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CELEBRATING 40 YEARS THE PRESIDENT’S REPORT OF THE SALK INSTITUTE FOR BIOLOGICAL STUDIES INSIDE SALK California Embraces Stem Cell with Proposition 71

On November 2nd, California pursue a fuller spectrum of the total National voters approved the of stem cell . Institutes of Health budget). adoption of Proposition 71, Restrictive Federal policies Proponents of Proposition the California Stem Cell had limited researchers to a 71 believe that stem Research & Cures Initiative, small number of established cell research will impact by an 18-point margin. cell lines, narrowing scien- the understanding and Proposition 71 provides stable, tific exploration of this field treatment of ills as diverse long-term support for human to a fraction of the Federal as diabetes, cancer, heart stem cell research so that research budget ($25 million disease, Parkinson’s, HIV/ California researchers may in 2003, or less than 0.1% AIDS, lupus, arthritis and Proposition 71 establishes the spinal cord injury. All told, California Institute for Regenerative these conditions affect Medicine to oversee Othe disbursal PROPOSITION 71 LEADERSHIP GROUP millions of children and of funds to scientists at Californian establishes standards and practices of the universities and research institutions. California Institute for Regenerative Medicine adults around the world, It taps statewide elected officials including an estimated and UC chancellors to appoint Chairperson & 130 million Americans. the Institute’s leadership, a group vice chairperson At the same time, scientists comprised of: five representatives Eight academic or emphasize that the stem cell of University of California campuses non-profit research institution with medical schools, eight representatives field is in its infancy and a Ten patient advocacy representatives of other non-profit great deal of basic research representatives or academic research institutions will be necessary before in California (including Salk), Four representatives these cells become useful four representatives of California’s of commercial life Five executive officers in treating clinical diseases. commercial life-sciences sector and science entities of UC campuses 10 Californian patient advocates. Proposition 71 issues with medical schools These 27 individuals, in turn, elect bonds to support $3 billion a chairperson and vice-chairperson. of stem cell research over 10 years, or an average of $295 million a year, with bond repayment deferred until 2010 to protect the state budget during its recovery. A granting agency called the California Institute for Regenerative Medicine will oversee the disbursal of funds to scientists at Californian universities and research institutions. At least 94% of its funds will go toward research support, with up to 10% earmarked for facilities construction or remodeling so that scientists may pursue Proposition 71-funded research in addition to lines, first steps in a process Medical researchers hypoth- Embryonic Stem Cell Derivation Federally supported projects. geared towards making initial esize that stem cells may and Drug Design. The size and structure of grant awards by summer 2005. one day be used to replace Research with human embryonic grant awards have yet to be Stem cells are unspecial- cells damaged by disease. stem cells may accelerate the development of cancer drugs. determined. However, strict ized cells that can give rise More immediately, these Embryonic stem cells, derived legal and ethical safeguards to the various tissues and cells could facilitate from the inner cell mass of late- will be adopted to ensure organs of the body. Adult novel investigations of the stage fertilized eggs (blastocyst), protection of patient rights, stem cells reside within fundamental processes may be directed to become safety and privacy, as well specific tissues and work underlying tissue development. cancer cells harboring a specific as a firm prohibition of to replace the cells of that This new knowledge base cancer-causing trait (like a genetic mutation). These cells may then human reproductive cloning. tissue following injury. Adult would open doorways to be used to investigate a drug’s Proposition 71 entrusts the stem cells are limited in the understanding some of activity in the presence or absence stewardship of this program number of specialized cell our most puzzling diseases, of the trait, point to possible side to 29 representatives of types that they can become, like Alzheimer’s and autism, effects or indicate which patients California’s patient and and thus far have been diffi- and even provide a platform will respond to a particular drug. medical research communities cult to grow in the . technology for the design Illustration by Jamie Simon. (see illustration on pg 1), In contrast, embryonic stem of more effective drugs including Salk President & cells—stem cells found very (see illustration above). CEO Richard Murphy. This early in embryonic develop- Proponents hope that group met to elect its leader- ment—may transform into Proposition 71 will acceler- ship in December of last nearly all specialized cell ate stem cell research so year. They met again in types, and can be grown that scientists can more mid-January to establish experimentally for long rapidly develop this funding and ethics guide- periods of time. therapeutic potential.

2 INSIDE SALK Research News

The Telomeres of Dorian Gray

Aging and death—once the preserve of religion, poets, and expensive face-cream—is now being subjected to the rigors of science. Salk Institute geneticists have begun to provide startling insights into why our clocks run down and what can be done to slow the hands of time. PhD student Laure Crabbe and Jan Karlseder have discovered that a small piece missing from a single chromosome may be sufficient to trigger the aging process. Crabbe and Karlseder made their discovery, published in Science in December, Awhile working on the genetics of Werner’s syndrome. In this rare genetic disorder people age rapidly from their mid-teens and frequently die of cancer in their 40s. Geneticists naturally ask the question, why does the Werner’s clock tick faster than normal? Laure Crabbe and Jan Karlseder The generally accepted of aging is that the ‘caps’ (telomeres) at the ends of all 46 chromosomes get shorter and shorter with each cell division throughout life, thus exposing the chromosome to genetic damage and triggering age-related changes in the cell. Crabbe and Karlseder expected to find that the telomeres wore down faster in Werner’s syndrome. To their surprise, the telomere shortening rate was no different to anyone else’s. They found instead that one or more telomeres were missing completely and a single missing telomere was enough to accelerate the aging process. Further investigation revealed that people with Werner’s are unable to create normal chromosomes during cell division because they lack a crucial protein called WRN. This protein acts as a ‘detangler’ that unravels knots in the DNA during the complicated process of chromosome replication. This discovery has wide-ranging applications in cancer research, said Laure Crabbe. Missing telomeres likely lead to a condition called genomic instability. “We know that genomic instability is involved in almost all cancers, likely caused by chromosome breakage and loss of gene function,” Crabbe said. She is currently trying to prove the link between telomere loss and genomic instability. The discovery also has potential implications for those of us reaching for the wrinkle cream because Crabbe and Karlseder were able to recreate the missing telomeres in cultured cells in the laboratory. “The wider implication of this work,” said Karlseder, “is that in normal people this discovery might lead to new approaches for therapies for cancer and even aging.” 3 SALK IN THE NEWS

Ron Evans Fred H. Gage Ned Landau Dennis O’Leary

 Ron Evans’ marathon mice  The Washington Post  San Diego Magazine has  Dennis O’Leary’s innovative have attracted significant media and the New Scientist have published a feature on the research on binocular vision was attention. Scientific American cited an investigation led by Salk Institute and “San Diego’s showcased in the November 25th featured his team’s research Fred Gage that has uncovered most celebrated hero of issue of the respected science on mice that were genetically flaws in current stem cell medicine,” Jonas Salk. The journal Nature. O’Leary and engineered to burn more fat research methods. Both articles article chronicled Salk’s polio his colleagues found that by activating PPAR-delta, reported that Gage, along with vaccine discovery and highlighted Islet-2, a regulatory protein, is a receptor that regulates Ajit Varki of UC San Diego, has some of the exciting advances responsible for determining the metabolism and the breakdown discovered that human stem in biology that have taken place degree of binocular vision in of fat. Evans’ work was hailed cells cultivated with mouse at the Salk Institute since its mammals. Their work appeared as a breakthrough in under- ‘feeder’ cells are attacked by first labs were set up in 1963. in Research Highlights, a section standing the link between the human immune system Several Salk Institute researchers in Nature devoted to outlining muscles and metabolism, with and killed – results that affect were mentioned, including notable articles appearing in other clear applications to humans all Federally approved stem , Joe Ecker, and journals, designed to connect its fighting obesity or athletes cell colonies. Ned Landau. readers with current and cutting- looking for that extra edge. edge scientific investigations. His research was also cited in a Research Highlights reviewed Science News story about gene an article by O’Leary and his therapy and mouse muscles. team published in the journal Cell in November, 2004.

4 INSIDE SALK Awards & Honors

Terry Sejnowski in honor of Francis Crick, observing what happens at brings it all together this cutting-edge research a macro level. By contrast, initiative is now becoming a molecular genetics allows Terry Sejnowski, reality, following its incep- scientists to manipulate and head of the Compu- tion at the Crick Lecture individual genes to under- tational Neurobiology in 2003. A roster of three stand function at the Laboratory has been new faculty members and cellular level. “It’s like a awarded the Francis Crick at least three junior fellows molecular scalpel,” said Chair, funded by the J.W. is planned that will bridge Sejnowski. “For the first Kieckhefer Foundation, Francis Crick’s two areas of time in history we have taking on the mantle of interest, molecular genetics the tools and techniques the late Francis Crick. and . “The to understand how neurons “It’s a great honor,” intention is to recruit faculty work and the challenge said Sejnowski. who are bringing genetic is to integrate all of that techniques into neuro- information.” science,” Sejnowski said, Integration is the power “to use them as tools for of the Crick-Jacobs Center understanding the higher and potentially offers the functions of the .” greatest rewards, says Computational neurobiol- Sejnowski. The nature of ogy is a hugely promising consciousness—what makes area of research, offering someone a person—is now the ultimate prize to neuro- within the grasp of science. biologists: an understanding “Areas such as these have of how the brain works. been off-limits to science Sejnowski’s team uses a up until now,” he said. suite of sophisticated “Francis Crick did more Terry Sejnowski electrical, chemical and than anyone to open up the “The intent is to reaffirm computer-based techniques study of consciousness to the important role of theory to measure and define scientific scrutiny. We are in biology that Francis communications within the now developing tools that represented.” , involved in will allow biologists over the One of the most important learning and , and next 10 years to integrate tasks currently engaging the cortex, which holds all the information from all Sejnowski and his colleagues all our knowledge of the the molecular techniques is the creation of the world and governs how and synthesize them, and Cricks-Jacobs Center for we interact with it. come up with a much better Theoretical and Compu- Traditional neuroscience picture of how synapses tational Biology. Endowed involves scooping out work, and ultimately, how by Joan and Irwin Jacobs regions of the brain and the brain works.”

5 INSIDE SALK Awards & Honors

Joe Ecker Scientific American Leader J.W. Kieckhefer Professorship for Joe Ecker of the Plant in 21,700 of these genes. Marc Montminy Molecular and Cellular A database of the mutations Biology Laboratory has is now accessible to The newly endowed J.W. been named to the ‘top 50 researchers worldwide Kieckhefer Professorship leaders’ by the journal (http://signal.salk.edu), has been awarded to Scientific American. Ecker who can instantly order Marc Montminy, professor was lauded for three ground- from a ‘seed bank’ to in the Clayton Foundation breaking publications in investigate mutations of for Peptide plant genomics during the interest. The site now Biology. Montminy has year, two in Science and receives over one million spent the last two decades one in Cell. In 2000, hits a year. Arabidopsis unravelling diabetes and Ecker’s group was part of mutations have already the complex chemical an international team that yielded many genes that relay-race in the liver and published a paper in confer important traits pancreas that controls Nature describing the first for crop plants, including glucose metabolism. The complete plant genome resistance to disease, significance of Montminy’s Marc Montminy sequence, using the reference drought, and cold. The work has increased plant Arabidopsis, revealing award also went to the Salk exponentially in recent of CREB target genes. its 25,000 protein-coding plant biology team in 2003, years as type 2 diabetes Recent work on mature- genes. In 2003, his group when Joanne Chory took rises to epidemic proportions onset diabetes of the young created insertion mutations the prize. worldwide. (MODY) genes, and their Montminy’s research has corresponding proteins, revealed many of the key offers the potential to find signalling pathways within a unifying explanation for cells that go awry to produce what goes wrong in type 2 the cornerstones of type 2 diabetes. “The reason this diabetes: insulin resistance is so exciting is that type 2 (in the liver and muscles) diabetes is a problem of and insulin deficiency insulin resistance and (in the islet cells of the insulin secretion,” said pancreas). Montminy’s early Montminy. “Because work revealed the existence these proteins do very of a pivotal transcription similar tasks in both the factor called CREB that islets and the liver, from regulates the body’s response a reductionist point of to changes in blood glucose. view, it allows us to explain His current research the two phenomena with focuses on the identification one molecule.” Joe Ecker

6 Catherine Rivier Double honors for Tony Hunter

At the close of last year, and many significant Tony Hunter received the advances in gene research. 2004 Louisa Gross Horwitz Hunter was also recently Prize, a leading national named a member of the scientific achievement Institute of Medicine of award, for a lifetime of the National Academies ground-breaking research. of Sciences. The National Hunter is best known for Academy elects new his discovery of a process members each year, called tyrosine phosphory- who serve as advisors on lation, the chemical ‘switch’ national health and health Catherine Rivier that can turn healthy cells policy. Hunter is the sixth receives cancerous. His work has led Salk Institute scientist Geschwind award to three new cancer drugs to hold this honor. Catherine Rivier has been awarded one of the most prestigious academic prizes in endocrinology, the Geschwind Award. Rivier, a professor in The Clayton Foundation Laboratories for Peptide Biology, received the award for her life-long contributions to the endo- crinology of stress responses. Rivier gave the Geschwind Memorial Lecture in 2004, speaking on nitric oxide as a mediator of the stress response in the brain. The award com- memorates Irving Geschwind, the ‘father of endocrinology’ and chief editor of the journal Endocrinology from 1973 to Tony Hunter 1977. It is endowed annually by the Department of Animal Science, University of California at Davis.

7 INSIDE SALK On Campus

The colorful parade Honoring Françoise of science Gilot-Salk

 A lively and fascinating in scientific publishing; hostile  On December 3, 2004, Jonas Salk Lecture was delivered reviewers and disputes between Françoise Gilot-Salk became on December 2, 2004 by co-authors; the peer-review the inaugural honoree in a new Donald Kennedy, Editor-in-Chief process itself; and the dangers donor holiday party tradition of Science. Kennedy shared of a “tournament model” for of paying tribute to individuals his “unique and revealing science, where few win and who have made significant perspective on the scientific many lose. He said researchers contributions to the Salk community” gained from his at all levels should foster quality, Institute. Ms. Gilot-Salk is “interesting perch” at one of not just citation tallies. He also an artist, honorary chair of the world’s pre-eminent journals. urged scientists to take seriously Symphony at Salk, and wife Through real letters to the their responsibility to speak of the late Jonas Salk. editor, Kennedy covered balance out on science policy. Françoise Gilot-Salk Razavi-Newman Center for Bioinformatics takes shape

 The bioinformatics initiative at Salk has now taken formal shape as the Razavi-Newman Center for Bioinformatics. Following a generous donation from Salk Board of Trustees member Howard Newman and his wife Maryam Razavi, the Center recently welcomed Gerard Manning director Gerard Manning, who will work on applying testing the mix for survival modern genomics and advantage,” explains Manning. bioinformatics techniques to “This decade, for the first time research topics throughout ever, we are starting to read Salk, as well as exploring out the result of that fundamental questions in in genome sequences. This genomics and evolution. treasure trove will help unlock “For over one billion years, the secrets of DNA sequence every organism that has and function and allow us to been born has been part of apply our findings to almost a cumulative experiment in every aspect of science carried mixing their parents’ DNA, out at the Salk.” making new mutations, and

Left Top: Donald Kennedy and Renato Dulbecco. Left Bottom: Françoise Gilot-Salk, Dianne Day, Mel Yoakum and Donald Kennedy

8 Leanne Jones Vicki Lundblad Satchidananda Panda DEVELOPMENT NEWS Academic Celebrating Salk supporters at the Annual Donor Holiday Party Appointments

 On December 3, 2004, 200 of the Salk the groundwork for future scientific discoveries  Leanne Jones has joined Institute’s donors, special friends, Symphony at through Proposition 71, California’s stem cell the Institute as an assistant Salk sponsors, and community leaders gathered research legislation. professor in the Laboratory of to enjoy champagne and hors d’oeuvres at the Finally, the Institute honored artist Françoise Genetics. Jones joins the Salk annual donor holiday party. Guests were treated Gilot-Salk, wife of the late Jonas Salk and from Stanford University and to the Caprice Strings, a musical quartet that honorary chair of Symphony at Salk. Ms. Gilot-Salk brings with her a research performed throughout the night, and a projected shared personal and expressed her background in the mechanisms photo montage of past Salk Institute events. delight in celebrating with so many Salk Institute that control stem cell differentia- Salk president and CEO Richard Murphy supporters, several of whom had been present tion. “I knew I had to come to the thanked attendees for making time during the busy during Salk’s early research endeavors. The Institute Salk,” Jones said, “People are so holiday season to recognize the essential role that presented her with a framed, inscribed photograph excited about their work here, so donor contributions have played in 2004’s exciting of Symphony at Salk 2004 in appreciation of her turned on to science all the time.” and successful research advances at the Salk continued efforts and enthusiasm. Institute. He acknowledged Salk board and faculty  Vicki Lundblad has been members, and highlighted the approaching appointed to the position of 50th anniversary of the Salk polio vaccine, 40th professor in the Molecular anniversary of a fully realized Salk Institute facility, and Cell Biology Laboratory. and 10th anniversary of Symphony at Salk. Lundblad's research interest Leanne Jones, who recently joined the Salk is the role of telomeres in cell as an assistant professor in the Laboratory of proliferation, a topic of central Genetics, also addressed the guests. She praised interest in both cancer and aging her Salk colleagues and the donors for their biology. Lundblad's appointment support, and discussed the anticipation of laying at the Salk follows 12 years on the faculty of Baylor College of Medicine in Houston, Texas.

 Satchidananda Panda joins the Regulatory Biology Laboratory to focus on the genetic and

Right: The Honorable Charles and Chin-Yeh Hostler molecular basis of circadian Below: Steve Milz, Gad Shannon and Martha Dennis rhythms, or the biological clock. Below right: Natasha Josefowitz and Herman Gadon Panda’s immediate goal is to determine how this mysterious structure located in the suprachi- asmatic nucleus of the brain allows us to readjust to changes in the light cycle. The answer could have wide-ranging implications for treating depression, jet lag, disorders, infertility and even heart disease.

9 INSIDE SALK Outreach

Ron Evans gives Board of Trustees students the welcomes skinny on fat Theodore W. Waitt

 Ron Evans was a featured  The Salk Institute welcomes speaker in the latest Howard Theodore W. Waitt as our Hughes Medical Institute’s newest Board of Trustees 2004 Holiday Lecture Series. member. Until recently, By following the fate of a fat Waitt was the founder and molecule as it journeys from chairman of Gateway, Inc., the a meal to the arteries, Evans third largest manufacturer of presented the “soup to nuts” computer products in the United story of the worldwide obesity States. Now an entrepreneur epidemic and scientific Jonas Salk inoculates a boy in Pittsburgh, Pa. during the field trials. approaches to solving the Courtesy of the Smithsonian Archives. problem. The interactive lecture, Smithsonian commemorates the polio vaccine called Understanding Fat: Syndrome X and Beyond, is  This year is the 50th anniver- effective. The exhibit will recount scheduled for broadcast by sary of Jonas Salk’s introduction the course of the polio epidemic PBS and can also be found of the first successful vaccine in the United States, the on the Salk Institute website for polio. The Smithsonian’s development of the vaccine, (www.salk.edu). The audience National Museum of American the current status of worldwide were science students selected History will commemorate this polio transmission control, and by their high schools. “The best medical triumph with a display the stories and influence of part was learning how talented called Whatever Happened to polio survivors. The presenting and enthusiastic the next Polio? that will open for one year sponsor of the exhibit is the generation of scientists is,” starting April 12, 2005, the exact March of Dimes, with additional said Evans. “It was amazing day 50 years ago when the funding from Rotary International seeing 100 hands go up when vaccine was declared safe and and the Salk Institute. I asked a question.” Theodore Waitt

and philanthropist, Waitt is the chairman and CEO of the Avalon Capital Group, a private equity company, and chairman of the Waitt Family Foundation, which brings technology to underserved communities. Waitt also sits on the board of directors for several charitable organizations and corporations, and has garnered numerous leadership and entrepreneur awards, as well as an honorary doctorate from the University of South Dakota.

Ron Evans

10 F ROM THE P RESIDENT

Proposition 71: Next Steps the Institute on questions related to patient’s rights, tissue Californians have voted to commit $3 billion in state funds and procurement, and the nature of scientific experimentation, to establish the California Institute for Regenerative Medicine to name just a few. (CIRM) to support human stem cell research over the next Finally, CIRM needs to launch an effective public ten years. This funding will kick-start research aimed at under- information effort to keep Californians informed about the standing the early stages of organ and tissue development, Institute’s research. No one can predict how long it will take for creating engineered cells that can help explain human for stem cell research to go from the laboratory to the bedside, diseases, and perhaps eventually for transplanting healthy but exciting results will undoubtedly emerge as soon as cells into patients suffering from degenerative diseases. California’s scientists begin their work. Frequent updates on The funds are ready to flow, and the time has come to scientific progress will increase the public’s understanding of face the thorny challenges of ensuring the program’s success. stem cell science—and help correct unrealistic expectations The first challenge will be to establish a funding agency that cures are just around the corner. that can run a large research grants program. CIRM’s The Salk Institute is ideally positioned to compete governing board, the Independent Citizen’s Oversight successfully for CIRM funding. Presently on our faculty are Committee (ICOC), made a good start by electing as its chair outstanding stem cell researchers who are studying the basic Robert Klein, the originator of the ballot referendum. Klein, principles of stem cell biology. Moreover, other Salk scientists a businessman whose son suffers from type 1 diabetes, who are not identified as stem cell biologists are nonetheless showed impressive leadership and administrative skills in answering fundamental questions of cell function that establishing a coalition of groups to support Proposition 71. are central to the field, including how gene expression is His efforts earned him Governor Schwarzenegger’s endorsement regulated and how genetic programs lead to the formation of for the chairmanship and that of the state’s other constitutional different tissues and organs. The interests and quality of these officers. Ed Penhoet, who was elected ICOC’s Vice Chair, scientists will also help us attract new stem cell biologists to has complementary skills, including experience in academic the Institute, should we decide to do so. The Institute could research, biotechnology, and grants management. Rounding also benefit from interactions with stem cell scientists at out the team will be CIRM’s president, yet to be selected. other California institutions and from capital funds for new Their first priority must be to develop funding mechanisms laboratories made available through the program. and conflict-of-interest guidelines that are above reproach. California may be just the first of many states to approve Structures need to be devised to protect ICOC members embryonic stem cell research. The stakes are high, and the from making decisions that could benefit their own academic challenges large, but the return on investment may be huge. organizations or businesses in which they have interests. If well implemented, California’s stem cell research program Furthermore, to ensure that research quality is the only will earn the confidence of voters—and be the start of a metric by which funding is decided, peer-review of grant historic scientific effort with extraordinary potential for applications should be carried out by researchers based advancing scientific progress and improving human health. outside California. CIRM’s ethical review board, which is mandated by the legislation, will need to sort out the myriad complicated dilemmas that will arise as stem cell technology develops. The country’s best bioethicists should be asked to guide Richard Murphy

11 INSIDE 40 SALK

CELEBRATING 40 YEARS

The year 2005 is the 40th anniversary of the Salk Institute for Biological Studies and the 50th anniversary of the Salk polio vaccine. Calendar The Salk Institute was founded in 1965 by Jonas Salk M.D., whose 1955 JANUARY 27 polio vaccine all but eradicated the crippling disease poliomyelitis. Salk's vision 3rd Annual Umesono Lecture of an independent research organization dedicated to the improvement of human Salk Institute health has been more than realized in the last 40 years. The Salk Institute is now renowned worldwide for its fundamental discoveries in the life sciences and FEBRUARY 8–9 its mentorship of the next generation of researchers. Adler Symposium on Alzheimer’s disease Salk Institute 1964. Construction at the Salk Institute

FEBRUARY 25 Renato Dulbecco Nobel Lecture Speaker: David Livingston Salk Institute

MARCH 11–12 La Jolla Origins of Humans Annual Symposium Salk Institute

MARCH 17–19 Molecular Medicine Symposium Salk Institute

Please note: the above represents a selected list of events. For additional information on these and other Salk events, please contact Institute Relations at 858.453.4100 ext. 1200.

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