The Sherlock Holmes of Rare Disease: We Need More Watsons
He’s been called a “medical mystery man,” a “super diagnostician,” and “one of the last, best hopes for people suffering from rare, debilitating and undiagnosed medical conditions.” But don’t compare him to Dr. House.
"I have been compared to him but it's inappropriate," William Gahl, M.D., Ph.D., told CNN in 2009 "He sees acute cases and solves them right away. We see chronic cases and often don't solve them."
It’s the painful paradox of modern medicine. Scientists have spent decades and billions of dollars studying the intricacies of all manner of disorders, logging major victories along the way; some cancers and HIV/AIDS are no longer death sentences, but manageable chronic conditions.
But it’s never enough. There are always patients whose mysterious, and often fatal, symptoms defy understanding or treatment—even for Gahl who, as clinical director of the National Institutes of Health (NIH) Undiagnosed Disease Program (UDP), has tackled some of the most difficult medical puzzles.
Since its inception in 2008, the UDP’s crack team of medical sleuths have brought their specialized knowledge to bear on the most baffling of symptoms. The program gets rave reviews from patients and the popular press. But it can’t keep up with demand for its services, which has exploded with the plummeting price of genetic sequencing, the rise of big data and public awareness of the program.
So, like an evangelist, Gahl is now crisscrossing the globe seeking to recruit more physician-scientist groups to the cause. The NIH’s program is now a national network of seven federally funded clinical sites, plus a coordinating center, two sequencing centers, and other core facilities. And that’s just the beginning.
Gahl is busy building alliances with undiagnosed disease efforts in Rome, Budapest, Vienna, Australia, Japan, India and Mexico. Just last week he stopped in Salt Lake to consult and share resources with architects of a new undiagnosed program at the University of Utah (see details below).
Science has the tools to get to the root of the most pernicious and persistent diseases, Gahl told the University’s medical personnel and administrators. It’s connecting all the knowledge that’s the challenge. “Half of our diagnoses are not made using next generation sequencing. Half of our diagnoses are made because as physicians we can get together and get good consultations and talk about things and get the tests done that we need to get without concerns about insurance.”
Strong phenotyping, or documenting of patients’ symptoms, is vital. “We have an incredible advantage with that at the NIH. It’s also a great advantage here,” Gahl said, referring to the Utah Population Database (UPDB), an 8-million-person repository of medical records matched with genealogical data dating back centuries.
And “functional” studies to understand the biology of disease—to confirm suspected disease-causing gene changes and document how they work—are another bottleneck best resolved through cooperation of the world’s scientists, Gahl said. “Patients are very desperate and it’s our job to lend a hand, and do that together, all of us together as physicians.”
A Guide to Rare Disease Sleuthing
Publicity Matters
As any detective knows, good policing can’t happen without public support. So it is with science. Were it not for public pressure and the limelight, the NIH’s Undiagnosed Disease Program would not exist, believes Gahl. “If I had asked, ‘Let’s do an undiagnosed disease program at the NIH,’ nobody would have supported me. But once it got started with a $280,000 seed grant from Steve Groth, [former director of the Office of Rare Disease Research] there was all this publicity, prompting further NIH support.”
Soon after launching the program, Gahl was besieged with patient inquiries; the program is only able to admit half the children who apply and even fewer adults. Feeling fatalistic, Gahl went to former NIH Director Elias Zerhouni and said, “We can’t keep up. I’m going to have to stop the program.” But without skipping a beat, Dr. Zerhouni proceeded to establish an ongoing source of funding.
Measure Success by Degrees
Crimes go unsolved, but communities can be healed and families comforted in the search for justice. When it comes to hunting disease, the oft-described goal is diagnosis. “But what is diagnosis?” asks Gahl. “Is a diagnosis putting a name on something? Is it about knowing the biochemical background? Is it having the pathology? Is it having the biochemistry or having the gene but not knowing what the gene does? Or is it all of these?”
However it’s defined, Gahl’s program diagnoses about 10 to 40 percent of the patients it accepts. The scientific tools are getting sharper, but he says, “We have to be careful about overselling, because we do fail most of the time.”
For patients, sometimes it’s enough to know they’ve tried every avenue open to them, says Gahl. Small clues can be a big comfort, and with every new clue and scientific advance, grows hope for the next patient.
Never Underestimate the Power of Listening
Trying to help a patient with ill-defined symptoms is “difficult not just for the family, but for the physician,” says Gahl. We humans inherently mistrust those things we don’t understand, and for this reason undiagnosed patients are often mistrusted by their friends, family, employers and caregivers. “It’s a terrible situation for them to be in.”
Yet being open to the possibility that it’s not “all in their head” can yield surprising discoveries, says Gahl, pointing to the well-publicized case of a 54-year-old woman who was inexplicably amassing muscle. She looked like a bodybuilder, except she hadn’t been spending hours in the gym. And instead of giving her strength, these muscles sapped her of energy, restricting movement in her joints and placing so much pressure on her chest that she found it hard to breathe. “I kinda feel like my muscles are just torturing me,” Sally Massagee told 60 Minutes in 2012.
Massagee had been to several experts, some of whom may have written off her muscle growth as the byproduct of steroid use. But an MRI of her head showed that even the muscles moving her eyes were three to four times the normal size, recalls Gahl, who, working with pathologists discovered signs of a blood cancer, multiple myeloma, in her biopsied muscle tissue. “We sent her to Mayo where she had a stem cell transplant. She recovered and I still get letters from her updating me on how she is doing,” Gahl says. “We’re able to treat some individuals even though we don’t know exactly what we’re doing.”
Kirsten Stewart is a senior writer at University of Utah Health Sciences
