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Conrad Prebys Accelerates Discovery
B U r n h a m R eport
Boar d of Trustees
I n T h is I ssue B urn h a m R ese a r c h
The Conrad Prebys Center for Chemical Genomics
The Gift of Discovery
What One Man Can Do
The Art of Collaboration
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B urn h a m N e w s
New Faculty
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Science News
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P h il a nt h rop y
Updates
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Aroun d B urn h a m
The Tools for the Job: President’s Message
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Partners in Science
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Officers
Trustees continued
Malin B urn ha m Chairman G regory T. Lucier Vice Chairman John C. Reed, M.D., Ph.D., President and Chief Executive Officer, Professor and Donald Bren Presidential Chair Kristiina Vuori, M.D., Ph.D., Executive Vice President for Scientific Affairs; Director, Professor, NCI Cancer Center Eric Lofgren Vice President, Finance; Chief Financial Officer; Treasurer Margaret Dunbar Director of Intellectual Property Management; Secretary
Alan Gleicher W.D. Grant David Hale Jeanne Herberger, Ph.D. Brent Jacobs James E. Jardon, II Daniel Kelly, M.D. Robert Lauer Sheila B. Lipinsky Papa Doug Manchester Robert Mandell Nico Nierenberg Douglas Obenshain Peter Preuss Stuart Tanz Jan Tuttleman Andrew Viterbi Bobbi Warren Allen R. Weiss Judy White Gayle Wilson Diane Winokur Kenneth J. Woolcott
Trustees Linden S. Blue Mary Bradley Brigitte Bren Arthur Brody Howard I. Cohen Shehan Dissanayake M. Wainwright Fishburn, Jr Jeannie M. Fontana, M.D., Ph.D.
Ex-Officio Raymond L. White, Ph.D. Chairman, Science Advisory Committee
O n T h e Cover
Conrad Prebys has made a $10 million naming gift to support chemical biology at Burnham. The Conrad Prebys Center for Chemical Genomics will expand the frontiers of discovery by identifying chemical compounds that can turn genes on or off. The results of these discoveries will help biologists answer fundamental questions about how our bodies function and how disease can take hold. Beyond that, this knowledge will lead to new ways to combat disease. In the photo, Mr. Prebys is accompanied by (clockwise from the left) Xochella Garcia, Michael Hedrick, Eigo Suyama, Ph.D., and Carlton Gasior.
B l air B lum Senior Vice President External Relations Eliza bet h G ianini Vice President External Relations Ed g a r G illenwaters Vice President External Relations C hris L ee Vice President External Relations An dre a M oser Vice President Communications
Jos h Bax t Editor, Burnham Report G avin & G avin Advertising Design Nad ia Borowski Sc ott Photography Please address inquiries to: jbaxt@burnham.org
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Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037 • 858.646.3100 Burnham Institute for Medical Research at Lake Nona, 8669 Commodity Circle, 4th Floor, Orlando, FL 32819 • 407.745.2000
B u r n h a m c h emi c a l genomi c s
The Gift of Discovery
Malin Burnham, Conrad Prebys and Dr. John Reed stand next to the Prebys Center’s screening robot. A powerful tool, the robot can test more than 200,000 compounds each day for biological activity.
Burnham’s efforts in chemical genomics are gaining national attention. In the past few months, the bi-coastal center was awarded a prestigious $98 million grant from the National Institutes of Health (NIH), was the key part of a drug discovery agreement with pharmaceutical giant Johnson & Johnson and received a $10 million naming gift from philanthropist Conrad Prebys.
If you were writing a definition of public/private partnerships, this could be a case study, but what does it mean for the science? In fact, what is chemical genomics? When the Human Genome Project was completed in 2003, science had a basic blueprint of our DNA and the genes it contains. But that was only the first step. While the project answered many questions about the locations and DNA sequences of thousands of genes, it also left many questions unanswered about their function. How and why are genes turned on and off? What proteins do specific
genes produce? How do slight variations in our individual genomes affect our health? The Conrad Prebys Center for Chemical Genomics (Prebys Center) seeks to answer these and many other questions. Fin ding th e On /Off Switc h( es) In our bodies, genes code for RNAs (ribonucleic acids), which are transcribed into proteins, which do the majority of the work in and around our cells. Understanding how and why specific genes get turned on and off, and how to intervene in that process, will have a dramatic impact on human
health. For example, in a developing fetus, cells migrate, then differentiate and multiply into specific tissues—so that brain, skin, bone and other cell types are in their appropriate locations. However, similar processes allow cancer to form and spread. Locating which genes are responsible for these transitions and finding ways to turn them off could be a tremendous weapon against disease. How do you control a gene? Genetic engineering is one way. By inserting a gene, scientists can add or subtract a particular attribute. But genetic engineering has
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its drawbacks. The process is expensive and time-consuming to perform, as DNA molecules are large and cumbersome to work with. It also yields a permanent change and not all genes can be successfully inserted. Another solution is finding small organic molecules to achieve the same end. That is what the Prebys Center does. “We’re looking for small molecule probes that can get into cells and specifically turn on or turn off an activity,” says Thomas Chung, Ph.D., project manager at the Prebys Center. “Unlike genetic engineering, the change is not permanent, so you can remove the chemical if it’s not working the way you like. You can also apply more or less of the chemical to adjust the effect, like a thermostat. There are hundreds of thousands to millions of chemical compounds to choose from, and chemists are quite adept at redesigning these molecules to make them more effective.” T he Adva ntage of Autom ation Finding a molecule that can control a gene, among so many potential compounds, requires a lot of work. It helps to have tools that can scan the activity of thousands of compounds very rapidly. At the core of the Prebys Center, robotic screening systems test large chemical libraries against biological material—like a
Mark Mercola, Ph.D.
single protein or a specific type of cancer cell. These screens are designed to find the handful of molecules that can regulate a specific gene or protein—by turning it on or off. To make these discoveries, small quantities of biological material (measured in nanoliters or one billionth of a liter) are combined in tiny wells with chemical compounds and reagents, which facilitate a reaction. Each experiment, or assay, is designed to send a signal if there is a reaction—like glowing green under fluorescent light. While a person could do hundreds of these assays in a day, a robot can do hundreds of thousands. In fact, the robotic system at Burnham’s Florida facility, when operational, will have
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the capacity to do more than 2 million assay data points per day. After the appropriate incubation period, a high resolution camera photographs each plate, which contains 1,536 wells or “nano” test tubes, and sends the image to a computer where researchers can review it and see if they’ve gotten any “hits.” These hits are then cherry-picked and re-tested to confirm their potency, selectivity, biological activity and toxicity. From there, medicinal chemists and pharmacologists can improve the hits to yield more potent and less toxic compounds. Probes an d M edi cines For researchers at Burnham, and those at institutions across the nation who
have access to the center through the NIH, the hits that come from these sophisticated assays are like chemical tweezers that dissect cellular biology. For example, Mark Mercola, Ph.D., Associate Director of the Del E. Webb Neuroscience, Aging and Stem Cell Research Center, is coaxing stem cells into becoming cardiomyocytes (heart muscle cells) and small molecules may hold the key. “Embryonic stem cells must go through several steps to become cardiomyocytes,” says Dr. Mercola. “The first couple of steps are fairly well understood. But for the latter steps, the ones where the cells are closer to becoming full-fledged cardiomyocytes, we need to find molecular probes that will make these cells differentiate properly.” As noted earlier, Burnham was awarded a $98 million grant to establish a program to produce these and other types of molecular probes. In the case of embryonic stem cells, probes are molecules that help stem cells differentiate into a specific type of cell. But molecular probes could also shut down a gene implicated in tumor growth, turn on a gene associated with cell death or control the on/off switch for thousands of other genes. In some cases, these molecular probes could be suitable drug candidates.
B u r n h a m c h emi c a l genomi c s
“In the heart, there are these ‘adult stem cells’ that can regenerate tissue but they are quite rare and regeneration is very limited,” says Dr. Mercola. “If we have the molecules that work at that stage, they could help us understand the process of how a stem cell becomes a cardiomyocyte, and importantly, they could also become drugs to stimulate heart regeneration after injury.” Enter t he C hemists On the other side of the continent at Burnham Lake Nona, Gregory Roth, Ph.D., is hunting for natural compounds that can alter the proteins that cause disease. Dr. Roth, a synthetic organic chemist with more than 20 years experience in the pharmaceutical industry, has
High throughput screening specialist Carlton Gasior scans a plate for chemical hits.
already had some success. Working with Dr. Amy Wright at the Harbor Branch Oceanographic Institute at Florida Atlantic University, the Roth lab has isolated a new natural product named aphro-
Burnham Inks Deal With Johnson & Johnson Burnham has signed an assay development and license agreement with Johnson & Johnson Pharmaceutical Research and Development, L.L.C. (J&JPRD). The agreement is Burnham’s first broad-based partnership with a large pharmaceutical company. Under this multi-year agreement, Burnham will provide J&JPRD with access to highthroughput assay screening
technologies to investigate drug targets for inflammatory diseases. “This collaboration offers great synergies,” says Dr. John Reed. “Burnham has expertise in finding new targets and screening compounds to identify chemical leads, and I believe this collaboration will foster the discovery of drug products with real clinical potential.”
callistin, found in deep ocean sponges. The molecule may prove useful against pancreatic and colon cancer. But finding a compound from a natural source or designing a chemical library is only the beginning. Roth and his team of medicinal chemists and pharmacologists are in the business of making these compounds more useful research tools for biologists and perhaps even suitable drug candidates. “Our chemists are trained to build molecules by putting fragments of different atoms together,” says Dr. Roth. “That new structure is then tested to see how well it interacts with a protein, or perhaps a family of proteins. When you find a compound that yields a net functional change on a protein, you then take a very systematic approach. You first validate the interaction with the disease-causing protein
target. If the active molecule comes from a natural source, you figure out how to make it. You make changes to the molecule by adding or subtracting atoms in a very rational and systematic way. And then you test to see if you have made a better hit.” Making a better hit means creating a molecule that has a greater affinity for the protein, binding well and thus regulating its function. Dr. Roth is also trying to make these new compounds more selective, so that they bind to a specific protein or family of proteins, to decrease unwanted side effects. The lab also tests how the compound functions inside a body: Is it soluble? Is it stable in a liquid environment? Is it metabolized into something that could be inactive or more active? “This process ultimately takes us to a chemical probe, Continued on page 12
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What One Man Can Do There was nothing “wintry” about January 29, 2009, in San Diego. The air was warm; the sun blazed in a cloudless sky and a projected rain storm was, mercifully, a no-show. It was a good day to celebrate, as more than a hundred people gathered to witness the unveiling of the Conrad Prebys Center for Chemical Genomics. For Prebys, the choice to support cutting-edge research at Burnham, like many of his philanthropic decisions, was
A Few
Friends
People from throughout the San Diego region converged on Burnham to praise Conrad Prebys for his foresight and generosity. The speakers list read like a who’s who of San Diego leadership.
deeply personal. He supported the Old Globe Theater to express his fondness for the dramatic arts; the music program at the University of California San Diego because he had considered becoming a concert pianist; and the Burnham Institute for Medical Research because cancer has taken a very personal toll. “I lost four close friends to cancer last year—one to a leukemia I didn’t even know existed,” said Prebys a few days before the event. “I have been very blessed in my life, and sometimes I wonder why.
The only answer I can come up with is that I’m here to do some good in the world.” But the decision to support Burnham was more than a reaction to loss. A real estate developer with a long track record of success, Prebys is a big believer in strong, efficient management, and he wanted to be sure Burnham fit that mold. “One of the things that attracted me to Burnham is the organization itself,” said Prebys. “It seems like it’s being run like a well-oiled machine. Knowing the value of a wellrun organization, this is always uppermost in my mind.” Honoring t h e M a n The speakers at the event painted a picture of a man
Here are the people, in order of appearance, who came to honor Conrad Prebys:
Lou Spisto
Dr. John C. Reed
Dr. Michael Sise
President and CEO, Professor & Donald Bren Presidential Chair Burnham Institute for Medical Research
Director of Trauma Services Scripps Mercy Hospital
Jerry Sanders Mayor, City of San Diego
CEO/Executive Director San Diego Zoo
Lesa Mitchell
Malin Burnham
Director of Development Boys & Girls Club of East County
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deeply committed to his community—to biomedical research, hospital care, the arts, species conservation and youth empowerment. “The life science sector feels like it has a new champion and that’s exactly what we need,” said Mayor Jerry Sanders at the ceremony. “That spirit of collaboration, that spirit within our community that people step forward to help create new jobs, new clusters and research that will help us not only nationwide but worldwide.” “I’m overwhelmed,” said Prebys as he took the stage. “Accelerating the process of getting a drug to a patient and easing the suffering of even just one individual, or maybe even saving his life, that’s remarkable. The possibility of maybe saving millions, just to be a part of that, stealing a line from a commercial, that’s priceless. This is a fantastic opportunity I’ve really been waiting for, and I’m just proud to be part of the organization.”
CEO/Executive Producer The Old Globe
Doug Myers
Chairman of the Board Burnham Institute for Medical Research
San Diego Mayor Jerry Sanders
F O C U S O N F L O R I DA
The Art of
Collaboration
Dr. Kristiina Vuori with M. D. Anderson-Orlando’s Dr. Clarence Brown.
Burnham researchers will publish more than 300 journal articles this year, and virtually every one will involve a collaboration, many with researchers at other institutions: UC San Diego, Dana-Farber Cancer Institute, Sanford Health, the list goes on. The desire to collaborate with scientists both inside and outside of Burnham is fundamental to the Institute’s core values, and the expansion to Florida is only increasing those possibilities. Among many collaborations, Burnham is partnering with the Cancer Research Institute at M. D. Anderson Cancer Center-Orlando. Combining the basic research findings at Burnham with M. D. AndersonOrlando’s clinical research capabilities will help lead to new cancer treatments.
“Joining forces is already paying dividends,” says Cheryl Baker, Ph.D., Director of M. D. Anderson-Orlando’s Cancer Research Institute. “Samples from our tissue bank have advanced research by Dr. John Reed’s laboratory in California, leading to a coauthored paper in the journal Clinical Cancer Research.”
Moving Treatments Forward Though Burnham is a basic research institution, improving patient care is our ultimate goal. The route a potential medicine can take from basic concept to approved treatment can be tortuous. It is not uncommon for the process to take fifteen or twenty years, and many people believe that is far too long. Burnham and M. D. Anderson-Orlando seek to reduce the wait for new medicines by advancing basic and translational cancer research, testing new drugs that may eventually enter clinical trials and dissecting cancer biology to better understand how the disease spreads and find better ways to treat it. Burn ham Researc h Briefings In January, Kristiina Vuori, M.D., Ph.D., director of Burnham’s NCI-designated Cancer Center, was the featured speaker at a Burnham Research Cancer Briefing
at the Orlando Museum of Art. The event was presented with M. D. Anderson Cancer Center-Orlando and Women Playing for T.I.M.E. (Technology, Immediate Diagnosis, Mammography and Education), an organization committed to the prevention and treatment of cancer. Dr. Vuori discussed Burnham’s research on tumor development and metastasis and underscored Burnham’s intent to build local collaborations to speed basic and translational research, such as the partnership with M. D. Anderson Cancer Center-Orlando.
Lake Nona Facility Nears Completion Construction of Burnham’s new East Coast campus at Lake Nona in Orlando is expected to be completed in April. Burnham will be located on Sanger Road, named for Dr. Frederick Sanger, who was twice awarded the Nobel Prize. Initially, 75 staff and researchers, who study diabetes, obesity, cardiovascular disease and cancer, will move into the 175,000 square-foot facility. New faculty are being recruited almost monthly. See page 6 to meet the newest Burnham researchers in Lake Nona and La Jolla.
Dr. Cheryl Baker, Director of M. D. Anderson-Orlando’s Cancer Research Institute.
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B u r n h a m F a cu l t y ne w s
New
Faculty
Duc Dong, Ph.D.
Assistant Professor and Sanford Investigator Duc Dong, Ph.D., came to Burnham’s La Jolla campus from the University of California, San Francisco and studies beta cell development in zebrafish. Beyond providing additional expertise in type I diabetes, Dr. Dong brings a new model organism to Burnham that offers powerful genetic analysis in a simple vertebrate species. “Through developmental studies, our goal is to gain insight into diseases and their
potential therapies,” says Dr. Dong. “Primarily, our intent is to decipher progenitor cell biology to genetically or pharmacologically manipulate cell differentiation in the body. The ability to change a certain tissue fate will help us manipulate stem cell differentiation, which will undoubtedly advance the field of regenerative medicine. Using zebrafish, we are researching how transcription and signaling factors regulate progenitors of the pancreas, liver and intestine with the overarching goal of curing diseases associated with these tissues.”
Tod Gulick, M.D.
Assistant Professor Tod Gulick, M.D., arrived at Burnham, Lake Nona, from Massachusetts General Hospital and Harvard Medical School. His research brings basic biochemical and molecular biological approaches to the Dr. Tod Gulick regulation of intermediary metabolism and mitochondrial function at the gene expression level. Dr. Gulick’s research is focused on Myocyte Enhancer Factor 2 (MEF2) factors, which play pivotal roles in muscle development, red versus white fiber type determination and metabolic enzyme gene expression. They also control numerous other processes, including neuron survival and synapse formation and lymphocyte activation and selection. The Gulick lab is examining the roles that different forms of MEF2 play in controlling these various processes. Dr. Gulick intends to develop genetically manipulated mouse models to extend prior observations. He will also take advantage of technology at Burnham to evaluate differential expression, how other forms of MEF2 function and transcription factors that control metabolism in muscle.
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Zhen Jiang, Ph.D.
Assistant Professor Zhen Jiang, Ph.D., is working at Lake Nona on insulin signaling networks and metabolism. Insulin regulates glucose metabolism, fat storage, protein synthesis and gene expression. Studies by Dr. Jiang and others have suggested that insulin signaling is Dr. Zhen Jiang selectively impaired under insulinresistant states, such as obesity and type II diabetes. Dr. Jiang uses a variety of sophisticated approaches to investigate how insulin stimulates glucose usage and fat cell metabolism to identify therapeutic targets for diabetes. “The most important physiological function of insulin in our body is to regulate glucose metabolism by enhancing glucose transport into muscle and fat tissues,” says Dr. Jiang. “It is known that insulin binds to its receptor on the cell surface and activates a stream of biochemical reactions inside cells leading to the movement of a glucose transporter called GLUT4 to the cell surface, where it can channel glucose into the cells for metabolism and energy production. These chain reactions are impaired in obesity and type II diabetes. Therefore, compounds that can improve insulin’s function on GLUT4 movement could potentially be used to lower blood glucose levels and treat diabetic complications.”
Sunyoung Lee, Ph.D.
Assistant Professor Sunyoung Lee, Ph.D., came to Burnham, La Jolla, from the University of California, Los Angeles. Dr. Lee’s research focuses on understanding the mechanisms by which growth factors regulate blood vessel formation in cancers. “By using transgenic mice as model systems, we aim to understand the role of genetic factors and environmental cues in endothelial cell biology and vascular morphogenesis (development) and their connection
with human diseases,” says Dr. Lee. “We focus on the biology of vascular endothelial growth factor (VEGF), which is essential for specification, morphogenesis, differentiation and homeostasis (equilibrium) of vessels, both in embryos and adults. This signaling pathway is an integral component of pathological blood vessel growth in retinopathies, arthritis and tumor expansion. Consequently, VEGF has remained one of the pivotal growth factors for therapeutic exploitation.”
B u r n h a m F a cu l t y ne w s
Tariq Rana, Ph.D.
Tariq Rana, Ph.D., Professor and Director of Burnham’s Program for RNA Biology, is a leader in the field of RNAi, including micro RNAs and other types of non-coding RNAs. He also studies virology and host-pathogen interactions, particularly HIV. Dr. Rana came to La Jolla from the University of Massachusetts Medical School. “A key goal for the lab is understanding the RNA-
induced silencing complex (RISC), the mechanism by which interfering RNA (RNAi) regulates transcription and keeps certain genes quiet,” says Dr. Rana. “Though RNAi is commonly used to silence specific genes and illuminate their function, not everything is understood about how this important mechanism actually works. RNA does a lot more than simply act as a messenger between our DNA and the ribosomes that make proteins. It plays a role in controlling which genes are turned on
Dr. Tariq Rana
or off, a process that could have a profound impact on human health. Because these small RNAs modulate protein synthesis, they represent another switch we can use
Devanjan Sikder, D.V.M., Ph.D.
Philip A. Wood, D.V.M., Ph.D.
Assistant Professor Devanjan Sikder, D.V.M., Ph.D., focuses on how orexin, a brain hormone, regulates metabolism, sleep patterns and feeding behavior and the role hunger plays in regulating Dr. Devanjan Sikder fat metabolism and insulin secretion. Also, Dr. Sikder investigates how lack of sleep
Professor Philip A. Wood, D.V.M., Ph.D., uses animal models to investigate human metabolic diseases. Dr. Wood is
dampens the ability to burn sugar and contributes to metabolic disorders. “Energy homeostasis has a tremendous impact on the intertwined functions of feeding behavior and sleep,” says Dr. Sikder. “Blood glucose levels control the amount of orexin. High blood glucose, after a meal, reduces orexin levels and induces inactivity and sleep. Plunging blood glucose, following overnight fasting, elevates orexin levels, which triggers wakefulness and hunger.” Nutrient and hormone signaling pathways are tightly linked to cell proliferation and survival. Dr. Sikder believes that orexin-bolstered metabolic boosts can confer selective survival advantages, allowing aggressive tumors to out-compete normal cells. Prior to joining Burnham at Lake Nona, he conducted research at the University of Texas Southwestern Medical Center in Dallas.
interested in rare inherited disorders of fat metabolism, particularly enzyme deficiencies of fatty acid beta-oxidation: rare, potentially fatal disorders that affect babies and young children who cannot burn fatty acids to supply energy during fasting or exercise. To understand the genetic and metabolic mechanisms underlying these conditions, Dr. Wood’s group has developed mouse models of these diseases. These different models demonstrate many of the symptoms experienced by the affected children, including fasting hypoglycemia, fatty liver and sudden death.
to understand and control disease. For example, we believe cancer can result when these mechanisms go out of control. But we need to better understand their regulation.”
Dr. Philip A. Wood
Dr. Wood came to Burnham, Lake Nona, from the University of Alabama at Birmingham. He authored the book How Fat Works, in which he reveals the role of genetics, nutrition, drugs and physical activity in the prevention and treatment of obesity, metabolic syndrome and diabetes. His research will use animal genetics to mimic human diseases and define the causes and metabolic conditions that promote obesity, diabetes and related conditions.
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B u r n h a m ne w s
Treating
Pandemic Flu
Researchers at Burnham, working with teams at the DanaFarber Cancer Institute and the Centers for Disease Control and Prevention, have identified human monoclonal antibodies that neutralize an unprecedented range of influenza viruses, including H5N1 bird flu, previous pandemic flu viruses and most seasonal influenzas. These antibodies have the potential, in combination with other treatments, to prevent or treat most types of avian and seasonal flu and do not have many of the problems associated with conventional vaccines. Also, the possibility of resistant strains emerging from their use is greatly reduced compared with existing viral treatments such as Tamiflu. The study was published online on February 22 in Nature Structural and Molecular Biology. “These antibodies show great promise because they bind to an unusual region of the virus surface,” says Robert Liddington, Ph.D., Professor and Director of Burnham’s Infectious Disease Program. “Most antibodies bind to the outer head regions of the virus, but this region typically changes from year to year and these changes can cause epidemics if the body’s immune cells do not recognize the new virus quickly enough. But our antibodies bind to a region just below the surface that is not normally accessible. This region is part of a sophisticated machine with many moving parts that must work perfectly if the virus is to enter our cells
New Insights into Programmed Cell Death Researchers from Burnham Cancer Center’s Apoptosis and Cell Death program have determined the structure of the interactions between proteins that form the heart of the death-inducing signaling complex (DISC), which is responsible for triggering apoptosis (programmed cell death). The research, performed
by Stefan Riedl, Ph.D., and colleagues and published online on December 31 in the journal Nature, highlights how protein-protein interactions between the Fas receptor and Fas-associated death domain protein (FADD) control DISC formation. The X-ray crystal structure of the FasFADD death domain complex
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The antibody (in red) binds to the vulnerable area of the viral protein.
and establish infection. Like any machine, every cog and chain must be the right type. Change one cog and the whole machine stops. When we looked at this region using X-ray crystallography, we found that the machine really has not changed significantly throughout evolution. In fact, we tried to force the virus to evolve to escape our antibodies, but it could not. So we think these antibodies will work against future epidemic and pandemic viruses as well. And if the region should change, because we understand the system in atomic detail, we know how to make new neutralizing antibodies.” While relatively expensive to produce, therapeutic antibodies can be made and modified quickly. In the event of a pandemic, antibodies could be used with antiviral therapies to contain the outbreak until a vaccine becomes available.
revealed a particular arrangement of four FADD death domains bound to four Fas death domains. The structure showed that Fas undergoes a conformational (shape) change, creating an open form of the protein that acts as a place for FADD to bind. Dr. Riedl proposes that Fas opening itself acts as a control switch for DISC formation and initiates apoptosis. “You need a special arrangement of Fas receptors to trigger opening of the Fas
death domain, and only then do you get activation,” says Dr. Riedl. “Another interesting point is that this work uncovered a general mechanism for receptor signaling solely by clustering of the receptor. Understanding the initiation of the death-inducing signaling complex is of great interest because if you can activate or inhibit cell death you can have a major impact on many diseases, such as cancer.”
B u r n h a m ne w s
Monitoring Damage Control During DNA Replication Scientists at Burnham have demonstrated important new roles for the protein kinase complex Ddk in monitoring damage control during DNA replication and reinitiating replication following DNA repair. Since Ddk is often deregulated in human cancers, this new understanding of its role in DNA
damage control could help shape new cancer therapies. The research was published in the December 24 issue of Molecular Cell. “This protein kinase complex is not only monitoring DNA replication, it’s also monitoring the S-phase (DNA quality control) checkpoint,” says Wei Jiang,
Fruit Flies Enhance
Understanding of Human
Heart Disease
Dr. Rolf Bodmer’s lab has shown, in both fruit flies and humans, that genes involved in embryonic heart development are also integral to adult heart function. Dr. Bodmer’s lab discovered that, in the Drosophila fruit fly, interactions between cardiac nmr genes (called TBX20 in humans) and other transcription factors are involved in regulating cardiac performance, rhythm and heart muscle structure. Dr. Rolf Bodmer TBX20, along with other congenital heart disease genes, has been shown to be critical to the development of the embryonic heart. This study is the first indication that nmr/ TBX20 also plays a role in adult heart function. These genes are highly conserved from flies to humans and Dr. Bodmer’s research showed that some individuals with structural congenital heart abnormalities, as well as problems with heart function including arrhythmias and heart failure, also exhibited TBX20 mutations. The study was published in Proceedings of the National Academy of Sciences. “These studies demonstrate that Drosophila has potential as a model system for exploring the genetics underlying human heart disease and for identifying new candidate genes that potentially cause heart disease,” says Dr. Bodmer.
is to stop replication in order to allow for DNA repair and to avoid catastrophe for the cell. Our study Co-authors Drs. Toshiya Tsuji, Gary Chiang and Wei Jiang demonstrates that Ddk not Ph.D., the study’s principal only activates the initiation investigator. “If replication of DNA replication, but it is accurate, then Ddk allows also monitors the checkpoint DNA synthesis to continue during DNA damage control normally. If there is DNA and eventually overrides the damage, replication is halted checkpoint to re-initiate DNA at this checkpoint. replication.” “The most important thing
Digital Communications Technology Gives Insights into
Personalized Medicine
Researchers at Burnham have shown that search algorithms used in digital communications can help identify effective multi-drug combinations. The study, led by Giovanni Paternostro, M.D., Ph.D., was published in the December 26 issue of PLoS Computational Biology. Using the stack sequential Dr. Giovanni Paternostro algorithm, which was developed for digital communications, the team searched for optimal drug combinations. This algorithm can integrate information from different sources, including biological measurements and model simulations. “Combination therapies have demonstrated efficacy in treating complex diseases such as cancer and hypertension, but it is difficult to identify safe and effective combination treatment regimens using only trial and error,” says Dr. Paternostro. “As personalized medicine moves from the present emphasis on diagnosis and prognosis to therapy, the problem of searching for optimal drug combinations uniquely suited to the genetic and molecular profile of each patient will need to be solved. This research is a first step in that direction.”
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P h i l a n t h r o p y up d a te
Where There’s a Will By Patt y Fuller
Now is a good time to ensure that your family and community interests are provided for in the future. A will, or living trust, is your instruction manual on how you would like your estate distributed. If you choose to support medical research through a bequest in your will, there are many advantages: — Your gift will play an important role in discovering tomorrow’s cures. — A bequest is private, revocable and doesn’t affect cash flow during your lifetime. — Contributions may ease estate tax burdens on your beneficiaries.
— You may establish a named fund in honor of your family or a loved one. — You may designate your bequest to support specific research, or direct your donation to Burnham’s Endowment Fund, securing the future of the Institute. Consult an attorney about the type of bequest that best suits your needs. You may donate property, cash, stocks, bonds, mutual funds, retirement plans, land or other assets. If you would like to receive sample language to provide for your attorney for unrestricted bequests, restricted bequests, contingent bequests or endowment gifts, contact Patty Fuller at 858.795.5231 or pfuller@burnham.org. Donors who make bequests to Burnham during their lifetime automatically become members of the Legacy Society. Please let us know of your gift, so we can recognize your generosity.
Team Burnham
Rides Again In its third year, Team Burnham raised nearly $200,000 to support biomedical research at the Burnham Institute for Medical Research. Following months of training, more than 80 runners from both coasts ran Disney’s half and full marathons, which take participants through all four Walt Disney World theme parks accompanied by live music and cheering Disney characters.
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The results speak to the commitment of Team Burnham volunteers. When training began in July, some participants could barely walk a mile, but they all rose to the challenge on race day. “I have never run long distance before, so to be able to finish the race was a great high for me,” said team member David Wood. “To be able to run it in support of such a great cause and to work with such wonderful people was icing on the cake.” Team Burnham provides a unique opportunity to
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Judy Wade and Antony Peake race for research.
raise funds for cutting-edge research and train with some of the scientists whose work is being supported. This year’s team included Orlando Mayor Buddy Dyer and Orange County Mayor Richard T. Crotty, as well
as Burnham’s President and CEO, Dr. John Reed and Lake Nona Scientific Director Dr. Daniel Kelly. Go to www. teamburnham.org for more information. Congratulations to all participants on a race well-run.
P h i l a n t h r o p y up d a te
HeadNorth
Foundation Funds Stem Cell Research HeadNorth Foundation has pledged $975,000 to advance cutting-edge stem cell research. The gift, part of HeadNorth’s Chronic Spinal Cord Injury Project, will support efforts by Dr. Evan Snyder, Stem Cell Program Director at Burnham and Dr. Mark Tuszynski, Director, Center for Neural Repair at the University of California, San Diego, to use stem cells to treat chronic spinal cord injuries.
Stem cells can be programmed to become many types of cells, including spinal cord neural cells. When used with biosynthetic scaffolds— bio-engineered materials that provide a foothold—stem cells have promoted the formation of neural cells in adult rats with acute spinal cord injuries. HeadNorth, Burnham and UCSD seek to translate this early research into new treatments that will ease suffering and transform lives.
California Bipolar Foundation Grant The California Bipolar Foundation has made a $50,000 one-year grant to Dr. Ilyas Singec, a postdoctoral fellow in Dr. Evan Snyder’s lab. Dr. Singec is using stem cells to find the underlying
mechanisms behind biopolar disorder. The foundation seeks to eliminate bipolar disorder through research, provide enhanced services for all affected and end the stigma associated with the disease.
Save the Date:
April 30th
The Burnham Institute for Medical Research and HeadNorth Foundation are combining forces with Terry and Stath Karras and the San Diego business community to raise support for stem cell research. Join us for fine food and wine, great company and an outrageously fun game show—in which you will be one of the stars.
So bring your competitive juices to the Mission Tower Ballroom at the Del Mar Fairgrounds on Thursday, April 30 at 6 p.m. How will you fare in the game? We don’t know, but the research you support will make everyone a winner. For more information, contact Chelsea Jones at 858.795.5239 or cjones@ burnham.org.
Las Patronas Supports Proteomics Las Patronas, a philanthropic organization based in La Jolla, has donated $75,000 to Burnham to purchase a Shimadzu Xcise robot, which is used to characterize proteins. The robot is a critical component in a relatively new form of protein analysis called two-dimensional difference gel electrophoresis. These analyses, carried out in the proteomics shared resource, enable direct comparison between two protein samples. Proteomics is the comprehensive study of thousands of different proteins in cells.
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B u r n h a m c h emi c a l genomi c s
This robotic arm moves assay plates for the Opera High Content Screening System, which can image and analyze as many as 60,000 wells a day.
The Gift of Discovery Continued from page 3
which is a chemical that perturbs a protein so we can better understand its biological role,” says Dr. Roth. “This is not a new medicine but rather an important research tool. The ultimate product of our work is knowledge. We use a compound to understand a protein, which helps us understand how a disease works. Once we know that, we can start working on potential treatments.” A S h arper I mage Inside the Prebys Center, a large yellow robot moves assay plates to different stations as biological material, chemicals and reagents are added to the wells and incubated. The plate
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reader can conduct thousands of experiments each day, but with relatively low resolution. While it can tell if a chemical is active in a cell, it cannot determine where it is active.
takes multiple images of individual cells and computes whether a chemical compound is active. But even more important, because the screener images single cells, it can give a more precise picture of what that chemical is actually doing within the cell. “We can measure proteins
The new screening technology being developed at Burnham could be a great boon to researchers worldwide. For that, you need images of individual cells. And that is where a less dramatic, but equally powerful, tool comes in—the image-based screening robot. The image-based screener
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as they move into the nucleus,” says Jeff Price, M.D., Ph.D. “The plate reader doesn’t have the resolution to see that level of detail.” Image-based screeners provide more information than plate readers, but they
are comparatively slow. While the plate reader can do more than 200,000 assays a day, the image-based reader will do around 60,000—a significant number but not quite the speed needed. Dr. Price and others are working to improve the technology to get that number over 100,000. “We received a grant from the NIH to investigate ways we could improve the speed,” says Dr. Price. “We believe we can get it up over 100,000 assays a day, which would be truly highthroughput. It would give us more opportunity to do imagebased screens, which would give us more information to work with.” The new screening technology being developed at Burnham could be a great boon to researchers worldwide. But even with existing equipment, researchers from Burnham and around the nation will be using the technologies in the Conrad Prebys Center for Chemical Genomics to find small molecule probes that influence our genes. Some of these probes will be tested as medicines and some of those—in the next 10 to 20 years—will move through the drug approval process and begin helping patients. It’s a long process that begins here.
p r e s i d e n t ’ s M ess a ge
The Tools for the Job In 2001, the leadership of Burnham, as part of our 10-year plan, decided to pursue a new initiative in chemical genomics. This was a difficult choice—one we did not make lightly. We knew that charting this course would require enormous investments of both time and money. On the other hand, we also recognized that this endeavor could bring great rewards. Having the ability to probe the functions of the human genome would offer many opportunities to tease out biological secrets and reveal the mysteries of disease. With this information, we could better understand how diseases gain a foothold, find new treatments for them and accelerate our overall research mission. Another factor in our decision to move forward was our firm belief that Burnham was ideally suited to pursue this research. Chemical genomics requires intense collaborations among
John C. Reed, M.D., Ph.D. President and CEO Professor and Donald Bren Presidential Chair
talented individuals from multiple disciplines, including biology, chemistry, engineering and biophysics. We had already proven our ability to integrate talents from diverse disciplines to solve problems. Given our collaborative approach to science, chemical genomics was an excellent fit for Burnham. Also, because it is broadly applicable to all fields of life science research, chemical genomics supports the work of many Burnham scientists. Virtually every facet of cell biology can be probed with this technology. Moreover, finding chemicals that modulate biological processes creates an abundance of opportunities that may be only a few steps away from translation into 15. John Reed essay the clinical realm as new prototype medicines. For example, chemical biology is highly syner-
gistic with our stem cell research. Making stem cells differentiate into specific tissues requires the right chemicals. We embarked on this path because we felt the science dictated it, and we are being recognized for that foresight. The $98 million Molecular Library Probe Production Network grant from the National Institutes of Health, the recent venture with Johnson & Johnson and the generous gift from Conrad Prebys all validate the choices we made in 2001. The Conrad Prebys Center for Chemical Genomics gives us superior tools to find medicinal chemicals and advance our mission to cure disease. Most importantly, the Prebys Center will provide research opportunities our scientists could only have dreamed of a decade ago. In turn,
Also, because it is broadly applicable to all fields of life science research, chemical genomics supports the work of many Burnham scientists. Virtually every facet of cell biology can be probed with this technology.
this enhanced research will lead to new product opportunities that can be moved from our nonprofit environment into the hands of for-profit partners. Increased capital investment will lead to more high quality jobs and will ultimately translate the fruits of our outstanding basic science into the new medicines of tomorrow.
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Vuori and Peter Preuss Dr. Kristiina
“To get a promising idea from basic research to actual treatments often requires an element of serendipity,” says Preuss. “By discovering basic facts, you reduce the distance to new therapies.”
Kristiina Vuori, M.D., Ph.D., and Peter Preuss share a common mission: Battling cancer As director of Burnham’s NCI-designated Cancer Center, Dr. Vuori works vigorously to uncover the basic mechanisms that cause disease and find novel ways to target them. Preuss, a new Burnham board member who has been involved for many years in biotech, understands the value of basic research and the challenges of moving these discoveries from the lab to the pharmacy.
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