Mapping the future of medicine

About six years ago, Thomas O. Carpenter, M.D., professor of pediatrics (endocrinology), wondered why he was seeing an increasing number of infants with nutritional rickets. He examined some of the infants’ medical records and found that although rickets is presumed to be caused by a vitamin D deficiency, fewer than half of the infants had low levels of the vitamin. Many appeared to be calcium-deficient as a result of being weaned from breast milk to juices and soda. With funding from the Gerber Foundation, Carpenter began a large-scale three-year study in 2005 that involved 800 babies from inner-city New Haven health clinics and the Primary Care Center at Yale-New Haven Hospital. By screening infants at their well-child visits, Carpenter aims to define the prevalence of early rickets in New Haven, determine how much of it is due to vitamin D deficiency versus calcium deficiency and look for changes in biomarkers that can be spotted before bone disease is evident. The study is already showing results: Carpenter found that elevated levels of parathyroid hormone, which is used to diagnose rickets, can also be used to predict who may eventually develop the disease, so that doctors can begin to treat children to ward off the disorder before symptoms are present. He is also searching for other genetic factors that may represent an increased susceptibility to the disease.

Such clinical research is not a novelty at Yale. But these efforts are now being organized and supported on a much broader scale under the umbrella of the Yale Center for Clinical Investigation (YCCI). The center was launched in early 2006 to coordinate research programs among Yale’s health science schools and the surrounding community. It is also intended to support faculty research efforts while at the same time ensuring that patients are protected and receive high-quality care. YCCI’s mission dovetails with the National Institutes of Health (NIH) Roadmap for Medical Research, which was implemented in 2002 near the end of a five-year period in which Congress doubled the NIH budget. The Roadmap helped garner public support for NIH-supported research and provided a framework for bringing medical knowledge from the laboratory to the patient. In October 2006 the School of Medicine was one of 12 institutions around the country to receive a Clinical and Translational Science Award (CTSA); at $57.3 million the five-year award is by far the largest NIH research grant in the school’s history (see related story, “Is the straight road too narrow?”). When fully implemented in 2012, the CTSA initiative is expected to provide $500 million annually to 60 academic health centers working in concert. NIH Director Elias A. Zerhouni, M.D., said that CTSA will “transform how clinical and translational research is conducted.”

Yale has traditionally been strong in basic science and has been successful in identifying drug targets and such other methods of combating disease as tissue engineering or large-scale public health interventions aimed at disease prevention. But until recently a center for translating basic science discoveries into clinical practice had never taken hold. “We just never had the necessary resources to set up the infrastructure we’re able to have now,” said Robert S. Sherwin, M.D., the C.N.H. Long Professor of Medicine and director of YCCI. The center is a one-stop shop that provides the support investigators need to translate their work from the bench to the bedside. YCCI is accomplishing this task through a mix of such initiatives as helping investigators implement their own clinical trials, nurturing a new generation of physician-scientists and clinical investigators, and supporting collaborations with local organizations to promote public health.

Expertise and an online database

No one is more cognizant of the difficulties of negotiating the clinical trial maze than Christopher K. Breuer, M.D., assistant professor of surgery (pediatrics) and pediatrics. Breuer and Toshiharu Shinoka, M.D., Ph.D., director of pediatric cardiac surgery at Yale-New Haven Children’s Hospital, have developed a technique for engineering blood vessels to connect the inferior vena cava to the pulmonary artery. Known as Fontan surgery, the technique corrects a single-ventricle anomaly—a heart defect in which a patient has a weakened or single ventricle instead of the usual two. Breuer starts by seeding mononuclear cells isolated from a patient’s bone marrow onto a tube made from a synthetic material similar to that used to make absorbable sutures. The cells attach to the synthetic scaffold and form new tissue; as the tissue forms the scaffold degrades, leaving a purely biological vessel. Blood vessels grown from a patient’s own cells are less prone to infection than the artificial vessels that have traditionally been used in this surgery. The natural vessels are biocompatible and—perhaps most important for pediatric applications—they grow with the child, precluding the need for further surgery.

When Breuer began experimenting with tissue engineering in the early 1990s, he broke down a blood vessel into its cellular components in order to grow a new one. But this approach required additional surgery to procure the blood vessel and up to four months to grow the cells in culture and allow them to attach to the scaffold. He can now perform a bone marrow aspiration, isolate a special fraction of stem cells, seed them onto the scaffold, and implant the engineered vessel into the patient in a single procedure that lasts about six hours.

Breuer is about to begin a Phase I study to test the procedure’s safety. He plans to try it in six patients over the next three years, staggering enrollment so that each patient can benefit from the one before. Although Shinoka has successfully performed the procedure on 23 patients in Japan, the regulatory requirements in the United States are more demanding. “One of the biggest challenges is the regulatory requirements,” said Breuer. “YCCI has offered a lot of help and expertise.”

Breuer is now well versed in running a clinical trial. For other researchers who lack the experience to put together an effective study, however, YCCI offers expertise in trial design, regulatory issues, protocol development, biostatistics and epidemiology, budget and recruitment. The center also offers research nursing support, data management, laboratory services, and both inpatient and outpatient facilities to conduct trials. A new online database at yaletrials.org provides detailed information about all clinical trials at Yale, so that patients interested in a specific disease can search for a trial related to it. YCCI also integrates the efforts of Yale’s institutional review boards (IRBs) into the process. These panels, comprising clinicians, faculty, students and members of the community, must approve every research project that involves humans, even a paper-and-pencil survey. The medical school’s two IRBs meet weekly to discuss the several hundred new proposals and more than 1,500 requests to renew ongoing studies that come their way each year.

In the world of clinical trials, some studies, such as Breuer’s work, attempt to treat an existing condition, while others try to answer basic questions about the course of diseases or ways to prevent them. Carpenter’s work does both. His nutritional rickets study is helping doctors treat the disease before it can do damage, but he also conducts research on X-linked hypophosphatemia (XLH), the most common form of inherited rickets in the United States. XLH can lead to deformed bones and debilitating arthritis. Carpenter established the Yale Center for XLH, an NIH-sponsored Center of Research Translation (CORT), one of eight in the country that serve as a model of translational research in academic medical centers. Some of the center’s projects interface with CTSA, such as clinical trials studying the effect of a medication specifically aiming to suppress the hyperparathyroidism that occurs with XLH. Carpenter is also conducting an observational study to characterize the disease in patients past childhood and he is trying to determine the chemical and skeletal features of XLH in older patients. “Understanding the disease has opened up a whole new mechanism of how minerals are regulated in the body,” said Carpenter. That area of research includes new therapies applicable not only to XLH but also to other disorders in which the body’s handling of phosphate has gone amiss, such as chronic renal failure.

Focus on training

Perhaps the single most important aspect of the CTSA—and by extension YCCI—is training young researchers to conduct clinical studies. “In the past, most physicians learned on the job, sort of like an apprenticeship,” said YCCI Director Sherwin. “But the kind of sophistication that’s now required to do clinical research and the kind of mentorship background you need to do research today are much more involved than a simple apprenticeship.” The Investigative Medicine Program, which serves as the administrative home for the educational component of YCCI, was developed at the School of Medicine in 1999 to award the Ph.D. to physicians training in clinical research. Under the CTSA it has expanded to offer courses to medical, nursing and public health students. In addition, 20 junior faculty members and senior fellows who are committed to careers in clinical or translational research have received 18-month grants for salary and research support through YCCI’s Scholar program. Drawn from the three Yale health schools, the grant recipients are pursuing research projects under the guidance of individualized mentorship committees. “We’re investing in them like we invest in training a Ph.D., which involves having people from diverse backgrounds looking at their work from different perspectives,” said Sherwin.

The work of Mary E. Tinetti, M.D., director of the Yale Program on Aging, serves as an example of the kind of research the program strives to advance. While training in geriatrics more than 20 years ago, she recognized that a slew of health conditions—such as incontinence, delirium and injuries caused by falls—were neglected by the health care system yet have a major impact on quality of life and functioning.

Tinetti identified characteristics linked to an increased risk of falls and conducted a study to determine whether interventions targeting these risk factors would prevent falls and injuries. Until that time, most clinical trials focused on a single intervention; however, Tinetti and her colleagues developed a new multifactorial trial design in which patients receive a combination of interventions tailored to their particular risk factors. For example, the intervention for patients who experience a drop in blood pressure when moving from lying or sitting to standing consists of increased hydration, specific exercises to do before getting up, and a reduction in medications likely to affect blood pressure changes on standing. In the mid-1990s, Tinetti and colleagues followed a group of 320 patients and controls for two years and found that patients who received such interventions reduced their risk of falling by about 30 percent. The next step was to see whether this reduction in falls would also occur when real-world clinicians, rather than investigators, were responsible for carrying out the interventions. For the past eight years, she and colleagues have been conducting a study in the greater Hartford area to train health care practitioners to incorporate components of fall prevention into their practice. The real- world trial was funded by the West Hartford-based Donaghue Medical Research Foundation, said Tinetti, the Gladys Phillips Crofoot Professor of Medicine (geriatrics) and professor of epidemiology (chronic diseases) and investigative medicine.

In an article published in the New England Journal of Medicine in July, Tinetti and her colleagues reported that the fall prevention programs resulted in an 11 percent reduction in falls compared to the control group, and 10 percent fewer fall-related hip fractures and head injuries. The reduced injury rate translated into some 1,800 fewer emergency room visits over a two-year period and health care savings estimated at $21 million.

“The research is done,” Tinetti said. “The next step is to put it into practice, by making physicians, nurses and physical therapists everywhere more conscious of fall risks among their patients and what can be done to prevent falls.”

From bedside to community

Tinetti’s application of her research to clinical practice ties in with another major goal of YCCI—forging research relationships with the local community to improve public health. The Community Alliance for Research & Engagement (CARE), supported in part by YCCI, fosters community-based research and translates these findings for the benefit of New Haven-area residents. “The specific goal of CARE is to go from bedside to the community,” said Jeannette R. Ickovics, Ph.D., deputy director of CARE and professor of epidemiology (chronic diseases) and public health and of psychology. The first major initiative of CARE was to sponsor a consensus conference in 2007 with more than 70 leaders from New Haven and Yale. CARE has awarded five grants totaling $110,000 for pilot research projects—including childhood obesity and violence prevention. CARE also publishes a quarterly newsletter highlighting community-based health information about how research is conducted, and “CAREtips”—easily accessible recommendations based on faculty findings. “There are so many important discoveries at Yale that land in the major medical journals but never benefit our neighbors right here in New Haven,” said Ickovics. “We’re looking to take the work of excellent Yale scientists and really give the science away. Our goal is to improve health in New Haven.”

Even when investigators reach the point where they are conducting trials with study participants, they often continue working in the lab. For example, as Breuer prepares for the clinical trial to implant tissue-engineered blood vessels in children, he is experimenting with mice to discover the mechanism that forms the new tissue. Working with colleagues in biomedical engineering, he has isolated the protein responsible for maintaining the vessel’s lumen (inner cavity), a finding that may eliminate the need for bone marrow aspiration in the next generation of tissue-engineered grafts for humans. Every investigation has the potential to advance the prevention and treatment of disease. The structure provided by YCCI is helping clinical investigators from different disciplines to pool their efforts, learn from one another, and take advantage of their collective expertise. “That’s how progress is,” said Breuer. “Everyone adds their own tiny step, and in the end you’ve gone a long way.” YM