In 1964, the US enacted the civil rights act, the Vietnam War was heating up, and the battle against cancer was being waged. That year, Dr. Jerome Horwitz published what was, by all accounts, a failure. Horwitz had synthesized and tested a throng of new compounds, one of which happened to be azidothymidine or AZT. In an era when cancer research consisted of the stifling pursuit of throwing random compounds at leukemic mice, Horwitz was doing something different. He was pursuing original, innovative strategies. A chemistry professor at Wayne State University in Detroit, he developed a unique class of compounds he hoped would be able to stop the growth of cancer cells. While AZT was an utter failure at treating cancer, two decades later the drug would find new life as the first effective agent in the treatment of HIV/AIDS. The passing of Dr. Horwitz on September 6th, 2012, is the loss of a brilliant member of the scientific community. His story carries a key lesson for scientists today.

Horwitz postulated that if you can’t directly target the cancer, you can modify what the cancer needs: the cell. He designed a new family of compounds all designed to trick the cell machinery. The idea here was to imitate the building blocks of life, the nucleotides that form DNA. These trick molecules would look just like the real thing but, when incorporated into a growing chain of DNA, they would hinder normal DNA creation and impair the growth of runaway cancer cells that simply can’t stop making DNA chains.

Horwitz tested these drugs in a mouse model of cancer. The compounds showed no activity. It was a disappointment for Horwitz, who had spent years developing the drugs. Frustrated, he wrote up the failure, and moved on to other drug families. He didn’t bother to patent the disappointing group of compounds. Why waste money patenting failed drugs? The compounds were archived, their records collected a thick layer of dust in the Detroit lab. In one of those boxes was AZT, one of many seemingly useless drugs.

Twenty years later, in 1984, a virus, HIV, was identified as the cause of AIDS. Now that massive quantities of the virus could be made, Burroughs Wellcome pharmaceuticals, today GlaxoSmithKline, began comprehensively screening available compounds against the virus. Early on, AZT stood out. The drug was able to fool the virus into accepting the ‘trick nucleosides.’ Once incorporated into the growing strand of genetic material, the DNA became truncated and the virus could no longer replicate.

As the AIDS epidemic ballooned, the US government became desperate for a treatment. Despite the risk, the FDA approved AZT at an unheard of rapid pace. AZT became the first drug to treat HIV/AIDS. However, what should have been a celebration soon turned into indignation. The high price tag kept many from receiving the new therapy: $10,000/year. In 1992, Burroughs Wellcome reported sales of $400 million for AZT, generating an enormous surge of profit for a drug that was developed and tested with heavy financial and scientific support from the U.S. government. Horwitz, who never patented the drug he developed, didn’t share in these profits.

The outrage over AZT was just beginning. The virus was able to rapidly develop resistance to the drug, mutating its own enzymes so that the AZT molecules would no longer be recognized. Even worse, the drug was highly toxic, impairing the ability of blood cells to develop normally. Indications of this bone marrow toxicity were evident in the earliest human trials of the drug but due to the accelerating epidemic, their implications were not fully considered. People were dying; the safety of treating with AZT was unimportant, the only thing that mattered was its effectiveness. HIV researchers worked single-mindedly to bring us something, anything, capable of beating back the virus.

AZT, born with the best intentions, mired in money and politics, continues to outrage many in the HIV community. Alone, AZT can’t keep up with the virus. But, when combined with drugs that target viral enzymes, the virus can be kept in check. Today, given in lower doses, Horwitz’s clever DNA imitator is still used to treat HIV, particularly in pregnancy. The patent ended in 2005.

Horwitz’s remarkable story has two important lessons for us in science and medicine. First, unlikely scientific miracles happen. Drugs that seemingly have no future may one day, years hence, be just what we need for diseases we can’t even contemplate. And second, get the patent.

Photo: The University Research Corridor