WINTER 2006/07 VOLUME NINE / NUMBER THREE THE SCRIPPS RESEARCH INSTITUTE RESEARCH SCRIPPS THE

NON-PROFIT U.S. POSTAGE PAID PERMIT 751 SAN DIEGO, CA THE SCRIPPS RESEARCH INSTITUTE

A PUBLICATION OF THE SCRIPPS RESEARCH INSTITUTE / / ENDEAVOR

Office of Communications—TPC20 ENDEAVOR 10550 North Torrey Pines Road

La Jolla, California 92037 www.scripps.edu breakthroughs oƒ 2006

WINTER 2006/07 2006/07 WINTER

PUBLISHER: Keith McKeown

EDITOR: Mika Ono Benedyk

DESIGN: Miriello Grafico

COVER ILLUSTRATION: Rachel Salomon

PORTRAIT PHOTOGRAPHY: VOLUME Dana Neibert

PRINTING: NINE NINE Precision Litho / NUMBER

© 2006 All material copyrighted by The Scripps Research Institute. THREE THE SCRIPPS RESEARCH INSTITUTE ENDEAVOR

VOLUME NINE / NUMBER THREE WINTER 2006/07

FEATURES: ALSO:

06 VACCINATING AGAINST OBESITY: 01 PRESIDENT’S LETTER STUDY OFFERS POTENTIAL NEW “Scripps Research is really a unique place in the collegiality APPROACH TO COUNTER WEIGHT 27 COMMENCEMENT CELEBRATES VITALITY, GAIN AND YO-YO DIETING INQUISITIVENESS, INNOVATION of its faculty and in the willingness of faculty to cross

28 VOICES FROM THE EDUCATION AND OUTREACH PROGRAMS specialized niches in order to undertake interdisciplinary 10 GETTING TO THE ROOT OF FRIEDREICH’S ATAXIA: 30 FINANCIAL HIGHLIGHTS JOEL GOTTESFELD COMES FULL CIRCLE research. The scientifc environment promotes collaboration, 31 LETTER FROM CHAIR OF THE BOARD allowing us to tackle big problems in creative ways.” 33 DEVELOPMENT REPORT 16 STRUCTURES WORKING FOR AND ERIC ZORRILLA, PH.D. AGAINST US: IAN WILSON REVEALS THE SHAPES OF PRESENT AND FUTURE PANDEMICS

22 FISHING IN TROUBLED WATERS: MICHAEL OLDSTONE REELS IN CLUES TO THE RAVAGES OF PRION DISEASE

ENDEAVOR IS A PUBLICATION OF THE SCRIPPS RESEARCH INSTITUTE

This issue of Endeavor features some of the many scientifc breakthroughs of 2006 from investigators at The Scripps Research Institute. Richard A. Lerner, M.D. President

Year in Review : 2006 01

PRESIDENT’S LETTER PRESIDENT’S LETTER PRESIDENT’S

One of the pleasures of being associated with The Scripps Research Institute is that we so often have good news to report. So it is this year, when we can share prog- ress on our site in Florida, new contribu- tions of our faculty, staff, and trustees in both Florida and California, and ground- breaking research in our understanding of health and disease. > New Scripps Research facilities and alliances advanced in 2006.

FLORIDA ADVANCES

With the Palm Beach County commissioners’ selection in February of a new site for Scripps Florida—on the Florida Atlantic University (FAU) north campus in Jupiter—we have moved forward with plans for a permanent facility. Scheduled to open in 2009, the facility will be a 350,000 square-foot, world-class biomedical research opera- tion focusing on basic biomedical science, drug discovery, and technology development. In the meantime, Scripps Florida opened a second temporary building this fall on the FAU site. The structure will provide 33,000 square feet of space to continue growing our faculty and staff while the permanent campus is under construction. 02 The state-of-the-art screening technologies at Scripps Florida have begun to make contributions to science, including published papers this year. The system, which relies on automated robots to analyze a large number of compounds at once, is available to Scripps Research faculty on both coasts. In January, the Access to Technolo- gies Program also opened the system to scientists from universities and research institutions throughout Florida, enhancing our other collaborations in the state. The State of Florida awarded its first research grant to one of our faculty members this year. Awarded on the basis of scientific merit, the Florida Department of Health’s James & Esther King Biomedical Research grant will provide support for Layton Smith, Scripps Florida associate director of pharmacology, who is conducting research in the field of metabolism.

PRESIDENT’S LETTER In another Florida development, this year we welcomed our first entering classman to our graduate program in Jupiter, where he joins several students who transferred from other institutions. A new two-way, web-based con- ferencing technology is enabling Florida students to participate in California lectures in real time, as well as open future Florida classes to interested California students.

NEW RESEARCH ALLIANCES

In 2006, we forged a number of new alliances, which will advance science at the institute in the years ahead. In February, we announced a collaborative initiative with IBM, called “Project Check-mate,” that will conduct research on pandemic viruses to develop ways to anticipate, manage, and contain infectious diseases. Check-mate capitalizes on Scripps Research’s world-class research in biochemical modeling and drug discovery and IBM’s expertise in computational biology bio-patterning and supercomputing. The joint research team will harness both IBM’s Blue Gene supercomputer and Scripps Florida’s screening technology. In March, we joined forces with three preeminent San Diego research institutions—The Burnham Insti- tute for Medical Research, the Salk Institute for Biological Studies, and the University of California, San Diego (UCSD)—to establish an independent, non-profit consortium dedicated to stem cell research. The alliance, called the San Diego Consortium for Regenerative Medicine, will explore the tremendous therapeutic potential of stem cells to repair and replace damaged tissue. In April, we became part of Microsoft’s new BioIT Alliance, a cross-industry group working to integrate sci- ence and technology to speed the pace of drug discovery and development. The alliance’s first project, Collabora- tive Molecular Environment, strives to make research more efficient through a data management solution targeting common technology problems faced in the life sciences. In May, a new robotic crystallization facility opened on the California campus, thanks to support from the Joint Center for Structural Genomics (funded through the NIH’s Protein Structure Initiative) and global nonprofit group International AIDS Vaccine Initiative. One of the largest machines of its kind, the integrated robotics system will enhance scientists’ ability to solve molecular structures, increasing our understanding of basic biology and strategies for combating a variety of diseases. A study found hundreds of novel Researchers solved the structure of WRN, which protects humans from genes that help the malaria premature aging and cancer. They also solved the bacterial gc type 2006 parasite avoid destruction. iv pilus filament, which enables antibiotic-resistant bacteria to cause persistent and recurrent gonorrhea infections.

GROUNDBREAKING RESEARCH Scripps Research continues to The institute’s science stands at the forefront of ba- make significant strides and sic biomedical research, a vital endeavor that seeks contributions to science. to comprehend the most fundamental processes of life. In addition to the research featured in this is- sue of Endeavor—on an anti-obesity vaccine, re- activation of the gene responsible for Friedreich’s ataxia, heart damage from prion disease, and the 03 threat of the avian flu virus—in 2006 Scripps Re- search scientists made many significant contribu- tions. To name just a few key studies: PRESIDENT’S LETTER PRESIDENT’S

+ Scientists demonstrated an innovative combination of immunotherapy and small molecule drug design for producing anti-cancer targeting antibodies. One study, led by Professor Carlos Barbas III, highlighted the Scientists discovered a class of potential of such an approach against melanoma. compounds that block the SARS Another study, led by Associate Professor Subhash virus from replicating. Sinha and myself, developed a compound against metastatic breast cancer.

+ Professor Chi-Huey Wong and colleagues discovered a tions for organ transplants, autoimmune disease, class of compounds that block the SARS virus from multiple sclerosis, and adult respiratory distress replicating, a finding that may open the door to new syndrome. drug targets against the deadly disease. + Immunology Department Chair Richard Ulevitch and + Professor Dale Boger and Kellogg School Ph.D. candi- colleagues uncovered a new and potentially important date Brendan Crowley re-engineered a well-known anti- function for the protein Nod1, inhibiting the growth of biotic to insure its effectiveness against sensitive as well estrogen sensitive human breast cancer cells. as resistant enterococci, a common strain of bacteria responsible for wide-spread hospital infections. + Associate Professor Elizabeth Winzeler and colleagues discovered hundreds of novel genes that may help the + Professor John Tainer and colleagues determined the malaria parasite evade destruction by the human im- crystal structure and molecular mechanisms of a key mune system and anti-malarial drugs. The findings part of WRN, a protein that protects humans from could lead to the development of new therapies or premature aging and cancer. They also uncovered the vaccines for the deadly disease. structural chemistry behind the bacterial GC Type IV pilus filament, which plays an essential role in allowing OTHER NOTEWORTHY DEVELOPMENTS antibiotic-resistant strains of N. gonorrhoeae to escape the immune system and cause persistent and recur- MNew agreements with Novartis and the Genom- rent gonorrhea infections. ics Institute of the Novartis Research Foundation (GNF) will provide approximately $50 million over + Professor Hugh Rosen and colleagues developed a chemical tool that allows manipulation of the passage the next five years to fund the Scripps Research of substances through the barriers between blood and laboratories of 20 investigators, including Profes- organ tissues, findings that have therapeutic implica- sor Peter Schultz, five scientists moving to Scripps A $40.7 million grant funds the collaborative study of the complex dynamics of protein-carbohydrate interactions.

Gerald Joyce, Ph.D., was appointed dean of the faculty

Research from GNF, and 14 assistant professors. The business leader and philanthropist John Moores Terms also facilitate the future funding of Scripps was unanimously elected new chair of the board—he Research faculty by Novartis. will bring enormous skill and energy to the position. The Consortium for Functional Glycomics, We also have the pleasure of welcoming back Ralph led by Scripps Research Professor James Paulson, J. Shapiro of Beverly Hills, California, chair of Avon- received a $40.7 million “glue” grant for the inter- dale Investment Company, and welcoming Marjorie 04 national group of some 300 participating scientists Fink of Palm Beach County, Florida, to the board. to continue collaborative study of the complex dy- With the appointment of Professor Gerald namics of protein-carbohydrate interactions. The Joyce as dean of the faculty and Professor Jeffrey five-year grant from the National Institute of Gen- W. Kelly as dean of graduate and postgraduate eral Medical Science of the National Institutes of studies, in July we formalized a new distribution Health (NIH) follows a grant of $34 million award- of administrative responsibilities. This change will ed in 2001. enhance efficiency and communication in our aca- The Integrative Neuroscience Initiative on Al- demic programs.

PRESIDENT’S LETTER coholism, led by Scripps Research Professor George Barbara Suflas Noble, who has been part of Koob, won renewal of support from the NIH’s Na- our administrative team in Florida, will assume the tional Institute on Alcohol Abuse and Alcoholism. position of director of external affairs for Scripps The grant, expected to total $38 million over five Florida. Peter Policastro joins our team as senior di- years, supports the efforts of a multi-institutional rector of business development for Scripps Florida. consortium of investigators to identify the molecu- We also welcome investigator John Cleveland, lar basis of alcoholism. who will head a new Cancer Biology Department Scripps Research launched a research and on the Scripps Florida campus. educational initiative with McDonald’s to drive progress toward a solution to childhood obesity AWARDS AND HONORS and Type 2 diabetes. McDonald’s will contribute $2 million to the institute to address these critical Many awards and honors lauded our faculty, post- health issues. doctoral fellows, and graduate students in 2006.

PEOPLE NEWS Among the faculty recognitions:

In 2006, Scripps Research continued to be served by + Professor Dale Boger was elected to the American Acad- an outstanding group of trustees and administrators. emy of Arts and Sciences. Fellows are selected through At our commencement ceremony in May that a highly competitive process that recognizes individuals graduated 31 students from the Kellogg School of who have made preeminent contributions to their disci- Science and Technology, we conferred two honor- plines and to society at large. ary degrees in recognition of Hon. Alice Sullivan + Chair of the Scripps Florida Department of Infectology (Ret.), retiring chair of the Scripps Research Board Charles Weissmann received the prestigious DART/NYU of Trustees who will continue as a trustee, and Al- Biotechnology Achievement Award from the Biotechno- exander Dreyfoos, also a member of the Board of logy Study Center of the New York University School of Trustees. Medicine for his elucidation of multiple interferon genes Dale Boger, Ph.D., was elected to Clare Waterman-Storer, Ph.D., won Professor Argyrios Theofilopoulos, Phil Baran, Ph.D., was recog- the American Academy of Arts and the 2006 R.R. Bensley Award in M.D., was honored several times for nized as an outstanding young Sciences for preeminent contribu- Cell Biology lifetime contributions to medicine researcher tions to the field of organic synthesis and autoimmune research

and the pharmaceutical development of Intron A (inter- from the American Association of Immunologists for exem- feron alpha2b). plary career contributions to a future generation of scientists. + Chair of the Department of Chemistry K.C. Nicolaou won both the 2006 American Chemical Society Auburn G.M. Our hardworking postdoctoral fellows were also rec- Kosolapoff Award and Germany’s Burkhardt-Helferich ognized by numerous grants and awards. As a few Prize. He is also an author of one of Chemical Abstracts examples, Ian Schneider of the Waterman-Storer lab 05 Service’s 10 most-requested papers (second quarter), won a Damon Runyon Fellowship Award; Adam “Palladium-catalyzed cross-coupling reactions in total Mullick of the Curtiss-Tobias lab, a fellowship from synthesis,” in Angewandte Chemie. the American Heart Association; Terry Meehan of PRESIDENT’S LETTER PRESIDENT’S + Two patents on “click chemistry” by Professor K. Barry the Havran lab, a Crohn’s & Colitis Foundation of Sharpless, Assistant Professor Valery Fokin, and Associ- America Research Fellowship Award; and Jeff Lee ate Professor M.G. Finn were among the Chemical Ab- of the Ollmann Saphire lab, the Canadian Governor stracts Service’s 10 most-requested patent families General’s Gold Medal. (second quarter). As for our Ph.D. candidates in the Kellogg School of Science and Technology, an unprecedented five + Associate Professor Clare Waterman-Storer won the 2006 R.R. Bensley Award in Cell Biology from the American students—Dan Bachovchin, Christine Fang, Graham Association of Anatomists (AAA), which recognized her for Johnson, Costas Lyssiotis, and Adrian Ortiz—were innovation in molecular microscopy and contributions to awarded National Science Foundation Fellowships the understanding of cytoskeletal dynamics in cell motility. this year. In addition, students garnered prestigious awards from private donors, the NIH, Novartis, + Professor Argyrios Theofilopoulos was honored several Baxter, and many other organizations, including the times this year for lifetime contributions to medicine and autoimmune research, receiving honorary doctoral degrees Hertz Foundation, the American Heart Association, from the Aristotle University of Thessaloniki, Medical Achievement Rewards for College Scientists, and the School and the Democritos Medical School of Alexandrou- American Chemical Society. polis, as well as election as corresponding member of the This year’s achievements make me proud to be Academy of Athens. part of The Scripps Research Institute. My congratu- lations go out to faculty, staff, postdoctoral fellows, + Professor Bruce Beutler won the Cancer Research students, trustees, and loyal supporters for another Institute’s 2006 William B. Coley Award for Distinguished Research in Basic Immunology for his contribution to our year well done. understanding of the events leading to the initiation of innate immunity.

+ Associate Professor Phil Baran received the Sloan Research Fellowship for “outstanding researchers early in their academic careers.” He also received the Bristol- Myers Squibb Unrestricted Freedom to Discover Grant (2006 - 2010), and a National Science Foundation Richard A. Lerner CAREER award (2006 - 2010).

+ Norman Klinman, who became professor emeritus this year, received the 2006 Excellence in Mentoring award

“Our vaccine slowed weight gain and decreased stored fat in rats. While food intake was unchanged in all testing groups, those who were given the most effective vaccines gained the least amount of weight.”

KIM JANDA, PH.D.

Scripps Research investigators Kim Janda (top) & Eric Zorrilla collaborated on a study that made headlines around the world

Vaccinating Against Obesity 07

STUDY OFFERS POTENTIAL NEW APPROACH TO COUNTER WEIGHT GAIN AND YO-YO DIETING VACCINATING AGAINST OBESITY AGAINST VACCINATING

The fight against obesity is the story of the year and TV, network syndicates, Univision, and GMTV we have Kim Janda, Eric Zorrilla, and colleagues (Europe’s most-watched morning show), and nu- at The Scripps Research Institute to thank for it. merous print and web-based media. “The coverage Since the publication of their scientific study in Au- was honestly more than I anticipated for a proof- gust, articles on their potential obesity vaccine have of-principle study,” Zorrilla said, “but emphasizes appeared in more than 100,000 publications world- both the need and desire for more effective treat- wide, while hits on the Scripps Research site have ments for obesity.” numbered in the hundreds of thousands. In addition to the media deluge, emails by the Janda, who is Ely R. Callaway Jr. Professor hundreds have come into Scripps Research from of Chemistry at Scripps Research, member of its people asking if they can sign up for clinical trials. Skaggs Institute for Chemical Biology, and director Some even sent personal photographs. Everyone, of the Worm Institute for Research and Medicine, it seems, is looking for the next pill, shot, or other has appeared in dozens of interviews including magic bullet that will make them thin… forever. Good Morning, America and the Today Show. He “We really did hit a grand slam on this, not just has talked to the BBC three times; reporters have a base hit,” Janda said of the breakthrough study. contacted him from places as disparate and distant as Japan, Australia, Russia, and Ireland—some of A PROMISING NEW APPROACH whom called at midnight to query him. “I think I’ve talked to every news source ev- What helped make this grand slam possible was the erywhere,” Janda said. “One day I was talking on fact that Janda’s group has been working through two phones simultaneously and finally had to drop some of the basic science of this approach—immuno- the cell phone on the floor—it got too crazy!” Janda pharmacotherapy—in other research areas, such as has now had his allotted 15 minutes of fame and cocaine and nicotine addiction, for the past 20 years. maybe a tad more: “It’s been unbelievable. I was in Also contributing to the score was the stun- a restaurant the other day and somebody came up ning failure rate of almost every other pharmaceu- to me and asked if I was the obesity guy.” tical approach to serious weight control. Zorrilla, also a faculty member at Scripps The old agonist/antagonist types of drugs Research, held up his end, speaking with KUSI- used to treat obesity were remarkably unsuccessful 08 VACCINATING AGAINST OBESITY energy balance in the body. the in balance energy regulate helps that hormone occurring naturally a is Ghrelin production ofghrelintostimulateeating reduce yo-yodietingbyinterferingwith the realpotentialtoprevent orseriously the numberonethreattohealth intheUnitedStates.” used to tackle obesity—which he describes as “soon to be be could immunotherapy if see to eager was Janda air, drug inquestion). the to bind to designed antibody monoclonal a of livery de direct (i.e., immunization passive or protein) carrier larger a to bound when formation antibody induce that molecules small are haptens conjugate; a hapten-protein with immunization (i.e., vaccination active through neuro alleviatedbe fact the in can use drug of effects physiological of many that shown has laboratory Janda The intake. drug from rewards physiological no brain, the in drug no chase: the to cuts munopharmacotherapy their tracks. wouldn’t, the immune system can stop some problems in reach the brain. Recognizing a molecule that it ordinarily can it before target a to bind that antibodies produce to taught be can body the that idea the on based is proach comes backon.” weight the stop, you “When Janda. noted them,” taking you’re when effective only are or effective not either are drugs “These weight. lose or maintain people helping at

and preserve bodyfat.Ourvaccine has as ifitwasstarvingandincreasesthe With those kinds of tantalizing possibilities in the in possibilities tantalizing of kinds those With im example, for abuse, drug of treatment the For ap immunopharmacotherapy the contrast, In “When youdiet,thebodyresponds

these actionsofghrelin.” ERIC ZORRILLA, PH.D. ZORRILLA, ERIC - - - -

percenttotalofU.S. health carecosts. Andsome110,000 nine or billion, $123 at pounds excess our to attributable and some forms of cancer. The NIH estimates direct costs pressure and is believed to increase the incidence of blood stroke high of risk the doubles than more It cases. betes disease cases and 80 percent cardiovascular of noninsulin dependent of dia percent 70 nearly in factor tributing Institutes of Health (NIH) estimates that obesity is a con National The depression. and arthritis, stroke, diabetes, Typecancers, various 2 disease, heart including diseases to dateofferlittlehopeofcounteringthetrend.” every statebutone,andgovernmentpolicies actions according to the report, obesity rates continued to rise “in Worse,obese. or overweight either are Americans, adult of percent 64.5 or Americans, million 119 approximately group, watchdog and research non-profit a Health, ica’s people billion worldwide. According a to a over 2005 report by for Trust problem for Amer serious a is Obesity reduce foodintake. and loss weight cause also can which response, matory inflam systemic a produce not did vaccine The system. digestive the not and body’suse, energy and metabolism These results indicate that the vaccine directly fat. effects the more burned and weight less gained yet normally, ate rats immunized the groups, control with Compared vaccine. anactive of types specific with rats male ture Sciences of Academy tional the of edition online advanced, an in August 4 online study,published the was In which BOX THE INSIDE GLIMPSE A to find non-fattening jewel-encrusted chocolate bars inside. was greetedwithgreatinterest. news this mumps, or measles for get they ones the than different so not vaccine, simple a with fat body reduce and gain weight slow to able be might people day one 2006), and they offered a glimpse into the possibility that focuses on energy homeostatis (see the U.S.Food andDrugAdministration. by market the from pulled been have mine/fenfluamine, fenflura drug the including several, and successful been havefew weight, body their control people help to tried deaths a year are due to poor diet and inactivity. OBESITY GOES GLOBAL GOES OBESITY Obesity is a major risk factor for a number of other of number a for factor risk major a is Obesity Itsounded tomany like opening Pandora’s Boxonly So, when Janda teamed up with Zorrilla, whose lab been have approaches of number a though Even , researchers immunized ma immunized researchers , Proceedings of the Na the of Proceedings Endeavor article, Fall ------

“Our vaccine slowed weight gain and decreased stored pharmacotherapy in combating obesity, these initial re- fat in rats,” Janda said. “While food intake was un- sults are extremely positive.” changed in all testing groups, those who were given the most effective vaccines gained the least amount of THE SIDE EFFECTS ISSUE weight.” But the idea of developing therapeutic vaccines itself is This study’s findings were especially encouraging not without controversy. because of what is known to every dieter on the face of Janda, like other researchers, is concerned about the earth—the yo-yo effect, the predictable cycle of re- long-term side effects of the team’s vaccine candidate. peated loss and gain of weight. The new vaccine, which Typical of that concern was the response of Bruce Dan, is directed against the hormone ghrelin (pronounced one-time editor of the Journal of the American Medical grell-in), a naturally occurring hormone that regulates Association, who pointed out the unknown effects of hunger and energy balance in the body, has shown the modifying the immune system to counter a natural reac- ability, in animal models at least, to stop that dangerously tion. “If you are going to try to protect yourself against futile struggle. the cold it is better to buy a fur coat than to change your Ghrelin, an endocrine hormone produced primar- 09 ily in the stomach, plays a physiological role in energy genetic system to grow hair,” he said. homeostasis, although the full extent of that role remains Janda wondered much the same thing when he sug- unknown. It was first identified in 1999 as a naturally gested that a vaccine may not be the best way to treat OBESITY AGAINST VACCINATING occurring ligand—a molecule that binds to another to obesity. form a larger molecular complex—for a growth hormone “No one knows if an active vaccine is the most ef- secretagogue receptor. What is known is that ghrelin cy- fective means to control obesity,” he said. “With an ac- cles between meals and thus promotes weight gain and tive vaccine like the one we have currently developed, we fat storage through its metabolic actions, decreasing the don’t know what kind of weight loss might happen over breakdown of stored fat for energy as well as energy ex- the long-term. Once the active vaccine is turned on, you penditure itself. During periods of weight loss such as di- have to wait until the immune response ends. That’s why eting, the body produces high levels of ghrelin to preserve we’re looking carefully at this before there’s even a hint body fat and encourage eating. of introducing it into humans.” “When you diet, the body responds as if it was starv- In an exciting extension of their research, Janda ing and increases the production of ghrelin to stimulate and Zorrilla have launched studies into passive vaccines eating and preserve body fat,” Zorrilla explained. “Our to control eating behaviors. “A monoclonal antibody to vaccine has the real potential to prevent or seriously reduce ghrelin, or what is known as a passive vaccine, might yo-yo dieting by interfering with these actions of ghrelin.” be more effective and more controllable in terms of how The study did note, however, that the immunized long it’s in the body,” said Janda. The researchers will rats were relatively lean and were fed low-energy, low-fat also conduct investigations with different types of obese and relatively less palatable chow diets. Whether active animals, and with different types of food, including fat- immunization against ghrelin would help prevent the de- rich food more typical of the Western diet. velopment of obesity caused by high-fat “Western” diets Zorrilla is looking forward to continuing the col- or whether it would facilitate weight loss once obesity is laboration. “I really enjoy working with Kim [Janda] and established remains uncertain. his group members,” he said. “Kim and his lab members “Our study was the first real published evidence are highly creative, highly skilled, and highly collabora- proving that preventing ghrelin from reaching the cen- tive. Scripps Research is really a unique place in the col- tral nervous system can produce a reduction in weight legiality of its faculty and in the willingness of faculty to gain,” Janda said. “We’re not claiming that our study cross specialized niches in order to undertake interdis- answers all the questions surrounding the treatment of ciplinary research. The scientific environment promotes obesity. What we are saying—and what our study con- collaboration, allowing us to tackle big problems in firms—is that this looks like a serious, workable solution creative ways.” to the problem. And while much more study is needed ERIC SAUTER AND MIKA ONO BENEDYK to understand the full therapeutic potential of immuno- 10 GETTING TO THE ROOT OF FRIEDREICH’S ATAXIA Friedreich’s Ataxia Getting totheRootof and diabetes.Mostpatientsdie bytheirearly20s. disease heart later and speech, slurred with walk, to unable patients leaves cord spinal the in tissue nerve the of degeneration eventual The States. ed about 10,000 children and young adults in the Unit disease neurological called Friedreich’s ataxia. confounding a confront to do good—andit’s beenatransformation.” could I that realization the to came I years several tion of my work,” said Gottesfeld. “But over the applica last practical any about thinking not clouds, to theother. extreme one from go career own his seen has tute, of molecular biology at The Scripps Research Insti real-world results. Joel Gottesfeld, Ph.D., professor to findings way,laboratory other abstract the from go work their see to enough lucky are scientists er Oth today’sgame. of academic top on stay to way only the is study of field narrow a into deeper go to ever-moreWithscience edge. drive the specialized, knowl of bits smaller on focused more getting and more careers their through go scientists Some CIRCLE FULL COMES GOTTESFELD JOEL Friedreich’s ataxia is one of several so-called several of one is ataxia Friedreich’s affects disease incurable progressive, The way a finding meant has this Gottesfeld, For the in head my with scientist basic a was “I with thediseaseandsomeofpatientsit would bejustadreamtoablehelpthem.” “I’ve mettheparentsofmanychildrenaffected - - - - - the journal in August break in ataxia Friedriech’s on paper through the published colleagues and Gottesfeld PAPER BREAKTHROUGH of many yearstoputthisideathetest. research own his on build to straightforward fairly be would it that thought Gottesfeld gene. the reactivating GAA—thereby case this repeats—in nucleotide the to bind to molecule a find could one some if developed be might therapeutic potential Chemistry the for disease the on paper scientific reviewinga while ago years three piqued cell’s energy-producingmitochondria. the of success the to key protein a frataxin, of tion produc the inhibit repeats the Friedreich’sataxia, Hunting ton’s disease and fragile X syndrome. In including the case of diseases, repeat triplet such 20 least at are There proteins. human vital certain for encode to unable therefore are and thousands genetic the by of sequences nucleotide their bits repeat material which in diseases repeat triplet It worked. Gottesfeld’s interest in Friedreich’s ataxia was . In passing, the author mentioned that a Nature ChemicalBiology JOEL GOTTESFELD, PH.D. GOTTESFELD, JOEL Journal of Biological of Journal . >

- - - -

About one of every 20,000 to 50,000 people in the United States has Friedreich’s ataxia, which is caused by a genetic defect that prevents adequate production of the protein frataxin.

Here, images from the Gottesfeld lab show lymphoid cells from a Friedreich’s ataxia patient.

12 A NEW THEORY

In the study, the team tested a variety of compounds While other labs across the country are working that inhibited a class of enzymes known as histone on rehabilitating the mitochondrial function that deacetylases in a cell line derived from blood cells is blocked in Friedreich’s ataxia and several drugs from a Friedreich’s ataxia sufferer. One of these in- are now in clinical trials, Gottesfeld wanted to at- hibitors had the effect of reactivating the frataxin tack the cause rather than the symptoms. gene, which enabled the production of the frataxin To do so, he drew on a new theory of why the protein. triplet repeats prevent transcription of the frataxin The researchers then went on to improve on gene in Friedreich’s ataxia, although the gene itself this molecule by synthesis of novel derivatives, remains intact. This explanation is known as the identifying compounds that would reactivate the “histone code theory.” frataxin gene in blood cells taken from 13 Fried- Histones are proteins that are the chief con- reich’s ataxia patients. stituent of the nucleosomes around which DNA is In fact, one of the compounds the researchers wrapped in cells. The new theory suggests that his- tested produced what amounted to full reactivation tones must contain certain chemical cues, includ- GETTING TO THE ROOT OF FRIEDREICH’S ATAXIA of the frataxin gene in 100 percent of cells tested. ing acetyl groups, for nucleosomes to assume the “They never failed,” said Gottesfeld, who goes formation that allows the genes they package to be out of his way to acknowledge the contributions expressed. of his lab members, including Research Associ- The paper’s authors suggest that the trip- ates David Herman, Kai Jenssen, Ryan Burnett, lets cause an unusual DNA structure that attracts and Elisabetta Soragni who were co-authors of the proteins such as histone deacetylases (HDACs), paper. Such therapeutic reactivation of a silenced removing critical acetyl groups from the histones, gene has only been achieved for a handful of other packaging the histones in an inactive form called diseases. heterochromatin, and ultimately silencing the Peter Wright, Ph.D., chairman of Scripps frataxin gene. Research’s Department of Molecular Biology, com- Based on this theory, Gottesfeld and col- mented, “It’s extremely important work. The tar- leagues attempted to reactivate frataxin produc- geting of specific genes is [Gottesfeld’s] approach, tion with compounds that might block the HDACs. and it’s a different approach than what everyone Luckily, a range of such products was commercial- else has been doing. It’s very promising.” ly available, as many HDAC inhibitors have been “I’ve met the parents of many children af- developed as tools for molecular biology research fected with the disease and some of the patients,” and as potential cancer treatments. Gottesfeld said, “and it would be just a dream to be Importantly, the team’s HDAC inhibitors able to help them.” have proven uniformly non-toxic to the blood cells “They never failed.” JOEL GOTTESFELD, PH.D., on an experiment that reactivated the frataxin gene in blood cells.

A NEW THEORY 13

used in the study and do not significantly affect cell A meeting between mentor and parents was called, growth rates. Ongoing animal studies also have not and Calvin convinced them that Gottesfeld had a revealed any toxicity. If the results of animal testing bright future as a scientist. His parents relented, ATAXIA FRIEDREICH’S OF ROOT THE TO GETTING remain positive for safety and efficacy, said Gottes- and Gottesfeld finished Berkeley with a degree in feld, the HDAC inhibitors could enter human trials biochemistry. A Fulbright fellowship to Oxford as a Friedreich’s ataxia treatment in as soon as 18 University followed. months’ time. There, he lived and studied at Merton College, one of the ancient colleges at Oxford founded in BACK TO THE FUTURE 1264. During university holidays, when British stu- dents went home and the campus was quiet, Got- In some ways, Gottesfeld has come full circle in his tesfeld often dined with one of the school’s visiting journey from basic research to investigations with resident fellows, an 80-year-old English lit teacher an applied bent. Growing up in Los Angeles, and as named J.R.R. Tolkien. By 1972, Tolkien’s “Lord of an undergraduate at the University of California, the Rings” trilogy had become a cultural icon, and Berkeley in the late 1960s, Gottesfeld was set to fol- was read by just about every backpack-toting col- low other family members and become a doctor. By lege student in the 1960s, Gottesfeld included. Tolk- his sophomore year, though—as protests rocked the ien died later that year, and Gottesfeld notes one campus and Gottesfeld found himself tear-gassed of his prized possessions is an autographed copy of between classes—it was time for a change. “The Hobbit.” He found a mentor of sorts in Nobel laure-

ate Melvin Calvin, who taught organic chemistry. ANOTHER PATH Even though classes were held in a crowded lec- ture hall, Gottesfeld often stayed afterward to talk Despite Oxford’s prestige and tradition, Gottes- science, including Calvin’s research in biochemical feld saw his path elsewhere. The university’s use reactions of photosynthesis. Through persistence, of nuclear magnetic resonance technology as a tool Gottesfeld convinced Calvin to give him a summer for exploring molecular biology wasn’t sufficiently job in his lab. That cinched it. Science trumped developed at the time, says Gottesfeld, so he instead medicine. The hard part was convincing his par- opted to enter the doctoral program at the Califor- ents, who actually drove up from Los Angeles to nia Institute of Technology (Caltech). change the young Gottesfeld’s mind. There, Gottesfeld became part of an exciting “They were totally appalled,” Gottesfeld re- lab run by James Bonner, who was exploring the members. “There had never been a scientist in the various functions of chromatin, which is the DNA family before.” plus the histone proteins (and RNA) that package A Longstanding Interest in DNA

In his early days as a Fulbright fellow at Oxford University, Joel Gottesfeld was attracted to a dusty jar in a back room. The jar contained a DNA sample dating back to the 1950s that is believed to be from one of the earliest DNA extractions. “It’s extremely important work. The targeting of specific genes is [Gottesfeld’s] approach, and it’s a different approach that what everyone else has been doing. It’s very promising.”

PETER WRIGHT, PH.D.

Scientist Joel Gottesfeld (center) and his research team: (L-R) Elisabetta Soragni, Kai Jenssen, Ryan Burnett, and David Herman.

DNA within the cell nucleus. Chromatin is impor- Since the mid-1990s, Gottesfeld has focused on tant for relaying transcription information to mes- gene expression, more specifically how to bind senger RNA for recombination and for DNA repair. small molecules that can be synthesized at will to Bonner theorized that histones, instead of just serv- read any particular DNA sequence. This was made ing as a structural component of the double helix, ac- possible with a long-term collaboration with Peter tually had an active role in regulating gene function. Dervan, an organic chemist at Caltech. Their first “Bonner was one of the first people to recog- success came in using this method to find cancer- nize the importance of the histone proteins in gene fighting agents. regulation rather than just as a passive glue,” says “We found a molecule that binds to a DNA Gottesfeld, whose research still builds on that in- sequence in a gene expressed in a wide range of dif- sight today. ferent cancers,” Gottesfeld explains. “This molecule 15 Gottesfeld continued working on chromatin turns this gene off. We’ve identified a molecule that during his doctoral thesis at Caltech, and again at blocks the growth of cancer cells. Using a micro- Cambridge, where he landed a postdoctoral fellow- array experiment, when we looked at a variety of ATAXIA FRIEDREICH’S OF ROOT THE TO GETTING ship at the MRC Laboratory of Molecular Biology. human cancers, we found that the gene was over-ex- His return to Great Britain, this time for three pressed in many human cancers, and that this mol- years, gave Gottesfeld the opportunity to meet an- ecule will down-regulate in many kinds of cancers.” other influential scientist—this time the godfather of Gottesfeld and Dervan have shown the meth- DNA, Francis Crick. Crick was chair of the depart- od has efficacy in colon cancer, chronic myelogenous ment in Cambridge, and for about 18 months, the leukemia, and prostate cancer cell lines. Further two talked frequently, often about the role of chro- animal studies are necessary before the molecule matin. While Gottesfeld is an easy-going Southern can enter human clinical trials. Californian, Crick could be brash and immodest, Using a similar approach, Gottesfeld has been sometimes rubbing colleagues the wrong way. Not forging ahead with research on Friedreich’s ataxia. Gottesfeld. This endeavor has been made all the more rel- “He made science so much fun,” Gottesfeld evant by meeting parents and victims of the disease said. “He didn’t tolerate stupid ideas one bit and through the Friedreich’s Ataxia Research Alliance he would let you know when he thought you had a (FARA), which has also funded his research. stupid idea. And you had to be able to take it. He “These people are grasping at straws for es- liked discussions and arguments. I was young and sential therapies,” Gottesfeld said. “They are so cocky enough to get along with him well.” pleased to find scientists out there working on the Crick also helped Gottesfeld get a job at disease because it’s not well known.” Scripps Research in 1978, where Gottesfeld later Raychel Bartek, a member of the group and became one of the first members of the Department mother of a child suffering from Friedreich’s ataxia, of Molecular Biology. has been eagerly following the scientific develop- ments at Scripps Research. BUILDING ON BASIC BIOLOGY “We know [a therapy] is a long way off,” she Over the years, Gottesfeld has seen his interests said from Arlington, VA. “But the whole Fried- evolve from “card-carrying molecular biologist” reich’s community is very excited.” into a new hybrid that includes a powerful dose of chemistry. ERIC NIILER AND MARK SCHROPE “Structures can tell us about function and evolution and how we might use that information to design drugs, better catalysts, or even vaccines.”

IAN WILSON, D. PHIL.

Structures Working For 16 and Against Us

IAN WILSON REVEALS THE SHAPE OF PRESENT AND FUTURE PANDEMICS

Ian Wilson has had another big year. Not only did the disease or been killed in an attempt to stop its his work shed light on the threat of an avian flu spread. pandemic and other hot topics, he presided over the But the greater worry is that the virus may opening of a new facility at The Scripps Research not stay in birds. To date, the spread to humans Institute that puts him on the fast track to solve of the H5N1 avian influenza virus—the strain of even more critical biological structures, faster. current concern—has been limited, with some 240 Why focus on structures? The architecture documented severe infections and 140 deaths in of a molecule can offer tantalizing clues about our Indonesia, Vietnam, Thailand, Cambodia, China, STRUCTURES WORKING FOR AND AGAINST US basic biology, health, and disease—including how Iraq, Turkey, Egypt, Djibouti, and Azerbaijan as we might combat some of the major scourges of the of August 2006, according to the World Health Or- modern world. ganization. “Structures can tell us about function and But these cases are troubling. For one, the high evolution and how we might use that information mortality rate confirms that our immune systems to design drugs, better catalysts, or even vaccines,” are ill prepared to combat pathogens derived from says Ian Wilson, D. Phil., who is a professor at other hosts. While most new influenza strains come Scripps Research, a member of its Skaggs Institute to humans from other animals, for example pigs, for Chemical Biology, and principal investigator our immune systems are particularly unprepared to for the Joint Center for Structural Genomics. fight off viruses that make the more unusual jump directly to humans from birds. BIRD FLU ALERT According to Wilson, this could be what hap- Take bird flu—near the top of the list of concerns pened in 1918, when the terrible epidemic known for infectious disease experts today. as the Spanish Flu swept the world. This outbreak So far, the disease has been largely a disease of took more lives than World War I and became the poultry and wild birds, with its impact mainly an largest and deadliest influenza outbreak in record- economic one as infected flocks have been culled. ed history, killing 675,000 in the United States and An estimated 150 million birds have either died of up to 40 million worldwide. >

“The potential for the emergence of a human-adapted H5 virus, either by reassortment or mutation, is a clear threat to public health worldwide.”

IAN WILSON, D. PHIL.

18

Now, as new cases of bird flu make the headlines, abled the researchers to look at the specificity with the public is increasingly aware of the current threat which the influenza proteins bind to these sugars. from an outbreak of bird flu. Earlier this year, a poll By including closely related recombinant forms of by Harvard School of Public Health reported that these proteins in the study, the team was able to more than 60 percent of Americans are concerned identify specific amino acid changes responsible for about the possibility of a bird flu epidemic. shifting the influenza virus’s specificity. But are today’s concerns overblown? Could “It would appear that two mutations could the particular strain of bird flu now appearing in Asia change the specificity dramatically going from and Central Europe ever fully cross species lines to avian to human for the 1918 virus,” Wilson noted become a communicable disease in humans? in January, when the study was published in the Journal of Molecular Biology. A CLEAR AND PRESENT DANGER? In March, in collaboration with the Centers for Wilson and colleagues set out to assess the risk. Disease Control, the researchers followed up with a STRUCTURES WORKING FOR AND AGAINST US An avian influenza could transform into a dis- paper in the journal Science describing a specific ease contagious among humans in one of two ways. possible pathway that could enable a particularly It could evolve through mutations—and infectious virulent subtype of the H5N1 virus, isolated from a viruses are constantly mutating. Or, in a case where 10-year-old Vietnamese boy who succumbed to the a person is infected with a human flu and the bird infection in 2004, “to gain a foothold in the human flu at the same time, the two viruses could swap population.” genes—reassort—creating a new flu variation. The paper showed that a relatively small Collaborating with the Consortium for Func- number of mutations to the hemagglutinin gene— tional Glycomics, led by Scripps Research Professor the “H” in the H5N1—resulted in partial switch- James Paulson, Wilson and colleagues compared a ing of the binding site preference of the avian virus number of avian and human viruses, including rare from receptors in the intestinal tract of birds to the samples from the 1918 influenza outbreak, to gauge respiratory tract of humans. how adapted various avian influenza strains are for “The potential for the emergence of a human- entering human cells. adapted H5 virus, either by re-assortment or muta- To do this, they used a new technology devel- tion, is a clear threat to public health worldwide,” oped by the Consortium for Functional Glycomics said Wilson. “One piece of good news, however, is called a glycan array, a grid of sugars resembling the glycan array could prove invaluable in the field those found on the outside of human cells. This en- for monitoring signs that bird flu has developed the Major Flyways H5N1 Outbreaks / 2005 of Migratory Birds (August 2005)

EAST ASIA / AUSTRALIAN FLYWAY DISTRICTS WITH H5N1 OUTBREAKS SINCE JANUARY 05 CENTRAL ASIA FLYWAY EAST AFRICA / WEST ASIA FLYWAY Compiled by FAO AGAH, EMPRES Programme. BLACK SEA / MEDITERRANEAN FLYWAY Data sources: AI outbreaks: OIE, FAO and Government sources. EAST ATLANTIC FLYWAY Flyways: Wetlands International ATLANTIC AMERICAS FLYWAY MISSISSIPPI AMERICAS FLYWAY PACIFIC AMERICAS FLYWAY

19 capability of crossing the species barrier.” the University of Edinburgh in 1971 (Wilson grew While the avian flu was the big story for Wil- up in Scotland), and his D. Phil. from the University son this year, his lab has been making significant of Oxford in 1976, Wilson was given a prestigious US AGAINST AND FOR WORKING STRUCTURES contributions to a wide variety of basic and applied fellowship to continue structural work in the large, topics. In February, in collaboration with Scripps well-established Oxford laboratory of his mentor Research Professor Kim Janda (see article, page 6), David Phillips. the lab shed light on a cocaine-degrading mono- Yet, after a few months, he chose to leave it clonal antibody Fab’ fragment, important for the behind for the startup lab of Don Wiley at Harvard chain of events that breaks cocaine into nontoxic University. In fact, Wilson arrived as the only other pieces. The Wilson group also recently solved sev- full-time member of the lab other than Wiley him- eral crucial immune system structures, including self and a graduate student. TLR3 and CD1a. What lured Wilson there was what he recog- And, in other notable work, the lab has made nized as the potential of a particular research proj- key contributions to the effort to develop an AIDS ect—the attempt to use x-ray crystallography to de- vaccine (see Winter 2003 Endeavor story, “It Had termine the structure of the protein hemagglutinin to Work”). Collaborating with Scripps Research from a strain of influenza virus. As Wilson’s recent Professor Dennis Burton, who heads a scientific work on the bird flu has underlined, hemagglutinin consortium of the International AIDS Vaccine Ini- is now recognized as the major virulence factor as- tiative, the team has now helped solve the structure sociated with the virus. of three antibodies—b12, 2G12, and 4E10—that ef- In x-ray crystallography, the technique that fectively neutralize human immunodeficiency virus still underpins Wilson’s work today, scientists ma- (HIV), the virus that causes AIDS. The huge poten- nipulate a protein or some other molecule so that a tial public health impact of this work, published in crystal forms. This crystal is then placed in front of 2001, 2003, and 2005, is still being played out. a beam of x-rays, which diffract when they strike the atoms in the crystal. Based on the pattern of dif- THE POWER OF PERSISTENCE fraction, scientists can reconstruct the shape of the This string of successes from the Wilson lab is no original molecule. accident. Wilson has been demonstrating unusual But by today’s standards, the technology was tenacity and scientific acumen since he entered the primitive. Wilson recalls the crystals weren’t good, field. the diffraction was poor, and it was difficult to make After earning his B.Sc. in Biochemistry from accurate measurements. Moreover, computer sup- 20 STRUCTURES WORKING FOR AND AGAINST US vision to highlight structure as a centerpiece of the of centerpiece a as structure highlight to vision Richard’s Furthermore, ignore. to good too were crystallography and computing facilities at Scripps up set to allocated being were that resources The professor. assistant starting a for opportunity big a was department the of direction the shape help as well as colleagues one’s choose help could one where venture new exciting an of part be to nity opportu “The says. Wilson component,” key a as structure with Biology Molecular of Department newa up set to ulty,proposing was president] now he liked. something saw Wilson But it. recommend to little have to biology, seemed lecular first at institute the structural community, no biophysics, and little mo shortly after the completion of the project. With no hit twoholes-in-one. which, in science, happens about as often as golfers change— without papers both accepted editors the journal the to papers two ted submit researchers the hand, by out carried it of what Wilson was doing most nights until 6 AM. University during off hours—which meant that was unreliableColumbiaantelephonetoover line data sending of consisting limited, extremely was port Rcad enr te a ebr f h fac the of member a [then Lerner “Richard 1982, in Research Scripps at arrived Wilson some work, painstaking of years four After Image courtesy of James Stevens. James of courtesy Image virus. influenza 1918 the from trimer HA0 hemagglutinin the of representation Ribbon Nature . Remarkably,. - - - - suggests that it originated in birds. in originated it that suggests history— recorded in outbreak influenza deadliest and largest Flu—the Spanish 1918 the caused that virus the from structure A STRUCTURES THROUGH ANSWERS FINDING huge scientific problems,” says Wilson. “The use of use “The says Wilson. problems,” scientific huge tackle to consortia large of formation from benefit to becomealarge-scaleproductioncenter. of onlyfourcenterstoadvancefromthepilotstage the program. In 2005, the JCSG was selected as one of phase first the in funding receiving initially ters Protein Structure Initiative, the JCSG was the one of nine cen called determination, structure tein pro on initiative Health’snationwide of Institutes Laboratory, andtheBurnhamInstitute. nia, San Diego, the Stanford Synchroton Radiation Califor of University the Foundation, Research Novartis the of Institute Genomics the Research, Scripps from researchers 70 than which more on (JCSG), draws Genomics Structural for Center light as principal investigator of a group called Joint for collaborationandteambuilding. other skillskeytohisrecentsuccesses—atalent him, hehashadtheopportunitytodemonstrate thriving communityofscientistsgrew uparound As Wilson’s calculatedriskagain paidoffanda new department was a bold move at that time and time that at move bold a was newdepartment A TALENT FOR TEAM-BUILDING FOR TALENT A was verycompellingtome.” “The JCSG has highlighted how science can science how highlighted has JCSG “The National the to response in 2000 in Created Recently, these qualities have been in the spot

- - - - “The use of high-throughput tools and robotics for experimentation, coupled with bioinfor- matics, is very powerful and enables problems to be tackled on an unprecedented scale.”

IAN WILSON, D. PHIL

21 STRUCTURES WORKING FOR AND AGAINST US AGAINST AND FOR WORKING STRUCTURES high-throughput tools and robotics for experimen- Built as a model system by Carlsbad company tation, coupled with bioinformatics, is very power- RoboDesign (since acquired by Rigaku/MSC, Inc.), ful and enables problems to be tackled on an un- the machine is one of the largest of its kind, with precedented scale. The structural genomics centers storage capacity for 4,000 plates at up to six differ- have shown how these high-throughput method- ent temperatures as well as fully automated imag- ologies and techniques can be exported back to the ing, scheduling, and analysis software. general scientific community to facilitate biological, “Robodesign offered a fully integrated proj- chemical, and biomedical research in individual ect,” says Research Programmer Marc-André Els- laboratories.” liger of the Wilson lab, who manages the JCSG’s The high-throughput methods the group has Administrative Core. “We didn’t have to buy com- developed brings the technique of x-ray crystallog- ponents from different vendors and worry about raphy to a new level. Instead of varying conditions, having them work together.” such as temperature, ionic strength, protein concen- In fact, the new system is so automated and tration, buffer, and pH one by one (which can take integrated that scientists can put a sample of pro- months, with no guarantee of success), scientists tein in at one end, and, if all goes well, some days can run dozens of conditions at once to see if any later pick up high quality crystals to solve the struc- work. ture—a far cry from how x-ray crystallography was “With robotic crystallization, you can do things done in Wilson’s early days as a scientist. faster, more reproducibly, and with much smaller The new facility will help Wilson and col- volumes of protein,” says Wilson. “This makes a leagues meet their ambitious goal of solving be- huge difference.” tween 100 and 200 structures a year—about one every three working days. While no one knows ex- INCREASING THE ODDS actly which structures will yield their secrets next, And now, thanks to support from the Protein the odds are good that more breakthroughs are on Structure Initiative, the International AIDS Vac- the way. cine Initiative, and Scripps Research, a dedicated MIKA ONO BENEDYK robotic crystallization facility opened in May on the Scripps Research La Jolla campus.

“Human beings will always come up against infectious agents that evolve strategies for their survival, often at the cost of our health.”

MICHAEL OLDSTONE, M.D.

Fishing in Troubled Waters 23

MICHAEL OLDSTONE REELS IN CLUES TO THE RAVAGES OF PRION DISEASE FISHING IN TROUBLED WATERS TROUBLED IN FISHING

For more than a century, accepted scientific dogma scrapie in the brain. Infectious prions found outside held that only bacteria, viruses, fungi, and parasites the brain raised the possibility that heart infection could cause infectious diseases. During the past 50 could be a new aspect of prion diseases in both hu- years, however, evidence accumulated of an infec- mans and animals. tious disease of another kind. Termed “transmissible spongiform encepha- NEW TERRITORY lopathies”, these include fatal neurodegenera- In the study, which appeared in the journal Science tive diseases of humans and animals—kuru and on July 7, 2006, Matthew Trifilo, Ph.D., a postdoc- Creutzfeldt-Jakob disease in humans, scrapie in toral fellow at Scripps Research, along with Old- sheep and goats, mad cow disease in cattle, and stone and colleagues, virologist Bruce Chesebro, chronic wasting disease of deer and elk. The cause M.D., at the National Institutes of Health (NIH) most likely lies with abnormally folded infectious proteins—dubbed “prions”—with the bizarre abil- Rocky Mountain Laboratory, and cardiologist Kirk ity to cause their normal counterparts to change Knowlton, M.D., at the University of California, their shape, transforming them into deadly biologi- San Diego (UCSD), reported that 300 days after cal bullets with a latent capacity to kill. A suscep- laboratory mice were infected with scrapie in the tible person eating prion-tainted beef, for example, brain, the animals exhibited the telltale misfolded could succumb to a dementia-like disease years, prion proteins in their hearts, along with amyloid, a even decades, later. protein deposit associated with tissue degeneration. Because the diseases caused by infectious pri- Knowlton found these prions with amyloid depos- ons lay waste to brain tissue, scientists and physi- its stiffen the heart and impede its ability to pump cians have thought of them as chronic neurological blood, similar to human amyloid heart disease. conditions affecting only the central nervous sys- Unusually high levels of scrapie prions were tem. But in July, a team led by Scripps Research also identified in the blood of the same mice used Institute Professor Michael Oldstone, M.D., an- in the heart study. “This was the first time prion nounced it had discovered infectious prion pro- disease agents were found reproducibly and reli- tein in the hearts of mice previously infected with ably in large amounts in the blood,” says Oldstone, 24 FISHING IN TROUBLED WATERS of an abnormal prion. abnormal an of structure proposed a shows illustration This fection. in initial after years death and disease causing shape, their change to counterparts normal their cause to ability the have “prions”— proteins—dubbed infectious folded Abnormally

- PRIONS: MYSTERIOUS AND DANGEROUS AND MYSTERIOUS PRIONS: creased byabout10percent.” blood collections in the United States have been de addition, “In says. Oldstone supplies,” blood its of amount significant a import to forced is England may donate. outbreak cow mad the after born people only land, or more, is prohibited from donating blood. In Eng years five for countries European other many in or disease, cow mad of outbreak major a experienced three months from 1980 to 1996, when that country than more for England in lived who States United the of away.resident turned Any are donors blood potential many meat, tainted eating products by as well as blood or blood contaminated acquired through be can disease the and exists currently tious prions.” infec remove to blood treat chemically or filter to way a possibly and diseases, prion identify to test blood a of development the in help may discovery the addition, In protein. carrier a to linked ample, ex bloodstream—for the in travel prions how as could help scientists to answer basic questions such finding “This groups. research independent other three and Oldstone with directly working six ers, Scripps Reserach consists of more than 16 research at laboratory viral-immunobiology eminent whose roste od s cmiain f “protein- of aceous” and combinationinfectious”—were discovered a by Stanley is word Prions—the “This has a major economic impact because impact economic major a has “This blood the in prions detect to test no Because “No oneknowswhetherthehumancases[ofpriondisease] we’ve seenhave comeattheendofanoutbreak,orwhether we willbeseeingmanymorecasesastimegoeson.”

- - - - -

incredulity—how could proteins that lack DNA DNA lack that proteins could incredulity—how with treated first at was work Prusiner’s 1997.in Francisco,receivedwhoNobelworkPrizehis fora Prusiner,UniversityCalifornia,theof ofM.D., San named for the German scientists who first diag first who scientists German the for named Creutzfeldt-Jakob, disease. Creutzfeldt-Jakob ant vari new cow, mad of form human the contract may protein abnormal the absorb otherwise who function inthebodyisstillnotunderstood. tion, temperature control, or perhaps memory, their regula sleep as such purpose, useful a serve may prions normal that hypothesize scientists Although tissue. living harm that methods chemicals, strong very with or temperatures high extremely at only killed are proteins—and down break normally can that body the in enzymes proteases—the to sistant re indestructible, nearly are They them. against response immune typical a mount not does body the protein, normal a of copies are prions fectious in Since result. may disease that prion infectious an with contact into comes prion normal a when body, even inhealthypeople andanimals;itisonly process. like reaction- chain a in protein prion harmful the of normal prion proteins to adopt the abnormal shape forcing by replicate to believed nonliving are and They matter. living between area an in some where existing unique, biologically are seems, it replicate in the body of a human or animal? Prions, actually reproduce to able not are and RNA and Humans who eat meat from infected cattle or cattle infected from meat eat who Humans the throughout found normally are Prions MICHAEL OLDSTONE, M.D. OLDSTONE, MICHAEL ------A New Aspect of Because the diseases caused by infectious prions lay waste to brain tissue, scientists and physicians have thought of them as chronic Prion Disease neurological conditions affecting only the central nervous system. But in July, researchers published a study showing abnormal prion protein in the heart.

25 nosed it, is a neurological disease that most often been reported 50 years after initial exposure.” strikes older people, causing dementia, memory loss, hallucinations, seizures and eventually, death. INTERRUPTING PRION INFECTIVITY WATERS TROUBLED IN FISHING New variant Creutzfeldt-Jakob causes similar This latest research on prions and heart amyloidosis symptoms, but strikes much younger people, often follows a novel finding in 2005 by Oldstone’s group, in their 20s and 30s. in collaboration with Chesebro, that a variant form “Normal proteins must be in specific configu- of prion protein that lacked an “anchor” on the cell rations in order to function properly,” Oldstone membrane may be unable to signal cells to start the says. “Mad cow demonstrates that infectious ani- lethal disease process. The prion protein is normal- mal protein can convert normal human protein into ly anchored, or attached, to the cell’s surface by a malfunctioning protein that both loses its ability glycosylphosphatidylinositol (GPI) anchor. to do its job and is infectious. The question now In the study, the research team exposed two is whether there will be other similar cross-species groups of six-week-old mice to different strains of jumps as has occurred in cattle and humans.” One the agent that causes scrapie. Within 150 days of area of particular concern is meat of infected deer being inoculated with scrapie, all 70 mice in the and elk, which may be able to transmit the disease control group whose prion protein is anchored to to humans. the cell’s membrane showed visible signs of infec- Although cases of prion disease in humans tion—twitching, emaciation, and poor coordina- are, so far, extremely rare—to date, there have only tion—as well as abnormally folded infectious prion been about 150 confirmed and probable cases of protein. These mice died in 160 days. In contrast, new variant Creutzfeld-Jacob disease worldwide— 128 mice, similarly inoculated with scrapie, that had they are worrisome because of the long incubation been engineered to produce prion protein without a period before the disease manifests. There is no cell membrane anchor exhibited no signs of clinical vaccine to protect against infection, and no known prion disease. These mice lived a normal lifespan of drug stops the progress of the spongiform degenera- between 500 and 700 days. Subsequent biochemical tion once it begins. and microscopic examination confirmed, however, “No one knows whether the human cases the animals produced an abnormal form of prion we’ve seen have come at the end of an outbreak, protein and this protein could transmit disease to or whether we will be seeing many more cases as normal mice. time goes on,” Oldstone says. “It is a concern that “The diseased brain tissue resembled that kuru in Fore natives of New Guinea [who engaged found in Alzheimer’s disease,” says Eliezer Masliah, in cannibalism as part of religious rites] has now M.D., head of neuropathology at UCSD and a col- 26 FISHING IN TROUBLED WATERS ing the classic the ing read after boy young a as medicine in interested DISEASE NewYorkin Born City,became Oldstone Michael INFECTIOUS BATTLING CAREER A with prionproteinanchoredtocells. interactions preventing toward emphasis shifting diseases, prion prevent to how on views scientists’ be importantinthediseaseprocess.” but rathersignalingvianervecellmembranesmay protein prion folded however, that the abundant deposits of abnormally show, studies Our neurons. kills that disease TSE of component toxic the were proteins prion folded abnormally and plaques thought researchers most study.“Previously,the adds, on Oldstone laborator to work with viruses (in his case, the viruses that viruses the case, his (in viruses with work to fact, he was one of the first scientists at the institute immunology—in and virology of interface the at Research— whereheisstillplayingouthiscareer. Scripps at fellowship postdoctoral a landed stone Old 1966 in Maryland, of University the at school medical from and science, as well as history and literature studied he where Tuscaloosa, in bama Ala of University the from graduating teur.After Pas Louis as scientists such of work virologic and bacteriological pioneering the dramatizes which tential at Scripps because it’s a place that encour that place a it’s because Scripps at tential environment. “A scientist can develop his or her po cally important questions in an intellectually fertile biomedi explore can scientists where place of type such asAIDS. used by scientists studying other infectious diseases tinues to study these viruses; his findings have been response in persistent viral infection. Oldstone con immune effective of lack the understand to try to measles) and choriomeningitis lymphocytic cause This ongoing research could eventually alter eventually could research ongoing This At Scripps Research, Oldstone began working Oldstone lauds Scripps Research for being the Microbe Hunters Microbe per se per may not cause disease, cause not may by Paul de Kruif, de Paul by

at Scrippsbecauseit’s aplacethatencourages “A scientistcandevelop hisorherpotential

------an individual’s imaginationtosoar.” continue thiseffort.” to researchers of generation next the train to and predators natural tiny, these outwit and derstand un to best our do to is scientists as job “Our stone. Old says health,” our of cost their the at often survival, for strategies evolve that agents infectious among thelatestofmankind’s infectiousfoes. only are diseases prion says Oldstone subject, his in tamingthesethreats. played has research scientific role the and zations, civili molded and cities out havewiped these how AIDS, and mad cow disease. Oldstone writes about hantavirus, fevers, hemorrhagic other and Ebola including years, recent more in headlines captured that have the diseases as well influenza—as fever,and yellow measles, polio, up against—smallpox, come has humanity viruses famous most the of several on focuses work The Section. Book day you want to catch trout you need to cast in a pool a in cast to need you trout catch to want you ing, and fishing. A fly fisherman whose motto is, “If read surfing, body watching, bird lab, the outside life enjoys Award—also Neurovirology in Pioneer the and Award, Flexner Abraham the Medicine, in Prize International Taylor Allyn J. the cluding in awards of numerous of recipient the and Sciences Academy National the of Medicine of stitute who workheretodothebestsciencepossible.” scientists superb many the enables “Scripps stone. ages an individual’s imagination to soar,” says Old favorably reviewed by reviewed favorably History and Viruses,Plagues Oldstone haswrittenabookforthegeneralpublic, collaborator. scientific as well as friend a Chesebro, with tana Mon in fishes often Oldstone are,” trout the where “Human beings will always come up against up come always will beings “Human for fascination abiding an with scientist a As lsoewo s o a ebr f h In the of member a now is Oldstone—who In addition to editing textbooks about viruses, The New York TimesYork New The MICHAEL OLDSTONE, M.D. OLDSTONE, MICHAEL (Oxford Press, 1998), Press, (Oxford ANNA SOBKOWSKI ANNA Sun ------Celebrates Vitality, Commencement Inquisitiveness, Innovation

Commencement On Friday, May 19, The Scripps Research Institute held its 27 Celebrates Vitality, 14th commencement, celebrating 31 graduating students

and honorary degree recipients Hon. Alice Sullivan (Ret.), OUTREACH + EDUCATION Inquisitiveness, former chair and current member of the Board of Trustees, Innovation and Alexander Dreyfoos, member of the Board of Trustees.

“In ways that the founders of this program had not antici- In her address to the graduates, Sullivan emphasized the pated, the graduate program has brought a spirit of vitality, importance of an open mind, illustrating her point with an inquisitiveness, and innovation to the institute,” said Jef- image that could be viewed as either a young or old woman. fery Kelly, dean of graduate and postgraduate studies. “Our “History abounds with chance discoveries, important students make us enormously proud.” scientific achievements by researchers whose perception al- Earning a Ph.D. degree from the Kellogg School of lowed them to see what others had not,” she noted. “So, Science and Technology takes an average of five years, in when you look in your Petri dish, or mass array, or at your which the candidate attends classes, completes lab rota- computer screen, remember to look not just for what you tions, and writes a dissertation that offers an original con- expect, but also for the surprises. Take note of what isn’t tribution to the field. With 31 graduates, this year’s class is there as well as what is.” among the largest in the institute’s history. Sullivan, formerly judge on the California Superior At the ceremony, held in the Neurosciences Institute Court, is founder and chief executive officer of Private auditorium, the two honorary degree recipients—whom Judge, a firm in San Diego that provides expertise in the President Richard Lerner described as exemplary lead- resolution of business disputes, particularly in the life sci- ers—passed on their advice to the new graduates. ences and technology fields. Elected to the Board of Trust- Dreyfoos, a resident of West Palm Beach, Florida, ees in 1995, she chaired the group from 2003 to 2006, a emphasized the importance of doing what you love and en- period when Scripps Research expanded to Florida, was a couraged the graduates to take advantage of opportunities leader in federal grant revenue, and founded the first joint for networking and collaboration. doctoral degree program with Oxford University. Dreyfoos owns and directs The Dreyfoos Group, a This year’s graduating students, who were honored private capital management firm that grew out of his pre- individually at the ceremony, have gone on to hold positions vious ventures, including Photo Electronics Corporation in academia and industry, including at Stanford University, and WPEC-TV-12 of West Palm Beach. He was elected to the University of California (Berkeley and San Francisco), the Scripps Research Board of Trustees in February 2004. The Rockefeller University, Sloan-Kettering Institute for Later that year, he and his wife, Renate, announced a gift Cancer Research, Nagoya University, the California Institute of $1 million to the institute. of Technology, the University of Stockholm, and Genentech. Voices From the Education and Outreach Programs

28 EDUCATION + OUTREACH

A Life-Long Love For some students, one summer experience sparks a life-long love of science. Justin Chartron, shown here, has kept returning to the Stout lab since his internship as a high school student in 2001—not only in high school, but also of Science throughout four years of college at the University of California, San Diego, and acceptance to the California Institute of Technology, where he will begin a graduate program in biology in the fall.

listen learn explore The Scripps Research Institute’s outreach programs in California and Florida spark an interest in science among young people and encourage them to consider careers in the life sciences. From career fairs to internships, from teacher training to lab tours, the initiatives reach out to share the thrill of discovery and the rigor of the scientific enterprise.

Here’s what people are saying about this year’s activities:

Matthew Poling, graduating senior at “[My summer] project was not only very fun, it was very interesting Steele Canyon High School, now attending the University of California, San Diego. and allowed me to learn so much more about biology and biological research—things that you just couldn’t learn from a textbook. It was an amazing experience.”

Ashley Wells, 11th grade student at Palm “The summer internship at Scripps [was] a fantastic way to gain ex- Beach Gardens High School, who plans to major in microbiology at the University of perience and further my knowledge…” 29 Florida.

Todd Linke, Instructor of biology and “[The Science Partnership Scholars Program] greatly enhanced my

honors science research, Mt. Miguel High OUTREACH + EDUCATION School, San Diego. classroom instruction... providing me with information on biomedical research from researchers on the ‘front line.’”

Sherry Bowen, Living Science Coordinator “Your presentation on ‘Introduction to Science’… received high marks for Indian River Community College, to Harry Orf, Scripps Florida’s vice president from everyone. They especially enjoyed the hands-on marshmallow for scientific support operations. and spaghetti molecular structure demonstration.”

Educator reviewing the booth prepared by “[This] really cool computer interaction with physical models… could Scripps Research Professor Art Olson’s lab for the Educational Technology Fair, at- show abstract properties like charge distribution and electrostatic tended by 2,500 San Diego middle and high school students. fields with ease. These concepts are typically very difficult to visualize and explain to students, but the computer visualization made it really clear, and really simple.”

Susan Shepard, biology teacher at Jupiter “Science Saturday was terrific and the students keep talking about it. High School, Florida. Many thanks to all at Scripps who set up and ran the lab activities, an- swered questions about themselves and their research, and provided an eye-opening experience…”

The Scripps Research education and outreach programs are made possible by many generous supporters. This year, the Biogen Idec Foundation made its first donation—$25,000 to fund San Diego teacher interns. Other supporters of the California programs include: the Maurice J. Masserini Charitable Trust (administered by Wells Fargo Bank), the Arthur Vining Davis Foundations, John and Susan Diekman, Ralph and Shirley Shapiro, the William Randolph Hearst Foundation, and Oliver and Norma James. The William R. Kenan, Jr. Charitable Trust funds the Florida programs. Scripps Research Financial Highlights

FISCAL YEARS ENDING SEPTEMBER 30

Sponsored Programs Total Assets (millions) (millions)

258.2 166.6 29.2 04 265.3 04 453.0

05 327.4 278.2 226.8 62.4 05 567.4 06 322.6 330.4 226.2 76.4 06 633.0

Investments Property Other

Net Assets (millions)

04 356.4 05 419.8 06 483.1

Asset/Debt Ratio Net Income (millions) (millions)

04 (454/36.8) 12.3 04 39.8 05 (567.4/60.6) 9.4 05 63.4 06 (633.0/58.9) 10.8 06 63.3 Letter from the John J. Moores Board of Trustees Chair Chair, Board of Trustees

Dear Friends:

As federal dollars from the National Institutes of Health and other government agencies diminish and become more restrictive, our donors become ever more important to our work. Your generosity has permitted the institute to continue to make significant prog- 31 ress in improving human health. DEVELOPMENT LETTER DEVELOPMENT Philanthropy – The Year in Review The Skaggs family continued their extraordinary commitment to the institution. The Skaggs Institute of Chemical Biol- ogy permits us to tackle the most complex research problems in innovative ways across disciplines and fields. The family also established the Skaggs Oxford Scholarships. Outstanding graduate students are spending time at both our Kellogg School of Science and Technology and Oxford before being awarded a joint Scripps/Oxford degree. It is the first joint degree offered by Oxford in its 800-year history. Continuing generous gifts from Helen Dorris have helped the Harold L. Dorris Neurological Institute and the Helen L. Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute on campus make significant strides in the study of schizophrenia, Alzheimer’s disease, and other neurological disorders. An ongoing financial commitment from Mark Pearson is helping our scientists combine the latest biomedical re- search with innovative clinical treatment to fight alcohol and drug addiction at the Pearson Center for Alcoholism and Addiction Research, established by an initial generous gift from Mark. A new alliance between Scripps Research and McDonald’s is fighting the critical and growing problems of child- hood obesity and Type 2 diabetes among children. McDonald’s is investing $2 million in the initial, two-year phase of an innovative research and public education partnership. This collaboration unites Scripps Research’s world-renowned sci- entists, committed to groundbreaking research in pediatric health concerns, with McDonald’s 50-year legacy of support- ing programs that impact children’s health, wellness, and everyday lives. Our shared hope and vision for this program is that it will lead to future generations of healthy adults in America. Four years ago, we were honored to name our graduate program “The Kellogg School of Science and Technology” after our good friend, benefactor, and trustee emeritus Jean Kellogg and her late husband, Keith. In spite of its short his- tory, the school is ranked among the top ten in the nation in biology and chemistry. This year, a bequest from Keith added $1.4 million in support of the school and institute. A generous gift of $1 million was contributed this year by George and Patsy Conrades to provide unrestricted sup- port to Scripps Florida. George, a fellow trustee, has been a long-time supporter of basic research and its role in providing American society with not only new knowledge, but also critical improvements in the welfare of its citizens. Finally, an extremely generous new gift from the Alafi Family Foundation is supporting the pioneering and break- through biomedical research of the internationally renowned Dr. Charles Weissmann at Scripps Florida. The gift is providing hope to patients with serious, chronic, and life-threatening illnesses, such as malaria, tuberculosis, and prion disease, as well as their families. While these gifts are significant, all gifts from the Scripps Research donor family—whatever the amount and wheth- er they are unrestricted or directed—make our work possible. > The Need for Unrestricted Gifts Each of the above directed gifts are extremely important and integral to improving quality of health in a variety of differ- ent areas. Just as necessary are unrestricted gifts… the lifeblood of the institute. With unrestricted gifts, Scripps Research has been able to both recruit internationally recognized new scientists to produce groundbreaking new disease research, and to support the education of outstanding young scientists at the Kel- logg School of Science and Technology. There is a word that appears repeatedly in scientific literature—serendipity. Coined by English writer Horace Wald- pole in 1754, the term refers to the heroes of a fairy tale, “The Three Princes of Serendip,” who wandered freely and were forever “making discoveries by accidents and sagacity of things they were not in quest of.” Modern science is a chronicle of serendipitous discovery. Serendipity is not just dumb luck. Unpredictable results and unanticipated external factors are as much a part of scientific endeavor as cool reason, but only when strong intellect responds to an unexpected situation does serendipity work. It is axiomatic of basic scientific research—chance favors the prepared mind. 32 The Scripps Research Institute is a treasure trove of prepared minds, brilliant scientists whose discoveries can be limitless if their insight and perseverance are given the room to pursue unexpected leads.

Government Cutbacks and Restrictions – Our Challenge It is becoming increasingly difficult for researchers to wander as freely as did the Princes of Serendip. Clearly, much effort must be directed towards solving immediate practical problems, but it is the unmapped routes of basic science research that often deliver us to the most remarkable destinations. Annual funding by the National Institutes of Health has helped Scripps Research maintain its preeminent position. However, faced with growing budget pressures, Congress has cut overall government investment in scientific research by DEVELOPMENT LETTER over $772 million for this year, making it harder for our researchers to secure federal dollars. The National Institutes of Health projects a decline in the number of research grants by over 400 for the second consecutive year. Scripps Research depends on private philanthropists, like you, to enhance and extend its work in new, often nontra- ditional directions.

The Need for Personnel, Equipment, and Buildings In addition to laboratory research—the heart of the institute’s work—unrestricted gifts help cover costs of personnel and buildings which in other institutions, such as state universities, are subsidized by taxpayers. At Scripps Research, every unrestricted dollar supports research by insuring that scientists have well-qualified personnel, well-operated equipment, and well-maintained buildings available to them at all times.

Thank You! Throughout this report, you’ll find compelling quotes from our donors as to why they have chosen to support Scripps Research with unrestricted gifts. Your contributions – whatever the amount—are helping to improve the welfare of humankind. On behalf of the 3,000 staff in La Jolla and Florida, I thank you and applaud you.

Sincerely,

John J. Moores Chair, Board of Trustees Development Report

MAJOR DONORS TO THE SCRIPPS RESEARCH INSTITUTE

The Scripps Research Institute would like to thank its generous donors. Your support has helped fulfill the institute’s mission to serve humanity by creating basic knowledge in the biosciences, by applying breakthroughs in research to the advancement of medicine, and by educating and training young scientists for biomedical research and its application to human welfare. Your contributions help build a foundation of knowledge that will have a profound impact on human- kind for generations to come. On the following pages, we recognize the commitment of contributors who have opened their hearts and supported Scripps Research this year. We give special recognition in sidebars to a few of the people whose gifts demonstrate how private philanthropy advances the work of Scripps Research scientists.

Asterisks (*) indicate trustees. Double asterisks (**) indicate trustees emeritus. Daggers (†) indicate deceased. Italics indicate faculty and staff.

33 SPECIAL ACKNOWLEDGEMENT FOR LIFETIME GIFTS The following are individuals and organizations who over the years have pledged or given $1 million or more to The Scripps Research Institute. They deserve special recognition for their lifetime dedication to the advancement of biomedical science. DEVELOPMENT REPORT REPORT DEVELOPMENT

Anonymous (9) Eli Lilly and Company Lucille P. Markey Charitable Trust Alafi Family Foundation/ Ellison Medical Foundation G. Harold and Leila Y. Mathers Margaret Alafi, Ph.D. George and Wilma Elmore Foundation The ALSAM Foundation/ Elizabeth Fago McDonald’s® Corporation Mr. and Mrs. L.S. Skaggs/ Rodney B.† and Marjorie S. Fink* Mrs. James Minor The Skaggs Institute for Research Juanita L. Francis† Mr.* and Mrs. John Jay Moores American Cancer Society Jim and Sue Gilstrap National Multiple Sclerosis Society American Heart Association Glaxo Incorporated NLM Family Foundation Gordon M. Anderson Charitable Maxwell H. Gluck Foundation, Inc. Office Depot Lead Trust Dr. and Mrs. Cecil H. Green† Mark A. Pearson Arthritis Foundation/ Mr.† and Mrs. Ernest W. Hahn/ Pitman Moore, Inc. Dr. John C. Whelton Ernest W. and Jean Hahn Charitable The Rockefeller Foundation William and Sharon Bauce Family Trust Mr.† and Mrs. Donald Roon Foundation Virginia Hale† Mr. and Mrs. Leo Roon† Donald E. and Delia B. Baxter Foundation Lita Annenberg Hazen† Damon Runyon Cancer Research Dr. and Mrs. Arnold Beckman†/ Howard Hughes Medical Institute Foundation Arnold and Mabel Beckman Donald L. Hulbert† Mr. and Mrs. John Safer Foundation International AIDS Vaccine Initiative The E.W. Scripps Family/ Becton Dickinson and Company Jewish Community Foundation/ Charles Scripps Burroughs Wellcome Fund Dr. Andrew J. Viterbi* and Margaret Scripps Buzzelli† Cancer Research Institute, Inc. Erna Viterbi Nackey Scripps Loeb† George H.* and Patsy Conrades Juvenile Diabetes Research Foundation Robert P. Scripps Richard A. and Alice D. Cramer W.M. Keck Foundation Samuel Scripps Cystic Fibrosis Foundation Mr.† and Mrs.** W. Keith Kellogg II Donald P. and Darlene V. Shiley Cytel Corporation Eugene V.† and Joyce F. Klein Betty L. Springer-Baker† Lawrence J. and Florence A. De George Gladys Q. Knapp† Sam & Rose Stein Charitable Trusts† Harold L. Dorris Neuroscience Thelma E. Kuehn Charitable Lead Trust Mrs. Frank E. Sugg† Foundation Dr. Richard A. Lerner* and Dr. Nicola Buddy Taub Foundation Helen L. Dorris Foundation Lerner JEAN KELLOGG Alexander W.* and Renate Dreyfoos Leukemia and Lymphoma Society Inc.

Such good work is done here. I might not understand its scientific aspects totally, but I understand its importance. THE SCRIPPS LEGACY SOCIETY The Scripps Legacy Society is composed of individuals who have included Scripps Research as a beneficiary in their estate plans.

Anonymous (28) Mr. and Mrs. John L. Hanes Donna Prendergast Corinne E. Abel† Gloria and Gene Harper Mary Ann Quinn Shirley Ahrens Homer Harris Vincent Rinando Eileen M. and John R. Anderson, IV Margaret E. Hastings James V. Robotnik† Kenneth and Ann Bacheller Mrs. Julie Hill Mrs. Donald Roon Mike and Stella Banich Alan R. Hunter Dr. and Mrs. William R. Roush Alma Lee Barker† Mr. Okey B. Johnson, Jr. Martin I. Samuel Bruce G. Barnes Virginia Kahse James H. Sands, M.D. Mrs. William McCormick Blair, Jr.* Mr.† and Mrs. William G. Karnes Estelle Schiller Mrs. Joseph Brock Mr.† and Mrs. W. Keith Kellogg, II** Mrs. Lesly Starr Shelton David and Maggie Brown Jeffery W. Kelly William and Barbara Short Mrs. Michael Buckley Robert and Mary† Kerney Guy Showley David S. and Pamela M. Carton Eugene† and Joyce Klein Selma and Irving Singer Catherine E. Cary Walter and Virginia Kurilchyk Mr. and Mrs. L. S. Skaggs Stanley Corbin Mr. Willett R. Lake, Jr. Iris Beryl Skene Gordon Corwin Mr. and Mrs. Norman Lassey Mr. Charles L. Snow Norbert and Judith Dean Mr. William G. Lignante and Mrs. Alma F. Ms. Mary C. Soares John J. Delibos Giroux-Lignante Sam† and Rose† Stein Frank and Marion Dixon Josephine R. MacConnell Sally Stokes-Cole Raoul M. Dixon Mr. and Mrs. Sheldon Magazine Norma J.† and Frank E. Sugg† 34 Mr. Robert L. Donley Walter and Eleanor Malen Allan and Anita Sutton Kim Doren Thelma Margolies Mrs. Elizabeth Lowell Sutton Harold L. Dorris Neuroscience Winona B. Mathews Mrs. Amos Swayne Foundation Lee E. and Ruth S. Mattei Nina S. Tate Helen L. Dorris Foundation Brian P. and Ann McDonald George E. Traub† Helen Trahan Farschon John D. McKellar† Mike and Alice Volechenisky James W. Farschon Joyce and Martin Nash George R. and Nancy A. Von Arx Rodney B.† and Marjorie S. Fink* Warren M. Nichols† Robert G. and Gloria R.† Wallace Thomas H. and Alice R. Foster Mr. Edwin W. Nystrom Charitable Foundation Mrs. Allan D. Gale Ms. Lillian Owens Dorothy Welker Allan R. Gilbert K. Arthur and Kay Pagenhart Hans and Dagny Wiener

DEVELOPMENT REPORT Stanley H. Gist Barton and Lorraine Palmer Melda I. Wilcox Eugenia C. Glow Cheryl Palmer Ms. Yvonne Wylie Mr.† and Mrs. John E. Goode, Jr. Robert G. and Janette Park John and Shirley Zeien Howard Leslie Gosch Virginia A. Phipps

THE SCRIPPS COUNCIL OF 100 $100,000 and above

Anonymous (10) Lance Armstrong Foundation Burroughs Wellcome Fund Alafi Family Foundation/ Arthritis Foundation/ Cancer Research Institute, Inc. Margaret Alafi, Ph.D. Dr. John C. Whelton Mr. and Mrs. David S. Carton† The ALSAM Foundation/ William and Sharon Bauce Family Conquer Fragile X Foundation, Inc. Mr. and Mrs. L.S. Skaggs/ Foundation George H.* and Patsy Conrades The Skaggs Institute for Research Donald E. and Delia B. Baxter Foundation Richard A. and Alice D. Cramer American Cancer Society, Inc. Dr. and Mrs. Arnold Beckman†/ Cystic Fibrosis Foundation American Foundation For AIDS Research Arnold and Mabel Beckman Cystinosis Research Foundation American Heart Association Foundation Cytel Corporation Gordon M. Anderson Charitable Lead Becton Dickinson and Company Charles A. Dana Foundation Trust Bruce and Anne Bundy Foundation

MARGARET E. HASTINGS

I set up a designation with Scripps Research because I was so impressed with its reputation compared to other schools, as well as the reach and variety of the research. $100,000 and above (cont.)

Lawrence and Florence De George International AIDS Vaccine Initiative National Multiple Sclerosis Society Charitable Trust Jewish Community Foundation/ NLM Family Foundation Harold L. Dorris Neuroscience Dr.* and Mrs. Andrew J. Viterbi Office Depot Foundation Juvenile Diabetes Research Foundation Mark A. Pearson Helen L. Dorris Foundation W.M. Keck Foundation Pediatric Dengue Vaccine Initiative Alexander W.* and Renate Dreyfoos Mr.† and Mrs.** W. Keitth Kellogg II The Rockefeller Foundation Eli Lilly and Company William R. Kenan, Jr. Charitable Trust/ Mr.† and Mrs. Donald Roon Ellison Medical Foundation Richard M. Krasno, Ph.D. Mr. and Mrs. Leo Roon† George and Wilma Elmore Eugene V.† and Joyce F. Klein Damon Runyon Cancer Research Elizabeth Fago Gladys Q. Knapp† Foundation Rodney B.† and Marjorie S. Fink* Thelma E. Kuehn Charitable Lead Trust The E.W. Scripps Family/ Juanita L. Francis† Dr. Richard A. Lerner* and Dr. Nicola Charles Scripps Friedreichs Ataxia Research Alliance Lerner Margaret Scripps Buzzelli† Jim and Sue Gilstrap Leukemia and Lymphoma Society Inc. Nakcey Scripps Loeb† Glaxo Incorporated Ms. Claudia Luttrell* Robert P. Scripps Maxwell H. Gluck Foundation, Inc. Lucille P. Markey Charitable Trust Samuel Scripps Dr. and Mrs. Cecil H. Green† G. Harold and Leila Y. Mathers Mr. Mark Skaggs* Mr. Wayne R. Green Foundation Ms. Betty L. Springer-Baker Leo Guthman Fund McDonald’s® Corporation Sam & Rose Stein Charitable Trusts Mr.† and Mrs. Ernest W. Hahn/ Thomas F. and Kathy Mendoza Mrs. Frank Sugg† Ernest W. and Jean Hahn Charitable Michaux Family Foundation/ Mrs. Iva Swayne Trust Richard and Virginia Michaux Buddy Taub Foundation 35 Virginia Hale† Mid-Atlantic Connection for PKU & Allied Mr. George Traub† Lita Annenberg Hazen† Disorders Mr. and Mrs. Mike Volechenisky Howard Hughes Medical Institute Mrs. James Minor

Donald L. Hulbert† Mr.* and Mrs. John Jay Moores REPORT DEVELOPMENT

FELLOWS’ CIRCLE CHAIRMAN’S CIRCLE $50,000 and above $25,000 and above

Anonymous (2) American Society of Hematology The San Diego Foundation/ Allergan Armstrong McDonald Foundation Mr. and Mrs. Norman Lassey American Diabetes Association Donald E. and Delia B. Baxter Foundation Alfred P. Sloan Foundation Factor Foundation/ Biogen Idec Foundation Buddy Taub Foundation Kim Madeiros David A. Case, Ph.D. Dr. and Mrs. Charles Weissmann The Edmund J. & Afton S. Greenwell Jane Coffin Childs Foundation Wellcome Trust Foundation Fraxa Research Foundation Howard Hughes Medical Institute Elizabeth Glaser Pediatric AIDS John D. McKellar, D.V.M.† Foundation National Alliance for Research on Helen Hay Whitney Foundation Schizophrenia & Depression Mr. Robert W. Kerney National Foundation for Cancer Research The Claire & Theodore Morse Foundation National Hemophilia Foundation Parseghian Medical Research Foundation National Multiple Sclerosis Society Peninsula Community Foundation/ The Gustavus and Louise Pfeiffer Mr.* and Mrs. Richard Elkus, Jr. Foundation Piziali & Associates/ Christopher Reeve Paralysis Foundation Mr. and Mrs. Robert Piziali Mr. Robert P. Scripps, Sr. Damon Runyon Cancer Research Carmen Walsh† Foundation

ALEXANDER W. DREYFOOS

I was immediately impressed by the power of Scripps Research to attract great researchers, provide them with the stimulating environment of a beehive—not a bureaucracy—and give them the freedom and encouragement to pursue their work without interference. PRESIDENT’S CIRCLE $10,000 and above

Alpha One Foundation, Inc. Ms. Shirley Reid Frahm Mr. and Mrs. Edward J. Quirk ARCS® Foundation, Inc. Freeman Foundation/ James Robotnik† Bank of America Gale Freeman Ellen Browning Scripps Foundation/ Dr. and Mrs. Ernest Beutler William A. Haseltine Charitable Mr. E. Douglas Dawson Mr. Louis L. Borick Foundation Seacoast National Bank Mr. J. Gary Burkhead* H. K. Management, Inc. Mr. William G. Sommerville The Colyton Foundation Lavinia E. Holmquist† Southern Wine Institute Mr. Clarence L. Conzelman Lawrence C. Horowitz, M.D.* Mrs. Ruth Stein Mr. Gerald C. Crowther Ludwig Institute for Cancer Research Harry L. and Alice Stillman Family Linda K. Curtiss, Ph.D. Lysosomal Storage Disease Research Foundation Thomas E. Dewey Fund/ Consortium Sun-Sentinel Company Mr. Thomas Dewey* Maurice J. Masserini Charitable Trust The Unforgettable Fund, Inc. The Ray Thomas Edwards Foundation Mr. and Mrs. Frank B. Merhar Mr. and Mrs. John Valenzuela H. Fort Flowers Foundation, Inc. Money Arenz Foundation/ Mrs. Betty Wachovia Wealth Management Mr. and Mrs. Eugene Foster/ Arenz Takao Yagi, Ph.D. The San Diego Foundation Northern Trust Bank of Florida N.A. Mr. Terrence L. Zehrer

FOUNDERS’ CIRCLE 36 $5,000 and above

Ms. Corinne E. Abel† The GEO Group, Inc. Dr. and Mrs. Daniel R. Salomon Amgen, Inc. Judy Goodman, P.A., and J. John Mr. Philip D. Schofield B.E. Aerospace, Inc. Goodman, M.D. Mr. and Mrs. John H. Sexton David B. Banghart† Mr. and Mrs. Jack Greening Mrs. Lesly Starr Shelton Barclays International Realty, Inc. Hollywood Media Corporation Mr. V. DeWitt Shuck Tamas Bartfai, Ph.D. David Kosowsky, Ph.D. and Ingrid Mr. Mace Siegel John C. Bills Enterprises, Ltd. Kosowsky STAPAD, Inc. Mr. Paul J. Bowron, Jr. Mr. and Mrs. Fred Krassowski Ray Stevens, Ph.D. The Breakers, Palm Beach Lambert Foundation for Education at Mr. Earl D. Stewart, Jr.

DEVELOPMENT REPORT The Harold and Colene Brown Family Union Bank of California John A. Tainer, Ph.D. and Elizabeth D. Foundation The William Low Company Getzoff, Ph.D. Mrs. Michael J. Buckley Marriot Palm Beach Gardens Vecellio Group, Inc. Dennis R. Burton, Ph.D. Mrs. Burton B. McRoy Mr. and Mrs. Barrie O. Wall Communities Foundation of Oklahoma William A. Meyer and Denise S. Meyer Mr. George Wernham† Mr. Lawrence F. DeGeorge Foundation Mr. and Mrs. Arthur Weiner Gregory J. Del Zoppo, M.D. Nabi Biopharmaceuticals Mr. and Mrs. Robert C. Weiss Mr. and Mrs. E. Llwyd Ecclestone Jr. Oxbow Corporation The Weitz Company Mr. and Mrs. Robert J. Eichenberg The Palm Beach Post Florida Power & Light Publix Super Markets Charities, Inc.

SHELDON AND IZETTA MAGAZINE When we moved to California, we started supporting The Scripps Research Institute. We had heard so much about Scripps scientists … and found their research was wonderful. We’re very fond of the institute—it’s a great organization, and we’re pleased to be able to help. The best part about giving to Scripps Research is knowing the difference Izetta and I have made toward solving various disease puzzles and offering hope to those with devastating diseases. 1,000 FRIENDS OF SCIENCE $1,000 and above

Anonymous (1) Mr. and Mrs. Chris Ground Mr. Edwin W. Nystrom Mr. Leonard B. Allen Jiahuai Han, Ph.D. Mr. and Mrs. Gary J. Pasquinelli Altria Group, Inc. Mr. and Mrs. John L. Hanes Mr. Mildred Pilot American Women’s League of Kuwait William J. & Bonnie L. Hefner Foundation Ms. Edna F. Pulver Mr. Mark Baber Ms. Charlotte Heller Mr. and Mrs. James L. Ramsay Bank of America Corporation Mr. Fred N. Hellmann Dr. and Mrs. Vijay Reddy Mrs. Michael Baron Mr. Thomas H. Henderson Mr. and Mrs. Henry Reed Mr. and Mrs. John M. Beard Mr. Gregory P. Herbert Mr. Joel O. Rem Mr. Jerry Best Mrs. Arthur H. Hill Mrs. Louis Roripaugh Jack and Katherine Bevash Family Trust Dr. and Mrs. W. Andrew Hodge Dr. and Mrs. Wolfram Ruf Douglas Bingham and Anita Noone Mr. and Mrs. Jerry Hollander Mrs. Mary Kiyoko Sakioka Biogen Idec Foundation Mr. and Mrs. Lee Houseman Mr. Bruce Sanbonmatsu Mr. and Mrs. William N. Blatt Mrs. Marilyn E. Howe Mr. and Mrs. Yoshiya Sanbonmatsu Dr. and Mrs. Gary M. Bokoch Mr. and Mrs. Roger Howe Michael F. Sanner, Ph.D. Michael J. Buchmeier, Ph.D., and Nancy Mr. Alan R. Hunter Mrs. Helen E. Saville A. Buchmeier, Ph.D. Mr.* and Mrs. Thomas H. Insley Mr. C. Hugh Friedman and Hon.* Lynn Buck Family Foundation Mr. and Mrs. Oliver B. James, Jr. Schenk Carlton Forge Works Kim D. Janda, Ph.D. Sandra L. Schmid, Ph.D. Mrs. Catherine Cary Ms. Virginia Karnes Russ Seh Trucking, Inc./ Mr. David T. Clapp and Ms. Gayle Jeffery W. Kelly, Ph.D. Mr. Russ Seh Barsamian Mr. and Mrs. Mark Kiesel Mr. and Mrs. James E. Seitz 37 Mr. Edward T. Clare Mr. and Mrs. Richard L. Kole Mr. and Mrs. George W. Shoen Mr. and Mrs. Robert H. Colvin, Jr. David Kosowsky, Ph.D., and Ingrid George R. Siggins, Ph.D. Community Foundation of Napa Valley/ Kosowsky Mr. and Mrs. Richard F. Silva

Piziali Family Foundation Mr. and Mrs. Walter Kurilchyk Dr. and Mrs. Eugene N. Smoley REPORT DEVELOPMENT Ms. Cher Conner Mr. and Mrs. Robert C. Kyle Ms. Mary C. Soares J. Michael Cook* Mr. and Mrs. Joel Labovitz Star Milling Company Ms. Susan M. Cook Mr. and Mrs. Banks C. Ladd Mr. Richard E. Stern Mrs. Van Blackie Cooke Mr. G. R. Ladd Ray Stevens, Ph.D. Mr. and Mrs. Frank J. Cosenza Mr. W. R. Lake, Jr. Ms. Fredricka Taubitz COVX Research, Inc. Mrs. Bess Lambron Mr. and Mrs. Michael Teach Mr. John H. Crichton Mrs. Cecelia Lance Mr. and Mrs. Peter Tearse Mr. and Mrs. Lyle Cripe Mr. Robert V. Lankford Mr. and Mrs. Jack H. Thompson Mr. and Mrs. Robert William Deruntz Mr. and Mrs. George W. Lattimer Bruce E. Torbett, Ph.D. Thomas F. Deuel, M.D. Mr. Richard G. Laughrin Mr. and Mrs. Ray A. Tritten Mr. and Mrs. Ralph Dexter Mr. John M. Leiman Unicorn Jewlery & Fine Gifts Mrs. Frances Dittmer Mr. and Mrs. Jackson T. Lewis Mr. James M. Van Vechten Dr. and Mrs. Frank J. Dixon Mr. William Lipsey D. L. Van Voorhis, M.D. Dowling and Yahnke, Inc. Mr. and Mrs. Gene Littler Vanguard Charitable Endowment Mr. Roland W. Eddy Cheng Liu, M.D., Ph.D. Program Dr. and Mrs. Thomas S. Edgington Ms. Elizabeth A. Logan Mrs. Gemma Jean Venard Ms. Della Jean Elden Mr. Carl S. Maggio Mr. Earl D. Williams Mr. and Mrs. Jack Fancher Mrs. Mary C. Mason Ian A. Wilson, Ph.D. Ms. Helen Trahan Farschon Mr. and Mrs. William J. Mason Mr. and Mrs. Andrew J. Wolf James A. Fee, Ph.D. The McGraw-Hill Companies Reverend Robert M. Wolterstorff Mr. and Mrs. Stanley Fishfader Mrs. Barbara J. Menard Ms. Sybille Wyman Mr. Mark P. Freeman Microsoft Giving Campaign Mrs. Kaye Wynne Global Impact Ms. Nelle F. Minnick Mark Yeager, M.D., Ph.D. Mrs. Eugenia C. Glow Mr. Neil Morgan Mr. Jason D. Zenk Judy Goodman, P.A., and J. John Mr. Clifford R. Motoike Ms. Josephine Zolin Goodman, M.D. Mr. John C. Nicholas Mr. Gordon C. Zwirtz

JEFFERY KELLY, Ph.D.

Scripps Research needs philanthropic support for innovations in science and is one of the best charities around. I can’t think of a better gift than improving the quality of life for humankind and pushing forward the frontiers of science. $100 AND ABOVE

Anonymous (1) Mr. Walter M. Bott Mrs. Dolores Childers Mr. Eugene Abramczyk Ms. Shirley A. Bowen Mr. and Mrs. Ernest E. Chipman Mrs. Doris Dixon Ahrens Mr. and Mrs. A. W. Boyce Mr. and Mrs. Andrew J. Chitiea Mr. David A. Ahumada BPOE 1561 Bingo Charity Fund Mr. and Mrs. Harry B. Christman Alberta Heritage Foundation Ms. Mary Anne Bracy Ms. Phyllis A. Cionni Mr. and Mrs. Edward J. Alford Jeanne G. Brady, R.N. Mr. and Mrs. Jay Roger Clark Mrs. Gail L. Allen Ms. Bonnie Brae Cliffside Enterprises, Inc. Allen H. Ladd Fund Mr. Steven Bramson Mr. and Mrs. David W. Clingman Mr. and Mrs. Vito J. Altieri Mr. and Mrs. William C. Brandt Ms. Betty B. Clopton Mr. and Mrs. Ben Amador Mr. Wilbur T. Breckenridge, Jr. Ms. Betty B. Conlin American Geriatrics Society, Inc. Mr. and Mrs. Stephen A. Brennen Mr. and Mrs. Louis W. Corell Mr. and Mrs. David D. Anderson Dr. and Mrs. Melvin A. Brenner Mr. Ronald Coss Mr. and Mrs. Stanley K. Anderson Mrs. Betty M. Brock Mr. Barry M. Crane Mr. and Mrs. Joseph Anvari Ms. Christine Broder Mr. and Mrs. Gordon C. Cruikshank Mrs. Eleanor S. Armstead Mr. and Mrs. Harold F. Broecker Mr. and Mrs. Edward H. Cummings Mr. J. G. Charles Ashford Mr. and Mrs. David J. Brown Mr. and Mrs. Bemanali H. Dadbeh Mr. and Mrs. Carl Baber Mr. Todd H. Brown Mr. Joseph A. Daley III Dr. and Mrs. Sven A. Bach Mr. and Mrs. Guy Bruni Mr. and Mrs. Edward W. Danforth Mr. and Mrs. Alton Baillif Ms. Charlene Buechner Mrs. Nancy J. Daniels Mrs. Jack Baker Mr. Robert J. Buehler Ms. Victoria C. Davis 38 Mr. and Mrs. William Balduff Mr. and Mrs. Thomas Burgess Ms. Geraldine C. Davis Mrs. Robert B. Baldwin Mr. and Mrs. William Burich Dr. and Mrs. Harold A. Davis Mr. and Mrs. Richard G. Ballantine Mr. and Mrs. Thomas W. Buskirk Ms. Margaret Jo Dawes Mr. Joseph Barilla Mr. and Mrs. Lowell Buys Mrs. Eunice G. Day Alma Lee Barker Estate Mr. Norbert A. Buzz Mr. and Mrs. Manuel J. De Loura Mr. and Mrs. Thomas S. Barry Mr. and Mrs. Stanley B. Cable Mrs. Joseph Deely Mr. and Mrs. John P. Barton Mr. and Mrs. Robert B. Cahall Ms. Joan M. Delao Mr. Paul Battenberg Mrs. Joann Callahan Mr. John J. Delibos Mr. William H. Baughn Mr. and Mrs. Robert F. Callahan Ms. Caroline S. DeMar Mr. John Becker Mr. and Mrs. Albert Rea Cameron Ashok A. Deniz, Ph.D. Mr. Jeffrey Scott Beckwith Mr. and Mrs. Guadalupe L. Cano, Jr. Ms. Charlene S. Dennis Ms. Vivian Benetatos Mr. and Mrs. Alan C. Caplan Mrs. Donna K. Dennis DEVELOPMENT REPORT Mrs. Miriam Benjamin Ms. Ramona F. Carlson Mr. and Mrs. Robert D. Dennis Mr. and Mrs. B. D. Bennett Mr. Thomas L. Carlson Mr. and Mrs. Alvah W. Deweese III Ms. Robyn Bennis Miss Ann T. Carroll Mr. William Disher Mr. John H. Blair Ms. Paula A. Cavy Mr. and Mrs. Jason J. Dittmer Mr. and Mrs. Robert H. Blayney Mr. and Mrs. Robert Cecconi Mr. and Mrs. Howard R. Dixon Ms. Merrill Block Mr. George P. Chandler, Jr. Mr. George L. Dorsey Ms. Caryl Bock Mrs. Amalia I. Changala Mr. and Mrs. S. Neville Dowding Mr. and Mrs. Dieter Boegner Mr. Charles Y. Chao Mr. William D. Drake Mr. and Mrs. John Bonfiglio Mr. Stuart Alan Chapman Mr. and Mrs. Jerry Dressel Mr. and Mrs. Earl M. Booth Mr. Roy Cheatwood Eric J. Drimmer, M.D. Mr. and Mrs. Edward M. Bosanac Mr. Victor Cherniak Ms. Mary L. Driver Mr. and Mrs. Herbert E. Boss Chevron Matching Gift Program Mr. and Mrs. Robert C. Drummond Mr. and Mrs. Joseph J. Botka Mrs. Esther M. Chew Mr. Dale Dubach

My husband, Rod, died of non-smoker’s lung cancer. The experience of that devastating disease, added to my general interest in science, prepared me to ask MARJORIE FINK questions and understand the answers I received when I began to look into Scripps Research. What I heard when I met the scientists in Florida, and what I saw when I toured the labs in California, convinced me to make a commitment to Scripps Research sooner rather than later. After seeing so much work in so many areas of science being started in Florida—and already under way in California—I decided not to restrict my gift to any particular area of science, but to make an investment in the future by allowing Scripps Research to put the money for research where it is most needed. $100 and above (cont.)

Mr. and Mrs. Michael Dunlap Mr. Raymond L. Gordon Mr. and Mrs. Anton J. Honczarenko Mr. Torrence W. Dust II Ms. Henrietta A. Gorski Mr. and Mrs. Donald E. Hopkins Mr. and Mrs. Milt Earnhart Mr. Harvey J. Gosch Mr. and Mrs. Richard Hornbeck Mr. Borje Ekberg Mr. Hugh Gottfried Ms. Tena M. House Mr. J. William Ekegren Mrs. Lois R. Gottlieb Mr. and Mrs. Robert W. Howey Mr. Henry E. Elizagaray Mr. Carl H. Gottwald Mrs. Frances G. Hunter Mr. and Mrs. Daniel R. Endresen Mrs. Mack E. Gould Mr. and Mrs. Nihad Hussain Mr. and Mrs. David D. Ernst Mr. B. W. Goulding Mr. Peter Barton Hutt Mr. and Mrs. James W. Evans Mr. and Mrs. J. Allen Graham Mr. George T. Ikeda Mr. and Mrs. John E. Evenson Mr. and Mrs. James V. Grasso Mr. and Mrs. John C. Ingram Mr. and Mrs. Richard L. Fanyo Mr. and Mrs. William A. Graul Mr. and Mrs. Jack Innis Mr. and Mrs. Gary Farber Mr. Sidney Grazi Mr. and Mrs. Howard H. Irvin Ms. Geraldine E. Faucett Mr. and Mrs. Matthew E. Greco Mr. and Mrs. David L. Isa Mr. and Mrs. Robert Faulk Dr. Oscar and Rita Greene P. J. Janssen, M.D. Mrs. Walter Feathers Mrs. Ruby L. Gregovich Ms. Patricia R. Jeane Ms. Martha L. Ferris Mr. W. H. Gremsgard Mrs. John A. Jenkins Ms. Louise M. Fienga Mr. and Mrs. E. Eugene Griep Mrs. Lula Belle Jenkins Mr. Michael H. Finnell Mrs. Juliette Grisay Ms. Charlotte E. Jenks Mr. Scott Hickman and Ms. Patricia Fisher Mr. and Mrs. Frank Grunow Mr. Gregory Johns Ms. Billie J. Flemins Mr. and Mrs. Larry R. Guglielmana Mr. and Mrs. Milton J. Johnson Mr. Toby Flores Mr. Bo Gustafson Mr. Roger L. Johnson 39 Mr. and Mrs. Gorman Fong Ms. Marian Guthrie Mrs. Carole F. Joyce Mr. and Mrs. Charles M. Forsyth Mr. and Mrs. Donald E. Guy Just Give.Org Mrs. Frances B. Fortson Mr. Jeffrey Hachlowski and Ms. Diane Mrs. Frances R. Kahan

Howard S. Fox, M.D., Ph.D. Baker Mr. and Mrs. Robert J. Kalinowski REPORT DEVELOPMENT Mr. and Mrs. Larry G. Frahm Mr. and Mrs. Raymond L. Haight III Mr. and Mrs. Kory Kassardjian Mr. Douglass H. Frapwell III Mr. Jack L. Halford Mr. Joseph E. Kelley Mr. and Mrs. Robert Frazier Dr. and Mrs. Harold R. Hall Ms. Adele Kelly Mr. Hubert I. Frey Miss Sally M. Hammes Mr. and Mrs. Robert L. Kerber Mr. and Mrs. Graham A. E. Gall Mr. and Mrs. James S. Hartung Mr. Jeff Keyes Ms. Ruth Gans Mr. and Mrs. Stephen L. Hayes Mr. and Mrs. Richard Kielhorn Ms. Linda Gates Ms. Sarah Hazel Ms. Donna L. Kisela Mr. and Mrs. L. Charles Gaunt Mrs. Dora B. Herbert Mr. and Mrs. Buster I. Kiyono Mrs. Jean A. Gay Ms. Judith D. Heslin Alan Klide, V.M.D. Mr. and Mrs. Ayyad R. Ghobrial Mr. and Mrs. Maurice J. Heyerick Mrs. Marie L. Kline Mrs. J. R. Gibbs Ms. Norma Hidalgo-Del Rio Mr. Robert K. Klinger Mr. David P. Giesing High Low Nursery Company, Inc. Ulla G. Knaus, Ph.D. Mr. Donald M. Gilbert Ms. Hildegard Hiller Knight AID Fund Ms. Ruth M. Gilbert Ms. Caroline Hobson Mr. and Mrs. Robert W. Krans Mrs. Judith Gillease Dr. and Mrs. Abram Hodes Mr. and Mrs. Robert D. Kravet Mr. and Mrs. Louis F. Giolzetti Mr. and Mrs. Frank W. Hoehn Ms. Elizabeth Kuhn Mr. Michael Glass Ms. Rosamond M. Hoerr Mr. and Mrs. Brad S. Kumagai Mrs. Edward Goldfarb Mr. and Mrs. Wayne W. Hoffman Dr. and Mrs. Mitsu Kumagai Mr. and Mrs. Larry Goodman Mr. and Mrs. Harold C. Holden Mr. Richard P. Laabs Mr. John Scott Gordon Mr. Robert G. Holder Dr. Gilbert Ladd

WILLIAM R. ROUSH, Ph.D.

The character of Scripps Research is every bit as exciting as Harvard or MIT, institutions where large endowments help pay for competitive and expensive scholarships, fellowships, and named professorships. That is why my wife Rosalie and I made the additional commitment of writing my new institution into our will shortly after moving our family from Michigan to join Scripps Florida. $100 and above (cont.)

Mr. and Mrs. David W. Lang David P. Millar, Ph.D. Pasadena Foundation Mr. and Mrs. William M. Laub, Sr. Mr. Donald E. Miller Ardem Patapoutian, Ph.D. Mrs. Jacquelin R. Leisz Mr. John L. Miller Ms. Genevieve Pawlowski Mr. and Mrs. Cecil E. Libbey Mr. Newell L. Miller Mr. and Mrs. Edward L. Pearson Ms. Barbara Lifland Mr. and Mrs. William A. Miller Mr. and Mrs. Ralph T. Peck, Jr. Ms. Ruth W. Littlefield Mr. Henry E. Millson III Mr. and Mrs. Robert L. Pelmear Mrs. Frank M. Long Mr. and Mrs. Dean S. Mitchell Ms. Jean E. Pepper Mr. and Mrs. Paul A. Longwell Wong K. Mon Ms. Milena Pesic Mr. and Mrs. Michael G. Lovas Mr. and Mrs. Richard P. Montelius Mrs. Ann F. Petersen Mr. William R. Machgan Robert Moore, Ph.D. Mr. Jeff Peterson Mr. Graham J. MacHutchin Mr. and Mrs. Eduard E. Morf Colonels Carl and Lorraine P. Phillips Mr. Wenceslao Magana, Jr. Mr. John A. Morrill, Jr. Ms. Catherene M. Phillips Mr. Michael D. Magee Mrs. Patricia B. Morris Mr. and Mrs. Rudolph E. Piltch Mr. Paul T. Mailander Mr. and Mrs. J. Mukai Mr. Albert Pinamonti Mr. and Mrs. Walter Malen Mr. David Mulholland Mr. and Mrs. Tori Pitruzzello Manchester Feeds, Inc. R. S. Mullen, M.D. and Barbara Mullen, Mr. and Mrs. Ronald J. Piziali Mrs. Mary V. Mandra M.D. Mr. and Mrs. Keith E. Plank Dr. and Mrs. Norman E. Mann Mr. and Mrs. Donald L. Mullin Ms. Sharon Jo Ponder Mr. Kenneth J. Marco Mr. and Mrs. Vincent R. Munar Ms. Natalie G. Pope Athina Markou, Ph.D. Judith Munoz, Ph.D. Mr. and Mrs. Kenneth N. Prairie Mr. Jacob H. Marquette Mr. and Mrs. James E. Munyon Mrs. Donna Prendergast 40 Mr. and Mrs. Christopher Marsh Ms. Rosemary Mae Murrey Princeton Produce Mrs. Stephanie Martin and Mr. Younes El Mr. and Mrs. Herbert Nagler The Prudential Foundation Cheddadi Mr. and Mrs. Vinay K. Nagpal Mr. Terry Quinn Mr. and Mrs. Frank E. Mason Ms. Monique Najafi Mrs. Steve F. Ramirez Rev. Hiroshi Matsushita Mr. Juan Naves Mr. and Mrs. Gerald H. Ramsey Mr. and Mrs. Lyle T. Mattes Mr. and Mrs. Robert D. Nelson Mrs. Jane B. Ramsland Mrs. Robert W. Mattson Ms. Vivien A. Nelson Mr. and Mrs. Rodney Rancik Mr. and Mrs. Norbert J. Mayer Ms. Linda A. Nelson Mr. Jason Ratledge Mr. and Mrs. James McCall Mr. and Mrs. Herman C. Nester Mr. Ronald D. Ribyat Mr. and Mrs. Don L. McCarty Network for Good Ms. Ida M. Ricci Mrs. Margaret Ann McClure Ms. Mary Lacey Nohrden Mr. and Mrs. Gerard A. Rich

DEVELOPMENT REPORT Ms. Bonnie E. McCosh Mr. William E. Norgren Mr. and Mrs. James K. Richardson Mr. James D. McCoy Ms. Frances F. Obler Mr. and Mrs. Ray Richardson Mr. Charles W. McCracken Mrs. Donovan O’Donnell Mr. Lyle L. Richmond Mr. and Mrs. G. Christopher McCullah Ms. Ruth Dale Ogilby Mrs. Ruby Riggle Mr. and Mrs. Brian P. McDonald Arthur J. Olson, Ph.D. Mr. and Mrs. Clarence B. Rimbey Mr. John T. McFarland Oregon Health & Science University Mrs. Montie C. Rimbey Mr. Stuart D. McIntosh Mr. Saghir A. Osmani Mr. Arthur Robbins Kenneth McLennan Mr. and Mrs. Maynard Ostrow Mr. Richard D. Robbins Mr. and Mrs. George M. McRoberts Ms. Felicia A. O’Sullivan The Roberts Bros. Foundation Mr. Donald E. McRoberts Joanne Overleese, M.D. Mr. Arthur M. Robinson Mrs. Natalie D. McWhinney Mr. and Mrs. James C. Paccione Mr. and Mrs. Howard C. Rodean Charles Otis McWhorter† Mrs. Lillian F. Paden Mr. and Mrs. Gary L. Rold Mr. and Mrs. William C. Mertz Mr. and Mrs. Dominic Panasiti Ms. Eleanor G. Rones Mr. and Mrs. Kenneth J. Metzgar Mrs. Anne G. Parker Mr. Ralph Roos Ms. Margery A. Mico Mr. and Mrs. John C. Parker Hugh Rosen, M.D., Ph.D. Microsoft Matching Gifts Program Ms. Rosemarie Paroz Mrs. Mary B. Rosenkoetter Mrs. Katherine A. Mikals Mr. and Mrs. Edgar Parsons Ms. Jolene Roth

MIKE AND ALICE VOLCHENISKY

We believe that Scripps’s outstanding researchers and scholars have contributed many seminal discoveries and will continue their superior efforts in their chosen fields. There are always new things to discover and we hope our gift will help—you can take one peel off the onion, but there’s more to follow. $100 and above (cont.)

Ms. Evelyn O. Roy Ms. Corinne St. Clair Mr. Ernest E. Van Dorn Royal & Ancient Order of Snowgoose Mr. and Mrs. Paul Stancik Mr. and Mrs. John G. Van Meter Club Mr. and Mrs. William F. Stansfield Mr. and Mrs. Charles O. Van Note Jr. Mr. and Mrs. Michael D. Rubin Mr. Harry R. Statler Ms. Patricia Van Sickel Mr. and Mrs. Robert E. Salrin Mr. and Mrs. Morris Stein Mr. and Mrs. Richard H. Vaughan Dr. Robert A. Sanchez Dr. and Mrs. Donald A. Stewart Ms. Maria C. Wallach The San Diego Foundation/ Mrs. Patricia Brander Stewart Ms. Lorene Walsh Manny Prupes Fund Mr. and Mrs. Scott D. Stone Ms. Jeanne M. Walthuis Erica Ollmann Saphire, Ph.D. Stowers Institute Dr. and Mrs. Brian W. Wamsley Mr. and Mrs. Horace D. Sapp Mr. and Mrs. Robert H. Street Mr. and Mrs. Allen M. Weinert Mr. and Mrs. David T. Sari Mr. Corbin T. Strickler Friedbert Weiss, Ph.D. Ms. Corinne Sawyer Dr. and Mrs. Paul J. Styrt, D.M.D. Ms. Eugenia Lerner Weissman SBC Employee Giving Mr. John D. Sullivan Ms. Kimberly Weisz Mr. and Mrs. Bernard Schatz Dr. and Mrs. John Sullivan Mrs. Eleanor J. Wildt Ms. Alice Thornton-Schilling Mrs. Elizabeth Lowell Sutton Victor H. Wildt Mrs. Vesta Jenks Schmidt Mr. Earl H. Swanson Mr. and Mrs. Grant H. Wilford Ms. Dorothy B. Schrickel Mr. Charles J. Sweeney, Jr. Mr. and Mrs. Harold J. Wilkins Ms. Virginia A. Schulz Mr. and Mrs. Peter Tagni Donald Grey Wilson, Ph.D. SCME Mortgage Bankers, Inc. Mr. and Mrs. Gilbert F. Tarin Mr. and Mrs. Virgil O. Wodicka Mr. and Mrs. Gerald A. Scott Mrs. Wanda W. Tarpey Mr. Enrique V. Wong Brig. General and Mrs. L. R. Seamon, Mr. Vern L. Taylor Mrs. Jer K. Woo USMC (Ret.) Mr. Nicholas S. Teel Mr. and Mrs. R. Keith Woodstra 41 Mr. and Mrs. Carl W. Sedler Temple Aliyah, Inc. Mr. John Worsley Mr. Harold E. Sells Mr. Edwin W. Terry Mr. and Mrs. Thomas M. Wright, Jr. Sempra Energy Mrs. George D. Thomas Mr. and Mrs. John E. Wright DEVELOPMENT REPORT REPORT DEVELOPMENT Mr. and Mrs. Raymond J. Settimo Mrs. Earl M. Thompson Mr. Jason S. Yamashita Ms. Jeanette Shammas William J. Thorpe, M.D. Mr. and Mrs. Charles Yanofsky Mr.* and Mrs. Ralph J. Shapiro Mrs. Carolyn F. Thorson Drs. David and Natalie Yates Mrs. Nina Blake Sharp Mr. and Mrs. Jerome A. Thrall Mr. and Mrs. Nick E. Yocca Mr. and Mrs. Michael Sherman Mr. and Mrs. Jack Togut Mrs. Lynne G. Zabka Mr. and Mrs. George J. Shipp Mr. and Mrs. Turk T. Tokita Mr. and Mrs. Albert W. Zarella Mr. and Mrs. Carter Shrum Mrs. John M. Tomasch Mr. and Mrs. John Thomas Zeien Mr. and Mrs. Bertram N. Shure Mrs. Meridona B. Tomlinson Mr. and Mrs. Marvin L. Zepede Mr. Lewis Silverberg Torrey Pines Bank Mr. and Mrs. Scott Zimmerman Mr. and Mrs. Alvin M. Singer Mr. and Mrs. James R. Troutt Mrs. Lawrence C. Zonker Mr. Kenneth L. Sleeper Mr. and Mrs. Philip D. Troyke Mr. and Mrs. Allen J. Smith Mr. and Mrs. Rudy K. Tsujimura Mr. and Mrs. James Lacy Smith Mr. and Mrs. Hsing C. Tuan We have done our best to make this list Mr. and Mrs. Kevin S. Smith Mr. and Mrs. William H. Tulloch an accurate reflection of gifts to Scripps Colonel and Mrs. Robert W. Smothers Ms. Nora J. Turner Research from October 1, 2005 to September Mr. and Mrs. Joel R. Smulson Mr. B. W. Ullmann 30, 2006. If errors or omissions exist, please Mr. and Mrs. Charles W. Snead United Way of San Diego County accept our apologies and call us at (858) Mr. John Soltis University of California - Irvine 784-2037. Thank you, Scripps Research Mr. and Mrs. Robert T. Sopko Mr. David Valentine Development Staff. Mr. and Mrs. Leon Spaugh Mr. and Mrs. Harvey C. Valley Mr. James E. Spear Valley Rentals

I contribute to Scripps Research because its research mission is so terribly important

to improving our health and that of future THOMAS E. DEWEY, Jr. generations. Opportunities for Giving

Gifts to The Scripps Research Institute fund cutting-edge research on prevention, diagnosis, and treatments for human disease by providing the margin of excellence and innovation that has distinguished the institute since its beginning.

EVERY GIFT IS IMPORTANT. Gifts made without restriction support laboratory work while helping provide the physical and human infrastructure required to support it. Gifts may also be designated for specific purposes, such as research on a particular disease, gradu- ate school fellowships, or specialized equipment and technology. Gifts of real estate, gifts by bequest, and gifts using other planned giving vehicles, such as trusts, can offer attractive tax advantages and can be customized to fit the donor’s needs.

For more details, or to discuss your gift, please contact the development office at (858) 784-9367 or (800) 788-4931. In Florida, please contact the office of external affairs at (561) 656-6400. Or simply go to the Give Now page atwww.scripps.edu/philanthropy .

Here is more information on some of the current opportunities for giving.

42 UNRESTRICTED GIVING

In addition to laboratory research—the heart of the institute’s by Tamas Bartfai, Ph.D., former head of central nervous system work—unrestricted gifts help to meet the costs of buildings and research at Hoffman-LaRoche (a pharmaceutical company in personnel which in other institutions, such as public universities, Basel, Switzerland) and former chairman of the department of are subsidized by taxpayers. At Scripps Research, every unre- neurochemistry and neurotoxicity at Sweden’s Stockholm stricted dollar supports research by insuring that scientists have University. well-maintained buildings, well-operated equipment, and well- qualified personnel available to them. Naming Opportunities

DEVELOPMENT REPORT The center seeks private funding to supplement the original grant DISEASE RESEARCH PROGRAMS of $10 million in order to recruit additional senior faculty (named faculty chairs at $1,500,000 each), establish named fellowships Gifts can be designated for centers, programs, or departments: ($1,500,000 each), and create visiting professorship appointments of four months ($50,000 each). Specific program funding in the THE CENTER FOR INTEGRATIVE MOLECULAR range of $50,000 to $300,000 for new scholars is also a priority. BIOSCIENCES The Center for Integrative Molecular Biosciences (CIMBio) is a THE HELEN L. DORRIS CHILD AND ADOLESCENT collaborative effort to foster multidisciplinary studies of molecu- NEURO-PSYCHIATRIC DISORDER INSTITUTE lar machinery, with the aim of determining molecular structure, The Helen L. Dorris Child and Adolescent Neuro-Psychiatric mechanisms of action, and dynamic behavior in the context of Disorder Institute was also established with a generous gift from living cells and whole organisms. Current work at CIMBio fo- Helen Dorris, a mental health advocate. cuses on developing critical new electron and light microscopy The institute was created to investigate the pathological ba- technologies for imaging molecular machinery at both structural sis of neurological and psychiatric disorders. Benjamin Cravatt, and cellular levels. Ph.D., its director, leads in recruiting an interdisciplinary team of scientists to focus on understanding neuropathology in children THE HAROLD L. DORRIS NEUROLOGICAL and adolescents and finding new treatments for their conditions. RESEARCH INSTITUTE The Harold L. Dorris Neurological Research Institute was found- Giving O pportunities ed in 1999 as the result of a long-term commitment by the Harold Gifts of all sizes are welcome. Contributions of $1,000 or more L. Dorris Foundation under the leadership of Helen L. Dorris. entitle a donor to annual membership in The Scripps Research Institute’s donor group, 1,000 Friends of Science. A commit- The center investigates a variety of neurological disorders, includ- ment of $150,000 will establish a research fellowship to support ing schizophrenia and Alzheimer’s disease, as well as increasing the work of a senior scientist for two years. A commitment of scientists’ understanding of the aging process in the brain. The $75,000 will help fund a laboratory bearing the name of the donor center has attracted an international team of brain specialists, led or loved one. THE INSTITUTE FOR CHILDHOOD AND The center aims to increase Americans’ awareness of growing NEGLECTED DISEASES health problems—such as the critical connection between obesity, For a number of years, researchers have attempted to use gene diabetes, and cardiovascular disease—and to translate advances therapy and other treatments against cystic fibrosis, muscular in basic research into improved clinical practice. dystrophy, childhood deafness, and certain forms of cancer. Al- The center’s work includes: 1) educational projects in col- though none of these efforts has led to consistent success, col- laboration with individuals, foundations, and corporations to lectively they have laid the groundwork for more successful ap- improve Americans’ health understanding and behavior from a proaches. In other cases, such as autism, scientists are only now solid scientific basis; 2) special centers, funded by philanthropy, uncovering genetic clues that may lead to better treatments. The to advance clinically directed research in disease areas of interest majority of the world’s population lives in developing countries to donors; and 3) worldwide referral and connection to the best where parasitic diseases such as malaria and river blindness re- medical specialists in any area of diagnosis or therapy, based on main pandemic. The institute uses the latest advances in biology individual and family consultations and preparatory conferral by to target therapies for these persistent problems. Dr. Van Herle with physicians and other health professionals who will be involved in the patient’s care. Naming Opportunities Gifts of all sizes are welcome; some naming opportunities are still Giving Opportunities available. A commitment of $150,000 will establish a research fel- Additional funding would facilitate: 1) the hiring of experts in lowship to support the work of a senior scientist for two years. A public health education to reach out to additional communities, 43 commitment of $75,000 will help fund a laboratory bearing the especially in underserved areas both locally and across the coun- name of the donor or loved one. try; 2) an expanded education program on health-related subjects in Scripps Research scientists’ areas of expertise; and 3) the de- DEVELOPMENT REPORT REPORT DEVELOPMENT THE PEARSON CENTER FOR ALCOHOLISM AND velopment of computer programs and other material for children, ADDICTION RESEARCH the elderly, and underserved populations. Established in 2003 through a gift from Mark A. Pearson, a real estate investor-developer in Palo Alto, California, the Pearson ENDOWMENT Center combines the latest biomedical research with new clinical treatments to fight the devastating, costly, and deadly disease of An endowment gift to establish a faculty chair at The Scripps alcohol and drug addiction. Research Institute is one of the most meaningful and lasting gifts The Pearson Center complements and reinforces traditional available to a donor. Such a gift perpetuates the donor’s philan- treatments by focusing on the physiological changes in the brain thropy by creating a permanently funded position, named by or that drive excessive drinking and drug use and create vulnerabil- for the donor, which may be occupied in succession by major fig- ity to relapse. Researchers are studying the ability of new com- ures in the world of biomedical science. The benefits far outlast pounds, designed at Scripps Research and elsewhere, to modulate the life of the donor and will be both enjoyed and acknowledged the neurological effects of alcohol, reduce excessive intake, and by generations to come. prevent relapse by normalizing the brain during an alcoholic or addict’s recovery. Naming Opportunities The prospects for enhancing traditional treatment of alcohol- A named faculty chair to be occupied by a dean, director, or de- ism, addiction, and relapse through pharmaceuticals have never partment chair can be established by a gift of $3,000,000; a senior been more promising. At Scripps Research, scientists have identi- faculty chair can be established for $2,000,000. Other endowment fied a large part of the neuro-circuitry involved in the reinforc- opportunities—such as the High School Student and Teacher ing action of alcohol, showing how this circuitry changes when a Science Training Program, which can be endowed with gifts of person progresses from social drinking to alcohol abuse and de- $100,000 or more—are tailored to the donor’s interests within the pendence and establishing working laboratory models that mimic programmatic priorities of the institute. this transition for use in preclinical and clinical drug studies. SCHOLARSHIPS AND FELLOWSHIPS COMMUNITY HEALTH EDUCATION THE KELLOGG SCHOOL OF SCIENCE AND As part of its new national platform, Scripps Research has estab- TECHNOLOGY lished the Center for Translational and Community Medicine in Financial aid opens doors and makes dreams possible. Scholar- La Jolla, under the leadership of Richard A. Lerner, M.D., the ships and fellowships support the best future scientists for Ph.D. institute’s president, and the direction of Katja Van Herle, M.D., study at the Kellogg School of Science and Technology, the gradu- M.S.P.H., professor of medicine and director of community health ate school of The Scripps Research Institute. education. In 1989, Scripps Research established a Ph.D. program in mac- romolecular and cellular structure and chemistry. A second Ph.D. UNDERGRADUATE SUMMER RESEARCH program, in chemistry, was created three years later to focus on INTERNSHIP PROGRAM synthetic and bio-organic chemistry. Both programs provide an Scripps Research’s Undergraduate Summer Research Intern- exceptional opportunity for a select group of outstanding and ship Program is an intensive eight-week research experience intellectually diverse students. U.S. News & World Report has for talented undergraduate students currently studying biology, ranked Scripps Research’s macromolecular and cellular structure chemistry, mathematics, physics, computer science, cognitive and chemistry program ninth in the nation in biological sciences, science, or neuroscience. The program exposes students to basic and the chemistry program sixth in chemistry and second in or- biomedical research, provides hands-on laboratory experience, ganic chemistry. and encourages them to continue their education in the sciences. Graduate and postdoctoral fellowships attract the very best The program is also committed to increasing the number of stu- applicants for graduate study—young men and women who will dents drawn from communities historically underrepresented in influence science, and society itself, as future leaders in education, the sciences. research, and industry. Their ability to study at Scripps Research, regardless of family income, is critically important for the insti- Giving Opportunities tute, for the nation, and for the future of world science. A gift of $2,500 will support the participation of one high school Gifts of all sizes are welcome. A gift of $25,000 will name or undergraduate student in the summer internship program. and support a graduate stipend for one year; a gift of $500,000 A gift of $5,000 will support the participation of one teacher in 44 will endow a graduate student stipend in perpetuity. A gift of the teacher training program or fund a one-day teacher training $10,000,000 will permanently endow the graduate program. seminar on contemporary issues in bioscience. A gift of $100,000 or more will endow an internship position INTERNSHIPS for a student or teacher. Such a gift perpetuates the donor’s phi- lanthropy by creating a permanently funded program, named by HIGH SCHOOL STUDENT RESEARCH EDUCATION or for the donor. PROGRAM Scripps Research’s High School Student Research Education BUILDINGS AND LABORATORIES Program exposes students to basic biomedical research, provides hands-on laboratory experience, and motivates young people— Investment in critically needed buildings and laboratories helps DEVELOPMENT REPORT particularly those students whose groups are historically under- ensure that The Scripps Research Institute can embrace the fu- represented—to continue their education in the sciences at this ture with confidence. The equipment Scripps Research scientists impressionable age. Students participate in spring enrichment need to do their work is as varied and sophisticated as the work tutorials in molecular biology and chemistry, a summer research itself. internship program in a research laboratory, and a mentoring In Florida, a gift of $10 million will name one of three new program with a Kellogg School graduate student who guides buildings under construction on land provided by Palm Beach them through SAT test preparation, college selection, the applica- County. In California, a gift of $8 million will name the immunol- tion essay, and financial aid search. ogy building.

SUMMER RESEARCH INTERNSHIP PROGRAM BUILDINGS AND LABORATORIES FOR TEACHERS Gifts can be made to fund the purchase of much-needed equipment Study after study has found that American schools fall short in or, in California, to support the renovation of existing facilities. helping students achieve scientific literacy. A critical element in Scripps Research enjoys one of the world’s leading private improving science education is effective teacher training. Scripps computational capabilities, with an array of computers. Research Research’s Middle/High School Science Teacher Summer Re- is also supported by x-ray crystallography laboratories, high per- search Program exposes teachers to new laboratory techniques formance NMR spectrometry including state-of-the-art 900 and and procedures, informs them about contemporary issues in bio- 750 MHz instruments, electron microscopy, optical spectroscopy, medical research, and forges long-lasting ties between secondary a centralized DNA sequencing laboratory, and a fluorescence-ac- school educators and Scripps Research scientists. The program tivated cell-sorting facility. emphasizes the scientific process, research planning, bench expe- Scripps Research scientists require state-of-the-art facilities rience, experimental design, data analysis, and interaction with and equipment to remain on the cutting edge of research and rap- laboratory personnel. In addition to an intensive, hands-on, eight- idly advancing technology. New laboratory equipment is continu- week summer experience, teachers are expected to use the labo- ally being developed to improve the efficiency and effectiveness ratory experience as a springboard to create and enhance their of basic research, and new technology provides ever-shorter paths curriculum and to become resources for other educators. from discoveries to their application in prediction, diagnosis, and treatment of disease. Gifts of discretionary funding are critically important to support the ongoing modernization of laboratories. IMMUNOLOGY DEPARTMENT GIFTS OF STOCK In 1961, internationally acclaimed immunologist Frank J. Dixon, Giving appreciated stocks or bonds may be more favorable than a Jr., M.D., came to the Scripps Clinic and Research Founda- cash donation. You can deduct the full fair market value of long- tion—along with a team of young scientists that included Charles term appreciated securities and avoid tax on the capital gains, G. Cochrane, M.D., who retired as professor of immunology in and you can deduct gifts of securities up to 30 percent of your 2005—to establish a department of experimental pathology—the adjusted gross income with a five-year carry-over option. Under genesis of The Scripps Research Institute. certain circumstances, you can also qualify for a 50 percent an- Today, Scripps Research scientists focus on potential solu- nual deduction by reducing the value of your gift. tions for some of the world’s most puzzling and pernicious dis- To answer questions about non-cash gifts of stock, bonds, or eases: lupus, diabetes, arthritis, prion disease, HIV, Ebola virus, property, call (858) 784-2037. bacterial meningitis, chronic inflammatory disease, cancer, and many others. NAMING GIFTS Using bonds, Scripps Research recently purchased its immu- The Scripps Research Institute provides many opportunities to nology building, designed specifically for the institute’s core de- name buildings, laboratories and public spaces; graduate and partment and located near both of the institute’s other signature faculty fellowships; and internships for talented students and buildings—the Beckman Building and the Skaggs Building. A teachers. naming gift of $8 million will assure the donor an unparalleled To discuss these opportunities, please call the major gifts office opportunity for legacy. at (858) 784-9365. In Florida, please call the office of external af- 45 fairs at (561) 656-6401. Other Naming Opportunities

Other naming opportunities in the immunology building include GIFTS IN MEMORY OR CELEBRATION REPORT DEVELOPMENT the following: You can make a tribute gift in memory of a friend or family mem- ber, in honor of someone special to you, or to recognize a person or Laboratory Floor / $1,000,000 couple on an anniversary, birthday, or other special occasion. Large Conference Room / $200,000 You can make your gift by phone, by mail, or at Individual Laboratory / $ 75,000 www.scripps.edu/philanthropy. We will send an acknowledge- ment card recognizing your gift to the person or persons you des- ignate. The amount of your gift will not be revealed, but you will receive an acknowledgment letter noting the gift amount. Ways to Give For more information on how to make a tribute gift or to make a gift by phone, please call (858) 784-2037.

GIFTS OF CASH, CHECKS, OR CREDIT CARDS CORPORATE GIFTS An outright gift of cash is often the simplest way to give. It is Gifts from businesses and corporations continue to pay dividends not subject to gift or estate taxes, and the gift amount can be de- by fostering the spirit of independence, innovation, and entre- ducted from your federal income tax return. If the gift exceeds preneurship that has characterized Scripps Research since its your gift ceiling for the year in which it is made, you may also be founding. Companies and their executives become involved in able to carry over the remaining deduction in succeeding years. the institution’s work as donors, as event sponsors, and at special This means that with careful planning, nearly every outright gift recognition events. Many companies encourage philanthropic to Scripps Research can be deducted. To make a credit card gift, giving by their employees and match an employee’s gift with a you can give at www.scripps.edu/philanthropy using our secure corporate contribution. server, or call (858) 784-9367—or (561) 656-6400 in Florida—to Donors interested in this opportunity should obtain the neces- provide your credit card information over the phone. sary matching gift form from their employer (usually the human To make your gift with a check, please make it payable to “The resources office), complete it, then mail it to: Scripps Research Institute,” send it with a letter or note stating whether it is unrestricted or restricted to a particular purpose, Development Office and mail it to: The Scripps Research Institute 10550 North Torrey Pines Road, TPC2 Development Office La Jolla, California 92037 The Scripps Research Institute 10550 North Torrey Pines Road, TPC2 Many companies also find that association with scientific, educa- La Jolla, California 92037 tional, or public events presented by The Scripps Research Insti- Phone: (858) 784-9367 tute provides a ready-made way to reach intelligent, motivated customers, reward clients and employees, and create community GIFTS THAT PAY INCOME FOR LIFE good will. Charitable Gift Annuity Through professional conferences such as the Scripps/Oxford A charitable gift annuity is a contract between you and The International Biotechnology Conference, public series such as Scripps Research Institute. You irrevocably transfer an asset to Frontiers in Science—held in both California and Florida—and the institute—often cash, stocks, or other securities—and the private events for donors, prospects, and community leaders, institute agrees to make fixed annual payments to you for life. Scripps Research offers a menu of corporate branding opportuni- These payments are regulated by the California Department of ties on both coasts. Insurance. To discuss ways in which your company can enjoy the divi- Payments are a set percentage of the value of your asset, and dends of being a donor or a sponsor, please call (858) 784-9367. the guaranteed rate you are paid is determined by your age when the gift is made. The older you are when you make the gift, the FOUNDATION GIFTS higher your percentage and your payment. If you choose pay- From the beginning, foundation support has helped make The ments to benefit two people, the rate is lowered, reflecting the Scripps Research Institute a world leader in science. payout for a longer span of time. The remaining value of your Almost every kind of foundation—public, independent, dis- asset at your death or the death of your loved one is the resulting ease-focused, family-run— is represented on the institute’s foun- gift to Scripps Research. dation wall of honor. The advantages to you are many. You can take an immediate 46 For more information about foundation giving, please contact charitable contribution deduction for a portion of the gift’s value, the foundation office at (858) 784-8274. and part of each annual payment may be tax-free. You may also be able to lower your estate taxes. If your asset is property that ALUMNI GIFTS has appreciated, you may be able to avoid capital gains taxes. Gifts from alumni of the institute’s Kellogg School of Science and Technology are especially appropriate. Through its graduate Charitable Remainder Trust school, the institution has invested in the future. From it, Scripps Through this plan, you establish an irrevocable trust with cash, Research alumni have gone on to positions of eminence in their securities, or other property, then determine the terms of the trust: field, reinforcing the top-ten national ranking in biology and who the beneficiaries are, the percentage of the trust’s value that chemistry given The Scripps Research Institute by U.S. News & will be paid out annually, how long the payments will be made,

DEVELOPMENT REPORT World Report. and which charity or charities receive the remainder. Gifts from alumni send a clear message of support, gratitude, A trustee (you, your financial professional, or someone else and respect, and they can be directed to the department that has you choose) manages the assets; the income beneficiaries can be had the greatest impact on the donor. They can also be made to you or others close to you. The percentage paid to you must be help provide graduate fellowships, including those named to hon- at least five percent of the trust’s value. Your income is either a or the donor or a faculty member chosen by the donor. fixed dollar amount or a set percentage of the value of the trust, depending on which plan you choose. You can also decide if you BEQUESTS want the payout to be a set period of years or for the designated A bequest is a gift by will or revocable living trust. This is an ex- persons’ lifetimes. When all of the payments have been met, or cellent choice if you want to support The Scripps Research Insti- upon the death of the last beneficiary, the trust is dissolved and tute in the future, but wish to maintain liquidity and use of your the remainder of the assets are paid to the charity or charities you assets during your lifetime. A bequest is flexible; you can adjust have designated. the terms of your gift after it is established. The full amount of For more information on gifts that pay income for life, please your gift is deductible from your taxable estate. call (858) 784-2380. A bequest can be unrestricted, enabling Scripps Research to

direct your funds where future need is greatest, or restricted for a REAL ESTATE particular program or purpose at the institute. A gift of a residence or vacation home is one of the most flexible The following is an example of an unrestricted bequest pro- in terms of benefits to you. Depending on how you structure your vision: “I give [insert dollar amount, property to be given, per- gift, you can minimize or eliminate taxes, earn additional income, centage of the estate, or ‘the remainder of my estate’] to The and continue to live in your home. Scripps Research Institute, a nonprofit corporation, tax identifi- Real estate is not limited to personal residences. It includes in- cation number 33-0435954, headquartered at 10550 North Torrey vestment or commercial properties, agricultural properties, par- Pines Road, La Jolla, California 92037, for its general use and cels of land, and more. All offer varying advantages, depending purposes.” on whether you own the property outright or share ownership, For more information on bequests, please call (858) 784-2380. and how much the property has appreciated. You can choose to give 100 percent or a percentage of the property to the institute. Although this property does need to be a personal residence You also can choose to donate any tangible personal property in- that you use, it doesn’t need to be your primary residence. It can side the building as a separate gift. be a vacation home or second home. As long as you have use of In most circumstances, your charitable contribution is based the property, you are responsible for maintenance, upkeep, insur- on the appraised value of the real estate at the time the gift is ance, and property taxes, and you are entitled to any income it transferred to the institute. Your deduction can equal up to 30 produces. percent of your adjusted gross income. On an appreciated prop- Your immediate tax deduction equals the value of the remain- erty, you avoid capital gains tax by donating the real estate to der interest, which the IRS code calculates as the present value of Scripps Research prior to its sale. the institute’s right to use your property in the future. With this Real estate is quite versatile as a gift. You can use it as an gift, you bypass the capital gains tax and you lower your estate outright gift or a bequest, or you can use it to fund a charitable taxes. When the property transfers to the institute, it is used as remainder trust, a charitable gift annuity, or a lead trust. You also you directed. can retain a life estate with your donation. Scripps Research’s planned giving counsel at (858) 784-2380 Life Estate Agreement with Gift Annuity can assist you in evaluating your property’s potential and analyz- When you pair a life estate agreement with a gift annuity, you ing the options to determine the most beneficial course for you. enjoy all the benefits of a life estate—a charitable deduction, pos- sible capital and estate tax savings, and retained exclusive use of your property—and you receive a fixed annual payment for life. 47 LIFE INSURANCE Your payment is determined by two factors: the value of the You can make a substantial gift by naming The Scripps Research remainder interest and your annuity rate established by your age Institute a beneficiary or owner of your life insurance policy. Of-

at the time of your gift. REPORT DEVELOPMENT ten, this plan enables you to make a larger gift to the institute For life estate plans, it is wise to consult with your attorney than you otherwise could. regarding the laws of your state. If you have an existing life insurance policy that is no longer For more information on gifts of residence with life estate re- needed to protect your children, your spouse, or your business tained, please call (858) 784-2380. interest, you can name the institute as the policy’s beneficiary. Because the beneficiary designation is a revocable gift, you are not entitled to an income tax deduction; the value of the policy is CHARITABLE LEAD TRUST deductible from your taxable estate. If you also transfer owner- Through this giving plan, you establish a trust that provides an- ship of the policy to the institute, you can immediately deduct nual income to Scripps Research for a set period, after which the the current value of the policy from your income taxes; if you are remaining trust assets are returned to you or your heirs. This plan still paying premiums, you can deduct the cost of those premiums can substantially lower your gift and estate taxes. each year. You also can purchase a new life insurance policy to benefit Charitable Lead Trust Plans the institute. With Scripps Research designated as the owner and A charitable lead trust is the reverse of a charitable remainder beneficiary, you are entitled to an income tax deduction for your trust. Rather than benefiting at the end of a trust’s term, as with a initial contribution and the premium payments each year. For charitable remainder trust, the institute benefits at the beginning more information on life insurance, please call (858) 784-2380. of a trust’s term. To establish a charitable lead trust, you transfer assets such as GIFTS OF RESIDENCE WITH LIFE ESTATE RETAINED cash, securities, real estate, or other property into an irrevocable When you donate your personal residence to Scripps Research, trust. The trust provides annual income to the institute for a set you earn an immediate tax deduction, and you can retain the term, then returns the assets to you or your heirs. The benefits— right to live in and use your property for the rest of your life. You which include income tax deductions and reduced or eliminated also may be eligible to earn supplemental income. gift and estate taxes—vary, based on the terms you establish for your trust and whether the trust is enacted during your lifetime or Life Estate Agreement as part of your will. You can make a substantial gift of your home to The Scripps For more information on charitable lead trusts, please call Research Institute without changing your day-to-day life at all. (858) 784-2380. When you irrevocably transfer the title of your personal residence or farm to the institute, you can maintain exclusive use of the property for life. Recognizing Our Donors

The Scripps Research Institute believes in informing and serving In addition, there are special benefits for annual contributors its donors. The institute’s excellent reputation for stewardship of at the following levels. Along with 1,000 Friends of Science, gifts, both large and small, has been well earned. they are recognized by giving level in the annual report issue of Scripps Research has three giving societies, each designed to Endeavor. inform and serve: Founders’ Circle: / $5,000 - $9,999 THE SCRIPPS COUNCIL OF 100 President’s Circle: / $10,000 - $24,999 Members of The Scripps Council of 100 support the institute’s Chairman’s Circle: / $25,000 - $49,999 mission by contributing $100,000 annually or by making a single Fellows’ Circle: / $50,000 - $99,999 contribution of $1 million or more. Gifts may be restricted or un- restricted. To learn more about opportunities and benefits for annual giv- Members are invited to meet each year in Indian Wells, Cali- ing, please contact Wil Burfitt, development officer for annual fornia, and in Palm Beach, Florida, where they enjoy private giving, at (858) 784-2037 or [email protected]. sessions specifically designed for them with Scripps Research To learn about opportunities for special gifts restricted for a 48 scientists who inform and update them on issues, trends, and particular disease, research area, or fellowships and scholarships, discoveries in biomedical research, and with Katja Van Herle, please contact Roz Hodgins, development officer for foundations M.D., M.S.P.H., professor of medicine and director of communi- and major gifts, at (858) 784-8274 or [email protected]. ty health education, who helps translate that research into terms of patient support and clinical practice. Educational sessions THE SCRIPPS LEGACY SOCIETY are interspersed with social events at which members meet and mingle with Scripps Research trustees, senior management, and The Scripps Legacy Society is composed of individuals who have scientists. made The Scripps Research Institute a beneficiary in their estate Throughout the year, members are invited to Scripps Re- plans, including those who have established a Charitable Re- search laboratories, in California and in Florida, to see firsthand mainder Trust, Charitable Gift Annuity, or Charitable Lead DEVELOPMENT REPORT how Scripps Research makes science history and helps make Trust; have given the remainder interest in their real property; or medicine’s future. have named Scripps Research as a beneficiary in their trust, will, To learn more about The Scripps Council of 100, please con- or retirement plan. tact Denise M. Scalzo, vice president of development, at (858) Members receive invitations for two to the annual Scripps 784-9365, (800) 788-4931, or [email protected]. Legacy Society luncheon, held in California, along with sub- scriptions to Endeavor, Scripps Discovers, and reserved seat- 1,000 FRIENDS OF SCIENCE ing at Frontiers of Science events. We are happy to honor any

Members of 1,000 Friends of Science support The Scripps Re- donor’s request to remain anonymous. search Institute by gifts from individuals or couples of $1,000 or For more information about becoming a member of The more a year. Scripps Legacy Society, please contact Cheryl H. Dean, planned giving counsel, at (858) 784-2380 or [email protected]. Members receive the following:

— An annual report outlining the impact of the member’s gift,

— An invitation for two to the annual 1,000 Friends of Science event, held on campus in California,

— Invitations and reserved seating for lectures and receptions called Frontiers in Science (in California) and Frontiers in Scripps Science (in Florida),

— Endeavor, Scripps Research’s magazine, and Scripps Dis- covers, a quarterly newsletter for donors. THE SCRIPPS RESEARCH INSTITUTE ENDEAVOR

VOLUME NINE / NUMBER THREE WINTER 2006/07

FEATURES: ALSO:

06 VACCINATING AGAINST OBESITY: 01 PRESIDENT’S LETTER STUDY OFFERS POTENTIAL NEW “Scripps Research is really a unique place in the collegiality APPROACH TO COUNTER WEIGHT 27 COMMENCEMENT CELEBRATES VITALITY, GAIN AND YO-YO DIETING INQUISITIVENESS, INNOVATION of its faculty and in the willingness of faculty to cross

28 VOICES FROM THE EDUCATION AND OUTREACH PROGRAMS specialized niches in order to undertake interdisciplinary 10 GETTING TO THE ROOT OF FRIEDREICH’S ATAXIA: 30 FINANCIAL HIGHLIGHTS JOEL GOTTESFELD COMES FULL CIRCLE research. The scientifc environment promotes collaboration, 31 LETTER FROM CHAIR OF THE BOARD allowing us to tackle big problems in creative ways.” 33 DEVELOPMENT REPORT 16 STRUCTURES WORKING FOR AND ERIC ZORRILLA, PH.D. AGAINST US: IAN WILSON REVEALS THE SHAPES OF PRESENT AND FUTURE PANDEMICS

22 FISHING IN TROUBLED WATERS: MICHAEL OLDSTONE REELS IN CLUES TO THE RAVAGES OF PRION DISEASE

ENDEAVOR IS A PUBLICATION OF THE SCRIPPS RESEARCH INSTITUTE

This issue of Endeavor features some of the many scientifc breakthroughs of 2006 from investigators at The Scripps Research Institute. WINTER 2006/07 VOLUME NINE / NUMBER THREE THE SCRIPPS RESEARCH INSTITUTE RESEARCH SCRIPPS THE

NON-PROFIT U.S. POSTAGE PAID PERMIT 751 SAN DIEGO, CA THE SCRIPPS RESEARCH INSTITUTE

A PUBLICATION OF THE SCRIPPS RESEARCH INSTITUTE / / ENDEAVOR

Office of Communications—TPC20 ENDEAVOR 10550 North Torrey Pines Road

La Jolla, California 92037 www.scripps.edu breakthroughs oƒ 2006

WINTER 2006/07 2006/07 WINTER

PUBLISHER: Keith McKeown

EDITOR: Mika Ono Benedyk

DESIGN: Miriello Grafico

COVER ILLUSTRATION: Rachel Salomon

PORTRAIT PHOTOGRAPHY: VOLUME Dana Neibert

PRINTING: NINE NINE Precision Litho / NUMBER

© 2006 All material copyrighted by The Scripps Research Institute. THREE