National Eye Institute Celebrating 25 Years Of Visionary Research

The National Eye Institute (NEI) celebrates its 25th anniversary this year. But, as institute director Carl Kupfer notes, while its accomplishments over the years have more than justified its formation as a separate research agency of the National Institutes of Health, it took a bit of persuasion to carry out that vision. FAR-SIGHTED FOCUS: Cal Kupfer, the institute's first director, recounts NEI's past successes and looks forward to achieving new goals in treating eye disease. "In the 1950s, ophthalmic research was a small branch in the National Institute of Neurological Disease and Blindness (NINDB)," recounts Kupfer, then a professor of ophthalmology and an NINDB grantee at the University of Washington. But many ophthalmologists felt that advances in the field would be limited under a research institution whose interest encompassed the entire neurosciences. Hence, they began to lobby for the formation of an independent institute that would focus on the eye. NEI came into being in 1970 by an act of Congress (Public Law 90-489), with a budget of $23 million. The initial investment in establishing NEI has "paid off handsomely," declares Kupfer, the institute's director since its inception. Among NEI's achievements are: establishing effective treatments to prevent blindness in such diseases as diabetic retinopathy--damage to the retina (Diabetic Retinopathy Study Research Group, Ophthalmology, 88:583-600, 1981)--and the retinopathy of premature infants (E.A. Palmer et al., Controlled Clinical Trials, 12:277-92, 1991) through NEI clinical trials; identifying the gene defects associated with retinitis pigmentosa (T.P. Dryja et al., Proceedings of the National Academy of Sciences, 88:9370, 1991) through NEIextramural grants; and isolating and characterizing the retinoblastoma genes implicated in certain rare forms of eye cancer (Y.K.T. Fung et al., Science, 236: 1657, 1987) through NEI- supported basic research. In fact, NEI officials point out, establishing a separate eye institute has paid off quite literally, given the socioeconomic costs of blindness and visual impairment. According to a study conducted by Leon Ellwein, special assistant to the director, to demonstrate the cost- effectiveness of NEI's research, vision-related impairments exact a heavy price--some $40 billion a year--in direct and indirect costs. The latter includes such factors as the loss of jobs and productivity of people who lose their sight. NEI-supported breakthroughs have made a dent in those losses, officials maintain. "Just the study establishing laser treatment as a safe and effective treatment for diabetic retinopathy has saved society close to $2 billion a year," Ellwein claims. Although its 1995 allocation of $300.9 million accounts for less than 3 percent of the NIH budget of $11.3 billion, NEI functions as the largest single funding body for eye- and vision-related research in the United States. More than $258 million, or about 85 percent of its budget, goes toward funding extramural scientists; $30.9 million, or 10 percent, is set aside for intramural studies; and the rest is used to cover administrative costs. Research activities and priorities are guided by Vision Research--A National Plan: 1994-1998, the fifth in a series of long-range planning documents prepared by NEI, the National Advisory Eye Council, and representatives of the broader vision research community. These plans contain overviews by expert panels on specific areas of eye research, policy recommendations, and scientific program priorities. "The plan comes from the research community--it looks at where the opportunities are and what the key questions are that need addressing," says Jack McLaughlin, associate director for extramural research. "While it is not a blueprint, we use it as a guide." NEI has set "a very high priority on basic research," states McLaughlin, noting that it accounts for about 85 percent of extramural research funds. The majority of NEI's 1,000 extramural grants go to single, investigator-initiated (R01- type) projects, as opposed to institutional grants. "We made a very early decision to focus on grants to individuals," says Kupfer. "As a rule, we do not issue requests for applications, believing that the best ideas come from the [research] entrepreneurs," McLaughlin adds. "We are very sensitive to the demands from the [scientific] community," agrees Peter Dudley, director of the division of basic vision research, "and move dollars to accommodate the intensity of activity." Hence, grant topics vary widely in subject matter; as Dudley describes it, "We take the eye, slice it up, and fund research anatomically." There are programs for research on the retina, cornea, and lens (including cataracts), as well as for such diseases as glaucoma. Like the extramural research, intramural investigations also emphasize basic research and include a broad sweep of subject areas: basic immunology of the eye, ocular genetics, retinal biochemistry, psychobiophysics, pharmacology, and biometry (biostatistics). But Robert Nussenblatt, director of intramural research, also stresses his division's strong commitment to clinical research: "We have an active clinical presence in many of the sections." For instance, Nussenblatt's own laboratory, which concentrates on immunology, "was the first to use cyclosporin" for treating certain putative autoimmune diseases of the eye (R.B. Nussenblatt et al., American Journal of Ophthalmology, 96:275-82, 1983). More recently, "we were able to alter the inflammatory course of [eye] disease by feeding antigens orally," thus conferring immunity against uveitis--an inflammation of the retina-- without compromising the immune system with immunosuppressive drugs (R.B. Nussenblatt et al., Journal of Immunology, 144:1689-95, 1990). A group of intramural scientists studying crystallins-- structural proteins of the eye lens required for refracting light--stumbled upon an unusual phenomenon brought about by the multifunctional capacity of some genes. "We expected that the crystallins would be encoded by extremely specialized genes," says Graeme Wistow, head of the section on molecular structure and function in the laboratory of molecular and developmental biology (LMDB). Instead, he reports, they found that "exactly the same protein that functioned as a structural protein in the lens had an entirely different function in other tissues." Certain ubiquitous crystallins were found to be the same as a protective, intracellular protein called the small heat- shock protein. Numerous metabolic enzymes have been found to be crystallins in an animal- or "taxon-specific" manner (G.J. Wistow, J. Piatigorsky, Science, 236:1554-6, 1987). "We still do not know why exactly these genes act this way," remarks Piatigorsky, LMBDchief. "Where and how much of the protein is produced directly determines whether it will be structural or enzymatic in function." The multifunctional protein is produced in much larger amounts in the lens than in other cells. Studying the regulation of these genes, researchers discovered that the overproduction of at least some of the proteins depends upon the presence of binding sites for Pax-6, a transcription factor known to be essential for eye development (A. Cvekl et al., Molecular and Cellular Biology, 14:7363-6, 1994; A. Cvekl et al., Mol. Cell. Biol., 15:653-60, 1995). "This work shows how important regulation of gene expression is for bringing about evolutionary changes, and for the innovation of new protein functions," comments Piatigorsky. Since its inception, the institute has sponsored numerous clinical trials to evaluate and develop treatments for a variety of eye-related diseases. NEI currently sponsors 16 multi-center extramural clinical trials nationwide, as well as five smaller trials conducted by intramural investigators at the Warren Grant Magnuson Clinical Center on NIH's Bethesda, Md., campus. "How NEI differs from other institutes is that the clinical trials are funded as cooperative agreements between us and the scientists," explains Richard Mowery, director for the division of collaborative clinical research. While ideas for trials originate from outside investigators, the institute maintains an active involvement, helping with the development and implementation of clinical programs, data assessment, and evaluation of effectiveness, he says. A recent trial that "had a major impact on clinical care" was the assessment of a cryotherapeutic treatment for retinopathy that afflicts prematurely born infants. The therapy produced dramatic improvement in clinical outcomes. In fact, Mowery points out, the procedure--which entails briefly freezing the edge of the retina--"proved so effective that the study was stopped early," in order to use it as a standard treatment (R.J. Hardy et al., Controlled Clin. Trials, 12:293-303, 1991). Currently, investigators are doing long-term follow-up studies to "see if the treatment has had any effects on the visual acuity of these children over time." Even as the institute celebrates its progress over 25 years, Kupfer stresses that it continues to pursue new goals, such as the development of drugs to delay or prevent cataracts, and potential gene therapies for blinding diseases like retinitis pigmentosa and age-related macular degeneration. "If the development of cataracts were delayed by just 10 years, it would reduce the need for operations almost by half," he says. In addition, this could translate to a saving of $2.5 billion to society annually, Ellwein estimates. "I personally feel that our duty doesn't stop with discovery. To make sure that our findings are clinically relevant, we need to educate both practitioner and patient" about various treatment options, their cost-effectiveness, and how these choices affect the quality of their lives, Kupfer declares. One concern he voices along these lines is that "although we have established the success of laser treatment for diabetic retinopathy, we are only reaching 50 percent of those at risk." In order to improve this communication gap, NEI established its National Eye Health Education Program in 1991. Set up in partnership with more than 50 public and private organizations, the program works through community educators to inform the public about the importance of early detection and timely treatment of blinding eye diseases. For more information about the institute, its programs, and grants, contact the information office at the National Eye Institute, 2020 Vision Place, Bethesda, Md. 20892-3655; (301) 496-5248. Fax: (301) 402-1065.

National Eye Institute Celebrating 25 Years Of Visionary Research

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