Alumni Profile: William A. Gahl, MD '76, PhD

It had been a long time since William A. Gahl had gazed at Lake Mendota from the vantage point of the Memorial Union Terrace at the University of Wisconsin-Madison.

But last summer, when he was visiting campus, the "super-diagnostician" who is at the center of the innovative and newly launched Undiag-nosed Disease Program at the National Institutes of Health (NIH) did just that.

"It was intriguing to see so many exciting changes on campus and at University Hospital," he says of his visit.
Gahl himself has recently overseen some exciting changes as well.

The NIH program he directs- the only undiagnosed disease program of its type in the country-opened in May 2008 as a pilot initiative.

It brings together a high-powered team of specialists to study mystery diseases in individual patients from the "big picture" perspective-by carefully and collectively analyzing one piece of the diagnostic puzzle at a time.

More than 40 senior NIH attending physicians representing endocrinology, immunology, oncology, dermatology, dentistry, cardiology and genetics are involved. They work together to help the relatively small number of often desperate patients whose cases do not correspond to any known conditions.

In the six months between October 2008, when the first patient was admitted into the program, and mid-March of this year, Gahl's team saw approximately 50 patients.

"On the plus side, this is very exciting science and academically fascinating," he says. "But on the down side, we have to reject 80 percent of patients who apply because they are not suitable for our studies."

The criteria are stringent, he explains, because patients truly must be undiagnosed.

"There must also be a chance that we can help with the diagnosis and/or learn something important about cell biology or biochemistry," he says. "Applicants often have been inadequately worked up or have a combination of known disorders. Or they just want a second opinion or treatment."

For some viewers of popular television, Gahl's position as a top NIH research scientist and clinician studying some of the rarest hard-to-diagnose diseases in the country brings to mind the hit show House. But comparisons between Gahl and the fictional House do not stand up.

The mild-mannered Wisconsinite considers the gruff House, who conveniently wraps up each baffling medical case at the end of an hour with an "aha moment," to be not the most compassionate physician in the world. And, as anyone who has watched the show knows, that description puts it mildly.

In the real world of studying mystery diseases, "aha moments" are rare, says Gahl.

"If we discover a disease previously not seen, that could be an ‘aha moment,'" he says.

Gahl's journey to becoming an NIH leader began at the UW-Madison, a campus he became well acquainted with over nine years as a student.

During his first year in medical school, he and his wife, Mary, were married. The couple, who now live in Kensington, Maryland, have four grown children and two grandchildren. Their second grandchild, born on Gahl's last birthday, was named after him.

There's no doubt about it, medicine is in the family genes. Gahl's brother Bob is a family practice physician in Two Rivers, Wisconsin; another brother, Fred, is an anesthesiologist in Rockford, Illinois.

After Gahl earned his medical degree in 1976, he completed his pediatrics residency at UW Hospital and Clinics. He then did oncology research under Henry Pitot, MD, PhD, former director of the McArdle Laboratory for Cancer Research, earning his PhD in 1981.

Shortly afterward, Gahl arrived at the NIH as a fellow in the new field of medical genetics, eventually becoming an expert on rare genetic diseases. Gahl was appointed clinical director of the NIH's National Human Genome Research Institute in 2002, and continues to serve in that capacity while leading the new Undiagnosed Disease Program.

What's different about the program? To sum it up succinctly-its collective team approach. The physicians go well beyond looking at a patient's various symptoms and visible signs of disease.

"We also look at the patient's DNA to discern if there is a specific gene mutation and to see if there is a missing or defective gene product," explains Gahl, adding that the program aims to advance general scientific knowledge by trying to understand how an undiagnosed disease works on the genetic level.
Patients with rare diseases usually do not fall into the domain of only one medical specialty. That's what makes such cases challenging for the NIH team, says Gahl.

"To get into a typical clinic, patients with undiagnosed medical problems usually see a specialist, since our medical system is organized into specialties," he says. "It's often hard for them to get into a healthcare system that may benefit them because their disease doesn't fit into a category."

By the time they get to the NIH, the patients, most of whom have chronic problems, have probably been seen by many specialists, to no avail.

About half the patients are referred by their physicians, while the other half of them initiate the process on their own. These proactive patients ask their doctors to lend support by writing a summary letter on their behalf.

Patients are flown to the NIH's Bethesda, Maryland, campus, where they typically stay for a week and see multiple specialists. The NIH pays for airfare, food, lodging and hospital costs. For most of the seasoned doctors, the patients may be the first and only ones they've ever seen with the exact set of symptoms or medical history.

People of all ages, including children with developmental delays, may be candidates for the program. Recently, a three-year-old was admitted with undiagnosed seizures that occur up to 40 times a day. She does not recognize her parents.

"We now have her DNA, fibroblasts and other information," notes Gahl, "so as we learn more and/or we see similar cases, it may lead to a breakthrough."

Most patients understand that being painstakingly assessed by this special group of physicians is probably their last hope. Unfortunately, the majority of the diseases the patients have been battling for most of their lives will never be diagnosed. Gahl estimates that for every diagnosis his team makes, another nine cases will remain unresolved.

How do patients and their families respond when they are told that some of the brightest doctors in the world can't determine what's wrong with them?

"When they go home, we tell many of them we do not have the answer to the problem-at least not yet," Gahl says. "But our patients are not upset with us. They know, from all the experiences they've been through up to that point, including a countless number of inconclusive tests, that we can provide hope."

So far the team has made two diagnoses. Both patients presented with neurological symptoms, and were diagnosed with rare forms of multiple sclerosis.

Despite the slim odds of success, there has been an outpouring of interest and a seemingly insatiable curiosity about the program from the national press. Gahl has been interviewed by The New York Times Magazine, CNN and Newsweek, as well as other media outlets.

Groundbreaking medical discoveries always make good stories because medical detective work is so fascinating, even when medical "aha moments" take years to occur.

Still, the fascination with the Undiagnosed Diseases Program is probably just getting started. As many see it, the program is already on its way to becoming the model for how medicine will be practiced throughout the 21st century-providing state-of-the-art genetic analysis along with a multidisciplinary approach.

Asked how ongoing interest and publicity has a direct effect on the program, particularly since it can accept only a small number of patients for study, Gahl responded from the perspective of a visionary and scientist.
"Depending on NIH funding, the current model may eventually be disseminated around the country. It is my hope to establish programs like this at medical centers throughout the U.S.," he says. "That might entail setting up a program at eight or 10 centers, and the NIH could serve as a referral point or central database."
But he cautions that the success of the program will be measured in decades, not months or years.

Last summer, as Gahl watched sailboats skim the waters of Lake Mendota and students engaged in other recreational pursuits, it got him thinking about something he has enjoyed for a long time: softball.

"I played baseball as a child, but when I was in medical school and graduate school, softball became more than just getting together to play an occasional game," says Gahl.

Today, it remains a hobby he thoroughly enjoys.

"I play shortstop and left center field on the national level for a senior softball team," he says. "We play between 80 and 100 games a year."

Off the softball field, Gahl is a team player of another sort. The team he leads is advancing scientific knowledge and working tirelessly to solve some of medicine's most baffling mysteries.