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Found in Translation

Moving laboratory discoveries from the bench to the bedside can be a tedious, time-consuming process. But now, UCLA scientists and their partners are embarking on an ambitious project to fasttrack scientific innovation for the benefit of patients and society.

By Dan Gordon
Illustration by Eva Tatcheva

MedMag-FallWinter11-Found in TranslationEach year in the United States, the government invests billions of dollars in basic-science research – laboratory-based studies that are designed to advance the frontiers of knowledge. But as exciting as these discoveries may be, they do little to enhance human health until they are seized upon and moved beyond the laboratory to develop a new treatment or inform an improved approach to promoting health or preventing disease. Even then, if the new therapy or health strategy isn’t widely known or appropriately applied, it does little good.

It is an unfortunate truth that, for a host of reasons, the process by which studies conducted at the laboratory bench are transformed into therapies that are effectively integrated into clinical and public-health practice – also known as translational science – has been far from optimal. A report by the National Institutes of Health (NIH) estimated that it takes an average of 17 years for only 14 percent of scientific discoveries to become standard treatment in the community.

“Seventeen years is too long to wait before the public begins to benefit from an important discovery,” says Carol Mangione, M.D., M.S.P.H., the Barbara A. Levey, M.D., and Gerald S. Levey, M.D., Endowed Chair and Professor of Medicine and Health Services in the David Geffen School of Medicine at UCLA. “The whole point of the translational-science movement is to shorten that time line.”

In an effort to speed up the pace, the NIH in June awarded UCLA, in partnership with Cedars-Sinai Medical Center, Charles R. Drew University of Medicine and Science, and the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, a five-year, $81.3-million grant to establish the UCLA Clinical and Translational Science Institute (CTSI). UCLA is one of 60 institutions across the country to receive such funding. The aim of the nationwide effort is not just to accelerate the creation of more effective treatments but also to more actively engage communities in clinical research and train future generations of researchers to think and work in this “bench-to-bedside” continuum.

Through the CTSI, UCLA and its partners have embarked on an ambitious path for using translational science to tackle the conditions that account for the greatest proportion of disability and early death in Los Angeles County, where rates of heart disease, diabetes, stroke, HIV/AIDS, depression, violence and other preventable conditions far exceed the national average.

In many ways, getting there involves fundamental changes in how scientists and clinicians are trained, work and think.

The concept of translational research isn’t new. The NIH has promoted it for more than two decades. But bottlenecks have developed that have kept the translational pipeline from flowing the way it should. One reason has to do with funding – whether it’s the expense associated with the infrastructure needed for clinical and community-based research or lack of financial support for the practical steps necessary to take laboratory findings to the clinic or from the clinic to the community.

“These NIH awards are recognition that we need a better-organized, better-funded approach to this area of investigation, and that increasingly the work in clinical translational science requires team efforts within individual academic medical centers and across academic medical centers,” says Steven M. Dubinett, M.D., director of the CTSI and UCLA associate vice chancellor for translational science. Renowned for his own translational lung-cancer research, Dr. Dubinett has served on the National Cancer Institute’s Translational Research Working Group, where he participated in designing pathways that characterize the transformation of scientific discoveries into new clinical approaches for oncology.

Others point out that historically there has been little incentive for basic-science researchers to take the next step in moving their discoveries to the clinic – or to forge the types of collaborations outside their discipline that would enable that transition to happen. “Translational research requires expertise in the disease, in how to translate, and in the underlying science, and it’s hard to capture that in a single person,” says S. Claiborne Johnston, M.D., Ph.D., professor of neurology and epidemiology and director of the UC San Francisco CTSI . “We’ve tended to have basic scientists who are driven by discovery and clinical researchers and clinicians who are driven by health problems, without either having much knowledge of each other’s work.”

Traditional training approaches, while producing top scientists, haven’t necessarily encouraged big-picture thinking. “If you think about it, the work of the basic scientist selects for people who can hone in on a narrow problem and make progress on it,” says Christopher Denny, M.D., professor of pediatric hematology/oncology and a member of the CTSI leadership team. “However, that means that your sphere of expertise and the way you see things are relatively limited. To take findings from the bench to the bedside usually requires a broader perspective, and that’s why our focus with the CTSI is on multidisciplinary research.”

In his studies on vitamin-D deficiency and its impact on the immune system, John S. Adams, M.D., professor of molecular, cell and developmental biology medicine and of orthopaedic surgery, is taking discoveries from the lab to his patients – and taking insights gleaned from his clinical practice back to the lab. The synergy from working across the traditional bench/bedside divide has paid off in a big way: Dr. Adams, along with UCLA Chief of Dermatology Robert Modlin, M.D., and colleagues discovered that bringing tuberculosis-infected white blood cells to normal vitamin-D levels could improve their ability to kill the TB-causing bacteria. Their 2006 paper on the discovery, published in Science, led to a major push for improving vitamin-D health as a strategy for boosting the immune system and combating infectious disease, particularly in the developing world, where vitamin-D insufficiency is epidemic.

Dr. Adams follows in the footsteps of widely heralded UCLA scientists who parlayed their laboratory discoveries into advances that today benefit millions of patients. For example, oncologist Dennis Slamon, M.D., Ph.D., director of clinical/translational research at UCLA’s Jonsson Comprehensive Cancer Center, and his colleagues conducted both the laboratory and clinical research in the development of the widely used drug Herceptin, which targets a specific genetic alteration found in more than 25 percent of patients with breast cancer. Michael Phelps, Ph.D., director of UCLA’s Crump Institute for Molecular Imaging, invented positron emission tomography, which is now used routinely for important clinical assessments in cancer, neurological disorders and cardiovascular disease.

With such examples in mind, “We want to look at these exceptional contributions and set up an infrastructure for research that would allow them to be far more common,” says Dr. Dubinett.

But he points out that researchers who are expert in both the lab and the clinic are rare; more often, translation requires teamwork, not only between basic scientists and clinicians, but also among individuals with disparate perspectives. “The major health issues cut across disciplinary lines, and there is now recognition that being able to bring laboratory studies to clinical fruition and engage communities in research require a team effort, a flexible research infrastructure and a broad spectrum of expertise,” says Dr. Dubinett.

“In the past, we have worked in silos – everyone in his or her own little world – and the communication among different groups has not been good,” says Isidro Salusky, M.D., associate dean for clinical research at the David Geffen School of Medicine at UCLA and director of UCLA’s new Clinical Translational Research Center. “The idea of the CTSI is to encourage team science as a way of accelerating advances.”

Like Drs. Dubinett and Adams, Dr. Salusky works in both the lab and the clinic in his studies of chronic kidney disease in children. In the last several years, his group has found associations between bone abnormalities, kidney disease and the cardiovascular system that have contributed to the recognition of a systemic disorder. By working together to learn more about the interrelationships among these different systems, Dr. Salusky and colleagues from other subspecialties hope to make an impact on the prevention and treatment of chronic kidney disease and its complications.

“Cardiovascular disease has been the major cause of death in adult and pediatric patients with advanced chronic kidney disease, and we have made very little progress in combating this problem over the last two decades,” Dr. Salusky says. “This is an example of an area in which we are broadening the approach to help us understand the process, in the hope that this will lead to better therapies.”

Part of the CTSI’s emphasis is to train a new generation of scientists skilled at seeing the clinical implications of laboratory findings, but also capable of working across the spectrum of disciplines. But nurturing this type of work also requires new types of reward systems. In the past, grant funding hasn’t encouraged multidisciplinary teams seeking new approaches to big problems, but that has begun to change. “It doesn’t work to just bring people together. You have to bring them together for a reason, and funding ends up being something that motivates people,” says Dr. Johnston.

While adopting such incentives, UCLA’s CTSI is also working to expand the opportunities for meaningful interactions. “There needs to be an active mixing process. You have to keep stirring the tank all the time or it’s going to settle, and people are going to go right back into their comfort zones,” says Dr. Denny. “You have to uproot people and use incentives to get them to go to seminars where they don’t know anyone, where they can learn something totally different. Often nothing will come out of it, but that one time when it does can make all the difference.”

A key part of the effort at UC San Francisco, Dr. Johnston explains, is to make the process of bringing discoveries to clinical fruition more efficient. “It doesn’t make sense for a scientist to learn all of the steps of a translational pathway,” he says. “What’s needed, which is what we have done, is to provide them with access to expertise and resources through core services that allow them to take these steps. That eliminates a lot of failure and a lot of waste.”

UCLA's CTSI is taking a similar tact. The newly established Center for Translational Technologies aims to provide the structure necessary for investigators across the four collaborating campuses to easily access the more than 100 biomedical cores that already exist, as well as to accelerate the transition of emerging technologies into translational resources.

Dr. Denny, the center’s director, notes that although UCLA and its partners have numerous core facilities in areas ranging from biomedical imaging and small-molecule screening to electron microscopy, transgenic mice and microarrays, many researchers aren’t aware of the resources that exist and how they can be used. Dr. Denny includes himself among that group, despite the fact that he has been at UCLA for more than 20 years. Thus, one of his initial priorities is to develop a searchable online database to help researchers access the facilities that can assist them. In addition to providing basic information and answers to frequently asked questions about the cores through the online resource, the center plans to employ technology officers, who can provide additional information and guide junior investigators through the process. The center will also provide funding to build existing cores through new technologies, equipment upgrades and other types of expansions.

Successfully and efficiently moving discoveries from the laboratory to the clinic requires significant infrastructure the likes of which have been lacking in the past. Dr. Adams’ work on the epidemic of vitamin-D deficiency and its impact on the immune system’s ability to ward off infectious diseases such as tuberculosis illustrates the point. In his clinic, he invites patients to participate in studies in which their blood samples are taken before and after their vitamin-D treatment and studied in culture to learn how vitamin-D levels affect the response to tuberculosis.

The support required for such work – including the staff needed to help identify, screen and enroll patients and then collect biological specimens and transport those specimens to the appropriate research laboratory – is made even more complex by the fact that Dr. Adams’ outpatient clinic is at Santa Monica-UCLA Medical Center and Orthopaedic Hospital, while his lab is in Westwood. “If I had to do this on my own, it wouldn’t be possible,” says Dr. Adams. “The idea behind the CTSI is to speed the transition from laboratory discoveries to clinical benefit by making it more efficient to do these types of studies.”

A major infrastructure boost is coming through the UCLA Clinical and Translational Research Center, which is designed to support outpatient research studies in a newly renovated area of UCLA’s Center for the Health Sciences. The 23,000-square-foot center will include individual patient rooms for clinical research, interviews and procedure rooms. The clinical-research activities will be supported by the new clinical and translational-research laboratory directed by Anthony Butch, Ph.D., professor of pathology and laboratory medicine, with the aim of promoting the latest advances in biomarkers and assay development to the CTSI community.

It’s been nearly 30 years since beta-blockers were first found to be protective for people with cardiovascular disease, yet only about half of patients who have had an acute myocardial infarction are being treated with the drugs six months later. Barely more than half of eligible Americans have received appropriate colorectal cancer screening despite overwhelming evidence of its value in preventing cancer morbidity and mortality. Tamoxifen and raloxifen have been shown to reduce the chance of getting breast cancer by 50 percent for high-risk women, yet the chemoprevention drugs are used by only one-third of these patients. From the time mammography screening was introduced until guidelines were first developed, decades passed, and untold women died of breast cancers that could have been detected at a more treatable stage.

When new therapies are proven in clinical trials to be effective, many assume that the public will immediately reap the benefits. But that is rarely if ever the case, and so the focus of CTSI partner institutions is as much on bringing proven therapies to the population through community engagement as it is on the bench-to-bedside work. “Translational science doesn’t end with a successful clinical trial,” says Dr. Dubinett. “We need to do a better job of disseminating what we know to be good practices.”

One CTSI member whose community translational work will be particularly important is Denise Aberle, M.D., professor of radiology. Dr. Aberle was the national principal investigator for the National Cancer Institute-sponsored National Lung Screening Trial, a large multicenter randomized study evaluating the benefits of low-dose helical CT scans vs. chest radiography for individuals at high risk for lung cancer. The results, recently published in the New England Journal of Medicine, were eye-opening: a 20-percent reduction in mortality for the high-risk patients screened with CT.

Dr. Aberle notes that there has never been an effective screening approach for lung cancer, which in the United States kills more people than colon, breast and prostate cancers combined. “This is potentially the most important advance for reducing lung-cancer mortality since the surgeon general related smoking to cancer in 1964,” Dr. Aberle says.

But she notes that her work is far from complete. “Now we need to take this evidence base and use implementation and dissemination research to try to incorporate it into the practice of medicine in a way that brings maximum benefit to all at-risk populations,” she says.

The emphasis on “bedside-to-community” translation is relatively new. “There has been a recognition that we have a leaky conduit between what we learn from clinical trials about best practices and what we actually do when we see patients,” says Dr. Mangione, who heads CTSI’s Research, Education, Training and Career Development Program. “It’s a challenging problem, and we haven’t really focused on training scientists who are good at that part of the translation. But what’s exciting is that we are beginning to do that.”

A key theme of the CTSI’s work involves bridging the divide that has existed between the academic medical center and the community through the development of bidirectional community partnerships. “The best science occurs when we are communicating across the spectrum of translation,” says Dr. Mangione. “That means the scientist is getting input from the community on important health problems and research needs, and communities are partners in everything from interventions to how we train scientists.”

New and established training programs at UCLA and its CTSI partners are focusing on training the next generation of translational researchers, skilled at thinking more broadly about health problems, participating in multidisciplinary teams and effectively working with communities and communicating findings to the public. CTSI is reaching across the educational spectrum, seeking to attract bright students to translational science through outreach to high schools and undergraduate programs, as well as in medical schools and Ph.D. programs.

The goal CTSI has set for itself – tackling the major health and disease burdens in Los Angeles County – is daunting. The county’s population of more than 10 million is larger than that of 42 states and far more diverse than most. Three-fourths of the residents are non-white, and one-third of the population was born outside the United States. Ninety languages are spoken across the county’s households. One-in-five household incomes is below the federal poverty line, and one-fourth of the county’s residents lack health insurance. A 15-year life expectancy gap separates the healthiest and sickest populations, so eliminating disparities, as well as addressing the major causes of premature death and disability, is a major focus.

“We are taking on a great challenge, but we also have a considerable opportunity to make a significant impact on the population,” says Dr. Dubinett. “We need to think creatively about how our discovery science, along with the unique resources of UCLA and our partner institutions, can be used to reach all communities to address these concerns.”

Dan Gordon is a regular contributor to UCLA Medicine.

 





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