Stone and his colleague Val C. Sheffield, who is also a physician and an HHMI investigator at the Roy J. and Lucille A. Carver College of Medicine at the University of Iowa, were caught in a dilemma. They could focus their efforts on finding additional genes involved in rare eye diseases, or they could focus on applying the knowledge of the genes that had already been discovered to the care of individual patients. Initially, they hoped that a commercial company would develop tests for known disease genes, allowing them to continue the search for novel ones. But they soon realized that it was unlikely that any company would develop inexpensive tests for genetic eye diseases that each occurred in fewer than 50,000 people in the United States.

"I used to think that all you had to do was get your gene published in Nature Genetics, and then little elves would convert that discovery into a genetic test that would benefit mankind," he says. "But over the past 10 years, I've had to deal with the realization that we need to be involved in developing and applying those tests ourselves—either that or stop writing that preamble to our grants."

Stone decided to meet the problem head-on. With Sheffield's assistance, he has developed an unprecedented genetic testing program designed to benefit patients while laying the groundwork for future research. In the process, he and Sheffield have found themselves embroiled in controversies involving insurance coverage, genetic counseling, and intellectual property protection. "They're going right into the lion's den," says Peter A. Dudley, program director for retinal diseases at the National Eye Institute at the National Institutes of Health. However, Stone and Sheffield are undeterred. "This program is going to succeed," Stone says. "I think the barriers are more apparent than real."

LOOKING FOR PATIENTS
The origins of the program date back to biotechnology's middle ages. In 1986, Stone arrived at Iowa for an ophthalmology residency and fellowship following an M.D.-Ph.D. program at Baylor College of Medicine. For his doctoral thesis, Stone had spent 14 months sequencing a 4,000-base-pair piece of DNA, something a commercial sequencer today could do in a few hours. He came to Iowa fired up about applying his knowledge of genetics in the clinic. "All I wanted to do," he says, "was to use my background in molecular biology to take better care of patients." At that time, Iowa had not yet built its 60,000-square-foot eye clinic, and Stone often had to go looking for patients rather than waiting for them to find him. He used to load his ophthalmology instruments in grocery sacks, plop them in the trunk of his Buick, and drive around the Midwest to examine patients with unusual eye conditions. As part of his examination, he always asked for a blood sample, even though in those days—before the widespread application of the polymerase chain reaction and inexpensive DNA sequencing—it was not clear what he would do with the samples. "I knew they had value," he says. "It was a matter of waiting for the technology to evolve to the point that the value in those samples could be released."

The technology arrived in an unexpected guise. In 1990, Sheffield moved into a lab near Stone's lab. He had just completed an M.D.-Ph.D. program at the University of Chicago Pritzker School of Medicine and a residency and fellowship at the University of California, San Francisco, where he had developed novel methods for identifying DNA sequence mutations. During his first week in Iowa, Sheffield stopped by Stone's lab to discuss how the two might work together. Stone went to his freezer and retrieved 60 blood samples from patients with retinitis pigmentosa, a group of vision-destroying diseases caused by the degeneration of cells in the retina. Geneticists knew that one form of retinitis pigmentosa behaved as if it were caused by mutations in the gene for the light-absorbing rhodopsin molecule. "I gave that box to Val and said, 'Have at it.' Something like 48 hours later, he had found the first rhodopsin mutation in the sample. That finding led to the first of more than 150 papers that we've written together."

Today, Stone and Sheffield are among the best known eye geneticists in the world, having tracked down the genetic origins of more than a dozen single-gene disorders. They are also key players in two major research operations at Iowa: the Molecular Ophthalmology Laboratory and Carver Laboratory for Molecular Diagnosis as well as the University of Iowa Center for Macular Degeneration. "They are right in the forefront of gene discovery," says Gerald J. Chader, chief scientific officer at the Foundation Fighting Blindness. "But where they are really singular is in applying this knowledge to help patients."

Stone and Sheffield have focused on the genetics of rare eye diseases for several reasons. As physicians, they see these diseases take their toll not only on individuals but on sizable groups of people. "Rare diseases are only individually rare," says Stone. "Collectively, they are common." Only by studying the genetic origins of these diseases can effective therapies be developed. And the study of rare disorders also will be essential, say Stone and Sheffield, to reveal the biochemical mechanisms involved in much more common diseases, such as age-related macular degeneration.

But working on rare diseases has a serious drawback, they discovered. Once the mutations responsible for a disease have been identified, how do you use that information to improve medical care? If all genetic diseases were regarded equally, DNA tests would routinely be developed to aid the inevitable search for a therapy. But for rare diseases, genetic tests tend to fall into the same category as "orphan" drugs: Potential markets are so small that commercial companies have little incentive to develop such therapies, much less the tests that precede them.

Yet, the information such tests can provide is invaluable to patients even when no therapy is available, Stone points out. In some cases, such as with the retinal tumors associated with von Hippel-Lindau disease, a genetic test can reveal a predisposition to the tumors before they become clinically manifest, so that ophthalmologists can intervene with laser photocoagulation when the tumors are still manageable. In other cases, relatives of an affected patient can be told that they need not fear contracting the disease. And in still other cases, patients' diseases can be connected to research designed to develop new treatments.

Genetic tests also can help couples make difficult decisions about having children. As with other genetic diseases, hereditary eye disorders can be inherited as dominant or recessive traits, and sometimes they are linked to the X chromosome. By learning which gene is responsible for a vision problem in a family, parents can know their chances of having an affected child or whether a subsequent child could have the same problem as an older brother or sister.

In addition, a growing database of genetic test results will be a valuable resource for researchers and for patients. Geneticists can analyze the data to search for patterns in the incidence and severity of a disease. And patients who undergo testing can opt to be alerted when a pertinent new therapy is developed. "For example, if you had a large database of patients with different types of mutations leading to retinitis pigmentosa," the National Eye Institute's Dudley says, "and you found that a certain kind of therapy is effective for a particular mutation, then you could go to your database and pull out a list of patients with that mutation."

Stone and Sheffield have designed their testing program to realize all these benefits. In addition, they have found that patients derive another benefit from being tested—the satisfaction of working to defeat a disease that has caused them great anguish. "People say, 'If it will help someone else who has my condition, I would be willing to come back and have this test done,'" Stone says. "For people who have an inherited disease, that's a very important way to fight back."

HACKING THROUGH THE BRAMBLES
The first explorers to forge a new trail often have to hack through the brambles, and Stone and Sheffield have encountered plenty. Money is the most immediate concern. The tests are conducted in the research labs that connect Stone's and Sheffield's offices at the University of Iowa, and the lab space can be used for testing when it isn't being used for research. But supplies, equipment depreciation, and technician salaries all have to be covered by the fees charged for the tests. By limiting the tests to those genes that might be involved in a given condition, the program keeps the costs to patients low—between $300 and $1,000. Still, to minimize administrative overhead, patients have to pay up front for the tests and then negotiate with their insurance companies over coverage.

The provision of genetic counseling has been another complication. "Patients have a whole range of sophistication about the genetics of disease," says Chader at the Foundation Fighting Blindness. "Some are very knowledgeable, while others know very little." In general, Stone and Sheffield prefer to work with a patient's ophthalmologist in delivering test results, so that the ophthalmologist can provide context for a result. But "ophthalmologists also have a range of sophistication," Chader observes. "If they're in an academic medical center, they're more likely to be up to speed than if they're single practitioners in a small town."

The greatest single concern, however, has been the possibility of running afoul of patent law. Multiple patents cover various aspects of the genes Stone and Sheffield are testing. In some cases, companies have patented the nucleotide sequences of the genes in the hope that the patents may someday prove profitable. In other cases, universities have taken out patents on sequences derived by faculty members.

Stone is opposed in principle to such patents. "Patenting the human genome is like patenting the normal structure of the brain," he says. If that were allowed, "you couldn't conduct an MRI, because 150 people would own the various parts of the brain you were scanning. So at some point, people have to say that the normal structure of the brain is just a fact. You can't patent Montana just because you were the first person to think of the idea."

To fend off problems, Stone and Sheffield hired a lawyer to find as many of the patent holders on the genes as possible and inform them of the researcher-physicians' intentions. They've also enlisted help from "high-level people in various agencies and foundations," Stone says, "who'd be willing to make phone calls to these [patent holders'] lawyers and front-office people if they come after us."

Stone and Sheffield believe that the proper way to address the issue is through legislation. They advocate amending the Rare Diseases Act of 2002 to allow access to intellectual property for nonprofit genetic testing for rare diseases when no commercial test is available. Kate H. Murashige, a lawyer at the firm Morrison & Foerster LLP and an expert on biotechnology patenting, thinks that's a good idea. Though it has proved difficult to carve out a patent exemption for "research" because the term encompasses so many different activities, she observes, an exemption for genetic tests aimed at rare diseases would be more limited. It's "eminently doable," she says, "because it would be possible to define the specific uses covered by the exemption."

As a last resort, Stone and Sheffield plan simply to withdraw any test plagued by patent concerns. On the Web site describing the program, they would gray out the problematic test and add a footnote explaining why the test can't be given. "If someone asserts their right to block a test while little Billy goes blind, well, I'd love to have that person say that on the seven o'clock news," Stone observes. "However, it would also be nice if we didn't drown in a sea of lawyers in the process."

BUILDING A ROAD
The program established by Stone and Sheffield is small, but they believe it can serve as a model for much more ambitious undertakings. As researchers uncover the links between genes and diseases, physicians and their patients will want and need to know how genes are contributing to a specific illness. For common diseases, commercial companies will develop and market genetic tests. But for many thousands of rare diseases, the only source of such tests will be researchers and clinicians dedicated to improving patient care. Now is the time to work out the problems these testing programs inevitably will raise, Stone believes.

Stone and Sheffield say that they have faith in biomedical research. Even though obstacles must be overcome, the new knowledge gained will improve lives. "You can couple the search for basic biological truths to helping society," Stone says. "That's what I find exciting—to operate at the interface where the pursuit of basic scientific knowledge has a huge societal impact."

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Photo: Michael L. Abramson

Reprinted from the HHMI Bulletin,
December 2003, pages 24-27.
©2003 Howard Hughes Medical Institute