoral fellow in Bio- the last 3 years or so: I was on the were fun, and as far as careers go, I chemistry at Stanford University be- faculty at the University of Iowa for had only ever imagined that I would fore joining the biochemistry faculty over 13 years, but in 2004 I started be a faculty member at a university. at the University of Iowa College a very stimulating year as a medical As I moved through the ranks in of Medicine in 1991. In 2004, he writer at Merck Research Labora- my department at the University of joined Merck Research Laborato- tories (MRL), and in 2005 I became Iowa, I received good support from ries as an associate director in the chief scientifi c offi cer (CSO) at Key- colleagues, enjoyed teaching and Medical Communications Depart- stone Symposia, a nonprofi t organi- interacting with students, and relished ment and then assumed his current zation that coordinates over 50 life research. Th e decision to change my position as chief scientifi c offi cer at science research meetings each year. career stemmed from dissatisfaction Keystone Symposia in 2005. I oversee the process of selecting with what evolved into a less enjoyable meeting topics and organizers; review position coupled with the allure of she felt like she was doing mission- meeting proposals and shepherd something new. Aft er a few years, I felt ary work.) Also, the curriculum at these proposals through additional like I was treading water scientifi cally: my undergraduate institution, the peer review by our Scientifi c Advi- with a relatively small research budget University of California, San Diego, sory Board; and help raise funds and a small lab, pursuing new research heavily emphasized writing. I did not from government agencies like the directions was diffi cult. On the other recognize then that I was acquiring National Institutes of Health (NIH). hand, I continued to enjoy writing. one of my most important—and very Th e mission at Keystone Symposia is I was fortunate to have some seri- transportable—professional skills. “connecting the scientifi c community,” ous writing teachers dating back to Once I settled on medical writing as so I truly feel like I found the ideal my “surfer” high school in southern my new career goal, I took steps in that job. And although I could not have California. (One of our oft en exas- direction. I considered myself a good anticipated it, I would probably not perated English teachers, originally writer but nevertheless took writing be CSO at Keystone Symposia if I had from the East Coast, remarked that classes to work on the craft . I joined

July 2007 ASBMB Today 23 career insights continued

professional organizations such as the positions: depending on the posi- I enjoyed that. In fact, I would happily American Medical Writers Association tion, I emphasized some parts of my still be at MRL if I had not spotted the and the Council of Science Editors, training and experience over others. ideal job description, for CSO at Key- and I started attending their meetings. Attending professional meetings stone Symposia, in a scientifi c journal. Th ese organizations off ered opportuni- turned out to be key to getting the Because my wife and I had already ties for training and for learning about job at MRL. At one such meeting, outlined the perfect job for me, no spe- medical and scientifi c writing. My I met my eventual boss, and the cial preparation was needed to apply membership also showed a commit- following week, I was invited for an for the CSO position. My broad inter- ment to the profession. interview. I learned later that I was est in biology, a background in both As I pursued a career in writing, hired because of my research and basic and clinical research, and good I heard the following rule over and over writing experience, oral communica- communication skills helped me move again: to get a job in writing, nothing tion skills, eagerness to learn new to the top of the list of applicants. is better than experience. In my case, material, ability to work in a team, Looking back, I had no plan that I had many scientifi c papers resulting and a commitment to writing. would take me to my ideal job. I did from my 20-plus years in research. I I was very happy at MRL. My have the nerve to change my career also sought additional writing oppor- co-workers were bright and highly when I wanted to do something new, tunities: I wrote a personality profi le motivated, the work was interesting, and I think that I succeeded by taking of another researcher for the medical and MRL off ered many opportunities advantage of valuable—and highly alumni magazine and had another arti- for professional development on both transportable—technical, problem- cle published in a regional magazine. the scientifi c and management sides. solving, and communication skills In applying for writing jobs, I Th is was also my fi rst exposure to that I acquired in studying for a Ph.D., tailored my resume to refl ect the real interdisciplinary teamwork, and doing basic research, and teaching.

Hendrix and Bradshaw Assume New Posts

SBMB President Heidi Hamm has announced that is a Distinguished Service Professor in the Depart- AMary J. C. Hendrix will replace William R. Brinkley ment of Molecular and Cellular Biology and serves as chair of the ASBMB Public Affairs as co-director of the W. M. Keck Center for Com- Advisory Committee and that Ralph putational Biology. In addition to chairing the Public A. Bradshaw will assume the post of Affairs Advisory Committee from 2000 to 2007, Society historian. Brinkley served as president of FASEB from 1998 Hendrix, who is president to 1999. and scientific director of the Chil- Bradshaw is professor in the Department of dren’s Memorial Research Center Pharmaceutical Chemistry and deputy director of the at Northwestern University, has Mass Spectrometry Facility at the University of Mary J. C. Hendrix been an ASBMB member since California, San Francisco. He has been involved in 1981. She has served on the writing the Society’s centennial ASBMB Public Affairs Advisory history book and has also contrib- Committee since 2001 and was uted articles on ASBMB history to president of FASEB from 2001 ASBMB Today. Bradshaw has been to 2002. an ASBMB member since 1971, Brinkley is currently senior vice was president of FASEB from 1996 president for Graduate Sciences to 1997, and is currently deputy and dean of the Graduate School chair of the Public Affairs Advi- of Biomedical Sciences at Baylor sory Committee and co-editor of William R. Brinkley Ralph A. Bradshaw College of Medicine, Houston. He Molecular & Cellular Proteomics.

24 ASBMB Today July 2007 professionaldevelopment Preparing Graduate Students and Postdocs: A Model Program

BY CHERIÉ BUTTS AND JAYNE REUBEN

aking a successful transition from graduate student 27 program included plenary talks, brown-bag lunch Mto postdoctoral fellowship to an independent discussion tables, and breakout sessions for graduate career was the focus of a national workshop at the recent students and postdocs. Th e April 28 program included Experimental Biology (EB) 2007 meeting. Th e National talks focused on mentoring and managing postdoc- Postdoctoral Association (NPA) and the Federation of toral fellows within the laboratory setting. Th ere were American Societies for Experimental Biology (FASEB) approximately 125 participants each day. Leaders in Career Resources/Minority Access to Research Careers scientifi c policy, experts in professional development, (MARC) Program jointly sponsored the fi rst-ever Post- and several outstanding researchers, educators, and doctoral Preparation Institute (Institute) at this gathering administrators from a variety of organizations provided of scientifi c societies and international researchers. Th e exhilarating discussions on a wide range of session Institute is an emerging model that assists early-career topics, including: scientists in navigating through these critical transition • Th inking about next steps points in their training and professional growth. Th e • Diff erent career paths available to scientists event took place in Washington, D.C., and included ses- • Considerations for funding opportunities sions on April 27 and 28 as a pre-conference event. • Th e keys to successful networking Th e primary goal of the Institute was to encourage • Th e importance of respecting cultural diff erences participants to consider their next professional steps • Best practices for increasing laboratory productivity and to provide helpful information and resources to • Structured mentoring make the transition smoother. Th e Institute was created • Reducing confl ict within the laboratory as FASEB leadership recognized the increasing need for • Results of the Sigma Xi Postdoc Survey enhanced professional development of today’s early- Th e following individuals served on the Organizing career scientists at the graduate student, postdoctoral, Committee for the event: Jayne S. Reuben (Baylor Col- and junior faculty levels. Both FASEB Career Resources/ lege of Dentistry/Texas A&M Health Science Center), MARC Program and the NPA have a history of sharing Cherié L. Butts (National Institute of Mental Health/ with early-career scientists valuable information essen- NIH), Phillip Cliff ord (Medical College of Wisconsin), tial for the development of a thriving scientifi c career. In David Burgess (Boston College), L’Aurelle Johnson addition, for the past 3 years the NPA and its Diversity (University of Minnesota), Joan Lakoski (University Committee have put together similar types of programs of Pittsburgh), Alyson Reed (National Postdoctoral in collaboration with the National Science Foundation- Association), and Jacqueline Roberts (FASEB Career funded Alliance for Graduate Education in the Profes- Resources Program). soriate (AGEP) programs at Howard University and Th e NPA is a professional association that provides a University of Texas at El Paso. Ultimately, the organ- unique, national voice for postdoctoral scholars and seeks izers hope that providing this information will help to enhance the quality of the postdoctoral experience. Th e participants avoid some of the more common mistakes NPA hopes that other scientifi c societies will host similar of many early-career scientists, including unfocused events and that other institutions will host local events research goals, unrealistic career aspirations, and lack of so that this information will enable as many early-career preparation for various career paths. scientists as possible to have successful careers. Th e program was divided into two days, with work- Additional information about the NPA can be found at shops that address the needs of early-career scientists www.nationalpostdoc.org. For more details about this as well as a session for heads of laboratories. Th e April event, please visit www.eb2007.org/pages/page7i.htm.

July 2007 ASBMB Today 25 education

Assessing What Students Learn

BY J. ELLIS BELL

ssessment is an issue that is not going to go away. As program’s goals, and it will encourage interactions between A educators we all should be thinking creatively about the courses. assessment of teaching, of programs, and of individual I know from my own experience that too oft en I have students. I believe that courses should work together assumed that students have mastered certain skills or to augment student learning and that while individual facts in an earlier course only to fi nd they haven’t. Neces- faculty may decide the majority of course content, the sary information could be categorized as “fully covered” department or program should interpret guidelines from or “introduced but in need of reinforcement,” allowing professional societies and ensure that courses provide faculty to plan appropriate repetition in the curriculum. adequate learning opportunities for the students. Th e Th is information base also provides a starting point for graduating student is the product of the program, and dynamic assessment tools for use in the classroom. Each because assessment is focused on student learning out- instructor devises several questions on each point of comes it refl ects the collective success or failure of the essential background knowledge or value-added knowl- program and not of any individual course or experience. edge during the course. Early in the course the appropri- So what type of assessment can be used to provide ate questions can be used in a take-home problem set more dynamic information that can truly help in edu- or in-class quiz. Instead of collecting and grading the cation? It must be course- or program-embedded, and answers, the instructor can go through the answer rubric needs to refl ect both the retention of knowledge and the in class, indicating where students should “grade” them- acquisition of skills. Too oft en you see in an “assessment” selves. At the end of the class the student-graded quiz/ plan that assesses knowledge in a course-embedded man- problem set is handed in and analyzed by the instructor ner. Th is usually means that the instructor keeps a record to assess the students’ state of knowledge. In this way, the of how well students perform in class and on exams. Such background material from previous courses is reviewed information is clearly expedient. Presumably the program in a way that allows learning points to be assessed without wishes to teach facts and information that the student students being threatened and in a context enabling them can carry on to later courses in the curriculum. If that to see how the instructor analyzes and answers a question. is the case then student retention, understanding, and Th is approach can also increase the dialog between use of the knowledge should be assessed in those later instructors: questions I think a student should be able courses. Th is brings up the issue of making courses work to answer coming into a course can be compared with together to benefi t both the student and the program. As questions the instructor of the prior course feels the a department or program, the faculty should decide on students should be able to answer aft er taking that what knowledge and skills the student should acquire and course. Any disconnects can be ironed to optimize the when they should acquire them. way the curriculum works for student learning. Some Most programs have a sequence of introductory think this approach breaks down academic freedom and courses that must be completed before upper level courses. that instructors should be able to teach whatever they If there is a defi ned order of courses, then each course want. Unfortunately such comments miss the point: with should build on the skills and knowledge taught in the academic freedom comes academic responsibility. When previous courses. Each instructor could, for example, list a course is a required part of a sequence and later courses the knowledge and skills needed to take the course as well depend on its content, then academic responsibility says as those required for successful completion of the course. that the content must be there. Professional responsibility Such an exercise in itself will assist faculty in understand- says that it must be there at an anticipated level and cov- ing the overall goals of the program and how the cur- erage. Academic freedom says feel free to teach content in riculum works to foster the fi nal outcomes. By examin- any way that you like provided you can demonstrate the ing and discussing this information as a department, all eff ectiveness of the style, which of course brings us back faculty will understand how the courses contribute to the to assessment.

26 ASBMB Today July 2007 sciencefocus Alexandra Newton: Understanding the Inner Workings of Cells

BY PAT PAGES

lexandra Newton, professor In Koshland’s laboratory, Newton Aof pharmacology at the discovered for the fi rst time that PKC University of California in San attaches phosphates onto itself by an Diego, has always been fascinated intramolecular mechanism, akin to a by how molecules work and how snake biting its own tail. Th is showed they interact with each other. that PKC did not need to be tagged During her 20-year career, Newton’s by other proteins to modify its func- curiosity and enthusiasm led her tion, which is now a common theme to explore how proteins and lipids in cell signaling. interact in cell membranes, how In 1988, aft er setting up her protein kinases are activated within laboratory at Indiana University in cells, and recently how proteins she Bloomington, Newton decided to nicknamed PHLPP are part of sig- study how PKC is activated in cells. naling pathways involved in cancer, Scientists knew that PKC was acti- diabetes, and heart disease. vated by calcium ions and diacylglyc- Newton’s interest in science started erol—a product of the breakdown of as a child. One of her most vivid Newton’s fi rst chance to investi- membrane lipids—but the activation memories was reading Th e Double gate the inner workings of proteins mechanisms were not completely Helix: A Personal Account of the started in 1981 while working on understood. One thing scientists had Discovery of the Structure of DNA, by her Ph.D. in chemistry at Stanford hypothesized was that the PKC active renowned biologist James D. Watson. University. Th e topic of her research site was blocked by a segment called “Th e book—which I read when I was was how membrane proteins inter- a pseudo substrate that needed to be 12—was a fascinating account of the act with lipids, sparking an interest freed to activate PKC. scientifi c race between Watson, work- in membrane biochemistry that Newton investigated how calcium ing with Francis Crick, and Linus has infl uenced her throughout ions, diacylglycerol, and PKC worked Pauling to discover the structure of her career. together and revealed a process that DNA,” Newton says. “Reading it fueled Aft er fi nishing her Ph.D., Newton would generate much attention from my desire to become a scientist.” went to the University of Califor- other biochemists working on this During her childhood, Newton nia, Berkeley, to work with Daniel protein. She showed that when cal- also spent many summers in Greece, Koshland, Jr., known for his “induced cium ions are released in the cell—by where she was captivated by the sea fi t” theory of enzyme interaction, the endoplasmic reticulum—they life of the Mediterranean. “I loved which states that enzymes change bind to PKC and allow it to tether to spending time near the water, snor- shape as they react with other mol- the cell membrane. Th e membrane- keling, or catching octopuses with ecules. Newton studied how lipids bound PKC then moves on the bare hands,” she says. “Th is made me control the activity of protein kinase membrane and, when it gets close to want to become a marine biologist.” C (PKC), an enzyme that attaches a a diacyl glycerol molecule, binds to During her academic years at phosphate group to specifi c proteins it as well (see Fig. 1). Th is induces a Simon Fraser University in Van- and is involved in pathways that con- change in the PKC internal confor- couver, Canada, Newton developed trol various physiological functions mation that releases the pseudo- a passion for chemistry, so instead such as learning and memory, the substrate, freeing the active site and of majoring in marine biology, she working of the immune system, and allowing PKC to attach phosphates decided to major in biochemistry. cell proliferation. on other proteins.

July 2007 ASBMB Today 27 inner workings of cells continued

Fig. 1. Schematic representation showing that diacylglycerol tethers protein kinase C (octopus) to the membrane, allowing the kinase to attach a phosphate molecule (sea shell) to a substrate ( yellow fi sh with gaping mouth).

“Th e chances that PKC fi nds regulatory switches in other kinases or Akt. Th e Akt signaling pathway is diacylglycerol on the membrane as well. critical in regulating cell growth and by simply bouncing on and off the Newton’s lab showed that PKC death and is linked to many common membrane are relatively low, so phosphorylation occurs in an orderly human cancers. nature has chosen a clever mecha- way. A protein called phosphoinositide- Instead of determining which nism to increase the effi ciency of this dependent protein kinase 1 (PDK1) proteins phosphorylate Akt—as she happening,” Newton says. “Binding of fi rst phosphorylates the activation had done with PKC—Newton won- calcium ions to PKC essentially pretar- loop, which then triggers PKC to dered whether a protein that removes gets it to the membrane, where it can phosphorylate itself at the turn and phosphates, or phosphatase, may be start a much more eff ective search hydrophobic motifs. involved in the Akt signaling pathway for diacylglycerol.” Aft er moving to the University as well. In 1994, Newton and her colleagues of California in San Diego in 1995, “By then, it was well known that made another discovery. Th ey showed Newton’s laboratory used imaging Akt, like PKC, needs to be phospho- that before PKC even binds to the cell technologies to visualize the dynamics rylated to become active, but the membrane, it needs to be phospho- of PKC in cells through a collabora- mechanisms terminating Akt activity rylated. Newton’s team, along with tion with Roger Tsien, a professor of were not well studied,” Newton says. Koshland’s team, identifi ed three sites pharmacology who has pioneered the “Removing the phosphates would on which PKC needs to be phospho- use of live cell imaging technologies. mean stopping the Akt pathway, rylated: a segment near the entrance Th is work showed when, where, and which also means knowing how to to the active site called the activation for how long PKC is active in the cell control pathways leading to important loop and two positions in the carboxyl and revealed for the fi rst time where diseases such as cancer, diabetes, and terminus that Newton named the turn PKC activity was sustained and where heart disease.” motif and the hydrophobic motif. Th is it was rapidly turned off . Newton and her colleagues noticed was important because these sites In 2000, Newton also turned her that many known proteins in the Akt are conserved in many other kinases, attention to another protein kinase pathway have a common domain showing that these sites could be related to PKC called protein kinase B called pleckstrin homology (PH). So

28 ASBMB Today July 2007 proteins would help treat patients with Growth factors diabetes, heart disease, and neurologi- cal disorders. PIP3 Akt 473 “We fi rst discovered that PHLPP 308 PI3K PDK-1 controls Akt, which is the driver on the PHLPP 1 pathway to tumor growth,” Newton Akt2 says. “PHLPP is like a brake that, when PTEN 473 HDM 2 308 Akt3 ‘on,’ slows the driver but when ‘off ’ 308 473 allows the driver to move. In cancer, we want the driver to brake, to prevent Akt3 PHLPP 2 GSK 473 cell proliferation leading to tumor 308 Akt1 growth. But in diabetes, heart, or 473 neurological disease, where we want to 308 p27 TSC-2 promote cell growth and survival, we don’t want to slow the driver down.” Newton is very excited about these new results. Th roughout her career, GSK FOXO1 not only has she revealed how known proteins interact with each other in Fig. 2. Schematic representation showing how the signaling pathways for key cellular pathways, but she also has Akt1, Akt2, and Akt3 are inactivated by PHLPP1 and PHLPP2 through specifi c discovered formerly unknown proteins complexes (blue-shaded ovals) of the PHLPP and Akt molecules. that now off er potentially new ways of curing major diseases. the scientists decided to scour signaling pathways, which involve “PKC has led our lab on an amaz- GenBankTM for a phosphatase with three diff erent Akt proteins called ing journey, with new discoveries at a PH motif. Th ey found only one Akt1, Akt2, and Akt3. every turn,” says Newton. “But perhaps protein, which they called PH domain Although both types of PHLPP what has been most rewarding is how leucine-rich repeat protein phos- proteins prevent tumors from grow- it led us to discover the phosphatase phatase (PHLPP, pronounced “fl ip”). ing, the researchers found that they that terminates signaling by PKC and Th e researchers then showed that are also involved in pathways that its close cousin Akt. Th is phosphatase PHLPP was indeed involved in the promote diabetes, heart disease, and is poised as a major therapeutic target, Akt pathway. neurological conditions. In particular, and I hope our results may one day Th e researchers next showed that PHLPP1 terminates the Akt2 pathway, lead to new cures against cancer, dia- PHLPP levels are markedly reduced which is involved in maintaining a betes, and heart disease.” in colon and brain cancer cells that constant level of glucose in the blood- had elevated Akt phosphorylation. stream, whereas PHLPP2 inactivates BIBLIOGRAPHY By introducing PHLPP in these cells, the Akt1 pathway, which promotes cell Brognard J., Sierecki E., Gao T., and Newton A. C. (2007) PHLPP and a second isoform, PHLPP2, they showed that tumor growth was survival (see Fig. 2). differentially attenuate the amplitude of Akt signaling dramatically suppressed. Th ese results show that varying by regulating distinct Akt isoforms. Mol. Cell 25, 917–931 In March 2007, Newton’s team pub- the levels of the PHLPP proteins can Newton A. C. (2004) Protein kinase C family. In Encyclopedia of Biological Chemistry, Vol. 3, lished their discovery of a second type have two opposing eff ects, which pp. 523–526 of PHLPP protein, which they dubbed can be used to treat various condi- Newton A. C. (2004) Diacylglycerol’s affair with protein kinase C turns 25. Trends Pharmacol. Sci. PHLPP2. Th e scientists showed that tions. Increasing the role of PHLPP 25, 175–177 PHLPP—now called PHLPP1—and proteins would help suppress tumors Violin J. D., and Newton A. C. (2003) Pathway illuminated: visualizing protein kinase C signaling. PHLPP2 terminate diff erent Akt in cancer patients, but inhibiting the IUBMB Life 55, 653–660

July 2007 ASBMB Today 29 sciencefocus Jack Griffi th: Seeing What No One Has Seen Before

BY PAT PAGES

ack Griffi th, a professor of of Energy about nuclear reactors and, It’s not easy, but when you succeed in Jmicrobiology and immunology while in high school, won the Alaska sci- doing it, it’s very rewarding.” at the University of Nor th Carolina in ence fair by building a miniature nuclear Using electron microscopes provided Chapel Hill, likes to see—literally— reactor complete with a neutron source. many such opportunities to Griffi th. His DNA and proteins. During his 38-year “I always enjoyed understanding fi rst chance was in 1965 when he was a career, he has been perfecting electron how machines or pieces of equip- Ph.D. student at the California Institute microscopes to do just that, reveal- ment work and then trying to see how of Technology. One of the questions ing how DNA and to improve them,” he says. “Physics scientists had tried to address was how proteins interact helped me do that, not so much from DNA is assembled in chromosomes. Th e with each other to the formulas that you are taught in resolution of the micrographs was too carry out replica- school but from understanding how crude to show the fi ner details of DNA, tion or recombina- and why things aff ect each other.” so Griffi th found a way to improve it. tion reactions and In 1960, Griffi th went to Occidental Until then, visualizing DNA with uncovering the College in Los Angeles with the goal of an electron microscope required coat- structure of chro- becoming a nuclear physicist. In 1963, ing the molecule with a thick layer of mosome ends. his interests changed when he was protein and then a metal layer to make Th ese discoveries and many others off ered a summer internship at Oak DNA appear thicker and more visible. have made Griffi th’s laboratory famous Ridge National Laboratory in Ten- But the fi ner details of the DNA were around the world. Biologists seeking to nessee to study how radiation aff ects lost. So Griffi th found ways to reveal understand how their molecules work DNA with Dick Setlow, a renowned these details by limiting the amount of oft en ask him to visualize their mol- physicist turned biophysicist. Th e coating materials and by attaching the ecules in action. “Most biochemists use internship was such a positive experi- DNA to better supports. indirect ways to study complex molecu- ence that, aft er returning to Occidental To prepare the metal coating, gold or lar mechanisms,” Griffi th says. “But com- College for his junior year, Griffi th platinum was heated until it evaporated, bining biochemical assays with electron decided to major in biophysics. and then it was sprayed over the sample microscopy makes the job much easier.” “At that point, I became aware that so that the outline of the metal coating What prepared Griffi th to become experimental physics was an area could be “seen” by the microscope. To an international expert in electron dominated by large groups of peo- view DNA, such metals would crudely microscopy was his love for photogra- ple working on big projects,” he says. cover it, so Griffi th tested other metals phy and things manual at an early age. “I was more interested in setting up and discovered that tungsten, which Raised in Alaska, he hunted caribou small—but original—experiments for melts at higher temperatures than gold and moose with his father for winter which you can get answers to your and platinum, produced a fi ner spray food, built the family homestead, and questions pretty quickly.” and a more detailed image. assembled outboard boats. He also Griffi th explains that he has always One of Griffi th’s initial results using loved taking things apart and spent been drawn to scientifi c questions that his new methods was the fi rst image of countless hours breaking down pieces he can address by setting up “simple and DNA bound to DNA polymerase—the of wrecked aircraft in a military dump elegant” experiments. “Sometimes, you enzyme responsible for DNA replication near the family house. don’t need to build complicated set-ups,” (see Fig. 1). Th e work was performed in Early on, Griffi th developed a keen he says. “You just have to fi nd an elegant 1969 at Caltech with Arthur Kornberg, interest for science, especially physics. He way to address your problem without who won the Nobel Prize for identifying read with interest scientifi c reprints of creating other problems that would DNA polymerase. Th e results showed papers published by the U.S. Department interfere with what you are looking for. that electron microscopy could do more

30 ASBMB Today July 2007 the new cells have shorter telomeres than the original one. As cell divisions proceed during a lifetime, the telomeres eventually become so small that the cells cannot divide anymore and die. So telomeres act as an aging clock, limiting the life span of cells, and help to stop cancer cells from dividing continuously. Until 1999, it was widely assumed that telomeres looked like the ends of shoelaces. But in 1999, Griffi th sug- gested that—based on his previous recA studies—telomeres might instead Fig. 2. Electron microscope image showing Fig. 1. The fi rst electron microscope form a large loop. So Griffi th’s team that DNA at the end of a chromosome— image of DNA polymerase bound to DNA. worked out ways of isolating human or telomere—forms a loop. telomeres and examining them directly than take pictures—it could also be in an electron microscope. What the an emerging technique called single- used to analyze how DNA interacts scientists saw confi rmed Griffi th’s molecule microscopy, which uses a light with proteins. hypothesis: long, lasso-like loops (Fig. microscope and cameras to follow the In 1978, Griffi th set up his laboratory 2). He was so happy that he personal- movement of molecules live in solution. at the University of North Carolina with ized the license plate of one of the cars Although this new technique does not the goal of using electron microscopy to he collects—an old Ferrari—with the allow one to “see” DNA or proteins, understand how proteins bind, fold, and word “Telomere.” their movement can nevertheless be loop DNA. One of the laboratory’s most Th ese results and those of other followed through fl uorescent tags. interesting results in the early 1980s was researchers may be used one day to When Griffi th talks about his to uncover the inner workings of recA, slow down the shortening of telomeres, research, he seems to be as excited as he a protein used by bacteria to recombine making people stay young longer, or to probably was the fi rst time he used an its DNA. Th ese results later paved the develop anti-cancer drugs that make electron microscope. “What I fi nd most way for studies of DNA recombination telomeres shorter in tumors. But more exciting about this technique is that it proteins in humans. studies are needed to understand the allows me to see things never before seen In the early 1990s, Griffi th and his structure and properties of telomeres. by the human eye,” he says. “It’s like when colleagues looked at unusual continuous Griffi th’s team is now using electron I used to hunt or hike with my father in three-base repeats in DNA known to microscopy to understand how telom- the backwoods of Alaska. It was always cause diseases such as Fragile X syn- eric DNA is folded by a set of a half- thrilling to go over a new valley or a new drome, a leading cause of mental retar- dozen proteins that the scientists had mountain and see what no other human dation, and myotonic dystrophy, a motor previously isolated. being had ever seen before.” neuron disease. In the case of Fragile X To make the most of the images BIBLIOGRAPHY syndrome, Griffi th’s team showed that collected with the electron microscope, Griffi th, J. D., Huberman, J., and Kornberg, A. (1971) the repeats caused a segment of the chro- Griffi th and his team also use other Electron microscopy of DNA polymerase bound to DNA. J. Mol. Biol. 55, 209–214 mosome to be very unorganized and biochemical techniques, including gel Griffi th, J. D. (1975) Chromatin structure: deduced from a minichromosome. Science 187, 1202–1203 unprotected, making it more susceptible electrophoresis, chemical probing, and Dunn, K., Chrysogelos, S., and Griffi th, J. D. (1982) to breaking than other parts of the chro- the generation of mutant proteins. EM visualization of RecA-DNA fi laments: evidence for a cyclic extension of duplex DNA. Cell 28, 757–765 mosome and turning off a critical gene. Combining both approaches helps the Wang, Y. H., Gellibolian, Shimizu, M., Wells, R. D., In 1995, the team started what researchers understand the properties and Griffi th, J. D. (1996) Long CCG triplet repeat blocks exclude nucleosomes: a possible mechanism would become a landmark contribu- of the molecules under study and verify for the nature of fragile sites in chromosomes. J. Mol. Biol. 263, 511–516 tion: the study of the structure of tel- what they see in the microscope. Griffi th, J. D., Comeau, L., Rosenfi eld, S., Stancel, omeres, which are structures at the ends In the future, Griffi th would like R., Moss, H., Bianchi, A., de Lange, T. (1999) Mammalian Telomeres End in a Large Duplex Loop. of chromosomes. When cells divide, to combine electron microscopy with Cell 97, 503–514

July 2007 ASBMB Today 31 biobits asbmb journal science

J. Biol. Chem. 2007 282: 18448-18457 Mass Spectrometry Reveals the Missing Links in the Assembly Pathway of the Bacterial 20 S Proteasome Michal Sharon, Susanne Witt, Elke Glasmacher, Wolfgang Baumeister, and Carol V. Robinson The 20 S proteasome is composed of 28 subunits (14 ␣-type and 14 Two possible assembly scenarios for ␤-type) arranged in a cylindrical architecture consisting of two outer the Rhodococcus 20 S proteasome. ␣-type subunit rings embracing two central ␤-type subunits rings. The formation of the 20 S proteasome is a complex process that involves a cascade of folding, assembly, and processing events. In this JBC paper, the authors use a real-time mass spectrometry approach to capture transient species along the assembly pathway of the 20 S proteasome from Rhodococcus erythropolis. By recording mass spectra throughout the reaction time course they were able to monitor the formation of an early ␣/␤-heterodimer as well as an unprocessed half-proteasome particle. Formation of the mature holoproteasomes occurred in concert with the disappearance of half-proteasomes. They were also able to determine in great detail the cleavage sites within the ␤-subunit propeptides during the different assembly states.

J. Biol. Chem. 2007 282: 18895-18906 C Internalized Antibodies to the Tg2576 A␤ Domain of APP Reduce Control 6E10 Neuronal A␤ and Protect against Synaptic Alterations Davide Tampellini, Jordi Magrane, Reisuke H. Takahashi, Feng Li, Michael T. Lin, Claudia G. Almeida, and Gunnar K. Gouras Immunotherapy against ␤-amyloid peptide (A␤) is a leading Ab42 therapeutic direction for Alzheimer disease. Experimental studies in ␤ transgenic mouse models of the disease have demonstrated that A Treatment with A␤ antibody 6E10 reduces immunization reduces A␤ plaque pathology and improves cognitive A␤42 immunofl uorescence. function. However, the biological mechanisms by which A␤ antibodies reduce amyloid accumulation in the brain remain unclear. The authors of this paper show that A␤ antibodies decrease levels of intracellular A␤ in Alzheimer disease mouse mutant neurons in culture. This reduction in cellular A␤ appears to require that the antibody bind to the extracellular A␤ domain of the amyloid precursor protein (APP) and be internalized. The authors also found that treatment with A␤ antibodies protects against synaptic alterations that occur in APP mutant neurons.

32 ASBMB Today July 2007 J. Lipid Res. 2007 48: 1293-1304 Ceramide Kinase Uses Ceramide Provided by Ceramide Transport Protein: Localization to Organelles of Eicosanoid Synthesis Nadia F. Lamour, Robert V. Stahelin, Dayanjan S. Wijesinghe, Michael Maceyka, Elaine Wang, Jeremy C. Allegood, Alfred H. Merrill, Jr., Wonhwa Cho, and Charles E. Chalfant In mammalian cells, ceramide kinase (CERK) phosphorylates ceramide to produce ceramide-1-phosphate (C1P). In this study, the

authors determined that the main forms of C1P in cells are C16:0 C1P

and C18:0 C1P, suggesting that CERK uses ceramide transportedto the trans-Golgi apparatus by ceramide transport protein (CERT). To confi rm this, they downregulated CERT by RNA interference and showed that it dramatically reduced the levels of newly synthesized CERK localizes to the trans-Golgi apparatus. C1P as well as the total mass levels of C1P in cells. The authors then localized CERK to the trans-Golgi network, placing the generation of C1P in the proper intracellular location for the recruitment of ␣ cytosolic phospholipase A2 . These results demonstrate that CERK localizes to areas of eicosanoid synthesis and uses a ceramide “pool” transported in an active manner via CERT.

Mol. Cell. Proteomics 2007 6:1000-1006 Diversity of Translation Start Sites May Defi ne Increased Complexity of the Human Short ORFeome Masaaki Oyama, Hiroko Kozuka-Hata, Yutaka Suzuki, Kentaro Semba, Tadashi Yamamoto, and Sumio Sugano Open reading frames (ORFs) are portions of DNA that contain bases that encode proteins. They are located between a start-code sequence (ATG codon) and a stop-code sequence. Surprisingly, some sequence analyses have indicated that several cDNAs have at least one ATG Structure of the 5'-UTRs of the human codon upstream of the presumed coding sequence, indicating the YTHDF3 transcripts. presence of potential coding regions in the genes’ 5'-untranslated regions (UTRs). In this study, the authors used an automated two- dimensional nano-LC system coupled with a high resolution hybrid tandem mass spectrometer to confi rm the presence of several upstream ORFs in the presumed 5'-untranslated regions of mRNAs. They also found evidence of novel short coding regions that were likely to be translated from the upstream non-AUG start site or from the new short transcript variants generated by utilization of downstream alternative promoters. These fi ndings reveal a novel post-transcriptional system that can augment the human proteome via the alternative use of diverse translation start sites coupled with transcriptional regulation through alternative promoters or splicing.

July 2007 ASBMB Today 33 for your lab

The information in For Your Lab has been provided Olis, Inc by manufacturers and suppliers of laboratory equipment. For further information about any of SOFTWARE FOR THE HP 8452™ these products listed, contacts are listed at the DIODE ARRAY bottom of each panel. When contacting any of Olis SpectralWorks software is available for the HP 8452 spectrometers. Our Windows XP program and interface these companies, please mention that you saw hardware enhance data acquisition rates of the classic their product in ASBMB Today. Please note that a diode array to 10 scans per second. listing in ASBMB Today does not imply an endorsement Data handling features include 2D and 3D data acquisition, presentation, and by the American Society for Biochemistry and Molecular fitting. Computerized use of many Biology or by any of its members or staff. original and third party accessories is Manufacturers and suppliers who would like to supported. include products in For Your Lab can contact Molly at [email protected] or 301-634-7157 For more information, please call Kristi at 1-800-852-3504 or email [email protected] (direct) or 1-800-433-2732 ext. 7157.

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34 ASBMB Today July 2007 career opportunities

The department is located within Johns Hopkins University is an equal opportunity/ Johns Hopkins Bloomberg affirmative action employer committed to recruit- a collaborative and highly interactive School of Public Health ing, supporting, and fostering a diverse community environment with superb core facilities of Biochemistry and of outstanding faculty, staff, and students. All the Johns Hopkins medical institutions. applicants who share this goal are encouraged Molecular Biology to apply. Within the department there is a well E.V. McCOLLUM established training program for Ph.D. PROFESSOR AND CHAIR and masters students. The Johns Hopkins Bloomberg School of Applications should include a CV, Public Health invites applications for the Thomas Jefferson statement of research interest, and vision University endowed E.V. McCollum Professor and of leadership for an outstanding basic sci- chair of the Department of Biochemistry ence department in the setting of a school RESEARCH INSTRUCTOR and Molecular Biology. The successful of public health. Submit applications by Research instructor sought by Thomas applicant will have an independently August 1, 2007, to: Jefferson University in Philadelphia, Penn- funded research program, leadership Chairman, Search Committee for Biochemistry sylvania. Requires Ph.D. in Biological skills, and a vision for the integration of and Molecular Biology Science, Animal Science, or related fi eld basic and public health-based sciences. c/o Ms. Susan Waldman, Special Assistant and 1 year of. experience in surgery This position offers a unique and exciting Offi ce of the Dean on small animals. Send CV and salary Johns Hopkins Bloomberg School of opportunity to recruit new faculty into requirements to: Public Health Attn: Job Code RI; Thomas Jefferson University, excellent facilities and to build new pro- 615 N. Wolfe St., Room W1041 grams at the intersection of basic science, Baltimore, MD 21205 1020 Locust St., Ste. M85 Jefferson Alumni medicine and population health. [email protected] Hall, Philadelphia, PA 19107. meet ing calendar

Senescence, Aging, and 234th American Chemical JULY 2007 Cancer Symposium Society National Meeting JULY 26–29, 2007 AUGUST 19–23, 2007 XXIst Congress of the International Society on AMES, IA BOSTON, MA Thrombosis and Haemostasis www.bb.iastate.edu/%7Egfst/homepg.html chemistry.org/meetings/boston2007 Tel.: 515-294-7978 JULY 6–12, 2007 21st Biennial Meeting of GENEVA, SWITZERLAND FASEB Summer Research the International Society www.isth2007.com Conference for Neurochemistry and Lipid Droplets: Metabolic Consequences the American Society for 32nd FEBSCongress: of Stored Neutral Lipids Neurochemistry Molecular Machines JULY 28–AUGUST 2, 2007 AUGUST 19–25, 2007 and Their Dynamics in VERMONT ACADEMY, SAXTONS CANCUN, MEXICO Fundamental Cellular RIVER, VT www.isn-asn2007cancun.org.mx/ Functions Organizers: Dawn L. Brasaemle, Rutgers, The JULY 7–12, 2007 State University of New Jersey, and Rosalind A. Drug Action and Coleman, University of North Carolina VIENNA, AUSTRIA Chemical Biology in src.faseb.org Registration is open until March31 the Post-genomic Era www.FEBS2007.org AUGUST 23–27, 2007 VIENNA, AUSTRIA Life Sciences 2007 AUGUST 2007 cwp.embo.org/w07–27/ A Joint Meeting of the Biochemical E-mail: [email protected]. Society, the British Pharmacological ac.at Society, and the Physiological Society 13th International Conference JULY 8–12, 2007 on Second Messengers and 13th Nordic Mass GLASGOW, UK Phosphoproteins Spectrometry Conference AUGUST 28–31, 2007 www.lifesciences2007.org/ AUGUST 1–4, 2007 SAN DIEGO, CA SAVONLINNA, FINLAND EUROCOMBI 4 Abstracts must be submittedbyJuly 1 www.nsms.no/moter.html JULY 15–18, 2007 www.smp-2007.com/ FLORENCE, ITALY www.polosci.unifi .it/eurocombi4 FASEB Summer Research SEPTEMBER 2007 E-mail: marta.cocchi@unifi .it Conference Lipid Signaling Pathways in Cancer 48th International Conference 21st Annual Symposium AUGUST 11–16, 2007 on the Bioscience of Lipids of the Protein Society SEPTEMBER 4–8, 2007 Proteins: From Birth to Death INDIAN WELLS, CA TURKU, FINLAND JULY 21–25, 2007 src.faseb.org www.icbl2007.abo.fi BOSTON, MA www.proteinsociety.org Kern Aspen Lipid Conference Diabetes, Obesity, and Atherosclerosis British Mass Spectrometry Society Meeting AUGUST 19–22, 2007 Gordon Research Conference SEPTEMBER 9–12, 2007 Molecular and Cellular ASPEN, CO EDINBURGH, SCOTLAND Biology of Lipids www.uchsc.edu/kernconference/ www.bmss.org.uk/meetings.htm JULY 22–27, 2007 E-mail: [email protected] E-mail: [email protected] WATERVILLE VALLEY, NH Tel.: 44-(0)-1480-880-669 www.grc.org 8th International Symposium on Mass Spectrometry in the Mass Spectrometry in Clinical 4th British Society for Health & LifeSciences Chemistry and Molecular Proteome Research/European AUGUST 19–23, 2007 Diagnostics Bioinformatics Institute SAN FRANCISCO, CA SEPTEMBER 14–18, 2007 Proteomics Meeting www.donatello.ucsf.edu/symposium/ PACIFIC GROVE, CA Integrative Proteomics: Maximizing the E-mail: [email protected] Value of Proteomics www.asms.org Tel.: 415-476-4893 E-mail: offi [email protected] JULY 25–27, 2007 Tel.: 505-989-4517 CAMBRIDGE, UK www.bspr.org/ E-mail: [email protected]

36 ASBMB Today July 2007

Sending Research in New Directions

NEW Categories in The Journal of Biological Chemistry Table of Contents: s$.!REPLICATION REPAIR RECOMBINATION CHROMOSOMEDYNAMICSs4RANSCRIPTION CHROMATIN EPIGENETICSs2.!PROCESSING CATALYSISs2.! MEDIATEDREGULATIONNONCODING2.!s0ROTEINSYNTHESIS POST TRANSLATIONALMODIlCATION DEGRADATION s'ENOMICS PROTEOMICS BIOINFORMATICSs0ROTEINSTRUCTUREFOLDINGs%NZYMECATALYSISREGULATIONs-ETABOLISM BIOENERGETICSs'LYCOBIOLOGYEXTRACELLULARMATRICESs,IPIDSLIPOPROTEINS s-EMBRANETRANSPORT STRUCTURE FUNCTION  BIOGENESISs-OLECULARBASISOFCELLDEVELOPMENTALBIOLOGYs-ECHANISMSOFSIGNALTRANSDUCTIONs"IOMOLECULARNETWORKS www.jbc.org