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Clinical and translational science is transforming across campus

As much as anyone, Robert McDonald MD, knows why medicine must form a better route from basic research to clinical application. He performed research in cell biology, genetics, microbiology and immunology before and during medical school at the University of Missouri. What he studied in labs at MU and elsewhere would later have a crippling effect on his family.

McDonald and his wife live in Jefferson City, Mo., with their nine children. Four years ago, the parents noticed that their youngest son had enlarged calf muscles and other developmental abnormalities.

Mark McDonald
Mark McDonald has Duchenne muscular dystrophy. His father, Robert McDonald, MD, finds hope in MU's gene therapy research.

"I was pretty sure what he had even before he was evaluated, but I didn't want to believe it," McDonald recalls. "I studied the disease during my days as a researcher, medical student and neurosurgery resident, and I remember thinking that it was something that I wouldn't wish on my worst enemy."

Tests verified that the 2-year-old had Duchenne muscular dystrophy (DMD), for which there is no known cure. Due to progressive muscle deterioration, children with the genetic disorder become paralyzed and usually die of respiratory or cardiac failure before their 30th birthday.

"When our worst fears were confirmed, my wife and I decided to do something about it," McDonald said. "We decided to work harder than the pain hurt. We wanted to improve research and treatment, not just for our son, but for other young men who have this disease."

McDonald immersed himself in studying DMD. His former mentor Jeffrey Robbins, PhD, who was a biochemist at MU before joining the University of Cincinnati, connected McDonald with Parent Project, the largest nonprofit organization focused on DMD. McDonald now serves on the organization's board of directors and as a member of its therapeutics committee.

He is particularly impressed with gene therapy research led by Dongsheng Duan, PhD, Margaret Proctor Mulligan Distinguished Professor in Medical Research in MU's Department of Molecular Microbiology and Immunology. Duan is developing a new gene therapy delivery method for DMD patients, which he has tested in mice and now dogs. Unlike other methods, Duan's is effective for both skeletal and cardiac muscle, and it can reach every muscle in a large animal.

"Since dogs are 250 times the size of mice, but only nine times smaller than a human on average, we have taken a significant step in understanding if this therapy can work," Duan said. "This development raises the hope of whole body correction of DMD."

Duan often discusses his research with McDonald and at conferences hosted by Parent Project, the Muscular Dystrophy Association and other organizations. "He is one of the most valuable people trying to find a solution for DMD," McDonald said. "Parents like me are looking to scientists like him to someday help our children grow up to be men, and hopefully old men."

McDonald is hopeful, but he isn't sure Duan's discoveries will be developed in time to help his son. The surgeon is painfully aware that it costs approximately $500 million to discover and develop just one new drug, and it takes an average of 12 to 15 years to bring a new drug from the lab to the clinic. The time, cost and complexity of the process has led the nation's medical community to adopt a radically different approach to research and development.

New course from lab to clinic

Recent remarkable advances in medicine were made possible by decades of steadily increasing political and financial support for research. The National Institutes of Health funded a new breed of scientists studying health and disease at the molecular and cellular levels. Their discoveries resulted in better treatments for cancer, heart disease and low birth-weight infants. Morbidity and mortality declined for tens of millions of Americans, who now live to an average of 78 years.

But just as discoveries seemed to peak with the completion of the Human Genome Project in 2003, support for research started to stagnate. NIH funding failed to keep up with inflation, and in 2006, its budget decreased for the first time in 36 years. With a backlog of promising discoveries poised for testing and development, the NIH charted a new course. It planned to focus on transforming scientific knowledge into tangible benefits for people. The new plan was described in the NIH Roadmap and embodied in the Clinical and Translational Science Award (CTSA) program.

Approximately 60 institutions — fewer than half of the nation's medical schools — are linked through a CTSA center consortium. The centers will work together to accelerate the process of developing laboratory discoveries into treatments for patients, train a new generation of clinical and translational scientists, and engage communities in clinical research.

MU is competing to join the nationwide network by applying for a CTSA grant, which would provide approximately $20 million in funding over five years for infrastructure projects. The projects will create a toolbox of resources for investigators, from biomedical informatics services to support for clinical trials. MU has already received a CTSA planning grant and an "outstanding score," as designated by the NIH, for the university's full grant application.

Jamal Ibdah, MD, PhD, right, and Jerry Parker, PhD
Jamal Ibdah, MD, PhD, right, and Jerry Parker, PhD, are leading MU in developing its Institute for Clinical and Translational Science. The institute, based in the medical school, is the university's highest research priority.

Jamal Ibdah, MD, PhD, and Jerry Parker, PhD, are MU's chief architects for translating collaborative science into better health for communities. Since 2005, they have developed MU's Institute for Clinical and Translational Science (ICATS) in line with the CTSA model. Based in the School of Medicine, ICATS is re-engineering and energizing bench-to-bedside research across campus.

"MU has tremendous potential and resources for clinical and translational research, but like most universities, our resources were organized on the basis of schools, colleges and specific scientific disciplines," Ibdah said. "With ICATS, we've created an entirely new framework that consolidates assets across campus and unites them in a common goal — to speed up the process from discovery to products that actually benefit people and their communities."

Twelve schools and colleges and nearly 50 faculty members provide core support for ICATS. The center benefits from the fact that MU is one of only five universities nationwide that offers law, medicine, veterinary medicine and a nuclear research reactor on one campus. The collaboration goes beyond traditional life sciences players to involve MU's business college for assistance in commercial development; the law school for assistance with patents, intellectual property protection and regulations; and the journalism school for assistance in communicating the benefits of clinical and translational research to community health care providers, policy makers and the general public.

Dozens of additional MU research centers and institutes, hospitals and clinics, and extension and outreach programs also are partners in ICATS' efforts to transform science and become a CTSA center. "Competing successfully for a CTSA application is my number one research priority for MU," said Robert Duncan, PhD, vice chancellor for research. "My conversations with other senior campus administrators, deans and research center directors reveal that they hold the same view. We are all of the same mind that a CTSA is critically important for our institution."

Signature research and resources

In many ways, MU and its medical school have been building toward the development of ICATS for at least a decade. Since 2000, more than 100,000 square feet of medical laboratory space has been created. MU's Life Sciences Center opened in 2004, and MU created labs for medical research through construction and renovation at the School of Medicine, Truman Veterans Hospital and Dalton Cardiovascular Research Center. New buildings supporting medical research that were completed last year include MU's Biochemistry Complex, International Institute of Nano and Molecular Medicine, and Regional Biocontainment Laboratory.

At the same time, MU's medical school recruited more than 200 faculty members, including many in- volved in research. The new researchers and laboratories have helped MU become one of the nation's fastest growing universities in terms of grant expenditures.

Ibdah arrived with the wave of recruited researchers. He came to MU in 2005 as director of gastroenterology. He also serves as senior associate dean for research and Raymond E. and Vaona H. Peck Chair in Cancer Research at the medical school. He became founding director of ICATS in 2007.

"Beyond our growing resources, MU hosts several research programs that have been leaders in their respective fields for many years and are producing world-class translational science discoveries," Ibdah said. "Combined with our distinctions in education, these signature re- search programs are allowing us to develop an outstanding clinical and translational science institute."

Rat Xrays
In partnership with Truman Veterans Hospital, MU operates one of the world's best biomolecular imaging centers. Scientists involved with the center, which produces images of rodents, and MU's Nuclear Research Reactor have developed such drugs as Quadramet, shown above in a human and its global commercial form.

Radiopharmaceutical sciences is a signature program involving medicine, veterinary medicine, nuclear science and other campus units. MU's Research Reactor is the nation's most powerful university research reactor and the largest producer of radioisotopes for biomedical and medical applications. At Truman Veterans Hospital, MU's medical school operates one of the world's best biomolecular imaging centers, which was created in part with a $10 million grant from the National Cancer Institute. The center produces high-resolution anatomic and molecular images of rodents for a variety of biomedical research. Scientists involved with the reactor and imaging center have invented several important commercial therapies, in- cluding TheraSphere for liver cancer, Quadramet for bone cancer pain, and Ceratec for brain imaging to diagnose stroke, Alzheimer's disease and other conditions.

Radiopharmaceutical science has been bolstered in recent years by nanomedicine leaders and radiology professors Fred Hawthorne, PhD, and Kattesh Katti, PhD. A Curator's Distinguished Professor, Katti led MU in becoming one of only 12 nanotechnology platform partners as designated by the NCI. Hawthorne leads MU's International Institute of Nano and Molecular Medicine. The National Academy of Sciences member and Priestley Award recipient is one of the world's best chemists.

Comparative medicine is a signature program that draws on the strong relationship between medicine and veterinary medicine at MU. MU is the only university with three NIH national centers in comparative medicine. MU's National Swine Resource and Research Center is the country's only repository and distribution site for swine models. MU also houses the only Rat Resource and Research Center and one of three regional Mouse Resource and Research Centers in the U.S. More recently, MU became one of 12 sites selected for a new NCI Comparative Oncology Trials Consortium, and MU has one of 13 regional biocontainment labs.

In partnership with MU's college of agriculture, MU's medical school has developed an international research program on the medical applications of plants. For example, a $7.6 million NIH grant awarded to biochemistry professor Dennis Lubahn, PhD, supports MU's Center for Botanical Interaction Studies. The center was established in 2010 as one of only five in the country selected to lead interdisciplinary and collaborative research on botanical dietary supplements.

Microcirculation researchers from MU's School of Medicine, College of Veterinary Medicine and Dalton Cardiovascular Research Center have also developed one of ICATS' four signature research programs. Supported by program-project grants exceeding $30 million, their studies address virtually all dimensions of microvascular research at its most fundamental levels. Investigations into exercise, diet, alcohol and gender are revealing basic biological mechanisms involved in cardiovascular disease, diabetes, obesity and the metabolic syndrome.

Training, communication and communities

While discoveries made by scientists have provided a large amount of new information, most physicians have not been adequately trained in research to apply that information to the benefit of patients. MU is in the process of developing a new advanced training program in clinical and translational science. The Tom and Anne Smith MD-PhD Program also encourages greater numbers of physician-scientists.

To help scientists connect with colleagues in academia and elsewhere, ICATS also is developing an innovative communication system that will help disseminate information to health care providers and the general public. The communication system is led by Esther Thorson, PhD, associate dean for journalism and an international expert on health-related communication. She and Parker, the medical school's associate dean for research and ICATS co-director, are editors of the new book "Health Communication in the New Media Landscape."

"Developing new and better ways of communicating with each other, patients and the general public is one of the most important components of improving clinical and translational research," Parker said. "At ICATS, we are linking our communication and informatics systems to take advantage of the latest digital, media-based resources. These new communication tools are designed to create an effective dialog between scientists, practitioners and the general public. We want to disseminate information about our research to everyone, and we want consumers to provide us with real-time feedback on our research priorities."

Consumers and community partners will be connected through ICATS in an organized effort to achieve tangible improvements in health and quality of life. MU's Center for Health Policy will lead ICATS in forming a collaborative network of public and private groups with expertise in health care research and delivery, poverty, education, nutrition, disability, social services and job development. MU's partnership with Cerner, which nhas resulted in the Tiger Institute, could help provide an information technology backbone for connecting MU's far-reaching network of hospitals, clinics, telehealth sites and pharmacies — and then extend to health care providers across Missouri.

"All of our efforts focus on delivering health solutions to hospitals, clinics, patients and the general public," Ibdah said. "The University of Missouri's primary mission has always been to improve the lives of all Missourians, and improving clinical and translational research could have a tremendous impact on people throughout our state and even the world."