Before Ed Stone started his surgical residency at the University of Iowa, the field of ophthalmic molecular genetics was brand new. Patients with rare eye diseases were few and far between, and few researchers were working on the genetic origins of these disorders. In a somewhat risky career move, Stone decided to fill that void and study the molecular basis of rare eye diseases, while simultaneously training to become a surgeon. So Stone, as a first-year resident M.D./Ph.D., loaded his station wagon with ophthalmology instruments and drove around rural Iowa to find his patients.

He launched his first mobile clinic after a chance conversation with the 30-year-old mother of a child scheduled for eye surgery. She mentioned that she had macular degeneration—a condition usually found in much older people. Stone discovered that several of her family members were afflicted with a rare form of macular degeneration and that they all lived about 90 miles away. He decided to go see them.

The family owned a pizza restaurant in Des Moines, which they closed for the night, and they gathered for Stone's examination. "I saw 20 people with a disease that affects 1 out of every 10,000 people. In one day I went from just having seen a textbook picture of this disease, called Best disease, to having more personal clinical experience than anyone in my department." In the late 1980s, Stone studied three large Iowa families with Best disease, and he has stayed in close touch with them since. In fact, when a 93-year-old man from one of these families died in 2005, he donated his eyes to Stone's laboratory.

The large number of patients to study and the stability of the patient population were two factors that drew Stone to Iowa. "Midwesterners often have large families," Stone says. "Plus they tend to stay put. In some cases, several individuals with a rare eye disease will all live in the same small town that their grandparents lived in." This means that Stone can trace diseases through generations, especially since people are so willing to help. "These folks will make sandwiches for you while you're drawing blood from them. It's just the most unbelievable place."

The University of Iowa also appealed to Stone because of its strong ophthalmology department, and because he would be allowed to start his own lab at the same time he began his residency. Stone had graduated from Baylor with an M.D./Ph.D. in cell biology and training in molecular genetics. He arrived at Iowa ready to do research, and the hospital there encouraged him to work as a scientist while he continued his clinical training as a doctor.

Stone's career progressed in the lab and the operating room. After he finished his residency, he began fellowship training to become a retinal surgeon and joined the faculty as an assistant professor. However, two years after finishing his fellowship, Stone realized that the time he spent in the operating room was taking away from his time in the lab. Stone was most interested in heritable eye diseases that couldn't be cured by surgery. He realized that only by understanding the genetic causes of these diseases could treatments be developed. So he decided to stop performing retinal surgery and to focus on caring for and studying patients affected with genetic eye diseases. At that time he met Val Sheffield, another assistant professor at the University of Iowa.

Sheffield and Stone have now collaborated for over 15 years, and they have published more than 150 papers together. Sheffield, also an HHMI investigator, is a pediatrician and geneticist.

When he met Stone, Sheffield had already helped develop new technology for screening DNA sequences for mutations. By then, Stone had collected scores of DNA samples from patients with rare eye diseases and needed to screen the samples for variations in the DNA sequence that could link the patients' genetic makeup to an inherited disease. The two began working together in 1990, searching for mutations in the samples that Stone had collected, and then tracing those genetic mutations to specific chromosomes.

Stone and Sheffield were able to locate several genetic mutations that cause rare eye diseases. Stone says they hoped to translate these discoveries into more accurate diagnostic tests and better treatment for patients. “Then I looked around and said, wait a minute, what about some of those genes that were found about ten years ago? Can you really troop down to the clinic and order a test for those? And the answer was no.”

It turned out that simply locating the mutations was not enough. There were a number of barriers that lay between the discovery of a disease gene and the creation of an affordable genetic test. In the early 1990s, the costs of obtaining access to the intellectual property of other scientists were often prohibitive, and the rarity of the diseases themselves provided little incentive for companies to develop commercial tests for these disorders. So Stone and Sheffield decided to start a nonprofit laboratory that would link genetic research to genetic testing.

The John and Marcia Carver Nonprofit Genetic Testing Laboratory at the University of Iowa can now screen people for more than 20 rare eye diseases (60 different genes), and researchers there are working to develop tests for others. They have found the cause of disease for more than 5,000 families from all around the world (more than 60 countries).

The new lab may be more sophisticated than his first family clinic in a Des Moines pizza restaurant, but it builds on that early experience. The rare genetic eye diseases Stone chose to study years ago are now closer to being understood, diagnosed, and treated.