The Challenges of Rare-Disease Research

With few resources and hesitant investors, basic scientists must rely on clinicians, patient advocates, and their own keen eye for biological connections.

By | September 1, 2016

© ISTOCK.COM/FANGXIANUOBecoming a mother changed Heather Etchevers’s life in more ways than she expected. After her daughter was born in 1999 with a rare skin condition known as giant congenital melanocytic nevus (CMN), the developmental biologist engaged with patient groups to understand the condition’s risks, which include myriad neurological disorders, malignancies, and cancer-like growths. But as the dearth of information about her daughter’s condition grew more apparent, she began to see a wealth of research potential. “I realized that things should be getting done that weren’t, and I had some special approaches that others weren’t doing or implementing at the time,” she says.

So Etchevers, who was using functional genomics to study malformations involving embryonic neural crest cells, decided to expand the focus of her research at the French National Institutes of Health (INSERM). But it would be another decade before any projects on CMN got off the ground. Because a rare disorder afflicts, by definition, fewer than 200,000 people in the U.S., patients are difficult to recruit without the help of a clinician, and clinical trials must be kept small so as to have any hope of filling them (giant CMN affects just 1 in 500,000 individuals). Funds are often scarce for research on conditions with such a small market, and the lack of existing literature and investigators working on the same disease can pose added professional barriers.

Due to these and other obstacles, Etchevers wasn’t able to fully launch her own CMN research until her daughter was 10 years old, when the head of the patient advocacy group Nevus Outreach offered her start-up funds and help getting samples. Even with that support, “publishable results have been much more difficult to achieve, especially while also financially bootstrapping and establishing my credibility as a newcomer in a barely existing field,” Etchevers  says.

The challenges can seem daunting enough to turn early-career researchers away from studies of rare disorders. “It’s often not easy to get young researchers or doctors interested in rare diseases,” says Petra Kaufmann, director of the Office of Rare Diseases Research at the National Institutes of Health (NIH). “They’re naturally exposed in their education and training to common conditions.”

But collectively, rare conditions are not so rare, affecting a total of nearly 25 million Americans. Studies in the NIH Undiagnosed Diseases Program have found that insights from investigations of rare disease can also help improve understanding of more-common conditions. Successes from this program have led to its expansion into an Undiagnosed Diseases Network linking academic medical centers around the U.S., and to rare-disease research playing a key part in the NIH strategic research plan for 2016–2020.   

And for researchers who venture into studies of such disorders, the experience can be uniquely rewarding. The work is almost always novel—some researchers find themselves essentially starting new fields—and projects typically involve collaborations with clinicians, patient advocates, and the patients whom discoveries may potentially benefit.

“In the next few years, there will be hundreds if not thousands of rare diseases that will be identified based on genomic data and exome sequencing,” says Hudson Freeze, director of the human genetics program at the Sanford Burnham Prebys Medical Discovery Institute in San Diego. “Each one of those is a potential project for a basic scientist to stitch together disease mechanisms.” (See “The Genetic Components of Rare Diseases,” The Scientist, July 2016.)

Making contact

Freeze spent his early career focused on understanding how sugars are added to and removed from proteins in the slime mold model Dictyostelium discoideum. At the time, his work focused on how certain lysosomal enzymes malfunctioned when the glycoproteins lacked a sugar called mannose-6-phosphate. But after a colleague sent him patients’ cells that showed similarly aberrant glycoproteins, and Freeze later met the patients whose cells he had studied, his career took a turn.

Inspired by their stories, Freeze and his colleagues began to search for other patients who suffered from this set of conditions, known as congenital disorders of glycosylation. In the late 1990s, the researchers stumbled across a listserv run by patients’ families—all trying to understand their children’s disorders—who were more than happy to work with Freeze and his team. For more than 20 years, Freeze has continued to collaborate with those families and others as he studies the underlying mechanisms of a range of rare glycosylation disorders in search of effective treatments. “It was not part of my big plan to do this,” he says. “It was just a series of opportunities that presented themselves.”

Developmental biologist Hamed Jafar-Nejad of Baylor College of Medicine in Texas had a similar segue into rare-disease research when he discovered that the gene he was manipulating in mice caused abnormalities in liver development that are typical of a human disease called Alagille syndrome. He had known that the gene, called jagged1, was mutated in Alagille patients, but he was surprised to find that removing one copy of the gene in mice led to abnormalities in liver development, which had not been previously seen on a different genetic background. Now, as he studies how specific mutations affect developmental pathways in animal models, he keeps an eye out for clinical links. “Although at heart I’m still a developmental biologist, I see my projects differently,” he says. “If exome sequencing identifies [the genes we’re working on] as being mutated in human patients, I can’t say, ‘I’m going to ignore this and wait and see how these genes work in my genetic screen.

Freeze suspects that experiences like his and Jafar-Nejad’s will become more common among basic researchers as sequencing efforts continue to unveil the mutations underlying rare diseases. And those basic scientists will be key to advancing the study of rare disease. “It’s going to be especially important [to establish clinical connections] when someone has been working on a particular set of genes in a model system, and then you find a disorder that’s affected by those genes,” he says.

Making those connections isn’t easy, however. For now, such discoveries are either serendipitous or stem from the efforts of a motivated person—researcher, patient, family member, or advocate—keeping abreast of the literature; there’s no centralized database that matches studies in model organisms to human rare diseases. One database, maintained by the NIH and the National Center for Advancing Translational Sciences (NCATS), the Global Rare Diseases Patient Registry Data Repository (GRDR), stores de-identified patient information, including symptoms, medications, or genetic test results, but does not yet link these data to preclinical studies. To keep a lookout for disease links, scientists should search genes and mutations of interest in databases such as GRDR, and also in PubMed and OMIM (Online Mendelian Inheritance in Man), which include case reports of individual patients, Etchevers says.

Once you find a rare disorder that you’d like to learn more about, try broadening your search beyond your disease of interest, suggests Devaveena Dey, a research fellow at Harvard University. “Be prepared to gather information from unrelated fields.” Dey transitioned from studying cardiac stem cells to working on the signaling pathways involved in fibrodysplasia ossificans progressiva, a rare condition in which muscles, ligaments, and tendons are gradually replaced by bone. “If you have a question but don’t know how to address it or get the protocols, start looking at other known diseases, or think about where the same problem or pathway might exist in other organs and tissues.”

Collaborating with the clinic

A crucial component of success with rare-disease research is establishing strong connections with physicians and the patient community. Unlike better-known conditions such as diabetes or some cancers, for which the disease’s natural history is well established and research can continue independent of the clinic, most rare-disease studies must rely heavily on input from those affected and the clinicians who care for them.

In the next few years, there will be hundreds if not thousands of rare diseases that will be identified based on genomic data and exome sequencing.—Hud­son Freeze
Sanford Burnham Prebys
Medical Discovery Institute

When starting her work on CMN, Etchevers already knew families and patients affected by the condition, but needed physicians to help collect patient samples and monitor study participants. In part to establish her credentials, she successfully crowdfunded a proposal to establish a biobank of such materials. “It was hard for me as a non-doctor to get physicians to contribute,” Etchevers says. “By putting the biobank together and getting the necessary ethical approvals and things, it made me look more serious to people who want to collaborate.”

To help scientists pick up skills such as working with physicians, consortia that are part of the Rare Diseases Clinical Research Network (RDCRN) offer mentoring and hands-on training. Universities, hospitals, and local groups of clinical researchers also occasionally provide such learning opportunities. In 2014, an initiative of RDCRN, which is part of NCATS, established a national training program that teaches postdocs and early-career faculty to design studies that have sufficient statistical power despite small numbers of patients; to find funding opportunities; and to establish and work with biobanks and registries. Trainees attend webinars twice a month and meet at the beginning and end of the program to discuss their individual projects. “We’re taking it beyond the regional level to bring common standards and homogeneity to the training,” says Kaufmann.

Patients and patient advocacy groups are also key. In addition to aiding patient recruitment for clinical studies, the patient community can help secure funding. For example, Jafar-Nejad’s work on disorders caused by a defective NGLY1 gene began when a foundation established by a patient’s family offered funding support. Funding from patient advocacy groups also commonly supports many academic projects; even if they’re not providing the funds themselves, representatives from these groups help keep track of new research on a particular rare disease and of drugs being developed for more-common disorders that may be relevant. “If these groups weren’t being really proactive and strong advocates, much of the work wouldn’t get done,” says Eleanor Perfetto, professor of pharmaceutical health services research at the University of Maryland, who last year received a grant from the National Organization for Rare Disorders (NORD) to train patient advocates to effectively collaborate with researchers.

Patients, too, are often involved in the research, and it’s important to clarify what their role will be—sample contributors, funders, collaborators, or something else—and what costs will be covered. “Both sides need to have a lot of transparency up front,” Perfetto says. “Researchers need to be aware of, understand, and embrace the role that patients can play in helping their research and making it not just richer, but more relevant to the patients.”

Rare diseases, common insights

The genetic and clinical research methods that rare-disease researchers employ are slowly gaining traction for studies of more-widespread diseases. Many common conditions are not single diseases but have varied origins, and as exome sequencing expands into clinical care, the promise of precision medicine continues to motivate the creation of smaller and smaller disease subgroups. This approach poses many of the same challenges that rare-disease researchers are familiar with: developing close clinical collaborations, recruiting sufficient patients for a trial, and finding statistically significant results in small cohorts. (See “Clinical Matchmaker,” The Scientist, June 2015.) Rare-disease researchers are proficient in studies of one or a few patients, for example. While such small cohorts were once frowned upon, proponents of personalized medicine consider clinical trials of smaller and smaller patient subgroups the ultimate goal. “Before precision medicine became a catchword, [our methods] weren’t always taken seriously,” says Etchevers. “I’d hear things like, ‘That’s not the way to sample a population’—but we’re not sampling a population, we’re identifying unique individuals. I hope that more-common conditions will take a page from the books of rare disease researchers.”

Sometimes there is more-direct overlap between common and rare diseases. In 2008, the NIH established its Undiagnosed Diseases Program, which combines genomic sequencing with clinical data to identify the origins of undiagnosed conditions. Case studies from the program have revealed many links between rare and common diseases. For example, a teenager with bone and neurological abnormalities was found to carry a mutation in one gene, SMS, that affects bone development and leads to osteoporosis. His condition, dubbed Snyder-Robinson syndrome, is being used as a model to test preventive options for osteoporosis, which is common in aging individuals even though they lack SMS mutations. Similarly, studies of progeria, a rare syndrome that causes premature aging, have revealed cellular workings that are important in many aging-related conditions, such as brittle bones or vascular disease. Based on these and other successes, the NIH program expanded in 2015 to include several clinical sites.

“The more we do rare-disease research, the more we then identify cellular pathways and processes that can apply to more-common disease,” says genetic specialist Debra Regier at the Children’s National Medical Center in Washington, DC. “We never know what we might be able to extrapolate.” 

Jyoti Madhusoodanan is a freelance writer based in San Jose, California.

Corrections (September 2): This story has been updated from its original version to correctly reflect that Hamed Jafar-Nejad was aware that jagged1 was mutated in Alagille patients. In addition, Heather Etchevers received funding from Nevus Outreach, Inc., not Naevus Global. Finally, rare diseases in the US are defined as those that affected fewer than 200,000 people, not fewer than 1 in 200,000. The Scientist regrets the errors.

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