Translational Research in Ophthalmology

TRANSLATIONAL RESEARCH is a process in which knowledge gained in the laboratory is applied or translated to the diagnosis or treatment of human disease. The National Eye Institute (NEI), Bethesda, Md, by its charter is committed to the eye care and vision of the American people. A major effort of the NEI during the past 25 years has been to foster the development of a cadre of scientists, mainly PhDs, whose research is relevant to the visual system and related diseases. The NEI has made remarkable progress in this effort and now supports more than 1200 research project grants. Ophthalmologists apply new basic discoveries to patients with ocular disease. Most ophthalmologists have limited or no formal training in basic or clinical research. Scientists and clinicians are providers and consumers, whereas the patient is the ultimate beneficiary.

Progress in laboratory research has been phenomenal; however, translation of new discoveries to the clinic proceeds at a snail's pace. What is the problem? It is, in many ways, a failure of communication. Scientists and clinicians do not speak the same language. To communicate effectively, they need a translator. Hence, the relevance of the term translational research. The translator is the physician-scientist: a clinician with special training in a science, with understanding of the laboratory milieu, and the ability to relate to and communicate comfortably with basic scientists. This specialist in translational research has expertise in the design and conduct of clinical trials.

There are numerous impediments to the transfer of information from the laboratory to the bedside. Pober et al¹ list the most common: (1) insufficient funding, (2) a shortage of qualified investigators(physician-scientists), (3) a widespread cultural/economic/intellectual barrier that inhibits interchange of ideas and discourages interdisciplinary studies involving the basic and clinical departments of medical centers, (4) a heavy regulatory institutional review board burden, and (5) failure of academia to correct the problem.

Translational research is conducted largely in clinics and hospitals associated with universities that possess expertise in clinical trials. Important studies are supported by the National Institutes of Health (NIH), Bethesda, as multicenter clinical trials involving hundreds or thousands of human participants. We must all emphasize the primary responsibility to and priority for the human participants. The Office of Human Research Protection has underscored the importance of maximum information and protection for human participants to everyone engaged in clinical research.

We are proud to recall that one of the first and most successful of these studies was supported by the NEI, which was the Diabetic Retinopathy Study. It remains the gold standard of multicenter trials. In terms of numbers, the drug industry probably funds most of the clinical studies carried out in university hospitals. There is less difficulty in moving discoveries made in industrial laboratories to the bedside. The process is motivated by profit. Industry designs the study and hires an institution or clinicians to conduct it. Ultimately, the American public and we physicians look to industry to provide the products (eg, drugs and devices) to treat diseases of patients and improve the health of the public.

In universities, discoveries are often made in research laboratories in the course of projects designed to reveal basic mechanisms of biology. The scientists may be unaware or not highly motivated to pursue potential clinical applications. Many scientists are isolated from those with clinical interests. But in specific cases, the association of clinicians and basic scientists can be a spectacular success. This happens when the interests of the latter are directly relevant to the needs of the former. An example is the association of an investigator interested in the basic biology of angiogenesis with a chemist interested in drug discovery, a pharmacologist interested in drug delivery, a clinician interested in the pathobiology of age-related macular degeneration with expertise in design of clinical trials, a specialist in bio-informatics and epidemiology, and industry partners. Together, they may identify, test, and bring to clinical practice specific inhibitors of choroidal neovascularization.

It is hoped that the MD/PhD programs of medical schools will provide some of the needed "translators" of translational research. The NIH currently supports MD/PhD training grants in a limited number of schools and also offers individual MD/PhD fellowships (F30). MD/PhD graduates are a special breed. After a long training (ie, the typical 8 years after college to attain the MD degree and the PhD degree), they can then complete an internship, a residency, and a clinical fellowship if they aspire to an appointment in a clinical department or a research fellowship and the postdoctorate route if they wish a laboratory research career. They rarely do both. Many emerge from this long and arduous training as either a clinician or a basic scientist. Either way, they are well qualified to bridge the gap between laboratory and clinic.

The life of the clinician-scientist is difficult indeed. As described in the recent editorial by Weinreb,² the "viability of the clinician-scientist in ophthalmology continues to be under assault." Despite a general recognition that they are a valuable resource, they often are burdened with clinical responsibilities that diminish their translation research effort. Part-time researchers are simply not competitive with full-time colleagues. Some new MD/PhD faculty have been discouraged by their inability to obtain funds and, thus, opt out of academia. For the past 20 years, there has been a decline in NIH awards to physicians and "increasingly fewer ophthalmologists are interested in careers as clinician-scientists."²

What can be done? The unique contribution of the physician-investigator should be better recognized, their problems with funding accepted, and provision for extended support provided. Ophthalmology departments should support clinical scientists with a special interest in translational research. Such individuals should be a member of the institutional review board and should share scientific interests with a basic scientist in the department or have a joint appointment in a basic science department, but should be trained and interested in clinical research. This paragon of translational research should enjoy collaborative, multidisciplinary studies and the exposure to these 2 disparate cultures. Many of our young MD/PhDs fit this job description. Their retention in academia must be a high priority. Not only do they play a pivotal role in translational research but also they are often educators and role models for students and residents, advocates for basic and clinical research, and leaders in academia and industry.²

We recognize the value of proximity of basic and clinical activities in an environment that fosters communication and exchange. The personality of the investigator plays a critical role through the combination of innovative questioning and single-minded persistence to see the project through to successful completion.

The importance of cooperative interaction between basic scientists and ophthalmologists is also being increasingly recognized and promoted by many ophthalmology departments, scientific journals, scientific organizations, and funding agencies. We applaud those departments of ophthalmology that have regularly scheduled meetings as a way to bring together the scientists and clinicians in their department. The ARCHIVES demonstrates in this issue with a "basic science" theme how basic studies can be brought to the attention of ophthalmologists to promote discussion and interaction. The Association for Research in Vision and Ophthalmology promotes translational research in the program of their annual meetings to bring scientists and clinicians together.

The NEI has taken the lead to actively foster translational research by announcing a new funding program titled "Collaborative Research on Therapy for Visual Disease" (PAR-01-022).³ As described in the introductory letter sent to vision scientists by Paul Sieving, MD, PhD, director of the NEI, this program will "support multidisciplinary translational research to develop novel therapies for visual system diseases." The program announcement describing the funding goes on to say, "It will make resources available to scientists from several disciplines to form research teams to address scientific and technical questions that would be beyond the capabilities of any one research group." The director and the NEI are clearly supportive and actively encourage translational research.

Collaborative initiatives among multiple institutes have also been recently announced. "Translational Research for the Prevention and Control of Diabetes"(PA-01-069)⁴ is a program funded by the National Institute of Diabetes and Digestive and Kidney Diseases, NEI, National Institute of Nursing Research, and the American Diabetes Association seeking "to enhance diabetes prevention and control research." In this program,

studies will take interventions that have been demonstrated to be beneficial by controlled laboratory or clinical investigations and extend or adapt these interventions to larger populations or other settings.

In recent years, we have seen remarkable progress in our understanding of the human genome, which is now being expanded into characterization of the even more diverse proteome. We have seen tremendous advances in understanding the physiology, embryology, and aging of visual cells. The development of novel drugs, stem cells, and gene transfer techniques to treat patients with glaucoma, retinal degeneration, and choroidal neovascularization seem to be imminent, yet progress has been too slow for those affected by these blinding disorders. The future offers remarkable opportunities for the diagnosis, prevention, and treatment of ocular disease. Through support of translational research programs, enhancing the training and retention of clinician-scientists, and promoting the collaborative and educational interactions between basic scientists and clinicians, we can ensure successful and rapid transfer of basic research into therapies that can benefit those in need.

Corresponding author: Stephen J. Ryan, MD, Doheny Eye Institute, 1450 San Pablo St, Los Angeles, CA 90033 (e-mail: sryan@hsc.usc.edu).