Adopting Orphan Diseases

Heng Ling Liou had the usual concerns 3 years ago when she went looking for a postdoc: She wanted something new, which would introduce her to new skills and technologies, while building on the theme of her thesis. So she joined up with Peter Lobel at the University of Medicine and Dentistry of New Jersey (UMDNJ).

Lobel and his UMDNJ colleagues had just discovered that the NPC2 protein was directly responsible for the rare condition Niemann-Pick disease, type C2. Niemann-Pick is a group of rare inherited diseases in which patients cannot metabolize cholesterol and other lipids properly within the cell. The result is neurological degeneration, from mental retardation to delayed development of motor skills. There is no cure.

With her postdoc in Lobel's lab, Liou is conducting studies that may provide insight into fundamental properties of the NPC2 protein. "You know that anything you do might be able to help the patients in one way or another," she said. "Not that I'm saying my thesis work has nothing to do with general human health. It has. But this is very direct."

Getting to Know Your Neighbors

Liou and other scientists working on rare medical conditions said that while the work brings special challenges, there are personal as well as professional rewards that might not be immediately apparent. Many of the challenges--and the rewards--stem from the fact that the community of people studying and suffering from these diseases is often quite small. In a small community, you get to know your neighbors.

Liou has met patients and families suffering from Niemann-Pick, and she has been affected by them. "You see them so alive and you want to make a difference for them; you want to help them out," she said. "Of course you go through cycles. Sometimes you get positive results and you're all excited; sometimes you get not very positive results and you're down."

Niemann-Pick is one of the family of rare diseases familiarly known as orphan diseases, because they are so rare that it can be difficult to interest people in them. Niemann-Pick type C has only 300 or so diagnosed cases worldwide. The National Institutes of Health (NIH) reports that roughly 25 million people in the United States are affected by an estimated 6000 rare medical conditions. In the United States, the term rare or orphan disease is defined by the Orphan Drug Act as a condition affecting fewer than 200,000 people in the country, or one with a greater prevalence but for which no reasonable expectation exists that the costs of developing and distributing a drug can be recovered from the sale of the drug in the United States.

And therein lies the difficulty. The term "orphan disease" captures well the loneliness many patients--and researchers--of these rare diseases face. Because the conditions are rare, they may go undiagnosed or misdiagnosed for longer periods than better-understood diseases. The small number of patients involved means there are few financial incentives for pharmaceutical companies to engage in research to combat them, nor any large voting bloc to encourage politicians to fund that work.

Currently, Liou is funded by the National Niemann-Pick Disease Foundation Inc., an international not-for-profit organization of parents, medical professionals, and others who are working to find a cure for Niemann-Pick. The foundation also provides Liou and others opportunities to attend scientific conferences and family conferences, where patients and their families meet and talk with scientists and researchers.

This personal contact helps reduce the isolation and puts a face to the long hours of lab work. "It's been a very good and special experience for me," Liou said.

Iain McIntosh began his work with Nail-Patella syndrome before there was a patient support or nonprofit group to make recruiting the families easier. "I think many people don't realize they have this syndrome," he said. "It's probably greatly underdiagnosed and people might think it's just an unusual little trait that runs in the family. So if no one is seen to have serious kidney disease, it can be seen to be an unusual family quirk."

Nail-Patella is an extremely rare inherited disorder that can result in improper development of fingernails or toenails, and absence or underdevelopment of the knee caps, among other symptoms. Kidney disease and glaucoma are also connected to the condition. McIntosh has been at Johns Hopkins University since 1991 and has been working on Nail-Patella for close to 10 years.

Because Nail-Patella is so rare, McIntosh said, when they first applied for funding NIH was concerned they might not find enough families to do the studies they proposed, but modern information technology has helped a lot. "I think a lot of the work we've done with the families would have been impossible without the use of the Internet in the second half of the 1990s," he said. He and his colleagues did a study of five large families; by the time the check arrived from NIH they had 50 families in the study. They have 220 families now, primarily in the English-speaking world.

Humans Can Be Quite Nice

"I think no disease is too rare or no field is too small to be worthy of study," McIntosh said. He had this advice for young scientists: "Assuming they're not medically trained, I'd say don't be frightened of getting in touch with humans. They can be quite nice, really."

Stephanie Cherqui is doing her postdoc at the Scripps Research Institute in La Jolla, California. She completed her doctorate in France in human genetics, where she worked with Corinne Antignac on cystinosis, a genetic metabolic disease. Without proper treatment, children with cystinosis can lose their kidney function at about 9 years of age. The condition also causes severe complications in other organs of the body.

While her postdoc work is not related directly to cystinosis, she hopes there are aspects of the gene therapy and cellular therapy skills she is learning at Scripps that will be transferable to her work with the disease. "Of course I know that I won't cure all the diseases; maybe not even one," she said via e-mail. "But I want to try."

Jerry A. Schneider, research professor of pediatrics, speaks with great enthusiasm about his work, whether he's talking about the breakthroughs he has made during his nearly 40 years of research into cystinosis, the colleagues he has worked with in the United States and abroad, the opportunities for travel and study his work has provided, or the scientists who trained with him and have gone on to distinguished careers of their own. He retired recently as dean of academic affairs for the medical school at the University of California, San Diego (UCSD), and continues to work on cystinosis.

"I think young scientists have to find their niche," he said. "That's easy to say and hard to do. We're all looking for a problem to study. But if it's too difficult you end up frustrated, and if it's too easy people will say it is a meaningless thing that you've done."

Schneider was introduced to cystinosis in 1965, when he joined NIH. After 4 years there and a further year of study in France, he took a position at UCSD. He wasn't sure what he wanted to do in terms of research, but "it was the families who got me involved," he said. Families who remembered his accomplishments in furthering the understanding of cystinosis at NIH sought him out with questions about the condition and "I sort of got pulled into it," he recalled.

What began as something of an obligation has become a driving passion and a fulfilling career. "I think to be successful in something like this you really need to have a passion for it," he said. "I felt I had to just work constantly." Schneider says he could probably name 500 cystinosis patients in the United States "and there might be another 500 patients I don't know about." But it's not just patients in the states who look to him for support.

Seandradh and Al O'Cathasaigh of County Cork, Ireland, were expecting their second child, Ailbhe, now 3, when their son Cian, now 5, was diagnosed with cystinosis. Ailbhe also has the disease. Every 6 hours, like clockwork, Seandradh and Al give their boys Cystagon (a trademarked drug with the generic name Cystagon), as well as oversee treatment of other related conditions. They say the generosity of time that people like Schneider have shown them has been a revelation.

"The thing we've found about all these researchers we've been meeting is that they're so approachable," Seandradh said. Al said, "For us it means that you can develop a bond with them. They're real people with real feelings who care about what they do."

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