Medical researcher truly ahead of his time with AZT breakthrough
Jerome Phillip Horwitz,
WHEN medical researcher Jerome Horwitz first synthesised the chemical compound AZT in the 1960s, he hoped it would be a successful treatment for cancer. At first, he thought he had failed.
And in the short term, he had. AZT was not a cure for cancer. But two decades later, it emerged as a treatment for a disease that had not yet been named when Dr Horwitz was toiling in his Detroit laboratory. The disease was HIV/ Aids. In 1987, AZT became the first treatment for the virus approved by the United States Food and Drug Administration.
AZT was not a cure, and it had downsides, including sky-high costs and dangerous side effects. But it was the first treatment that significantly decreased HIVrelated mortality rates – at a time when many scientists considered HIV an untreatable disease. It later became part of a drug combination that curbed deaths even further.
Even as those ‘‘cocktails’’ were supplanted by other more effective regimens, scientists say, AZT has continued to serve as a model for treatment of the disease.
Samuel Broder, a US National Cancer Institute scientist who headed a group of scientists that helped discover the therapeutic nature of AZT in the 1980s, said: ‘‘AZT stood up and said, ‘Stop your pessimism. Stop your sense of futility. Go back to the lab. Go back to development. Go back to clinical trials. Things will work.’’’
Dr Horwitz worked for nearly five decades at Wayne State University in Detroit and the affiliated institution now known as the Barbara Ann Karmanos Cancer Institute.
His most noted achievement – the creation of AZT – began with a moment of frustration in 1964, when he was director of chemistry at the oncology institute. At that time, floundering in their efforts to find a cure for cancer, researchers were testing any drugs with even the most remote potential to see what worked.
‘‘I got tired of randomly selecting drugs for cancer, just pulling chemicals off the shelves and trying them out to see if they would work,’’ he told The Washington Post in 1986.
So Dr Horwitz decided to begin creating his own chemical compounds and testing them on cancer cells. One of them was azidothymidine (later widely known as AZT).
The compounds would work, or so he hoped, by interfering with the division and growth of cancer cells. To divide, cells use base elements called nucleosides to produce new DNA chains. Dr Horwitz referred to his compounds as ‘‘fraudulent nucleosides’’. Like chemical Trojan horses, the compounds would enter the cancer’s DNA and sabotage its growth. At least that was the idea. Scientists tested AZT in mice with leukaemia but it failed. He compared the feeling to ‘‘a blow to the solar plexus’’.
He wrote a paper on the topic, decided not to pursue a patent and put the compounds on a shelf. For two decades, they were occasionally tested for new uses, a common practice, but mostly they collected dust.
In the next decade or so, however, scientists began to understand the special viruses known as retroviruses. HIV, which causes Aids, is one of them. Together with Dr Broder and other researchers at the National Cancer Institute, the pharmaceutical company Burroughs Wellcome began testing chemical compounds that showed potential to hinder HIV. Dr Horwitz’s semiforgotten AZT compound was one of those that showed promise.
‘‘It’s a wonderful example of how science works,’’ said Robert Gallo, the founder of the Institute of Human Virology at the University of Maryland School of Medicine and a scientist who has been credited with identifying HIV as the cause of Aids.
As the deaths from HIV/Aids reached into the many thousands, the urgency for a cure grew. After AZT was tested in cell lines, the FDA deliberated for only one week before agreeing to allow it to be tested in humans.
That development was on July 3, 1985. After promising tests, the FDA licensed the treatment for commercial distribution in 1987.
The drug attracted controversy because of its high cost – US$8000 or more a year. In 1989, the New York Times wrote that it was said to be ‘‘the most expensive prescription drug in history’’.
To his chagrin, Dr Horwitz did not patent the compound and did not profit financially.
AZT was never a cure for HIV/ Aids and side effects in some patients were severe. Used alone, it decreased short-term mortality. Its real value, however, emerged when it was used in combination with two other anti-retroviral drugs in what became known as an ‘‘Aids cocktail.’’ Such combinations can stop HIV from replicating and prolong life for years. Today, however, AZT has been largely supplanted by other, less toxic drugs.
‘‘It is not an exaggeration to say that everything we have done since started with the development of AZT,’’ said Paul Volberding, the director of the Aids Research Institute at the University of California, San Francisco.
Dr Horwitz decided to pursue science after reading Paul de Kruif’s book Microbe Hunters as a teenager. He received a bachelor’s degree in 1942 and a master’s in 1944, both in chemistry from the University of Detroit Mercy, and a doctorate in organic chemistry from Michigan University in 1948. In 1956, he joined Wayne State University. He was a professor of internal medicine in the oncology division.