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A New Weapon Against HIVFeedback loops will be able to produce machines that can assemble themselves and respond to their environment. Biotechnology researchers, on the other hand, are on the verge of producing smart vaccines and anticancer drugs that could potentially save tens of thousands of lives.
At the 14th International AIDS Conference in Barcelona in July, researchers announced that the U.S. and Thai governments would shortly begin the largest trial yet of an AIDS vaccine, testing a combination of vaccines on more than 16,000 Thai subjects. Dr. Donald Francis, cofounder and president of VaxGen, the maker of one of the vaccines in the study, caused a stir when he said that a vaccine could be available as early as 2005. Having helped eradicate smallpox as a young scientist in Africa in the 1970s, Francis is one of the world's preeminent retrovirologists. But some of his peers have doubts that an AIDS preventative can be developed so soon. As Peggy Johnston, associate director for Vaccine and Prevention Research at the National Institute of Allergy and Infectious Diseases, points out, it's unclear whether any vaccine can block all forms of the virus. The problem is viral diversity: There are at least nine subtypes of HIV and countless variants within each subtype. HIV also has a fiendish ability to outwit drugs or antibodies that attempt to halt its propagation.
This, of course, is the deadly genius of viruses. Viruses are essentially a simple parasite consisting only of an envelope that contains genetic material ready for transportation from one host to another. They can reproduce only after infecting a host cell. But viruses that target the immune system, such as HIV, which causes AIDS, have evolved sophisticated feedback loops that allow them to mutate in response to the immune system's defensive response. That's why almost 80% of Americans who have been on the "cocktail" of drugs known as "highly active antiretroviral therapy," and who still have measurable HIV in their blood, now carry resistant strains of the virus in their bloodstream. It's also why Francis muted expectations for his vaccine by adding that a drug that prevented AIDS in even 30% of patients would be a significant achievement.
The problem with cancer is the converse: Because the cancer cells are self-generated tissue, not unlike other tissue except that they lack governors on their growth, the body's immune system tolerates the emergence of tumors because it "reads" them as benign--or on the home team, as it were. Some of the most promising cancer research focuses on immunotherapy that will help the patient's own defenses recognize and halt the runaway growth of tumors.
Philip S. Low, the Joseph F. Foster Distinguished Professor of Chemistry at Purdue University, has for years been studying the affinity of many types of cancer cells for folate--a water-soluble B vitamin that the cancer uses to grow. In 1996 he formed a company called Endocyte to develop and market vitamin-based cancer therapies. Along with former graduate student Christopher Leamon, Low has developed a "Trojan horse" therapeutic approach called folate-targeted immunotherapy, which exploits tumors' reliance on folate to slip in anticancer agents along with the folate molecules absorbed by the cancer. In an even more ingenious strategy, Low and Leamon devised a way to use folate cells as a beacon attached to the cancer cells, to alert the immune system and generate a defensive response. Another perfect feedback loop: The physician vaccinates the cancer patient against a hapten (a small, inert organic chemical), for instance, and the body generates antibodies to destroy the hapten and the tumor hosting it. Then folate molecules with the hapten attached are injected, and the cancer cells eagerly gobble them up. Now the immune system can "see" the cancer and attack it along with the hapten, for which it's already been vaccinated.
Even more striking is that the immune system seems to remember the cancer cells it's battled previously. Researchers testing mice that had been cured of tumors using the folate-based therapy later reinjected the same line of tumor cells--and the rodents fought off the cancer with no further therapy. Faced with a "re-challenge," as the scientists call it, the mice's immune systems again recognized the tumors and suppressed them. The feedback loop was complete.
Endocyte hopes to begin clinical trials of the folate-based immunotherapy called FolateImmune by December. If all goes well, the new therapy could be widely available within a few years. Many researchers believe we are on the verge of a new era of immunotherapies that make use of similar feedback loops. The opposite of brute-force medicines that rely on drugs foreign to the body to attack disease, these therapies harness biological feedback loops to enable the body to heal itself. It's a spontaneous, observant form of science, one that requires not only new ways of understanding the natural world but also new ways of harmonizing with it.
Humans already have set in motion other, less benign feedback mechanisms in nature: the awful positive feedback of nuclear fission, for instance, and the inexorable loop of global warming. Given these, it is perhaps a form of grace that we are now learning the discipline of natural feedback loops that can be controlled and made constructive, attending to the order found in nature rather than imposing our own.
Richard Martin is a freelance writer living in Boulder, Colorado.
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