revolutionizing science. enhancing our lives. Institute for Systems Biology 2006 Annual Report table of contents Report from the Chairman

The report that you have in your hands charts the This annual report provides persuasive evidence of the remarkable progress that we have made at the Institute importance of the vision originally articulated by Drs. Report from the Chairman 1 for Systems Biology (ISB). Indeed, in just a few short years, Hood, Aderem and Aebersold. As Lee Hood notes in his Report from the President 3 ISB has become a global leader in the advancement of letter, ISB is focusing increasing effort on the application Scientific Achievements 5 “systems biology” research. In its simplest form, systems of tools developed through systems biology research to biology provides a framework for thinking about how the the realization of personalized, predictive, preventive and Transference of Knowledge to the Community 9 building blocks of biological machines interact to yield the participatory (P4) medicine. Financial Tables 10 properties that we associate with living organisms. Recognizing that research grants, especially given current Financial Highlights 11 Having participated in the sequencing of human and federal budget constraints, cannot possibly support the Development and Public Relations 13 other genomes in the 1990s, Lee Hood, together with full development of the Institute for Systems Biology, the Scientific Publications 14 immunologist Alan Aderem and proteomics specialist Ruedi ISB Board of Directors has, together with management, Aebersold, recognized that a new sort of research entity chartered a process aimed at developing new sources of Strategic Partnerships 16 would be required to fully realize the potential benefit to long-range funding. I look forward to sharing the details of Board of Directors, Executive Management, Faculty, Senior Scientists, Senior Engineers 17 human health created by advances in our understanding this plan with you next year. In the meantime, the attached of genetics. It would need to be a place where physicists, summary of our activities in 2006 makes plain that the chemists, mathematicians, computer scientists and Institute for Systems Biology has adopted a truly pioneering biologists could work together to build the tools necessary approach, one that will dramatically advance biomedical to understand the emergent properties of living systems. research and, ultimately, the practice of medicine.

Lee, Alan and Ruedi created just such a place in ISB. Sincerely,

In six short years the Institute has tripled in size to more than 200 employees. It now occupies 65,000 square feet of state-of-the-art laboratories at the north end of Seattle’s Roger M. Perlmutter, MD, PhD Lake Union and in 2006 ISB maintained an operating Chairman of the Board budget of $25 million. In addition, the faculty and senior scientists published 79 peer-reviewed articles and attracted $25.4 million in new grants from government funding agencies. Private grants, gifts and commitments to the Institute yielded an additional $6.2 million.

P4 Medicine

Medicine of the future will be personalized, predictive, preventive and participatory, examining the unique biology of an individual to assess their probability of developing various illnesses and then designing appropriate treatments, even before the onset of disease.

Institute for Systems Biology 2006 Annual Report Page 1 Report from the President

One of the grand challenges of the 21st century is to decipher This is the basis of the new medicine based on systems the complexity of the biological systems upon which our biology: a medicine that will quickly evolve over the life depends. Systems biology, pioneered by ISB, is the most next generation from a reactive practice to a predictive, powerful approach to meeting that challenge, understanding personalized, preventive and participatory (P4) process. the intricacy of biological function, and harnessing the body’s biological networks to improve human health. At ISB the systems approach is producing spectacular results. We have demonstrated how perturbed biological Until recently, biologists largely studied cellular and networks function abnormally, explaining many features molecular phenomena without observing or measuring of prostate cancer and mad cow disease (in mice). We their extraordinary connectivity. The complexity of that are making significant progress on new technologies for connectivity within human biological networks requires vaccine development. We have demonstrated that our approaching biology as an information science. Each organs secrete protein biomarkers into the blood that allow component of the biological systems — proteins, DNA, one to distinguish health from disease, and in fact, which RNA — can be represented as digital information. Using type of disease is present. Our scientists are developing measurement technologies to generate data and computer nanotechnologies that will enable the measurement of analyses, and modeling to test hypotheses, scientists can thousands of these proteins from a droplet of blood. We are develop strategies for predicting what happens to the working to develop new DNA sequencing methods, which functioning of a biological system when one or more will enable us to sequence inexpensively entire individual elements is destroyed or mutates. That understanding will genomes within 10 years. Finally, ISB is working on new allow us to think about new strategies for early diagnosis (and computational and mathematical approaches to the analyses hence the cure of most cancers) as well as new strategies of genomes and blood protein content. for designing drugs for therapy, or even the prevention of cancers, neurological disorders, Type 1 Diabetes and many Together, these and many other advances represent the more diseases. excitement and the immense promise of ISB’s research community. They constitute a driving force for the Disease arises from environmentally or genetically perturbed emergence of P4 medicine. networks that do not return to their normal states. Thus, studying biological network malfunctions and determining how to re-engineer them to restore healthy function will provide new insights into diagnosis, therapy and prevention. Leroy Hood, MD, PhD President

Predictive

“My DNA will be a crystal ball, One drop of blood is all it will take. One drop on a chip placed into a handheld device in your physician’s office will tell you if you have an 85 percent chance of developing heart disease, a 12 percent chance of developing diabetes, allowing me to see into my health future.” a 70 percent chance of developing Parkinson’s disease, or cancer, or virtually any other disease influenced by your genetic makeup. That knowledge will give you power.

Institute for Systems Biology 2006 Annual Report Page 3 scientific achievements

ISB researchers made significant progress in 2006, Sciences, The Journal of Experimental Medicine, The Journal of publishing nearly 80 peer-reviewed articles in scientific Infectious Diseases, The Journal of Immunology and AIDS. journals, receiving substantial government awards to advance systems biology approaches, broadening the scope Gene mutation a potential herald of Type 1 Diabetes of ISB’s strategic partnerships and receiving worldwide In the October 2006 issue of The American Journal of Human recognition for the excellence of their work. Genetics ISB researchers identified a gene, ITPR3, which is associated with Type 1 Diabetes. ITPR3 regulates calcium A new window on inflammatory disease flow within cells and had not previously been associated Using a systems approach, scientists at ISB discovered with diabetes. This finding gives deeper insight into that the absence of the transcription factor ATF3 leads mechanisms underlying Type 1 Diabetes, a debilitating illness to inflammatory disease in mice. The inflammatory which generally strikes the young. response is required for immune responses to infection, New means of defense against E. coli and but uncontrolled, it leads to a variety of illnesses such as Salmonella promise new therapies rheumatoid arthritis and lupus. ATF3 appears to control ISB researchers identified two new mechanisms by which the balance between the beneficial and destructive arms the immune system defends us from infection. In the first, of inflammation, and a complete understanding of this reported in Nature, the scientists found that immune cells regulation could point to novel therapeutics for these secrete a protein, lipocalin, which limits E. coli infections diseases. These findings were published in Nature. by competing with the bacterium for iron. In the second, Mutations in immune system genes increase reported in Nature Immunology, investigators identified risk for infectious diseases and point the way a protein, Ipaf, which detects the flagella of Salmonella to better drugs and vaccines and triggers a robust immune response to the bacteria. ISB researchers found significant links between mutations Knowledge of these novel pathways could lead to the in innate immune genes and human susceptibility to a development of new antibiotics. number of infectious diseases. The mutations are in a family of molecules called Toll-like receptors (TLRs), which alert Computational methods facilitate development of new approaches to P4 medicine the body to the presence of infectious agents. The results The prediction of traits, including diseases and responses suggest new drug targets and vaccine strategies. The studies to therapies, is greatly complicated by the intricate ways demonstrate, for example, that a mutation in TLR9 leads to in which combinations of gene variants interact. This rapid progression from HIV infection to the development complexity underlies the genetic challenges of predictive of AIDS and a mutation in TLR2 predisposes patients to and personalized medicine. ISB researchers have genital herpes, tuberculosis and leprosy. These observations developed computational methods that accurately predict were published in the Proceedings of the National Academy of genome-wide gene activity and precise trait outcomes

Preventive

“My DNA may reveal that I have an 85 percent If your genetic structure tells doctors you have a 95 percent chance of developing Parkinson’s disease, and you know that by taking a pill and exercising starting at age 20 you could reduce that chance to less than three percent, what chance of developing breast cancer. Knowing would you do? If protein biomarkers in your blood told physicians that your pancreas cells were beginning to mutate that gives me options and could save my life.” and become cancerous, would you take a drug that would tell your immune system to attack those cells and cure you before you experienced even a single symptom?

Institute for Systems Biology 2006 Annual Report Page 5 scientific achievements (continued)

for combinations of mutations. This work, reported in Genetic diversity of TB bacteria influences Molecular Systems Biology, provides a core strategy for the disease transmission systems biology of complex genetics. ISB researchers demonstrated that mycobacterial lineages adapt to particular human populations, and that Mathematical models lead to a better host-pathogen co-evolution impacts the transmission understanding of genetic diseases of tuberculosis. This led to the further observation that ISB scientists developed a mathematical model for the strain genetic diversity can influence the transmission of genetic program leading to the formation of an essential drug-resistant bacteria. These are important findings for organelle, the peroxisome. Peroxisomes have a variety of the design of new tuberculosis diagnostics, drugs and metabolic roles that implicate them in many human health vaccines. These observations were published in Science, concerns, including aging, neuropathology, cancer, heart the Proceedings of the National Academies of Science and disease, obesity and diabetes. These findings were reported PLOS Pathogens. in Molecular Systems Biology. ISB selected by NIH to host national Metals research could lead to remedy for Center for Systems Biology some genetic diseases In spring 2006, ISB received a five-year, $16.3 million ISB researchers developed a model that explains how cells grant from the National Institutes of Health (NIH) to respond to metals in the environment. These results, and fund a Center for Systems Biology. The Center provides the systems biology approach used to map the process, may professional development in systems biology approaches be useful in understanding the pathophysiology of a number and fosters collaboration among the diverse researchers of genetic maladies that are known to be linked to metals, at the Institute: biologists, chemists, computer scientists, such as Menkes and Wilson’s diseases. This work was engineers, mathematicians and physicists. Core research reported in Genome Research. funded by the grant includes genomics, proteomics, microfluidics and imaging, and informatics. The Center Quantitative methods developed to identify biomarkers also provides support for K-12 education in inquiry-based Blood biomarkers form one of the cornerstones of P4 science. The NIH is funding six additional centers to support medicine. In 2006 ISB scientists developed new methods systems biology work pioneered at institutes like ISB. to identify and quantify molecules in the blood that can serve as early diagnostic markers for cancer, heart disease, and the efficacy of vaccines. This work was reported in Proteomics, Science, Genome Biology, Nature Biotechnology, and Nature Methods. Alan Aderem, PhD Co-Founder and Director

Personalized

“In the future I will be cured by In the future, having your genetic structure will allow physicians to provide you with medicine made for you and no one else. Not one of the hundreds of thousands of other people who share your disease but not your personal biology. These medications designed just for me.” medicines will have no side-effects. They will eliminate the need for trial and error treatments that allow for disease progression, and they will cure you before you know you are sick. Having your genetic structure will give you knowledge, and that knowledge will give you the power to live intentionally rather than reactively, and to live longer and more fully.

Institute for Systems Biology 2006 Annual Report Page 7 Transference of Knowledge to the Community

ISB enhances people’s lives and improves the human condition Building scientific literacy: Center for Inquiry Science by transferring knowledge gained through its research ISB’s Center for Inquiry Science (CIS) exemplifies the to the community. It accomplishes this through support of Institute’s commitment to improving science education for science and math education in public schools and the transfer every child in the state. Excellence in science education for of new technologies to the commercial sector. K-12 students is critical for providing the skilled employees Growing new biotech companies: Washington’s research and development sectors require Accelerator Corporation in the next generation, as well as equipping an educated citizenry to make wise choices about the many scientifically A key component of ISB’s commitment to the community related challenges facing our society. is Accelerator Corporation, a novel partnership among ISB and life science leaders Amgen Ventures, ARCH Mission of CIS Venture Partners, MPM Capital, OVP Venture Partners, To enable schools and districts to have the capacity Versant Ventures and Alexandria Real Estate Equities, Inc. to produce scientifically literate and capable students Accelerator creates early-stage companies arising from by creating and supporting a statewide infrastructure, scientific discovery at the Institute and elsewhere. comprised of collaborative and regional partnerships among schools, districts, and community partnerships that Accelerator grew five emerging biotechnology companies will train and support science educators. in 2006: VieVax Corp., VLST Corp., Spaltudaq Corp., Homestead Clinical Corp. and Allozyne, Inc. These CIS 2006 highlights companies focus on: • Programming supported teachers and administrators • novel approaches to vaccine development; in 21 districts representing 24 percent of Washington • faster development of effective therapeutics for state’s student population. inflammatory and autoimmune diseases; • CIS developed, coordinated and/or facilitated 76 • developing tumor-specific therapeutic antibodies to treat professional development events serving 1,135 cancer; science educators. • commercializing ISB technologies with broad utility for • CIS generated more than $800,000 in grants, gifts and developing diagnostic, prognostic and theranostic tools; fee-based revenue, approximately $543,000 of which came from outside Washington state, to help schools • commercializing technologies that improve the efficacy build strong, inquiry-based scientific literacy among the of protein-based therapeutics. state’s student population. Grants were provided by such organizations as the National Institutes of Health, the VLST Corp., focused on developing therapeutics for Boeing Company, the National Science Foundation, the autoimmune and inflammatory disorders, raised $55 million Washington State Office of the Superintendent of Public during 2006 as the first Accelerator company to receive Instruction/Pacific Science Center and the Arthur Vining series B financing. Davis Foundations.

Participatory

“One day my DNA could reveal that I’m highly P4 Medicine will give you more information, more choices and more control than any other healthcare advance in history. You will control whether your genome is sequenced. You will control who gets to view your genetic makeup. likely to die young of heart disease. If it does, I’ll You will sign up for biomarker tests every six months and you — no one else — will adhere to therapies (whether work with my doctors to create a different future.” physical, nutritional or medicinal) to cheat your genetic destiny. Or you won’t. That’s the participatory part. You will have the power, and the responsibility, of using resources never before available to live your longest and best life.

Institute for Systems Biology 2006 Annual Report Page 9 FINANCIAL TABLES Financial HIGHLIGHTS Fiscal Year Ended December 31, 2006 (Dollars in thousands)

GROWTH IN OPERATIONS REVENUES Revenue from grants and contracts, the Institute’s major seven-figure awards from the Bill and Melinda Gates Over A Seven Year Period FY 2006 source of funding, increased $1.4 million to $20.4 million in Foundation and The Boeing Corporation. Unrestricted 2006, a seven percent increase over 2005. gifts totaled more than $2.0 million, and investment $30,000 and other income exceeded $1.4 million, a 30 percent This positive outcome was very welcome, as 2006 was a increase over 2005. $25,000 fiscally challenging year for independent research institutions such as ISB, which heavily depend on ISB invested just over $800,000 in new equipment and $20,000 government grants and contracts. Nationally, awards from equipment upgrades in 2006. Proteomics is a core the National Institutes of Health (NIH), the largest source competency of the Institute, and almost half of these $15,000 of biomedical research funding, dropped slightly in inflation- funds were spent to acquire a triple quadrupole/linear adjusted terms for the second year in a row. Furthermore, ion trap mass spectrometer ideal for drug discovery and $10,000 it remained very difficult for younger investigators to development, protein discovery, protein identification $5,000 receive grant funding, which made the climate particularly and biomarker validation. ISB also invested significantly competitive for our relatively young cadre of investigators. in two state-of-the-art Leica microscopes to enhance $0 image analysis. 2000 2001 2002 2003 2004 2005 2006 The excellence of the Institute’s science countered these market forces, however. Looking to grow and diversify its revenue sources to advance its mission, ISB began in 2006 to expand its Total Research Operation Grant and contract revenue ISB was awarded more than $25 million in new fundraising and marketing efforts, hiring a Vice President Grant Funding Contributions government grants during 2006, including a prestigious for Development and other related staff. Building on Investment and other income center grant in systems biology from the NIH, which the successes of 2006, ISB faculty and administrators will bring ISB $16.3 million over the next five years. In began developing a new strategic plan for the next addition, ISB received new grants and contracts from decade and beyond. private sources totaling more than $6.2 million, including

FINANCIAL STATEMENTS UNRESTRICTED REVENUES & EXPENDITURES Gary Raisl, EdD Balance Sheet Revenues Vice President of Finance and Administration Cash and investments 11,662 Grant and contract revenue 20,364 Other assets 7,440 Contributions 2,222 Property and equipment, net 8,094 Investment and other income 1,414 Total Assets 27,195 Total Revenues 24,000

Accounts payable and accrued expenses 1,964 Expenditures Deferred revenues 913 Research and direct costs 19,447 Notes payable 11,337 Management and general 5,305 Total Liabilities 14,213 Fundraising and other 433 Total Expenditures 25,185 Unrestricted net assets 891 Temporarily restricted net assets 3,419 Decrease in Net Assets (1,185) Permanently restricted net assets 8,672 Total Net Assets 12,982

Page 10 Institute for Systems Biology 2006 Annual Report Page 11 Development and Public Relations

Since its founding in 2000, more than $50 million in gifts Looking to ISB’s future, the board of directors in 2006 and grants have been awarded to ISB by the private decided to professionalize operations in development sector. This philanthropic investment has unleashed and public relations. The position of vice president of systems biology as the model for biological inquiry and development was established, and I was delighted to discovery in the 21st century, leveraged millions of dollars join the Institute in September. ISB immediately began in government grants and contracts for our scientists, and to increase substantially the number of individuals, enabled ISB to build key strategic partnerships. ISB is truly a corporations and foundations to whom the Institute can remarkable example of the power of philanthropy. turn for gifts and grants, to boost unrestricted gift income, focus fund-raising on strategic objectives, and begin a In 2006, the Institute recorded $2.6 million in cash concerted effort to raise endowment funds. All these income from private sources. Nearly $2.1 million was endeavors are integrated with ISB’s strategic planning, in unrestricted funds, which are invaluable in that they which began in late fall. The Institute is also launching a help launch the research and careers of our junior faculty communications program to educate the public about ISB’s and meet costs of other research and administrative achievements and the impact of our systems approaches on opportunities. Program support totaled almost $500,000, future medical care. primarily advancing the work of ISB’s Center for Inquiry Science, Washington’s premier center of training and ISB intends to continue providing many opportunities for support for secondary school science teachers. In addition, visionary and generous donors who want to enhance lives we received a commitment of $1 million from the Boeing through our revolutionary science. Foundation, payable over four years, to support CIS. The McDonnell Foundation provided another major gift.

Sponsorship income of more than $60,000 supported the 5th Annual ISB International Symposium, “Systems Biology Laurence W. Herron and Medicine.” This two-day event in April attracted Vice President for Development more than 250 attendees, the Institute’s most successful symposium ever.

Major Donors

Anonymous Invitrogen Alexandria Real Estate Equities, Inc. James S. McDonnell Foundation Allen Institute for Brain Science Lake Union Travel Amgen Foundation Valerie Logan and Leroy Hood Awards and Recognition Bill and Melinda Gates Foundation Merck & Co., Inc. The Boeing Company OVP Venture Partners ISB co-founder and president Lee Hood received the 2006 Heinz Award in Technology, the Economy and Employment. California Institute of Technology Pacific Northwest National Laboratory Cancer Research Institute Roger M. Perlmutter Hood and ISB co-founder Reudi Aebersold were elected to the prestigious European Molecular Biology Organization. Fermentas, Inc. Puget Sound Refrigeration ISB co-founder Alan Aderem was recognized by the Society for Biomolecular Sciences for the most outstanding paper at Frederick Frank Henry Riggs the organization’s 2006 conference in Seattle. GVA Kidder Matthews The Runstad Foundation Harbor Properties, Inc. University of Washington Charles L. Hirsch Vulcan, Inc. IDT

Institute for Systems Biology 2006 Annual Report Page 13 2006 scientific publications

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Molecular & Martin D, Ranish J, Raught B, Schmitt R, Werner D: Genomics and Proteomics 1: 77-88, 2006. analysis using isotope-coded affinity tags and Wollscheid B, Cooke K, Yi EC, Lee H, Peskind Disentangling information flow in the Ras-cAMP Developmental Cell 10: 587-600, 2006. M, Kennedy K, Hai T, Bolouri H, Aderem A: Cellular Proteomics (accepted), 2006. T, Kuster B, Aebersold R: A computational mass spectrometry. Nature Protocols 1: 139-45, ER, Zhang J, Smith RD, Aebersold R: UniPep, signaling network. Genome Research 16: 520- Fischback MA, Lin H, Zhou L, Yu Y, Abergel Systems Biology Approaches Identify ATF3 as a approach for identifying and predicting 2006. a database for human N-linked glycosites: a 526, 2006. Jimenez-Corona ME, Garcia-Garcia L, R RJ, Liu DR, Raymond KN, Wanner BL, Strong Negative Regulator of Innate Immunity. Nature proteotypic peptides for quantitative proteomic resource for biomarker discovery. Genome DeRiemer K, Ferreyra-Reyes L, Bobadilla- Smith JJ, Sydorskyy Y, Marelli M, Hwang D, Chen R, Pan S, Cooke K, White KN, Bronner RK, Walsh CT, Aderem A, Smith KD: The 441: 173-8, 2006. experiments. Nature Biotechnology (accepted): Biology 7: R73, 2006. Del-Valle M, Cano-Arellano B, Canizales- Ramsey S, Smith JJ, Orrell D, Marelli M, Bolouri H, Rachubinski RA, Aitchison JD: MP, Goodlett DR, Aebersold R, Brentnall TA: pathogen-associated iroA gene cluster mediates 2006. Glusman G, Qin S, El-Gewely R, Siegel A, Quintero S, Martinez-Gamboa A, Small Petersen TW, de Atauri P, Bolouri H, Aitchison Expression and functional profiling reveal Zhang W, Shmulevich I: Computational and Comparison of pancreas juice proteins from bacterial evasion of lipocalin 2. Proceedings of Roach J, Hood L, Smit AF: A third approach PM, Sifuentes-Osornio J, Ponce-de-Leon A: Malmström J, Lee H, Nesvizhskii AI, Shteynberg JD: Dual feedback loops in GAL regulon distinct gene classes involved in fatty acid Statistical Approaches To Genomics, 2nd cancer versus pancreatitis using quantitative the National Academies of Science USA 103: to gene prediction suggests thousands of Gender differentials of pulmonary tuberculosis D, Mohanty S, Brunner E, Ye M, Weber suppress cellular heterogeneity in yeast. Nature metabolism. Molecular Systems Biology 2: 0009, Edition, Springer, 2006. 16502-7, 2006. proteomic analysis. Pancreas (in press): 2006. additional human transcribed regions. PLoS transmission and reactivation in an endemic G, Eckerskorn C, Aebersold R: Optimized Genetics 38: 1082-1087, 2006. 2006. Zody MC, Garber M, Sharpe T, Young SK, Chen R, Pan S, Crispin DA, Brentnall TA: Gene Flory MR, Lee H, Bonneau R, Mallick P, Computational Biology 2: e18, 2006. area. Thorax 61: 384-53, 2006. peptide separation and identification for mass , Ozinsky A, Clark A, Smith KD, de Ramsey S Stewart JJ, White JT, Yan X, Collins S, Drescher Rowen L, O’Neill K, Whittaker CA, Kamal M, expression and proteomic analysis of pancreatic Serikawa K, Morris DR, Aebersold R: spectrometry based proteomics via free-flow Atauri P, Thorsson V, Orrell D, Bolouri H: Guo Z, Hood L, Malkki M, Petersdorf EW: CW, Urban ND, Hood L, Lin B: Proteins Chang JL, Cuomo CA, Dewar K, FitzGerald cancer: a recent update. Cancer Genomics and Quantitative proteomic analysis of the budding electrophoresis. Journal of Proteome Research 5: Transcriptional noise and cellular heterogeneity Long-Range Multi-Locus Haplotype Phasing of K Associated with Cisplatin Resistance in Ovarian MG, Kodira CD, Madan A, Qin S, Yang Proteomics 3: 1-10, 2006. yeast cell cycle using acid-cleavable isotope- 2241-2249, 2006. in mammalian macrophages. Philosophical the MHC. Proceedings of the National Academies Cancer Cells Identified by Quantitative X, Abbasi N, Abouelleil A, Arachchi HM, coded affinity tag reagents.Proteomics 6: Kaur A, Pan M, Meislin M, El-Gewely R, Baliga Transactions of the Royal Society London, Chen R, Pan S, Yi EC, Donohoe S, Bronner of Science USA 103: 6964-6969, 2006. Marzolf B, Deutsch EW, Moss P, Campbell D, Proteomic Technology and Integrated with Baradarani L, Birditt B, Bloom S, Bloom T, 6146-6157, 2006. NS: A systems view of haloarchaeal strategies Johnson MH, Galitski T: SBEAMS Microarray: Biological Sciences 361: 495-506, 2006. mRNA Expression Levels. Molecular & Cellular MP, Potter JD, Goodlett DR, Aebersold R, Gupta N, Wollscheid B, Watts JD, Scheer Borowsky ML, Burke J, Butler J, Cook A, to withstand stress from transition metals. Database software supporting genomic Proteomics 5: 433-443, 2006 Brentnall TA: Quantitative proteomic profiling Foltz G, Ryu GY, Yoon JG, Nelson T, Fahey J, B, Aebersold R, DeFranco AL: Quantitative Reiss DJ, Baliga NS, Bonneau R: Integrated DeArellano K, DeCaprio D, Dorris L 3rd, Dors Genome Research 16: 841-854, July 2006. expression analyses for systems biology. BMC of pancreatic cancer juice. Proteomics 6: 3871-9, Frakes A, Lee H, Field L, Zander K, Sibenaller proteomic analysis of B cell lipid rafts reveals biclustering of heterogeneous genome-wide M, Eichler EE, Engels R, Fahey J, Fleetwood 2006. Z, Ryken TC, Vibhakar R, Hood L, Madan A: Bioinformatics: 7: 286, 2006. P, Friedman C, Gearin G, Hall JL, Hensley G, that ezrin regulates antigen receptor-mediated King N, Deutsch EW, Ranish J, Nesvizhskii AI, datasets for the inference of global regulatory T Genome-Wide Analysis of Epigenetic Silencing Eddes J, Mallick P, Eng J, Desiere F, Flory M, networks. BMC Bioinformatics: 7: 280, June Johnson E, Jones C, Kamat A, Kaur A, Locke Chung Y, Yang X, Chang SH, Ma L, Tian Q, lipid raft dynamics. Nature Immunology 7: 625- Miao EA, Alpuche-Aranda CM, Dors M, Identifies BEX1 and BEX2 as Candidate Tumor Martin D, Kim B, Lee H, Raught B, Aebersold 2006. Tian Q: Proteomic exploration of the Wnt/ DP, Madan A, Munson G, Jaffe DB, Lui A, Dong C: Expression and regulation of IL-22 in 33, 2006. Clark AE, Bader MW, Miller SI, Aderem A: Suppressor Genes in Malignant Glioma. Cancer R: Analysis of the S. cerevisiae proteome with beta-catenin pathway. Current Opinion in Macdonald P, Mauceli E, Naylor JW, Nesbitt CD4+ T lymphocyte. Cell Research 16: 902-7, Cytoplasmic flagellin activates Caspase 1 and Research 66: 1-10, 2006. Roach JC, Deutsch K, Li S, Siegel AF, Bekris R, Nicol R, O’Leary SB, Ratcliffe A, Rounsley PeptideAtlas. Genome Biology 7: R106, 2006. IL-1 secretion through Ipaf. Nature Immunology Molecular Therapeutics 8: 191-7, June 2006. November 2006. LM, Einhaus DC, Sheridan CM, Glusman G, S, She X, Sneddon KM, Stewart S, Sougnez 7: 569-75, 2006. Hood L, Lernmark A, Janer M, on behalf of the C, Stone SM, Topham K, Vincent D, Wang S, Swedish Childhood Diabetes Study Group and Zimmer AR, Birren BW, Hood L, Lander ES, the Diabetes Incidence in Sweden Study Group: Nusbaum C: Analysis of the DNA sequence and duplication history of human chromosome 15. Nature 440: 671-5, March 2006.

Page 14 Institute for Systems Biology 2006 Annual Report Page 15 Strategic Partnerships: Bridging Academia and Industry

As a private, non-profit institute, ISB is positioned In 2006, ISB maintained partnerships with the Institute for Systems Biology between academia and industry, leveraging the strengths following organizations: 2006 Board of Directors

and advantages of both. It is an organization without Roger Perlmutter, MD, PhD Fred Frank George Rathmann, PhD Applied Biosystems departments, which enables the cross-disciplinary Chairman of the Board Vice Chairman Director Emeritus science, training and teamwork required today to pioneer Executive Vice President, Lehman Brothers, Inc. Chairman Aviva Systems Biology technologies and address fundamental problems in biology. Research and Development Nuvelo, Inc. Amgen, Inc. Chuck Hirsch Battelle Memorial Institute Managing Director Henry E. Riggs ISB’s relatively small size and open organization facilitates Alan Aderem, PhD Madrona Venture Group President Emeritus internal collaboration and the agility to tackle complexity in California Institute of Technology Director Keck Graduate Institute of those areas of technology development and computation Institute for Systems Biology Leroy Hood, MD, PhD Applied Life Sciences President where we enjoy unparalleled expertise. ISB cannot by Cyntellect, Inc. Steve Clifford Institute for Systems Biology H. Jon Runstad itself, however, pursue all the systems biology approaches The Fred Hutchison Cancer Research Institute Secretary/Treasurer Co-founder, Chairman and Chief necessary for P4 medicine. As a visionary and integrating Chairman Garry Menzel, PhD Executive Officer Managing Director force in biology, ISB has established strategic partnerships National Mobile Television Wright Runstad & Company Helicos Global Head of Life Sciences with private companies, universities and other institutions. Credit Suisse IBM ISB’s academic collaborations leverage an array of Institute for Systems Biology expertise to undertake comprehensive analyses of scientific Lumera Corporation 2006 Executive Management problems. ISB’s partnerships with industry demonstrate NimbleGen Systems, Inc. how non-profit and for-profit alliances can rapidly develop Leroy Hood, MD, PhD John Aitchison, PhD Gary Raisl, EdD President Associate Director Vice President of Finance and disseminate new methods and technologies with global The Nanosystems Biology Alliance impact in predicting and preventing diseases. Alan Aderem, PhD Laurence W. Herron The Rockefeller University Director Vice President for Development

The Scripps Research Institute Faculty University of California at Los Angeles Alan Aderem, PhD David Galas, PhD Jeff Ranish, PhD Ruedi Aebersold, PhD Tim Galitski, PhD Ilya Shmulevich, PhD John Aitchison, PhD Leroy Hood, MD, PhD Peter Small, PhD Nitin Baliga, PhD Dan Martin, MD Examples of 2006 strategic partner initiatives Aimée Dudley, PhD Adrian Ozinsky, MD, PhD

• GenoLogics Life Sciences Software Inc., in partnership • Helicos Biosciences Corporation and ISB established with ISB, announced integrated open source software a partnership that employs the company’s new high Senior Research Scientists that broadened the dissemination of new technologies throughput DNA sequencing platform to study the and computational tools for proteomics research to transcriptomes (populations of mRNAs in cells or tissues) Pierre-Yves Bochud, MD Marta Janer, PhD Lee Rowen, PhD scientists and labs worldwide. of normal and cancer cells. John Boyle, PhD Christopher Lausted, MS Alistair Rust, PhD Greg Carter, PhD Simon Letarte, PhD Arian Smit, PhD • In October, Lumera Corporation and ISB extended their Eric Deutsch, PhD Bin Li, PhD Jennifer Smith, PhD Alan Diercks, PhD Biaoyang Lin, PhD James Spotts, PhD productive relationship to develop detection methods Sebastien Gagneux, PhD Monica Orellana, PhD Vesteinn Thorsson, PhD for an array of diagnostic biomarkers aimed at various Mark Gilchrist, PhD Shizhen Qin, PhD Qiang Tian, MD, PhD types of cancer. Gustavo Glusman, PhD Stephen Ramsey, PhD Julian Watts, PhD Liz Gold, MD David Reiss, PhD Nat Goodman, PhD Jared Roach, MD, PhD

Senior Software Engineers

Bill Longabaugh Paul Shannon

Page 16 Institute for Systems Biology 2006 Annual Report Page 17 Institute for Systems Biology 1441 North 34th Street Seattle, WA 98103-8904 www.systemsbiology.org