INSTITUTE FOR SYSTEMS BIOLOGY A N N U A L R E POR T 2 0 0 9

ENHANCING LIFE  | INSTITUTE FOR SYSTEMS BIOLOGY 2009 ANNUAL REPORT |  Report from the Chairman and President

Scientific researchers around the globe are which is on its way to becoming a powerful new approach to direct measurement of the rate at which mutations accumulate As you can see we’ve been busy. Next year, however, will improving their understanding of human biology at a dazzling solving the complexities of 21st century biology and medicine. from one human generation to the next. be something really special for ISB. In 2010 we’ll officially pace. We are on the verge of changes in the field of healthcare celebrate our 10th birthday. We’ll look back on a remarkable so fundamental that in the not-so-distant future what were once A second metric that argues for the success of systems biology is Ruedi Aebersold, PhD, developed powerful new mass spectrometry first 10 years and look forward to what we expect will be an remarkable cures will become commonplace and what was once a National Academy of Science report released in 2009 on the techniques for assaying human (and other) proteins—and these are even more remarkable second decade, a decade that will see considered impossible will become probable. “new biology” which touts it as the biology of the future. The now being applied to the human proteome project—an attempt to profound advances in pre-symptomatic diagnosis of disease new biology is nothing more than systems biology with its cross- create assays for each different human protein. and stratification of a given disease into its discrete types This is the Institute for Systems Biology’s 10th anniversary. disciplinary environment, its commitment to measuring large — thereby enabling much more effective treatment. ISB will At such times one seeks metrics for how well the Institute Alan Aderem, PhD, and Ilya Shmulevich, PhD, used systems data sets and its commitment to discovering new technologies continue to pioneer groundbreaking developments in biology, has done. Fortunately, a report released by the Spain-based approaches to discover one way in which the innate immune system and computational and mathematical tools. This stands in medicine, technology, computation and mathematics. We will SCImago Research Group at the end of 2008 demonstrated regulates its response to invading pathogens, an important step in stark contrast to the traditional “siloed” academic research also be moving into a building in 2011 that will more than the exceptional performance of ISB and its researchers over learning how to correct overactive immune responses that can lead environments, where disciplines are segregated by departments double our space and bring all of ISB back into one building this time period. that seldom interact effectively. to autoimmune diseases and a key step in beginning to think about how to make more effective vaccines. as well as enable the continued growth of ISB faculty, ISB The report, which analyzed the impact of scientific papers ISB was launched in 2000 with a vision of wanting to be nimble, research projects, new ISB measurement and imaging facilities published by more than 2200 research institutes around the globe reducing bureaucratic barriers that inhibit scientific creativity In addition to scientific advances and the SCImago ranking, ISB and new strategic partnerships. between 2003 and 2007, found that ISB research papers had the had a number of successes in 2009: at large organizations, fostering interactions among disciplines, We are proud of what has been achieved at the Institute for highest scientific impact in the United States and the third highest in fashioning new approaches to transferring knowledge to society ü ISB successfully concluded the first year of its key strategic Systems Biology in its first 10 years and are excited by the the world. SCImago looked at institutions representing 84 countries (through K-12 science education and start-up companies) and partnership with the University of Luxembourg to attack two prospects of the on-going revolution in biological research on six continents. Other ranked US institutes include MIT, Harvard, pioneering a systems approach to biology and medicine — that fundamental problems of P4 medicine. ISB put together an that we have helped to catalyze. The best is yet to come. the California Institute of Technology, Stanford and similar elite is, gain a better understanding of how all the components of effective international partnership of labs across the world research organizations. This is strong testimony to the success not biological systems interact to generate health or disease. by helping to hire an outstanding director for the Systems only of ISB, but of the emerging discipline of systems biology— Biomedicine Center at the University of Luxembourg and ISB has assembled some of the best scholars and scientists in by doing excellent science in pioneering research projects; I

m the world, from biologists, mathematicians and engineers, to p

act computer scientists and physicists, in an interactive and cross- ü The Scientist Magazine identified ISB as being among disciplinary environment. the top 10 best places for academic researchers Roger M. Perlmutter, MD, PhD Leroy Hood, MD, PhD Ja n ua ry and postdoctoral fellows to work; Chairman of the Board Co-founder and President The Spanish research Examples of Research in 2009: firm SCImago released a Tim Galitski, PhD, and his colleagues used microfluidic ü ISB received a number of large grants from the National Institutes report finding that ISB’s technologies to assess the complex behaviors of single yeast of Health and the National Institute for Standards and Technology, research papers have the cells in response to environmental stimuli. supporting cancer research, the development of new technologies highest impact of any research for advancing scientific research and the human proteome project; institute in the US and third David Galas, PhD, Lee Hood, MD, PhD, and their colleagues highest in the world. determined the entire genome sequences of four members of ü ISB launched discussions with Ohio State University to a family with two genetic diseases. This first-of-its-kind approach co-found the P4 Medicine Institute, a non-profit organization allowed them to rapidly identify the correct defective gene for designed to demonstrate the benefits of medicine that is Publications each disease. This approach also provided, for the first time, a predictive, preventive, personalized and participatory; and Graph visualization created by Gustavo Glusman, PhD, Institute for Systems Biology

JANUARY FEBRUARY MARCH APRIL MAY JUNE JULY AUGUST SEPTEMBER OCTOBER NOVEMBER DECEMBER  | INSTITUTE FOR SYSTEMS BIOLOGY 2009 ANNUAL REPORT |  A BREAKTHROUGH IN FINDING THE GENETIC CAUSE OF DISEASE finding and killing cancer cells

MILLER SYNDROME Cell surface PROTEINs Ever since the first human genome sequence was published children affected with Miller Syndrome, these advances allowed Cancer cells that cannot be identified cannot be killed. researchers were able to identify and monitor changes in 2003, people have had high expectations about the for the identification of just four disease-gene candidates out of The inability to find and target cancer cells hidden among in more than 300 cell-surface proteins at the same contribution that this richness of genetic information would the some 25,000 human genes—and the correct disease gene millions of healthy cells has long confounded researchers in time as the cells transformed from stem cells into a make to the diagnosis and curing of diseases. was then readily identified by looking at the DNA from other the fight against cancer. Since killing healthy cells cannot be neural cell type. Prior to this breakthrough, scientists patients with Miller syndrome. well tolerated, specifically targeted killing is key. One reason had only been able to measure up to 10 target Though science has advanced rapidly as a result of the first it is so hard is that cancer cells are highly variable and proteins on a cell surface per experiment genome sequence the promise of the human genome to Advances in sequencing technology have so reduced the change as they progress from early to late stage, and medicine has been elusive. ISB researchers have now taken cost, from $300,000 three years ago to less than $10,000 from localized to metastatic or invasive states. Among the many potential applications of this work, a major step towards changing that in announcing a new today and perhaps less than $1000 in five years, that whole researchers are hopeful that protein surface signatures approach to uncovering the genes that cause disease. This genome sequencing of entire families is likely to become both In 2009 ISB scientists took a significant step in advancing will contribute to early stage cancer diagnosis, the approach is likely to change fundamentally how genetic a research and clinical standard of practice in the near future. the ability of researchers to both distinguish cancer cells identification of the best treatment for each patient’s research is conducted in future. The techniques that ISB is developing will be central to the from healthy cells and to identify how far the disease has specific cancer, and the identification of new and more future of human genetics. progressed. A research paper reporting this advance was effective therapeutic targets for cancer. In 2009 ISB researchers and their collaborators conducted published in Nature Biotechnology in April, 2009. Much like the first whole genome sequencing of an entire family (mother, The paper reporting the work, performed largely in 2009, a fingerprint, some cells have unique “signatures” on their ISB-affiliated contributors to the paper were: Bernd father and two children), which led rapidly to the discovery of appeared in Science in April of 2010. ISB authors of the surfaces that consist of varying types and numbers of Wollscheid, PhD, Christine Henderson, Robert O’Brien, a gene responsible for Miller syndrome, a rare craniofacial and paper were: Jared Roach, MD, PhD, Gustavo Glusman, PhD, proteins. The protein “cell-surface signature” for a cancer PhD, Ruedl Aebersold, PhD, and Julian Watts, PhD. limb deforming disorder. Arian Smit, PhD, Robert Hubley, PhD, Paul T. Shannon, PhD, cell can be very different from that of a healthy cell. Protein Lee Rowen, PhD, Nathan Goodman, PhD, Lee Hood, MD, signatures for brain cancer cells differ from those of breast From the information in genomes of the whole family they PhD, and David Galas, PhD. could infer the most accurate genome sequence of human cancer cells. In fact, the protein signature of a breast cancer DNA to date. Simple inheritance rules allow sequence error ISB scientists are now developing ever more complex analysis cell (or any cancer cell) will change over time, depending on identification and thus enable the accurate detection of rare methods and are next planning to apply this groundbreaking the stage of the disease. With this new method ISB sequence variants (the family had 230,000), which can play a approach to Huntington’s disease, congenital heart defects, central role in genetic diseases. In this family, with the two and later, to Alzheimer’s disease.

Gustavo Glusman, PhD Jared Roach, MD, PhD Arian Smit, PhD Julian Watts, PhD Ma r c h The Scientist Magazine identified ISB as one of the 10 best places to work for Postdoctoral fellows.

JANUARY FEBRUARY MARCH APRIL MAY JUNE JULY AUGUST SEPTEMBER OCTOBER NOVEMBER DECEMBER  | INSTITUTE FOR SYSTEMS BIOLOGY 2009 ANNUAL REPORT |  improving THE tools of discovery Immune Response Regulation

Microfluidic Technology IMMUNE RESPONSE REGULATION Since its inception as the world’s first systems biology-focused The new technology, an advance in an existing platform (general) Atherosclerosis, sepsis, type 1 diabetes, rheumatoid Using leading edge technologies as well as mathematical research institute in 2000, ISB’s founders have operated under a technology called microfluidics, allows researchers to create and arthritis, lupus, multiple sclerosis, anemia, graves disease and computational modeling, they predicted and then simple yet powerful maxim; If the technology required to answer change unique environments in each of hundreds of microscopic and celiac disease. experimentally validated a previously unknown biological a biological question does not exist, then invent it. compartments that contain live individual cells. Think of the network in the immune system that is critically important plumbing in all the houses on your block shrunk down to the size These are only a few examples of approximately 80 autoimmune for determining the duration of an infection and the At ISB, biological inquiry and technology development form of a pencil dot, with valves being opened and closed to direct disorders, which are caused by an immune system that functions appropriate response. an inventive “cycle” of discovery. Researchers start with the flow of water in appropriate compartments. This microfluidic in an uncontrolled manner and attacks healthy tissues as though a question about how a biological system functions, with plumbing allows scientists to provide each of hundreds of cells they were foreign bacteria, viruses, toxins or cancer cells. The goal of learning about these networks, their biological the long-term goals of understanding biology, diagnosing with unique environments and measure their responses. Each components and their role in immune response is to The reason people develop autoimmune diseases is not clear. disease early or curing disease. If the technology doesn’t experiment allows researchers to learn in hours what formerly identify and influence elements of a biological system that The benefit of being able to moderate or shut down an exist to answer the question, biologists collaborate with ISB could only be measured in large populations of cells—individual may be malfunctioning, as in autoimmune disease, or that overzealous immune response, however, is readily apparent. technologists, physicists, computer programmers and others cell measurements were impossible. may need a boost, such as that supplied by new vaccines. to develop it. The new technology hopefully answers the This is why ISB researchers used a systems biology approach The goal is to be able to turn on or turn off the immune original question and generates new data that in turn catalyzes In addition, the technology allows for real-time monitoring of the to better understand how the innate immune system, the system as needed. biological insights, which in turn lead to new questions. The continuous responses of cells, rather than just taking snapshots of body’s first line of defense against pathogens, manages to new questions require the development of additional new cells at specific time points during the experiment. And the entire mount appropriate responses to the invasion of pathogens, A paper addressing the findings was published in Nature technologies, and the cycle continues. process is automated. Researchers pre-program the experiment, and why under pathological conditions the innate immune Immunology in April of 2009. ISB authors include Vladimir push a button and step back while the device does all the work, system helps attack the patient’s own body. The primary Litvak, PhD, Stephen A. Ramsey, PhD, Matti Nykter, PhD, That cycle is the impetus behind a new platform ISB allowing scientists to spend more time analyzing findings and question is how does the innate immune system know when a Alistair G. Rust, PhD, Daniel E. Zak, PhD, Kathleen A. researchers developed in 2009 for conducting experiments deciphering the mysteries of complex biological problems that threat has been neutralized and what triggers the return to an Kennedy, PhD, Aaron E. Lampano, Ilya Shmulevich, PhD, on thousands of individual live cells simultaneously. provide insights into cancer, heart disease, Alzheimer’s and more. observational mode from an aggressive response mode? and Alan Aderem, PhD.

A paper about the research appeared in the Proceedings of the ISB researchers studied macrophages, which are immune cells National Academy of Sciences in January of 2009. ISB authors on that track down and kill diseased cells in the body. the paper included James Taylor, PhD, Stephen A. Ramsey, PhD, and faculty members Ilya Shmulevich, PhD, and Tim Galitski, PhD. au g ust James Taylor, PhD Vladimir Litvak, PhD The National Academy J u ly Lee Hood and ISB were of Sciences released a featured in the Science report describing the value Channel program of a “new science” that reflects “The Future of…” the systems approach pioneered at ISB since its founding in 2000.

JANUARY FEBRUARY MARCH APRIL MAY JUNE JULY AUGUST SEPTEMBER OCTOBER NOVEMBER DECEMBER  | INSTITUTE FOR SYSTEMS BIOLOGY 2009 ANNUAL REPORT |  FINANCIAL HIGHLIGHTS

Finacial Highlights FINANCIAL STATEMENT: For the Year Ended December 31, 2009 Financially, 2009 was another good year for ISB, despite expertise and the abilities of our faculty and staff. the weak economy: At the same time we have to be realistic in our expectations. Considering the state of the US economy Growth in operations 2009 REVENUES ü Revenue from grants and contracts increased by and budget deficits it may not be realistic to expect 26 percent, from $28.0 million to $35.2 million, continuing increases in US government grants and $45,000 Grant & contract revenue (US) led by income from our multi year strategic contracts, despite our successful track record. $40,000 Grant & contract revenue (foreign) partnership with the University of Luxembourg; Contributions Based on our growth and our confidence in the future, $35,000 Investment & other income ü Total revenue increased from $39.3 million to however, we have committed to move from our current $30,000 $39.6 million; buildings to a beautiful, nearly new and nearly fully-equipped $25,000 ü Research operations increased 22 percent research building |in the South Lake Union area of Seattle. Our $20,000 from $33.9 million to $41.3 million; and new building will be much larger than our current facilities, enabling us to again have all our staff in one building with room $15,000 ü Our balance sheet remains strong, with over $15 to grow. In addition, the South Lake Union area has rapidly $10,000 million in net assets at year end and healthy cash flow. become the primary location for Seattle’s biomedical research organizations, enabling more convenient collaboration with $5,000 As we look to the future, we expect our strategic partnership colleagues in nearby institutes. $0 with the University of Luxembourg to grow to a higher level 2005 2006 2007 2008 2009 in 2010 that will be sustained for additional years. We also We look forward to the opportunities that continue to come to BALANCE SHEET expect to form new strategic partnerships with organizations, us, and to managing our finances and operations in the most Research Operations Grant Funding ASSETS both in the U.S. and abroad, that value our areas of research productive ways possible. Cash & investments 24,335 Other assets 5,950 Property & equipment, net 8,491 STATEMENT OF ACTIVITIES TOTAL ASSETS $38,776 REVENUES SEPTEMBER Grant & contract revenue 35,154 liabilities Jim Ladd, Senior Vice President Accounts payable & accrued expenses 6,742 1. ISB received an $8 million Contributions 1,791 for Finance and Operations Investment & other income 2,681 Deferred revenues 7,080 grant from the National Notes payable 9,908 TOTAL REVENUES 39,626 Cancer Institute. TOTAL LIABILITIES 23,730 EXPENDITURES 2. ISB received a $4.6 Research & other direct costs 30,582 Net Assets Management & general 10,062 Unrestricted net assets 5,508 million grant from the Fundraising & other 702 Temporarily restricted net assets 866 National Human Genome Permanently restricted net assets 8,672 TOTAL EXPENDITURES 41,346 Research Institute. Change in Net Assets $1,720 TOTAL NET ASSETS 15,046

JANUARY FEBRUARY MARCH APRIL MAY JUNE JULY AUGUST SEPTEMBER OCTOBER NOVEMBER DECEMBER  | INSTITUTE FOR SYSTEMS BIOLOGY 2009 ANNUAL REPORT | 10 STRATEGIC PARTNERSHIPS

Strategic partnerships are unique University. Professor Balling was trained in genetics There were also other important partnerships initiated relationships developed with other institutions – academic and developmental biology. He served as the Director in 2009, and several discussed that seem promising. or research institutes, companies or government agencies of the Institute for Mammalian Genetics (Helmholtz An important partnership started in 2009 was the P4 – for mutual benefit. For our part they are intended to Zentrum München) from 1993 to 2000, and as the Medicine Institute (P4MI), launched in collaboration with increase ISB’s access to scientific and technology expertise, Scientific Director of the Helmholtz Centre for Infectious the Ohio State University. P4MI’s goals are to address financial and other resources, which complement and Disease Research from 2001 to 2009. Professor Balling potential impacts of scientific innovation on healthcare, enhance our internal research strengths, and enable us is widely regarded as an influential leader in European helping to define specific, transformational innovations, to to better fulfill our mission. Access to more expertise science and policy, having successfully built numerous advocate key changes to the system and to consider their and capabilities can help drive our innovations. We are scientific programs and institutes, and being an early many sociological, economic and ethical impacts. highly selective and new opportunities for additional advocate of systems biology and biomedicine. partnerships are frequently being evaluated. This partnership enhances ISB’s research resources By far ISB’s largest and most important partnership to substantially and has already led to significant scientific date began with the 2008 signing of a five-year strategic accomplishments. Among these, the completion and alliance with the University of Luxembourg. This partnership analysis of whole genome sequences of an entire family David Galas, PhD, Senior Vice President for Strategic Partnerships underlined ISB’s emergence as an international leader in for the first time were reported in a widely noted systems biology research. Science paper that garnered front page coverage in both the New York Times and the Seattle Times. Family genome A notable accomplishment in 2009 was the ISB- analysis, which this paper describes, will be a new ADDITIONAL PARTNERSHIPS aided recruitment of distinguished European scientist direction for ISB’s research and a powerful new tool Professor Rudi Balling as the founding director of the PARTNER FOCUS for medical science. The Luxembourg partnership makes new Luxembourg Centre for Systems Biomedicine at the possible very ambitious science that can drive the next wave of technology and scientific advances at ISB. It also supports collaborative research among the faculty, J. David Gladstone Institutes Human genetics, neurodegenerative disease the enhancement of our essential core facilities and advances training and technology development, California Institute of Technology New protein detection/measurement technology among other benefits. NOVEMBER ISB hosted the first Luxembourg’s partnership is also about translating Department of Defense Traumatic brain injury, post-traumatic stress disorder, liver and lung toxicity international symposium biological knowledge into economic development focusing on peroxisome opportunities and improving healthcare. In 2009, a new disorders in the diagnostics company was launched from ISB and funded National Institutes of Science and Technology (NIST) Proteomics, miRNA technologies, imaging 21st centuy. by private sources in the US, the UK and Luxembourg. We expect that Integrated Diagnostics will be a significant help in transforming scientific discoveries National Cancer Institute Tumor systems biology

David Galas, PhD into real products that impact healthcare.

JANUARY FEBRUARY MARCH APRIL MAY JUNE JULY AUGUST SEPTEMBER OCTOBER NOVEMBER DECEMBER 11 | INSTITUTE FOR SYSTEMS BIOLOGY 2009 ANNUAL REPORT | 12 CENTER FOR INQUIRY SCIENCE

IMPROVING SCIENCE EDUCATION ü Hosted 99 professional development sessions, The development of a scientifically literate which served 800 science educators over society has always been a core ISB objective. a period of 292 workshop days; and

A basic understanding of the sciences is ü Funded its own operations through approximately essential to the rational evaluation of many $1 million in grants from federal and state agencies, critical public policy issues such as biomedical as well as with philanthropic support from ethics, global warming and energy independence. corporations, foundations and individuals. That is why the Institute’s founders created the Center for Inquiry Science (CIS) at ISB. Other Highlights from 2009: ü CIS extended its Observing for Evidence of Learning The mission of CIS is to help kindergarten (OEL) professional development model to include through grade 12 educators produce scientifically high school science departments through a partnership literate students by creating and supporting with Everett Public Schools. Over the last five years, collaborative partnerships among schools, with funding from the National Science Foundation, districts and community stakeholders. CIS has developed and implemented the OEL model in partnership with all middle schools in the Seattle, In 2009 CIS: Shoreline, Highline and Bellevue school districts. 1. CIS continued to foster community engagement in 3. CIS engaged as a partner in planning the ü Worked with educators from 44 school science education, hosting three “Celebrating Science” development of the Washington state STEM districts representing 45 percent of The OEL model has resulted in improved student events in the Renton School District attended by 662 (Science, Technology, Engineering and Math) Center. the state’s student population; achievement compared to non-OEL schools, as family members of elementary students. Funded by The STEM Center will provide support to teachers confirmed by an external evaluator. The Everett program the Howard Hughes Medical Institute, the Celebrating and schools, seed innovation through regional grants, was funded through the Washington state Office of the Science events included direct engagement by ISB identify and accelerate programs proven to boost Superintendent of Public Instruction by the US Department researchers and were designed to introduce parents student achievement and advocate for policies that of Education as part of the No Child Left Behind Act. to science and science education, with the goal of position all Washington students for success. fostering support for science learning in the home. Dana Riley Black, PhD Director, Center for Inquiry Science 2. CIS investigated and analyzed strategies for teaching Pr o f eSSi ona l science to students whose first language is not English. DEV e loPm e n t The findings will be incorporated into CIS professional Science teachers attend development programming and be made available to professional development practitioners locally and nationally as a white paper training at ISB. highlighting the most effective strategies for improving student learning of both science and English.

JANUARY FEBRUARY MARCH APRIL MAY JUNE JULY AUGUST SEPTEMBER OCTOBER NOVEMBER DECEMBER 13 | INSTITUTE FOR SYSTEMS BIOLOGY 2009 ANNUAL REPORT | 14 DEVELOPMENT AND PUBLIC RELATIONS

Development and Public Relations Since its founding less than a decade ago, ISB has received ISB enjoyed robust media relations in 2009: our more than $60 million in gifts from the private sector. scientists and their research discoveries earned This philanthropic investment was essential to creating a an extraordinary degree of media attention. For cross-disciplinary foundation, recruiting the faculty and example, ISB President and Co-founder Lee Hood and generating the high throughput measurement facilities that colleagues were interviewed by Newsweek International, constitute the powerful infrastructure of ISB. This unique Newsweek US, New Scientist, Forbes, the New York infrastructure has catalyzed the realization of more than Times, BusinessWeek, WIRED and other national and $100 million in federal funding and more than $100 million international newspapers and magazines. The Science from strategic partnerships. These leveraged supports have Channel and Popular Science filmed a part of their allowed ISB to pioneer systems approaches both to biology series on future technologies at ISB, featuring Lee and medicine that are transformational, as evidenced by Hood. Alan Aderem, ISB co-founder and director, was the SCImago Report. ISB truly exemplifies the power of featured in an interview on Seattle’s public television philanthropy to catalyze a fundamental scientific change. station KCTS, discussing swine flu and what ISB is doing to combat future pandemics. In 2009, the Institute recorded $1.8 million in contributions, a substantial decrease from 2008. ISB’s drop-off in this support ISB will continue providing many opportunities mirrored the experiences of non-profit research institutions for visionary donors who want to help our across the country. Institute leaders and faculty, nonetheless, scientists address complex biological questions nurtured long-term relationships during the year that bore and improve the human condition through progress fruit, as demonstrated by more than $8 million in new in predictive, personalized, preventive and gift commitments in early 2010. participatory (P4) healthcare.

NOVEMBER S uppo rt i n g ISB The Scientist Magazine For information about how to support ISB research efforts, contact identified ISB as one of the ISB Development Department at (206) 732-1232 or go to the 10 best places to www. systemsbiology.org/support_isb. work in academia.

JANUARY FEBRUARY MARCH APRIL MAY JUNE JULY AUGUST SEPTEMBER OCTOBER NOVEMBER DECEMBER 15 | INSTITUTE FOR SYSTEMS BIOLOGY 2009 ANNUAL REPORT | 16 BOARD OF DIRECTORS AND MAJOR DONORS

2010 Board of Directors 2009 Executive Management Senior Research Scientists Senior Software EngineerS Senior IT Analyst

ü Roger Perlmutter, MD, PhD | Chairman of the ISB Board ü Leroy Hood, MD, PhD | President ü Peter Askovich, PhD ü Hector Rovira ü Kerry Deutsch, PhD Executive Vice President, Research and Development, Amgen, Inc. ü Alan Aderem, PhD | Director and Co-founder ü Greg Carter, PhD ü Lisa Iype, PhD Senior Research Engineer ü Mark Ashida | Managing Director, OVP Venture Partners ü Eric Deutsch, PhD ü Sarah Killcoyne ü John Aitchison, PhD | Associate Director ü Alan Diercks, PhD ü Bill Longabaugh, MS ü Chris Lausted, MS ü Bill Bowes | Co-founder, U.S. Venture Partners ü James R. Ladd | Senior Vice President for ü Richard Gelinas, PhD ü Hector Rovira Finance and Operations ü Thomas J. Cable | Board Member, Omeros Corporation ü Gustavo Glusman, PhD ü Paul Shannon ü Chuck Hirsch | Founding Partner, MHz, LLC ü David Galas, PhD | Senior Vice President ü Mark Gilchrist, PhD Director of Informatics Core for Strategic Partnerships ü ü Leroy Hood, MD, PhD | President and Co-founder, Elizabeth Gold, MD ü Institute for Systems Biology ü Cathryn Campbell, JD, PhD | General Counsel ü Nat Goodman, PhD John Boyle, PhD ü Richard Johnson, PhD ü Louis G. Lange, MD, PhD | Senior Adviser, Gilead Faculty ü Andrew Keller, PhD ü Garry Menzel, PhD | Executive Vice President, ü Alan Aderem, PhD ü Kathleen Kennedy, PhD DONORS LIST Corporate Development and Finance, Regulus Therapeutics ü Ruedi Aebersold, PhD ü Inyoul Lee, PhD ü Robert T. Nelsen | Co-founder and Managing Director, ü John Aitchison, PhD ü Monica Orellana, PhD ARCH Venture Partners $25,000 - $1,200,000 $2,500 - $9,999 ü Renee Duprel ü Raul A. Saavedra ü Nitin Baliga, PhD ü Jacques Peschon, PhD ü Anonymous (1) ü Accelerator Corporation ü GVA Kidder Matthews ü Georges C. St. Laurent ü George Rathmann, PhD | Director Emeritus Chairman, Nuvelo, Inc. ü Aimée Dudley, PhD ü Shizhen Qin, PhD ü Frederick Frank ü Adam J. Weissman Foundation ü Laurence W. Herron ü Erich C. Strauss ü Roger Perlmutter ü Bristol-Myers Squibb ü Myron Hood ü Shawn J. Swift ü David Galas, PhD ü Stephen Ramsey, PhD ü David A. Sabey | President, Sabey Corporation & Sabey Construction ü Swedish Neuroscience Institute ü Center for Systems Biology ü Douglas O. Howe ü Alvin J. Thompson ü Tim Galitski, PhD ü David Reiss, PhD for Seattle Brain Cancer Walk ü Lee Hood and Valerie Logan ü Kathlyn Huson ü Tate Tsnag ü Leroy Hood, MD, PhD ü Jared Roach, MD, PhD ü Intellectual Ventures, LLC ü Bruce and Bett Jansson ü Victoria $10,000 - $24,999 ü Schwabe Williamson & ü Rhoda Jensen VanBruinisse ü Dan Martin, MD ü Lee Rowen, PhD ü Alexandria Real Estate Wyatt, P.C. ü Jennifer Keys ü Peter and Shannon ü Robert Moritz, PhD ü Ramsey Saleem, PhD Equities, Inc. ü Nathan Labenz H. van Oppen o c to b e r ü Amgen, Inc. $1 - $2,499 ü Lawrence A. Loeb ü Dan Williams ü Adrian Ozinsky, MD, PhD ü Arian Smit, PhD 1. Integrated Diagnostics ü Amgen Foundation ü Kasra R. Badiozamani ü Ward Merkeley ü Elaine Woo was launched based on ü Jeff Ranish, PhD ü Jennifer Smith, PhD ü William and Phyllis Draper ü Martha W. Bond ü Damion Mullins ü ü ü technology developed at ISB. ü Ilya Shmulevich, PhD ü James Spotts, PhD William and Barbara Edwards BP America, Inc. James D. O’Hanlon ü Life Technologies Corporation ü Anna Bran ü Perkins+Will ü Peter Small, PhD ü Vesteinn Thorsson, PhD ü OVP Venture Partners ü Dennis and Christi Carlson ü Shizhen Qin 2. Thomas J. Cable and Louis ü Qiang Tian, MD, PhD ü Runstad Foundation ü Janet M. Carlson ü Gary F. Raisl G. Lange, MD, PhD, joined ü Sean Clisham ü Lorna C. Roebke ü Kai Wang, PhD the ISB Board of Directors. ü Roy Currence ü Rob Rogalski ü Julian Watts, PhD ü Jennifer Dougherty ü Sherri Rogalski ü Robert West, PhD ü Amanda L. Dunkin ü Mike Ruland

JANUARY FEBRUARY MARCH APRIL MAY JUNE JULY AUGUST SEPTEMBER OCTOBER NOVEMBER DECEMBER 17 | INSTITUTE FOR SYSTEMS BIOLOGY 2009 ANNUAL REPORT | 18 2009 Scientific publications

A B E ü Aebersold, R. (2009) A stress test for ü Beck, M., Malmstrom, J.A., Lange, V., Schmidt, A., ü Carter, G.W., Galas, D.J., and Galitski, T. (2009) ü Eisenacher, M., Martens, L., Hardt, T., Kohl, M., Barsnes, mass spectrometry-based proteomics. Deutsch, E.W., and Aebersold, R. (2009) Visual Maximal extraction of biological information H., Helsens, K., Hakkinen, J., Levander, F., Aebersold, R., Nat Methods 6: 411-2. PMID:19448640 proteomics of the human pathogen Leptospira interrogans. from genetic interaction data. PLoS Comput Vandekerckhove, J., Dunn, M.J., Lisacek, F., Siepen, J.A., Hubbard, ü Aebersold, R., Auffray, C., Baney, E., Barillot, E., Brazma, Nat Methods 6: 817-23. PMID:19838170 Biol 5: e1000347. PMID:19343223 S.J., Binz, P.A., Bluggel, M., Thiele, H., Cottrell, J., Meyer, H.E., A., Brett, C., Brunak, S., Butte, A., Califano, A., Celis, ü Bochud, P.Y., Sinsimer, D., Aderem, A., Siddiqui, M.R., ü Chaturvedi, C.P., Hosey, A.M., Palii, C., Perez-Iratxeta, Apweiler, R., and Stephan, C. (2009) Getting a grip on J., Cufer, T., Ferrell, J., Galas, D., Gallahan, D., Gatenby, Saunderson, P., Britton, S., Abraham, I., Tadesse C., Nakatani, Y., Ranish, J.A., Dilworth, F.J., and Brand, proteomics data - Proteomics Data Collection (ProDaC). R., Goldbeter, A., Hace, N., Henney, A., Hood, L., Argaw, A., Janer, M., Hawn, T.R., and Kaplan, G. (2009) M. (2009) Dual role for the methyltransferase Proteomics 9: 3928-33. PMID:19637238 Iyengar, R., Jackson, V., Kallioniemi, O., Klingmuller, Polymorphisms in Toll-like receptor 4 (TLR4) are G9a in the maintenance of beta-globin gene U., Kolar, P., Kolch, W., Kyriakopoulou, C., Laplace, associated with protection against leprosy. Eur J Clin transcription in adult erythroid cells. Proc Natl F F., Lehrach, H., Marcus, F., Matrisian, L., Nolan, G., Microbiol Infect Dis 28: 1055-65. PMID:19430824 Acad Sci U S A 106: 18303-8. PMID:19822740 ü Fagarasanu, A., Mast, F.D., Knoblach, B., Jin, Y., Brunner, M.J., Pelkmans, L., Potti, A., Sander, C., Seljak, M., Singer, ü Bollyky, P.L., Bice, J.B., Sweet, I.R., Falk, B.A., Gebe, J.A., Clark, ü Claassen, M., Aebersold, R., and Buhmann, J.M. (2009) Logan, M.R., Glover, J.N., Eitzen, G.A., Aitchison, J.D., D., Sorger, P., Stunnenberg, H., Superti-Furga, G., A.E., Gersuk, V.H., Aderem, A., Hawn, T.R., and Nepom, Proteome coverage prediction with infinite Markov models. Weisman, L.S., and Rachubinski, R.A. (2009) Myosin- Uhlen, M., Vidal, M., Weinstein, J., Wigle, D., Williams, G.T. (2009) The toll-like receptor signaling molecule Bioinformatics 25: i154-60. PMID:19477982 driven peroxisome partitioning in S. cerevisiae. J M., Wolkenhauer, O., Zhivotovsky, B., Zinovyev, A., Myd88 contributes to pancreatic beta-cell homeostasis in Cell Biol 186: 541-54. PMID:19687257 and Zupan, B. (2009) Report on EU-USA workshop: response to injury. PLoS One 4: e5063. PMID:19357791 D ü Foltz, G., Yoon, J.G., Lee, H., Ryken, T.C., Sibenaller, Z., Ehrich, how systems biology can advance cancer research (27 ü Boyle, J., Rovira, H., Cavnor, C., Burdick, D., ü Di Paolo, N.C., Miao, E.A., Iwakura, Y., Murali-Krishna, M., Hood, L., and Madan, A. (2009) DNA methyltransferase- October 2008). Mol Oncol 3: 9-17. PMID:19383362 Killcoyne, S., and Shmulevich, I. (2009) Adaptable K., Aderem, A., Flavell, R.A., Papayannopoulou, T., mediated transcriptional silencing in malignant glioma: a ü Akiyoshi, B., Nelson, C.R., Ranish, J.A., and Biggins, data management for systems biology investigations. and Shayakhmetov, D.M. (2009) Virus binding to a combined whole-genome microarray and promoter array S. (2009) Quantitative proteomic analysis of purified BMC Bioinformatics 10: 79. PMID:19265554 plasma membrane receptor triggers interleukin-1 alpha- analysis. Oncogene 28: 2667-77. PMID:19465937 yeast kinetochores identifies a PP1 regulatory subunit. ü Brentnall, T.A., Pan, S., Bronner, M.P., Crispin, D.A., Mirzaei, mediated proinflammatory macrophage response in Genes Dev 23: 2887-99. PMID:19948764 H., Cooke, K., Tamura, Y., Nikolskaya, T., Jebailey, L., Goodlett, vivo. Immunity 31: 110-21. PMID:19576795 G ü Akiyoshi, B., Nelson, C.R., Ranish, J.A., and Biggins, D.R., McIntosh, M., Aebersold, R., Rabinovitch, P.S., and ü Diercks, A., Kostner, H., and Ozinsky, A. (2009) ü Galas, D. and Hood, L. (2009) Systems biology and emerging S. (2009) Analysis of Ipl1-mediated phosphorylation Chen, R. (2009) Proteins That Underlie Neoplastic Resolving cell population heterogeneity: real-time PCR for technologies will catalyze the transition from reactive medicine of the Ndc80 kinetochore protein in Saccharomyces Progression of Ulcerative Colitis. Proteomics Clin simultaneous multiplexed gene detection in multiple single- to predictive, personalized, preventive and participatory cerevisiae. Genetics 183: 1591-5. PMID:19822728 Appl 3: 1326-1337. PMID:20098637 cell samples. PLoS One 4: e6326. PMID:19633712 (P4) medicine. Interdisciplinary Bio Central 1: 0006. ü Anderson, N.L., Anderson, N.G., Pearson, T.W., ü Diercks, A.H., Ozinsky, A., Hansen, C.L., Spotts, J.M., ü Gehlenborg, N., Hwang, D., Lee, I.Y., Yoo, H., Baxter, D., Petritis, Borchers, C.H., Paulovich, A.G., Patterson, S.D., C Rodriguez, D.J., and Aderem, A. (2009) A microfluidic B., Pitstick, R., Marzolf, B., Dearmond, S.J., Carlson, G.A., and Gillette, M., Aebersold, R., and Carr, S.A. (2009) A ü Carapito, C., Klemm, C., Aebersold, R., and Domon, device for multiplexed protein detection in nano-liter Hood, L. (2009) The Prion Disease Database: a comprehensive human proteome detection and quantitation project. B. (2009) Systematic LC-MS analysis of labile post- volumes. Anal Biochem 386: 30-5. PMID:19133224 transcriptome resource for systems biology research in prion Mol Cell Proteomics 8: 883-6. PMID:19131327 translational modifications in complex mixtures. J ü Domon, B., Bodenmiller, B., Carapito, C., Hao, Z., Huehmer, diseases. Database (Oxford) 2009: bap011. PMID:20157484 ü Auffray, C., Chen, Z., and Hood, L. (2009) Systems Proteome Res 8: 2608-14. PMID:19284785 A., and Aebersold, R. (2009) Electron transfer dissociation ü Gehlenborg, N., Yan, W., Lee, I.Y., Yoo, H., Nieselt, K., Hwang, D., medicine: the future of medical genomics and healthcare. ü Carter, G.W. and Dudley, A.M. (2009) Systems Genetics and in conjunction with collision activation to investigate the Aebersold, R., and Hood, L. (2009) Prequips--an extensible Genome Med 1: 2. PMID:19348689 Complex Traits, in Encyclopedia of Complexity and Systems Drosophila melanogaster phosphoproteome. J Proteome software platform for integration, visualization and analysis Science, (R.A. Meyers, Editor), Springer Publishing. Res 8: 2633-9. PMID:19435317 of LC-MS/MS proteomics data. Bioinformatics 25: 682-3. PMID:19129212

JANUARY FEBRUARY MARCH APRIL MAY JUNE JULY AUGUST SEPTEMBER OCTOBER NOVEMBER DECEMBER 19 | INSTITUTE FOR SYSTEMS BIOLOGY 2009 ANNUAL REPORT | 20 2009 Scientific publications

G (continued) H K L ü Gillespie, M.A., Le Grand, F., Scime, A., Kuang, S., von ü Hawn, T.R., Scholes, D., Li, S.S., Wang, H., Yang, Y., Roberts, ü Hu, L., Hittelman, W., Lu, T., Ji, P., Arlinghaus, R., ü Kao, S.C., Wu, H., Xie, J., Chang, C.P., Ranish, J.A., ü Lausted, C., Hu, Z., Hood, L., and Campbell, C.T. ü Loevenich, S.N., Brunner, E., King, N.L., Deutsch, E.W., Stein, S.E., Maltzahn, J., Seale, V., Cuenda, A., Ranish, J.A., and P.L., Stapleton, A.E., Janer, M., Aderem, A., Stamm, W.E., Shmulevich, I., Hamilton, S.R., and Zhang, W. (2009) NGAL Graef, I.A., and Crabtree, G.R. (2009) Calcineurin/NFAT (2009) SPR imaging for high throughput, label- FlyBase, C., Aebersold, R., and Hafen, E. (2009) The Drosophila Rudnicki, M.A. (2009) p38-{gamma}-dependent gene Zhao, L.P., and Hooton, T.M. (2009) Toll-like receptor decreases E-cadherin-mediated cell-cell adhesion and signaling is required for neuregulin-regulated Schwann cell free interaction analysis. Comb Chem High melanogaster PeptideAtlas facilitates the use of peptide data silencing restricts entry into the myogenic differentiation polymorphisms and susceptibility to urinary tract infections increases cell motility and invasion through Rac1 in colon differentiation. Science 323: 651-4. PMID:19179536 Throughput Screen 12: 741-51. PMID:19531009 for improved fly proteomics and genome annotation. BMC program. J Cell Biol 187: 991-1005. PMID:20026657 in adult women. PLoS One 4: e5990. PMID:19543401 carcinoma cells. Lab Invest 89: 531-48. PMID:19308044 ü Knijnenburg, T.A., Wessels, L.F., Reinders, M.J., and ü Lee, S.I., Dudley, A.M., Drubin, D., Silver, P.A., Krogan, Bioinformatics 10: 59. PMID:19210778 ü Glatter, T., Wepf, A., Aebersold, R., and Gstaiger, ü Hawn, T.R., Scholes, D., Wang, H., Li, S.S., Stapleton, A.E., ü Huang, A.C., Hu, L., Kauffman, S.A., Zhang, W., and Shmulevich, I. (2009) Fewer permutations, more accurate N.J., Pe’er, D., and Koller, D. (2009) Learning a M. (2009) An integrated workflow for charting the Janer, M., Aderem, A., Stamm, W.E., Zhao, L.P., and Hooton, Shmulevich, I. (2009) Using cell fate attractors to P-values. Bioinformatics 25: i161-8. PMID:19477983 prior on regulatory potential from eQTL data. M human interaction proteome: insights into the PP2A T.M. (2009) Genetic variation of the human urinary tract uncover transcriptional regulation of HL60 neutrophil ü Koide, T., Lee Pang, W., and Baliga, N.S. (2009) The PLoS Genet 5: e1000358. PMID:19180192 ü Majeti, R., Becker, M.W., Tian, Q., Lee, T.L., Yan, X., Liu, system. Mol Syst Biol 5: 237. PMID:19156129 innate immune response and asymptomatic bacteriuria differentiation. BMC Syst Biol 3: 20. PMID:19222862 role of predictive modelling in rationally re-engineering ü Leidel, S., Pedrioli, P.G., Bucher, T., Brost, R., Costanzo, R., Chiang, J.H., Hood, L., Clarke, M.F., and Weissman, ü Goetze, S., Qeli, E., Mosimann, C., Staes, A., Gerrits, in women. PLoS One 4: e8300. PMID:20016852 ü Huber, A., Bodenmiller, B., Uotila, A., Stahl, M., biological systems. Nat Rev Micro 7: 297-305. M., Schmidt, A., Aebersold, R., Boone, C., Hofmann, K., I.L. (2009) Dysregulated gene expression networks in human acute myelogenous leukemia stem cells. Proc B., Roschitzki, B., Mohanty, S., Niederer, E.M., Laczko, ü Heath, J.R., Davis, M.E., and Hood, L. (2009) Nanomedicine Wanka, S., Gerrits, B., Aebersold, R., and Loewith, ü Koide, T., Reiss, D.J., Bare, J.C., Pang, W.L., Facciotti, and Peter, M. (2009) Ubiquitin-related modifier Urm1 Natl Acad Sci U S A 106: 3396-401. PMID:19218430 E., Timmerman, E., Lange, V., Hafen, E., Aebersold, targets cancer. Sci Am 300: 44-51. PMID:19186705 R. (2009) Characterization of the rapamycin- M.T., Schmid, A.K., Pan, M., Marzolf, B., Van, P.T., Lo, acts as a sulphur carrier in thiolation of eukaryotic R., Vandekerckhove, J., Basler, K., Ahrens, C.H., ü Hemmi, H., Idoyaga, J., Suda, K., Suda, N., Kennedy, K., Noda, sensitive phosphoproteome reveals that Sch9 F.Y., Pratap, A., Deutsch, E.W., Peterson, A., Martin, transfer RNA. Nature 458: 228-32. PMID:19145231 ü Malmstrom, J., Beck, M., Schmidt, A., Lange, V., Deutsch, Gevaert, K., and Brunner, E. (2009) Identification M., Aderem, A., and Steinman, R.M. (2009) A new triggering is a central coordinator of protein synthesis. D., and Baliga, N.S. (2009) Prevalence of transcription ü Lin, B., Wang, J., Hong, X., Yan, X., Hwang, D., Cho, J.H., Yi, D., E.W., and Aebersold, R. (2009) Proteome-wide cellular and functional characterization of N-terminally receptor expressed on myeloid cells (Trem) family member, Genes Dev 23: 1929-43. PMID:19684113 promoters within archaeal operons and coding Utleg, A.G., Fang, X., Schones, D.E., Zhao, K., Omenn, G.S., and protein concentrations of the human pathogen Leptospira acetylated proteins in Drosophila melanogaster. Trem-like 4, binds to dead cells and is a DNAX activation ü Huttenhain, R., Malmstrom, J., Picotti, P., and sequences. Mol Syst Biol 5: 285. PMID:19536208 Hood, L. (2009) Integrated expression profiling and ChIP-seq interrogans. Nature 460: 762-5. PMID:19606093 PLoS Biol 7: e1000236. PMID:19885390 protein 12-linked marker for subsets of mouse macrophages Aebersold, R. (2009) Perspectives of targeted mass ü Kuhner, S., van Noort, V., Betts, M.J., Leo-Macias, A., Batisse, analyses of the growth inhibition response program of the ü Miles, G.P., Samuel, M.A., Ranish, J.A., Donohoe, S.M., ü Goudreault, M., D’Ambrosio, L.M., Kean, M.J., Mullin, and dendritic cells. J Immunol 182: 1278-86. PMID:19155473 spectrometry for protein biomarker verification. Curr C., Rode, M., Yamada, T., Maier, T., Bader, S., Beltran- androgen receptor. PLoS One 4: e6589. PMID:19668381 Sperrazzo, G.M., and Ellis, B.E. (2009) Quantitative M.J., Larsen, B.G., Sanchez, A., Chaudhry, S., Chen, G.I., ü Hertz, A.L., Bender, A.T., Smith, K.C., Gilchrist, M., Amieux, Opin Chem Biol 13: 518-25. PMID:19818677 Alvarez, P., Castano-Diez, D., Chen, W.H., Devos, D., ü Lin, B., White, J.T., Wu, J., Lele, S., Old, L.J., Hood, L., proteomics identifies oxidant-induced, AtMPK6-dependent Sicheri, F., Nesvizhskii, A.I., Aebersold, R., Raught, B., P.S., Aderem, A., and Beavo, J.A. (2009) Elevated cyclic ü Hwang, D., Lee, I.Y., Yoo, H., Gehlenborg, N., Cho, J.H., Guell, M., Norambuena, T., Racke, I., Rybin, V., Schmidt, and Odunsi, K. (2009) Deep depletion of abundant changes in Arabidopsis thaliana protein profiles. and Gingras, A.C. (2009) A PP2A phosphatase high AMP and PDE4 inhibition induce chemokine expression Petritis, B., Baxter, D., Pitstick, R., Young, R., Spicer, D., A., Yus, E., Aebersold, R., Herrmann, R., Bottcher, B., serum proteins reveals low-abundant proteins as Plant Signal Behav 4: 497-505. PMID:19816138 density interaction network identifies a novel striatin- in human monocyte-derived macrophages. Proc Natl Price, N.D., Hohmann, J.G., Dearmond, S.J., Carlson, Frangakis, A.S., Russell, R.B., Serrano, L., Bork, P., and Gavin, potential biomarkers for human ovarian cancer. ü Mirzaei, H., Brusniak, M.Y., Mueller, L.N., Letarte, S., Watts, J.D., interacting phosphatase and kinase complex linked to Acad Sci U S A 106: 21978-83. PMID:19959669 G.A., and Hood, L.E. (2009) A systems approach to A.C. (2009) Proteome organization in a genome-reduced Proteomics Clin Appl 3: 853-861. PMID:20559449 and Aebersold, R. (2009) Halogenated peptides as internal the cerebral cavernous malformation 3 (CCM3) protein. ü Ho, L., Ronan, J.L., Wu, J., Staahl, B.T., Chen, L., Kuo, A., prion disease. Mol Syst Biol 5: 252. PMID:19308092 bacterium. Science 326: 1235-40. PMID:19965468 ü Litvak, V., Ramsey, S.A., Rust, A.G., Zak, D.E., Kennedy, K.A., standards (H-PINS): introduction of an MS-based internal Mol Cell Proteomics 8: 157-71. PMID:18782753 Lessard, J., Nesvizhskii, A.I., Ranish, J., and Crabtree, ü Kutlu, B., Burdick, D., Baxter, D., Rasschaert, J., Flamez, Lampano, A.E., Nykter, M., Shmulevich, I., and Aderem, A. standard set for liquid chromatography-mass spectrometry. ü Gradolatto, A., Smart, S.K., Byrum, S., Blair, L.P., Rogers, G.R. (2009) An embryonic stem cell chromatin J D., Eizirik, D.L., Welsh, N., Goodman, N., and Hood, (2009) Function of C/EBPdelta in a regulatory circuit that Mol Cell Proteomics 8: 1934-46. PMID:19411281 R.S., Kolar, E.A., Lavender, H., Larson, S.K., Aitchison, J.D., remodeling complex, esBAF, is essential for embryonic ü Jeong, S.K., Kwon, M.S., Lee, E.Y., Lee, H.J., Cho, L. (2009) Detailed transcriptome atlas of the pancreatic discriminates between transient and persistent TLR4-induced Taverna, S.D., and Tackett, A.J. (2009) A noncanonical stem cell self-renewal and pluripotency. Proc Natl S.Y., Kim, H., Yoo, J.S., Omenn, G.S., Aebersold, R., beta cell. BMC Med Genomics 2: 3. PMID:19146692 signals. Nat Immunol 10: 437-43. PMID:19270711 N bromodomain in the AAA ATPase protein Yta7 directs Acad Sci U S A 106: 5181-6. PMID:19279220 Hanash, S., and Paik, Y.K. (2009) BiomarkerDigger: a ü Kutlu, B., Kayali, A.G., Jung, S., Parnaud, G., Baxter, D., ü Liu, Y., Warfield, L., Zhang, C., Luo, J., Allen, J., Lang, W.H., ü Nana-Sinkam, S.P., Hunter, M.G., Nuovo, G.J., Schmittgen, chromosomal positioning and barrier chromatin activity. ü Hohmann, L., Sherwood, C., Eastham, A., Peterson, A., versatile disease proteome database and analysis platform Glusman, G., Goodman, N., Behie, L.A., Hayek, A., and Ranish, J., Shokat, K.M., and Hahn, S. (2009) Phosphorylation T.D., Gelinas, R., Galas, D., and Marsh, C.B. (2009) Integrating Mol Cell Biol 29: 4604-11. PMID:19581291 Eng, J.K., Eddes, J.S., Shteynberg, D., and Martin, D.B. (2009) for the identification of plasma cancer biomarkers. Hood, L. (2009) Meta-analysis of gene expression in human of the transcription elongation factor Spt5 by yeast the MicroRNome into the study of lung disease. Am J ü Gstaiger, M. and Aebersold, R. (2009) Applying mass Proteomic analyses using Grifola frondosa metalloendoprotease Proteomics 9: 3729-40. PMID:19639590 pancreatic islets after in vitro expansion. Physiol Genomics Bur1 kinase stimulates recruitment of the PAF complex. Respir Crit Care Med 179: 4-10. PMID:18787215 spectrometry-based proteomics to genetics, genomics and Lys-N. J Proteome Res 8: 1415-22. PMID:19195997 39: 72-81. PMID:19622797 Mol Cell Biol 29: 4852-63. PMID:19581288 ü Nykter, M., Lahdesmaki, H., Rust, A., Thorsson, V., and network biology. Nat Rev Genet 10: 617-27. PMID:19687803 Shmulevich, I. (2009) A data integration framework for prediction of transcription factor targets. Ann N Y Acad Sci 1158: 205-14. PMID:19348642

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O ü Omenn, G.S., Aebersold, R., and Paik, Y.K. (2009) ü Picotti, P., Bodenmiller, B., Mueller, L.N., Domon, ü Schiess, R., Mueller, L.N., Schmidt, A., Mueller, M., Wollscheid, ü Sherwood, C.A., Eastham, A., Lee, L.W., Risler, J., Vitek, Gstaiger, M., Aebersold, R., Shevchenko, A., and Buchholz, ü Whitehead, K., Pan, M., Masumura, K., Bonneau, R., and 7(th) HUPO World Congress of Proteomics: launching B., and Aebersold, R. (2009) Full dynamic range B., and Aebersold, R. (2009) Analysis of cell surface proteome O., and Martin, D.B. (2009) Correlation between y-type F. (2009) Comparative profiling identifies C13orf3 as a Baliga, N.S. (2009) Diurnally entrained anticipatory behavior the second phase of the HUPOPlasma Proteome proteome analysis of S. cerevisiae by targeted changes via label-free, quantitative mass spectrometry. ions observed in ion trap and triple quadrupole mass component of the Ska complex required for mammalian in archaea. PLoS ONE 4: e5485. PMID:19424498 Project (PPP-2) 16-20 August 2008, Amsterdam, The proteomics. Cell 138: 795-806. PMID:19664813 Mol Cell Proteomics 8: 624-38. PMID:19036722 spectrometers. J Proteome Res 8: 4243-51. PMID:19603825 cell division. EMBO J 28: 1453-65. PMID:19387489 ü Wollscheid, B., Bausch-Fluck, D., Henderson, C., O’Brien, R., Netherlands. Proteomics 9: 4-6. PMID:19053147 ü Price, N., Edelman, L., Lee, I., Yoo, H., Hwang, D., Carlson, ü Schiess, R., Wollscheid, B., and Aebersold, R. (2009) ü Shmulevich, I. and Aitchison, J.D. (2009) Deterministic ü Tu, L.C., Foltz, G., Lin, E., Hood, L., and Tian, Q. (2009) Targeting Bibel, M., Schiess, R., Aebersold, R., and Watts, J.D. (2009) G., Galas, D., Heath, J., and Hood, L. (2009) Systems Targeted proteomic strategy for clinical biomarker and stochastic models of genetic regulatory networks. stem cells-clinical implications for cancer therapy. Curr Stem Mass-spectrometric identification and relative quantification P biology and the emergence of systems medicine, in discovery. Mol Oncol 3: 33-44. PMID:19383365 Methods Enzymol 467: 335-56. PMID:19897099 Cell Res Ther 4: 147-53. PMID:19442199 of N-linked cell surface glycoproteins. Nat Biotechnol 27: ü Pan, S., Aebersold, R., Chen, R., Rush, J., Goodlett, Genomic and Personalized Medicine: From Principles to ü Schmid, A.K., Reiss, D.J., Pan, M., Koide, T., and Baliga, N.S. (2009) ü Smith, J.J. and Aitchison, J.D. (2009) Regulation of peroxisome 378-86. PMID:19349973 D.R., McIntosh, M.W., Zhang, J., and Brentnall, Practice, (G. Ginsburg and H. Willard, Editors), Elsevier. A single transcription factor regulates evolutionarily diverse dynamics. Curr Opin Cell Biol. PMID:19188056 U T.A. (2009) Mass spectrometry based targeted ü Ptak, C., Anderson, A.M., Scott, R.J., Van de Vosse, D., but functionally linked metabolic pathways in response to ü Stanford, J.L., FitzGerald, L.M., McDonnell, S.K., Carlson, ü Ulintz, P.J., Yocum, A.K., Bodenmiller, B., Aebersold, R., Andrews, Y protein quantification: methods and applications. J Rogers, R.S., Sydorskyy, Y., Aitchison, J.D., and Wozniak, nutrient availability. Mol Syst Biol 5: 282. PMID:19536205 E.E., McIntosh, L.M., Deutsch, K., Hood, L., Ostrander, P.C., and Nesvizhskii, A.I. (2009) Comparison of MS(2)-only, ü Yan, W., Aebersold, R., and Raines, E.W. (2009) Proteome Res 8: 787-97. PMID:19105742 R.W. (2009) A role for the karyopherin Kap123p in ü Schmidt, A., Claassen, M., and Aebersold, R. (2009) Directed E.A., and Schaid, D.J. (2009) Dense genome-wide SNP MSA, and MS(2)/MS(3) methodologies for phosphopeptide Evolution of organelle-associated protein profiling. ü Pan, S., Chen, R., Reimel, B.A., Crispin, D.A., Mirzaei, microtubule stability. Traffic 10: 1619-34. PMID:19761543 mass spectrometry: towards hypothesis-driven proteomics. linkage scan in 301 hereditary prostate cancer families identification. J Proteome Res 8: 887-99. PMID:19072539 J Proteomics 72: 4-11. PMID:19110081 H., Cooke, K., Coleman, J.F., Lane, Z., Bronner, M.P., Curr Opin Chem Biol 13: 510-7. PMID:19775930 identifies multiple regions with suggestive evidence for ü Urwyler, S., Nyfeler, Y., Ragaz, C., Lee, H., Mueller, L.N., ü Yu, B., Yang, X., Xu, Y., Yao, G., Shu, H., Lin, B., Hood, L., Wang, H., Goodlett, D.R., McIntosh, M.W., Traverso, W., Aebersold, Q ü Schrimpf, S.P., Weiss, M., Reiter, L., Ahrens, C.H., Jovanovic, linkage. Hum Mol Genet 18: 1839-48. PMID:19251732 Aebersold, R., and Hilbi, H. (2009) Proteome analysis of Yang, S., Gu, J., Fan, J., and Qin, W. (2009) Elevated expression R., and Brentnall, T.A. (2009) Quantitative proteomics ü Querec, T.D., Akondy, R.S., Lee, E.K., Cao, W., Nakaya, H.I., M., Malmstrom, J., Brunner, E., Mohanty, S., Lercher, M.J., ü Sumara, G., Formentini, I., Collins, S., Sumara, I., Windak, R., Legionella vacuoles purified by magnetic immunoseparation of DKK1 is associated with cytoplasmic/nuclear beta-catenin investigation of pancreatic intraepithelial neoplasia. Teuwen, D., Pirani, A., Gernert, K., Deng, J., Marzolf, B., Hunziker, P.E., Aebersold, R., von Mering, C., and Hengartner, Bodenmiller, B., Ramracheya, R., Caille, D., Jiang, H., Platt, reveals secretory and endosomal GTPases. Traffic 10: 76-87. accumulation and poor prognosis in hepatocellular carcinomas. Electrophoresis 30: 1132-44. PMID:19373808 Kennedy, K., Wu, H., Bennouna, S., Oluoch, H., Miller, J., M.O. (2009) Comparative functional analysis of the K.A., Meda, P., Aebersold, R., Rorsman, P., and Ricci, R. (2009) PMID:18980612 J Hepatol 50: 948-57. PMID:19303159 ü Pan, S., Cheng, L., White, J.T., Lu, W., Utleg, A.G., Yan, Vencio, R.Z., Mulligan, M., Aderem, A., Ahmed, R., and Caenorhabditis elegans and Drosophila melanogaster Regulation of PKD by the MAPK p38delta in insulin secretion X., Urban, N.D., Drescher, C.W., Hood, L., and Lin, Pulendran, B. (2009) Systems biology approach predicts proteomes. PLoS Biol 7: e48. PMID:19260763 and glucose homeostasis. Cell 136: 235-48. PMID:19135240 W Z B. (2009) Quantitative proteomics analysis integrated immunogenicity of the yellow fever vaccine in humans. ü Selinummi, J., Ruusuvuori, P., Podolsky, I., Ozinsky, A., Gold, ü Wan, Y., Saleem, R.A., Ratushny, A.V., Roda, O., Smith, J.J., Lin, ü Zak, D.E. and Aderem, A. (2009) Systems biology of innate with microarray data reveals that extracellular matrix Nat Immunol 10: 116-25. PMID:19029902 E., Yli-Harja, O., Aderem, A., and Shmulevich, I. (2009) T C.H., Chiang, J.H., and Aitchison, J.D. (2009) Role of the immunity. Immunol Rev 227: 264-82. PMID:19120490 proteins, catenins, and p53 binding protein 1 are Bright field microscopy as an alternative to whole cell ü Tan, C.S., Bodenmiller, B., Pasculescu, A., Jovanovic, M., histone variant H2A.Z/Htz1p in TBP recruitment, chromatin ü Zak, D.E. and Aderem, A. (2009) A systems view of host important for chemotherapy response in ovarian R fluorescence in automated analysis of macrophage Hengartner, M.O., Jorgensen, C., Bader, G.D., Aebersold, R., dynamics, and regulated expression of oleate-responsive defense. Nat Biotechnol 27: 999-1001. PMID:19898453 cancers. OMICS 13: 345-54. PMID:19422301 ü Reiter, L., Claassen, M., Schrimpf, S.P., Jovanovic, M., images. PLoS One 4: e7497. PMID:19847301 Pawson, T., and Linding, R. (2009) Comparative analysis reveals genes. Mol Cell Biol 29: 2346-58. PMID:19273605 ü Pascal, L.E., Vencio, R.Z., Page, L.S., Liebeskind, E.S., Schmidt, A., Buhmann, J.M., Hengartner, M.O., and ü Sherwood, C.A., Eastham, A., Lee, L.W., Peterson, A., Eng, J.K., conserved protein phosphorylation networks implicated in ü Wang, K., Zhang, S., Marzolf, B., Troisch, P., Brightman, A., Hu, Shadle, C.P., Troisch, P., Marzolf, B., True, L.D., Hood, Aebersold, R. (2009) Protein identification false discovery Shteynberg, D., Mendoza, L., Deutsch, E.W., Risler, J., Tasman, N., multiple diseases. Sci Signal 2: ra39. PMID:19638616 Z., Hood, L.E., and Galas, D.J. (2009) Circulating microRNAs, L.E., and Liu, A.Y. (2009) Gene expression relationship rates for very large proteomics data sets generated by Aebersold, R., Lam, H., and Martin, D.B. (2009) MaRiMba: a ü Taylor, R.J., Falconnet, D., Niemisto, A., Ramsey, S.A., Prinz, potential biomarkers for drug-induced liver injury. Proc between prostate cancer cells of Gleason 3, 4 and tandem mass spectrometry. Mol Cell Proteomics 8: software application for spectral library-based MRM transition S., Shmulevich, I., Galitski, T., and Hansen, C.L. (2009) Natl Acad Sci U S A 106: 4402-7. PMID:19246379 normal epithelial cells as revealed by cell type-specific 2405-17. PMID:19608599 list assembly. J Proteome Res 8: 4396-405. PMID:19603829 Dynamic analysis of MAPK signaling using a high- ü Wang, K., Zhang, S., Weber, J., Baxter, D., and Galas, D. transcriptomes. BMC Cancer 9: 452. PMID:20021671 ü Sherwood, C.A., Eastham, A., Lee, L.W., Risler, J., throughput microfluidic single-cell imaging platform. Proc (2009) Mammalian cells in culture actively export specific S ü Peterson, A., Hohmann, L., Huang, L., Kim, B., Eng, J.K., Mirzaei, H., Falkner, J.A., and Martin, D.B. (2009) Rapid Natl Acad Sci U S A 106: 3758-63. PMID:19223588 microRNAs. Nature Precedings: hdl:10101/npre.2009.3718.1. and Martin, D.B. (2009) Analysis of RP-HPLC loading ü Saleem, R.A. and Aitchison, J.D. (2009) Quantitative optimization of MRM-MS instrument parameters by ü Theis, M., Slabicki, M., Junqueira, M., Paszkowski-Rogacz, ü Wepf, A., Glatter, T., Schmidt, A., Aebersold, R., and Gstaiger, conditions for maximizing peptide identifications in shotgun phosphoproteomics in fatty acid stimulated subtle alteration of precursor and product m/z targets. M., Sontheimer, J., Kittler, R., Heninger, A.K., Glatter, M. (2009) Quantitative interaction proteomics using mass proteomics. J Proteome Res 8: 4161-8. PMID:19601632 Saccharomyces cerevisiae. J Vis Exp. PMID:19823167 J Proteome Res 8: 3746-51. PMID:19405522 T., Kruusmaa, K., Poser, I., Hyman, A.A., Pisabarro, M.T., spectrometry. Nat Methods 6: 203-5. PMID:19198594

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