October 2012

American Society for Biochemistry and Molecular Biology contents OCTOBER 2012 On the cover: In this issue, we complete our preview coverage of the news ASBMB annual meeting. 12 2 President’s Message Being clear about transparency

5 News from the Hill Presidential science debate responses

6 Washington Update 7 Member Update 2013 annual meeting 8 Tabor awards In this issue and the previous one, we’ve featured the thematic programming planned 9 On the scene: Hill Day for the ASBMB annual meeting to be held April 20-24 in Boston. essay September: Overview 10 Tribute to Bob Hill Catalytic Mechanisms RNA Function & Protein Synthesis features Lipids & Membranes Chemical & Systems Biology 18 The evolving molecular view of bone Mechanisms of Gene Transcription & Regulation 22 Biologically inspired innovation Protein Modication, Trafcking & Degradation departments In the October issue: 27 Lipid News 12 Genome Replication & Repair FIT and fat 13 Glycobiology 13 Education: Transitions 28 Journal News 14 Minority Affairs: Triple-Negative 28 JBC: Prion and other amyloid diseases: Breast Cancer Reed Wickner shares lessons from yeast cells 15 Computational Tools for Assigning 29 JBC: Everything is illuminated: ‘Re ections’ Enzymatic Functions (workshop) on light and life by Lubert Stryer 15 Outreach: From the Lab to the Kitchen 30 JLR: Late Swedish lipidologist Olofsson Table – Communicating Science to a remembered by colleagues Lay Audience 31 MCP: Secretions of bone-forming cells 17 Signal Transduction Mechanisms

October 2012 ASBMB Today 1 president’s

A monthly publication of ag The American Society for Biochemistry and Molecular Biology Transparency is particularly important for Being clear about a taxpayer-funded enterprise. Aspects of this Officers were formalized in the NIH Reform Act of 2006, After months of effort, I turned Jeremy M. Berg President transparency Suzanne R. Pfeffer Past President which established the Scientific Management Mark A. Lemmon Secretary BY JEREMY BERG Review Board “to advise the NIH Director … to another vehicle for promoting Toni Antalis Treasurer on the use of … organizational authorities” Council Members transparency in government (for example, adding, removing or transferring Karen N. Allen Levi Garraway David Sabatini Melissa Starovasnik hortly after I became a graduate student in the chemistry department at offices, centers and institutes) and to “identify operations, the Freedom of Wesley I. Sundquist Jonathan S. Weissman Harvard University, the great biochemist Jeremy Knowles assumed the the reasons underlying the recommendations” Natalie Ahn Anjana Rao S Information Act. Daniel Leahy department chairmanship. He instituted semiannual town-hall-style meet- (5). When advising on “specific contemplated Ex-Officio Members ings with graduate students at which we could raise issues of concern and organization changes,” the SMRB is charged Carol Fierke Patrick Sung Knowles could describe ongoing and planned activities within the department. with consulting with stakeholder groups both Co-chairs, 2013 Annual Meeting Program Committee Peter J. Kennelly, Chair, Education and Professional He attended to the issues that were easy to fix and at least acknowledged inside and outside the NIH. This was reinforced in the first months before. Shortly after the translational medicine and Development Committee the harder problems. These meetings had a substantial positive effect on report produced by the SMRB, “Deliberating Organiza- therapeutics report (8) was presented to the full SMRB Daniel Raben, Chair, Meetings Committee Fred Maxfield, Chair, Mentorship Committee my morale and that of my colleagues. Although I was only slightly aware of it tional Change and Effectiveness,” which highlighted the and approved by a 12−1 margin (I was the sole vote Terri Kinzy, Chair, Membership Committee at the time, this practice made a big impression on my view of the power of importance of transparency and communication when against), the NIH director sent a memo to the secretary Squire J. Booker, Chair, Minority Affairs Committee transparency in leadership. considering substantial reorganizations (6). of the U.S. Department of Health and Human Services Bettie Sue Masters, Chair, Public Affairs Advisory Committee A decade later, I found myself in the unexpected position of being a depart- The SMRB embraced this approach in considering the urging her to recommend to Congress both that a new Charles Brenner, Chair, Publications Committee ment chairman. I remembered Knowles’ lesson and met with the faculty, staff, potential merger of the National Institute on Alcohol and translational center be established and that the NCRR be Martha J. Fedor, Editor-in-chief, JBC Herbert Tabor, Co-editor, JBC postdocs and students regularly and encouraged them to bring their concerns Alcohol Abuse and the National Institute on Drug Abuse. abolished, as the secretary subsequently did. Ralph A. Bradshaw to me. I also revealed as much as was reasonable about our department’s The SMRB and its working group evaluating this reorgani- Despite several attempts, I was unable to learn of A. L. Burlingame Co-editors, MCP finances so that the faculty and staff could understand both our capabilities zation consulted extensively with stakeholders, including any clear rationale for the abolishment of NCRR or what Edward A. Dennis and our limitations and help shape our priorities. Should we provide more the advisory councils of the two institutes, scientific and alternatives had been considered. After months of effort, Joseph L. Witztum Co-editors, JLR resources to our departmental facilities or use the funds to hire new faculty or patient-advocacy groups, and the public. Their compre- I turned to another vehicle for promoting transparency in ASBMB Today Editorial Advisory Board staff members? Without this information, staff participation in such decisions hensive efforts culminated in the report “Substance Use, government operations, the Freedom of Information Act Alex Toker (Chair) would have been difficult, and the potential level of frustration about why we Abuse, and Addiction Research at NIH” (7). Not everyone (9). In April 2011, I filed a FOIA request with Health and Mike Bradley Craig E. Cameron were pursuing some actions and not others likely would have been higher. agreed with the final recommendation to create a new, Human Services requesting information about the NCRR A. Stephen Dahms Alex C. Drohat Ben Ellington Irwin Fridovich Yet another decade later, I became director of the National Institute of merged institute, but the SMRB and NIH leadership took abolishment decision. After receiving an initial acknowl- Richard W. Hanson Gerald Hart General Medical Sciences at the National Institutes of Health. NIGMS is a sub- into account considerable information and feedback, and edgment of my request, I waited a full year until I received Peter Kennelly Carol C. Shoulders ASBMB Today stantially more complex organization than a basic science department, with all stakeholders had ample opportunity to provide input the first materials. The emails and other communications Angela Hopp Editor more, and more diverse, stakeholders. Furthermore, I knew from my experi- before the decision to pursue the merger was made. were substantially redacted, and I have yet to receive all [email protected] ence as an applicant, a grantee and a department chairman that NIH policies The next major reorganization for which the SMRB was materials responsive to my request. The materials pro- Rajendrani Mukhopadhyay Sr. Science Writer / Editor and procedures can be opaque. Why would a given percentile score result in enlisted involved making “recommendations for organizing vided to date have not shed much light on the rationale [email protected] funding in one year but not the next? Why had my budget been cut despite the agency’s existing components to optimize a transla- for abolishing the NCRR. I did learn that the secretary of Marnay Harris Designer an outstanding score and a clear justification that I needed the full budget to tional medicine and therapeutics program.” In the course Health and Human Services and her staff were briefed by [email protected] Andrew Harmon Science and Technology complete the aims? Once I felt that I had mastered at least some aspects of of its deliberations, the assigned working group decided the NIH leadership about the likely SMRB working group Publishing Manager, [email protected] the NIH’s workings, I sought to share these insights with the scientific com- to recommend the transfer of the Clinical and Transla- recommendation, including the abolishment of the NCRR, Nancy J. Rodnan Director of Publications [email protected] munity, initially through periodic emails and later through a blog, the NIGMS tional Science Award program from the National Center before the SMRB had even met to discuss it and that Barbara Gordon Executive Director Feedback Loop (1). These efforts were well received by the community, for Research Resources to a new center focused on legal staff at the NIH had objections to even attributing the [email protected] particularly posts that included data curves showing the probability of being translational science. The CTSA program accounted for recommendation for the creation of the new translational For information on advertising, funded as a function of percentile score and analyses of scientific output as a about 40 percent of the NCRR budget, with the remain- center to the SMRB. These discoveries further contact Fox Associates Inc. at 800-440-0231 or [email protected]. function of various parameters. I found the subsequent blog comments and der spread over programs focused on animal research highlight the lack of transparency in considering emails from scientists and administrators useful for understanding the con- resources, institutional capacity building, shared instru- these reorganizations. cerns of the community, collecting some creative ideas and shaping institute mentation and other areas. Given the proposal to transfer a large program from policies. I shared my experiences with others in the NIH leadership and have Based on this pending recommendation, the NIH the NCRR to the new translational center, was abolish- www.asbmb.org/asbmbtoday been pleased to see recently posted funding data from some other institutes leadership decided to abolish the NCRR without further ing NCRR the best course of action? I do not know, but I (2, 3) as well as an informative blog written by Sally Rockey, the NIH deputy evaluation by the SMRB of the repercussions of doing would argue that neither did the NIH director. In bypassing director for Extramural Research (4). so, ignoring the principles established by the SMRB only the transparent, deliberative process established by the

2 ASBMB Today October 2012 October 2012 ASBMB Today 3 president’s ag continued from the hill (11), but, again, the likelihood of success of the program would seem only to increase ws In my experience, transparency through the broad release of the structural information. almost always improves In my experience, transparency almost In case you missed it outcomes and has a positive always improves outcomes and has a BY PUBLIC AFFAIRS STAFF positive impact on the perceptions and impact on the perceptions and attitudes of even those who do not agree s Election Day grows nearer, the citizens of the widespread applications and potential. attitudes of even those who do with a decision. Certainly, some information A nation are now inundated with political ads, Research and the future: Given that the next is sensitive and cannot be shared widely making the case for and against certain candidates as Congress will face spending constraints, what prior- not agree with a decision. without causing difficulties. Furthermore, parties and special interests work to frame this election ity would you give to investment in research in your achieving transparency is not always in the most beneficial way. As a nonprofit organization, upcoming budgets? simple, even when desired, because effec- the American Society for Biochemistry and Molecular OBAMA SMRB, the NIH director deprived himself and others of tive communication and engagement can Biology is not permitted to engage in partisan activi- • says he strongly supports investments in research the input from different stakeholders that could have be quite challenging. Nonetheless, all will benefit if we ties. We are not permitted to donate to campaigns or and development that spur innovation and proposed informed this important decision before it was made. encourage or even insist on greater transparency from political parties, and we are not permitted to endorse that the U.S. invest more than 3 percent of its gross Furthermore, the manner in which this significant reor- organizations with which we are involved. A well-known a candidate for office. We are, however, permitted to domestic product in public and private R&D, “exceed- ganization was conducted substantially undermined the part of Jeremy Knowles’ scientific legacy involves educate our members on the candidates’ positions. ing the level achieved at the height of the space race.” standing of the SMRB as a vehicle for transparency. wrestling with the concepts of efficiency and perfection Earlier this year, the ASBMB was invited to join 14 of ROMNEY I am now examining other situations that would in enzymatic catalysis. In the spirit of fostering a different the nation’s top scientific societies to play an advisory • says “continued funding would be a top priority appear to benefit from greater transparency. One relates component of his legacy related to the effective opera- role in the development of a science debate in an in my budget” and that policies must ensure “federal to indirect costs and facilities and administrative rates tion of organizations, I encourage you to come to me attempt to nail down the candidates’ positions as they research is being amplified in the private sector and at different institutions. Surprisingly, there does not with any questions or suggestions you may have with relate to science. The full responses from Democratic that major breakthroughs (can) make the leap” from the seem to be any available tabulation of such rates, and regard to the operations of the American Society for President Obama and Republican Mitt Romney can be lab to the market. the ability to locate such information varies substantially Biochemistry and Molecular Biology. viewed at www.sciencedebate.org. Science in public policy: We live in an era when from one institution to the next. Given that these costs Innovation and the economy: What policies will science and technology affect every aspect of life are the topic of considerable discussion and affect the and society and so must be included in well-informed Jeremy Berg ([email protected]) is the associate senior best ensure that America remains a world leader in amount of research federal science agencies can afford vice-chancellor for science strategy and planning in innovation? public policy decisions. How will you ensure that policy to fund, I would argue that having such data readily the health sciences and a faculty member in the OBAMA and regulatory decisions are fully informed by the best available would only facilitate accurate analysis related computational and systems biology department at • says “we must create an environment where inven- available scientific and technical information and that to these issues. A second involves the new NIH pro- the University of Pittsburgh. tion, innovation and industry can flourish”; the public is able to evaluate the basis of these policy gram Discovering New Therapeutic Uses for Existing • commits to doubling funding for key research decisions? REFERENCES Molecules (10), which provides academic investigators 1. https://loop.nigms.nih.gov/ agencies to support scientists and entrepreneurs; and OBAMA access to study 58 compounds from eight pharma- 2. https://deaissl.nci.nih.gov/roller/ncidea/entry/funding_patterns • set the goal of preparing 100,000 science and • says policies should be based on “the best sci- ceutical companies that were tested for safety but 3. http://www.niams.nih.gov/about_us/budget/pattern_fy2011.asp math teachers over the next decade to meet “the ence available and developed with transparency and then abandoned for their initial therapeutic indication. 4. http://nexus.od.nih.gov/all/rock-talk/ urgent need” to train 1 million science, technology, public participation” and that he appointed advisers 5. http://smrb.od.nih.gov/charter Although the list of code numbers is available, the struc- engineering and math graduates. “based on their credentials and experience, not their 6. http://smrb.od.nih.gov/documents/announcements/DOCE_112010.pdf tures of the compounds are not, despite their impor- 7. http://smrb.od.nih.gov/documents/announcements/SUAA_112010.pdf ROMNEY politics or ideology” and tance for, among other things, computationally screen- 8. http://smrb.od.nih.gov/documents/reports/TMAT_122010.pdf • says the promotion of innovation “will begin on day • pledges to keep looking for new ways to improve ing these compounds against potential targets. Some 9. http://www.foia.gov/ one” by simplifying the corporate tax code, fixing job- transparency. 10. http://www.ncats.nih.gov/research/reengineering/rescue-repurpose/ academic investigators have used creatively a variety therapeutic-uses/therapeutic-uses.html retraining programs, reducing regulatory burdens and ROMNEY of sources to prepare a partial list of these structures 11. http://cdsouthan.blogspot.se/2012/08/ncats.html protecting U.S. intellectual property; • pledges to let the best science and information • emphasizes immigration reform to attract and guide his administration’s decisions and to “avoid the FOLLOW ASBMB AND ITS TEAM ON TWITTER retain skilled workers and says he’ll raise visa caps for manipulation of science for political gain” and them and give permanent residence status to foreign • says “the costs and benefits of regulations will be The official ASBMB feed: @ASBMB Marnay Harris, graphic designer: @MarnayH students who earn advanced degrees in relevant fields; properly weighed.” and The ASBMB strongly encourages you to stay Angela Hopp, ASBMB Today editor: @AngelaHopp Benjamin Corb, public affairs director: @BWCorb • credits federally funded basic research with mov- engaged, to read the full statements from the candi- ing the U.S. forward “in astonishing ways” and says dates on these and other issues of importance to you, Rajendrani Mukhopadhyay, senior science writer: @RajMukhop Geoff Hunt, public outreach coordinator: @GoodbyeShoe funds should go to research programs that advance and to make informed decisions. Above all else, we the development of knowledge and technologies with strongly encourage you to get out and vote Nov. 6!

4 ASBMB Today October 2012 October 2012 ASBMB Today 5 faseb t b r update Three members Introducing myIDP: an interactive, online receive Lasker career-planning tool for scientists awards In early September, the Albert and Mary BY JENNIFER A. HOBIN Lasker Foundation announced seven winners of the annual Lasker awards. Three members of the American t comes as no surprise to most graduate students those interested in the different career paths, including Society for Biochemistry and Molecular and postdocs that, even after years of rigorous traditional research positions in academia and indus- Biology were among the recipients. I SPUDICH VALE BROWN scientific training, landing a tenure-track academic try as well as options with which trainees may be less Members James Spudich of the Stanford University School of Medicine position is not easy. Nor is it the norm. In fact, data familiar, such as research administration, regulatory and Ronald Vale of the University of and unveiled key aspects of how observations of how cells control gene affairs and science policy, just to name a few. show that less than half of all biomedical researchers California, San Francisco, won the basic molecular engines convert chemi- activity, are credited with ushering in are employed in academia, and less than 15 percent In addition to providing guidance on exploring these medical research prize for laying the cal energy into mechanical work. the recombinant DNA era. Outside the will wind up in tenure-track positions three to five years career options, myIDP helps users set career and foundation for the study of cytoskeletal Member Donald Brown of the lab, Brown founded and led the Life after they obtain their degrees. What may come as a professional-development goals. A summary report motor proteins. Also a co-winner was Carnegie Institution for Science in Sciences Research Foundation, and surprise is the number of nonacademic career options presents those goals in chronological order, and the Michael Sheetz, who, with Spudich, Baltimore won his prize for exceptional Maniatis created the Molecular Cloning available to those with doctoral-level scientific train- application allows users to sign up for automated developed the first biochemical assay achievement along with co-winner manual, which has been used all over ing. Now, a new interactive career and professional- reminders to help them meet their goal deadlines. A to reconstitute myosin motor activity in Thomas Maniatis. The foundation the world. In a statement, the founda- development tool is available to help research trainees series of articles providing a more in-depth explana- vitro and showed that myosin and ATP lauded Brown’s “leadership and citizen- tion said, “Through their relentless were enough to direct transport along ship in biomedical science, exemplified pursuit of the questions that fascinated make sense of and prepare for the many career options tion of each component of myIDP will be published in actin filaments. Vale and Sheetz later by fundamental discoveries concern- them and their willingness to help their available to them. Science Careers and linked to the relevant pages of the looked into transport along a microtu- ing the nature of genes, by selfless peers as well as students, they have Called myIDP, the tool is designed to help graduate Web module. bule in giant squid axon extracts and commitment to young scientists and by achieved success and have set a high students and postdocs in the sciences create indi- myIDP is based on the Individual Development Plan discovered a new molecular motor — disseminating revolutionary technolo- of exemplary behavior for members of vidual development plans, or step-by-step plans for for Postdoctoral Fellows, a four-step career-planning kinesin — that runs along that track. gies to the scientific community.” Brown the biomedical research community.” identifying and reaching their career goals – whatever framework developed by the Federation of American Ultimately, the trio set the stage for established the biological function of Each Lasker prize category they may be. This free online tool walks users through Societies for Experimental Biology in 2002. The goal figuring out how motor proteins drive the organelle known as the nucleolus carries a purse of $250,000. The the process of assessing their proficiencies in a host of FASEB’s IDP is to help scientists identify their short- transport of a host of molecules that and co-discovered gene amplifica- award ceremony was in late of science-related skills and knowledge areas, includ- and long-term career objectives and professional- play roles in many cellular processes tion. Those findings, along with his September in New York. ing research and technical skills, communicating to development needs and to create, in conjunction with scientific and lay audiences, managing and leading their mentors, written plans for meeting those goals. people and projects, navigating peer review, and career The process has received considerable attention in ASBMB journal-sponsored lectureships planning. Because skills are only a part of the picture, the research-training community: The National Post- The Journal of Lipid Research of Western Ontario and The journal Molecular & Cellular myIDP also includes exercises to help users assess doctoral Association recommended the IDP as a best sponsored six lipid research con- Robarts Research Institute, Proteomics sponsored three meet- their science-related interests (Do you like designing practice in postdoctoral training; the National Institute ferences around the world this Kern Aspen Lipid Conference: ings. Below are the researchers experiments and reading papers in your field but hate of General Medical Sciences endorsed the IDP; and, year. Below are the researchers Systems Biology, Lipidomics and selected for those award lectures: writing grants and serving on committees?) and their most recently, the National Institutes of Health Advi- selected for award lectures: Cardiometabolic Diseases, July • Angus Lamond, University career-related values (How important is it for you to sory Committee to the Director’s Biomedical Research • Deborah M. Muoio, Duke • Julie Saba, Children’s Hospital of Dundee, Keystone Symposium: work in a team? Be the boss? Have a stable salary and Workforce Working Group recommended that the NIH University, Keystone Symposium Oakland Research Institute, FASEB Proteomics, Interactomes, May benefits?). require IDPs for all NIH-supported graduate students on the Pathogenesis of Diabetes: Conference: Phospholipid Metabolism • Susan L. Lindquist, Emerging Insights into Molecular – Disease, Signal Transduction Massachusetts Institute After a user has completed these self-assessment and postdoctoral researchers. In addition, the majority Mechanisms, January and Membrane Dynamics, July of Technology, The Human exercises, myIDP provides him or her with a list of 20 of postdoctoral offices surveyed by FASEB reported • Bruce Spiegelman, • Stephen G. Young, University Proteome Organization’s 11th common scientific career options ordered from best fit that they recommended that postdocs develop IDPs. Harvard Medical School, Deuel of California, Los Angeles, Frontiers World Congress, September to worst fit based on how the user’s skills and interests Perhaps most importantly, postdocs who develop Lipid Conference, March in Lipid Biology, a joint confer- match each career. The match is calculated by com- IDPs benefit. A FASEB survey revealed that it helped • Ruth McPherson, University ence by the American Society for paring the user’s skills and interests to those that career postdocs assess their skills and abilities and identify the of Ottawa Heart Institute, Biochemistry and Molecular Biology, Please submit member-related advisers knowledgeable about job opportunities for skills they need to advance their careers. Reflecting on XIV International Symposium the International Conference on the news and accolades to scientists say are needed for each option. on Atherosclerosis, March Bioscience of Lipids, and the Canadian [email protected]. myIDP also has an extensive list of resources for Continued on page 32 • Robert Hegele, University Lipoprotein Conference, September

6 ASBMB Today October 2012 October 2012 ASBMB Today 7 firstn continued b news Two more Tabor young investigators ASBMB young scientists head to Capitol Hill

On Sept. 11, 30 American Society for Biochemistry At meeting in the Netherlands, emerged suggesting novel mecha- and Molecular Biology members conducted more than nisms of drug interaction with 70 meetings and met with legislators from 26 states to Catherine Bell was lauded advocate for increased funding for biomedical research. T-cells.” for project on T-cell-mediated Bell explains that patients drug-hypersensitivity reactions expressing the HLA-B*57:01 allele are at significantly increased risk of BY ADITI DAS abacavir hypersensitivity reactions. Catherine Bell, a doctoral student at the Medical BELL In fact, the U.S. Food and Drug Research Council Centre for Drug Safety Science at Administration recommends pretherapy screening for the University of Liverpool, won a Journal of Biologi- the presence of the HLA-B*57:01 allele and the selec- cal Chemistry/Herb Tabor Young Investigator award in tion of alternative therapies for patients who carry it. June at the 19th International Symposium on Micro- “We have generated abacavir-specific T-cell clones somes and Drug Oxidations and 12th European Inter- from healthy individuals expressing this allele to study national Society for the Study of Xenobiotics Meeting how they are activated,” Bell said. “Our data suggest in Noordwijk aan Zee, Netherlands. Bell was acknowl- that both direct and processing-dependent pathways edged for her work on the role of metabolism in drug are involved.” hypersensitivity reactions. Originally from Lincolnshire, Bell moved to Liverpool Drug-induced, T-cell-mediated hypersensitivity reac- in 2005 to embark on her undergraduate studies in tions are a cause of concern for clinicians and pharma- pharmacology under the mentorship of Kevin Park and ceutical companies. They are usually detected during Dean Naisbitt. She is now in her final year of doctoral late stages of drug development and occur at low studies and has used quantitative methodologies, such frequency; however, they remain a cause of mortality. as mass spectrometry, to study drug metabolism fate in “I am particularly interested in the drug abacavir,” a patient immune cells as well as bioinformatic analyses, nucleoside analog used to treat AIDS and known by such as those used to examine human leukocyte anti- the brand name Ziagen, Bell said. “This is quite a hot gen haplotype relationships among the alleles associ- Top left: From left, Rebekah Bullard, David Coleman, Ben Corb, Mark Stewart topic at the moment, and a lot of new data has recently ated with organ-specific human diseases. Top right: From left, Danny Miller, Robert Palazzo, Liz Andrews Bottom left: From left, Matthew Evans, Rose Willett Bottom right: From left, Bob Matthews, Emily St. Amant, Melissa Englert

At meeting in France, Tomé won in Strasbourg, France. radiation. Then she set out on a course “to understand This semester, Tomé is revisiting her alma mater in award for work on muscular Tomé was recognized for her work to unravel novel the mechanisms of CAG/CTG repeat instability in DM1 Paris to team up with Gourdon again to identify the mechanisms and factors that regulate the genetic insta- patients using a transgenic mouse model of DM1,” she genetic factors causing repeat contractions, rather dystrophy and other triplet repeat bility and subsequent pathobiology of the trinucleotide explained. than expansions, observed in some patients. She said expansion disorders repeat expansion disorder myotonic dystrophy type 1. She collaborated with Christopher Pearson’s group she is moved by the potential translational impact of in Canada, with whom she pursued a postdoc fellow- their research, adding, “Reversing repeat expansions in BY ADITI DAS Also known as Steinert disease, DM1 is the most com- mon adult form of muscular dystrophy and one of more ship. She has investigated the role of the DNA mis- the mutant genes to the shorter lengths present in the Stéphanie Tomé, a postdoctoral fel- than 40 diseases caused by unstable repeating DNAs. match repair proteins MSH2 and MSH3 in the forma- nondiseased population is a worthy therapeutic goal, low at the Hospital for Sick Children Tomé earned her doctorate in human genetics in tion of CTG expansions and identified the role of ligase as the DNA is a single target that is the basis for the and the University of Toronto, won 2009 at Paris Diderot University under the guidance of I in the formation of maternal CTG repeat expansion in multitude of downstream events and symptoms.” the Journal of Biological Chemis- Geneviève Gourdon. She said she became vivo. “I participated in the development of an efficient try/Herb Tabor Young Investiga- “fascinated by genetic instability” initially during a stint antibody specific to MSH3 with the laboratory of Dr. Aditi Das ([email protected]) is a Washington, tor Award at the 7th International in 2004 in Stockholm, where she worked with the lab Glen Morris in the United Kingdom,” she said. “This D.C.-based science writer and research consultant at the National Institutes of Health and Maryland Conference on Unstable Microsat- of Ulf Rannug analyzing the instability of CEB1 (human new tool was important for my subsequent studies and Biotech Center. Connect with her on LinkedIn. TOMÉ ellites and Human Disease in June minisatellites) in Swedish people exposed to ionizing for other labs.”

8 ASBMB Today October 2012 October 2012 ASBMB Today 9 firstn continued essay

central role. Robert L. Hill retires as JBC associate HISTORIAN AND HISTORY MAKER Hill’s role with Classics was to identify appropriate Bob Hill was a co-curator research areas and the key JBC papers and to over- editor after five decades of service of the JBC Classic articles see the preparation of the description of the time and for many years. In 2006, BY THE JBC ASSOCIATE EDITORS* context of the research. Given Hill’s own remarkable the feature highlighted research career, he knew many of the authors of the three of his own papers: Classics and was able to contribute behind-the-scenes • The complete amino acid and personal insights about the work, the authors and obert L. “Bob” Hill, a Journal of Biological Chem- sequence of α-lactalbumin the times. All his insights were interesting, and a few R istry associate editor whose long tenure coincided A NATURAL LEADER (1970) were even suitable for publication! with the journal’s exponential growth and its ascent Bob Hill assumed many leadership positions in bio- • The disulfide bonds Collections of JBC Classics are available online, and to become the best in its field, retired last month after chemistry and was recognized with numerous honors of bovine α-lactalbumin almost five decades of editorial service. Hill is credited and awards: (1970) many biochemists have reported that they are useful for teaching biochemistry. with overhauling how the JBC recruits editorial board • In 1969, he was named the James B. Duke pro- • The purification and properties of the A protein of members and with curating a popular series of JBC fessor of biochemistry and in 1974 the chairman lactose synthetase (1971) A man deserving of our thanks and more articles that highlight groundbreaking work found in the of the biochemistry department at Duke University, See all the Classics at Hill’s career as a scientist, science leader and journal journal’s archives. a position he held until 1993. During the nearly 20 years of his chairmanship, the department became http://www.jbc.org/content/by/section/Classics. editor has been remarkable. The JBC and the field of Hill joined the editorial board of the JBC in 1965 and one of the best in the world. biochemistry owe him great thanks, and we will miss his served a second term from 1972 to 1977. He became • He was secretary of the American Society of standards to the editorial process and made the JBC wise counsel. an associate editor in 1988. His tenure spanned 47 Biological Chemistry from 1972 to 1975 and presi- a premier place to publish papers in these important years and was one of the longest editorial services in dent in 1976. research areas. the journal’s history — and nearly as remarkable as that *This article was written by JBC Associate Editor Robert Simoni • He served on the Federation of American Societ- Beyond editorial work, Hill made many other con- of former Editor-in-Chief and current Co-Editor Herbert on behalf of and in consultation with the journal leadership, includ- ies for Experimental Biology board from 1972 to tributions to the JBC. He recognized that the editorial ing Editor-in-Chief Martha J. Fedor, Co-Editor Herbert Tabor and Tabor, who first joined the editorial board in 1961. 1978. board is the heart of the journal, and, as the size of the Associate Editors Norma Allewell, Ruma Banerjee, Judith S. A renowned scientist • He was elected to the National Academy of Sci- board began to increase to keep pace with the expo- Bond, George M. Carman, Joan W. Conaway, Peter Cresswell, and respected mentor ences in 1975, the Institute of Medicine in 1978, nential growth in the number of papers submitted, he John Exton, Paul E. Fraser, Joel Gottesfeld, F. Peter Guengerich, and the American Academy of Arts and Sciences Richard W. Hanson, Gerald W. Hart, Vincent Hascall, John M. Born in Kansas City, Mo., in 1928, Hill earned a transformed the process of selecting new board mem- in 1974. Kyriakis, I. Robert Lehman, Jerry Lingrel, Kenneth E. Neet, Luke bachelor’s degree in chemistry in 1949 and a Ph.D. in bers from what had largely been an ad hoc process to • He served as general secretary of the Interna- O’Neill, Charles E. Samuel, James Siedow, William Smith, Linda biochemistry in 1954, both from the University of Kan- one with rigorous review of prospective candidates. tional Union of Biochemistry from 1982 to 1991. Spremulli, F. Anne Stephenson, James T. Stull, Thomas Vanaman With a current board of about 800 members serving sas. He then went on, as a National Institutes of Health and Xiao-Fan Wang. We thank Jeanne Gladfelter, a longtime JBC • He chaired the organizing committee of the very staggered five-year terms, it is necessary to identify and postdoctoral fellow, to work under Emil L. Smith, a staff member, for gathering the data included in the article. successful 17th International Congress of Bio- recruit about 150 new board members each year. Hill pioneer in protein chemistry, at the University of Utah. chemistry and Molecular Biology in San Francisco Hill’s postdoctoral studies with Smith introduced him in 1997. established criteria that required the collection of cur- ricula vitae from candidates, thereby ensuring that each to protein chemistry and enzymology research, areas JOURNAL MAKES ITS MARK • He received the William C. Rose Award from the new member had the experience, accomplishments, he has pursued over his entire career. Hill remained American Society for Biochemistry and Molecular During Bob Hill’s long ten- at the University of Utah as a faculty member of the Biology in 1991, the North Carolina Gold Medal respect and judgment to provide the credible peer ure, the JBC clearly estab- (for science) in 1985 and the Karl Meyer Award review for which the JBC is known. biochemistry department until 1961, when he joined lished itself as the premier from the Society for Glycobiology in 2001. the faculty of the Duke University School of Medicine, A serious conservator of science history journal of biochemistry in where he remains. the world. Importantly, Hill also helped initiate and sustain a popu- After arriving at Duke, Hill established one of the provided a fertile training ground for countless graduate lar JBC feature called Classics. In this feature, landmark • The number of papers most highly regarded protein/enzyme chemistry labs in students and postdoctoral fellows, many of whom have papers published in the JBC, including many seminal published annually the world and did work on a range of proteins: abnor- increased to a peak of become leaders in biochemistry research. contributions that led to Nobel prizes, are reprinted mal hemoglobins, blood-coagulation proteins, immu- 6,434 in 2004 from 600 in along with brief biographical information about the 1965. noglobulins, lysozyme, acyl carrier protein and, most A visionary and reformer for the journal authors. notably, lactose synthase. His work on glycosytransfer- Hill’s primary role at JBC was to review and manage • The size of the editorial Thus far, nearly 250 Classics have been published ases and other glycobiology problems identified him as the review of papers on all aspects of protein chem- board increased to 833 in 2012 from 41 in 1965. featuring more than 500 papers published since the a glycobiologist. istry, blood coagulation and especially glycobiology. • The number of associate editors increased to 28 in JBC began in 1905. These articles trace a remark- Beyond Hill’s research accomplishments, he also He brought good judgment, strong values and high 2012 from three in 1965. able history of biochemistry in which the JBC played a

10 ASBMB Today October 2012 October 2012 ASBMB Today 11 Beyond template- These talks, focused on a single sugar modification of nuclear and cytosolic proteins, will illustrate the wide BOSTON, April 20 – 24, 2013 driven control: variety of protein functions that can be modulated by glycans that regulate nontemplate-driven glycosylation. Pamela Stanley (pamela.stanley@ The third session will highlight current investigations of cell signaling einstein.yu.edu) is the Horace W. Goldsmith professor of cell biology at Genomic replication DNA damage-signaling mechanisms, including initiation BY PAMELA STANLEY AND LANCE WELLS the Albert Einstein College of and optimization of damage checkpoint signaling, regu- Medicine. Lance Wells (lwells@ccrc. and repair lation of recombination and threading of the damage- large body of evidence has demonstrated that uga.edu) is the Georgia Research Alliance Lars G. Ljungdahl distinguished investigator and an associate professor at the BY STEPHEN BELL AND LEI LI signaling cascade via ubiquitination. A post-translational modification of proteins by University of Georgia. The last session will cover mechanistic aspects of individual sugars or glycans composed of many sugars enome integrity is central to maintaining cel- how compromised genome stability leads to cancer. modulates key properties of glycoproteins. No post- Glycobiology Thematic Sessions lular and organismal identity and preventing the Clearly, a large set of genetic alterations is required translational modification is better suited for increasing G O-Mannose Glycans & Muscular Dystrophy development of diseases including cancer. Although to render a cell cancerous. At the chromosomal level, functional diversity of proteins than glycosylation. During early studies focused on DNA polymerase fidelity and tumor-suppressing mechanisms can be compromized this program, the focus will be on how the non-tem- Glycoslytransferases that Control Cell Growth DNA repair mechanisms, it has become clear that many by cumulative and selective deletion of regions encom- plate-driven addition of sugars to key proteins plays a & Differentiation other events contribute to genome maintenance. For passing antiproliferation genes, invoking the cancer critical regulatory role in modulating mammalian signal Roles for Glycans in Notch Signaling example, the replication fork not only replicates the DNA gene island concept. At the DNA level, endogenous transduction and how aberrant glycosylation causes a Regulation of Gene Expression by O-GlcNAc but also coordinates many other functions required for metabolites can be a major source of mutations when variety of developmental diseases and promotes cancer genome stability. pathways countering their actions are defective. These progression. The speakers in the first session will address how the recent advances are mechanistically informative and The first session will concentrate on how defects in replication fork facilitates chromatin assembly, detect- pertinent to cancer etiology. the O-mannose glycosylation pathway are the underly- ing DNA damage and eliminating potential roadblocks. ing cause of multiple forms of muscular dystrophy. The The coordination revealed by these studies illustrates Stephen Bell ([email protected]) is a O-mannose glycans on dystroglycan are essential for Transitions: We all professor at the Massachusetts how replication forks are the focus of many aspects of Institute of Technology and a Howard interactions of the cell with the extracellular matrix, and go through them chromatin function beyond simple DNA replication. Hughes Medical Institute investigator. the pathophysiology of congenital muscular dystrophy In addition, it has become clear that activation of Lei Li ([email protected]) is a can be attributed directly to enzymes and proteins that BY PETER J. KENNELLY AND DORIT ZUK professor at the University of Texas MD Anderson Cancer the eukaryotic replicative helicase is a multistep event Center. participate in the O-mannosylation pathway. involving both DNA and protein remodeling. The second The second session will discuss glycans that regulate o matter where you are today — student, post- session will explore the mechanisms that drive these T-cell differentiation, cancer progression and spermato- N doc, just starting out in your professional career events and how higher chromatin order structure influ- Genome Replication & Repair genesis. These talks will illustrate the key roles that or well into your chosen career path — sometime in ences the temporal regulation of origin activation during Thematic Sessions various classes of glycoproteins play in modulating both the future, you’ll be facing the prospect of a change. S phase. Coordinating Functions at the Replication Fork normal and disease-related signaling and differentiation. This could come about because you’re moving on to When DNA damage occurs, cells need to respond The third session will center on the glycans of a the next step in your career or because you decide it’s Mechanism and Control of Replication Initiation instantly to prevent structural alterations on DNA from single glycoprotein, Notch, and explore critical roles time to change direction. With change comes transition, converting into heritable mutations. This response Activation of DNA Damage Signaling that various sugars play in Notch signaling pathways. the experience of moving from one situation to another, involves complex signaling pathways that extend well Mechanisms of Genomic Stability Glycans on Notch modulate ligand binding and Notch which can be exhilarating or challenging — and often beyond the enzymes that remove the DNA damage. activation. This session will focus on this one glyco- both at the same time. protein as a model for how glycosylation can increase This year, the Education and Professional Develop- functional diversity of proteins. ment Committee decided to focus its program on those The final session will move inside the cell and focus transitions we all go through during our careers and on the nucleocytoplasmic O-GlcNAc transferase, func- to try to answer some questions about these transi- tions for O-GlcNAc in CREB-mediated regulation of tions. How do we decide to make a change and which transcription in long-term memory, and the control of change to make? When should we make it? How do we metabolism during oncogenic signaling via O-GlcNAc. cope with the transitions we encounter along the way?

12 ASBMB Today October 2012 October 2012 ASBMB Today 13 How do we train for a world in transition? women. Stefan Ambs at the National Cancer Institute Identifying Novel Biomarkers During these sessions, we will consider transitions seeks to identify the racial/ethnic differences in tumor to Better Manage Breast Disease from the perspectives of those making the changes and biology that influence the presentation of the disease or Back to the Basics: the Biology of Breast Cancer of those training others. Speakers will share their personal its response to therapy. Ambs will discuss novel targets experiences as well as professional knowledge, providing in advanced breast cancer in black patients. Patricia Breast Cancers that Elude Successful Treatments: insights and tips into transitioning into a variety of career Thompson of The University of Arizona Cancer Center will Triple-Negative Breast Cancer paths away from the bench (e.g., law or high-school highlight ethnic differences and imbalances in outcomes of Genomics: Successes & Challenges in Identifying experimentation. teaching) and transitioning at multiple career phases. early-stage breast cancer. KiTani Parker–Johnson of Xavier 2) Homology modeling methods can expand the use Novel Targets in Breast Cancer Everyone knows you have to transition through train- University of Louisiana will discuss the role of the external of structural modeling to guide function assignment to ing — college to graduate school, graduate school to microenvironment in recruiting breast cancer cells to prolif- proteins without structures. postdoc (typically but not always), postdoc to first “real” erate, migrate and invade other tissues. 3) Computational docking methods can leverage job. But those of us in midcareer positions make changes The second session will address an emerging break- structure to guide functional assignment by suggesting too and often aren’t sure how to go about it. So we’ll have through in TNBC: a concurrence that it is not one disease Workshop: substrates for biochemical experimentation. a session that focuses on this type of transition and hear but instead a result of diverse genotypes. Matthew Meyer- computational The presentations will be followed by a question-and- both from people who’ve done it and from a professional son of the Dana–Farber Cancer Institute has been involved answer session to identify potential collaborations between career adviser. We’ll also discuss how to train students for in one of the most successful sequencing efforts that con- tools for assigning the audience and the EFI. a world in transition and hear about timeless skills we all firms this, and his group observed a fusion of MAGI3 and should develop. AKT3 in TNBC that presents a potential therapeutic target. enzymatic functions John A. Gerlt ([email protected]) We hope you will attend these sessions and come Brian Lehmann, a postdoc in the lab of Jennifer Pieten- is a professor at the University of BY JOHN A. GERLT AND PATRICIA C. BABBITT Illinois at Urbana–Champaign. Patricia away with some insights and tools you may be able to use pol at the Vanderbilt–Ingram Cancer Center, is working C. Babbitt ([email protected]) is a when contemplating your next transition — be it exhilarat- to elucidate molecular differences to identify targets and s of July, the nonredundant TrEMBL protein professor at the University of California, ing, challenging or both. shape drug-discovery efforts. Eddie Reed of the University A database contained 23,165,610 nonredundant San Francisco. of South Alabama has had a successful career in research sequences; a conservative estimate is that one half of SPEAKERS Peter J. Kennelly ([email protected]) is a and clinical practice and will discuss the possible role of these proteins have unknown, uncertain or incorrect (all co-investigators in the EFI) professor and the head of the depart- translational nucleotide excision repair in TNBC. functional annotations. Without correct annotations, the ment of biochemistry at Virginia Polytechnic Institute and State University The third session will feature Chindo Hicks of the Uni- unlimited potential for medicine, chemistry and industry Patricia C. Babbitt, University of California, and chairman of the ASBMB Education versity of Mississippi Medical Center, who studies bioinfor- that could be obtained from functional and mechanistic San Francisco and Professional Development Committee. Dorit Zuk (zukd@mail. matics and genomics of complex human diseases. Hicks, understanding of nature’s complete repertoire of enzymes nih.gov) is a science policy adviser to the National Institutes of John A. Gerlt, University of Illinois who is developing and applying these tools to identify bio- and metabolic pathways cannot be realized. Health deputy director for Extramural Research. Matthew P. Jacobson, University of California, markers and targets from gene-expression data, will focus The Enzyme Function Initiative (supported by NIH San Francisco on breast cancer in minorities. Rick Kittles of the University U54GM093342) is devising an integrated sequence/ of Illinois College of Medicine at Chicago will present his structure based strategy for predicting and assigning Andrej Sali, University of California, San Francisco use of genomewide association studies to identify com- functions to previously unknown enzymes discovered in Brian K. Shoichet, University of California, Health disparities mon genetic factors that influence health and disease and genome projects to meet this challenge. San Francisco to predict targets for cancer in black patients. He seeks To accomplish this goal, the EFI has brought together in breast cancer to identify genetic and environmental factors to better multidisciplinary expertise in bioinformatics, experimental BY GLORIA THOMAS AND KITANI PARKER JOHNSON understand the complex issues surrounding race, genetic structural biology and structural modeling/docking so that ancestry and health disparities using GWAS and other predictions of in vitro enzymatic functions can be made From the lab to the t least five subtypes of breast cancer have been -omics tools. Fatima Jackson of the University of North and experimental enzymology, microbiology and metabo- A identified on the basis of their patterns of biomarker Carolina at Chapel Hill is using genetic mapping to link lomics studies can be pursued. The goal is to validate and kitchen table expression. Triple-negative breast cancer, or TNBC, is and predict black breast-cancer patient outcomes in the confirm enzymatic functions found in vitro as the actual defined as breast epithelial cancer cells that lack the United States based on tribal roots in continental Africa. physiological functions of the enzymes in vivo. Communicating science HER-2/neu receptor, the estrogen receptor and the pro- This workshop will feature presentations describing the to a lay audience gesterone receptor. TNBC patients have a high mortality Gloria Thomas ([email protected]) is development and application of high-throughput computa- BY GEOFF HUNT rate, and, while breast cancer occurs in all races, the rate an assistant professor at Xavier University tional tools to facilitate functional assignment of unknown of TNBC is higher in black women. of Louisiana and a member of the enzymes: he ASBMB Public Outreach Committee makes its ASBMB Minority Affairs Committee. Ki The first session of this program will cover the basics of Tani Parker–Johnson (kparker1@xula. 1) Bioinformatic analyses can cluster sequences into T debut at Experimental Biology 2013 with a wide array breast cancer, particularly the subtypes that affect black edu) is an assistant professor at Xavier University of Louisiana. probable isofunctional groups, thereby assigning tentative of formal and informal activities designed to get you fired functions to be investigated by structure determination, up about taking your science out of the lab and into the structural modeling and docking, and biochemical streets!

14 ASBMB Today October 2012 October 2012 ASBMB Today 15 Science cafés: the new social network Mechanisms Mechanisms of Signal Transduction As the EB2012 Tweet and Meet demonstrated, events Thematic Sessions at science conferences are way better with beer. For EB2013, we will still have the beer, but we are changing of signal transduction Mechanisms of Cell Growth & Autophagy Regulation the format: In conjunction with the team at BY KUN-LIANG GUAN AND CAROL LANGE Protein Phosphorylation Networks sciencecafes.org, we will be hosting “Science Cafés: The G-proteins in Cellular Regulation New Social Network,” a special, two-part science café for ow do cells select and translate myriad signals into EB attendees on the evening of Monday, April 22. H specific biological responses? Mechanisms of Signaling Specificity in Cell Fate: For those of you who don’t know, science cafés repre- Understanding the full complexity of signal transduction Growth, Proliferation or Death? sent a rapidly growing, informal science-education activity, is essential to understanding the many contexts for altered with more than 250 versions spread across 48 states and signaling, such as pathophysiological conditions related to dysregulation to the development of human diseases. the District of Columbia. Cafés are typically held at local stress or the development of cancer. Sessions within this A final session will deal with mechanisms of signal- establishments (for example, bars, coffee houses or res- broad theme will cover new findings in autophagy signal- ing specificity and cell fate. The strength and duration of taurants) on a regular basis (like the third Tuesday of every ing, protein kinases and phosphatases, G-protein–cou- signaling can have profound effects on signaling output; month), with scientists invited to participate in interactive pled-receptor signaling and mechanisms of cell-signaling cells reuse the same pathways in subtly different ways to discussions on their areas of expertise with crowds of specificity in cell fate. regulate disparate biologies. Outreach buffet dedicated followers and interested bystanders. Highlights of the session on autophagy include details Related to this theme, the ser/thr protein kinase mTOR, Outreach can come in a wide variety of flavors. Come get For our event at EB2013, we will start by having the of the biochemical mechanisms and cell biology of the mammalian target of rapamycin, plays a critical role a taste during our interactive roundtable session, “From team from NOVA ScienceNow present a how-to session autophagy machinery regulation, including novel aspects in many pathophysiological processes. The Blenis lab (Yu the Lab to the Kitchen Table — Communicating Science that explains how to set up and run your own science of the VPS34 lipid kinase complex function and regulation et al., Science 2011) has discovered a tumor-suppressive to a Lay Audience,” at 12:30 p.m. Monday, April 22, in café. Immediately following, we will host an actual sci- in response to nutrient signals. role for Grb10, a novel mTOR substrate that, when phos- Boston. ence café! See what it is like to be part of the hottest trend Protein phosphorylation is a fundamental regulatory phorylated, inhibits both PI3K and ERK-MAPK signaling. Daniella Scalice of the NASA Astrobiology Institute will in science outreach. Come, ask questions, learn a little mechanism that affects nearly every aspect of cellular Loss of Grb10 may contribute to the elevated signaling discuss FameLab, the revolutionary science-communi- something (and, of course, have some beer). behavior. Recent findings from the Dixon lab (Tagliabracci and altered cell fate that typify cancer. cation competition, while Ann Merchant of the National et al., Science 2012) reveal that protein kinases are not Academy of Sciences will demonstrate how the Science ‘What is a Germ?’ Challenge confined to the cell interior: A family of Golgi-localized Kun-Liang Guan ([email protected]) is a and Entertainment Exchange works with Hollywood to get The annual meeting isn’t till April. Why wait that long to get protein kinases are secreted and phosphorylate extracel- professor of pharmacology at the accurate science into movies and television shows. involved? Try out your outreach and communication skills lular proteins implicated in bone biomineralization. The University of California, San Diego. If working at the grass-roots level is more your thing, right away! We are inviting ASBMB members to become G-protein–coupled-receptor session will highlight not only Carol Lange ([email protected]) is a professor in the departments of medicine take some time to talk with Cambridge Science Festival part of the 2013 “What is a Germ?” Challenge. the recent progress in the mechanistic understanding of and pharmacology at the Masonic Cancer Center at the University Director P.A. D’Arbeloff about Science on the Streets, or This activity, co-sponsored by the Cambridge Science GPCR signaling but also will cover the relevance of GPCR of Minnesota. find Morgan Thompson of Harvard University, who will Festival and inspired by Alan Alda’s Flame Challenge, convey her experience running Science in the News, a invites ASBMB members to use any platform to submit Annual Meeting student-run outreach group at Harvard. their best explanation for answering the question “What is Advocacy for For those who want to get your institutions involved a germ?” RENEW YOUR ASBMB MEMBERSHIP & SAVE ON Science Funding with outreach, Hannah Alexander of the University of We want you to frame your response so that an ele- Missouri and Jon Dattelbaum of the University of Rich- mentary school student can understand it. Why? Because ANNUAL MEETING REGISTRATION Positive Member mond will describe how outreach is incorporated into the they are the ones who will be judging you! Schools from Belief in Directory Your Ability courses they teach at their respective universities, and the greater Boston area will be grading the entries and let- Tom Baldwin will share how he organized a public lecture ting our participants know which ones they like best. The Map Your Journey Passion to Success with about Your series at University of California, Riverside. best part: Finalists will be invited to present their submis- Goals Events Networ sions before a live audience during the 2013 Cambridge Motivation Outreach and you Science Festival’s Curiosity Challenge on Sunday, April 21. Determination ASBMB ki Do you have an outreach program that you would like Our website goes live in November, so get your entry ng

to showcase for your ASBMB colleagues? Submit an ready. Step up to the challenge! The American Society for Biochemistry Symposi Special Scientic Peer-reviewed abstract for our poster session, to be held during the and Molecular Biology is committed to Journal helping you achieve your professional goals. Subscriptions Experimental Biology 2013 opening reception on the You have the drive, and we have the resources a Support Network of Geoff Hunt ([email protected]) is the public outreach 12,000 Peers evening of Saturday, April 20, and take advantage of this coordinator for ASBMB. to help you take your career to the next level. special opportunity to share your activity with an energetic Maximize Your audience. Check out our abstract topic categories online. Career Potential.

16 ASBMB Today October 2012 October 2012 ASBMB Today 17 feature try

the bone, studying them had been especially hard, and the phosphate,” says Kronenberg. “It was interesting and surprising difficulty led a number of researchers to ignore the cells. As when it was first realized that the major source of FGF23 was Henry Kronenberg at the Massachusetts General Hospital quips, the osteocyte.” That osteocytes signaled to the kidneys when the conventional thinking used to be that osteocytes were just the body needed to hold onto phosphate alerted researchers to “stupid osteoblasts that got buried and stuck in bone.” that fact that bone actively manages mineral metabolism. Lynda Bonewald at the University of Missouri in Kansas The connection between bone and energy expenditure was City, an immunologist and hematologist by training, became first proposed by the group of Gerard Karsenty at Columbia intrigued by the osteocytes inside the bone matrix in the late University. His group used genetic approaches to show that 1980s because of their striking resemblance to neurons with leptin, the hormone released from fat tissue to regulate appetite dendritic protrusions. When she asked experts in the bone field and metabolism, inhibited bone formation through the nervous

what osteocytes did, “I was told they were just placeholders,” system. The work tied together appetite, energy metabolism The Bare she says. “I couldn’t accept that explanation. I started thinking and bone remodeling.

of ways to make cell lines.” Osteocalcin was another surprise in the energy-expenditure Starting in 1997, picture. The protein Bonewald’s group began to “ has been cited in the Bones report osteocyte lines, such Do what you love. Know your literature for more than as MLO-Y4, which gave own bone; gnaw at it, bury it, 40 years and is used as BY RAJENDRANI MUKHOPADHYAY researchers a better idea unearth it, and gnaw it still. a marker for osteoblast of what the cells actually “ activity. But “we didn’t do. Osteocytes act as the – Henry David Thoreau know what osteocalcin mechanosensors of bone, did,” says Thomas probably sensing changes in fluid flow and how the skeleton is Clemens at Johns Hopkins University. weighted during rest or exercise, a hypothesis Bonewald says In the 1990s, the Karsenty laboratory made a knockout Our skeletons do more than just hold us upright histomorphologists proposed decades ago. She says osteocytes mouse missing osteocalcin. The mouse was expected to have a are probably not important as mechanosensors in the embry- bone phenotype, but, unexpectedly, it was a plump animal with onic skeleton or very active postnatally during growth. But they only minor skeletal abnormalities. Around 2008, the Clemens are extremely important in adults. Osteocytes direct osteoclasts group created a different mouse that lacked the insulin receptor and osteoblasts where to degrade old bone and set down new on its osteoblasts. That mouse also became fat and looked just material. They also secrete hormones. “Instead of being thought like the osteocalcin-null mouse that the Karsenty group had of as pitiful cells that got confused and stuck inside bone, they made a decade before. Like the Clemens group, the Karsenty ost of us appreciate that if it weren’t for our the reason you don’t have the same skeleton today as you did are now thought of as the master cells,” says Kronenberg. group had made the mouse missing the insulin receptor in skeletons, we’d be bags of protoplasm oozing on 10 or so years ago. “They are the brains of the outfit.” osteoblasts and had gotten the same phenotype. The mouse Mthe ground. But beyond that, a common perception of bone is Understanding how bone remodeling happens at the cellular studies “linked insulin signaling in the osteoblasts to the pro- that it’s simply an inert mineralized tissue that does only a few and molecular levels was a challenge for decades because the NOT INERT duction of osteocalcin,” says Clemens. things: protect delicate organs, help us to walk, act as a mineral mineralized matrix of bone, containing calcium and phosphate, Perhaps the biggest shift in how bone is perceived is in its The thinking now goes that insulin stimulates osteocalcin store and house the blood-making machinery. had made culturing bone cells by conventional methods dif- function as an endocrine organ. Bone used to be thought production by osteoblasts. The osteocalcin molecule gets stored But that perception has started to shift over the past two ficult. But now a clearer picture is starting to come into focus. of as a tissue that responded only to a couple of hormones, decades. Thanks to advances in cellular and molecular biology There are thought to be three types of bone cells: osteoblasts, such as the parathyroid hormone sent out by the parathyroid tools, experts now say that bone is a dynamic tissue that sends osteoclasts and osteocytes. Osteoblasts build bone by putting glands and estrogen made by the ovaries. But findings in the In 2002, President Bush proclaimed the decade to out and receives messages from organs. It even tweaks the down the mineralized matrix. Osteoclasts chew down bone. past two decades have given indications that the bone doesn’t be the National Bone and Joint Decade. The functions of organs and actively participates in maintaining They are unique in that they are the only cells in the body just passively take orders from other organs: It makes its Bone and Joint Decade recently renewed its mandate mineral and energy homeostasis throughout the body. designed to destroy their host tissue. Both cell types sit on the own hormones to modulate mineral metabolism and energy for another 10 years to 2020. Every October 12–20, surface of the bone. expenditure. the Bone and Joint Decade and US Bone and Joint OLD TO NEW The challenge of studying bone is most evident when it The role of bone in mineral metabolism came as a surprise Initiative recognize the week as their National Bone constantly turns over. This process is called bone remod- comes to the osteocytes, cells derived from osteoblasts that less than 15 years ago when a hormone called fibroblast Action Week to inform the public about eling and rebuilds the skeleton bit by bit. Bone remodeling is make up 90 percent of bone. Because they sit deep inside growth factor 23 was discovered. FGF23 “has potent effects on musculoskeletal disorders. the proximal tubule of the kidney to regulate the reabsorption of

18 ASBMB Today October 2012 October 2012 ASBMB Today 19 osteoblasts All these drugs are catabolic agents in that they stop the For one, they need to understand how bone cells communicate breakdown of bone. Given their numbers, Scott Simonet of and respond to mechanical and biochemical signals both at bone surface Amgen says, “That area of the market is pretty saturated.” local and systemic levels. For example, “bone is an incredibly sclerostin The excitement lies in drugs that can help build bone. The locally focused tissue,” says Kronenberg. “If you break a leg, only anabolic agent on the market is a recombinant version of you want to fix that fracture right where it is. You don’t want a osteocytes parathyroid hormone called teriparatide, marketed as Forteo by systemic response to a fracture.” How bone senses when to Lilly. The drug stimulates osteoblasts to put down new bone. work locally and when to act globally is a question. bone Parathyroid hormone’s classical role is to stimulate bone break- Another interesting idea that is emerging is that there is IMAGE CREDIT: LYNDA BONEWALD Scanning electron micrograph of an down so that calcium is released to maintain serum calcium two-way communication between muscle and bone. “We osteocyte in resin. levels. But, for reasons not yet known, the hormone does the always think of muscle affecting the skeleton” by pulling and opposite and builds bone when injected once daily. The drug is pushing on the bones, says Rosen. “But there’s the converse effective for only 12 to 18 months. side: How does the skeleton regulate muscle?” Experts are excited about a drug that Amgen, in partner- This is work Bonewald has undertaken in collaboration with Sclerostin inhibits osteoblast-mediated bone formation. IMAGE CREDIT: AMGEN ship with a company called UCB, has in phase III clinical trials. the groups of Marco Brotto and Mark Johnson, also at the Simonet says that the drug is being developed for osteoporosis University of Missouri in Kansas City. “We took some of our in the mineralized matrix. When osteoclasts dissolve bone, begging to be done. and fracture repair. The anabolic drug AMG 785 is a monoclo- osteocyte-conditioned media and put it on muscle cells. [Brotto] osteocalcin enters the bloodstream. From there, researchers nal antibody that targets a molecule called sclerostin. was absolutely blown away to see that the osteocytes secrete have shown, one of the post-translationally modified forms of OSTEOPOROSIS DRUGS The story of sclerostin best illustrates how molecular biology factors that support myogenesis,” Bonewald says. “If you put osteocalcin increases insulin secretion from the pancreas and Understanding fundamental bone biology has had great has been pivotal for bone therapeutics. In 1958, sclerosteosis the conditioned media on intact muscles that are contracting, it enhances the ability of adipocytes to use glucose. repercussions for one of the most recognized diseases of bone: was first described in two South African girls of Dutch-Afrikaner increases muscle force.” She says the collaborators are work- Because bone remodeling demands a lot of energy, “this osteoporosis. Osteoporosis appears in postmenopausal women, descent. Sclerosteosis patients have heavy, thick bones with ing on figuring out the factors secreted by the osteocytes and new paradigm really allows us to think about the skeleton as the elderly and people suffering from some diseases, such as large jaws and protruding foreheads; their thick facial bones how they affect signal-transduction pathways in muscle. the sensor for metabolic activity and also as a fine-tuner for anemia. The bones become fragile and easily snap. Accord- pinch their facial nerves. Several research groups established Indeed, factors secreted by bones are high on the explora- insulin sensitivity,” says Clifford Rosen at the Maine Medical ing to the National Osteoporosis Foundation, about 34 million that the gene involved was SOST and that sclerosteosis was a tion list. This is especially true for the relatively new discovery Center Research Institute. “It takes a lot of energy to make Americans are at risk for the disease. By 2025, the foundation loss-of-function mutation of that gene. that bone senses and possibly influences metabolism. In bone. We don’t know anything about the dynamics of how projects, osteoporosis will cost the American healthcare system “We didn’t know where sclerostin was coming from, but, Rosen’s opinion, “the skeleton is secreting lots of endocrine these cells use their energy.” $25.3 billion per year. after several years of soul-searching, it became clear that it factors. We know about FGF23, sclerostin and osteocalcin. We The knockout mice have been critical in revealing Osteoporosis happens when osteoclasts outstrip osteoblasts was coming from the skeleton,” says Rosen. Coincidentally, don’t know enough about those, and my guess is there are also osteocalcin’s purpose, but there is a question mark hanging in performance. The reason postmenopausal women are more at the same time, the Bonewald group’s osteocyte lines were other substances being produced.” over the extent to which osteocalcin influences the insulin at risk is thought to be that estrogen indirectly inhibits the coming out. Those cell lines helped researchers establish in the As schoolchildren, our earliest encounters with bone are pathway in humans, say Clemens and Rosen. “The mouse activity of osteoclasts. But after menopause, estrogen’s protec- mid-2000s that osteocytes were secreting sclerostin to stop with the jangling skeleton hanging in the back of the high- has given us tremendous insights, but moving to humans, tion disappears, and the osteoclasts start breaking down bone bone formation. Amgen’s AMG 785 shuts down sclerostin by school biology laboratory. But with new findings emerging about it’s much more complicated,” says Rosen. “We need to get more quickly than osteoblasts can keep up. The speeding up of blocking its inhibitory activity on osteoblasts. the inner workings of the skeleton, bones can no longer be a better idea of how important is osteocalcin in fine-tuning osteoclasts starts happening in the elderly for reasons yet to be Clemens and others take delight in pointing out that viewed as stiff and inert structures that simply hold us upright. insulin secretion.” deciphered. This causes elderly people to grow hunched, shrink researchers had known about sclerostin’s existence for many Bone is truly a dynamic, living tissue that is constantly listening Clemens and Rosen explain that in some mouse mod- in height and become more susceptible to broken bones. years. But once its molecular biology was established, it took and responding to the way we live. els osteocalcin looks to be critical for regulating the insulin But in the past 20 years, drugs have appeared to treat less than a decade to get a drug against it in the pipeline. “It’s pathway. But mice aren’t metabolic equivalents of us, because osteoporosis. Most of the ones on the market inhibit bone really remarkable,” says Clemens. Rajendrani Mukhopadhyay ([email protected]) is their metabolic rates are 100 to 1,000 times faster than ours. breakdown, or resorption, one way or another. One class of the senior science writer for ASBMB Today and the technical Both Rosen and Clemens say the differences in metabolic rates drugs is the bisphosphonates, which trigger apoptosis in osteo- LOTS MORE TO DO editor for the Journal of Biological Chemistry. Follow her on raise the question of whether the osteocalcin effects seen in clasts. “The bisphosphonate category is probably about 80 Experts interviewed for this story were unified in their upbeat Twitter at www.twitter.com/rajmukhop. mice come about simply because of the peculiarities of mouse percent of the osteoporosis drug use in the United States right enthusiasm for the future of molecular biology research into metabolism. “It’s a big challenge,” says Rosen. “How do we now,” notes Art Santora of Merck. bone simply because there are so many rich hunting grounds apply what we see in mice to humans?” Another drug is a monoclonal antibody called denosumab, in both basic and clinical endeavors. Experts are unrestrained And that is exactly what the next research steps should which is produced by Amgen. It is an inhibitor of RANK ligand, in their enthusiasm when they say that new anabolic drugs will answer, says Clemens. He says that, while association stud- which was shown in the 1990s to be the key stimulator of be developed in the next decade to help patients with post- ies in humans seem to suggest osteocalcin has an effect on osteoclast development through the Wnt/β-catenin pathway. menopausal, age- or disease-induced osteoporosis and skeletal Be sure to check out the MCP Journal News in this insulin secretion, there haven’t been any studies that show a By inhibiting RANK ligand, the drug prevents osteoclasts from fragility. issue for a story on osteoblasts! See Page 31. clear cause-and-effect relationship. Those kinds of studies are maturing and chewing away the bone. For basic researchers, there are many directions to pursue.

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The Wyss Institute’s pursuit of WHAT IS THE WYSS? The institute emerged in 2008, when it was known initially as BY THE NUMBERS the Harvard Institute for Biologically Inspired Engineering. In a alternatives is gaining momentum 3: The number of years it took to generate initial funding bid to blend the understanding of basic engineering and biologi- for the institute cal processes, fields that had a long and successful history at Harvard University, and apply them to the burgeoning number $125 million: Harvard’s largest single philanthropic of medical and environmental issues in the modern world, a donation in its history – from alumnus Hansjörg Wyss Biologically multidisciplinary team of Harvard-based faculty were convened 9: The number of universities and hospitals around by the provost to discuss the future of bioengineering in Boston. Boston collaborating with the institute, including the Then, in 2009, Harvard business school alumnus and Swiss Dana Farber Cancer Institute and the Massachusetts engineering magnate Hansjörg Wyss donated $125 million, and General Hospital inspired the story of the Wyss Institute began in earnest. That money from Wyss, who was then chief executive officer of the medical- 25: The number of open positions on the institute’s implant manufacturing company Synthes, which recently was recruitment page sold to Johnson & Johnson, allowed those at the institute to $12.3 million: The amount received from the Defense pursue high-risk scientific endeavors and to begin to realize the Advanced Research Projects Agency to develop a innovation potential of a new research model, described in the institute’s spleen-on-a-chip device to diagnose sepsis rapidly mission statement as one of “innovation, collaboration and BY CONNOR BAMFORD technology translation.” 53: The number of peer-reviewed publications the insti- tute produced in the first five months of 2012 ORGANS ON A CHIP 1: The average number of Science or Nature papers t lab benches and computer desks throughout the Wyss This capital injection has allowed one of Wyss’ groups to published per month by the institute’s 17 faculty over Institute for Biologically Inspired Engineering in Boston, confront, head-on, one major challenge facing modern drug- A the first three years of its existence researchers are attempting to solve some of humanity’s most discovery programs: Why do animal models so often fall short of pressing problems. The questions its scientists are asking are predicting the biological effects of drugs in humans? 17: The number of faculty members affiliated with the not uncommon: How can we discover more effective drugs? “Animal models often fail to predict results in human clinical institute How can we solve the global energy crisis? But the possible trials, and this has had a devastating effect on drug develop- answers they’re developing are atypical, such as using autono- ment,” says Don Ingber, who is the leader of the biomimetic mous microrobots to diagnose and treat diseases. microsystems platform and founding director of the Wyss synthetic tissues but creating synthetic organs where multiple Part engineer, part biologist, researchers at Wyss (pro- Institute as well as a professor at Harvard Medical School and tissues types interact. nounced “Vees”) are combining the power of synthetic biology, Boston Children’s Hospital. “Not only have costs skyrocketed, The team was able to co-culture the three major tissue microfabrication technology and tissue engineering principally to but fewer and fewer good drugs are in the pipeline, and so components of the lung within a hollow channel in a single understand how biological systems work and to manipulate and fewer good drugs are reaching patients.” microfluidic chip composed of a clear, flexible silicone. Span- re-engineer them in the lab in a way we could never have done Researchers need to model human biology accurately in ning the channel was a malleable and porous membrane coated before. Researchers such as Pamela Silver and George Church, the lab to develop new treatments. Think of heart disease or with extracellular matrix. On one side resided human lung both synthetic biologists, hope that their work — and their col- lung cancer: Scientists simply can’t test novel drugs on human epithelial cells with air introduced above their surface to mimic leagues’ work — will have far-reaching health, environmental beings, yet the kinds of models they do use on a day-to-day the air sac, while on its underside grew human lung capillary and economic benefits. basis (cell lines or rodents, for example) are the kinds of models endothelial cells with flowing culture medium representing blood Silver and Church are among 17 full-time faculty members that might lead them astray if they are not careful. But imagine within a pulmonary vessel. This channel was bordered on both at Wyss whose research programs are supported in part by a if they were able to model human physiology without turning to sides by two additional hollow channels that experienced cyclic more than $125 million institutional gift intended to foster a rodents or nonhuman primates; this is where Wyss’ researchers suction, which caused the neighboring tissue–tissue interface very special kind of environment. “The Wyss has been instru- come in. to undergo rhythmic stretching and relaxation, thus mimicking mental in bringing the right people together and providing the In 2010, the Ingber group reported in the journal Science the physiological breathing motions. right atmosphere,” Silver emphasizes. The institute allows the development of a human “lung on a chip.” This in vitro model This device recapitulated pulmonary barrier functions researchers the freedom to operate in entirely new fields, and system was designed to mimic the functioning of a lung alveolus normally seen only in vivo, and, when human immune cells this is at the heart of the institute’s mission. and uniquely showcases the group’s focus on not just creating were added to the flowing blood, they were able to respond to

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medicine via chemistry and science policy. There is no handbook for synthetic biologists to follow; they have had to develop their own sets of principles and rules, and those at the Wyss are at the leading edge of that work. As Silver explains, “Biology is not like electrical engineering in that it works in three dimensions — no wires — and over time scales that can be long. We seek new computational strategies and to move beyond trial and error in building complex biological systems.” Meanwhile, Silver and Church recently co-headed Harvard’s International Genetically Engineered Machine — or iGEM — team, a group of biology students in an annual international synthetic biology competition aimed at the creation of devices to solve a particular issue. The team’s project focused on the development of a system to engineer synthetic gene circuits in plants rapidly and easily. The team altered existing plasmid vectors to accommodate Don Ingber, founding director of the Wyss Institute and a DNA modules from the Biobricks parts registry, a standardized professor at Harvard Medical School and Boston Children’s catalogue of genes, vectors and regulatory elements. As a proof Hospital, leads the biomimetic microsystems platform that is of principle, they inserted a gene encoding the protein miraculin engineering new human tissue models. (a peptide that makes sour tastes become sweet) into Arabidop- In attracting so many successful researchers and bringing sis to alter the taste of a bitter plant significantly without altering them into close contact, the Wyss Institute has addressed one The Wyss Institute aims to foster a friendly, collaborative research environment for scientists and clinicians. sugar content. key problem with modern science: How do we make it easier to the addition of pathogenic bacteria to the surface of the lung by lung disease at Queen’s University in Belfast, U.K., stresses Christina Agapakis, a postdoctoral researcher at the make important discoveries quickly? adhering to the endothelium, migrating across the two tissue the importance of not forgetting human testing. “[We] probably University of California, Los Angeles, and one of the research- “It is easier to do cutting-edge science when mixed in layers and engulfing invaders. Moreover, because the chip is need better characterization of existing models to confirm data ers supervising the iGEM team, explains that the team wasn’t with developing — not just buying — the most cutting-edge clear, all of those processes could be visualized at high resolu- identified in models translates to human disease rather than allowed actually to taste their plants, so officially nobody knows engineering, and vice versa,” Church underscores. This is made tion and in real time. It is this system that is being pioneered to new models,” he says. He predicts that no in vitro model will for sure what it tasted like. However, she emphasizes, “We hope easier at a research institute fostering the development of study the effects of novel treatments for lung disease. completely replace human testing, but they “might be useful as that these tools inspire and enable other iGEM teams to work life-inspired materials and medical devices that can anticipate For nearly three decades, Ingber and co-workers have been a stop point in drug development.” with plants so that the toolkit can grow further.” disease and correct it before it gets out of hand. championing the idea that one of the most important factors Furthermore, Ingber’s team is actively pursuing ways to The Wyss has aligned itself with a range of medical centers in controlling the function of a particular organ or tissue is the combine its cell biology work with the other projects going on at BRINGING IT ALL TOGETHER around the city of Boston, including the Dana–Farber Cancer mechanical forces that the cells experience in their natural the institute, such as those being done by synthetic biologists As Ingber looks to the future of his group’s organs-on-chip Institute. “The opportunity to couple engineering expertise at the microenvironments. “In the early days, biologists were skeptical like Silver and Church. model, he says, “Finally, we can start by building the simplest Wyss Institute with clinical investigation expertise at the Dana– or had no interest” in the role of tissue mechanics, Ingber says, model that re-creates physiological functions of interest and Farber has dramatically accelerated the translation of exciting but now this research is showing that it clearly has an effect A SYNTHETIC WAY OF LIFE then add back cells one by one to explore their relevance for preclinical findings to testing in cancer patients,” says Glenn that scientists can harness, in this case to create new in vitro Silver’s lab — along with colleagues James Collins and any response of interest.” But beyond cell biology, synthetic Dranoff, associate faculty member at the Wyss Institute and assays. Church — focuses on the manipulation of both prokaryotic biology and genomics will have large parts to play as Wyss professor of medicine at Dana–Farber, Brigham and Women’s The team has another nine systems in development (includ- and eukaryotic genomes and on developing new ways to do researchers come better to understand and manipulate human Hospital and Harvard Medical School. ing the previously published gut on a chip) and is currently so. These synthetic biologists seek to engineer and build novel, biology, which hopefully will pay off in terms of novel treatments We may never truly understand life until we are able to pursuing ways to connect them together to generate “an man-made alternatives to our genes and pathways to construct for now-incurable diseases. reconstruct it from scratch, and, as demonstrated by the Ingber, instrument that can probe, manipulate and analyze multiorgan living organisms or cells with well-defined outputs and, hence, “We are collaborating with Don on enabling us to move from Church and Silver labs, the researchers at the Wyss Institute are system responses to replace animal testing,” Ingber says. The new or improved functions. organs on chips to personalized and synthetic versions,” Church trying to get us there with the great hope of answering some of group recently entered into a project with the Defense Advanced The Church lab has been at the forefront of developing explains. He is planning on aligning his work on personalized our most pressing questions. Research Project Agency worth up $37 million to develop an easier and cheaper genomic technologies. “We’ve helped lower genomics with the Ingber group to uncover how our genetics influence cell or organ functioning. This fits nicely with Silver’s Connor Bamford ([email protected]) is a Ph.D. automated human-body-on-a-chip model leveraging its organ- the cost of sequencing about a million-fold and of engineering student at Queen’s University in Belfast, U.K. on-chip technologies. genomes using DNA from chips by similar amounts,” Church vision of introducing her synthetic DNA into Ingber’s systems Still, Danny McAuley, a clinical professor in intensive care says. His lab, by helping to make genomics cheaper, faster and in a way that truly reflects what the Wyss Institute is all about: medicine with an interest in developing novel therapies for more accessible, has advanced fields ranging from ecology to innovation through collaboration.

24 ASBMB Today October 2012 October 2012 ASBMB Today 25 lipid ws FIT and fat 2014ASBMB SPECIAL SYMPOSIA BY DAVID L. SILVER The current view of the CALL FOR PROPOSALS pathophysiology of the lipid atural selective pressure through- droplet in adipocytes is N out evolution of the Eukarya has generated a staggering array of control that increased capacity or mechanisms that maintain energy expandability of the adipocyte lipid homeostasis, such as allosteric regula- Partner with the American Society for tion of glycolysis, nutritional control of droplet is beneficial to maintaining Biochemistry and Molecular Biology to bring your gene expression, and the nutritional glucose and insulin sensitivity. community together! ASBMB Special Symposia control of triglyceride hydrolysis and provide you, as a specialized researcher, a unique oxidation. The latter process of opportunity to present cutting-edge science mixed with triglyceride hydrolysis and oxidation in solubilizing membrane triglyceride to nucleate a de active networking opportunities in an intimate setting. provides a major source of energy for most eukaryotes, novo forming droplet within the endoplasmic reticulum and, as such, triglycerides are deposited in a phylo- membrane. genetically conserved, ubiquitous organelle called the FIT1 and FIT2 have distinct tissue distributions in lipid droplet. The lipid droplet plays an important role in mice and humans — with FIT1 primarily expressed in storage of cellular triglycerides and has the capacity to skeletal muscle and in lower levels in heart and with How We’re Different: expand and contract dependent on caloric intake and FIT2 ubiquitously expressed at low levels in tissues energy demand. but highly expressed in adipocytes of white and brown Format: Majority of talks selected from abstracts, One unresolved issue in lipid droplet biology is deter- origin. The disparate tissue distributions of FIT1 and invited speakers, 2–4 days in length mining the mechanisms for lipid droplet biogenesis. FIT2 and the observation that FIT1 produces small lipid

There is substantive new evidence that lipid droplets droplets characteristic of skeletal muscle lipid droplets Attendees: 75–200 attendees, including are formed from the endoplasmic reticulum (1). More and that FIT2 produces large lipid droplets more akin to investigators, industry professionals, recently, our research group discovered a two-gene adipocyte lipid droplets indicate that each might have graduate and postdoctoral students family of endoplasmic reticulum membrane proteins a unique physiological role in metabolism. Skeletal-

having six transmembrane domains that we named muscle-specific overexpression of FIT2 in mice resulted Venues: Unique locations for outdoor recreation fat-storage-inducing transmembrane (FITM1/FIT1 and in a marked increase in intramyocellular triglycerides and informal networking opportunities FITM2/FIT2) protein. FIT proteins are phylogenetically but paradoxically a decrease in fatty-acid oxidation and conserved from yeast to human. Genetic evidence from expression of PPARalpha target genes and an increase Funding: ASBMB provides initial funding as well as overexpression and knockdown studies in mammalian in the utilization of glucose and branched-chain amino complete meeting management! cells indicates that FIT proteins play an important role in acids (4). These findings suggest that FIT2 produces the generation of lipid droplets (2−4). lipid droplets that are not coupled to mitochondria fatty FIT2 is the anciently conserved FIT family member. acid beta-oxidation. Learn More About the Special Symposia Series and Indeed, human FIT2 can complement several phe- FIT1 is more abundant than FIT2 in skeletal muscle. Proposal Submission Guidelines at notypes found in an S. cerevisiae strain deleted for What might its physiological role be in lipid metabo- FIT2, SCS3, indicating conservation of function (5). lism? It recently has been shown (7) that PGC1alpha, a major exercise-induced regulator of mitochondria bio- www.asbmb.org/specialsymposia How might FIT proteins mediate lipid droplet forma- tion? Structural information on the FIT family is lacking, genesis and function, can induce expression of FIT1 in making it difficult to infer function based on sequence primary human skeletal myocytes. Given this finding, it alone. Biochemical evidence indicates that FIT proteins is tempting to speculate that FIT1 plays a causative role do not mediate fatty-acid or glycerolipid biosynthesis in the exercise-induced intramycocellular accumulation but rather partition newly synthesized triglycerides into of triglycerides noted in the athletes paradox (8). lipid droplets (2). Part of the biochemical mechanism The current view of the pathophysiology of the lipid appears to require direct binding of triglyceride (6), PROPOSALS DUE NOV. 1, 2012 raising the possibility that FIT proteins might play a role Continued on page 32

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working on yeast problems in cell biology. They are uniquely amenable an emeritus professor in chemistry at the University of viruses. During that to the application of a large number of biochemical and Chicago, were just as important to his career path. Stryer THE JOURNAL OF BIOLOGICAL CHEMISTRY time, he came across genetic techniques. Their fully sequenced genome is worked as a waiter during his time at the university, and research articles by easy to manipulate, they have a short life cycle, and they Franck was a frequent customer who always ordered the Francios Lacroute are inexpensive to grow and maintain. The discovery of same thing. This left ample time for conversations about and Michel Aigle the prion system in yeast is a major step forward in prion science. Stryer and Franck discussed Franck’s initial Prion and other that reported that research, as we now have added to our arsenal the power research on energy transfer, which revealed that excitation mutations in the of yeast genetics and biochemistry. Wickner’s research energy can be transferred through direct electromagnetic amyloid diseases: yeast protein ure2 underscores this, as he was able to conrm the concept interaction. At some point, Franck told Stryer, “One day, Reed Wickner affecting the regula- that proteins can be infectious, extend this to show that you too might work on energy transfer.” This, in fact, tion of the enzyme protein conformation can be inherited, and study the turned out to be the case. shares lessons aspartate transcar- mechanisms involved in the generation and propaga- Stryer’s rst foray into studying uorescence energy bamylase had the tion of yeast prions. Wickner’s work has not only laid the transfer came when he was a summer research stu- from yeast cells same phenotype groundwork for understanding the rare and very debilitat- dent under Douglas Smith at Argonne National Labora- BY KAREN MUINDI as a spontaneous, ing TSEs but also other more prevalent amyloid diseases, tory. Smith introduced Stryer to photodynamic action, a Bovine spongiform encephalopathy, commonly referred nonchromosomal Reed Wickner such as Alzheimer’s and Parkinson’s. process whereby light activates a photosensitizing dye to as mad cow disease, and variant Creutzfeldt-Jakob mutant, [URE3], Wickner’s studies are another example of how basic in the presence of oxygen, leading to cellular damage. At disease, which (rarely) develops in humans who have which requires ure2 for propagation. That a nonchro- biochemical studies with no apparent relation to a human Smith’s urging, Stryer read the literature about Theodor eaten diseased tissue, are transmissible spongiform mosomal element dependent on a certain gene for its disease can lead unpredictably to insights into an impor- Förster’s theory of energy transfer. Stryer was intrigued encephalopathies, or TSEs. While most TSE cases arise existence could share the same phenotype as mutants tant human disease. Wickner was able to carry out these by the theory’s prediction of the absolute dependence spontaneously, inherited genetic mutations also can of the very same gene got Wickner thinking: It struck him studies only because of his extensive background in yeast on the distance of the two dipoles. Stryer viewed this as cause these rapidly progressive, fatal and still untreatable that it was just what one would expect of a prion of the genetics and yeast biochemistry. a potential way to develop new knowledge of biological neurodegenerative syndromes. The fear caused by the URE2 gene product Ure2p. The lack of mammalianlike macromolecules using energy transfer in proteins. Karen Muindi ([email protected]) is a postdoctoral very mention of a case of mad cow disease has immedi- prion pathology might have kept others from drawing a fellow at the U.S. Food and Drug Administration. Stryer entered medical school at Harvard Univer- ate effects across the globe and leads to bans on beef similar conclusion, but Wickner had decided to focus on sity under the mentorship of Elkan Blout. He performed imports from the affected country, resulting in enormous heritable features that would not depend on the particular research investigating polyglutamic acid and polylysine socioeconomic consequences. phenotype produced by the prion. complexation with dyes and effects on optical rotation. In the late 1960s, Tikva Alper presented evidence Using then-new genetic approaches, Wickner showed Everything Stryer devoted his career to basic research during his that the infectious agent of TSEs was not a nucleic acid, that the [URE3] phenotype is indeed dependent on the fourth year in medical school. Blout planned Stryer’s post- and John Grifth suggested it was self-propagation of a gene ure2, conrming the ndings of Lacroute and Aigle. is illuminated: doctoral research career, making sure Stryer boned up on protein conformer. In 1982, neurologist Stanley Prusiner He then went on to show that [URE3] yeast cells grown ‘Reflections’ his physics, chemistry and mathematics, and then Stryer isolated the TSE infectious agent, nding that its main with low concentrations of guanidinium chloride lose the headed off to the Medical Research Council Laboratory component was a protein, which he named PrP. He [URE3] phenotype. However, out of these cured cells, the on light and life in Cambridge, England. It was an exciting time for Stryer, coined the term “prion” to mean “infectious protein.” In [URE3] phenotype spontaneously arose again without and he says his years in the two Cambridges were some 1997, he received the Nobel Prize for this important work. its introduction from other cells. He also showed that by Lubert Stryer of the best in his life. Many aspects, however, were still uncertain and difcult overproduction of Ure2p resulted in a 100- to 200-fold BY PUMTIWITT C. McCARTHY Stryer’s independent research career began at Stan- to clarify in experiments involving humans or animals. increase in the frequency of [URE3]. This rst demon- Lubert Stryer, professor emeritus at Stanford University, ford University. Surprisingly, the ndings that permitted detailed studies stration of protein-based inheritance involving a protein has spent his research career harvesting the power of One of his major and answers came from studies of proteins in yeast by unrelated to the mammalian prion protein was truly light. Some of his most important work has used light to accomplishments Reed Wickner. groundbreaking and was published in the journal Science develop tools to explore the structure and function of bio- there came while Wickner, who recently wrote a “Re ections” article in 1994. logical macromolecules. In his recent “Re ections” article investigating how for the Journal of Biological Chemistry, describes in his Having broadened the prion concept beyond its for the Journal of Biological Chemistry, Stryer recounts his uorescence energy article how his background and skills positioned him to restriction to mammals, Wickner went on to show that, life experiences and gives praise to many of the students, transfer can serve undertake these studies. He graduated with a mathemat- at least for Ure2p, amino-acid content — and not amino- postdoctoral fellows and collaborators who have helped as a way to mea- ics degree from Cornell University in New York and then acid sequence — determines the ability to form a prion. him produce a successful career. One common thread in sure the distance went on to study medicine at Georgetown University in He also has shown that, like mammalian prions, yeast his life has been his interest in trying to understand the between two sites in Washington, D.C. Upon graduation, he honed his research prions are self-propagating amyloids (lamentous protein “interplay of light and life.” a protein. Using the skills studying enzymes and nucleic acids in postdoctoral multimers) with in-register parallel beta-sheet architecture Stryer’s interest in light-catalyzed reactions was rst recently introduced fellowships with Herbert Tabor at the National Institutes and has proposed a mechanism for how these prions may piqued in an introductory biology course at the University solid-phase peptide of Health and Jerry Hurwitz at Albert Einstein College of template the prion fold of the normal protein. of Chicago. Stryer writes in his “Re ections” essay that he synthesis tech- Medicine. (Tabor was editor of the JBC for four decades The highly genetically amenable yeast are well suited can “vividly recall my excitement on seeing this graphic nique, Stryer’s group and today serves as co-editor.) for these studies, which would not have been possible in demonstration of key features of photosynthesis in a test synthesized a series In 1973, Wickner returned to the NIH and started mammals. Yeast have long been used to dissect complex tube.” Conversations with Nobel laureate James Franck, of polypeptides with Lubert Stryer

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chromophores at known distances and determined their Research Institute heavily involved as part of the medical faculty of the “Mesenchymal stem cells are being introduced into transfer efciencies. Their study demonstrated that energy demonstrated that university, supervising 17 successful doctoral candidates, clinical trials, and some of the putative benecial effects transfer can serve as a “spectroscopic ruler.” Much of caldesmon, an and was known to his patients as a knowledgeable yet of these cells are related to their secreted factors,” the labeling work that is done today using FRET can be actin-binding pro- empathetic cardiologist, his colleagues Jan Borén, Göran explains Moustapha Kassem at the University Hospital credited to the pioneering work of Stryer. tein, increased the Bondjers and Olov Wiklund explain in their “In Memoriam” of Odense in Denmark. “However, the nature of these Another one of Stryer’s signicant accomplishments Arp2/3-mediated article that it was research that remained Olofsson’s true secreted factors and their change during osteoblast was offering a better understanding of the biochemical branching activity at passion. differentiation are poorly documented and understood.” basis of visual amplication. Rhodopsin is a photosen- newly formed actin His legacy includes his many studies on the assembly So in a recent Molecular & Cellular Proteomics paper, a sitive membrane protein that undergoes a cis-to-trans laments. By using and secretion of apolipoprotein B100-containing very low- team led by Kassem and Jens S. Andersen at the Uni- isomerization in the presence of light. This isomerization in vitro and imaging density lipoproteins, including elucidating the many steps versity of Southern Denmark described a mass spectro- starts the cascade of events leading to the eventual ring assays, Wang and of VLDL1 assembly. His more recent research included metric analysis of the proteins secreted by osteoblasts of the optic nerve and visualization. Stryer and his team colleagues found innovative exploration into lipid-induced in ammation and over a period of two weeks as the cells developed and were the rst to elucidate successfully the components that caldesmon had the development of insulin resistance, identifying the solu- matured from mesenchymal stem cells in culture (1). The and mechanism of the cGMP cascade responsible for no effect on branch ble NSF attachment protein-reception protein SNAP23 as investigators used an isotope-labeling approach that rhodopsin activation. formation at older a new link between how fat accumulates in cells and the allowed them to tell apart proteins that were secreted Stryer has had a number of fruitful collaborations that actin laments, but development of diabetes. by the cells and contaminants in the culture media. One were born from his interest in light. These collaborations the younger, fresher actin laments were twice as active He handily took the knowledge he learned from the of the things the investigators established was that a have led to the development of important light-based in forming branches than the mature actin laments. This bench to treat lipid disorders at the university’s teach- hormone called stanniocalcin 2 behaved in an autocrine tools that have moved the eld forward and are still in use suggested that caldesmon maintains freshly polymerized ing hospital, where he was beloved by his patients. This fashion to promote today. Stryer and researchers from the University of Cali- actin in a state with a higher afnity for the Arp2/3 com- human touch, along with his many scientic contributions, the differentiation fornia, Berkley, developed multicolor uorescent probes plex. Wang explains the group is now working to deter- will be remembered for years to come. of the mesenchy- conjugated to biological molecules for ow cytometry and mine if other actin-binding proteins have the same effect mal stem cells into uorescence microscopy. Also, as a scientic adviser to as caldesmon in modulating actin cytoskeletal dynamics Mary L. Chang ([email protected]) is managing editor osteoblasts. The of the Journal of Lipid Research and coordinating journal what is now known as Affymetrix, Stryer directed efforts and if caldesmon can affect cell migration and tumor investigators also manager of Molecular and Cellular Proteomics. to produce light-activated combinatorial synthesis librar- metastasis by manipulating actin dynamics. discovered nine ies on a solid support for peptides and oligonucleotides. novel factors that Now that Stryer’s research career has ended, he Rajendrani Mukhopadhyay ([email protected]) is are secreted by explores his fascination with light in other ways. Since his the senior science writer for ASBMB Today and the technical MOLECULAR & mesenchymal stem editor for the Journal of Biological Chemistry. Follow her on CELLULAR PROTEOMICS retirement from Stanford, Stryer has spent much of his Twitter at twitter.com/rajmukhop. cells. Kassem says time enjoying his two interests: photography and adven- they will now focus ture travel. He has traveled to Antarctica, the Arctic, the Secretions of on these nine fac- Galapagos Islands and Africa to take pictures. Although tors to better under- he is retired, science is still on Stryer’s mind. He says, bone-forming cells stand their role in THE JOURNAL OF BY RAJENDRANI MUKHOPADHYAY “Photography has heightened my awareness of color LIPID RESEARCH mesenchymal stem in the natural world and deepened my interest in color Osteoblasts secrete various proteins that make up bone cell biology. vision.” as well as growth factors and cytokines that interact Rajendrani Mukhopadhyay ([email protected]) is the with organs outside of bone. Despite their critical role in Pumtiwitt C. McCarthy ([email protected]) is a research fellow Late Swedish senior science writer for ASBMB Today and the technical editor in the National Institutes of Health Pharmacology Research bone formation and communication with other organs, for the Journal of Biological Chemistry. Follow her on Twitter at Associate Program of the National Institute of General Medical lipidologist Sven-Olof the proteins that osteoblasts secrete are not very well twitter.com/rajmukhop. Sciences. understood. Osteoblasts evolve from stem cells in the 1. Kristensen, L. P, et al. Mol. Cell. Proteomics DOI: 10.1074/mcp. Olofsson remembered bone marrow, which are called mesenchymal stem cells. M111.012138 (2012) BY MARY L. CHANG How actin goes The October issue of MORE JOURNAL NEWS ONLINE the Journal of Lipid Minireviews about the ENCODE project Taking serine metabolism seriously in new directions Research includes a The National Human Genome Research Institute Do you think serine metabolism is important? If you BY RAJENDRANI MUKHOPADHYAY tribute to Sven-Olof announced in September the results of a ve-year study the brain, development or epigenetics, it may The cytoskeleton protein actin plays a critical role in cell Olofsson, a principal international study of the regulation and organization be of value to you. Serine is involved in all of these movement by assembling at cell protrusions. The assem- researcher at the Uni- of the human genome. The project is named ENCODE, processes in addition to many others. In a recent bly process involves actin-binding proteins, one of which versity of Gothenburg’s which stands for the Encyclopedia of DNA Elements. In Journal of Biological Chemistry minireview, Satish is the actin-related protein 2/3, or Arp2/3, complex. This Sahlgrenska Center conjunction with the release of those results, the Journal C. Kalhan of the Cleveland Clinic Lerner College of complex helps to form branched actin structures, which for Cardiovascular and of Biological Chemistry published a thematic minireview Medicine and Richard W. Hanson of the Case Western allow actin to push the membrane envelope forward and Metabolic Research, series entitled “Results from the ENCODE Project: Reserve University School of Medicine argue that get the cell to migrate. But how Arp2/3 picks out specic who passed away sud- Integrative global analyses of regulatory regions in the serine is underappreciated, and the authors make quite actin networks is not well understood. In a recent “Paper denly in December at human genome,” that focuses on several aspects of the a case for it, underscoring the signicance of serine of the Week” in the Journal of Biological Chemistry, a the age of 64. ndings. metabolism. team led by C.-L. Albert Wang at the Boston Biomedical Though he was Sven-Olof Olofsson

30 ASBMB Today October 2012 October 2012 ASBMB Today 31  ngt update continued lipidws continued Continued from page 6 Continued from page 27 the transition from graduate school to postdoctoral droplet in adipocytes is that increased capac- training, one postdoc noted, “You are responsible ity or expandability of the adipocyte lipid droplet for your own progress. An IDP helps outline key is beneficial to maintaining glucose and insulin questions to answer and allows you to prioritize sensitivity. For example, PPARgamma activators goals for the near future.” improve glucose and insulin sensitivity but increase myIDP was co-developed by scientists at body weight, in part due to adipocyte differentia- FASEB; the Medical College of Wisconsin; the Uni- tion and expansion (9). In light of these findings, it versity of California, San Francisco; the American might be significant that mouse and human FIT2 Association for the Advancement of Science and are direct targets of PPARgamma (10), suggesting Science Careers with support from the Burroughs that enhancing FIT2 expression would be beneficial Wellcome Fund. to improve metabolic parameters in obese, insulin- FASEB is proud to have played a role in devel- resistant people. These ideas await testing using oping this important new tool and hopes that the mouse FIT1- and FIT2-deficiency models as well resources provided through myIDP will encourage as the identification of human mutations in these more graduate students and postdocs to develop interesting, anciently conserved fat-storing genes. career and professional-development plans. “As a community, we must do more to help our RESOURCES trainees prepare for a broader range of scientific 1. Yang, H.et al. Curr. Opin. Cell Biol. (2012). careers,” said FASEB President Judith Bond. “It is 2. Kadereit, B. et al. Proc. Natl. Acad. Sci. USA 105, 94–99 our hope that training institutions and faculty advis- (2008). 3. Gross, D. A. et al. PLoS One 5:e10796 (2010). ers will encourage their graduate students and 4. Miranda, D. A. et al. J. Biol. Chem. 286, 42188–42199 postdocs to use myIDP and that it will help trainees (2011). communicate with their mentors about their career 5. Moir, R. D. et al. PLoS Genet. 8:e1002890 (2012). plans.” 6. Gross, D. A. et al. Proc. Natl. Acad. Sci. USA 49,19581– To access myIDP, visit 19586 (2011). http://myidp.sciencecareers.org. 7. Mormeneo, E. et al. PLoS One 7:e29985 (2012). 8. Goodpaster, B. H. et al. J. Clin. Endocrinol. Metab. 86, 5755–5761 (2001). Jennifer A. Hobin ([email protected]) is 9. Anghel, S. I. and Wahli, W. Cell. Res. 17, 486–511 director of science policy in FASEB’s Office of (2007). Public Affairs. 10. Soccio, R. E. et al. Mol. Endocrinol. 25, 694–706 (2011).

32 ASBMB Today October 2012 BostonASBMB ANNUAL MEETING April 20–24, 2013 www.asbmb.org/meeting2013 ABSTRACT SUBMISSION SITE NOW OPEN DEADLINE: 5 p.m. Eastern Nov. 8, 2012 VISIT: www.experimentalbiology.org

THEMATIC TRAVEL AWARD SESSIONS DEADLINE: Nov. 28, 2012 Catalytic Mechanisms

Chemical and Systems Biology

Genome Replication and Repair

Glycan Regulation of Signaling Pathways Lipids and Membranes

Mechanisms of Gene Transcription and Regulation

Mechanisms of Signal Transduction

Protein Modification, Trašcking and Degradation

RNA Function and Protein Synthesis

Transitions, Education and Professional Development

Triple Negative Breast Cancer

Beyond College: SPECIAL EVENTS Coping with Some Common Challenges Undergraduate workshop, Saturday, April 20 Professional Development for Graduate/Postdoctoral Trainees Undergraduate Breakfast with ASBMB Award Winners Saturday, April 20 Sunday, April 21, and Monday, April 22

ASBMB Opening Reception ASBMB Welcome and Networking Reception Saturday, April 20, immediately follows Sunday, April 21 the Opening Lecture ASBMB Thematic Fermentation Happy Hour Undergraduate Orientation: Monday, April 22 A Student’s Guide to the ASBMB Annual Meeting Saturday, April 20 ASBMB Women Scientists Networking Event Tuesday, April 23 17th Annual Undergraduate Student Research Poster Competition Y.E.S. Mixer (Young Experimental Scientists) Saturday, April 20 Consult program for details