Sand Fly Saliva May Prevent Blood Clots

This is the first in a series of reports on basic research discoveries at Harvard that have led to new start-up companies and to novel products and processes in the biomedical, electronics, and other industries.

By William J. Cromie

Gazette Staff

A marvelous molecule has been found in the saliva of the common sand fly by Harvard researchers.

This small protein offers the potential of fighting blood clots and high blood pressure, modifying the immune system, and serving as a vaccine against leishmaniasis, a parasitic disease that disables about 12 million people worldwide. It was even tested for growing hair on bald heads, but with inconclusive results.

Scientists at the School of Public Health (SPH) came across the protein while working out the life cycle of parasites that transmit disease to humans and domestic animals. They were particularly interested in a creature called leishmania, whose larvae live in the sand fly's saliva. When a sand fly bites someone to get a meal of blood, the parasite in its saliva gets under human skin.

The researchers wondered why the powerful human immune system does not destroy leishmania before they attack the host's skin and internal organs. In an attempt to solve that mystery, Charles Shoemaker and Richard Titus, both of the SPH Department of Tropical Public Health, discovered maxadilan, a protein that suppresses white blood cells that destroy invading parasites.

Further study of the protein revealed another startling effect of the little protein that could. It has the ability to open up blood vessels, enhancing movement of the parasite into the body and blood into the parasite.

"Leishmania needs a reliable flow of blood that won't clog and cut off its food supply," explains Titus, who has since moved to Colorado State University.

"Maxadilan is many times more potent than nitroglycerine for opening arteries and getting blood to flow," noted Kevin Heyeck of Harvard's Office of Technology and Trademark Licensing. "We immediately thought about the possibility of using the protein for treatment of cardiovascular problems."

Harvard filed for a patent on maxadilan in 1989.

Hair Restorer

It was another quality of the amazing protein, however, that got the attention of industry -- the ability to grow hair.

"My experiments included shaving the rumps of mice into which I injected sand fly saliva," Titus said. "To my surprise the hair grew back so quickly it was annoying. I guessed that maxadilan accelerated hair growth by increasing blood flow. That's how baldness treatments, such as Rogaine, work."

The researchers do not do such experiments by gathering thousands of sand flies and squeezing the saliva out of them. Shoemaker, Titus, and Ethan Lerner, an assistant professor of dermatology at Massachusetts General Hospital, cloned the gene that carries instructions for making maxadilan, allowing it to be produced artificially.

This ease of getting the protein and the huge potential market for a baldness cure prompted a large Japanese cosmetics company to license the patent for maxadilan.

The story doesn't have a rich and happy ending, however. Three years of tests of the protein on higher animals haven't achieved the hoped-for result.

That decision leaves Harvard free to license the protein to companies interested in the protein as an immune system suppresser and cardiovascular drug, capabilities that the cosmetics-maker wasn't interested in pursuing. As a suppressant, maxadilan could find use in preventing rejection of organ transplants and treating diseases such as rheumatoid arthritis and diabetes, wherein the body's immune system attacks healthy tissues.

Heyeck also sees good possibilities in using maxadilan to treat or prevent blood clots and to help lower high blood pressure.

"I think the market is wide open for such cardiovascular applications," he comments.

Vaccine Potential

Shoemaker, now working temporarily in New Zealand, continues to work on the possibility of using maxadilan in a vaccine against leishmaniasis. That's tricky because he has to modify a protein that suppresses immunity so that it will suppress its own activity. That is, the vaccine must cancel out the effects of its sister protein in the sand-fly saliva.

Shoemaker thinks this can be done by modifying maxadilan itself or the genetic material that causes the protein to be made. On the basis of his work, Harvard has filed for a second patent.

In addition to the biological difficulties, however, there are economic ones. Although travelers from developed countries and Gulf War veterans have gotten the disease, it is mostly confined to poorer nations in Asia, Africa, South America, and the Middle East. Biotech and drug companies in the U.S. are reluctant to invest millions of dollars and years of development for such a market.

Heyeck hopes that the World Health Organization will be willing to fund development and testing of the vaccine. Once it has passed safety and effectiveness tests, drug makers are more likely to take up manufacturing and distribution.

Seeing how a basic discovery might be used to treat and cure disease is easy enough. But obtaining the added knowledge, technology, and funds to go from laboratory bench to bedside or factory is often a long and frustrating effort. And no guarantee exists that a discovery will produce something people need or want: the hair inducer that only works on the rumps of lab mice, for example.

When things go right, however, it's all worthwhile.

The ultimate goal of the research pursued by Shoemaker and Titus is nothing less than to prevent the transmission of disease from blood-sucking parasites like flies, mosquitoes, and ticks to humans and domestic animals. Such diseases include malaria, lethal varieties of hemorrhagic fever, and sleeping sickness.

Basic research is the only vehicle for producing the new knowledge necessary to achieve such goals. Transferring that knowledge to the public sector is often "a hard sell," Heyeck admits, "but it's something that is important for Harvard to pursue."