From Bench to Bedside

Pitt medicine furthers a long tradition of developing clinical research into life-sustaining therapy.

"Translational medicine" is a phrase commonly used in the medical community to explain how new treatments are developed.

In reality, many medical discoveries are indeed made at the "bench" of the basic scientist as he or she investigates how a disease functions at its most basic level. Then, after long periods of study and clinical trials, that researcher's discovery may actually be "translated" into a clinical treatment, thus being taken to a patient's "bedside."

Although the phraseology may change, translational medicine is as old as the practice of medicine itself.

"The University of Pittsburgh School of Medicine has been participating in translational medicine since the school's founding 118 years ago," says Arthur S. Levine, senior vice chancellor for the health sciences and dean of the School of Medicine. "The ultimate goal of all research is to take a discovery and develop it into something that will one day help patients."

One of the University of Pittsburgh's most notable early accomplishments in translational medicine was the development of the polio vaccine 50 years ago. The late Jonas Salk, Distinguished Service Professor Emeritus Julius Youngner, and other Pitt researchers began their search for the vaccine in 1947 at the basic science level. A year later, a team of Harvard University researchers discovered how to culture cells ex vivo, enabling the Pitt scientists to speed up their research by testing cellular response to the killed virus. Five years later, in 1952, the Pitt researchers performed their first clinical trial in human patients. The vaccine was finally introduced to the public in 1955. Now, almost 50 years later, polio, a disease that affected more than 21,000 Americans in 1952, is practically nonexistent in the United States, and the number of cases worldwide is dwindling.

Removing Roadblocks

Today, regulatory oversight of research has increased significantly, and it would be astounding for a therapy to go from bench to bedside in less than 10 years. Yet agencies like the National Institutes of Health (NIH) as well as individual institutions like Pitt are taking steps to accelerate the process. In October 2003, the NIH, citing a need to expedite the development of the increasing number of important scientific discoveries made during the past few years, named translational research one of its top priorities. It hopes to facilitate the process by creating an infrastructure that will increase interaction between basic and clinical scientists, providing the resources necessary to help scientists take discoveries from the lab to the clinic and, at the same time, removing roadblocks that impede progress.

This need to facilitate and expedite translational research and research in general has been recognized by the administration at the University for years. In 2001, Pitt's schools of the health sciences opened the Office of Clinical Research (OCR) to address this need.

"We, as an institution, wanted to make sure that we didn't leave one stone unturned when it came to clinical research," says Levine. "By providing a robust and sophisticated infrastructure, we can support current research, help our researchers delve into new research, and be supportive to young researchers."

The OCR, led by Associate Vice Chancellor for Clinical Research Steven E. Reis, associate professor of medicine, consists of the Clinical Research Support Unit, Education Unit, Informational Management Unit, and Sponsored Clinical Trials. Through these four units, OCR offers the support of institutional data and safety monitoring boards; assistance with preparing for the University's regulatory committee, the Institutional Review Board; statistical assistance for clinical trials; access to the research coordinator registry; and help with patient recruitment. The OCR also maintains an education program-including research coordinator orientation and certification-and organizes seminars and training sessions on recruitment of trial participants, community outreach, and research practice fundamentals.

"The Office of Clinical Research helps us achieve one of the major goals of research-getting the newest in medicine to patients-by providing a service that helps researchers to navigate the administrative complexities and nuances of the research process, putting the focus on research, not the red tape," says Levine.

The Physician-Scientist

Another significant roadblock to progress in translational medicine has been the waning number of physician-scientists, or clinical scientists. According to the American Association for the Advancement of Science, physician-scientists are medical researchers who are trained to ask clinically relevant questions in the health research environment and transform clinical observations into research studies and medical advances. Many of these researchers are MDs who devote a great part of their professional endeavors to research and MD/PhDs who work at "the interface between science and medicine."

The dwindling numbers of clinical scientists is not a new realization; in fact, 25 years ago in a report published in the New England Journal of Medicine, NIH labeled clinical scientists an endangered species. Again ahead of the curve, the University of Pittsburgh has addressed this problem through the creation of the Clinical Scientist Training Program, a novel program that was highlighted in the fall of 2003 in the Academic Innovations section of the Journal of the American Medical Association.

In the article, Levine was quoted as saying that "no matter how many molecular discoveries we make at the laboratory bench, they can only be translated ultimately into remedies for human disease by physicians who engage in clinical investigation and who design and implement trials."

The training program, led by Wishwa Kapoor, Pitt professor of medicine, provides a structured approach to helping students develop the skills necessary to pursue a career in research. Participating medical students can add a year of study to their medical education and receive both their medical degree and the Master of Science in Clinical Research degree. Those who choose a shorter curriculum can receive a certificate in clinical research.

Most importantly, medical students entering the program may be eligible for full-tuition scholarships or for loan forgiveness through an NIH-sponsored program. According to Levine, the growing level of debt incurred by medical students is perhaps the main reason they choose not to go into research.

"We won't get anywhere in research if we don't address this fundamental problem," says Levine. "Ninety percent of our 2004 graduates graduated in debt, with the average debt being $140,000. After interest is compounded during residency, that amount grows to between $200,000 and $250,000. It makes it difficult for a student to make the choice to go into research, which initially pays much less than some of the clinical specialties."

Levine hopes that scholarship and tuition reimbursement programs will flourish, allowing students to enter research-based programs like those at Pitt.

In addition to offering the Clinical Research Training Program, the School of Medicine has an Interdisciplinary Biomedical Science Graduate Program with a common interdisciplinary curriculum and the opportunity to choose from nine specialties: biochemistry and molecular genetics, cell biology and molecular physiology, cellular and molecular pathways, human genetics, immunology, molecular pharmacology, molecular toxicology, molecular virology and microbiology, and neuroscience. To make a career in research more economically feasible, it also offers tuition remission and a stipend.

Programs that encourage young researchers and a new and developing infrastructure for advancing translational medicine will undoubtedly bolster the University's abilities in the field, but entities already in place to support translational research have yielded some remarkable success stories.

"Every department, center, and institute at the University of Pittsburgh School of Medicine supports translational medicine," says Levine. "Programs that have done an exceptional job of integrating a translational component include, but by no means are limited to, the University of Pittsburgh Cancer Institute (UPCI), Magee-Womens Research Institute (MWRI), the McGowan Institute for Regenerative Medicine, the Molecular Medicine Institute, and the Starzl Transplantation Institute."

Levine also notes the very substantial and significant contributions made to translational medicine not only by all of the schools of the health sciences, but by many other schools and departments throughout the University. For example, the Department of Bioengineering in the School of Engineering has collaborated seamlessly with the School of Medicine's Department of Surgery in making breakthrough advances over many years; the McGowan Institute for Regenerative Medicine is staffed by faculty from both schools who work side by side in developing unique cardiac- and pulmonary-assist devices. Faculty in the Department of Chemistry in the School of Arts and Sciences and the Department of Pharmacology in the medical school have collaborated extensively in the area of combinatorial chemistry, a new and major platform for drug discovery. Innovative strategies for the diagnosis and treatment of neurologic and psychiatric disorders are emerging from the close collaboration between the Department of Neuroscience in the School of Arts and Sciences and the Department of Neurobiology in the medical school. The partnership of these departments is well reflected also in their joint PhD program (at least two other joint PhD programs between Arts and Sciences and the medical school are now being established or planned). Finally, Levine points out, many points of intersection in the broad area of informatics exist between the medical school and Arts and Sciences programs in computer and information sciences.

Cancer Research

The UPCI has seen a great deal of success in the field of translational research, both within its own walls and on an international level.

"Cancer is a very complex set of diseases that continues to lead to much suffering and many deaths in almost half of those affected," says Ronald Herberman, associate vice chancellor for cancer research at the University and director of UPCI.

Clearly, translational research is needed to develop effective approaches to cancer prevention, tools for its early diagnosis, and treatments for advanced cases of the disease, as well as to relieve severe symptoms and prolong life.

"To develop the best therapies and diagnostics for cancer, we need to understand its complexities and utilize multiple approaches to reach the desired benefits," Herberman adds.

According to Herberman, the research community made an important advance in recent years when it started to unravel the biology of cancer, namely the abnormalities in genes and proteins that cause the development and progression of cancer. This advance-combined with researchers gaining a greater understanding of how the immune system works and how it interacts with cancer-have led to a number of successes in the fight against cancer.

Basic research in animal tumor models by Pitt faculty members Hideho Okada, assistant professor of neurosurgery, and William Chambers, associate professor of pathology, led to the development of a gene therapy using the cytokine, interleukin-4. This discovery then was translated by researchers-including Dade Lunsford, Pitt's Lars Leksell Professor of Neurosurgery-into a treatment that led to significant shrinkage in brain tumors in the first two patients treated.

John Kirkwood, Pitt professor of hematology and leader of UPCI's Melanoma Program, was able to use information on the biology of cancer to develop one of the only treatments available for advanced melanoma. Kirkwood began with basic research into the mechanisms of how melanoma develops, leading him to study the effectiveness of interferon alpha as a treatment for melanoma-both alone and in combination with innovative melanoma vaccines. His international multicenter trials led to the FDA approval of interferon as the only drug found to be beneficial for the treatment of melanoma.

In addition to Kirkwood, a number of other UPCI researchers are leading innovative studies into cancer vaccines that show promise of being translated into therapies. They are Louis Falo, professor and chair of dermatology, for a form of lymphoma in the skin; Hassane Zarour, assistant professor of immunology, for a variety of carcinomas; Kenneth Foon, professor of medicine and UPCI deputy director for clinical investigations, for chronic leukemia and lymphoma; and Olivera Finn, professor and chair of immunology, for breast and pancreatic cancer.

Pitt faculty members Jill Siegfried, professor of pharmacology and coleader of UPCI's Lung and Thoracic Malignancies Program, and Jennifer Grandis, associate professor of otolaryngology and leader of UPCI's Head and Neck Cancer Program, have completed basic research into the abnormalities in intracellular signaling pathways that occur in cancer cells. They are now developing these insights into innovative approaches to the treatment of cancers of the lung, head, and neck.

Other researchers are investigating and developing early tests for the diagnosis of cancer. William Bigbee, Pitt professor of environmental and occupational health and epidemiology, and his colleagues are using the newly realized field of proteomics—the study of the shape, function, and expression of proteins and proteins' effect on disease—to develop tests for cancer by analyzing proteins in a single drop of blood. In a different approach using another test involving a small amount of blood, Anna Lokshin, visiting research professor of obstetrics, gynecology, and reproductive sciences, has obtained promising results for diagnosing and differentiating patients with early stages of ovarian, pancreatic, and other cancers from those without cancer.

Although these accomplishments stem from the work of talented UPCI researchers, they also are the result of UPCI's faculty and staff community outreach efforts.

A number of studies have shown that people in rural communities do not have access to the same level of care as those who live in urban areas. The UPCI has joined the University of Pittsburgh Medical Center in forming the UPMC Cancer Centers, a network of community physicians and facilities that bring the latest in clinical trials to cancer patients in outlying communities.

"When we say the goal of research is to translate research to clinical applications that help patients, it is hard to say we have achieved this goal when the majority of people are unable to reap the benefits, whether it is because of a lack of doctors or not having health insurance," says Levine. "By bringing the latest developments in medical science and clinical trials to more rural settings, we can begin to bring care to the people who may need it the most."

Women's Health

Another area where clinical trials were lacking was in women's health. Historically, clinical research has focused on systems directly related to the health of men; in the past few decades, NIH has tried to correct this disparity by increasing trials specific to women. In 1992, Magee-Womens Hospital and the University of Pittsburgh created MWRI as a multidisciplinary institute for research on women and infants.

Staffed by faculty members from the Department of Obstetrics, Gynecology, and Reproductive Sciences and the Department of Pediatrics—along with faculty from other departments within Pitt's Graduate School of Public Health and the Schools of Medicine, Nursing, and Pharmacy—MWRI focuses on both basic and clinical research in a plethora of areas affecting women's health.

The MWRI supports one of the largest centers in the country for research into sexually transmitted diseases in women and one of the few centers in the country dedicated to family-planning research; it also houses the nation's largest group studying the basic biology of preeclampsia, a disorder characterized by high blood pressure during pregnancy and the postpartum period and a leading cause of maternal and infant illness and death. Members of the institute participate in several large NIH clinical trial networks, including the Maternal-Fetal Medicine Network, the Gynecology Oncology Group, Studies of Women Across the Nation, and the Incontinence Network.

The Magee-Womens Hospital Clinical Research Center—the only NIH-funded clinical research center devoted to research related to women's health—supports clinical trials of innovative therapeutic interventions.

In 2001, MWRI established the collaborative Pittsburgh Development Center, which focuses on aspects of human development and reproduction and the discovery of effective treatments for diseases and disabilities through the use of animal models in hopes that these discoveries can be translated into clinical applications.

Molecular Medicine

The University also has recognized molecular medicine—the study of genomics and proteomics—as a promising area for the future of medicine ripe for translation. Genomics and proteomics are analyses of the structure and function of genes and proteins, and how changes in genes and proteins, respectively, can contribute to disease.  Molecular medicine studies at the University of Pittsburgh include exciting research in gene therapy, although Joseph Glorioso, William S. McElroy Professor of Biochemistry and chair of the Department of Molecular Genetics and Biochemistry, is hesitant to call advances in gene therapy made in his laboratory a translational medicine success story-at least not yet.

"The field of gene therapy is very young; we've only been doing clinical trials in humans for less than 15 years," says Glorioso. "Gene therapy is a very promising area for the treatment of many diseases, and although we have seen a great deal of advancement, we have yet to see a great success."

Since the late 1980s-when researchers at the Massachusetts Institute of Technology first discovered that viruses could be modified and used to carry genetic information into a cell-the rush to find the best way to use genes as drugs has been ongoing.

The translation of gene therapy from bench to bedside experienced a major setback when an 18-year-old participant in a University of Pennsylvania study died from complications believed to have been caused by gene therapy. Another study that used gene therapy to treat an x-linked immune disease in children cured 12 children, but two of the children in the study developed leukemia. As it turned out, researchers were inadvertently inserting the life-saving gene near another gene that causes cancer.

"As we continued in gene therapy research, we realized that we needed a better method to introduce genes into the body and a better way to regulate gene expression," says Glorioso. "We've run the gamut of viral and nonviral systems for gene delivery, and we've come up with what may be the best uses for each vector. Now, when developing trials of gene therapy, we pay greater attention to the risk-reward ratio of this therapy."

University of Pittsburgh researchers have one of the largest gene therapy enterprises in the United States, participating in an array of preclinical and clinical gene therapy and gene transfer research programs to treat a wide array of health problems. To date, researchers have received more than $50 million in grants to support research on the use of gene therapy in a number of disorders. Trials are under way using gene therapy to treat the inherited lysosomal storage disorders Gaucher's disease and Fabry disease. In Gaucher's and Fabry diseases, gene mutations cause deficiencies in enzymes needed to break down certain types of fats. Gene therapy trials for more common diseases and disorders-including cardiovascular disease, Duchenne Muscular Dystrophy (DMD), spinal cord injury, cancer, diabetes, arthritis, Parkinson's disease, and peripheral nervous system diseases that include pain and nerve degeneration-are also being conducted by Pitt researchers.

Among the University's more notable research funding awards has been a $14.3 million grant establishing a National Heart, Lung, and Blood Institute Program of Excellence for Gene Therapy in cardiovascular disease. The University was also the site of the first clinical trial of gene therapy in arthritis.

In addition, Pitt is home to a facility that produces clinical-grade vectors for gene therapy that are used by laboratories nationwide. The Human Gene Therapy Applications Laboratory, led by Acting Director Paul Robbins, professor of molecular genetics and biochemistry, makes sure that all vectors are produced to standards for clinical research set by the U.S. Food and Drug Administration.

With such an active program in gene therapy, Pitt formed in 2002 the Molecular Medicine Institute (MMI), which works closely with scientists and clinicians to develop their research and help translate completed studies into clinical applications. The institute acts as a nucleus for gene and protein therapy research at the University, providing an umbrella for all research into molecular medicine, specifically research relating to genomics and proteomics.

The MMI was created to foster the growth of multidisciplinary preclinical and clinical research programs emphasizing novel molecular therapies, including gene transfer technologies and protein therapeutic models for the treatment of human disease. It provides the infrastructure and resources needed for scientists to rapidly translate gene therapy protocols while offering a forum for exchange and collaboration between scientists and clinicians and training in molecular medicine.

Regenerative Medicine

Founded in 2001, the McGowan Institute for Regenerative Medicine explores new therapies for genetic disorders, among other conditions. It was launched to realize the potential of tissue engineering and other techniques aimed at repairing damaged and diseased tissues and organs. A joint program between Pitt's School of Medicine and the University of Pittsburgh Medical Center, the McGowan Institute serves as a focal point for the University's leading scientists and clinical faculty who are working to develop tissue engineering, cellular therapies, treatments for wound healing, synthetic blood additives, biosurgery, and biohybrid organ devices. Faculty and staff are encouraged to devise innovative clinical protocols and pursue rapid commercial transfer of technologies relating to regenerative medicine. Alan Russell, Pitt professor of surgery, directs the McGowan Institute.

The institute's cellular therapies program seeks to repair bone fractures, injured muscle, and damaged organs and treat and hopefully cure such genetic disorders as Duchenne Muscular Dystrophy (DMD).

Johnny Huard, associate professor in the School of Medicine's Department of Molecular Genetics and Biochemistry and deputy director of the McGowan Institute, isolated the first line of myogenic-derived (muscle-derived) stem cells that have been used to treat DMD in animal models. 

Huard's lab is now working on developing this discovery into a minimally invasive treatment for DMD that will involve isolating the patient's own stem cells, altering them to incorporate a gene that encodes dystrophin, the protein these patients lack. They hope that by reinserting the cells into the patient's dystrophin-lacking muscle they will be able to stop the progression of this muscle-wasting disease.

What is unique about the type of stem cells used by Huard is that they are taken from the subject's own muscle. Although they don't have the potential to differentiate into any type of tissue as normal stem cells do, the myogenic-derived stem cells have shown a high level of plasticity in that they can differentiate into smooth muscle and certain other types of cells, thus possibly leading to promising treatments for a variety of conditions beyond muscle disorders, including bone healing, cartilage and ligament repair, and the treatment of urinary incontinence.

The McGowan Institute also supports a successful clinical translation program in wound healing. Currently under way at the institute are basic research projects in applying molecular biology to analyze fetal- versus adult-wound healing, tissue engineering of soft and hard connective tissues of the upper aero-digestive tract, cell-based therapy to regulate wound healing and reduce scarring, and the development of animal and tissue culture models to understand the mechanisms of tissue repair. Results of this research will be available for applications in the University of Pittsburgh Medical Center Wound Healing/Limb Preservation Clinic, which accommodates more than 4,000 patient visits each year.

One of the most successful programs now housed under the auspices of the McGowan Institute is the Clinical Artificial Heart Program, led by Robert Kormos, Pitt professor of surgery. Since its inception in 1987, the program has become one of the largest of its kind. It was the first in the world to discharge from the hospital patients supported with the left-ventricular-assist device and has, to date, provided support to more than 250 patients with end-stage congestive heart failure.

Program researchers are now taking lessons they have learned in the clinical arena back to basic science researchers, who are using those lessons to improve current therapies that will help patients needing transplants survive until donor hearts become available.

In addition to developing a safe, affordable, and reliable artificial heart, McGowan researchers are working on developing artificial blood and organs, including lungs, liver, pancreas, and kidneys. One of McGowan's most promising technologies is the Hattler Catheter, being developed by Brack Hattler, Pitt professor of surgery. The Hattler Catheter, an artificial device that temporarily takes over the work of the lungs, is expected to enter clinical trials within a year.

A Remarkable History in Transplantation

This is not the only "translated" research that has helped transplant patients. The University of Pittsburgh has had numerous successes in translating discoveries developed in the lab into significant advances in transplantation.

In 1981, Distinguished Service Professor of Surgery Thomas Starzl and colleagues performed Pitt's first liver transplant. That year also marked the start of two decades of major advances by University faculty-advances whose influence has been felt throughout the entire field of transplantation. These have included the development of the immunosuppressant drug FK506, the refinement of small intestine transplantation, pivotal work on transplant tolerance, progress in artificial organ research, and efforts to explore alternative sources of human organs.

Starzl began translational work on the immunosuppressant drug cyclosporin while at the University of Colorado in 1979. He brought that research with him to Pittsburgh. To this day, research is being conducted on cyclosporin at Pitt. In 2004, researchers presented the results of a 12-year clinical study using an aerosol version of the drug to prevent rejection in lung transplants.

In 1989, Starzl and colleagues announced the results of the clinical development of FK506, which is 50 to 100 times more powerful than cyclosporin.

"It’s important to realize that translational research doesn't end after the clinical trials of a therapy are completed," says Levine. "Once we make a clinical breakthrough, we take observations from the clinic back to the lab and start all over and try to improve on our discovery.

"The University of Pittsburgh has had great successes in translational medicine," says Levine, "and we expect to see a great deal more. Basic science leads to clinical discovery, and we will continue our efforts to support basic and clinical research, as we have for the past 118 years."