OHSU pediatrician takes on 'orphan' diseases as families push for funding

by: TRIBUNE PHOTO: CHRISTOPHER ONSTOTT - OHSU scientist Maureen Hoatlin, searching for genes associated with Fanconi anemia, says rare disease researchers are medicines version of high stakes gamblers.Twenty-two years ago, Susan Hayflick was practicing as a geneticist in Buffalo, N.Y. She encountered an Amish family, the Millers, who had four daughters, three of whom appeared to be stricken by one disease.

The eldest was still crawling at age 6. By 8 she had lost the muscle control that allowed her to chew and swallow. The second daughter exhibited similar symptoms. The third, Susie, couldn’t open her mouth to eat and regularly bit her tongue. She would have all her teeth pulled when she was 4. Drug after drug failed to help control her spastic muscles. Eventually she was put on a feeding tube.

Hayflick spent hours getting to know the Millers. She collected blood from each of the children. She found four other children in the Millers’ small Amish community with the same symptoms. Until then, Hayflick had intended to practice as a family doctor, maybe in a small town somewhere. Another physician eventually made the diagnosis for the Millers. They had PKAN, a neurological disorder with only a few hundred sufferers in the United States.

Children diagnosed with PKAN and its larger universe of Neurodegeneration with Brain Iron Accumulation (NBIA) usually die by their 20s. Those with a milder version can live until middle age. Nobody, Hayflick learned, was looking for the defective PKAN gene. The Millers had come to Hayflick for help, but it was they who changed her life. They turned her into a hunter for the genes that were causing their disease.

Hayflick, a pediatrician and medical geneticist at Oregon Health & Science University, doesn’t act like anybody’s rock star. She doesn’t, on first appearance, radiate the charisma that might launch nationwide bake sales, golf tournaments and letter-writing campaigns on her behalf. But in her own small universe, she is the brightest of stars.

Imagine, for a moment, you’re a scientist. You’re going to devote your entire career to one field of medical study. Maladies such as heart disease, cancer and Alzheimer’s beckon, with millions of sufferers desperately hoping for a cure. You can probably count on funding from pharmaceutical companies and the National Institutes of Health.

Or, you could choose to work on a single rare disease, with few patients, little funding and very few colleagues.

This year marks the 30th anniversary of the 1983 passage of the federal Orphan Drug Act, which was intended to encourage drug companies to invest in the search for cures for rare diseases. There are more than 7,000 rare diseases with names such as Sturge-Weber syndrome and Dubowitz syndrome. Some of those diseases have one or a handful of scientists searching for their cures. Some have none.

Hayflick recognized that the Miller children’s gene pool offered a unique research opportunity. Three children in one family with a defective gene for one rare disease would provide a rare statistical opportunity to discover which gene was defective.

“There’s all the power we need right there to get to the gene, in one family,” she says.

Hayflick began to contact physicians around the world who had patients with PKAN, asking them to send her blood samples. In 2000, she found the gene associated with PKAN, and since then she and collaborators around the world have discovered four more NBIA genes. She’s convinced that the five known defective genes represent the cause of most NBIA cases. Now, she needs to find a model to explain how and when those genes are failing.

She does so knowing that she will be too late to save those who inspired her. The last of the three PKAN-stricken Miller children died five years ago, but Hayflick continues to correspond with their mother.

Personal patient ties

Patricia Wood understands very well why a doctor would want to devote an entire career to studying one rare disease. Researchers working in high-profile areas such as cancer rarely get the personal connection to their work that comes with studying a rare disease, says the president of the NBIA Disorders Association.

“They don’t know every single family,” Wood says of most scientists. “They don’t know who is being affected by their research. That’s important. It’s a very personal relationship. We consider (Hayflick) a friend. Wouldn’t you be motivated if it was your friend who was dying of something?”

Wood’s story is a familiar one in the rare disease community. By the time her daughter, Kimberly, was 15 months old it was clear something was wrong, but initially none of the physicians who saw her were familiar with NBIA, so none were able to diagnose her. When doctors at the Mayo Clinic were able to tell Wood that Kimberly had NBIA, they offered little hope.

“They said they’d seen about five cases in the last 30 years, and I should take her home to die,” Wood recalls.

Wood, who lives in San Diego, did more than that. She networked with other NBIA families and was told about Hayflick. Hayflick had moved to OHSU in 1993 and her clinic has become something of a mecca for families with NBIA children from all over the globe. Wood brought Kimberly to see Hayflick, who suggested medications to help control Kimberly’s spasms. Hayflick also drew blood to add to her collection, which now numbers 492.

Soon after, Wood founded the nonprofit NBIA Disorders Association, which has made her the unofficial go-between connecting families with Hayflick.

For years, she says, she would get calls from desperate families at hospital emergency departments. Typically, their child had just been admitted suffering a dystonic storm, a rare symptom of NBIA which involves whole body muscle spasms so severe that the child loses all muscle control and his or her body gets locked in a painful arched position. In some cases, patients are put into comas as the only way to get their bodies to relax.

“I’d get calls from parents,” Wood says. “The hospital would say, ‘There’s nothing to be done, they’re in the last stages, they’re going to die.’ “

Wood would tell the parents to immediately call Hayflick, who could help doctors dealing with a situation they likely had never seen before.

Funding lost, regained

by: TRIBUNE PHOTOS: CHRISTOPHER ONSTOTT - OHSU pediatrician and medical geneticist Susan Hayflick thought shed end up as a family practice doctor, until she encountered patients with a rare disease.The relationship between Hayflick and Wood changed dramatically in 2009, when Hayflick called to let Wood know she had lost her NIH funding and would have to close her lab. Wood says she asked Hayflick how much it would take to keep the OHSU lab open. Hayflick told her $250,000.

That led to the nationwide Hayflick Lab Campaign, with fundraisers big and small culminating in a $200,000 check sent to OHSU in October, 2010, specifically to keep Hayflick’s lab open. Hayflick was able to find the rest of the funding from other sources.

“The researchers for rare diseases are so important because they give the families hope,” Wood says. “If you take away hope, what have you got?”

Veronica Bonfiglio, whose son was diagnosed with PKAN in 2003 at a hospital in Oakland, Calif., understands well the value of hope.

“I was told that this was a rare disease, that each day would be worse than the day before, that there was nothing we could do, and there was very little research going on so probably a cure would not be found in his lifetime,” Bonfiglio says. “And that there was only one researcher in the world and that was Dr. Hayflick.”

Bonfiglio has kept up a constant conversation with Hayflick during the past 10 years. When she read that turmeric might help Alzheimer’s sufferers, she called Hayflick to ask if it might help her son. When her son stopped taking omega supplements and appeared to be drooling and falling down a little bit less frequently, she called Hayflick hoping that somewhere down the line that bit of information might be useful.

“We see her like our saint and the person who is most likely to find a cure for him,” Bonfiglio says.

When a patient — child or adult — from anywhere in the world is suspected of having NBIA, they either come to see Hayflick or visit her via Skype.

Every two years the NBIA Disorders Association holds a three-day clinic somewhere in the United States so that patients can more efficiently see Hayflick along with other researchers and treatment providers.

Hope is not the only emotion Hayflick witnesses there. At each NBIA meeting she sees parents who no longer bring their children with them because the children have died.

“It feels like pressure,” Hayflick says. “It’s hard to go to family meetings every two years and not have a cure. That feels like a failure.”

Insight to other diseases

Hayflick is one of about 60 OHSU principle investigators working on rare diseases. Maureen Hoatlin, who co-chairs OHSU’s rare disease consortium with Hayflick, says the purity of rare disease science drew her to the field. When few people get a disease, the molecular pathways responsible are usually fewer and more distinct.

“When scientists think about things, they’re trying to get the clearest signal-to-noise ratio they can,” Hoatlin says. “And rare patients offer you a very clear signal.”

And sometimes, Hoatlin says, those clear signals for rare diseases have much wider application. She uses as an example OHSU oncologist Brian Druker’s discovery of Gleevac as a targeted cure for chronic myelogenous leukemia, a rare form of the disease. In time, Druker and others discovered Gleevac also could work, to varying degrees, on other forms of leukemia.

“Once you have an indication that’s very clear and you have a clear target and a way to determine if you knock that target down or not, you can think about shared mechanisms,” Hoatlin says. “In other words, what other diseases are similar to this, might share the same target?”

Hoatlin’s research has focused on identifying genes and pathways for a rare disease called Fanconi anemia, best known locally because ex-Oregon Attorney General Dave Frohnmayer set up a research fund when his daughter was diagnosed with the disease. Hoatlin says the fact that little was known about Fanconi anemia has made it more appealing as a career-long obsession.

Also, she says, working with rare diseases feeds her natural gambler’s instinct, even as she realizes the odds of her being part of a breakthrough are smaller than if she were part of a team studying a high-profile disease.

“I like high-risk projects,” she says. “This is a high-risk project. If it works, it’s going to be amazing.”

Part of that risk involves securing funding in a decade when research dollars across the board have been disappearing. Hoatlin says NIH funding for her work has almost completely dried up and she has had to stop working in the lab, for now. She continues to teach medical students and write as she searches for new funding. Nationally, many rare disease researchers are now primarily or exclusively funded by money raised by the families of stricken children.

Hayflick can sympathize with Hoatlin, having come perilously close to the same juncture with her work. But whether she finds the cure for PKAN or not, she won’t regret having devoted a career to an area of medicine seen by few. She’s been too connected for too long with her NBIA patients and family members, such as Mary Miller, to consider another path.

“We may think we make choices,” Hayflick says. “But the choices also partially get made for us.”

Contract Publishing

Go to top
Template by JoomlaShine