Fall 2009

VO LU M E 6 N U M B E R 3 | FA L L 2 0 0 9

From Research,The Power to Cure

Inside

> D iabe t e s Re s earc h

>B urnh am N ews

the Quest

>Phi lanth ropy

to Cure Diabetes

B U r n h a m R epor t

In T h i s I s s ue

Founders

Trustees, continued

B urn h am R e s ear c h

Wi lliam H . Fish man, Ph.D. Lillian Fish man

Alan Gleicher W.D. Grant David Hale Jeanne Herberger, Ph.D. Brent Jacobs James E. Jardon II (Florida) Daniel P. Kelly, M.D. Robert J. Lauer Sheila B. Lipinsky Gregory T. Lucier Papa Doug Manchester Robert A. Mandell (Florida) Nicolas C. Nierenberg Douglas H. Obenshain Peter Preuss John C. Reed, M.D., Ph.D. Stuart Tanz Jan Tuttleman, Ph.D., MBA Andrew J. Viterbi, Ph.D. Kristiina Vuori, M.D., Ph.D. Bobbi Warren Allen R. Weiss (Florida) Judy White Gayle E. Wilson Diane Winokur Kenneth J. Woolcott

The Quest to Cure Diabetes

1

Honorary Trustees

Diabetes and its Consequences

3

A National Quest

5

Joe Lewis Conrad T. P rebys T. D enny Sanford

Trustees and Officers B urn h am N e w s

The View from Lake Nona

7

Science News

8

New Faculty

11

Collaborations

13

P h i lan t h rop y

Burnham Welcomes Julie Johnson

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Lake Nona Events

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La Jolla Events

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A round B urn h am

President’s Message

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Partners in Science

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Mali n B urn ham Chairman Jo h n C. R eed , M.D., Ph.D. President & Chief Executive Officer Professor and Donald Bren Presidential Chair G ary F. R ais l, E d.D. Chief Administrative Officer Treasurer Margare t M. D unbar Secretary

Trustees Linden S. Blue Mary Bradley Brigitte Bren Arthur Brody Malin Burnham Howard I. Cohen Shehan Dissanayake, Ph.D. 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

Drs. Timothy Osborne, Stephen Gardell and Daniel Kelly are committed to finding new ways to treat type 2 diabetes and related diseases. As director of the Metabolic Signaling and Disease Program, Dr. Osborne wants to illuminate the normal signaling mechanisms that control metabolism and how those signals differ in diseased tissue.

Dr. Steve Gardell directs Translational Research Resources, which seeks to move basic research findings from the laboratory to the clinic. Scientific Director Dr. Daniel Kelly investigates cardiovascular disease and wants to expose its different causes and discover new treatments.

B lai r B lum Senior Vice President External Relations Eliz abeth Gi an ini Vice President External Relations

Jo sh Ba xt Editor, Burnham Report G avi n & G avin Advertisi ng Design

Edgar Gi llenwat er s Vice President External Relations

Mic h ael Cairn s Mar k Dast rup Nadi a Borowski Sc ott Photography

C hr is L ee Vice President External Relations

Ken G. Covene y, Esq. Fab ian V. Fi l ipp, Ph.D. Contributors

Andrea M os er Vice President Communications

Please address inquiries to: jbaxt@burnham.org

www.burnham.org

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 6400 Sanger Road, Orlando, FL 32827 • 407.745.2000

B u r n h a m D i abe t e s re s ear c h

the Quest

to Cure Diabetes

Pancreatic beta cells – photo by Ifat Geron, Levine and Itkin-Ansari laboratories

In 1922, insulin was first administered to treat type 1 diabetes, transforming a deadly disease into a chronic one. But insulin is not a cure.

Periodic blood sugar monitoring and insulin injections cannot match the 24/7 efficiency of insulin-producing beta cells. According to the Juvenile Diabetes Research Foundation, type 1 diabetes

reduces lifespan, on average, by seven to 10 years.

Type 2 diabetes—a quite different disease—is associated with obesity and is fast becoming an epidemic in the United States. While type 1 results from a lack of insulin, type 2 appears when cells lose the ability to respond to insulin (See box, page 3).

According to the American Diabetes Association, more than 23 million people have diabetes, mostly type 2.

Though treatments for both forms of diabetes have advanced, cures remain elusive. At Burnham, significant work is being done on both coasts to understand these conditions and find new treatments.

Making N ew In suli nProducing Cell s Both type I and type II diabetes are caused by a deficiency of the cells that produce insulin. Type 1 is an

autoimmune disorder, in which the body’s immune system attacks and destroys beta cells, which monitor blood glucose and release insulin. In type 2 diabetes, high levels of fatty acids attack beta cells. As beta cells die, glucose accumulates in the blood, leading to deadly complications. However, if we could transplant or renew beta cells, the body could once again produce its own insulin.

Currently, beta cells are transplanted from cadavers

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Dr. Fred Levine chats with postdoctoral fellow Dr. Seung-Hee Lee

but quantities are very low.

Fred Levine, M.D., Ph.D., directs the Sanford Children’s Health Research Center and is trying to solve the problem of making new beta cells—either outside the body for transplantation or by activating adult stem cells within the pancreas.

“Our initial intent was to make a cell line that would mimic beta cells so well they could be transplanted,” says Dr. Levine. “While that goal proved overly ambitious, the cells that

we made turned out to be ideal for high-throughput screening to search for drugs that affect beta cells. This project, done in collaboration with Burnham investigators Drs. Mark Mercola, Pamela Itkin-Ansari and Jeff Price, as well as the Conrad Prebys Center for Chemical Genomics, has been a long road but has recently borne fruit, with a number of compounds entering preclinical trials.”

In addition to the studies with high-throughput

Dr. Levine is collaborating with Burnham stem cell scientists, such as Dr. Alexey

Terskikh, to understand the genes that induce adult stem cells in the pancreas to

become functioning beta cells.

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screening, Dr. Levine’s laboratory is also pursuing other avenues. What if adult stem cells, or mature endocrine cells, could be transformed into beta cells? Dr. Levine is collaborating with Burnham stem cell scientists, such as Dr. Alexey Terskikh, to understand the genes that induce adult stem cells in the pancreas to become functioning beta cells.

Possibi liti es in Regeneration Like Dr. Levine, Duc Dong, Ph.D., is trying to regenerate beta cells from cells that already exist in our bodies.

“Usually in diabetes there are a few beta cells left,” says Dr. Dong. “How can we replenish them? If we understand the developmental

biology, we may find therapeutic targets where you add a drug or apply gene therapy to encourage the body to regenerate the cells.”

The Dong laboratory, which uses zebrafish as a research model, is also trying to encourage pancreatic exocrine cells, which produce digestive enzymes, to become beta cells.

“They come from the same precursors,” says Dr. Dong.

“We found that a particular gene helps decide the fate of these precursors. We hope that, by manipulating this gene, we can help make more beta cells.”

Taking a different approach, Alex Strongin, Ph.D., is interested in what happens if the immune system can be selectively blocked. Dr. Strongin studies an enzyme that helps invasive cancer cells migrate to other parts of the body. The enzyme, called MT1-MMP, is a proteinase, a protein that cuts up other proteins.

MT1-MMP interacts with a cell surface receptor called CD44, which plays a number of roles in cancer cells and autoimmune T cells—the culprits in beta cell destruction. Dr. Strongin has found that inhibiting MT1-MMP keeps T cells out of the pancreas.

“We found that if you stop the killer cells from getting into the pancreas, it gives beta

B u r n h a m D i abe t e s re s ear c h

cells the opportunity to regenerate,” says Dr. Strongin.

The tricky part is finding the right inhibitor. Dr. Strongin notes that an MT1-MMP inhibitor has failed in clinical trials for late-stage cancer. To be useful, the compound must be minimally toxic.

“We would have to develop a less toxic inhibitor because patients would be taking it for the rest of their lives,” says Dr. Strongin. “It’s one thing to have a toxic treatment for cancer and another entirely for diabetes, where insulin is an effective treatment. So, there’s still a great deal of work to be done.”

P rot ec t ing Cell s from t he Immune System For transplantation to be a viable treatment, the immune

system must be controlled.

Current transplant recipients must take immunosuppressive drugs to prevent their T cells from attacking replacement beta cells, presenting a stark choice between diabetes and a suppressed immune system.

Recently, Burnham adjunct professor Pamela Itkin-Ansari, Ph.D., placed pancreatic precursor cells in an immunoprotective device and transplanted them into mice. She was testing whether precursor cells would mature into productive beta cells in the body and whether the protective device, made from a material akin to Gore-Tex, could prevent the immune system from attacking transplanted cells.

“We wanted to see if we could protect the cells from

Diabetes and its

Consequences

Insulin is produced in the pancreas by beta cells, which measure glucose (the main source of energy from food) in the blood and secrete insulin to control glucose concentrations. Insulin acts as a key, binding to receptors (locks) expressed by all

cells and telling them to let glucose inside.

In type 1 diabetes, beta cells are destroyed by the body’s own immune system.

White blood cells that ordinarily protect us from bacteria and viruses mistakenly recognize beta cells as

Dr. Duc Dong in the zebrafish facility

the immune system rather than suppressing the immune system,” says Dr. Itkin-Ansari.

Early studies have been very positive, as the transplanted cells responded to

foreign and destroy them, reducing or eliminating insulin production.

In type 2 diabetes, the problem is with the insulin receptor—the lock that allows glucose to enter. For reasons that are not clear, the receptor mechanism does not work properly, even when insulin is present. The body responds by producing more insulin.

While that works for a time, it overworks the beta

glucose and produced insulin and the immunoprotective device kept the immune system at bay.

“We are excited to see how well they did,” says Dr.

cells, which ultimately fail and die.

High circulating glucose levels damage cells. Because glucose moves primarily through blood, the cells lining blood vessels are the most severely hurt. These consequences extend to virtually every organ in the body. Diabetes is a leading cause of blindness, kidney disease, amputation, heart disease and many other conditions.

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Dr. Philip Wood

Itkin-Ansari. “We could see evidence of beta cells forming and replicating. That means the environment in the device was conducive to beta cells continuing to develop and survive.

Also, we thought that T cells, although unable to penetrate the device, would cluster around it. But we found no evidence of an active immune response, suggesting that the cells in the device were invisible to the immune system.”

Th e Problem w ith Fat At Burnham’s Orlando, Florida campus, researchers are focused on the underlying

mechanisms behind type 2 diabetes, in which insulin levels are normal (or elevated) but cells do not respond to its signals. Scientists want to know why insulin resistance happens in the first place, how diabetes affects the heart and the role fat plays in diabetes, metabolic syndrome and other conditions.

Philip A. Wood, D.V.M., Ph.D., is interested in fat: fat metabolism, fatty acids, fat signaling, fatty liver disease.

Dr. Wood is trying to unravel the consequences of too much fat.

“I’m interested in how the body reacts to excess fat and how fat metabolism and the genetics of fat metabolism

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play a role in insulin resistance and fatty liver disease,” says Dr. Wood.

Given that recent statistics show a third of Americans are obese, the research being done by Dr. Wood and others could have a profound impact on the nation’s health. One key focus is the underlying genetics that make certain people susceptible to disease.

“We’re not likely to find specific genes that cause type 2 diabetes,” says Dr. Wood. “Perhaps they exist in rare cases, but not enough for a genetic risk assessment. We’re not looking for the cause of the disease; we’re looking at the genetic and environmental determinants of the body’s response to this burden of excess fat.

Why do some people have a predisposition towards

fat is linked to higher blood pressure and triglycerides and makes that person a candidate for heart attack, diabetes, or both,” says Dr. Wood. “Visceral fat tissue leaks fatty acids, which go to the liver and cause fatty liver disease, enter the blood as triglycerides and also cause inflammation.

The most disturbing part is that today’s children may be the first in history to have a shorter lifespan than their parents because of obesityrelated diseases.”

While Dr. Wood is focused on what goes wrong for people with type 2 diabetes, Tim Osborne, Ph.D., wants to understand the processes that make the metabolism run normally.

“There’s a lot of synergy between Dr. Wood’s

The most disturbing part is that today’s children may be the first in

history to have a shorter lifespan

than their parents because of obesity-related diseases.

insulin resistance in the face of obesity? So we’re looking at the genetics of response, not the genetics of cause.”

On a practical level, Dr. Wood is particularly concerned with visceral fat, the extra baggage we may have hanging over our belts in front.

“Excessive abdominal

research and mine,” says Dr. Osborne. “He comes at it from the disease side, and we’re interested in identifying the pathways that occur normally. If we can understand the normal processes and how they go awry, it will help us find ways to reverse or alleviate

bu r n h a m D i abe t e s re s ear c h

A National Quest Burnham is committed to uncovering the underlying mechanisms behind diabetes and finding new ways to treat it. But the Institute is not alone. Burnham has numerous collaborations, large and small, with organizations around the country that share our desire to beat diabetes. In particular, Sanford Health and the Juvenile Diabetes Research Foundation (JDRF) are working with Burnham to cure type 1 diabetes.

Paul Burn, Ph.D., is professor of Pediatrics at the Sanford School of Medicine of the University of South Dakota and the Broin Chair and director of the Sanford Project, a venture sponsored by Sanford Health that seeks to develop new therapies for type 1 diabetes as quickly as possible. Dr. Burn notes that the collaboration between Burnham and the Sanford Project bridges the gap between basic and clinical research.

“The capabilities of Burnham and Sanford nicely complement each other,” says Dr. Burn. “Burnham’s strengths lie in the early phases of discovery, while Sanford

the complications of the disease itself.”

The collaboration between Drs. Wood and Osborne is typical of the Institute’s approach to research— different labs investigate pieces of the larger puzzle and pool their knowledge. As director of the Metabolic Signaling and Disease Program at Lake Nona, Dr. Osborne is eager to recruit new scientists who will carry on that tradition.

“Right now, we are working to integrate people who study various cellular signaling pathways,” says Dr.

is more focused on the translational aspects of diabetes.

Together, we cover the space from the gene, to novel drug targets, screens and clinical candidate molecules, followed by proof of concept studies in animals and humans. These are all aimed at delivering innovative cures for diabetes to the patient.”

Both the Sanford Project and Burnham partner with JDRF to accelerate the research. Alan Lewis, Ph.D., is President and CEO of JDRF, which has funded diabetes research at Burnham for many years. JDRF supports research into new treatments, as well as new devices.

JDRF is also working to help talented researchers, such as Drs. Fred Levine and Pam Itkin-Ansari, and recruit young scientists.

“We need to encourage researchers to go into the field by giving them seed funding, as well as a sense they can partner with JDRF,” says Dr. Lewis. “This research takes time, and we want researchers to know they will have the support they need.”

Osborne. “All these pathways have common nodes. We want to bring this knowledge together to understand how these mechanisms function.”

T h e L anguage of Fat Traditionally, people have thought of fat as being a relatively passive part of the body. But fat is no innocent bystander. Researchers are learning more about how fat signals other areas of the body, including the brain.

Devanjan Sikder, Ph.D., is looking at how these signals can affect both biological

Dr. Devanjan Sikder

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processes and perceptions of food.

Dr. Sikder studies the hormone orexin, which controls hunger and sleep/ wake cycles. High glucose after a meal reduces orexin levels and the activity of orexin-producing neurons, making us feel sluggish.

Plunging glucose levels, following overnight fasting, elevate orexin, which wakes us to find food.

The cyclic waxing and waning of orexin appears to be perturbed in type 2 diabetes, obesity and even cancer. “Several epidemiological studies have reported a correlation between lower orexin levels and a higher incidence of obesity and type 2 diabetes,” says Dr. Sikder.

incentive to stop eating. This may be one reason why it can be so difficult for obese people to lose weight.”

M ov i ng D i s c over i e s F or ward Steve Gardell, Ph.D., director of Translational Research Resources, came to Burnham Lake Nona to help move basic science discoveries from the laboratory to the clinic. With more than 20 years experience in the pharmaceutical industry, Dr. Gardell understands the challenges of translating basic scientific knowledge into new medicines.

However, he sees many opportunities in the work being done at Burnham.

“My job is to help shepherd some of these incredible

“Metabolomics is a powerful way to identify disease markers that could lead to new tests and early detection,”

says Dr. Gardell.

Dr. Sikder is also interested in how leptin affects the brain. Leptin is a hormone that controls appetite, telling us to stop eating. Mice without leptin become perilously obese.

“Fat tissue produces leptin, which tells us to stop eating,” says Dr. Sikder. “But if you lose weight, the body produces less leptin and you have lost a physiological

discoveries and check them for clinical effectiveness,” says Dr. Gardell.

One area where Dr. Gardell hopes to have a big impact is metabolomics.

Biochemical reactions produce small molecules, or metabolites, which can be measured. Dr. Gardell and others at Burnham are hoping to capitalize on this

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Dr. Layton Smith

burgeoning young discipline to create new diagnostics.

“Metabolomics is a powerful way to identify disease markers that could lead to new tests and early detection,” says Dr. Gardell.

Dr. Gardell will also be working closely with Drs. Gregory Roth and Layton Smith to screen for compounds in the Conrad Prebys Center for Chemical Genomics. This painstaking process could lead to new chemical probes to illuminate the underlying mechanisms behind disease and possibly new medicines.

One of the targets they aim for is specificity: finding the right chemicals that influence the exact protein to

provide great clinical benefit with few side effects.

“Medicine has done all the easy things,” says Layton Smith, Ph.D. “It’s not that difficult to knock out a protein. Vioxx (an antiinflammatory drug that was pulled from the market due to increased risk of heart attack) is a good example. It worked too well because it completely knocked out the Cox2 enzyme. Vioxx created Cox2-deficient people. So we need to create compounds that work more subtly. We’ve done the chainsaw; it’s time for a scalpel.”

B u r n h a m f l o r i d a ne w s

The

View from Lake Nona

The landscape outside Dr. Daniel Kelly’s office at Burnham’s new Lake Nona campus is a work in progress. There is a sandy plain, a few puddles from a recent rainstorm, trees in the distance. But Dr. Kelly sees beyond this temporary sparseness to what Lake Nona will become as new hospitals, research facilities and a university building spring up around Burnham.

He sees multiple collaborations leading to new insights into human biology and new treatments for heart disease, diabetes, cancer and other conditions. He sees Burnham’s basic science and translational research expertise as a critical piece of Lake Nona’s burgeoning medical city.

“This is the perfect environment to create a truly innovative style of research,” says Dr. Kelly.

“We are already breaking down the silos that separate physicians and basic researchers. The Florida Hospital – Burnham Clinical Research Institute (see article, page 13), along with our emerging collaborations with the University of Central Florida, M. D. Anderson Cancer Center-Orlando, the Stedman Center at Duke University, the University of Florida and others will advance science and bring new treatments to patients—faster.

Burnham has an incredible track record of breaking down disciplinary barriers and we plan to continue that tradition.”

One area Dr. Kelly wants to explore is diabetic heart disease. He notes that heart failure is not a single condition that will respond to one-sizefits-all medicines. Researchers and clinicians need to understand the underlying distinctions between different types of heart disease, so that the best treatments can be prescribed based on a clear understanding of what is going wrong in the heart.

“Diabetic heart disease is more aggressive and different from other forms of heart disease,” says Dr. Kelly. “If we follow diabetics after a heart attack and give them the usual therapies—cholesterol lowering drugs, ACE inhibitors—we’ve found that those treatments don’t work as well. We’re only beginning to understand that heart and vascular disease in diabetics may have a completely different basis.”

Leverag i ng Te c h nology One of Burnham’s trademarks is the strategic use of sophisticated technologies. For example, Lake Nona’s Conrad Prebys Center for Chemical Genomics, like the facility in La Jolla, will identify small molecule compounds that

Daniel Kelly, M.D., Scientific Director, Burnham at Lake Nona

can help regulate proteins implicated in disease. In addition, the Cardiovascular Pathobiology program at Lake Nona will enhance the study of fat metabolism, type 2 diabetes, heart disease and other conditions. This will be supported by the emerging Cardiometabolic Phenotyping Core, which will diagnose cardiovascular disease and metabolic disturbances in small animal models.

Dr. Kelly is particularly excited about the collaboration with Duke University’s Stedman Center to establish a metabolomics core facility.

Every chemical reaction in the body produces compounds called metabolites, which can be measured and catalogued.

These markers can help physicians detect diseases or metabolic defects and test treatments for effectiveness.

Metabolomics provides a link between the laboratory and the

clinic. As researchers learn more about the metabolome (the list of all metabolites), they can develop better diagnostic tools.

“There are different kinds of cancer, and we are very sophisticated in describing them,” says Dr. Kelly. “But in heart failure, we lack the sophistication to distinguish between different disease types and causes. We just call it heart failure. In our research, we are trying to recapitulate different types of heart failure to find the metabolic or genomic signatures that will help us individualize treatment for each patient based on the precise nature of their disease.

If we can recognize these signatures, or markers, we will be able to tell whether a person’s heart failure is more related to diabetes or high blood pressure or heart attack. Physicians will know the exact condition they are seeing and that will lead to innovative treatments.”

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Embryology Study Offers

Clues to Birth Defects Gregg Duester, Ph.D., professor in the Development and Aging Program at Burnham, Xianling Zhao, Ph.D., and colleagues have clarified the role that retinoic acid plays in limb development.

The study showed that retinoic acid controls the development (or budding) of forelimbs, but not hindlimbs, and that retinoic acid is not responsible for patterning (or differentiation of the parts) of

limbs. This research corrects longstanding misconceptions about limb development and provides new insights into congenital limb defects. The study was published online in the journal Current Biology on May 21.

“For decades, it was thought that retinoic acid controlled limb patterning, such as defining the thumb as being different from the little finger,” says Dr. Duester. “However, we have demonstrated in mice that retinoic acid is not required for

Drs. Kazu Matsumoto and Yu Yamaguchi

New Insights into

Limb Formation

Investigators at Burnham and the University of Connecticut Health Center (U.C.H.C.) have gained new understanding of the role hyaluronan (also known as hyaluronic acid or HA) plays in skeletal growth, cartilage maturation and joint formation in developing limbs.

Significantly, these discoveries were made using a novel mouse model in which the production of hyaluronan is blocked in specific tissues. The Yamaguchi laboratory genetically modified the Has2 gene, which is a critical enzyme for hyaluronan synthesis, so that the gene can be “condition-

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Dr. Gregg Duester

limb patterning but rather is necessary to initiate the limb budding process.”

By providing a more complete understanding of the molecular mechanisms involved in normal limb development, these findings may lead to new

therapeutic or preventative measures to combat congenital limb defects, such as Holt-Oram syndrome, a birth defect characterized by upper limb and heart defects.

ally” disrupted in mice. This is the first time a conditional Has2 knockout mouse has been created, a breakthrough that opens vast possibilities for future research. The paper was published online in the journal Development on July 24.

HA is a large sugar molecule that is produced by every cell in the body and has been thought to play a role in joint disease, heart disease and invasive cancers. Yu Yamaguchi, M.D., Ph.D., a professor in the Sanford Children’s Health Research Center at Burnham and Robert Kosher, Ph.D., a professor in the Center for Regenerative Medicine and Skeletal Development at U.C.H.C. and colleagues

showed that transgenic mice, in which Has2 was inactivated in the limb bud mesoderm, had shortened limbs, abnormal growth plates and duplicated bones in the fingers and toes.

“Because hyaluronic acid is so prevalent in the body, it has been difficult to study,” said Dr. Yamaguchi. “Systemic Has2 knockout mice died mid-gestation and could not be used to study the role of hyaluronan in adults. By inactivating Has2 in specific tissues, we give ourselves the opportunity to study the many roles hyaluronan plays in biology. This mouse model will be useful to study the role of hyaluronan in arthritis and skin aging, as well as cancer.”

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Dr. Tariq Rana

MicroRNAs and HIV Tariq Rana, Ph.D., director of the Program for RNA Biology at Burnham, and colleagues have discovered that specific microRNAs (non-coding

RNAs that interfere with gene expression) reduce HIV replication and infectivity in human T cells.

In particular, miR29 plays a key role in controlling the HIV life cycle. The study suggests that HIV may have co-opted this cellular defense mechanism to help the virus hide from the immune system and antiviral drugs. The research was published on June 26 in the journal Molecular Cell.

The team found that the microRNA miR29 suppresses translation of the HIV-1 genome by transporting the HIV mRNA to processing bodies (Pbodies), where they are stored or destroyed. This results in a reduction of viral replication and infectivity. The study also showed that inhibition of miR29 enhances viral replication and

Carbohydrate Acts as Tumor Suppressor Minoru Fukuda, Ph.D., and colleagues have discovered that specialized complex sugar molecules (glycans) that anchor cells into place act as tumor suppressors in breast and prostate cancers.

These glycans play a critical role in cell adhesion in normal cells, and their decrease or loss leads to increased cell migration by invasive cancer cells and metastasis. An increase in expression of

the enzyme that produces these glycans, β3GnT1, results in a significant reduction in tumor activity. The research was published July 6 in the journal Proceedings of the National Academy of Sciences.

The specialized glycans are capable of binding to laminin and are attached to the α-dystroglycan cell surface protein. This binding facilitates adhesion between the epithelium and basement membrane and prevents cells

Dr. Minoru Fukuda

from migrating. The team demonstrated that β3GnT1 controls the synthesis of laminin-binding glycans in concert with the genes LARGE/LARGE2. Downregulating β3GnT1 reduces

infectivity. The scientists further demonstrated that strains of HIV-1 with mutations in the region of the genome that interact with miR29 are not inhibited by miR29.

“We think the virus may use this mechanism to modulate its own lifecycle, and we may be able to use this to our advantage in developing new drugs for HIV,” says Dr. Rana.

“Retroviral therapies greatly reduce viral load but cannot entirely eliminate it. This interaction between HIV and miR29 may contribute to that inability. Perhaps, by targeting miR29, we can force HIV into a more active state and improve our ability to eliminate it.”

the amount of the glycans, leading to greater movement by invasive cancer cells. However, when the researchers forced aggressive cancer cells to express β3GnT1, the lamininbinding glycans were restored and tumor formation decreased.

These results indicate that certain carbohydrates on normal cells and enzymes that synthesize those glycans, such as β3GnT1, function as tumor suppressors,” says Dr. Fukuda. “Up regulation of β3GnT1 may become a novel way to treat cancer.”

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Caspase 8 and Invasive Cancer Cancer Center director Kristiina Vuori, M.D., Ph.D., and colleagues have found that the Caspase-8 protein, long known to play a major role in promoting programmed cell death (apoptosis), helps relay signals that can cause cancer cells to proliferate, migrate and invade surrounding tissues.

Dr. Kristiina Vuori

The study was published in the journal Cancer Research on June 15.

The team showed that Caspase-8 caused neuroblas-

toma cancer cells to proliferate and migrate. For the first time, Caspase-8 was shown to play a key role in relaying the growth signals from epidermal growth factor (EGF) that cause cell division and invasion. The researchers also identified an RXDLL amino acid motif that controls the signaling from the EGF receptor through the protein kinase Src to the master cell proliferation regulator protein MAPK. This same signaling pathway stimulates neuroblastoma cells to

migrate and invade neighboring tissues—a critical process in cancer metastasis.

“Caspase-8 has a well defined role in promoting apoptosis, especially in response to activation of the so-called death receptors on the outside of cells,” says Darren Finlay, Ph.D., first author on the paper. “Although Caspase-8 is involved in apoptosis, it is rarely deleted or silenced in tumors, suggesting that it was giving cancer cells a leg up in some other way.”

What Makes Stem Cells Tick Investigators at Burnham and The Scripps Research Institute (TSRI) have made the first comparative, largescale phosphoproteomic analysis of human embryonic stem cells (hESCs) and their differentiated derivatives.

The data may help stem cell researchers understand the mechanisms that determine whether stem cells divide or differentiate, what types of cells they become and how to control those complex mechanisms to facilitate development of new therapies. The study was published in the August 6 issue of the journal Cell Stem Cell.

“While the field of stem cell biology has become accustomed

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to looking at changes in genes, we have come to realize that proteins are the real work horses and ultimately determine cell behavior,” says Evan Snyder, M.D., Ph.D., professor and director of Burnham’s Stem Cell and Regenerative Biology program. “This study represents the first comprehensive study of genes being activated during differentiation and offers predictions on cell behavior.”

Protein phosphorylation, the biochemical process that modifies protein activities by adding a phosphate molecule, is central to cell signaling. Using sophisticated phosphoproteomic analyses, the team of Laurence Brill, Ph.D., senior scientist at

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Drs. Evan Snyder and Laurence Brill

Burnham’s Proteomics Facility, Dr. Synder and Sheng Ding, Ph.D., associate professor at TSRI, catalogued 2,546 phosphorylation sites on 1,602 phosphoproteins. Prior to this research, protein phosphorylation in hESCs was poorly understood. Identification of these phosphorylation sites provides insights into known and novel hESC signaling pathways and highlights signaling

mechanisms that influence selfrenewal and differentiation.

“This research will be a big boost for stem cell scientists,” said Dr. Brill. “The protein phosphorylation sites identified in this study are freely available to the broader research community, and researchers can use these data to study the cells in greater depth and determine how phosphorylation events determine a cell’s fate.”

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Cells Respond to Low Oxygen Unraveling How

Gary Chiang, Ph.D., and colleagues have elucidated how the stability of the REDD1 protein is regulated.

The REDD1 protein is a critical inhibitor of the mTOR signaling pathway, which controls cell growth and proliferation. The study was published in the August 2009 issue of EMBO Reports.

As part of the cellular stress response, REDD1 is

expressed in cells under low oxygen conditions (hypoxia).

The Burnham scientists showed that the REDD1 protein rapidly undergoes degradation by the ubiquitin-proteasome system, which allowed for the recovery of mTOR signaling once oxygen levels were restored to normal.

“Cells initially shut down the most energy-costly processes, such as growth, when they’re under hypoxic stress,” says Dr. Chiang. “They do this by

New Faculty Jamey Mart h , P h . D.

Dr. Marth joins Burnham as director of the U.C. Santa Barbara-Burnham Center for Nanomedicine.

The center will focus on the emerging fields of nanotechnology and bioen-

gineering to identify the molecular and cellular origins of disease and develop new approaches to diagnosis, prevention and cure.

Dr. Marth’s laboratory is known for integrating molecular and cellular biology as a means to discover the origins of disease. His

Dr. Marth’s discoveries have spanned multiple fields including immunology,

hematology, metabolism, oncology, glycobiology, neurobiology and infectious diseases and are unique in combined breadth and accomplishment.

Drs. Enbo Liu and Gary Chiang and Christine Knutzen

expressing REDD1, which inhibits the mTOR pathway. But when the cell needs the mTOR pathway active, REDD1 has to be eliminated first. Because the

research has enumerated the building blocks of the four fundamental components of all cells and combined them into a research platform that has revealed pathophysiologic origins of autoimmune disease, sepsis and dietary-induced type 2 diabetes. The Marth laboratory previously developed the Cre-loxP technology that is now used throughout the world as a mainstay technique in biomedical research. Dr. Marth’s discoveries have spanned multiple fields including immunology, hematology, metabolism, oncology, glycobiology, neurobiology and infectious diseases and are unique in combined breadth and accomplishment.

REDD1 protein turns over so rapidly, it allows the pathway to respond very dynamically to hypoxia and other environmental conditions.”

Dr. Jamey Marth

Dr. Marth earned his Ph.D. in pharmacology from the University of Washington, where he worked under Dr. Edwin G. Krebs, a 1992 Nobel laureate in medicine and Dr. Roger M. Perlmutter, now executive vice president of Research and Development at Amgen.

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B u r n h a m s c i en c e ne w s

New Faculty continued Timothy Osborne, Ph.D.

Dr. Osborne joins Burnham at Lake Nona as professor and director of the Metabolic Signaling and Disease Program.

Dr. Timothy Osborne

Ranjan P erera , Ph.D.

Dr. Perera comes to Burnham from Mercer University’s School of Medicine, where he was an associate professor and director of Genomics and research and development at Anderson Cancer Institute.

His research seeks to understand how the body senses dietary content to alter nutrient absorption with an

He received his Ph.D. in Molecular Genetics from Moscow State University and the University of Ghent-Belgium. Dr. Perera completed his post-doctoral studies in gene targeting and DNA recombination at Massachusetts Institute of Technology. He has many years of industry experience and holds numerous patents related to gene regulation.

As an associate professor at Lake Nona, Dr. Perera seeks to identify prognostic and diagnostic markers for melanoma and will lead Burnham’s analytical genomics lab and establish expertise in RNA biology. His research is partly supported by a Department of Defense grant to study the link between obesity and cancer.

J uli o Ayala , Ph.D.

Dr. Julio Ayala

12 12

emphasis on how this influences molecular mechanisms relevant to diabetes and obesity.

Dr. Osborne received his doctorate in microbiology and molecular biology from the University of California, Los Angeles, conducted postdoctoral research at the University of Texas at Southwestern Medical School and was most recently chair of Molecular Biology and Biochemistry at the University of California, Irvine. He has received a Chancellor’s Award for mentoring undergraduate research, was recognized as an Established Investigator of the American Heart Association and received a Lucille P. Markey Scholar Award in Biomedical Science.

An assistant professor at Lake Nona, Dr. Ayala, comes to Burnham from Vanderbilt University School of Medicine, where he was a research faculty member and director of Technology Transfer at the VanderbiltNIH Mouse Metabolic Phenotyping Center.

The The BBurnham urnham Repor Reportt || www.burnham.org www.burnham.org

Dr. Ayala received his Ph.D. and conducted his postdoctoral work in molecular physiology and biophysics at Vanderbilt. He has studied factors that increase the production and secretion of insulin. His research has shown that the hormone GLP-1 affects not only the secretion of insulin but also insulin action on the liver and

Dr. Ranjan Perera

skeletal muscle. At Burnham, he will focus on the control of inter-organ fuel metabolism with emphasis on the regulation of glucose production and utilization. He seeks to reveal how metabolic syndrome is influenced by errors in sugar and fat metabolism and to use those findings to pursue new treatments for diabetes and obesity.

B u r n h a m ne w s

Burnham Chosen for

National Chemical Biology Consortium Burnham has been selected as one of three comprehensive centers in a new National Cancer Institute (NCI) Chemical Biology Consortium, an integrated network of chemical biologists, molecular oncologists and chemical screening centers.

The consortium will translate knowledge from leading academic institutions into new drug treatments for cancer patients. Burnham’s La Jolla and Lake Nona campuses will both participate.

The NCI seeks to coordinate their own drug discovery efforts with academic institutions and private companies

to expedite the development and distribution of new cancer treatments. The consortium will expand current NCI programs in personalized medicine to identify and advance

Clinical Research Institute Moves Forward

Steven R. Smith, M.D., an internationally-renowned diabetes and obesity researcher, has been

appointed executive director of the Florida Hospital – Burnham Clinical Research Institute, which will investigate diabetes, obesity and cardiovascular disease.

Burnham Collaborates with

Duke University Metabolomics Center

Burnham and the Sarah W. Stedman Nutrition and Metabolism Center (Stedman Center) at Duke University Medical Center have announced a new collaboration to use metabolomic profiling to clarify the basic mechanisms

of disease and identify biomarkers for diagnosis and treatment.

The agreement will establish an extension of Duke’s Stedman Center laboratory at Burnham’s Lake Nona campus and combines the Stedman

“Our vision was to recruit a world-class physician and scientist to lead our mission,” says Dr. Daniel Kelly, Scientific Director of Burnham at Lake Nona. “We have found the very best and are delighted that Dr. Smith will be

Center’s metabolomics expertise with Burnham’s complementary technologies.

The Stedman Center is well known for its metabolic research, particularly metabolomic profiling of biological samples using mass spectrometry-based technologies. The Burnham-Stedman metabolomics platform will create collaborative opportunities and expand the research capacity of both Duke University and Burnham.

novel drug candidates in highrisk, under-represented areas of cancer biology.

“Burnham’s strategic focus for the past five years has been on building our capabilities in chemical genomics and drug discovery,” says President and CEO John Reed, M.D., Ph.D. “The Chemical Biology Consortium gives Burnham an additional platform to use our advanced technologies, some of which are virtually unprecedented in the not-for-profit research world.”

directing the new institute.”

Florida Hospital will also build a state-of-the-art, 35,000 square-foot facility to house the Clinical Research Institute.

Groundbreaking is scheduled for early 2010. The Institute will combine scientists and clinicians with sophisticated technology to enhance translational research and bring new treatments to patients.

“Burnham and Stedman Center scientists will be able to exploit the power of these technologies to define disease signatures relevant to diabetes, heart disease, cancer and other diseases” says Dr. Daniel Kelly, Scientific Director, Burnham at Lake Nona. “Metabolomic approaches show great promise for identifying diagnostic markers that will aid clinicians in distinguishing disease patterns and in developing individualized treatment plans.”

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P h i l a n t h r o p y upda t e

Burnham Welcomes

Julie Johnson

Lake Nona’s new associate director for external relations Julie Johnson is a seasoned development professional with more than 26 years experience.

“I became interested in nonprofit work when I was a student at the University of Florida,” says Johnson.

“I had an internship with the Muscular Dystrophy

Association (MDA) over the summer and that’s where the love affair began.”

Johnson graduated with a degree in journalism and continued with the MDA as an events coordinator.

Later, she served as assistant executive director for the Leukemia and Lymphoma Society; president and CEO of the Mental Health Association of Northeast

Estate Planning In

Challenging Times Ken G. Coveney, Esq. Burnham Planned Giving Advisory Council

Every cloud has a silver lining. We have been in difficult economic times for awhile, but most people remain optimistic about the future. Now is the time to take advantage of these circumstances.

Interest rates are near historic lows. Make loans to children and grandchildren or trusts for their benefit. A loan at the applicable federal rate (AFR) for long-term loans (more than nine years) is 4.33 percent. A loan at the AFR is not a gift. If the children/borrowers can obtain a higher return than the AFR, they will reap future value at no transfer tax cost to the parents/ lenders. If the parents see a good investment opportunity, they can allow the children to capture it by lending them the funds to acquire the investment.

Installment sales use the same interest rates as loans. A sale of an appreciating asset transfers the appreciation from the seller

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Julie Johnson

Florida; regional vice president of the Arthritis Foundation of Northeast Florida; president of Expedition Inspiration Fund for Breast Cancer Research and, most recently,

director of development for the College of Engineering at the University of Florida, Gainesville.

“I’m excited to be part of Burnham at Lake Nona,” says Johnson. “My sister died from a heart attack at 47 as a result of uncontrolled type 2 diabetes. Obesity and diabetes are challenging health issues, and I am certain that researchers at Burnham will make significant discoveries that will advance our ability to treat them.”

to the buyer without gift tax cost. If the asset is depressed real property selected with location in mind, it likely will come back eventually. Allow children to capture the recovery by selling it to them now.

Outright gifts while values are depressed are even better than sales. If a parent sells to a child (or a trust for the child’s benefit), and if the sale price is less than the parent’s basis, the parent’s loss on sale will be disallowed, but the child (or trust) will be stuck with lower basis. If the parent gives the property to the child (or trust), the recipient will take the donor’s higher income tax basis for purposes of computing gain when they dispose of the property.

Consider transfers in trust with remainder interests to children or the Burnham Institute for Medical Research. If a donor transfers assets to a grantor retained annuity trust (GRAT), the value of the retained annuity interest will be higher in this low interest environment.

Similarly, if a donor transfers assets to a charitable lead annuity trust (CLAT), the value of the annuity interest given to the Burnham will be higher in this low interest environment and the value of the remainder interest gifted to the children will be lower.

Remember, in both a GRAT and a CLAT, the present value of the remainder interest is what counts for gift tax purposes.

So don’t surrender!! The iron is hot; now is the time to strike.

P h i l a n t h r o p y upda t e

The

Chair-iot Society

Just as the ancient chariot was critical to warfare, Burnham’s Chair-iot Society seeks to battle disease by raising funds and awareness of Burnham’s mission.

Please consider being an inaugural supporter of Burnham at Lake Nona by placing your name on one of the 201 chairs in our

state-of-the-art auditorium. Membership in the Chair-iot Society is $1,000 and entitles you to annual briefings about Burnham’s cutting edge science at the Lake Nona campus.

“As Florida natives, my husband and I were excited to be able to put our name on the future of science

Team Burnham Walt D i sney World, O rlando , F lor i da January 9 and 10 , 2010

Team Burnham for Medical Research will be running the Walt Disney World Half Marathon & Marathon to raise support for Burnham’s cutting-edge biomedical research.

Regardless of age or experience, we welcome all runners to join us and run for discovery.

Our coaches have put together a training program that can get anyone over the line for either the half (13.1 miles) or full (26.2 miles) marathons. Or, if you are feeling Goofy, you can do both — and there is still time to join.

“I had never run a step in my life, and certainly never thought I could run a half marathon,” says Catlin Potter Valmont, who is returning for her second half marathon. “Training with Team Burnham was the inspiration I needed to get into shape and complete what I thought to be impossible.”

Each team member raises $2,500 to fund Burnham research, with the overall goal of raising more than $150,000. The top fundraiser will receive two free tickets anywhere AirTran flies. All participants will have their own fundraising page and will receive

For more information, please call 407-745-2061.

Sponsors in Central Florida,” says Dr. Nicole Beedle. “And as a doctor, I am personally proud of the research going on in Orlando.”

The Chair-iot Society will host an Unveiling Event October 9, 2009 at 7 p.m.

professional training, race gear by Brooks, personal shoe fittings and discounts at Fleet Feet, all race weekend accommodations, local transportation, all meals, a one-day Disney pass and the only courtesy RV at the finish line.

To become a member of Team Burnham, please contact Kathy Pierson at 407-595-8099 or log onto www.teamburnham.org.

Gold Sponsors

Silver Sponsors

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P h i l a n t h r o p y upda t e

The Power to Cure Gala 2009

Saturday, November 14, 2009 Hyatt Regency La Jolla Aventine 6:00 pm 7:00 pm

Cocktail Reception Dinner, Auction, Dancing This award-winning image of Osteoclasts was produced by Dr. Melanie Hoefer in the Rickert laboratory.

The basic biomedical research at Burnham produces knowledge, treatments and even art. Co-chaired by Caroline Nierenberg and Kathryn Stephens, this year’s gala celebrates the art of science, as the ballroom will be transformed into a gallery of

inspiring images taken directly from the research bench.

Snea k P ee k The Fund-A-Need will support talented young scientists and help purchase essential technology to enhance Burnham research on cancer, as well as infectious

“The art and science of asking questions is the source of all knowledge.”

—Thomas Berger

and inflammatory, neurodegenerative and childhood diseases. The live auction will feature a jet trip and dinner in Napa Valley, a dinner party at Pamplemousse Grille and an internship with John C. Reed, M.D., Ph.D, Burnham President and CEO, Professor and Donald Bren Presidential Chair.

This year’s presenting sponsor is Life Technologies

Thursday, October 15, 2009 5:30 pm at Burnham Institute for Medical Research 10901 North Torrey Pines Road, La Jolla

and lead sponsors include Jeanne and Gary Herberger, Roberta and Malin Burnham and Peggy and Peter Preuss.

The Burnham Gala sells out every year, so be sure to reserve your seats today.

Tickets and sponsorship opportunities are still available. For more information, please contact Chelsea Jones at 858-795-5239 or cjones@ burnham.org.

Each year, the Fishman Fund Award, established in honor of Dr. William and Lillian Fishman, recognizes a group of outstanding postdoctoral fellows for their hard work and scientific vision.

Burnham and the Fishman Fund cordially invite you to this year’s reception to recognize the 2009 Award recipients.

Please RSVP by October 12 to Wendy Sunday at wendys@ burnham.org or 858-646-3100, extension 3420.

H E L P I N G Y O U N G R E S E A R CH SCI E N TISTS S O TH E Y C A N H E L P TH E W O R L D

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The B urnham Repor t | www.burnham.org

p r e s i d e n t ’ s M e s s age

Scientific

Excellence Fuels Strong Growth

In our 33rd year, Burnham has surpassed significant milestones in scientific achievement, research staffing and infrastructure development. As of July 1, the Institute exceeded 1,000 employees, including 74 full-time faculty and 800 scientific staff.

With the opening of Burnham’s Lake Nona campus in Orlando, Florida, the acquisition of an additional research building in La Jolla, California and the creation of the joint Center for Nanomedicine with the University of California, Santa Barbara, we have increased our space from 382,000 square feet in January 2009 to more than 671,000 square feet today. This continued growth is creating many opportunities to expand the boundaries of scientific knowledge and

John C. Reed, M.D., Ph.D.

increase employment opportunities during these challenging times.

President and CEO

Although we are growing rapidly, we have also maintained strong attention to quality, as evidenced by Burnham’s number one ranking for the past decade in scientific journal citations per

Professor and Donald Bren Presidential Chair

publication in the fields of biology and biochemistry among all organizations worldwide.

In the past two years alone, the Institute has published more than 600 research papers in scientific journals. These papers advanced understanding of the mechanisms underlying cancer, Alzheimer’s, HIV, diabetes and many other conditions. Among many recent advances, Burnham researchers have helped discover monoclonal antibodies that attack a variety of flu strains, illuminated how HIV co-opts cellular mechanisms to create persistent infections, devised novel chemicals that attack anti-death proteins responsible for sustaining malignant cells and thus providing a means to kill chemoresistant cancer cells, elucidated how protein misfolding and protein oxidation

15. John Reed essay

contribute to the demise of brain cells in Parkinson’s, Alzheimer’s and other neurodegenerative diseases and generated replacement heart cells from synthetically-produced stem cells as a new approach to treating heart attack and heart failure.

We have also increased our overall grants and contract revenue. We are the only organization in the nation to achieve more than five consecutive years of growth in funding from the National Institutes of Health (NIH), averaging 11.5 percent annual growth for the past 8 years. Last year, Burnham received a $98 million contract from the NIH to support a national network in chemical genomics, as well as an $8 million NIH grant to establish a national Parkinson’s disease research center. While covering more than 90 percent of costs from competitive grants, we have also secured important philanthropic gifts to help accelerate our research programs. South Dakota banker T. Denny Sanford donated $20 million to create the Sanford Children’s Health Research Center, San Diego developer Conrad Prebys gave $10 million to name the Conrad Prebys Center for Chemical Genomics and Irvine Companies owner Donald Bren contributed $2.5 million to

In the past two years alone, the Institute has published more than 600 research papers in scientific journals. These papers advanced understanding of the mechanisms underlying cancer, Alzheimer’s, HIV, diabetes and many other conditions.

create the Donald Bren Presidential Chair at Burnham.

At Burnham, our motto is From Research, the Power to Cure. By adding more scientists to our team and providing them with additional laboratory space, we hope to accelerate our efforts to translate basic science discoveries into better treatments that reduce human suffering around the world.

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Nonprofit Organization U.S. Postage

PAID 6400 Sanger Road Orlando, FL 32827

The Burnham Institute

Philanthropy

Partners

in Science: Denny Sanford and Dr. Fred Levine Denny Sanford wants to help medical scientists cure type 1 diabetes in his lifetime. He has created the Sanford Project to achieve this goal. Fred Levine, M.D., Ph.D., director of Burnham’s Sanford Children’s Health Research Center, is also working to find a cure. Both a research scientist and a practicing physician, Dr. Levine knows well the suffering type 1 diabetes can cause. His laboratory

“Injected insulin does not cure type 1 diabetes,”

says Denny Sanford. “But by gathering the best scientific minds to investigate the immune system

and beta cell regeneration, we will find a cure.”

is investigating new ways to replace insulin-producing beta cells, either through transplants or regeneration.

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