A Detroit boyhood
Jerome Phillip Horwitz was born in Detroit on January 16, 1919, into a Jewish family. His father was a businessman who sold poultry. Horwitz graduated from Detroit’s Central High School in 1937. As a teenager he read Microbe Hunters, Paul de Kruif’s 1926 bestseller about the pioneers of microbiology, and it decided his future. “A light bulb went on” he recalled in 2001. “I knew what I wanted to do.”
His widow later put it with a smile: he went into science because he wanted to make a difference, and also because he didn’t want to go into the poultry business with his father.
Training as a chemist
Horwitz studied chemistry at the University of Detroit, earning his bachelor’s degree in 1942 and a master’s two years later. Old high-school football injuries kept him out of military service in the Second World War. He went on to the University of Michigan, where he received his doctorate in chemistry in 1948, followed by postdoctoral training at Northwestern University and at Michigan.
In 1951 he joined the Illinois Institute of Technology, where he worked on a team developing solid rocket fuels for the Navy. He disliked working with explosives, and in the mid-1950s he returned to Detroit to join the Detroit Institute of Cancer Research, later the Michigan Cancer Foundation and today the Barbara Ann Karmanos Cancer Institute, and the faculty of Wayne State University School of Medicine. He would stay for the rest of his career, retiring in 2005 at the age of eighty-six.
“Fraudulent nucleosides”
In the early 1960s, much cancer drug research consisted of testing large numbers of chemicals almost at random to see whether any slowed tumours in mice. Horwitz found that approach intellectually unsatisfying. He wanted to design a drug for a specific target. Cancer cells divide relentlessly, and to divide they must copy their DNA, built from units called nucleosides. Horwitz’s idea was to make what he called “fraudulent nucleosides”: molecules similar enough to the real thing that a cell would take them up, but altered so that once built into a growing DNA chain they would stop it in its tracks.
Working with colleagues, he synthesised a family of such compounds. One of them, made in 1964, was 3′-azido-3′-deoxythymidine, azidothymidine, or AZT. The approach, designing a molecule to interfere with a known biological process, anticipated what is now called rational drug design.
A failure on the shelf
When Horwitz tested AZT on mice with leukaemia, nothing happened. The drug did not work against cancer. Disappointed, he wrote up the negative results, published them, and moved on to other projects. He did not apply for a patent: there seemed no point in patenting a failure. The samples, as one account put it, went into storage and gathered dust. He consoled himself, colleagues remembered, by joking that he had made a very interesting set of compounds that were waiting for the right disease.
He kept working in the same field. In the mid-to-late 1960s his laboratory also made dideoxycytidine (ddC) and 2′,3′-didehydro-3′-deoxythymidine, later known as stavudine or d4T. In 1964 he also published the first description of X-gal, a compound that turns blue when a particular bacterial enzyme is present. X-gal became one of the most widely used tools in molecular biology: the “blue-white screening” it makes possible is still used in laboratories around the world to tell at a glance which bacteria have taken up a piece of engineered DNA.
The right disease
In the early 1980s a new and terrifying epidemic appeared. By 1984 scientists had identified its cause, HIV, a retrovirus that copies its genetic material into DNA using an enzyme called reverse transcriptase. That made Horwitz’s fraudulent nucleosides suddenly relevant: a molecule that could trick the viral enzyme into building it into a DNA chain would cut the chain short and stop the virus from replicating. Retroviruses had been barely known when Horwitz first made the compound.
Researchers at the drug company Burroughs Wellcome, which was screening existing compounds for antiviral activity, found that AZT stood out early among the many compounds tested, and scientists at the U.S. National Cancer Institute showed in 1985 that it blocked HIV in the laboratory. Clinical trials moved at unprecedented speed, and in March 1987 the U.S. Food and Drug Administration approved AZT, under the brand name Retrovir, as the first drug for HIV and AIDS. Horwitz’s ddC and d4T were later approved as HIV drugs as well, in the early 1990s.
Hope, controversy and lives saved
AZT’s arrival was both a breakthrough and a source of anger. It was the first treatment proven to prolong the lives of people with AIDS, but at the high doses first used it caused serious side effects, including damage to the bone marrow, and the virus could quickly develop resistance when it was used alone. Its price, around 8,000 to 10,000 dollars a year at launch, made it one of the most expensive drugs ever sold and provoked protests by AIDS activists, while Burroughs Wellcome reaped large profits from a compound first made with public research funding in Detroit.
Its lasting value proved immense. In 1994 a landmark trial showed that giving AZT to HIV-positive pregnant women and their newborns cut the rate of transmission to the babies by about two-thirds, and the drug became a cornerstone of efforts to prevent mother-to-child transmission worldwide. Combined with newer drugs in the multi-drug “cocktails” introduced from the mid-1990s, nucleoside drugs descended from Horwitz’s idea helped turn HIV from a death sentence into a manageable chronic condition for millions of people.
The economics of AZT became a case study in pharmaceutical policy. In 1992 Burroughs Wellcome reported AZT sales of about 400 million dollars, for a drug whose development had been heavily supported by the U.S. government and whose molecule had been made at a publicly funded cancer institute. The company’s patent expired in 2005, after which generic versions became widely available.
No patent, no fortune
Horwitz never earned money from AZT. The patent and the profits belonged to Burroughs Wellcome, which had tested and developed the drug for HIV. The company did help establish a chair at Wayne State in his name, but he spoke candidly of his frustration that neither he nor his cancer institute shared in revenues that ran into billions of dollars. His story is often cited by scientists as a cautionary tale about intellectual property.
Fame came briefly. When AZT made headlines he was profiled as ABC News’s “Person of the Week” and People magazine named him one of the twenty-five most intriguing people of 1986. Dr. Paul Volberding, a leading AIDS researcher, later said that while it was impossible to be sure, it would have taken considerably longer to develop antiretroviral drugs without Horwitz’s pioneering work.
Later work and private life
Horwitz kept working into his eighties. He wrote more than a hundred scientific papers, and in his eighties he shared a five-year, 900,000-dollar grant from the National Cancer Institute to develop drugs against solid tumours; that work brought him his first royalty cheque, at the age of eighty-six. Among his honours were Michigan Scientist of the Year in 1993, election to Wayne State’s Academy of Scholars the same year, a Distinguished Service Award from Wayne State in 1995, an Outstanding Achievement Award from the University of Michigan for the synthesis of AZT, and selection as Michiganian of the Year by The Detroit News in 2000. A fund for AIDS research at Wayne State bears his name.
He lived in the Detroit area all his life. He was married to Sharon Horwitz and had two daughters, Carol and Suzy. Little has been published about his religious life; his funeral was held at a Jewish chapel in Southfield, and the family asked that memorial donations go to the Karmanos Cancer Institute, Henry Ford Hospice and the synagogue B’nai Moshe.
Death and legacy
Jerome Horwitz died on September 6, 2012, in Bloomfield Township, Michigan, at the age of ninety-three. Karmanos’s chief executive said that his work had helped thousands of people live long and productive lives, a modest estimate, given how many millions have been treated with AZT and its relatives.
His legacy is a lesson in the unpredictability of science. A molecule designed for one disease, judged a failure and left on a shelf, became the first weapon against another disease that did not yet exist when it was made. The principle he pioneered, designing fake building blocks to sabotage the copying of genetic material, remains at the heart of antiviral medicine, used against HIV, hepatitis and herpes viruses.
For working scientists, his career carries two lessons that are still repeated in laboratories and lecture halls. The first is that a negative result is not necessarily a dead end: a compound that fails one test may be exactly what is needed for a problem nobody has yet imagined. The second, as one tribute put it bluntly, is to get the patent.
Sources & further reading
Jerome Horwitz, Wikipedia · AIDS drug AZT inventor and famed cancer scientist Jerome Horwitz dies at 93, Wayne State University · Jerome P. Horwitz, AZT developer, 93, Philadelphia Inquirer (NYT obituary) · Remembering Dr. Jerome Horwitz and AZT, Scientific American guest blog · Billions from drug bypassed creator, InvestSmart (obituary reprint) · Researched from the sources above and checked against them. Spotted an error? Tell us.
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