CIRM California Institute for Regenerative Medicine Annual Report 2010 Autoimmune Diseases Arthritis Crohn’s

Disease Devic’s Syndrome Multiple Sclerosis Osteoporosis

Systemic Lupus Erythematosus (Lupus) Systemic Sclerosis Type 1

Diabetes Cancers Bladder Brain/Central Nervous System Breast

Colon/Lower Bowel Endometrium/Cervix Ovary Esophagus Kidney Leukemia

Liver Lungs/Respiratory System Lymphoma Myeloma Oral Cavity Pancreas

Prostate Skin Stomach Cardiovascular Diseases Acute Ischemic Heart

Disease (angina) Myocardial Infarction (heart attack) Chronic Ischemic Heart Disease

(athersclerotic heart disease) Cardiomyopathy Cerebrovascular Disease (stroke)

Circulatory/Respiratory Diseases Chronic Obstructive Pulmonary Disease

Pulmonary Fibrosis Injuries Severe Burns Spinal Cord Injury Eye Disorders

t u rnin g s t em ce l l s in t o c u re s Macular Degeneration Retinitis Pigmentosa Infectious Diseases HIV/AIDS

Metabolic Diseases Adrenoleukodystrophy Aspartylglycosaminuria Canavan’s

Disease Cystic Fibrosis Fabry Disease Fucosidosis Gaucher Disease Leukodystrophy “During this time of uncertainty at the federal level, with a continuing potential for NIH shutdown by lawsuit, California carries on as a leader in funding Mucopolysaccharidoses Niemann-Pick Disease Pompe Disease Porphyria stem cell research, as approved by California voters. To date, over $1 billion Sickle Cell Disease Tay-Sachs Disease Type 2 Diabetes Muscular Dystrophies in bonds have been sold to invest here on the frontier of medical science, in research that promises hope for more effective treatments Becker Duchenne Emery Dreifuss Facioscapulohumeral Fukuyama Limb and cures for chronic disease and injuries afflicting so many families.” Girdle Myasthenia Gravis Myotonic Dystrophy Neurological Diseases of California State Treasurer Bill Lockyer Adulthood Alzheimer’s Disease Huntington’s Disease Lou Gehrig’s

Disease (ALS) Parkinson’s Disease Neurological Diseases of

Childhood Asperger Syndrome Autism Cerebral Palsy

Childhood Disintegrative Disorder Down Syndrome

Epilepsy Hydrocephalus Rett Syndrome

California Institute for Regenerative Medicine

Today’s InvestmentCIRM • Tomorrow’s Therapy • Future Cures 4 A Message from the Chair 10 The Governing Board of CIRM 12 President’s Letter 15 Major Facilities Openings 16 News at CIRM: Embryonic Stem Cells Remain the Gold Standard 18 News at CIRM: Stem Cells Move Toward Clinical Trials 20 News at CIRM: Keeping the Research Pipeline Fueled 22 News at CIRM: Taking Control of Cell Fate 24 News at CIRM: Unraveling the Role of iPS Cells 26 The Bridges to Stem Cell Research Awards 27 Global Partnerships 30 Spotlights on Disease: Amyotrophic Lateral Sclerosis 32 Spotlights on Disease: Huntington’s Disease the mission of 34 Spotlights on Disease: HIV/AIDS 36 Spotlights on Disease: Epidermolysis Bullosa 38 Spotlights on Disease: Stroke 40 Spotlights on Disease: Leukemia Update 41 Spotlights on the Human Embryo 42 Outreach 43 Financial Statement URL 44 Governing Board Subcommittees and CIRM Working Groups 45 Grants Approved Through April 2011 c i rTo support M and advance stem cell research and regenerative medicine under the highest ethical and medical standards for the discovery and development of cures, therapies, diagnostics and research technologies to relieve human suffering from chronic disease and injury. The California Institute for Regenerative Medicine (CIRM) was established by Proposition 71, the California Stem Cell Research and Cures Initiative. The statewide ballot measure, which provided $3 billion in funding for stem cell research at California universities and research institutions, was approved by 59 percent of California voters on November 2, 2004, and called for the establishment of a new state agency to make grants and provide loans for stem cell research, research facilities and other vital research opportunities. The Independent Citizens Oversight Committee (ICOC) is the 29-member Governing Board of the Institute; the Governing Board members represent expertise from California’s leading public and private universities, nonprofit hospitals and research institutions, patient advocacy groups and biotechnology. chairman’s letter

robert N. Klein, J.D. Here, in outline, I highlight a few major accom- tific capacity of California’s Stem Cell Research by a) plishments, by category: connecting with the world’s leading scientists and b) Building The Research Leadership Infrastructure: building internal California structures and incentives To build the research leadership opportunities for the for sharing discoveries, shared facilities and collabora- best and brightest young faculty of this country, the New tion is a strategic goal with progress best illustrated by Faculty Awards Program has awarded 45 new faculty po- focusing on three examples: sitions; each of these individual leaders has attracted an 1) First, 11 international government funding agen- average of six to eight post docs and graduate students to cies have now signed collaborative agreements with their labs, building an aggregate discovery force of ap- CIRM—pledging to fund their scientists on teams proximately 315 brilliant young researchers. with California scientists, if they succeed in obtaining “ Building The Research Technical Work Force: The an approval from both CIRM’s peer review process and vast expansion of stem cell research and therapy devel- the Governing Board review. This program brings in- opment efforts require a concurrent and rapid develop- ternational scientific leverage to California’s mission. [ ]have promises to keep, and miles to go ment of the research technician workforce. To meet this 2) Second, The Shared Research Laboratory Pro- before [we] sleep”1; but, the Milestones of Progress of California’s stem need and provide an entry platform for students from gram at 17 sites exemplifies the scientific leverage we every economic background to enter the stem cell field, that can be gained by providing leading edge research cell scientists are undeniable, as they advance toward stem cell therapies for CIRM developed the Bridges Program, conceived by equipment, training, and supplies at strategic locations within the state’s leading research institutions, to drive chronic disease and injury. Proposition 71, the California Stem Cell Research and the Governing Board, to bring together 32 of the lead- ing stem cell research institutions and companies with minimally funded early discovery experiments targeting Cures Initiative, approved by the voters in 2004 drives this stem cell research progress. 28 state colleges, city colleges and independent regional preliminary data to qualify for future research grants. Although its initial scientific funding was almost entirely delayed from 2005 to May 2007 colleges’ best and brightest young students who seek a Stanford University, for example, credits its $4.14 mil- by litigation brought by ideologically motivated plaintiffs, an extraordinary body of research is under way with more career in the stem cell research and therapy field. In the lion Shared Research Laboratory grant, with providing than 800 scientific discoveries published, FDA-approved human trials in progress, and nine nations and two inter- first five years, this program should reach 750 students. the launch of new scientific studies that have now led national states joined together with California as international funding partners. Proposition 71 projects have gen- Constructing The Research Facilities Infrastructure: to approximately $41 million in additional grants from erated 25,000 job years and attracted over $1 billion in matching funds from private donors, institutions, industry To develop the world-class research platforms to launch the NIH and other leading funding sources, with an- and foreign governments; these matching funds almost equal the $1.25 billion in funding commitments made by this new field, CIRM has funded 12 Institutes, Cen- other $14 million in pending grants (just in the three CIRM’s Governing Board, after peer review, to stem cell research and facilities. ters of Excellence and Specialized Research Centers years after the lab’s installation). —bringing nearly a million square feet of new research 3) Third, CIRM’s Intellectual Property Policies space on line by the end of 2011. push the spread of new biomedical materials through- EXTERNAL REVIEW AND VALIDATION Advancing The Therapy Candidates Through Phase out the state, leveraging the immediate value of the Beyond the validation of the scientific importance of this work, implicit in attracting over $1 billion in match- 1 and Phase 2 Human Trials: Seven human trials have discovery and speeding the propagation of the knowl- ing funds and the 11 foreign governments electing to join stem cell research with California, an independent been approved by the FDA and/or are seeking a final edge. For example, when a grantee publishes a dis- external advisory panel, including some of the world’s most distinguished medical research leaders, evaluated release to commence their human trials. These trials covery that includes biomedical research materials CIRM’s performance in 2010. The review panel members included: have benefited from the contributions of CIRM either first produced by the CIRM-funded research, those Dr. Alan Bernstein, Dr. George Daley, Professor Sir Martin Evans, Dr. Igor Gonda, Dr. Judy Illes, Dr. Rich- in the initial development of the science driving the materials must be shared for research in California, ard A. Insel, Dr. Richard Klausner, and, Dr. Nancy Wexler2. trial (through research, shared facilities, or GMP facili- either: a) free or at actual cost; or b) the information The External Advisory Panel concluded that, “CIRM has already delivered extraordinary results in a remark- ties funding), the trial itself, or in the case of brain can- necessary to reconstruct or obtain identical biomedi- ably short period of time. This accomplishment is especially noteworthy given the limited administrative budget cer the second phase of the trial’s development will be cal material must be provided.4 and correspondingly small staff. The agency has awarded 364 grants and loans for research and facilities to 54 funded by CIRM. For a current list of Milestones of Progress, institutions totaling $1.07 billion.” Developing A Therapy Pipeline For Human Trials: see the 2010 Annual Report page on CIRM’s website: To date, the agency has issued 22 rounds of funding. CIRM has established systems and processes An additional 14 Disease Teams are proceeding toward www.cirm.ca.gov/2010AnnualReport for soliciting, evaluating, and monitoring high quality, targeted research projects and has done this in human trials for diseases ranging from AIDS to Diabe- an ethically sound manner. CIRM has established a rigorous peer review process that engages world tes to Age Related Macular Degeneration and Stroke. California’s modern experts in stem cell research who are called upon for their advice and recommendations. In a short Supporting A Broad Portfolio Of Preclinical Ad- few years, CIRM has created a robust, world-class stem cell research effort in California, with a greatly vances: A broad portfolio of preclinical therapy candi- Medici empowered the people expanded workforce, state of the art facilities and the requisite physical and intellectual infrastructure dates (or development bottlenecks) is in development of California, first giving them the needed to accomplish its scientific goals. supported by 37 separate grants. opportunity to vote their vision and then leading the In summary, progress during this first stage of CIRM’s development has been remarkable…” Broadening The Base Of Knowledge Necessary To effort to raise $1 billion in matching funds to carry out the com- Identify And Develop Therapy Candidates: More than mitments of Proposition 71. (Report of the External Advisory Panel, p. 8)3 800 discoveries have been published in the four years since the full funding began after the defeat of litiga- MILESTONES OF PROGRESS tion that attempted to block implementation of the Proposition 71 funding has built an extraordinary human and physical infrastructure to develop stem cell therapies in initiative’s programs. California, while driving the frontiers of the field into human trials and a broad spectrum of discoveries that promise Leveraging California’s Internal Scientific Capac- to revolutionize medicine (see pages 16 to 25). ity And Global Collaborations: Leveraging the scien-

4 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 5 years and approximately $260 million in new state tax issued a decision that served as a stark reminder of revenue and nearly $70 million in local government the importance of Proposition 71.7 Judge Lamberth CHAMPIONS OF STEM CELL RESEARCH: CALIFORNIA’S MODERN MEDICI tax revenue, using a very conservative economic mod- granted a preliminary injunction in a challenge to the el. If the industry “clusters model”6 initially developed Obama Administration’s Guidelines for Human Stem The Medici of Florence, Italy of the 1650s and the 1660s protected and financially supported an empirically based by Michael Porter of Harvard is incorporated into the Cell Research (the “Guidelines”), which authorizes Scientific Renaissance from religious suppression that lead to the creation of the Hand Book of Empirical tax revenue model, the State and Local Government federal funding for research using human embryonic Science from the Accademia Del Cimento and the birth of the Royal Academy of London in 1660 and the Royal revenues should increase substantially. Three of the stem cells that were derived from human embryos cre- Academy of Paris in 1661: the expansion of the Scientific Renaissance. largest biotech clusters in the United States, one in ated for reproductive purposes8 but which prohibits California’s modern Medici of stem cell research are the great philanthropic patron families who committed the San Francisco Bay Area, one in San Diego and funding for research involving the derivation of hu- resources at vital moments and, through their support, have led the stem cell revolution. These visionaries include one in formation in the Los Angeles basin, could well man embryonic stem cells. The decision, before it was the following, all of whom provided major support for the world-class discovery platforms embodied in CIRM’s produce a substantially greater economic synergy for stayed by the Court of Appeals, effectively halted fed- Major Facilities Program. California, than the conservative basic economic mul- eral funding of human embryonic stem cell research, Eli and Edythe Broad Ray and Dagmar Dolby Edward and Vivian Throp Kat Taylor and Tom Steyer tiplier used in the current economic impact study. including funding that would have been permitted Lorry Lokey T. Denny Sanford The Keck Family Trust under President Bush’s 2001 executive order. Li Ka Shing William and Sue Gross Regina and John Scully THE LONG-TERM Plaintiffs (two adult stem cell researchers, the Chris- FUNDING MODEL: ESSENTIAL TO tian Medical Association and others) filed an action to Their leadership followed the courageous intervention of the philanthropic individuals and foundations that REACHING PATIENTS prevent the Guidelines from taking effect. The plain- bought CIRM bonds despite the overhang of litigation, which could have nullified the bond obligations; Californians made a critical choice to authorize ap- tiffs argued, among other things, that the Guidelines those champions included: proximately 10 years of funding (which formally com- violated the Dickey-Wicker Amendment, which pro- John and Ann Doerr Eli and Edythe Broad The David and Lucille menced in June of 2007), with the final funding com- hibits the use of federal funds for “research in which Richard Blum Gordon and Betty Moore Packard Foundation mitments currently scheduled for the summer of 2017, a human embryo or embryos are destroyed, discarded, William Bowes Henry Samueli Stewart and Linda Resnick financing research through 2020. It is only with this or knowingly subjected to risk of injury or death . . .” John Moores Steven and Mary Swig Herb and Marion Sandler unbroken chain of funding commitments that new J. Taylor Crandall Irwin and Joan Jacobs Gerson Bakar Family discoveries can be translated into therapies and car- ried forward to phase 1 and phase 2 FDA human trials; n April 29, 2011, the U.S. Court of All of the great people and families listed above built their contributions upon the visionary commitments of the at that point, the biotech industry should pick up the Appeals reversed the District Court’s individual donors to the Proposition 71 campaign. promising new therapies and develop them for broad- order, concluding that the National This extraordinary group of California’s modern Medici empowered the people of California, first giving them the based patient access. Institutes of Health (NIH) had rea- opportunity to vote their vision and then leading the effort to raise $1 billion in matching funds to carry out the com- California families made a commitment for the sonably construed the Dickey-Wick- mitments of Proposition 71. Without their vision, their commitment and their courage, Proposition 71 would have benefit of their own families, families of the country er Amendment to prohibit federal funding for research faltered, broken by political misrepresentations and litigation—all of which was designed to block the mandate of 7 and families of the world, to empower research that oinvolving the derivation of human embryonic stem cell million California voters. Without the decisive endorsements and financial backing of all of these modern day heroes, actually reached patients and was not cut off by the lines (hESCs), while permitting funding for research in the stem cell revolution would have stopped, a broken vision of the potential to empower the understanding of chronic episodic financial crises so typical of short-term state which hESCs will be used.9 Although the Court of Ap- disease and injury. The world would have missed an historic opportunity to reduce human suffering. revenue and budget cycles. California families and peals’ decision currently permits the NIH to continue businesses (all of the state Chambers of Commerce to fund hESC research, it is just the first step in a long along California’s coast—from San Diego to San Fran- process. The case will now return to the District Court cisco—endorsed the initiative along with the State and is likely to be subject to additional appeals before Chamber of Commerce) voted to invest today in de- the case finally concludes. Because of Proposition 71, veloping Stem Cell Therapies that might intervene in California is not subject to the NIH guidelines or to the One must also acknowledge with profound respect ing Proposition 71 in November of 2004. Proposition chronic disease and injury—to reduce the severity or courts’ orders; CIRM, therefore, may continue to fund and appreciation, the critical contribution of the peer 71 was structured with the bond interest capitalized for cure (in whole or in part) the condition, rather than embryonic stem cell research regardless of the outcome reviewers, from other states and countries, to this prog- the first five years, with no payments from the general being left with a health care system focused on finan- of the Sherley litigation or future federal litigation. ress; without them the scientific quality achieved would fund; the original economic projections, reconfirmed cially crushing chronic therapies. The sanctuary in California for hESC research is of not have been possible. (See list of reviewers on p. 44.) by a December 2010 study, projected that the new A primary objective of Stem Cell Research is to de- global importance. In Europe, the European Court of state tax revenue generated from the research and de- velop interventionist therapies that can substantially re- Justice is considering the opinion of its Advocate Gen- velopment funding—just through 2010—would offset duce or eliminate the long-term cost of chronic therapies eral that stem cell patents are “contrary to ethics and REVENUE POSITIVE AND state general fund bond payments in the sixth through and complications for patients, their families, employers public policy” because they require “industrial use” of JOB GENERATING the eighth project year: 2010–2012. and the State. The 10- to 15-year stable research fund- human embryos.10 It is rare for the court of 13 members The California Mandate: Revenue Positive to 2014. After considering the new economic activity in the ing commitment is possible because the bond structure to reject the recommendation of its Advocate General. California’s voters approved a bond-financed structure sixth through ninth project year, along with over $1 of Proposition 71 spreads the cost of stem cell therapy In an open letter opposing the opinion, other leading for stem cell research to permit the research and therapy billion in donor and institution matching funds, cur- development over 40 years and the multiple generations European stem cell researchers wrote: development to drive forward from concept to human rent projections estimate that new state tax revenue who will benefit from the new therapies. It is premature to suggest that human em- trials, even during times of intense economic stress for will offset all state bond interest payments through the bryonic stem cells can be replaced in de- the state. In 2004, California experienced a period of ninth project year and a portion of the (2014–2016) CALIFORNIA AS A RESEARCH velopment of therapies. Although induced maximum financial stress, similar to 2010–11, with the 10th through 12th project years.5 SANCTUARY pluripotent stem cells offer additional pos- voters approving $15 billion in deficit funding bonds in The first $2 billion of research funding, along with On Aug. 23, 2010, Judge Royce Lamberth of the sibilities, particularly for disease modeling, April of 2004, to keep the state solvent before approv- matching funds, is expected to produce 25,000 job Federal District Court for the District of Columbia the reprogramming process is still imper-

6 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 7 fect. Scientists working in stem-cell medi- cially given that the progress has been driven by a board, cine will not be able to deliver clinical ben- and a staff that averaged in the low forties in number, LIST OF BOARD LEADERSHIP, SUBCOMMITTEE, TASK FORCE AND WORKING GROUP LEADERS efits without the involvement of biological further limited to expenditures of approximately 5 per- (See pages 44 – 47 for complete membership lists) industry. But innovative companies must cent of the agency’s cumulative, annual grant and loan have patent protection as an incentive to budgets. Each member of the small, highly creden- Current and Former Board Leadership • Dr. Tina Nova, Vice-Chair, Governance Subcommittee become active in Europe. The advocate- tialed staff is a remarkable, dedicated contributor, in- • Robert Klein, Chair • Dr. Ed Penhoet, Vice-Chair, Science Subcommittee general’s opinion therefore represents a spired by the mission, working endless hours with an • Sen. Art Torres (Ret.), Vice Chair • Dr. Gerald Levey, Chair, Evaluation Subcommittee blow to years of effort to derive biomedical intense effort, to advance stem cell science and thera- • Duane Roth, Vice Chair • Robert Klein, Chair, Presidential Search Committee applications from embryonic stem cells in pies. (For a staff list please see p. 47.) • Dr. Ed Penhoet, Former Vice Chair • Robert Klein, Chair, Legislative Subcommittee areas such as drug development and cell- Motivating most staff members are memories of a • Robert Klein, Vice-Chair, Legislative Subcommittee replacement therapy. If implemented, Eu- family member or friend suffering from chronic dis- Current Board Subcommittee Leadership ropean discoveries could be translated into ease or injury or one whose life ended with an early, • Sherry Lansing, Chair, Governance Subcommittee Board Task Force Leadership applications elsewhere, at a potential cost untimely death. Through the commitment and sac- • Dr. Claire Pomeroy, Vice-Chair, Governance Subcommittee • Dr. Ed Penhoet, Chair, IP Task Force to the European citizen. rifice of each staff member, we move one step closer • Michael Goldberg, Chair, Finance Subcommittee • Duane Roth, Chair, Loan Task Force Peter Andrews (Univ. of Sheffield), to empowering new discoveries, new therapies for • Marcy Feit, Vice-Chair, Finance Subcommittee • Marcy Feit, Co-Chair, Bridges Program Development Austin Smith (Wellcome Trust), a better world with less suffering and greater hope. • Jeff Sheehy, Chair, Science Subcommittee Task Force Katherine Verfaille (Katholieke Univ., Leuven) When the story is told, years later, of the extraordi- • Dr. Oswald Steward, Vice-Chair, Science Subcommittee • David Serrano Sewell, Co-Chair, Bridges Program nary medical discoveries and advances funded by the • Dr. Francisco Prieto, Chair, Evaluation Subcommittee Development Task Force CIRM Board and staff, many may paraphrase Win- • Dr. Ted Love, Vice-Chair, Evaluation Subcommittee • Gayle Wilson, Co-Chair, Task Force on Congressional egardless of the final decision of ston Churchill’s words, (rarely) “in human history • Sen. Art Torres (Ret.), Chair, Legislative Subcommittee Policy on Human Embryonic Stem Cell Research the European Court of Justice, the potential have so many owed so much to so few”; but, all will • Dr. Francisco Prieto, Vice-Chair, Legislative Subcommittee • Robert Klein, Co-Chair, Task Force on Congressional future of instability of European patent pro- also remember, this great dedicated experiment—led • Sen. Art Torres (Ret.), Chair, Communications Subcommittee Policy on Human Embryonic Stem Cell Research tection signaled by these events will further by the “few”—was made possible by the vision of the enhance the value of Proposition 71 and the voters of California. Past Board Subcommittee Leadership California Constitution’s protection of human embryonic • Dr. Ed Holmes, Chair, Grants Working Group Search rstem cell research and its funding. MILESTONES OF PROGRESS HONOR Subcommittee The importance of preserving access to human em- OUR PROMISES • Dr. David Kessler, Chair, Standards Working Group Search bryonic stem cell research has recently been empha- As I watched my mother die with Alzheimer’s, Subcommittee sized by the multiple top line journal articles describing stripped of every memory of family, friends, chil- • Dr. Michael Friedman, Chair, Facilities Working Group the critical differences between iPS derived stem cells dren—every hope and dream of her life—I prom- Search Subcommittee and embryonic stem cells. A number of these derivation ised her I would do my best to see that others would • Dr. Phillip Pizzo, Vice Chair, Presidential Search differences could have major negative impacts on thera- not suffer her same death while “living” out their Subcommittee peutic applications; at this point, human embryonic last years. Stem cell research for Alzheimer’s is in its • Dr. Tina Nova, Chair, Legislative Subcommittee stem cells remain the bench mark, the gold standard, for early stages. Although surprising progress has been validating the accuracy of cell derivations and the best, made with Proposition 71 funds, “there are [still] existing option for many types of cellular therapies. miles to go before [we] sleep;” but, our Milestones of Progress honor our promises and provide hope The Privilege of Service: that years of future commitment by all of us, patient A Tribute to the governing Board advocates and scientists, business and biotech lead- for our children’s lives. Indeed, our lives may depend regulations: http://www.cirm.ca.gov/reg/pdf/Reg100304_ It has been a great privilege, as Chairman, to serve with ers, may deliver on those promises for my mother, on the discoveries born from the sacrifice and com- IP_NonProfit_Org.pdf each and every member of the distinguished and com- your father or brother, and all of our children, to mitments of California’s scientists and physicians. The 5 The general fund of the State of California is not projected mitted Board. I wish to convey my deepest admiration protect them from chronic disease or injury that Milestones of Progress of Proposition 71 serve as wit- to be burdened by the bond debt services for the Stem Cell and gratitude for the service of the Board members dur- might otherwise steal their lives and hopes. ness to the dawn of the California Stem Cell Renais- research funding through 2013, on a net economic basis. It ing my tenure. Each member of the Board has brought sance, a new hope for the future of mankind to reduce is paying the debt service with new state tax revenues gener- a treasury of talent and experience that has left an in- A MESSAGE TO CALIFORNIA’S CITIZENS the suffering of every child, every woman and every ated by the research funding and the tax revenues created delible impact, improving the quality and outcomes of In 2004, the voters of California gave Proposition 71 man on this planet from chronic disease and injury. by research facilities construction funded through matching the Board’s contribution to this mission. Many Board the largest vote total for any major funding initiative fund contributions from private donors and institutions. members have served on one or more Subcommit- in California’s history. At 7,018,000 votes, Proposition 1 Robert Frost, “Stopping by Woods on a Snowy 6 Clusters and Entrepreneurship; Journal of Economic Geog- tees, Task Forces and/or Working Groups, representing 71 received more votes in 2004 than any US Senator Evening,” 15-16 raphy; Delgado, Porter and Stern; May 28, 2010 hours of their invaluable time spent on additional work in California’s history. The mandate from this vision- 2 See this letter online for links to the External 7 Sherley v. Sebelius, 704 F. Supp.2d 63 (D.D.C. 2010) toward meeting our mission, with those in leadership ary vote by California citizens has given birth to a new Advisory Panel report including biographies: 8 The family must have completed their family planning and roles dedicating yet more effort over the years. We can- renaissance in the understanding of the human body www.cirm.ca.gov/2010AnnualReport_Chair these cells would otherwise be thrown away. not thank them enough. and its battles with millennia of suffering from chronic 3 See this letter online for links to the presentation to the 9 Sherley v. Sebelius, ___ F.3d ___, 2011 WL 1599685 (D.C. disease. board by Dr. George Daily, Dr. Rick Klausner, Cir. 2011). THE DEDICATION OF STAFF The future of mankind is in your hands, Califor- Dr. Nancy Wexler and Dr. Alan Bernstein: 10 http://www.independent.co.uk/news/science/ruling- The External Review Panel found that CIRM had nia. A gateway to medical discoveries and therapies has www.cirm.ca.gov/2010AnnualReport_Chair on-stemcell-patents-may-spell-end-of-research-in-eu- made remarkable progress in less than six years, espe- opened. Let us support and defend this opportunity 4 See section 100304 of CIRM’s intellectual property rope-2275771.html

8 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 9 Patient advocates o u t r e a c h Marcy Feit, R.N., M.S.N. Joan Samuelson, J.D. Representing patients, researchers, biotechnology – and you Type II Diabetes Parkinson’s Disease President & CEO, Founder, Parkinson’s Action ValleyCare Health Systems Network

CIRM is governed by 29 dedicated Californians representing patients, researchers and the Leeza Gibbons David Serrano Sewell, J.D. biotechnology industry whose knowledge, passion Alzheimer’s Disease MS/ALS Founder & Board Chair, Amyotrophic Lateral Sclerosis and commitment to CIRM’s mission has guided The Leeza Gibbons Memory Association, National Multiple the organization through a successful first six years. Foundation Sclerosis Society Leadership Biotechnology representatives These board members serve on six subcommittees and on the three working groups that provide Robert Klein, J.D. Michael Goldberg Sherry Lansing Jeff Sheehy (chair) General Partner, Mohr, Cancer HIV/AIDS recommendations to the board regarding CIRM President, Davidow Ventures Founder and Chair, Director for Communications, funding, ethical standards and facilities. Member, International Advisory Sherry Lansing Foundation UCSF AIDS Research Institute Board, JDRF

CIRM Public Meetings: Art Torres, J.D. Ted W. Love, M.D. Francisco J. Prieto, M.D. Jonathan Shestack ICOC meetings: 69 (vice chair) Executive Vice Type I Diabetes Mental Health Subcommittee meetings: 114 Board of OneLegacy Transplant President, Head of Research President, Founder & Vice President, Donor Network and Development, Sacramento-Sierra Chapter, Cure Autism Now Standards working group Onyx Pharmaceuticals American Diabetes Association meetings: 23 Grants working group meetings: 28 Duane J. Roth Ed Penhoet, Ph.D. Robert A. Quint, M.D., F.S.C.A.I. Oswald Steward, Ph.D. (vice chair) Director, Alta Partners; Heart Disease Spinal Cord Injury Facilities working group CEO and Board Member, Board Member, Charter Member & Chair and Director, Reeve–Irvine meetings: 19 CONNECT Gordon & Betty Moore Founding Fellow, Society for Research Center, University of Foundation Cardiac Angiography California, Irvine Interventions

Research representatives

Ricardo Azziz, Susan V. Bryant, Ph.D. Jeannie Fontana. M.D., Ph.D. Gerald S. Levey, M.D. Nancy Milliken, M.D. John C. Reed, M.D., Ph.D. M.D., M.P.H. M.B.A. Vice Chancellor for Research and (Alternate) Vice Chancellor, Medical Sciences (Alternate) CEO, Chairman, Department of Professor, School of Biological Director, Sanford-Burnham & Dean, School of Medicine, Uni- Director of UCSF Women’s Sanford-Burnham Obstetrics and Gynecology, Sciences, University of Medical Research Institute versity of California, Los Angeles Health, UCSF School of Medical Research Institute Cedars-Sinai Medical Center California, Irvine Medicine

Robert Birgeneau, Ph.D. Kenneth C. Burtis, Ph.D. Michael A. Friedman, M.D. Jacob Levin, Ph.D. Philip A. Pizzo, M.D. Leonard Rome, PH.D. Chancellor, University of (Alternate) President & CEO, (Alternate) Dean of the Stanford University (Alternate) California, Berkeley Professor of Genetics, Dean of City of Hope Assistant Vice Chancellor, School of Medicine; Carl and Senior Associate Dean of the College of Biological Sciences, Research Development, Elizabeth Naumann Professor, Research, University of California, Molecular and Cellular Biology, University of California, Irvine Professor of Pediatrics and of Los Angeles University of California, Davis Microbiology and Immunology

Floyd E. Bloom, M.D. Donald C. Dafoe, M.D. Gordon Gill, M.D. Alexandra Levine, M.D. Claire Pomeroy, M.D., M.B.A. Kristiina Vuori, M.D., Ph.D. Executive Director, (Alternate) [Alternate] (Alternate) Vice Chancellor for Human President of the Science Communication, Director, Pancreas Transplanta- Professor of Medicine and of Chief Medical Officer, Health Sciences and Dean of the Sanford-Burnham Medical The Scripps Research tion, Kidney and Pancreas Cellular & Molecular Medicine, City of Hope School of Medicine, Research Institute Institute Transplant Center, Dean of ScientificA ffairs, Univer- University of California, Davis Cedars-Sinai Medical Center sity of California, San Diego

David Brenner, M.D. James Economou, M.D., Ph.D. Sam Hawgood, M.D. Bertram Lubin, M.D. Robert Price, Ph.D. A. Eugene Washington, Vice Chancellor for Health [Alternate] Dean, President and Chief Executive (Alternate) M.D., M.Sc. Sciences and Dean, School of Vice Chancellor for Research, USCF School of Medicine and Officer ofC hildren’s Hospital & Associate Vice Chancellor for Vice Chancellor of Health Medicine, University of University of California, Chair, Department of Research Center, Oakland Research and Professor of Science, Dean of the David Geffen California, San Diego Los Angeles Pediatrics Political Science, School of Medicine, University of University of California, Berkeley California, Los Angeles

William Brody, M.D., Ph.D. M. Elizabeth Fini, PH.D. Theodore G. Krontiris, Shlomo Melmed, M.D., FRCP Carmen A. Puliafito, Kim Witmer President, Salk Institute (Alternate) M.D., Ph.D. Senior Vice President for M.D., M.B.A. [Alternate] for Biological Studies Vice Dean for Research, [Alternate] Academic Affairs, Dean of the Dean, Keck School of Medicine, Chief Financial Officer, Professor and Director, Professor of Molecular Medicine, Medical Faculty, University of University of Southern The Salk Institute for Keck School of Medicine of the Director Emeritus, City of Hope California, Los Angeles California Biological Studies University of Southern California Comprehensive Cancer Center

10 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 11 president’s letter

alan trounson, ph.d. most important recommendations and our preliminary grants award processes and developing mechanisms plans for carrying them out. for industry to more quickly seek grant review. We will The first two recommendations simply encour- be increasing the number of industry reviewers on our age us to maintain the scientific excellence of what grant review panels and we will be developing ways to we fund and to continue to sustain fundamental encourage industry to use the patents and other intel- discovery by supporting the most creative basic sci- lectual property created by CIRM-funded projects. ence. These simply require us to maintain the high The EAP also suggested we broaden our collabora- standards and effective systems we have in place tive funding partnership program beyond the current thanks to the highly dedicated members of our sci- nine countries and three U.S. states and foundations. ence office team. We will be looking for ways to encourage multiple in- In paving a path from fundamental to translational ternational and interstate partnerships on projects. At research the panel called for CIRM to develop a more the same time we will continue looking for additional aggressive, proactive approach to identify innovation hubs of excellence around the world that can be added across the whole therapeutic landscape. We believe to the current network. We are also exploring options we can accomplish this by more aggressively reviewing for partnering with the National Institutes of Health “hot areas” of breaking science and using the insights Clinical Center and its newly created National Center of an industry advisory group and of our collaborative for Advancing Translational Sciences. ew things are more fulfilling than setting goals funding partners around the globe. Once we find a CIRM’s efforts to increase its education and outreach and seeing them met—and to have a panel of outside reviewers agree that hot spot of innovation we will need to move quickly to activities with the public were strongly encouraged by the identify suitable California partners and arrange link- committee, which called for a significant increase in the CIRM has been a real success. • In December 2006, our Governing Board f ages no matter where the hot spot is. breadth of this work. We intend to expand a program we adopted a strategic plan with very ambitious five-year and 10-year goals for The EAP said CIRM needs to create a process for began last year using a team of patient advocate outreach prioritizing its portfolio, particularly its therapeutic can- coordinators to work directly with the many disease-spe- These goals were set a year prior to my arrival at CIRM and to be frank, the agency. didates. We need a way to use expert advice to identify cific groups in the state. We also hope to enlist more of when I looked at the goals the first time I thought several of them might be a stretch in which programs deserve continued support and which our grantee researchers in public education projects and do not. Our outside grant review panels’ consideration expand our work with media outlets of all types. the given time frame, and one or two still may be difficult to achieve. But the progress in the of “relevance,” along with the milestone/progress com- The last recommendation from the EAP, to re-ex- past three years has certainly exceeded my initial expectations. • The 2006 plan called for a review of progress mittee we are setting up, could go a long way toward amine the roles of the Governing Board and CIRM after three years, so during the second half of 2010, agency staff undertook a thorough self-assessment followed setting priorities most likely to result in broadly adopt- managers, is an ongoing process. Our board is actively by an extensive review by an eight-person external advisory panel (EAP) made up of world leading stem cell re- ed therapies. Relevance is a term used by industry to engaged in looking at the criteria its members believe searchers, science policy experts, and patient advocates and an ethicist (names of the panelists can be found here: measure clinical impact on patients combined with a are the top credentials for a new chair to succeed our http://www.cirm.ca.gov/Announcement_092810). Staff presented their self-assessment to the EAP in October reasonable business/practice model for delivery. visionary founding chair, Robert Klein. and the panel presented its findings to our board in December. • We found that half the 10 five-year goals had Creating a “porous pipeline,” the EAP said, would As we enter CIRM’s “phase II,” looking for ways to already been met, including creating new methods of making stem cell lines. The remaining five-year goals are allow potential clinical projects to come from either in- implement these recommendations, it is clear to all of on a plausible track for completion in the next year or two, well within the five-year window. Also, CIRM grant- side or outside of CIRM’s current funding, or even from us at the agency that we are taking on these sometimes ees have published papers advancing progress toward nearly all 10 of the 10-year goals, including the ultimate outside of California. We believe we should be able to daunting tasks for one reason: to fulfill the mission of goal of seeing embryonic stem cell–derived cells in clinical use. They have made sufficient progress to believe create more flexible funding processes that add a rolling CIRM to accelerate the development of new therapies that these goals are achievable. This finding was hugely satisfying, as was the assessment of the EAP regarding funding cycle that could capture innovative projects at for patients. That is what we owe the voters of Califor- the agency’s early years: • “Progress during this first stage of CIRM’s development has been remarkable; CIRM the time they are most ripe for support rather than only nia. Thank you for your support. has built significant additional research capacity in the state, has attracted scores of talented young people to within set Request for Application schedules. stem cell research, and has catalyzed large and important stem cell developments across the state. The EAP was The panel asked that we not ignore social, ethical, most impressed with this rapid startup, the overall quality of the scientists and projects that have been funded, regulatory and health care delivery issues, saying we We are taking the development of major buildings and other facilities for stem cell research, the forging of a raft of important should stimulate the research that is needed to move international partnerships and the innovative training programs that are in place.” the field to everyday practice. To this end we are con- on these sometimes However, the report doesn’t leave time for CIRM to rest on these laurels. The panel provided a number of sidering creating an advisory group to identify critical daunting tasks for recommendations for CIRM to accelerate the field by making its funding more flexible, opportunistic and able issues in these areas and hope to take a leadership role to quickly respond to major discoveries, particularly those that are close to the clinic. The panel made some very in developing standards for manufacturing and cell one reason: to fulfill the mission of IRC M thoughtful and helpful recommendations that will enable CIRM to deliver its mandate by becoming an even integrity for clinical use. We are also studying the pos- to accelerate the development of new more effective organization. sibility of establishing CIRM-sponsored clinical units therapies for patients. The EAP report voiced confidence in CIRM’s ability to be nimble and make the adjustments suggested. “The for the delivery of cell therapies. EAP feels confident that CIRM is poised to build on the success of the first stage to drive further growth toward its The EAP saw enabling more significant engage- long-term mission of providing significant health and economic benefits to the people of California.” ment with industry as critical to the next phase of The panel grouped its findings into 10 key recommendations. Since December, CIRM’s management team CIRM. We were told we needed to be more accommo- has been drafting a new operations plan that will spell out the tactics it proposes for carrying out those recom- dating to industry timelines and financial restraints. In mendations. We presented that plan to our board in March and here I would like to walk you through some of the response we will be looking for ways to streamline our

12 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 13 M A J O R fac i l i t i e s op e n i n g s

“C i r M ’ s i n v e s t m e n t A Seven CIRM major facilities i n s t e m c e l l opened this past year, creating state-of-the art space for carrying r e s e a r c h b u i l d i n g s out stem cell research. CIRM’s initial investment of $271 million leveraged private donations c r e at e d j o b s a n d B and institutional commitments toward 12 buildings and recruitments r e v e n u e f o r t h e s tat e A . Stanford University worth more than a Lorry I. Lokey Stem Cell Research Building Total: $200 M billion dollars. Lorry Lokey: $75 M a n d s o l i d i f i e s That investment CIRM: $43.6 M created 13,000 job B . University of California, Los Angeles C Eli and Edythe Broad Center of Regenera- California’s position years and $100 million tive Medicine and Stem Cell Research Total: $43 M in tax revenues The Eli and Edythe Broad Foundation: $20 M a s t h e l e a d e r i n for the state at a time CIRM: $19.8 M when they were C . University of Southern California Eli and Edythe Broad CIRM Center for critically needed. Regenerative Medicine and Stem Cell d e v e l o p i n g t h e Research Total: $80 M CIRM: $27 M D E s t e m c e l l t h e r a p i e s The Eli and Edythe Broad Foundation: $30 M D . University of California, Irvine Sue and Bill Gross Stem Cell Research Center o f t h e f u t u r e . Total: $80 M CIRM: $27.2 M Sue & Bill Gross: $10 M

O ne of the next g r e at E . University of California, Davis Institute for Regenerative Cures F Total: $62 M California industries CIRM: $20 M F . University of California, San Francisco Ray and Dagmar Dolby Regeneration will be bio m e d i c a l Medicine Building Total: $123 M CIRM: $34.9 M Ray and Dagmar Dolby: $36 M r e s e a r c h , a n d C i r M i s The Eli and Edythe Broad Foundation: $25 M G . University of California, Merced G Stem Cell Instrumentation Foundry l e a d i n g t h e way. ” Total: $7 M Ed and Jeanne Kashian: $100,000 CIRM: $4.4 M – California A s s e m b ly S p e a k e r J o h n P é r e z

14 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 15 on funding for embryonic stem cells set the discovery of reprogrammed iPS cells back by about five years. He wrote in the Dec. 3, 2007 Wash- marrow transplant (it’s the ington Post, “Work by both blood-forming stem cells in the U.S. and Japanese teams the bone marrow that rebuilt that reprogrammed skin cells the blood system). Those cells depended entirely on previous are now in clinical trials for embryonic stem cell research.” a range of diseases, and adult Creating the initial iPS neural stem cells are just start- cells and the newer techniques ing to be tested for spinal cord that followed (See “Making a injury and ALS, among other Better iPS Cell,” p. 24) came conditions. about, in part, by studying To some, the fact that adult embryonic stem cells to under- stem cell clinical trials have stand what it is that makes a started means embryonic stem cell able to form all cell types cells came along too late. By of the body. that logic, cancer patients Even with improvements would still be receiving the news at CIRM in creating iPS cells, there’s very first extremely toxic and a lot we still don’t know. Paul only somewhat effective che- Embryonic stem cells Knoepfler at the University of motherapies. California, Davis says there Instead, scientists con- remain the gold standard are hints that iPS cells when tinued testing new ideas as

Scientists in the Lurch On Aug. 23, 2010 federal Soon after the ban of funding for human embryonic stem cell research went into place, CIRM surveyed our grantees to learn judge Royce C. Lamberth started a series of companies the impact on California scientists. • Twenty-two percent of respondents said they had NIH funding for embryonic stem cell ruled federal funding of dedicated to developing thera- research and only 5 percent of grantees said the ruling would make no difference to their overall research strategy. human embryonic stem pies based on those discoveries. Also, 65 percent of grantees who had NIH support said that if the NIH freeze holds they’ll need to reduce or eliminate positions cell research impermissible By September 9 the U.S. Given that Weissman’s “These cells are restricted in their labs. The most telling finding from the CIRM survey was that 76 percent of grantees said the funding freeze would under current laws. This de- Court of Appeals put a hold on reputation and personal in what they can do,” Weiss- impact their ability to carry out research with adult, cancer or iPS stem cells. cision suspended the ability that ruling, allowing funding income are invested in the man said. “No adult stem cell of the NIH to fund research to continue, though the final future of adult stem cells you’d can ever go on to be an- using human embryonic outcome of the case is still think he would be their biggest other cell type, even one that’s stem cells, a result that NIH unknown. With this surprising fan. Instead, Weissman, who is closely related.” clinical trials for spinal cord stem cells is as a research tool. transplanted are more prone to they emerged. Through that director Francis Collins turn of events, one question now the director of Stanford’s By contrast, embryonic injury and they can also form Weissman’s team has relied forming tumors than embry- clinical trial and error process likened to pouring sand in kept surfacing: Why do we Institute for Stem Cell Biology stem cells can form every sin- structures in the eye that are on knowledge gained from onic stem cells. But then, we now have highly targeted the engine of discovery. even need embryonic stem and Regenerative Medicine, is gle cell type in the body. They now being tested as a therapy embryonic stem cells to guide those studies were done on iPS antibody-based cancer thera- cells when the science of adult one of the most vocal support- come from embryos discarded for two forms of blindness. their adult stem cell discover- cells created using an outdated pies as well as more effective stem cells and reprogrammed ers of funding for embryonic after a couple completes in Other research teams have ma- ies. Rather than sifting through method. How do the newer standard chemotherapies. This iPS cells is so advanced? stem cells. vitro fertilization treatment, tured the cells into types that mouse tissues looking for adult techniques compare? Nobody range of therapeutic options Adult stem cells, or tissue- can be frozen or grown indefi- could become therapies for stem cells, his team matured will know until they’ve done would never have been devel- In the Beginning specific stem cells, reside nitely in the lab and with a bit diabetes, skin diseases, heart embryonic stem cells until the comparisons against em- oped if scientists were satisfied In 1988, Irv Weissman of Stan- within the bone marrow, brain, of coaxing can mature into any disease, neuronal diseases or they reached the adult stem bryonic stem cells. with their earliest attempts. ford University isolated the first blood, skin, liver or other tis- desired cell type. cancer, among others. cell stage. They could then use Funding restrictions for adult stem cells. These were sues until disease or injury calls This flexibility is what what they’d learned about those Keeping embryonic stem cells would the blood-forming stem cells upon them to finish maturing accounts for much of the By Way of Comparison stem cells to find the counter- the Pipeline Full mean not only fewer embry- from the bone marrow of mice. to repair the damage. therapeutic hope for embry- A less discussed but equally parts in actual animal tissues. Adult stem cells were first onic stem cell-based therapies He soon isolated the same cells onic stem cells. They’ve been critical role for embryonic James Thomson, one of successfully used in humans to be tested, but also fewer in humans, and over the fol- matured into nervous system the first to reprogram skin in 1968 in the form of a bone adult, cancer, or iPS cell lowing decade he isolated stem precursor cells that are now in cells into embryonic-like iPS therapies as well. cells in additional tissues and cells, has said that restrictions

16 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 17 edge of stem cell-based treat- ments for patients and these projects will load our frontline More Candidates portfolio with promising stud- for Cures ies on autism, muscular dystro- As the disease team projects phy, Canavan disease and grow closer to human clinical liver disease,” said CIRM trials, CIRM continues to fund president Alan Trounson. new work in the earliest stages “These projects will enhance of that pathway. CIRM’s Early the potential medical options Translation II Awards fund the available for patients and transition of a basic discovery hopefully in the near future about a disease into a drug or produce cures for such debili- therapy that could eventually tating handicaps and diseases.” news at CIRM benefit patients. The awards cover a broad This year, the awards came spectrum of diseases. Some STem Cells Move in two categories: One funds award recipients are looking all the steps needed to produce for alternative paths to the Toward Clinical Trials a drug candidate worthy of clinic for diseases such as HIV costly pre-clinical testing. The and brain tumors, which are

Treating Osteoarthritis In naming Proposition 71 Forty million Americans live with constant pain caused by degeneration of the cartilage in the joints or osteoarthritis. the California Stem Their only hope for pain relief comes from costly surgery to entirely replace the joint. • One of the Early Translation II projects at Cell Research and Cures milestones. At the University the Scripps Research Institute aims to provide an alternative to surgery. The plan is to activate a patient’s mesenchymal Act its authors emphasized of Southern California, Paula stem cells within the joint to form new cartilage and prevent further damage. • The team has already tested compounds on stem the goal of delivering life- Cannon, who is working with sistant immune cells that cells in a lab dish to find ones that promote new cartilage and that protect existing cartilage from additional damage. With their CIRM saving regenerative medical the team headed by John Zaia can eventually win the battle award, they now hope to develop a promising drug candidate to protect and restore cartilage, and give hope to the 1.8 million treatments and cures to of City of Hope, has published against HIV,” said Cannon in people predicted to need joint replacements in 2015. the people of California a proof of principle paper a USC press release. and the world. This past The most significant ad- on the team’s effort to create Karen Aboody, also of City year brought considerable vancement was the announce- blood-forming stem cells that of Hope, received Food and progress toward that goal. ment that Geron’s therapy for can produce HIV-resistant T Drug Administration approval chemotherapeutic agent. team has reported that a test other, a Feasibility Award, already under investigation spinal cord injury based on cells. Her team showed that in in June to begin a clinical trial A third team, led by drug could cure non-Hodgkins funds one or two of those steps by CIRM grantees. Others embryonic stem cells would mice, genetically modified hu- with neural stem cells that act Stanford’s Irv Weissman, is in mice in 60 percent of cases. that move the research further address conditions and injuries begin enrolling new patients. man blood-forming stem cells as carriers for an enzyme that developing an antibody-based The Disease Team Awards down the pipeline but not to new to CIRM’s drug candidate Soon after, two additional trials were able to form a new blood converts a pro-drug to an active drug to treat leukemia. The required teams including basic the point of a drug candidate. portfolio, including degen- based on embryonic stem cells system that could control cancer chemotherapeutic drug binds to a protein that scientists and clinicians from Altogether the CIRM Gov- erative bone conditions (see joined Geron with approval HIV infection. agent. While the FDA approv- leukemia stem cells use to both industry and academia erning Board issued awards for sidebar), blindness and autism. to begin trials. “This hybrid of gene and al came for a different agent avoid being ingested and to show a roadmap for getting $71 million in grants for 21 One award went to Univer- stem cell therapy shows that and a different protocol than removed by the body’s im- to clinical trials in four years. Early Translational II Awards sity of California, San Diego Early Progress Toward it is possible to create HIV-re- the one she has proposed for mune system. This protein is These collaborations speed the making a total of 37 Early scientist Alysson Muotri, who the Clinic the CIRM disease team, the found on some other cancer process of establishing clinical Translation Awards to date. will be following up on her ini- Three of the 14 disease teams cell type is the same, and this stem cells, including those for trials by ensuring that clinically “We are looking for ways tial work developing a model awarded in October 2009 should greatly speed approval non-Hodgkins lymphoma. The relevant issues are considered to complement our leading for understanding and treating have already achieved major of the CIRM-funded clinical early and by avoiding safety forms of autism (see Under- trial application. The CIRM issues being discovered late standing Autism p. 22). regimen uses a more powerful in the process.

18 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 19 stem cell scientists to form partnerships with transplant immunologists in order to ap- ply for the awards. “It has significant value to have some of the world’s lead- ing stem cell scientists being part of a team with some of the world’s leading immunolo- gists,” said CIRM governing board member Jeff Sheehy ing at aging and the possibility just prior to the board vote news at CIRM of using systemic proteins, on the grants. which are found abundantly Two California stem cell Keeping the in young brains but less so in teams availed themselves of older ones, to try to make older CIRM’s international Col- Research Pipeline Fueled brains more able to regrow laborative Funding Partner neural tissue. Program to find immunologist

Full Cycle for Diabetes From its inception, CIRM Type 1 diabetes occurs after a child’s immune system has gone out of control and attacked the child’s own insulin has been invested in producing cells. But the body does have cells capable of stopping this self-attack. These cells could allow the immune system pumping fuel—in the form The strategy clearly worked. to come full cycle and stop the progression toward diabetes by preserving the insulin producers. • Jeff Bluestone at the of new researchers and new CIRM has documented 102 University of California, San Francisco, has been granted an early translational award to do just that. He is trying to research ideas—into the faculty-level stem cell scientists when it launched the Research harness the natural immunosuppressive properties of T regulatory cells to counter autoimmunity against insulin producing research pipeline that leads who have moved to California Leadership Awards, which beta cells. • The research team also set its sights on using T regulatory cells to promote tolerance of stem cell grafts designed to new therapies. Recruiting the Brightest from other states and other help recruit established or to replace already damaged insulin producing cells. This would ease the path to using stem cells to reverse diabetes. This effort includes CIRM aimed its earliest rounds nations since 2006. Thirty-nine emerging leaders in stem cell recruiting top scientists— of funding at creating a robust of those are senior level faculty science. The grants provide young and established—to stem cell research community regarded as leaders in the field. six years of salary and research California and to stem cell in California to attract new Joanna Wysocka, a Stanford support intended to enable questions about what makes a road blocks to projects that are A Foundational Hurdle collaborators at a hotbed of im- science, while also funding stem cell investigators to the researcher who won the Out- these researchers to pursue stem cell a stem cell and what already close to the clinic.” “In writing Proposition munology research: Monash the basic studies that lead state. This began with its first standing Young Investigator highly innovative projects. The pushes some of them to ma- The Basic Biology II Grants 71, we anticipated the need University, in the Australian to new ways of understand- ever grants for training in 2006 Award at last year’s meeting of firstL eadership Award went to ture into very specific tissues. run the gamut of human de- to overcome the immune state of Victoria. The Victorian ing and eventually treating and continued with its Jump the International Society for the Sanford-Burnham Medical Last year the agency funded velopment. One seeks to turn response in order to fulfill government has committed disease. Start Program in 2007, which Stem Cell Research, cited the Research Institute to aid in re- 16 Basic Biology II Grants for a immature “pre-egg” follicles in one of the ultimate promises $1.2 million to fund the work included SEED grants to bring CIRM SEED program cruiting Robert Wechsler-Reya, total of $22.4 million, creating the ovaries removed from can- of regenerative medicine,” on these projects in Australia. new investigators and innova- for bringing her into stem a thought leader in neural fodder for future therapies. cer patients into mature eggs said Robert Klein, chair of the tive ideas to the field, Com- cell research. development and cancer stem In addition to opening that could be used for nuclear CIRM governing board. prehensive Grants to support This year CIRM poured cells from Duke University. up new avenues of research, transfer—so-called therapeutic By issuing $25 million for mature projects by researchers more fuel into the pipeline this fundamental work can cloning. Obtaining sufficient 19 Stem Cell Transplantation with a track record in stem cell Fundamentals Foster help therapies already well eggs has held back this line of and Immunology Awards, the research and Shared Labs to Cures along the pipeline, accord- research. Another grant is look- agency made significant strides provide critical infrastructure Throughout its existence ing to CIRM president Alan toward achieving this goal. and training in human embry- CIRM has funded research Trounson. “We expect many These unique awards force onic stem cell use. that addresses fundamental of these outstanding projects to provide answers that remove

20 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 21 professor in the Salk’s Labora- tory of Genetics. The team took the work an additional step, exposing those scrappy neurons to an experimental drug and thereby reversing some abnormalities. Now they hope to study neu- signals to propagate along the rons developed from people nerve; when damaged, signal- with other forms of autism to ing is interrupted. start understanding the full When myelin corrodes, spectrum of symptoms. Lane discovered, inflammatory cells activate receptors Scene of the Crime on neural stem cells. Adult neural stem cells take Those stem cell receptors advantage of the body’s 911 recruit protein guides called system when they rush to the chemokines, which lead them scene of damage in mouse to the accident and guide the news at CIRM models of multiple sclerosis. stem cell’s eventual fate. As the Once in place, the cells take stem cells travel through the taking control on a mature fate. central nervous system, they Tom Lane, an investigator begin to differentiate. of cell fate at the Sue & Bill Gross Stem They reach the repair site Cell Research Center at the in the form of oligodendro-

Blocking Tumors Between a dish of stem Stem cells have an inherent disposition to form tumors called teratomas which raises concerns for transplantation therapies. • CIRM grant cells and hope for a cure recipient Yang Xu, a biology professor at the University of California, San Diego, has uncovered a way to reduce the growth of teratomas, stands the pesky problem of switches, including one by suggesting a hope for their complete eradication. • In a paper appearing in the Proceedings of the National Academy of Science, turning those stem cells into Stanford scientist Marius Xu reported he was able to reduce the mass of teratomas formed in mice by inhibiting a gene that regulates their ability to form all cell a therapeutic cell type—a Career Switch Wernig, a CIRM grantee, heart are fibroblasts, so the types, called pluripotency. • Xu speculates that teratoma formation may be eliminated entirely by targeting several pluripotency retina for eye disease, or a Dogma once held that if a who turned skin cells into ability to call upon this factors simultaneously. • Calling the approach a “proof of concept,” Xu said, “At this point, we only see a significant but partial effect pancreatic cell for diabetes. cell was a doctor it would need nerve cells. reservoir of cells already in because we are targeting only one pathway.” • The experiment stopped teratoma growth after transplantation of pure, undifferentiated Research this past year has to go back to kindergarten Later in the year, CIRM the organ to become beating stem cells, reducing their mass by 70 percent. • “Once we identify more pathways required for teratoma formation by embryonic stem shown that adult cells may before it could grow up to grantee Deepak Srivastava, heart cells has tremendous cells, we might be able to completely suppress the formation,” Xu said. change their identities, cell become a lawyer: An adult cell director of the Gladstone Insti- promise for cardiac regenera- transplants can be made needed to be reprogrammed tute of Cardiovascular Disease tion,” Srivastava said. Nearly 6 safer and someday the blind back to an embryonic-like state at the University of California, million Americans suffer from may see, thanks to advances and from there, these so-called San Francisco, coaxed mouse heart failure because the heart grantees at the Salk Institute autistic neuron different. University of California, Irvine, cyte precursor cells and finish CIRM scientists throughout iPS cells would be shepherded cardiac fibroblasts, the heart’s is unable to repair itself after for Biological Studies were They had smaller cell bodies discovered the interactions that maturing onsite. Three weeks California have made in to a new adult fate. support cells, to turn directly a heart attack, but only 2,000 able to study neurons and fewer connections help stem cells home in on after a stem cell treatment controlling stem cell fate. That changed in 2009 into primitive heart muscle hearts become available for predisposed to autism spec- between neurons. damage in research published initiates, the cells are mature. when Harvard Stem Cell In- cells. The research appeared in transplanting each year. trum disorders. “Being able to study Rett in the Proceedings of the “In this study, we’ve taken stitute researchers successfully the August issue of Cell. The team took skin cells neurons in a dish allows us National Academy of Science. an important step by showing converted one type of mouse Srivastava’s heart cell Understanding Autism from people with a genetic to identify subtle alterations Lane, a CIRM grantee, earlier the navigational cues in an pancreatic cell directly into research could have important In May 2009, CIRM held a form of autism called Rett’s in the functionality of the showed that adult neural stem inflammatory environment insulin-pumping pancreatic implications for the treat- workshop in which leading syndrome, reprogrammed neuronal circuitry that we cells improved motor function like MS that guide stem cells,” beta cells. Cellular doctors, ment of heart failure. scientists discussed ways in those back to iPS cells, and never had access to before,” in mice with multiple sclerosis. said Lane. “Hopefully, these it turned out, could become “Half of the cells in the which stem cell research could matured those embryonic- said lead author Fred Gage, a MS destroys myelin, the cues can be incorporated into lawyers after all. benefit people with autism. A like cells into neurons. The insulating sheath that covers stem cell–based treatments 2010 brought several key recommendation came unusual neurons that resulted nerves. Intact, myelin allows to enhance their ability to additional cellular career to pass this year when CIRM provided scientists with a first repair injury.” glimpse of what makes an

22 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 23 the origin of diseases. CIRM grantees have taken skin samples from people with genetic forms of autism, premature aging, Parkinson’s disease and schizophrenia, reprogrammed them into iPS cells and matured those into the affected cell type. The resulting cells have provided a first glimpse of what might be happening at the cellular level in those conditions. Take Parkinson’s disease, for example. Work by CIRM grantees at Stanford University and The Parkinson’s Institute news at CIRM has led to neurons in a lab dish that exhibit signs of the unraveling the disease. The cells, matured from iPS cells created from a role of ips cells woman with a genetic form of Parkinson’s disease, produce

Assessing Reprogrammed Cells In the three years since Recent studies have shown that some iPS cells are not as pluripotent as scientists had hoped, and they contain anomalies scientists successfully compared with embryonic stem cells. • A team working at Harvard, which included one CIRM trainee at Stanford, found turned back the clock on number of genes needed has that iPS cells derived from blood and bone favored making their tissue of origin. Researchers linked the inflexibility to human adult skin cells, been whittled down and that differences in the chemical adornments called methylation that decorate the DNA. This methylation affects which genes are CIRM researchers have the efficiency has improved, The team used so-called active and are characteristic of particular cell types. • A second Harvard team confirmed the findings of the first and showed been devising more efficient Making a Better iPS Cell with 2010 bringing significant minicircles of DNA to repro- it could reduce the differences between the iPS cells and embryonic stem cells by culturing the reprogrammed cells for a ways of making these Since 2006, when Shinya advances by CIRM grantees. gram the cells into pluripoten- longer period of time. • Related work led by CIRM grantee Jeanne Loring of The Scripps Research Institute shows that iPS cells reprogrammed cells and Yamanaka of the Gladstone In February, CIRM cy. These minicircles contain have significant genetic differences compared with embryonic stem cells. They found that iPS cells tended to have gene duplications harnessing them to study Institutes and Kyoto University grantees at Stanford University just the four genes needed or deletions that could cause those cells to become cancerous—a concern for those hoping to use the cells therapeutically. disease. As CIRM scientists first reprogrammed mouse discovered a way to transform to transform the cells, along improve techniques for skin back to an embryonic-like fat cells into iPS cells without with a fluorescence gene that creating the flexible cells, state, stem cell scientists have requiring viruses. allows the cells to be tracked. they are also discover- been scurrying to improve on “This technique is not only The minicircles are about half family with heart problems, creation of iPS cells. In that excess protein that is a hall- ing that iPS cells do not the technique in humans. safer, it’s relatively simple,” the size of naturally occurring reprogram the cells and make work, the scientists used tran- mark of the disease and also behave—for better or for The problem was that Michael Longaker, Stan- DNA rings called plasmids that cardiac cells to study in a lab sient RNA in a technique show signs of a form of cellular worse—exactly like their despite the cells’ obvious use- ford University professor of have been used in other iPS dish. Wu, the senior author of that also appears to be stress associated with Parkin- embryonic counterparts. fulness in understanding and surgery, said in a press release. transformations, and unlike in- the study, notes: “This would much more efficient than son’s disease. possibly treating disease, creat- Longaker is a co-author of the tegrating viruses, the minicir- be much easier and less inva- previous techniques. In addition to providing ing them involved permanently study that appeared in Nature cles are lost over time along sive than taking cell samples insights into a disease, these inserting cancer-causing genes. Methods in February, 2010. with the potentially dangerous from a patient’s heart.” Modeling Diseases models can be used for the Plus, techniques to generate reprogramming genes, making Later in the year a team at in a Dish first time to screen for drugs the cells were extremely the cells safer for therapy. Harvard University developed Despite concerns about that halt or reverse disease inefficient. The idea, said Stanford another method for virus-free genetic anomalies in iPS cells, symptoms in human cells. Papers quickly began ap- cardiologist Joseph Wu, is (see sidebar) they are proving pearing demonstrating that the to one day take a fat or skin valuable in understanding biopsy from a member of a

24 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 25 Bridges awards “CIRM’s $24 million Bridges to Stem Cells Program continues to be a great success within our portfolio of programs. It provides broad access to state universities and commu- nity college undergraduates and master’s-level students to receive high level training needed to build a strong foundation for the stem cell biomedical industry. The Bridges to Stem Cell Research Awards Particularly during this time of state funding cuts, the Governing CIRM’s 16 Bridges to Stem Cell Research Awards to un- Board’s commitment to ensure that a diverse array of Californians have dergraduate and masters-level programs train the next generation of stem cell scientists to fill jobs in California’s these opportunities makes me especially proud of my seven years of service.” growing stem cell research sector — filling a void predict- — D a v i d Serrano Sewell, C i r M G o v e r n i n g B o a r d M e mb e r ed by BayBio and the California Public Policy Institute. As the first participants graduate, students are already being hired into technician jobs, and being accepted into medi- cal and graduate schools in large numbers. global partnerships

•Internship Hosts •Bridges Participants

Bridges Programs California Polytechnic State University, San Luis Obispo California State Polytechnic University, Pomona California State University, Channel Islands California State University, Long Beach UK California State University, Sacramento Canada California State University, San Marcos Germany France Humboldt State University Wisconsin New York Spain Pasadena City College Maryland California Japan San Diego State University China

San Francisco State University India San Jose State University California State University, Fullerton California State University, Northridge San Francisco California State University, San Bernardino City College of San Francisco Berkeley City College Educational partners Australia Irvine Valley College Oxnard Community College Moorpark Community College Ventura Community College East Los Angeles College CIRM has formed partnerships with international funding Citrus College Mira Costa College agencies in nine nations and two international states to San Diego Miramar College create collaborations connecting the best scientists from Cal State Los Angeles around the world. To date, 16 California stem cell scien- San Bernardino Valley College Riverside Community College tists have partnered with colleagues in five different coun- Los Angeles Moreno Valley College tries in an effort to develop new disease therapies.

San Diego

26 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 27 s p o t l i g h t o n d i s e as e s At each board meeting, a Spotlight on Disease presentation features patients, clinicians and researchers speaking about the hope of stem cell research. These are their stories...

Videos of these presentations are available on the annual report website: www.cirm.ca.gov/2010AnnualReport Amyotrophic lateral scleroSIS The neighborhood is bad. Some neighbors are downright toxic, and everybody else suffers for it. That’s the situation with the degenerative disease amyotrophic lateral sclerosis, where cells in the neighborhood of motor neurons damage those neurons and cause a slow bodily degeneration. And it’s leading researchers to focus on a community improvement campaign, said Don Cleveland, Ph.D., chair of cellular and molecular medicine at the University of California, San Diego School of Medicine. • The symptoms of ALS appear when motor neurons detach from the muscles they control. Once disconnected, the neurons die and the muscles waste. ALS patients lose the ability to do things for themselves: to walk, to speak and even to swallow. Eventually, the muscles that control breathing fail—the cause of most ALS deaths. What is it like to live Although the roots of ALS are uncertain, three genetic mutations have been linked to with ALS? it. But researchers had to determine just where the mutations did their dirty work. Were mo- Dan Desmond caught himself using tor neurons damaged by their own genes, or was the damage caused by gene expression in a hoe as a crutch as he walked his neighboring cells? 6-acre property east of San Diego. It Using rodents genetically engineered to develop ALS, researchers first shut off the ALS was one of the little hints he ignored gene in the motor neurons, but kept it running everywhere else. As expected, the onset of until the day four years ago when he disease was delayed, Cleveland said. But there was little meaningful improvement. “The couldn’t finish a hike. “My legs just speed by which the disease progresses is unchanged.” weren’t working,” he said. Then they reversed the experiment, keeping the gene going in the motor neurons, but He had amyotrophic lateral sclero- shutting down its operation in its “intimate partner,” the starburst-shaped astrocytes. In this sis, the doctors told him, Lou Gehrig’s case, symptom onset was unchanged, but the disease’s progression slowed dramatically. It disease. He went online to learn more turns out astrocytes with the ALS mutation release a toxin that damages the motor neurons. and spent two hours at the ALS As- “In fact, the animals live more than twice as long,” Cleveland said. The team hopes to sociation office in San Diego. “I did replace mutant-expressing astrocytes with normal ones in ALS patients. not like what I was hearing,” he said. Life Technologies Corp. of Carlsbad, Calif., is growing embryonic stem cells and coax- “I did not like the way things were ing them to become astrocyte precursor cells that will then be injected into the spinal cords going.” But he found a way to cope. of ALS patients. That trial will begin within four years if animal trials succeed. “I still have a great life with my Researchers will inject the cells in either the lumbar or lower spine, where the leg muscles children, grandchildren and friends,” are innervated, or in the cervical spine (the neck), where motor neurons control breathing. the 64-year-old said. But the disease In preliminary animal studies, the astrocytic precursor cells survived and traveled along progresses. He’s in a wheelchair. The the spinal column, becoming astrocytes. Later trials will see if they spruce up the vicinity. muscles in his chest, arms and hands “What we learned is neighborhood really matters,” Cleveland said. are growing weaker. He subscribes to a philosophical attitude. “Everyone has depression at different times, and everybody’s going to die at one time or another. So what we’re talking about, from “What kind here to death, what kind of quality of of quality of life do you want, and what can you life do you do to impact the quality? That’s how I look at life.” want, and He says he knows stem cell re- what can you search underway today is not likely to do to impact help him, “but the research is going the quality? to help thousands of people down the That’s how road, and I think that’s wonderful.” I look at life.” d a n d e s m o n d

31 30 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 huntington’s disease Like emergency responders at an accident scene, mesenchymal stem cells move from brain cell to brain cell, looking for the injured. • Jan Nolta, Ph.D., director of the University of California, Davis Institute for Regenerative Cures, intends to harness the paramedic services of these bone marrow–derived cells and treat Huntington’s disease. “They are very social,” she says of the cells. “They seem to query other cells and ask them if they need anything.” Inserted into the brain, they actually seek out damage. • Some 2,000 people are diagnosed with Huntington’s every year in the United States. Unlike many inherited diseases, which require two copies of a disease- causing gene to wreak havoc, Huntington’s rears its head with a single mutant gene. That What is it like means children of someone with Huntington’s have a 50-50 chance of developing the to live with always-fatal disease. huntington’s disease? The errant Huntington’s gene is a copy machine run amok, repeating the recipe for Sherry lives balanced on the odds the same three nucleic acids 38 times or more. The protein created by this wild repetition, of a coin toss. • Since she was 9, called huntingtin or htt, damages a class of brain cells called medium spiny neurons. when her father was diagnosed with When a medium spiny neuron is healthy, it is shaped something like a spider web, with Huntington’s disease, she’s known axons extending in all directions, controlling movement, cognition and emotion. But under that she has a 50-50 chance of htt’s influence, it pulls in those axons. Cell-to-cell communication stops, and the person receiving the same diagnosis. During develops involuntary dance-like movements. The condition leads to behavior changes; a the next 11 years, as she watched her sweet-tempered person becomes irascible. Cognitive function declines. father fail tragically, his personality To disrupt this destruction, Nolta married the mesenchymal cell’s charitable tendencies changing, his body growing weaker, with an htt-killer. On their own, mesenchymal cells secrete neural growth factors that can she coped by staying busy, swimming restore synaptic connections, though they cannot touch the htt, which continues to plunder. and playing water polo. But animal studies showed that strands of RNA can be tailored to chop the htt RNA, Just knowing she might develop decreasing Huntington’s symptoms and prolonging survival. Nolta’s team of researchers Huntington’s is a burden. So many engineered mesenchymal stem cells to manufacture short interfering RNA, or siRNA. things worry her. “If I trip or fall Videos of mesenchymal cells engineered to make this siRNA show cells pouring the siRNA or mess up at work, I think, ‘Oh, I into any sick cells they encounter. Her team has a patent pending on this technology. might have HD.’ If I’m moody or The first human studies will use the mesenchymal cells without siRNA, to study the something, I wonder, ‘Is this like effect of the neural growth factors that mesenchymal stem cells produce. The next study the first sign?’” will add the siRNA to the mesenchymal cells. That’s one reason the 27-year- “I’m excited we’ve now shown that the technology CIRM funded is working, and that old hasn’t taken the genetic test to mesenchymal stem cells are safe to implant into the brain,” Nolta said. “There are so many learn her status. “If I tested positive, people in the Huntington’s community whom we care about deeply, and we are hoping to I would symptom search even more have a real impact in treating this disease.” than I do now.” Another complication: She doesn’t give her last name because she fears the discrimination that could follow if her risk status were revealed. “I just don’t She worries even more about want to give losing the abilities that matter to up those her. “I love outdoor activities. I love traveling, reading, talking, walking, things I love eating—I’m very good at eating. I just most in life: don’t want to give up those things I my relation- love most in life: my relationships, my ships, my independence.” Still she is optimistic about stem independence.” s h e r ry cell research. “Whenever I’m having a rough day, I think about it. It just gives me hope.”

w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 33 HIV/AIDS Call it molecular jujit- su.The human immunodeficiency virus that causes AIDS is a wily adversary, evolving around opponents enlisted to defeat it. But researchers at City of Hope in Duarte, Calif., led by John Zaia, M.D., intend to employ the strength of the virus against itself, the way jujitsu practitioners leverage an enemy’s force to shape his downfall. • The lynchpin in this strategy is the protein CCR5, which makes a doorway HIV uses to enter an immune cell. Individuals resistant to HIV have a mutation in the CCR5 gene. German researchers “rein- vigorated the field,” Zaia said, with a paper in theNew England Journal of Medicine in 2009 about a stem cell transplant using cells from an HIV-resistant donor. The transplant not only successfully treated the patient’s myeloid leukemia, but cleared his HIV as well. Since the treatment, doctors have What is it like to live been unable to detect any HIV in the patient using even the most sensitive tests. with HIV? Because of the odds against finding a matching donor with the CCR5 mutation for It was perhaps the biggest moment every person with HIV, the paper didn’t show the way to a cure. But it did highlight the of Loring Leeds’ life, but as he lay hope of stem cell transplants. Zaia will use stem cells to create HIV resistance with the waiting for doctors to return his stem help of molecular scissors—an engineered molecule called a zinc-finger nuclease, a cells to his body, Leeds realized it was technology developed by Richmond, Calif., company Sangamo BioSciences Inc. a signature moment for the crowd in Zinc “fingers” are peptides selected to bind to a specific area of DNA. The fingers the room as well. • It was 1998, and grab a targeted sequence and sever it. Normally, the CCR5 protein snakes through the surrounding him were the doctors and cell membrane in a series of hairpin curves. But cut the CCR5 gene, and the protein scientists who had developed a treat- no longer appears on the cell surface; HIV’s entryway disappears like a vanishing door ment for non-Hodgkin lymphoma in in a Harry Potter novel. AIDS patients—something most of To make the door fade forever, the gene must be disabled in a patient’s stem cells, the medical community at the time which will hand the mutation down to future cell generations. Animal studies show that considered pointless and hopeless. only a fraction of the stem cells need the CCR5 mutation to create disease resistance. But Leeds’ stem cell treatment was Whereas other genetic engineering approaches must alter great numbers of cells to cre- even more dramatic, because some of ate lasting change, and must keep those new cells running for a lifetime, the jujitsu his cells were genetically modified to nature of the zinc-finger approach means the zinc fingers must operate only briefly, express an enzyme researchers hoped mutating only a small percentage of all the stem cells. would short-circuit AIDS. Animal studies show HIV’s killing efficiency becomes its undoing, jujitsu style. The “There was this deafening silence, disease attacks the unmutated cells. The survivors all carry the mutation, and the virus and I realized that moment was the has no one to plunder. Viral levels fall. culmination of their life’s work,” Zaia says the first patients to try mutated cell transplants will be those with AIDS Leeds said. Today, Leeds, an artist, lymphoma who need a complete stem cell transplant to combat that cancer. is cancer free, and though the AIDS “There is a need for improved treatment of HIV/AIDS,” Zaia says. “The zinc-finger enzyme treatment did not work, his technology offers real promise.” HIV is undetectable. The treatment he received was a precursor to the “I truly believe HIV work now being carried out by our best hope two CIRM disease teams. for better “These people are the most dedicated, the most compassionate, treatment, the most passionate people I’ve and ultimately ever met,” Leeds said. “They a cure, will are visionaries. They are the best come from humanity has to offer. I truly believe our best hope for better treatment, the hands and and ultimately a cure, will come from hearts and the hands and hearts and minds of minds of these these astonishing people.” astonishing people.” loring leeds

34 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 Epidermolysis bullosa An infant’s skin peels off in sheets, revealing angry red flesh below. In the disease called dystrophic epidermolysis bullosa, there is something wrong with the collagen tethers that an- chor the top layer of skin to the dermis beneath. The skin sloughs off or blisters at the slightest insult—the rub of a shirt collar, the touch of a hand, the movement of the eye during dreams. Even birth. • The skin’s impermanence results from a misstep in a gene that forms the collagen tethers. • EB comes in a less severe dominant form or a more devastating recessive form. Four to eight babies in the United States are born each year with this latter form. Forty percent will die before age 35, said Alfred Lane, M.D., chair of dermatology and What is it like to live pediatrics at the Stanford University School of Medicine. But even the 24 to 28 children with EB? born annually with the dominant form of EB suffer from fragile skin, painful wounds, Chuck and Christine Anderson frequent blisters and scarring. • A team of Stanford University researchers hopes to grow were butterfly children.• Born with new, genetically corrected skin for these children. Skin that stays where it belongs. an inherited condition that made Key to the strategy are induced pluripotent stem cells, grown-up cells that are their skin as fragile as a butterfly convinced to return to their embryonic youth. Cells of the embryo may mature into wing, Chuck died at 27 of skin any cell type; that is, they’re pluripotent. With induced pluripotency, investigators will cancer. His sister, Christine, died take a patient’s fully differentiated skin cells and coax them back to pluripotence, says of heart failure at 14. • “These chil- Marius Wernig, M.D., an assistant professor at the Institute for Stem Cell Biology and dren taught me an incredible Regenerative Medicine at Stanford. lesson in resilience, determination While the cells are in their pluripotent state, researchers will repair the gene using and good cheer,” says their mother, homologous recombination. The correction takes advantage of DNA’s willingness to Lynn Anderson. She is the president swap genetic material with complementary—that is, homologous—DNA strands. The and founder of the Epidermolysis complementary strands introduced to the pluripotent cells will carry a correction for Bullosa Research Foundation. the error that causes EB. Although as few as 1 percent of the cells may adopt the correc- They were born with the recessive tion, that’s enough. Cells identified with properly correct genomes will be grown into form of dystrophic epidermolysis skin cells for transplant to patients. bullosa. “The glue that holds the “If you look at this entire project, every step is, in principle, established. In prin- skin together is missing,” Anderson ciple we know how we can do it,” Wernig said. “The challenge is to pull all the pieces explains. “The skin tears or blisters at together in a way that works reliably.” the slightest provocation.” Things as simple as putting on a shoe can cause chronic wounds. “Stiff pants make blisters. Pull on the arm, and the skin comes off,” she says. “Imagine not being able to swal- “These children low because you have scarring in taught me your esophagus. You have difficulty an incredible eating because you have sores in your mouth,” she says. The disease brings lesson in chronic anemia, malnutrition and resilience, growth retardation because most determination nutrition goes toward skin repair. and good When Chuck Anderson was 27, he weighed 59 pounds. cheer.” ly n n a n d e r s o n Anderson says she has great hopes for EB research. She is grateful for the researchers “who have helped my children’s suffering come to something good, who have helped me believe that EB is not forever.”

w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 37 “Within two months I went from using a walker, to a cane, to walking on my own.” Theresa Blanda

stroke Stem cells at first seemed ideal replacement parts, living Legos for stroke-damaged brains. But when Gary Steinberg, director of neurosurgery at Stanford University’s School of Medicine, put human stem cells into the brains of rats with induced stroke, he saw the cells didn’t just turn into new neurons to swap for the damaged ones. While about half of the cells became functioning neurons, the benefits went beyond their contribution. The stem cells seemed to respond to a suite of signals the damaged brain sent in its attempt to quell the stroke-triggered chaos. The result: reduced inflammation, increased blood supply, new growth on existing neurons and new neuronal connections. In addition, rats treated with stem cells recovered function in limbs af- fected by stroke. • Normally, the brain’s stroke distress calls rarely summon sufficient re- What is it like to live pair. Fifteen percent of people with ischemic stroke – that is, stroke caused by blockage with stroke? in an artery – die from it, and stroke caused by a burst blood vessel kills half its victims. If K. Michael Cooper ever thought Among the survivors of both kinds of stroke, damage can be devastating. A third can no about giving up after his stroke longer care for themselves, and three-quarters lose the ability to complete some tasks of Thanksgiving morning 2003, his wife, daily living. • Steinberg hopes that cells derived from embryonic stem cells, with their Annemieke Wiegman, wouldn’t ability to travel directly to damaged areas in the brain, could bring dramatic change. let him. • He was 56 years old when Stem cells implanted in rodents with stroke worked to repair damaged areas, summoned the sudden loss of circulation in his there, apparently, by signaling chemicals called chemokines. Further research showed brain changed the Redwood City that the stem cells emit a signaling protein called vascular endothelial growth factor. man’s life. He couldn’t speak. When Steinberg blocked VEGF using the cancer drug Avastin, many of the stem cell’s He couldn’t swallow. He couldn’t positive effects disappeared. move his right side. But almost Stem cells act as an efficient delivery device for VEGF and other growth factors, from the start, Annemieke treated Steinberg said, integrating into the environment, responding to nearby signals, and re- her husband like a man with a leasing the growth factor only where and when needed. very important deadline. Although his goal is to begin a phase 1 stroke trial with human embryonic stem “She kept telling me, I only had cells by 2014, his group recently opened enrollment in a Phase 1 trial sponsored by the six months to get better,” he said. Mountain View company, SanBio, using bone-marrow derived stem cells. In this safety While other patients were wheeled to study, surgeons will implant cells in patients whose stroke occurred six months to a year lunch, Annemieke insisted Cooper earlier. In a previous small trial using these cells, there were no adverse effects, and some use a walker. While other families participants saw improvements in movement, memory and spatial processing. helped loved ones eat, “My wife let me “I believe that stem cells transplantation for stroke holds great promise,” Steinberg struggle and make a mess.” Annemieke said. “Over the next probably two decades we will see remarkable advances.” launched a rehabilitation program, lifting her husband’s unresponsive arm and leg 12 times every day. “She did not give up on me, and I did not want to give up, “he said. “There are Released from rehab on so many Christmas Eve, Cooper continues things to work on his recovery, especially his speech, still peppered with small doctors can hesitations and stutters. do with stem While Cooper believes in working cells that on recovery, he relishes the promise will really of stem cells. “There are so many things help. doctors can do with stem cells that will Oh yes, really help,” he said. “Oh yes, I’m I’m very hopeful.” very hopeful.” K. Michael Cooper

38 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2009annualreport Drug Based on Stem Cell Studies Brings Health Three years ago Theresa Blanda was too sick to work. Her blood disease forced her to use a walker to move around. A bone marrow transplant was her only hope for a cure. Bone marrow transplants are risky and expensive—the proce- Studying the earliest dure costs roughly $250,000. stages of embryo Today, she’s back at work. development has helped Blanda participated in a trial for a improve the success rate of in vitro drug initially discovered through fertilization. Events work by CIRM grantee Catriona in the first few days of Jamieson at the University of development might also underlie California, San Diego. The drug, common diseases. co-developed by the San Diego- based company TargeGen, Inc, treated her pre-leukemic disease and took her off the bone marrow transplant list.

Spotlight on the human embryo and human embryonic stem cell research “I can’t believe the progress we’ve made in the past years with human embryonic stem cells and embryology. We have unprecedented tools to understand human development and we can begin to understand basic questions like where does sporadic disease come from in the population.” Renee Reijo Pera Director, Stanford Center for Human Embryonic Stem Cell Research and Education

w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 41 o u t r e a c h

bridging the divide

Outreach within the stem cell community keeps those scientists connected and the research pushing forward. • Our CIRM Bridges trainees, who are undergraduate Inside California and abroad, and master’s students doing work in California stem cell labs, rubbed elbows at a CIRM has worked to meeting in the summer. Students from around the state presented their internship projects and discussed their plans for the future. • The students, many of whom are broaden understanding of from lower economic level homes, have plans for graduate school, medical school, stem cell research—the science and or careers in California’s flourishing stem cell industry. “I love it and I think that I’ll never turn my back on biology now,” said Nicole the hope—and to strengthen communities Haste, a Bridges student at San Francisco State University. A Day of researchers themselves. Even established stem cell scientists benefit from a bit of face time. The CIRM to Remember grantee meeting in spring 2010 brought together grantees and their lab members to The third annual Stem Cell present results, talk about obstacles and form collaborations. Awareness Day expanded In June, 2010, many of these same scientists met some 4,000 of their interna- CIRM’s stem cell outreach to 20 tional colleagues at the yearly meeting of the International Society for Stem Cell schools within California, eight california and beyond Research, co-sponsored by CIRM and held in San Francisco. educational events in the state, Within California, people had three opportunities this year to learn more about work funded Events like these bring scientists together to overcome barriers in translating six events in other U.S. states, by CIRM in their neighborhoods. Town Hall Forums in San Diego, Los Angeles and San stem cell science into cures. and activities in four countries. Francisco brought CIRM scientists together with community members to discuss ongoing sci- The day, held October 6, was ence and the progress toward cures. • The San Francisco Town Hall Forum, co-sponsored by proclaimed state-wide by the the International Society for Stem Cell Research, which was holding its annual meeting in the reachng across governor of California. Scien- city, focused on the growing trend of stem cell tourism. • Unregulated clinics throughout the borders tists within California visited world have been offering unproven therapies at great cost to desperate patients. Not only might CIRM only funds research Science Category 20 schools with lectures and those treatments not help, Jeanne Loring, Ph.D., a CIRM grantee at Scripps Resarch Institute carried out in California. By award number school-wide assemblies about However, excellent stem Awarded grants stem cell science. In addition, who spoke at the forum, warned that they could be dangerous. •Basic research 7.5% 4% “Stem cell tourism is an exploitation of the promise of stem cells,” she said. The forum was cell science is taking place 7% •Translational research 20 events world wide included recorded and is available on the CIRM web page. worldwide. In order to connect •Pre-clinical research 55.1% tours or public lectures to 8% The ISSCR has offered to investigate clinics at no cost through its new web page: the leading minds in stem cell •Facilities educate their local community •Training A Closer Look at Stem Cell Treatments, www.closerlookatstemcells.org. science, CIRM has formed about this important field

CIRM’s educational mission expands beyond once-per-year forums. A new education partnerships with 11 interna- 50% of research and the work portal on the website now provides a series of five modular curricula available to high school tional funding agencies and Applications that’s going on at institutions 7% teachers. Each can fit within existing California teaching requirements, and provides lesson one U.S. state, and one state- 31% near them. 9% plans and hands-on activities. based foundation. Internationally, Monash The extensive set of course materials and activity resources will help high school and other These partnerships connect University in Victoria, Australia educators prepare the youth of California to join the fast-growing biotech economy and help outstanding scientists without 12% held a day-long event that sector find the workers its leaders say are already in short supply. regard to geographic location. 47% with talks and activities, and When an award that includes events in Ireland, England, an international collaborator Australia and Canada educated is approved for funding, CIRM 25% people about stem cell science funds the scientists in Califor- in those countries nia and the funding partner is responsible for the international “Collaborations between our Canadian scientists and California- portion of the research. Disease Category Human Cell Type Usage based scientists and institutions have been among the most re- This past year the CIRM 200 2% 2% By award number Governing Board approved four 3% By award number markable international endeavors in science that I have witnessed. 4% (some awards Early Translational Awards 4% •Neurological disorders % Although no money from CIRM was invested in Canada, intellectual 32% use multiple cell types) Cancer % and one Basic Biology III Award 5% • capital was, and in a two-way fashion the whole greatly exceeded •Heart disease •Embryonic the sum of the parts. The pace of development in the cancer stem that include German collabora- 6% •Blood/immune disorders •iPS cell cell area, for example, has been nothing short of outstanding and our tors, one Basic Biology II award •Sensory organs •Adult 6% understanding of that disease process has been turned on its head that includes a Japanese •Multiple disorders •Cancer 10 66 SCNT 46 all because CIRM, and its Chair Robert Klein, saw the multiplier collaborator, and two Stem Cell •Diabetes • 9% •Other Transplantation Awards with 15% •Bone/cartilage disorders effect that could be had through global collaboration.” 10 12% •Muscular disorders 3 4 Australian collaborators, Cal Stiller, Former Chair, Genome Canada; •GI/liver disease Chair, Ontariåo Institute for Cancer Research; 2010 Canada bringing the total to 16 interna- •Reproductive disorders Gairdner Award recipienT tional teams. •Other disorders For a full report on the CIRM finances see the annual report online at www.cirm.ca.gov/2010AnnualReport

42 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 43 Board and working group mem b e r s h i p

Governing Board Legislative Scientists Amelia Bartholomew, Jay Edelberg, M.D., PH.D. Brian Harfe, PH.D. Olle Lindvall, M.D., Subcommittee Subcommittee Susan Bonner-Weir, M.D. Bristol-Myers Squibb University of Florida PH.D. Members Susan Bryant PH.D. University of Illinois, Lund University Total grants approved for funding Through April 2011 Michael Goldberg Joslin Diabetes Center Chicago Kevin Eggan, PH.D. Richard Harvey, PH.D., Biotech Loan Robert Klein Harvard University FAA Christian Lorson, PH.D. Institution Total Grants total Funds Task Force Claire Pomeroy Ali Brivanlou, PH.D. Sangeeta Bhatia, M.D., Victor Chang Cardiac University of Missouri Stanford University 56 $186,489,478 Floyd Bloom Francisco Prieto (Vice The Rockefeller University PH.D. Wafik El-Deiry, M.D., Research Institute University of California, Los Angeles 43 $140,596,577 Marcy Feit Chair) Massachusetts Institute of PH.D. Hai-Quan Mao, PH.D. University of California, San Francisco 36 $112,364,241 Michael Goldberg John Reed Jeff Bulte, PH.D. Technology University of Pennsylvania John Hassell, PH.D. Johns Hopkins University University of California, San Diego 35 $82,819,851 Robert Klein Joan Samuelson Johns Hopkins McMaster University University of Southern California 19 $71,933,514 Ted Love Jeff Sheehy Lauren Black, PH.D. James Ellis, PH.D. William Matsui, M.D. University of California, Irvine 27 $71,878,458 Ed Penhoet Art Torres (Chair) Patricia Donahoe, M.D. Navigator Services Hospital for Sick Children Franz Hefti, PH.D. Johns Hopkins University University of California, Davis 19 $61,187,635 Duane Roth (Chair) Harvard Medical School Avid Radiopharmaceuticals Sanford Consortium for Regenerative Medicine 1 $43,000,000 Jeff Sheehy Science Bruce Blazar, M.D. Stephen Emerson, M.D., Todd C. McDevitt, PH.D. City of Hope National Medical Center 9 $41,586,199 Oswald Steward Subcommittee Ian D. Duncan, PH.D. University of Minnesota PH.D. Shelly Heimfeld, PH.D. Georgia Institute of The Scripps Research Institute 14 $37,377,357 Susan Bryant University of Wisconsin Haverford College Fred Hutchinson Cancer Technology University of California, Berkeley 14 $39,692,934 Finance Marcy Feit Paula M. Bokesch, M.D. Research Center The Salk Institute for Biological Studies 15 $39,154,585 Subcommittee Michael Friedman Alexandra Joyner, PH.D. Cubist Pharmaceuticals Todd Evans, PH.D. David McKenna, Jr., M.D. Buck Institute for Age Research 6 $33,017,217 Ricardo Azziz Robert Klein Memorial Sloane Kettering Albert Einstein College of Anthony Hollander, PH.D. University of Minnesota Burnham Institute for Medical Research 17 $30,982,832 Robert Birgeneau Francisco Prieto Cancer Center Michael Boulton, PH.D. Medicine University of Bristol Medical School ViaCyte, Inc. 4 $26,281,356 Floyd Bloom Ed Penhoet (Vice Chair) University of Florida The J. David Gladstone Institutes 13 $22,633,004 Marcy Feit (Vice Chair) Philip Pizzo Judith Kimble, PH.D. Charles ffrench-Con- Marc Jenkins, PH.D. Ivar M. Mendez, M.D., University of California, Santa Cruz 9 $19,468,564 Michael Goldberg (Chair) John Reed University of Wisconsin Barbara Boyan, PH.D. stant, PH.D., FRCP University of Minnesota PH.D., FRCS Children’s Hospital of Los Angeles 8 $18,040,423 Robert Klein Duane Roth Georgia Institute of University of Cambridge Dalhousie University University of California, Santa Barbara 6 $13,496,575 Ted Love Joan Samuelson Stuart Orkin, M.D. Technology Henry Kaplan, M.D., Cedars-Sinai Medical Center 5 $10,940,472 Ed Penhoet Jeff Sheehy (Chair) Dana Farber Cancer Richard Finkel, M.D. F.A.C.S. Freda Diane Miller, University of California, Merced 5 $8,494,301 Philip Pizzo Oswald Steward Institute Patrik Brundin, M.D., The Children’s Hospital of University of Louisville PH.D. iPierian, Inc. 2 $7,123,887 Duane Roth Art Torres PH.D. Philadelphia School of Medicine Hospital for Sick Children University of California, Riverside 4 $6,055,762 David Serrano Sewell Jeffrey Rothstein, M.D., Lund University The Parkinson’s Institute 2 $5,029,749 Jeff Sheehy PH.D. Gordon Fishell, PH.D. Douglas Kerr, M.D., PH.D. C. Randall Mills, PH.D. BioTime, Inc. 1 $4,721,706 Oswald Steward Johns Hopkins University Scott Burger, M.D. New York University School Biogen Idec Osiris, Inc. The Jackson Laboratory West 1 $3,841,240 Art Torres Scientific and School of Medicine Advanced Cell and Gene of Medicine San Diego State University 2 $3,464,360 Medical Research Therapy Ann Kiessling, PH.D. Stephen Minger, PH.D. Scripps Health 1 $3,118,431 Governance Funding Working Pablo Rubinstein, M.D. Alan Flake, M.D. Harvard Medical School GE Healthcare Fluidigm Corporation 2 $2,693,424 Subcommittee Group New York Blood Center Jose Cibelli, PH.D., D.V.M. University of Pennsylvania Gamma Medica-Ideas, Inc. 2 $2,478,347 Robert Klein Michigan State University Olle Korsgren, M.D., Sean Morrison, PH.D. Ludwig Institute for Cancer Research 3 $2,473,053 Sherry Lansing (Chair) Patient Advocates of John Sladek, PH.D. Joyce Frey-Vasconcells, PH.D. University of Michigan Palo Alto Institute for Research and Education, Inc. 2 $2,408,275 Ted Love the Governing Board (Administrative chair) Hans Clevers, M.D., PH.D. PH.D. Uppsala University Medical School California Institute of Technology 1 $2,318,580 Philip Pizzo Robert Klein, J.D. University of Colorado Hubrecht Institute PharmaNet San Jose State University 1 $1,756,260 Claire Pomeroy (Vice Chair) (ex-officio) Diane Krause, M.D., PH.D. Christine Mummery, PH.D. California State University, Channel Islands 1 $1,755,906 John Reed Governing Board Chairman Dennis Steindler, PH.D. Anne Cooke, PH.D. Mark Furth, PH.D. Yale University School Leiden University Medical California State University, San Marcos 1 $1,754,664 Duane Roth University of Florida University of Cambridge Wake Forest University of Medicine Center Pasadena City College 1 $1,750,491 David Serrano Sewell Marci Feit, R.N., M.S.N. McKnight Brain Institute Baptist Medical Center San Francisco State University 1 $1,736,058 Jeff Sheehy Type II Diabetes Chad Cowan, PH.D. Paul Kulesa, PH.D. Stephen Navran, PH.D. Humboldt State University 1 $1,638,863 Oswald Steward Rainer Storb, M.D. Harvard University John Gearhart, PH.D. Stowers Institute for Medical Synthecon, Inc. California State University, Northridge 1 $1,627,220 Art Torres Sherry Lansing Fred Hutchinson Cancer University of Pennsylvania Research La Jolla Institute for Allergy and Immunology 1 $1,503,998 Cancer Research Center Charles Cox, Jr., M.D. Laura Niklason, M.D., California State Polytechnic University, Pomona 1 $1,459,297 IP Task Force University of Texas Medical Gary Gibbons, M.D. Andrew Kung, M.D., PH.D. PH.D. Escape Therapeutics, Inc 1 $1,453,040 Subcommittee Francisco Prieto, M.D. Wise Young, M.D., PH.D. School at Houston Morehouse School of Dana Farber Cancer Yale University GMR Epigenetics 1 $1,452,693 Susan Bryant Type 1 Diabetes Rutgers University Medicine Institute California Polytechnic State University, San Luis Obispo 1 $1,419,009 Michael Goldberg Marc Diamond, M.D. John Nilson, PH.D. California State University, Long Beach 1 $1,355,700 Ted Love Joan Samuelson, J.D. Alternate Washington University Jonathan D. Glass, M.D. Joanne Kurtzberg, M.D. Washington State University California State University, Sacramento 1 $1,343,940 Ed Penhoet (Chair) (Vice chair) Scientists School of Medicine Emory University Duke University Children’s California State University, Fullerton 1 $1,281,180 Philip Pizzo Parkinson’s Disease Gyula Acsadi, M.D., PH.D. Hospital Jon Odorico, M.D. California State University, San Bernardino 1 $1,161,017 Francisco Prieto Connecticut Children’s John DiPersio, M.D., PH.D. Marcie Glicksman, PH.D. University of Wisconsin City College Of San Francisco 1 $1,110,608 John Reed David Serrano Medical Center Washington University Brigham and Women’s Brian Kwon, M.D. Berkeley City College 1 $1,086,819 Duane Roth Sewell, J.D. School of Medicine Hospital University of British Sean Palecek, PH.D. VistaGen Therapeutics, Inc. 1 $971,558 Jeff Sheehy MS/ALS Judy Anderson, PH.D. Columbia University of Wisconsin Vala Sciences, Inc. 1 $906,629 Oswald Steward University of Manitoba Gary du Moulin, M.P.H., Margaret Goodell, PH.D. Human BioMolecular Research Institute 1 $714,654 Jeff Sheehy PH.D. Baylor College of Medicine John Lake, M.D. Grace Pavlath, PH.D. Childrens Hospital Oakland Research Institute 1 $55,000 (deputy Vice chair) Jonathan Auerbach, Genzyme University of Minnesota Emory University Grand Total 406 $1,186.456,991 HIV/AIDS PH.D. Kevin Gregory-Evans M.D., GlobalStem, Inc. Douglas C. Eaton, PH.D. Ph.D. FRCS, FRCOphth Ihor Lemischka, PH.D. John Rasko, PH.D., FRCPA, Jonathan Shestack Emory University School of University of British Mount Sinai School of FRACP Mental Health Andrew Balber, PH.D. Medicine Columbia Medicine University of Sydney Aldagen Kurt Gunter, M.D. Theodore Rasmussen, Margaret Baron, M.D., Hospira PH.D. PH.D. University of Connecticut Mount Sinai School of Medicine

44 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 45 Board and working group membe r s h i p c o n t i n u e d

Frank Rauscher, PH.D. James Schwob, M.D., Amy Wagers, PH.D. Scientific and Ethicists Robert Taylor, Ed Chow, M.D. CIRM Employees Don Gibbons Zachary Scheiner, ph.d. The Wistar Institute Cancer PH.D. Harvard University Medical Research Bernard Lo, m.d. M.D., PH.D. Physican; Executive Direc- Chief Communications Science Associate Center Tufts University Facilities Working (Co-Chair) Emory University School tor, Chinese Community Arie Abo, Ph.D. Officer John Wagner, M.D. Group Members University of California, of Medicine Health Care Association; Science Officer Kelly Shepard, ph.d. Pamela Raymond, PH.D. Norman Sharpless, M.D. University of Minnesota San Francisco Reproductive biology; IVF and Network of Ethnic Physi- Uta Grieshammer, ph.d. Science Officer University of Michigan University of North Carolina Patient Advocates of the Biomedical ethics related egg donation cians Organization, San Amy Adams Science Officer Herman Waldmann, FRS, Governing Board to oocyte, embryo and stem Francisco Communications Manager Chila Silva-Martin Yair Reisner, PH.D. Steven Sheridan, PH.D. PH.D., M.B. BChir. Marcy Feit, R.N., M.S.N. cell research John Wagner, m.d. Douglas Guillen Financial Services Officer Weizmann Institute of Millipore, Corp. University of Oxford Type II Diabetes University of Minnesota Arthur Flemming, M.D. Elona Baum, j.d. Office Manager Science Ted Peters, ph.d. Stem cell transplant biology, (Chair) General Counsel Bettina Steffen, m.d. Paul J. Simmons, PH.D. Samuel Weiss, PH.D. Joan Samuelson, J.D. Pacific Lutheran Theologi- clinical trials Network of Ethnic Physi- Lynn Harwell, m.b.a., j.d. Associate Director Camillo Ricordi, M.D. The University of Texas University of Calgary Parkinson’s Disease cal Seminary, Graduate cians Organization; Chair, Pat Beaupre Becker Deputy to the Chair, Fi- of Scientific University of Miami Health Science Center at Theological Union James Willerson, m.d. Region VI, National Medi- Senior Executive Assistant to nance, Policy & Outreach Activities – Development Houston Hartmut Wekerle, M.D. David Serrano Sewell, Biomedical ethics of stem cell University of Texas cal Association, Los Angeles the President Gail Robertson, PH.D. Max-Planck Institute of J.D. (Vice Chair) research; genetics Health Sciences Center Rebecca Jorgenson, Ian Sweedler, j.d. University of Wisconsin, Harinder Singh, PH.D. Neurobiology MS/ALS Texas Heart Institute Pamela Freeman Fobbs, Karen Berry, d.v.m., ph.d. ph.d. Deputy Legal Counsel Madison University of Chicago Dorothy Roberts, j.d. Stem cell biology & cardiac J.D. (chair) Science Officer Science Officer Margaret Werner-Wash- Jeff Sheehy Northwestern University tissue (applications to treat Past President, Auxiliary to Sohel Talib, ph.d. Mauricio Rojas, M.D. G. Sitta Sittampalam, burne, PH.D. HIV/AIDS School of Law damaged heart tissue); the National Medical As- Odell Berry Rick Keller Science Officer University of Pittsburgh PH.D. University of New Mexico in Bioethics and the interplay clinical trials sociation, Fresno Senior Administrative Facilities Analyst Kansas University Albuquerque of gender, race, and class in Coordinator Rahul Thakar, ph.d. Raymond Roos, M.D. Real-Estate legal issues concerning Diane Harris-Wilson, Doug Kearney Science Associate University of Chicago Igor Slukvin, M.D., PH.D. Theresa Whiteside, PH.D. Specialist reproduction and bioethics Ph.D. Rosa Canet-Aviles, ph.d. Grants Management University of Wisconsin, University of Pittsburgh Members Citizens’ Financial Professor of Psychology, Science Officer Specialist Gabriel Thompson Michael R. Rosen, M.D. Madison Deborah Hysen Patrick Taylor, J.D. Accountability San Francisco State Deputy Grants Columbia University David Williams, M.D. Facility Planning, Construc- Children’s Hospital Boston, Oversight University; Fellow, Center Ingrid Caras, ph.d. Melissa King Management Officer Glyn Stacey, PH.D. Children’s Hospital Boston tion and Management for Legal, ethical, compliance and Committee (CFAOC) for Health Disparities Science Officer Executive Director, ICOC Alan Rosmarin, M.D. National Institute for the California Department policy issues Research and Training, Scott Tocher, j.d. University of Massachusetts Biological Standards and Barbara Wirostko, M.D. of Corrections John Chiang (Chair) San Francisco Tricia Chavira Robert Klein, j.d. Legal Counsel to the Control University of Utah California State Controller Grants Review Specialist Chairman of the Board Chairperson Theodora Ross, M.D., Edward Kashian Scientists/ Keith Norris, M.D. PH.D. Clifford Steer, M.D. Scoot Wittemore, Ph.D. Lance-Kashian & Company Clinicians Daniel Brunner President, Charles Drew Amy Cheung Jenny Lam, M.P.A. Art Torres, J.D. University of Michigan University of Minnesota University of Louisville Kevin Eggan, PH.D. Executive Vice President University of Medicine and Administrative Assistant to Grants Management Vice Chair of the Board School of Medicine Stuart Laff Harvard University (retired), FirstHealth Science (Los Angeles) the Executive Director of Specialist Janet Rossant, PH.D. Gustav Steinhoff, M.D. Formerly DMJM Epigenetics, SCNT the ICOC Alan Trounson, ph.d. University of Toronto University of Rostrock Robin Wright, PH.D. Consulting/AECOM Loren G. Lipson, m.d. Keda Obledo Amy Lewis, m.b.a. President University of Minnesota, Timothy Kamp, M.D., Ph.D. Professor Emeritus of Co-Founder, Mexican Lila Collins, ph.d. Grants Management Officer Anne Rosser, M.D., PH.D. Charles D. Stiles, PH.D. St. Paul David Lichtenger (Chair) University of Wisconsin Medicine, Keck School of American Legal Defense Science Officer Mani Vessal, Ph.D. Cardiff Brain Repair Group Dana Farber Cancer Integrated Facility Solutions Cardiac stem cell therapy Medicine, University of and Education Fund, Geoff Lomax, Dr.PH. Science Officer Institute Michael B. Yaffe, M.D., (IFS) and Intrepid Capital Southern California Sacramento Meybel Cortez Senior Officer for Medical Josh Rubin, M.D., PH.D. PH.D. Ann Kiessling, PH.D. Grants Technical Assistant & Ethical Standards Nick Warshaw Washington University Stephen Strom, PH.D. Massachusetts Institute Harvard University School Jim Lott, m.b.a. Mario Obledo, j.d. & Compliance Officer Senior Administrative University of Pittsburgh of Technology of Medicine Executive Vice President, Co-Founder, Mexican Alexandra Campe Degg Coordinator Michael Rudnicki, PH.D. Scientific and SCNT & oocyte derivation, Policy Development and American Legal Defense Chief Human Resources Susan Marton Ottawa Health Research Lorenz Studer, M.D., Peter Zandstra, PH.D. Medical IVF and egg donation Communications, Hospital and Education Fund, Officer Grants Technical Assistant Kevin Whittlesey, Ph.D. Institute PH.D. University of Toronto Accountability Association of Southern Sacramento Science Officer Memorial Sloan-Kettering Standards Working Jeffrey Kordower, PH.D. California Todd Dubnicoff, ph.d. Patricia Olson, ph.d. Alan Russell, PH.D. Cancer Center Thomas Zwaka, M.D., Group Members Rush Presbyterian-St. Luke’s Randal Pham, M.D. Multimedia Editor/Science Executive Director of Michael Yaffe, ph.d. University of Pittsburgh PH.D. Medical Center Gurbinder Sadana, M.D. Chair, Ethnic Medical Writer Scientific Activities Associate Director of Scien- Megan Sykes, M.D. Baylor College of Medicine Patient Advocates of the Neurodegenerative diseases Physician, Medical Director Organization Section, tific Activities – Research David Sachs, M.D. Harvard Medical School Governing Board of Critical Care Services at California Medical Margaret Ferguson Jennifer Pryne Massachusetts General Marcy Feit, r.n., m.s.n. Kenneth Olden, PH.D. the Pomona Valley Hospital Association, San Jose Finance Officer Assistant Secretary to the Hospital Viviane Tabar, M.D. Ad Hoc Scientists Type II Diabetes Schools of Health Profes- Medical Center Board Memorial Sloane Kettering George Daley, M.D., PH.D. sions, City University of Barbara Young, Ph.D. Ellen Feigal, M.D. David Scadden, M.D. Cancer Center Harvard University Robert Klein, j.d. New York, Hunter College Consultant, California State VP Research and John Robson, Ph.D. Harvard Medical School Governing Board Cellular biology/biochemistry, University Office of the Development Vice President of Operations Shuichi Takayama, PH.D. John Trojanowski, Chairman hematopoietic stem cells Diversity Advisory President, Los Angeles Michael Schneider, M.D. University of Michigan, M.D., PH.D. Committee Nini Gabra Gil Sambrano, PH.D. Imperial College London Ann Arbor University of Pennsylvania Sherry Lansing Janet Rowley, m.d. Administrative Assistant Senior Officer for Grants Cancer University of Chicago Malik Baz, M.D. to the VP of Operations and Working Group Hans Scholer, PH.D. Catherine Verfaillie, Josh Sanes, PH.D. School of Medicine Board of Directors, General Council Max Planck Institute for M.D. Harvard University Francisco Prieto, m.d. Oncology, molecular American Lung Association Cynthia Schaffer, j.d. Molecular Biomedicine K.U. Leuven Type I Diabetes genetics, and cell biology, of Central California; Presi- Contract Administrator and Allan Spradling, PH.D. hematopoietic stem cells dent, Baz Allergy, Asthma Compliance Officer Joel Voldman, PH.D. Johns Hopkins University Jeff Sheehy and Sinus Center, Fresno Massachusetts Institute of HIV/AIDS Technology Jonathan Shestack Mental Health

46 California I nstitute for R egenerative Medi c i n e A n n u a l R e p o r t 2 0 1 0 w w w . c i r m . c a.gov/2010annualreport California I nstitute for R egenerative Medi c i n e 47 PaTienT advoCaTe retinal pigment epithelium PhoTograPhy derived from human Pages 31-37 Jamie Kripke embryonic stem cells San Francisco, CA (D Av iD BUCHHol Z at the University www.jamiekripke.com of California, Santa Barbara)

Page 39 Colin Clark Neurons derived from “The Institute’s Berkeley, CA human embryonic stem cells www.colinclarkphoto.com (X i ANMiN ZENg at the Buck institute for Age research) innovations and investments Page 40 Ethan Hill New York, NY Page 28 Human embryos www.ethanhill.com (S USAN F i SHEr at the University of continue to make it a California, San Francisco)

STem Cell PhoTograPhy Page 30 Smooth muscle cells Cover, from upper left: derived from mouse world leader in stem cell Motor neuron progenitors neural crest stem cells derived from human (DEEpAK Sr i vAS tAvA at the embryonic stem cells gladstone institutes) research. The new (SHA r YN r o SSi at the University of California, irvine) Page 33 Adult neural stem cells (D Av iD S CHAFFEr at the University of Bridges Program builds on Neural precursors California, Berkeley) generated from human embryonic stem cells Page 34 retinal pigment epithelium the Institute’s past successes by (X i ANMiN ZENg at the Buck precursor cells institute for Age research) (D Av iD BUCHHol Z at the University of California, Santa Barbara) providing a boost Smooth muscle cells derived from mouse neural Page 37 Adult neural stem cells crest stem cells (D Av iD S CHAFFEr at the University of (DEEpAK Sr i vAS tAvA at the California, Berkeley) to California’s economy gladstone institutes) t u r n i n g s t e m c e l l s into cures Page 38 Neurons derived from human Adult neural stem cells embryonic stem cells and developing the (D Av iD S CHAFFEr at the University (X i ANMiN ZENg at the Buck institute of California, Berkeley) for Age research)

next generation of scientists Smooth muscles cells Page 41 time lapse image of a derived from human developing human embryo “During this time of uncertainty at the federal level, with a continuing embryonic stem cells (S USAN F i SHEr at the University of (A l EXEY t Er SK iKH at the California, San Francisco) andpotential resear for NIH shutdownc byhers lawsuit, California who carries on willas a leader in funding Sanford-Burnham Medical research institute) stem cell research, as approved by California voters. To date, over $1 billion miSCellaneouS PhoTograPhy changein bonds have been thesold to invest lives here on the frontierof of medical science, Dopaminergic neurons Page 2 Nikolaevich derived from human Page 16 Alexander raths in research that promises hope for more effective treatments embryonic stem cells Page 18 olivier le Queinec thoseand cures for chronicwho disease andsuffer injuries afflicting fro so manym families.” (A NDrEi Ko CHEg A r o v at the University Page 20 Fenton of California, riverside) Page 22 Michael taylor California State treaSurer Page 24 Kentoh debilitating diseases. Human embryonic stem cells Bill Lockyer differentiating into neurons deSign (gUop iNg FAN at the University of David Armario Design California, los Angeles) glen Ellen, CA The Institute is creating jobs www.davidarmariodesign.com Adult neural stem cells (D Av iD S CHAFFEr at the University PrinTing while saving lives.” of California, Berkeley) Advanced printing pleasanton, CA — California S enate President p r o T e mp o r e retinal pigment epithelium www.advancedprinting.com derived from human D a r r e l l S t e i n b e r g embryonic stem cells ediTorial (D Av iD BUCHHol Z AND SHEr r Y HiK i tA Amy Adams, Don gibbons, at the University of California, Jenni laidman, Santa Barbara) Camille Mojica rey, ph.D.

Neurons derived from human embryonic stem cells (X i ANMiN ZENg at the Buck institute 48 California I nstitute for R egenerative Medi c i n e for Age research)

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210 King Street, San Francisco CA 94107 415. 396. 9100 Fax 415. 396. 9141 [email protected] www.cirm.ca.gov