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Target: Toxin

You can excuse Louis Schofield’s impatience to begin human testing. His search for an effective malaria vaccine is now in its third decade. His quest began in the late 1980s, when as a postdoc at New York University, he went hunting for the malaria toxin. His idea, even then, was that vaccinating against the toxin rather than the parasites could prevent the actual disease-the fever and uncontrolled inflammation that are the deadly hallmarks of malaria. Unlike the parasites, Schofield reasoned, the toxin exists outside the blood cells and should be readily accessible to the immune system.

In general, vaccines work by inciting the immune system to produce proteins called antibodies; each antibody specifically reacts with one particular molecule-say, a protein on the surface of a parasite. This interaction typically focuses the killing effects of the immune system on the invader. But the antibodies recruited by an antitoxin vaccine like the one Schofield has in mind simply bind to the toxin, neutralizing it. The concept is not unique: two of the world’s most successful vaccines, against diphtheria and tetanus, are such antitoxin vaccines.

But to create an antitoxin vaccine, you first have to find the toxin. Much of malaria research has focused on proteins, but Schofield took a different tack, going after a suspicious molecule, a carbohydrate studded with fats, found on the parasite’s cell surface. He thought that this molecule could be the villain causing the inflammation problems characteristic of malaria. “That turned out to be a good guess,” he says. Over 18 months, at the National Institute for Medical Research in London, he painstakingly extracted the toxin from malaria parasites. Once he had enough of it in hand, he injected it into mice; the rodents grew sick, experiencing a slew of symptoms-“pretty much those that you see in people sick and dying of malaria,” he recalls. He had found the malaria toxin.

But a tremendous hurdle still remained. Without a way to make a completely pure version of the toxin’s carbohydrate backbone-and do it relatively quickly-Schofield could not prove it would make an effective vaccine, much less produce it commercially.

The technological breakthrough came several years later from research being done in Cambridge, MA. Then at MIT, chemist Seeberger, working with graduate student Obadiah Plante, had invented a machine that automated the laborious and time-consuming synthesis of sugars. Seeberger’s machine tantalized Schofield: it could churn out large quantities of a pure version of the basis for a vaccine cheaply and quickly, possibly within weeks or days.

Optimistic and determined, Seeberger took on the project-and a partnership was born. “He undertook to do the synthesis on the strength of my conviction,” Schofield says. Seeberger first made a stripped-down version of the toxin. Though the process initially took 10 months, he soon had it down to a matter of hours. Then, in Schofield’s lab, researchers infected mice with malaria parasites. Normally, almost all of the animals would have died within a week. But injection with a prototype vaccine based on Seeberger’s molecule apparently negated the effects of the toxin, raising the rodents’ survival rate to between 65 and 75 percent. “The results were very clear,” Seeberger says.

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Tagged: Biomedicine

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