Rare Opportunity

The study of uncommon diseases that mimic some aspects of aging, such as Hutchinson-Gilford progeria syndrome and Werner syndrome, could reach beyond the lives of afflicted individuals and cast light on more common medical conditions.

Four years ago, when her son was diagnosed with an extremely rare condition called Hutchinson-Gilford progeria syndrome (HGPS), Leslie Gordon did a bit of exploring. Within days, she learned that the U.S. National Institutes of Health (NIH), the organization that handles grants for publicly funded medical research, wasn't investing in studies on HGPS. And they hadn't sponsored any--"ever," says Gordon. So she set out to rectify that oversight. Unlike most parents whose children suffer from often-neglected rare diseases, Gordon had recently completed her M.D.-Ph.D. She used her medical knowledge to raise awareness of HGPS among university and government scientists, organizing a workshop on the disease.

Since the 2001 conference, NIH has funded two studies on HGPS, and the nonprofit Progeria Research Foundation, run by Gordon's sister, has bankrolled five others. Researchers at the National Human Genome Research Institute have identified the gene responsible for HGPS, a disorder that makes its victims appear to age prematurely. Children with HGPS lose their hair and develop wrinkled skin, and they often die of severe atherosclerosis--hardening of the arteries--by their early teens. Because HGPS mimics some aspects of aging, studies of the disease could lead not only to treatments but to broader insights into the biology of disorders that plague us as we grow old and perhaps the process of aging itself.

With regard to age-related illnesses, a recent report published in the British medical journal The Lancet suggests that the investigation of premature aging syndromes, or "progerias," might shed light on the mechanisms that underlie atherosclerosis. In this study, researchers at the University of Washington, Seattle, found an unexpected genetic overlap between HGPS and Werner syndrome, another rare disorder whose symptoms mirror aspects of the natural aging process. Like victims of HGPS, children with Werner syndrome develop atherosclerosis and many other age-related conditions such as diabetes and cataracts, although the disease strikes later in life. In most cases, the two diseases stem from alterations in two different genes, but in the recent Lancet study, researchers found that a small subset of patients diagnosed with the latter disease have mutations in the gene responsible for HGPS rather than in the typical Werner gene. The commonality intrigues researchers, as it ties together these two progerias, both of which trigger atherosclerosis.

Considering that atherosclerosis is a form of cardiovascular disease--the leading cause of death in America--the payoff from further study of these progerias could be huge. And the same could be said for investigations into other rare diseases, which could cast light on other common maladies. For Gordon, now a medical scientist at Tufts University School of Medicine in Boston, the policy upshot couldn't be clearer: Legislators and funding agencies need to realize that the value in studying rare diseases goes far beyond the lives of the individuals afflicted. Right now, says Gordon, "rare diseases are clearly understudied, clearly underfunded."

Today NIH recognizes more than 6000 rare diseases, defined as conditions that afflict fewer than 200,000 people in the United States. Since the 1983 passage of the Orphan Drug Act, which granted pharmaceutical companies financial incentives to develop medicines for rare diseases that might not make it to market otherwise, scientists and their funders have invested much more effort into studying and treating these conditions. In 1993 NIH opened an Office of Rare Diseases (ORD), which last year became a permanent fixture of NIH under the Rare Diseases Act of 2002, sponsored by Senators Edward Kennedy and Orrin Hatch.

Still, advocates for patients with rare diseases say that much remains to be done. Although some 200 new drugs for rare diseases have been brought to market since the passage of the Orphan Drug Act, that number pales in comparison to the total number of rare diseases, says Diane Dorman, vice president for public policy of the National Organization for Rare Disorders. Dorman would also like to see better federal management of research into rare diseases: ORD, which coordinates NIH-sponsored research activities in this area, has yet to receive the full $24 million authorized by the Rare Diseases Act.

In making the argument for increased government investment in researching rare diseases, Dorman points out that "four-fifths of these rare diseases are genetically based," and the genes responsible could also play a role in more common disorders. Rare diseases are cruel to those who suffer from them. But as medical geneticist W. Ted Brown of the Institute for Basic Research in Developmental Disabilities in Staten Island, New York, observes, they also represent "experiments of nature that very likely will tell us about a basic process."

Biomedical research has already delivered on that promise. For example, work on familial hypercholesterolemia (FH)--a rare, heritable disorder caused by a genetic deficiency that prevents cells from removing cholesterol from the blood--led to a major breakthrough in our understanding of cholesterol metabolism. In 1985, biochemists Michael Brown and Joseph Goldstein won a Nobel Prize for their discovery that patients with the most severe form of FH lack functional low-density lipoprotein receptors, the proteins that cells use to take up cholesterol. With increased amounts of cholesterol in the blood, people with FH run the risk of developing atherosclerosis and high blood pressure that can prove fatal. Thanks to studies of this rare disorder, researchers have developed a whole line of statin drugs that are now used to control cholesterol concentrations in millions of people.

At this point, no one can say whether research into HGPS and Werner syndrome will have ramifications as immense as was the case with research into FH. Time will tell whether progeroid syndromes will reveal anything about the universal process of aging. But insights into atherosclerosis or other common ailments that arise from studies on HGPS and Werner syndrome would add to the growing body of evidence that supports the need for funding more studies of rare diseases.

Chris Mooney a journalist living in Palo Alto, California, wonders what sort of insights into rare psychology could result from studying the brains of freelance writers.