A Lab for "Orphans"

Seeking cures for neglected diseases

Like other biomedical research facilities, it experiments with rodents of all sorts, is filled with glassware of every shape and size, and has the latest scientific gadgetry. Yet there is something special about this particular lab at New York's Rockefeller University. For the past decade, its doctors, chemists and biologists have been engaged, largely unheralded, in an unusual task. They are fighting what they call "orphan diseases," a group of widely differing illnesses that have one thing in common: no one has done very much to develop drugs for them.

The explanation for this neglect is largely economic. Although pharmaceutical houses have produced an astonishingly rich arsenal of drugs--sometimes with little prospect of making money--they have not found it feasible to develop medicines for many diseases that might be prevented or cured, particularly those that strike the impoverished.

It was to fill this gap that Biochemist Anthony Cerami created the orphan-diseases lab. Unlike the drug companies, the scientists could not afford to screen thousands of compounds in hopes of finding one that might work. Instead, they concentrated on combining what was already known about a disease with their own ingenuity.

Indeed, it was brainstorming that got the lab's first project--a study of sickle-cell anemia--off to a heady start. The Rockefeller scientists realized that any treatment for this genetic disease, which affects perhaps 2 million people around the world, had to be directed at stopping the characteristic sickling, or distortion, of the red blood cells that occurs after they unload their cargo of oxygen. But how? During cocktail-party chatter, Lab Director Cerami learned from a colleague that a byproduct of urea--a chemical called cyanate--can prevent sickling. Tests on both animals and humans confirmed this, but the cyanate also had toxic side effects on the nervous system. So the Rockefeller scientists suggested adding the cyanate directly to the blood. That idea has led to the experimental development elsewhere of machines, somewhat like artificial kidney units, which allow the cyanate to react with the blood outside the body.

The Rockefeller group used equal inventiveness in tackling thalassemia (Cooley's anemia), which afflicts an estimated 3 million people globally--most of them of Mediterranean and Asian origin. Victims of this genetic disorder can usually be kept alive by regular blood transfusions. But because the body is not easily able to rid itself of the iron added by repeated blood donations, it accumulates to such an extent that by the age of 20 the heart, liver and other organs can be threatened. Looking for a way to remove the excess iron, the Rockefeller scientists turned to bacteria and fungi. In the course of billions of years, these tiny organisms have evolved complex molecules that gather up iron essential for their survival. The researchers developed similar compounds--chelating agents (from the Greek word for claw)-- of their own. Injectable chemicals of this kind have been available for some time, but the Rockefeller team hopes their work will lead to an inexpensive oral drug.

The lab's most recent triumph is against trypanosomiasis, or sleeping sickness, a disease that makes large areas of Africa virtually uninhabitable. Studying trypanosomes, the microscopic parasites that cause this disease, a young biomedical student, Steven Meshnick, found that they contained an unusually high concentration of hydrogen peroxide--a compound that reacts vigorously with metals. Turning that bit of elementary chemistry against the bugs, the Rockefeller scientists injected compounds into mice infected with sleeping sickness that, in effect, duped the parasites into picking up metals already in the rodents' bodies. Result: the parasites literally exploded--without harming the mice. The team is now working on similar compounds to do the job in both people and cattle.

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