When scientists and politicians got together in Washington this July to announce the completion of the Human Genome project, they described a monumental achievement for science and mankind. The human genome is the sum of all DNA, or the genetic building blocks of the body, and the project set out to identify the entire genetic code that produces our bodies. That genetic map would allow scientists and doctors to be able to identify the genes associated with diseases, thereby greatly increasing the possibility of avoiding them or treating them.

     The human genetic code was mapped in just thirteen years, way ahead of schedule. The rapid completion of the massive undertaking was due in part to the consolidation of both public and private resources.

     But while the overall project was earning worldwide headlines, more specific groundbreaking work was taking place in many unacknowledged places around the globe. One such place is Wills Eye Hospital, where genetic research into the causes of several eye diseases has been an ongoing commitment.

     "Research at this level is nothing new to Wills," notes William Tasman, M.D., the Hospital's Ophthalmologist-in-Chief. "Throughout the years of the Human Genome project we have committed more and more resources toward discovering the causative genes of some of the most damaging hereditary eye conditions. But we are planning to place even more emphasis on genetic research in the future, dedicating more talent and money. In fact, we are currently planning to build a new hospital building that will include facilities designed expressly for the purpose of research."

     Research at Wills has been focusing on several specific eye conditions over the last several years. These include Stickler syndrome, von HippieLindau syndrome, retinoblastoma, glaucoma and macular degeneration. And even though the work members of the Wills Medical Staff and Research Department have been doing was not directly a part of the Human Genome project, it is a piece of the overall genetic puzzle.

     "We are not officially a part of the project and we are working on a smaller segment of the code," says Nina Ahmad, Ph.D., a staff member in the Molecular Biology Research Division of the Wills Research Department. "But when we do discover a mutation that information gets fed into the huge genetic map. It can turn out to be extremely useful for another researcher even if they're not investigating eye conditions."

     The reason the genetic information on eye diseases is important not only to people with eye diseases is because of the complexity of unraveling the human code. The nucleus of every cell in every human contains 23 pairs of chromosomes, one chromosome in each pair from the mother and one from the father. Each chromosome contains one long twisting ladder of DNA called a double helix. DNA in turn is comprised of even smaller chemical units that come in pairs.

     Some of the long double sections on the DNA ladder are called genes and those genes are the materials that determine the specific characteristics of every human. This includes characteristics like height and haircolor. But if a gene is changed, which scientists call a mutation, that change is often passed on to the next generation. It is those mutations that carry the propensity for disease and health and that scientists at Wills and around the world are trying to identify.

     The sum total of the genes a person (or creature) has is called a "genotype.' Every person's genotype is unique - that is, different from every other person's complement of genes, or genotype. But genes are not always "active," many genes he dormant; they don't "express" themselves. Sometimes, active genes become dormant and dormant genes become active. In fact, these changes are happening all the time! As a result of this changing activity of genes, people's natures also change. The way a person looks and acts is a result of the genes that are active, and is called the "phenotype." The genotype stays the same but the phenotype changes! Much research deals with what turns genes on and off and the resulting changes in phenotype.

     Genetic research at Wills falls into three categories. There is the ongoing molecular research attempting to identify the specific genes, work with other centers and with industry to attempt to find specific parts of genes, and research using genealogical records to trace the pattern of transmission.

Molecular research at Wills is done in the Hospital's Research Department. The department is currently investigating the causative genes of three hereditary eye conditions: Stickler syndrome, von Hippel-Lindau syndrome and retinoblastoma. All are caused by mutations that are passed from generation to generation, although some people are only carriers and never develop the diseases.

Stickler syndrome is a severe and debilitating connective tissue disorder characterized by marked nearsightedness, arthritis and retinal detachments. What makes identifying the gene difficult is that a disease like Stickler syndrome can be caused by as many as 100 mutations. Will is working with the DNA of families who have exhibited a predisposition for the disease. At present 27 different mutations with the Stickler syndrome gene have been identified.

     "Our research has two goals," states Dr. Ahmad of the Molecular Biology Research Division." Our initial goal is to give us the ability to screen for the disease with a high degree of success. Our long-range and ultimate goal is to engineer a model of the gene so we can start addressing ways to fix it. We're making progress but we're not there yet and not many people are working on the problem. That's why our effort is so important."

     Studies underway in the Wills Glaucoma Service are attempting to find a genetic marker associated with the types of glaucoma that gets worse. Not all glaucoma causes blindness, but some do. Wills is trying to identify the "bad" types of glaucoma.

     "Glaucoma is the leading cause of blindness in adults around the world," George L. Spaeth, M.D., Director of the Wills Glaucoma Service, points out. "Before we are able to do meaningful research on the disease we must first be able to identify the phenotypes. Defining the different types of glaucoma is something we do everyday, and we believe we do it better than anybody else."

     Wills' contribution is important because the Glaucoma Service under Dr. Spaeth is an internationally renowned center for research and treatment of the disease. As a result, the physicians at Wills possibly see more cases and in more varieties than anywhere else in the world. There are many different types of glaucoma, perhaps 50 or so. The pressure inside the eye can be elevated or average in glaucoma, but for many reasons (many not yet understood) some eyes are more easily damaged than others.

     One part of the Wills study involves sending patient DNA samples to a California company to try to identify a genetic marker for the type of glaucoma that gets progressively worse. Dr. Spaeth's commitment to patient care will also ensure that samples can be tracked through all stages of the condition and improve the usefulness of the results.

     "Marking the gene would be a finding of extraordinary importance," notes Dr. Spaeth.

The Hospital's Glaucoma Service also plans to be involved in a study that will try to determine if there is one or several genes for angle-closure glaucoma, one of the most common and damaging forms of the disease. Genes for some of the rare forms of glaucoma have already been discovered.

     "If we can determine the gene for angle-closure glaucoma it could have great impact because the disease is so common in some parts of the world," adds Dr. Spaeth. "Determining the gene or genes for that specific type could potentially help a great many people."

     Wills has also been the site of an ongoing research study into the genetic causes of the hereditary form of macular degeneration, a disease that causes millions of adults around the world to lose their central field of vision. The long term study tracks families suffering from the disease in an attempt to identify the gene defect.

     "We are interested in discovering large families with this condition because it can help identify which genes play a role in this disorder," says Larry Donoso, M.D., Ph.D., Director of the Wills Research Department.

     Recently the study at Wills successfully traced one family back many generations to England, and was able to accurately identify a large number of patients in another family.

     Dr.Tasman is optimistic about the research being done at Wills. But he doesn't feel that the recent discoveries should signal a deceleration of effort or intensity.