NIH grants contribute to the ultimate goal of developing new treatments for diseases and improving the quality of life for millions of Americans and people worldwide. The research supported by these grants also generates U.S. patents that fuel the biotechnology industry and creates thousands of jobs across the nation. NIH funding supports the training of our biomedical research workforce and strengthens the foundation of a 21st century knowledge-based economy.

Ultimately, NIH funding is the key to driving down health care costs, as well as improving productivity and the quality of life of Americans. Currently, the NIH invests more than $31 billion annually in medical research, creating 350,000 jobs. Pharmaceutical companies and biotechs spend approximately $70 billion annually for research, creating an additional 580,000 jobs. In total, $1 of public basic science funding stimulates $3.50 of pharmaceutical industry investment (based on 2007-2010 data).

In his Congressional briefing, Reed pointed out that with health care costs rising from $714 billion in 1990 to $2.3 trillion in 2008, it is important to invest in medical research, which in turn will eventually lower health care expenditures. At present, NIH funded research is estimated to save an average of $3.2 trillion in health care costs annually.

A current petition on the White House’s We the People page asks the Administration to increase NIH spending to $33 billion next fiscal year. The petition can be viewed and signed here.

“As president of one of Florida’s leading research universities, I am honored to join Sanford-Burnham’s Board of Trustees,” said Machen. “My relationship with Sanford-Burnham dates back to 2006, when the Institute first considered opening a new campus in Orlando. Over the years we’ve developed strategies that will benefit our individual and shared scientific endeavors. I look forward to my role on the board and the many new partnership opportunities to come.”

Machen was appointed UF’s 11th president in January 2004. During his tenure, he has expanded the university’s research and scholarship endeavors, elevated its educational programs and increased access to students from diverse economic backgrounds. A member of the Florida Council of 100, he has held several prominent positions in statewide and national higher education. He earned his doctorate in dental surgery from St. Louis University and doctorate in educational psychology from the University of Iowa, both of which have honored him with distinguished alumnus awards.

“We are thrilled to have Bernie join our Board of Trustees. His longtime support of our Institute and commitment to furthering medical research make him a perfect fit. With the opening later this year of UF’s Research and Academic Center adjacent to our Orlando campus, we welcome a new Medical City neighbor and superb partner,” said Sanford-Burnham CEO John Reed, M.D., Ph.D.

Already, researchers at Sanford-Burnham and UF are exploring opportunities for collaborations in such fields as diabetes and aging. Several Sanford-Burnham faculty members also hold joint faculty appointments at UF, including Dr. Reed, who is an adjunct professor.

Click here to watch the interview [video]

In the interview, Dr. Collins talks about sequencing the human genome and what it means for personalized medicine. Here’s an excerpt:

Right now, for instance, we are learning an increasing amount about how to prescribe drugs in a more precise, individualized way. We’re not all quite the same.

Physicians listening to this interview will no doubt agree. You have somebody who has a particular condition, you’re pretty sure you have the diagnosis right, you write the prescription, you give the dose that’s recommended, and it doesn’t always turn out right. Some people don’t get the benefit; some people even have a surprising toxic reaction. A lot of that variability is based on DNA, and at least for some drugs, now more than a dozen, we think we have a pretty good handle on what that’s about. It’s possible to make those predictions ahead of time so that you could write the prescription a little differently, knowing that person’s particular makeup.

For more commentary from Sanford-Burnham’s medical experts—on everything from stem cells to exercise in a pill—watch Medscape’s Developments to Watch series.

Complement is an ancient and important component of the body’s immune system and consists of a set of proteins (C1 through C9) that directly bind to bacteria. Complement assists in the removal of bacteria in two ways: 1) by “tagging” the bacteria for cells of the immune system to clear out, and 2) by forming pores or holes in the membrane of bacteria causing the bacteria to die. These deadly membrane pores are known as the complement membrane attack complex, or MAC.

While necessary to fend off infection, in some pathological conditions, over-activation of complement triggers the MAC to destroy our own cell—as in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, for example.

While researchers have known which complement proteins get together to form the MAC (C5-C9) and the order in which the MAC proteins are assembled, important questions remained. First, nobody knew exactly how the MAC assembled. Also, how is assembly regulated and why does it always occur in a certain order?

Using x-ray crystallography, a technique that allows scientists to capture the 3D structure of proteins, researchers recently solved the 3D crystal structure of C6, the first component of the MAC pore. The study was led by Sanford-Burnham’s Robert Liddington, Ph.D. and Alexander Aleshin, Ph.D., in collaboration with Richard DiScipio, Ph.D., from the Torrey Pines Institute for Molecular Studies.

In a paper published January 20 in the Journal of Biological Chemistry, the team not only solved the 3D structure of C6, but they went one step further and compared their C6 structure with that of another MAC component, C8, as well as with the structures of other pore-forming proteins.

With this data at hand, the researchers were able to create a detailed model of how the different MAC components fit together to form holes in bacteria. What they propose is that C6 joins the complex in a “closed” state but then “opens,” allowing the parts that insert into the bacterial membrane to be exposed. C6 “opening” also allows MAC proteins to fit together like pieces of a puzzle, forming the pore.

These findings were deemed so significant that their paper was selected as a “Paper of the Week” by the journal, making it among the best papers the Journal of Biological Chemistry receives for publication.

“We are now anxious to test our model of MAC assembly, especially the ‘shape-shifting’ by C6,” Liddington said. “If we are right, then we should be able to figure out how to inhibit MAC formation by designing small molecules that prevent C6 from changing shape. That could lead to novel therapies for a whole range of inflammatory diseases.”

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Original paper:
Aleshin AE, Schraufstatter IU, Stec B, Bankston LA, Liddington RC, & Discipio RG (2012). Structure of Complement C6 suggests a mechanism for initiation and unidirectional, sequential assembly of the Membrane Attack Complex (MAC). The Journal of biological chemistry PMID: 22267737

CONNECT, a regional program that catalyzes the creation of innovative technology and life sciences products and companies in San Diego County, described the significance of this undertaking by saying, “As life science research institutions increase their focus on commercialization of discoveries and develop strategies to help start-up companies succeed, it is imperative that Congress and the Obama administration understand how federal research funding results in successful discoveries, start-ups, and job creation.”

In their presentations, both Reed and Salka illustrated the link between federal funding for scientific research and economic growth. Reed detailed the impact of NIH funding on job creation. ‘‘When you look at the number of jobs NIH research generates and the average job wage, you can make a decent argument that the jobs more than pay for the investment NIH makes,’’ he said. ‘‘In total, $1 of public basic science funding stimulates $3.50 of pharmaceutical industry investment.’’

Reed and Salka then discussed the challenges faced by research institutes trying to translate their discoveries into viable products and companies. They highlighted CendR as an example of how federally funded research can lead to commercial success. Sanford-Burnham is helping CendR turn groundbreaking, federally-funded cancer research into a viable start-up company. CendR is commercializing a new, promising treatment for cancer that will target and penetrate tumors, enabling specific delivery of therapeutics deep into tumors–research pioneered by Sanford-Burnham’s Erkki Ruoslahti.

Reed went on to say, “…74 percent of all U.S. biotechnology and biopharmaceutical companies have licensed patents from NIH-funded academic research, 59 percent of these companies indicate that licensed technology is central to their business, and 17 percent of Food and Drug Administration-approved drugs cite NIH patents as their source.’’

As regulatory decisions and predicted budget cuts continue to play out, industry attention will undoubtedly continue to focus on Washington. CONNECT has shared photos, video, and the slide presentation from the briefing.

I grew up being told one thing over and over again by my parents, “All that matters is that you’re healthy. Nothing is as important as your health.” I never fully understood or appreciated the extent to which that was true until six years ago, when I became someone with a disease…

It was during my intern year of my psychiatry residency when people started to comment on the way I walked. They asked me why I was limping or whether I had injured myself. Initially, I didn’t understand to what they were referring, but over time, I started to see it myself.  Of course, I didn’t make much of it, I knew there couldn’t possibly be anything serious wrong with me. I had always been such a healthy and active person. I’d been exercising for as long as I could remember, I’d climbed various mountain peaks from the Grand Teton to Mount Kenya, I had run half-marathons and cycled from San Francisco to Los Angeles as part of the AIDS Ride. So, naturally I just figured it was nothing; maybe something was “out of alignment” in my hips or maybe I just needed new orthotics. But then I started having  trouble running.  I couldn’t quite figure out how or why, my legs just felt clumsy. And then I started to trip more often and lose my balance. Eventually, I couldn’t even do a slow jog.

…

The physician who came to see me first happened to be of Persian Jewish descent. After a few minutes of listening to my story and examining me, he told me that he thought I had a progressive neuromuscular disease found among Persian Jews called Hereditary Inclusion Body Myopathy or HIBM, a disease which, on average, leads to severe incapacitation within 10 to 15 years from diagnosis.  And in that moment, my world stood still.

Where do new medicines come from? The first step in the drug discovery process often involves screening small molecules (chemicals) to determine their potential to produce innovative biological research tools. Sanford-Burnham’s Conrad Prebys Center for Chemical Genomics uses robotic technology to sift through chemical compounds by the millions to find the few that could potentially be developed into new medicines

In 2009, Sanford-Burnham was selected as a comprehensive center in the National Cancer Institute’s new Chemical Biology Consortium (NCI-CBC), an integrated network of chemical biologists, molecular oncologists, and chemical screening centers. The consortium works to translate knowledge from leading research institutions into new treatments for patients with cancer. Scientists from around the country rely on the expertise and resources of the screening centers to identify active compounds. In turn, these compounds become the starting points for innovative new medicines.

Sanford-Burnham’s La Jolla campus recently hosted a meeting of the NCI-CBC steering committee, where attendees shared updates on ongoing projects and held strategy sessions to discuss milestones. The day ended with a public mini-symposium featuring scientific presentations by Sanford-Burnham’s Ze’ev Ronai, Ph.D. and Robert Wechsler-Reya, Ph.D., as well as UC San Diego’s Michael Karin, Ph.D. and the Salk Institute’s Reuben Shaw, Ph.D.

“We enjoyed participating in this event. Our membership in the NCI-CBC gives us the chance to take a leadership role in the search for the next-generation of anti-cancer therapies,” said Kristiina Vuori, M.D., Ph.D., Sanford-Burnham’s president and director of Sanford-Burnham’s NCI-designated Cancer Center.

Current NCI-CBC members include:
Sanford-Burnham Medical Research Institute
Emory Chemical Biology Discovery Center
University of California-San Francisco Fragment Discovery Center
Georgetown University Medical Center
The NIH Chemical Genomics Center
North Carolina Comprehensive Chemical Biology Center
Southern Research Institute
SRI International
University of Minnesota Chemical Diversity Center
The University of Pittsburgh Chemical Diversity Center
University of Pittsburgh Specialized Application Center
Vanderbilt Chemical Diversity Center

The study, published February 17 in Science, not only helps decipher the molecular mechanism underlying TLR5 recognition and function, but it also advances knowledge that’s key to the design of new therapeutics.

“The structure of the TLR5-flagellin complex visualizes molecular events that occur on the cell surface to trigger flagellin-induced host immune responses, and provides significant insights into the structural basis for TLR5 recognition and signaling,” said Ian Wilson, D.Sc., Hansen Professor of Structural Biology at Scripps Research who led the study with Andrei Osterman, Ph.D., professor in Sanford-Burnham’s Infectious and Inflammatory Disease Center.

“Gaining knowledge of a molecular interaction and action—as we did in this study— is critically important to the further development of therapeutics based on agonists and antagonists of the TLR5 receptor,” said Osterman.

Flagellin is a component in some vaccines and a derivative of this protein is currently being developed as a medical countermeasure to radiation by Cleveland BioLabs, Inc. (NASDAQ:CBLI), also a contributor to the new study.

Keeping an eye out for infection

Some of the body’s first lines of defense against invading bacteria are Toll-like receptors (TLRs), sensors that sit on the surface of many different types of cells. There are roughly a dozen different TLRs, each keeping an eye out for a particular sign of infection.

TLR5, for example, specifically recognizes and binds to flagellin. Like most TLRs, TLR5 does more than just sense bacteria—it also sends signals that call up immune cells to destroy the intruder. But to fully understand how TLR5 works, scientists needed to be able to see its 3D shape and how it binds to flagellin.

The structures of several other TLRs had already been solved, but each of these binds non-protein molecules, such as RNA or lipids. For technical reasons, determining the structure of TLR5—the only TLR that binds a protein—had long been a challenge.

In this study, the Scripps Research team was able to overcome these hurdles using TLR5 found in zebrafish as a proxy for the human protein. The scientists were then able to apply a technique called X-ray crystallography, which uses powerful X-ray beams to produce 3D images of proteins at the atomic level.

At Sanford-Burnham, Osterman and his team used biochemical and protein engineering methods to unravel the mechanistic details of interactions between TLR5 and flagellin and its derivatives.

Scientists at Roswell Park Cancer Institute and Cleveland BioLabs, Inc. in Buffalo, N.Y., under the leadership of Andrei Gudkov, Ph.D., performed complementary experiments in human cells expressing TLR5 and validated the fish TLR5 as a good surrogate for human TLR5.

This research was funded by the National Institute of Allergy and Infectious Diseases, the Skaggs Institute for Chemical Biology at Scripps Research, and Cleveland BioLabs, Inc.

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Original paper:
Yoon, S., Kurnasov, O., Natarajan, V., Hong, M., Gudkov, A., Osterman, A., & Wilson, I. (2012). Structural Basis of TLR5-Flagellin Recognition and Signaling Science, 335 (6070), 859-864 DOI: 10.1126/science.1215584

“The data generated thus far lays the groundwork for analysis of how individuals respond differently to disease,” said Steven R. Smith, M.D., director of the Florida Hospital – Sanford-Burnham Translational Research Institute for Metabolism and Diabetes (TRI), where the clinical studies are being performed with volunteers. “This partnership with Takeda, TRI, and Sanford-Burnham establishes a model to accelerate the development of safe and effective therapies.”

During the first year of the partnership, the modeling of fit and obese states provided the basis for discovery of a candidate drug for metabolic disease. Clinical research at the TRI assessed the physiological response to changes in food consumption, such as high-sugar or high-fat foods. At Sanford-Burnham, patient-derived samples were analyzed using advanced technologies, such as metabolomics, to measure individual response. Ultimately, these metabolic fingerprints may serve as biomarkers and novel drug targets to project how subgroups of patients may respond to new therapies.

“Our research projects have progressed extremely well and we were anxious to provide a research update to our partners in Japan,” said Daniel Kelly, M.D., Ph.D., scientific director of Sanford-Burnham at Lake Nona in Orlando.

This was not, however, Takeda’s first glimpse at the data. Researchers from Takeda met earlier this year in Lake Nona and a visiting Takeda scientist works in a Sanford-Burnham laboratory. “This type of close collaboration during the fundamental discovery phase is part of a new model for academic-commercial partnerships designed to expedite new drug candidates into the development pipeline,” said Kelly.

The partnership was launched in February 2011 and combines the organizations’ complementary strengths in biomedical research, clinical research, and drug development to identify and validate obesity-related biomarkers and new drug targets. The multi-disciplinary team of basic scientists and clinical researchers at Sanford-Burnham and the TRI provides Takeda with a research continuum from laboratory bench to patient bedside.

“We’re optimistic that this collaboration will contribute to Takeda’s goal of identifying novel targets that will lead to the development of new therapeutics to treat patients suffering from obesity,” said Paul Chapman, Ph.D., general manager of Takeda’s Pharmaceutical Research Division.

The partners expect the research agreement to set the stage for future collaborative drug discovery programs aimed at novel therapeutics to treat obesity.

Sanford-Burnham scientists have now developed a new mouse model for studying medulloblastoma. The animal model mimics the deadliest of four subtypes of the human disease, a tumor that is triggered by elevated levels of a gene known as Myc. The study, published February 13 in the journal Cancer Cell, also suggests a potential strategy for inhibiting the growth of this tumor type. This achievement marks an important milestone toward personalized therapies tailored to a specific type of medulloblastoma.

“Being able to use an animal model as a tool to test treatments has been very valuable in medulloblastoma, as in other types of tumors. But for Myc-associated tumors, that hasn’t been an option because there hasn’t been a model of the disease. This is the first step to developing therapies for this type of tumor,” said Robert Wechsler-Reya, Ph.D., director of the Tumor Development Program in Sanford-Burnham’s National Cancer Institute-designated Cancer Center, member of the Sanford Consortium for Regenerative Medicine, and senior author of the study.

In this latest study, Wechsler-Reya, postdoctoral researcher Yanxin Pei, Ph.D., and colleagues showed that cerebellar stem cells engineered with the Myc oncogene initially gave rise to large masses of cells when transferred to mice, but after four weeks these cells disappeared. Researchers have known for years that the Myc oncogene causes cells to grow but also, paradoxically, to die. The reason is that Myc activates another gene called p53, which senses that something is wrong with the cell and causes it to self-destruct. The next step was to inactivate p53, which the researchers did by giving the cells a mutant form of the gene to block its effects.

The result was striking: the newly engineered cerebellar stem cells, carrying Myc and mutant p53, formed large tumors in mice that continued to grow over time. Moreover, these tumors resembled those seen in humans with Myc-driven medulloblastoma.

The researchers then profiled the genes that are expressed in the tumors and found particularly high levels of genes that are activated by an enzyme called PI3-kinase. PI3-kinase is an important part of the mechanism that cells use to stay alive, and its activity is often elevated in cancer cells. Armed with this information, the team tested whether inhibiting PI3-kinase could block the growth of Myc-driven tumors.

“We found that PI3-kinase inhibitors significantly increased mouse survival,” said Pei, the study’s first author.

PI3-kinase inhibitors are in clinical trials for several types of cancer, but no one has tried them as a treatment for medulloblastoma. Wechsler-Reya said his lab is now taking steps toward testing these inhibitors as a potential therapy for the disease.

“Obviously there are many steps between screening compounds in the lab and giving drugs to patients,” Wechsler-Reya said. “But some of the steps can be cut short if you use drugs that are already in trials or in use for other diseases.”

The team plans to screen other compounds using the new mouse model to test their effectiveness in stopping tumors. Wechsler-Reya’s lab is also working on developing new mouse models to study other medulloblastoma subtypes.

“The key is to take compounds that show promise in pre-clinical studies in the lab and partner with clinicians to evaluate their effectiveness in the clinic,” Wechsler-Reya said. “Our hope is that this approach will bring new therapies to children who are suffering from this extremely aggressive disease.”

This research was funded by the California Institute for Regenerative Medicine, the National Cancer Institute, and Alex’s Lemonade Stand Foundation.

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Original paper:
Pei, Y., Moore, C., Wang, J., Tewari, A., Eroshkin, A., Cho, Y., Witt, H., Korshunov, A., Read, T., Sun, J., Schmitt, E., Miller, C., Buckley, A., McLendon, R., Westbrook, T., Northcott, P., Taylor, M., Pfister, S., Febbo, P., & Wechsler-Reya, R. (2012). An Animal Model of MYC-Driven Medulloblastoma Cancer Cell, 21 (2), 155-167 DOI: 10.1016/j.ccr.2011.12.021

Sanford-Burnham, Fresno State, and the Central Valley Health Policy Institute share this collaborative project, funded by the National Cancer Institute. Their mission is to train undergraduate and graduate students for future cancer research careers and enhance cancer research potential at Fresno State (a minority-serving institution). The three-year grant gives Fresno State minority students the opportunity to spend a summer in Sanford-Burnham laboratories, where they become more familiar with biomedical research.

Faculty, students, and administrators gathered for a full day of presentations and a tour of the campus. Kristiina Vuori, M.D., Ph.D. and  Guy Salvesen, Ph.D. led Sanford-Burnham’s involvement, with Lynnette Zelezny, Ph.D. and Jason Bush, Ph.D. leading the Fresno State group. A number of other faculty participated, including Ze’ev Ronai, Ph.D. and Maurizio Pellecchia, Ph.D. Fresno State intern Monica Gonzalez also took part.

Learn more about the Cancer Health Disparities project on their website.

Some unusual alliances are necessary for you to wiggle your fingers, researchers report.

Understanding those relationships should enable better treatment of neuromuscular diseases, such as myasthenia gravis, which prevent muscles from taking orders from your brain, said Lin Mei, Ph.D., director of the Institute of Molecular Medicine and Genetics at Georgia Health Sciences University.

During development, neurons in the spinal cord reach out to muscle fibers to form a direct line of communication called the neuromuscular junction. Once complete, motor neurons send chemical messengers, called acetylcholine, via that junction so you can text, walk, or breathe.

As a first step in laying down the junction, motor neurons release the protein agrin, which reaches out to LRP4, a protein on the muscle cell surface. In turn, this activates MuSK, an enzyme that supports the clustering of receptors on the muscle cell surface that will enable communication between the brain and muscle. The precise alignment between the neuron and muscle cell that occurs during development ensures there is no confusion about what the brain is telling the muscle to do.

A missing piece was how agrin and LRP4 get together.

A study published February 1 in the journal Genes & Development shows that in the space between the neuron and its muscle cell, agrin and LRP4 first form two diverse work teams: each team has one agrin and one LRP4. The two teams then merge to form a four-molecule complex essential to MuSK activation and to the clustering of receptors that will receive the chemical messenger acetylcholine on the muscle cell.

It was expected that the two agrins would get together first, then prompt the LRP4s to merge. “This is very novel,” said Mei, and an important finding in efforts to intervene in diseases that attack the neuromuscular junction.

Mei and Rongsheng Jin, Ph.D., neuroscientist and structural biologist in the Del E. Webb Neuroscience, Aging and Stem Cell Research Center at Sanford-Burnham, are co-corresponding authors of the study. To reveal the novel mechanism, they used a technique known as X-ray crystallography, which produces 3-D “pictures” of protein at the atomic level using powerful X-ray beams.

Myasthenia gravis, which paralyzes previously healthy individuals, targets these protein workers. The condition, which can run in families, likely results from a process called mimicry in which the immune system starts making antibodies to the body’s own proteins. The majority of patients have antibodies to acetylcholine receptors and a smaller percentage have antibodies to MuSK. More recently, Georgia Health Sciences University researchers also helped identify LRP4 as an antibody target.

The scientists already are looking at the impact of the antibodies on the LRP4 complex. Understanding its unique structure is essential to designing drugs that could one day block such attacks. “Prior to this we had no idea how they interacted,” Mei said.

In addition to providing new information on muscle diseases, this study might also have a far-reaching ripple effect in the field of neuroscience.

“This is just the beginning,” says Jin. “Now that we know more about how signals are transferred during the formation of neuromuscular junctions, we can start looking at how a similar system might work in brain synapses and how it malfunctions in neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases. If we can figure out how to trigger the formation of new brain synapses, maintain old synapses, or simply slow their disappearance, we’d be much better equipped to prevent or treat these diseases.”

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Original paper:
Zong Y, Zhang B, Gu S, Lee K, Zhou J, Yao G, Figueiredo D, Perry K, Mei L, & Jin R (2012). Structural basis of agrin-LRP4-MuSK signaling. Genes & development, 26 (3), 247-58 PMID: 22302937

The organizations will utilize new molecular and genomic technologies to discover, translate, and personalize interventions for preventing and treating diseases more efficiently to improve outcomes, while reducing costs. The partnership will speed up the discovery and development of new treatments by bringing together the complementary strengths of Florida Hospital’s large patient population and clinical research expertise; Sanford-Burnham’s fundamental research expertise and technology platforms; and Moffitt’s biospecimen bank (samples of tissue, cells, blood, etc.), data warehouse, and personalized medicine capabilities.

“As a statewide resource for cancer research and treatment, Moffitt seeks to foster relationships such as this one to maximize the state’s investment in the overall health and well-being of patients,” said William S. Dalton, CEO and center director of Moffitt. “We feel this partnership will enhance Florida’s national and international reputation in the discovery, translation, delivery and dissemination of care.”

Moffitt’s approach, called Total Cancer Care™, is a treatment path that begins by mapping the more than 30,000 genes making up a tumor to find its unique genetic fingerprint. Through personalized medicine, Moffitt is working to create individualized therapies specific to each patient’s type of cancer.

“PMP Florida is a model for combining research and clinical-care expertise to advance personalized care. Sanford-Burnham will deploy our most advanced technologies to discover molecular signatures of disease that can provide insight for determining appropriate therapeutic interventions,” said John Reed, M.D., Ph.D., Sanford-Burnham’s CEO. “The technology platforms, collections of patient samples, and medical information sharing create a powerful combination for improving patient outcomes and reducing costs.”

Through PMP Florida, researchers at the partnering institutions will access a robust research and clinical care infrastructure. Bio-samples representing a variety of diseases are available from Florida Hospital’s extensive patient population. Pilot projects will utilize Moffitt’s genome mapping, information systems, and clinical research protocols. The research will be empowered by Sanford-Burnham’s scientific expertise in genomics and metabolomics technology platforms.

“PMP Florida is a unique partnership including three organizations with very complementary areas of expertise and experience,” said David Moorhead, M.D., senior vice president and chief medical officer at Florida Hospital. “Moffitt has demonstrated world class experience and competency in acquiring, categorizing, and storing biologic specimens. Sanford-Burnham is renowned for its internationally recognized scientific faculty, multiple sophisticated diagnostic platforms and a commitment to transforming basic science research into clinically available treatments. Florida Hospital is the largest hospital in Florida with broad, innovative and superior clinical expertise. Together, our organizations will have the potential to quickly and successfully advance the scientific development and availability of personalized medicine and to benefit the economic development of our communities.”

One of the objectives of the partnership is to attract industry clients, including pharmaceutical and biotech companies, who will want to utilize this unique resource for discovery and development of new advances in health care. This partnership will exemplify how personalized medicine discoveries made in research labs will improve health care in hospitals, clinics, and medical offices in Florida and nationally.

Sequencing a patient’s entire genome to discover the source of his or her disease is not routine – yet. But geneticists are getting close.

A case report, published February 2 in the American Journal of Human Genetics, shows how researchers can combine a simple blood test with an “executive summary” scan of the genome to diagnose a type of severe metabolic disease. In the study, researchers at Emory University School of Medicine and Sanford-Burnham used whole-exome sequencing to find the mutations causing a glycosylation disorder affecting Liam, a boy born in 2004.

Whole-exome sequencing reads only the parts of the human genome that encode proteins, leaving the other 99 percent of the genome unread. This method is cheaper and faster than whole-genome sequencing, but is still an efficient strategy for reading the parts of the genome scientists believe are the most important for diagnosing disease. It is estimated that most disease-causing mutations (around 85 percent) are found within the regions of the genome that encode proteins, the workhorse machinery of the cell. The report illustrates how whole-exome sequencing, which was first offered commercially for clinical diagnosis in 2011, is entering medical practice. Emory Genetics Laboratory is now gearing up to start offering whole-exome sequencing as a clinical diagnostic service.

Liam, the boy in the case report, was first identified by Hudson Freeze, Ph.D., director of the Genetic Disease Program at Sanford-Burnham, and his colleagues. A team led by Madhuri Hegde, Ph.D., associate professor of human genetics at Emory University School of Medicine and director of the Emory Genetics Laboratory, identified the gene responsible for Liam’s condition. Mutations in the gene (called DDOST) had not been previously seen in other cases of glycosylation disorders.

“This is part of an ongoing effort to develop diagnostic strategies for congenital disorders of glycosylation,” Hegde says. “We have a collaboration with Dr. Freeze to identify new mutations.”

Glycosylation is the process of attaching sugar molecules to proteins that appear on the outside of the cell. Defects in glycosylation can be identified through a relatively simple blood test that detects abnormalities in blood proteins. The sugars are important for cells to send signals and stick to each other properly. Patients with inherited defects in glycosylation have a broad spectrum of medical issues, such as developmental delay, digestive and liver problems, and blood clotting defects.

Liam was developmentally delayed and had digestive problems, vision problems, tremors, and blood clotting deficiencies. He did not walk until age three and cannot use language. The researchers showed that he had inherited a gene deletion from the father and a genetic misspelling from the mother.

“Over the years, we’ve come to know many families and their kids with glycosylation disorders. Here we can say that Liam is a true ‘trail-blazer’ for this new disease,” Freeze said.

The researchers went on to show that introducing the healthy version of the DDOST gene into the patient’s cells in the laboratory could restore normal protein glycosylation. Thus, restoring normal function by gene therapy is conceivable, if still experimental. However, restoration of normal glycosylation would be extremely difficult to achieve for most of the existing cells in the body.

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Original paper:
Jones MA, Ng BG, Bhide S, Chin E, Rhodenizer D, He P, Losfeld ME, He M, Raymond K, Berry G, Freeze HH, & Hegde MR (2012). DDOST Mutations Identified by Whole-Exome Sequencing Are Implicated in Congenital Disorders of Glycosylation. American journal of human genetics PMID: 22305527

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Want to learn more about glycosylation disorders?
Attend our 3rd Annual Rare Disease Day Symposium on February 24.

Read more blog posts about genetic disease research at Sanford-Burnham:
My moment with Corinna
Chance encounter saves a child’s life
Collaboration helps a young Iranian girl

“Before this study, fructose’s effect on insulin release was not appreciated. Fructose, and especially high-fructose corn syrup, is found in everything from sodas to cereals, but it remains to be seen whether dietary fructose is good or bad for beta cells and human metabolism,” said Björn Tyrberg, Ph.D., adjunct assistant professor in the Diabetes and Obesity Research Center at Sanford-Burnham’s Lake Nona campus in Orlando and senior author of the study.

After a meal, beta cells in the pancreas typically respond to the suddenly high levels of glucose, another type of sugar in the blood, by releasing insulin. Insulin then binds to receptors present on many cells in the body. Like a key unlocking a door, insulin binding allows glucose to enter the cell and be used for energy. But most meals are a mix of different types of sugar. This study shows that glucose is not the only sugar that triggers insulin secretion—fructose also plays a role.

Using human and mouse pancreatic cells, Tyrberg, along with postdoctoral researchers George Kyriazis, Ph.D. and Mangala Soundarapandian, Ph.D., found that fructose activates sweet taste receptors on beta cells. Together with glucose, fructose helps amplify insulin release. To substantiate this observation, the team took a look at cells genetically engineered to lack the taste receptor gene. Without the gene, fructose did not stimulate insulin release, underscoring the role beta cell taste receptors play in insulin signaling.

“These findings are interesting because we know that insulin affects blood glucose levels, indicating that these newly identified beta cell taste receptors might play a role in metabolic diseases such as obesity and diabetes,” said Kyriazis, first author of the study. “We’re now trying to understand how beta cell taste receptors are regulated and how their expression might differ between healthy and disease states. We’re also now designing human studies to substantiate what we’ve found in mice.”

Click here to read more about diabetes research at Sanford-Burnham

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Original paper:
Kyriazis GA, Soundarapandian MM, & Tyrberg B (2012). Sweet taste receptor signaling in beta cells mediates fructose-induced potentiation of glucose-stimulated insulin secretion. Proceedings of the National Academy of Sciences of the United States of America PMID: 22315413