As predicted, the tagged protein had joined with other proteins, creating the microscopic machines that in a real infection would assemble the rabies virus shell. Why would this matter? Because a drug developed by Lingappa's firm, Prosetta Antiviral, has been shown to interfere with this protein, blocking it from functioning in these shell-making machines. If his gamble pays off, this is the pathway by which an antiviral drug will stop cells from replicating the rabies virus. At moments like these, Lingappa's voice swells from its normal, mellow pedagogical tone to a near-talk-radio thunder; he clenches his fist and paraphrases one of his favorite lines from the philosopher John Dewey. "The givens of experience are not given," he says. "They are taken! With great difficulty!"
Man Against Virus
A Brief History
Doctors in India use an early version of vaccination against smallpox, introducing small amounts of dried pus from smallpox sores into the skin of healthy patients.
Lady Mary Wortley Montagu introduces smallpox variolation—direct exposure to dried pus or sores—to England, having witnessed it in Constantinople. Although variolation carries a 2 to 3 percent risk of death, the practice spreads through Europe.
Benjamin Jesty, an English cattle breeder, is credited with performing the first vaccination in history. Jesty had long known that dairymaids didn't get smallpox. He guessed it was because of their exposure to cowpox, a similar disease in cows. Jesty inoculated his wife and children with cowpox, protecting them from smallpox for years.
Edward Jenner, a British physician, publishes the first scientific report of a vaccination experiment using cowpox.
Louis Pasteur invents a vaccine for rabies. It was the first to use a laboratory-weakened strain of the target virus, rather than a related virus like cowpox, to induce immunity.
A Dutch biologist named Martinus Beijerinck searches for the cause of a disease killing tobacco plants. He passes sap from infected leaves through porcelain filters so fine that bacteria can't get through. Yet the sap can still cause healthy tobacco leaves to wilt. He argues that the disease is caused by a tiny agent smaller than a bacterium.
Oxford biologists Howard Florey and Ernst Chain discover how to produce large quantities of antibiotic and test it on humans. Industrial-scale production of penicillin soon begins.
American virologist Wendell Stanley reports that penicillin and other antibiotics have no effect on viruses.
Interferons, antiviral proteins produced naturally by infected cells, are discovered. They are hailed as a potential miracle drug but prove to be risky and unreliable as an antiviral.
William Prusoff of Yale University discovers idoxuridine, the first effective antiviral. It fights herpes by interfering with the assembly of new virus genes. Approved in 1963 by the FDA, it can only be used topically for herpes infections in the eye because of dangerous side effects in other parts of the body.
After screening thousands of compounds for antiviral activity, scientists get a hit: a compound called amantadine proves effective against influenza. It is approved in the late 1960s.
The World Health Organization launches a campaign to eradicate smallpox, which still kills some 15 million people a year.
Researchers discover a broad-spectrum antiviral, which can work against a number of viruses. Known as ribavirin, it is now mainly used against hepatitis C. It's not widely prescribed because it can cause anemia and other side effects.
Acyclovir, an antiviral for herpes viruses, is discovered.
The last known death from smallpox occurs. In 1980, WHO declares its eradication campaign a success. Three decades later, stocks of smallpox still remain in American and Russian laboratories, and there are suspicions that some stocks of virus are unaccounted for. If smallpox were to emerge again, doctors would have no antiviral drug to combat it.
Scientists discover the first antiviral effective against HIV. Known as AZT, it is later joined by a number of other drugs.
AZT-resistant strains of HIV are discovered. Doctors soon begin prescribing cocktails of several different antivirals to slow the evolution of resistance.
Gilead Sciences researchers discover a new antiviral for influenza, marketed as Tamiflu.
Scientists report influenza viruses that are resistant to Tamiflu. Since then, resistant strains have spread around the world.
Vertex Pharmaceuticals and Merck win FDA approval for highly effective new antivirals for hepatitis C, which infects 170 million people worldwide.
Lingappa came relatively late to his obsession with antivirals. He trained as a cell biologist in the late 1970s in the laboratory of Günter Blobel, a Rockefeller University cell biologist who went on to win the Nobel Prize in 1999. Blobel studied how cells work by grinding them up and running experiments on their loose contents. This type of cellular soup, known as a cell-free system, can simulate the inner workings of a cell, including the assembly of new genes and proteins. By adjusting its composition—leaving out a single enzyme, for example—scientists can figure out how a cell's molecules work together to keep it alive. Under Blobel's tutelage, Lingappa became a cellular chef de cuisine in his own right. For example, he ran experiments to figure out how newly made proteins were ferried through a cell to the place where they were needed. After earning his PhD, Lingappa headed west to UC San Francisco to continue his research.