Sunday, April 10, 2011

Dayenu, Coming Home - The Fountainheads Passover Song

W. H. Prusoff, Who Developed AIDS Drug, Is Dead at 90

William H. Prusoff, a pharmacologist at the Yale School of Medicine who, with a colleague, developed an effective component in the first generation of drug cocktails used to treat AIDS, died on Sunday in New Haven. He was 90 and lived in Branford, Conn.

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William H. Prusoff worked at the Yale School of Medicine.
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George Ruhe for The New York Times

The death was confirmed by his son, Alvin.

Dr. Prusoff spent most of his long career studying molecular derivatives of thymidine, a building block of DNA. His work led him to develop two important antiviral drugs.

In the early 1950s, he synthesized idoxuridine, a successful treatment for infant keratitis. The condition, an inflammation of the cornea caused by the herpes simplex virus, was the leading infectious cause of blindness. Idoxuridine disrupted the virus’s ability to reproduce.

This was an important breakthrough. At the time, it was believed that antiviral agents powerful enough to be effective would be too toxic for human use and that those safe for use would be too weak to counteract a virus.

Idoxuridine overturned medical dogma and, after winning approval by the Food and Drug Administration, became the first clinically used antiviral drug. For this reason, Dr. Prusoff is sometimes called the father of antiviral chemotherapy.

In the mid-1980s, as the AIDS epidemic spread, Dr. Prusoff and a Yale colleague, Tai-shun Lin, began looking at thymidine derivatives that had been developed to treat cancer but discarded when they proved ineffective. One of these was stavudine, also known as d4T, a molecular cousin of the first AIDS drug, AZT. Both had been synthesized in the 1960s by Dr. Jerome P. Horwitz at the Michigan Cancer Foundation, now the Karmanos Cancer Institute, in Detroit.
Dr. Prusoff and Dr. Lin resynthesized the molecule and found in laboratory tests that it short-circuited the viral enzyme in H.I.V., causing it to produce short, incomplete pieces of DNA rather than complete strands.

Yale took out a patent in the doctors’ names and licensed it to Bristol-Myers Squibb for development. In 1992, it became the first drug to be tested under the F.D.A.’s parallel-track policy, which allowed patients with life-threatening illnesses to obtain drugs undergoing clinical trials.

After F.D.A. approval, stavudine was brought to market in pill form in 1994 and sold under the brand name Zerit. It joined three other drugs, known as nucleoside analogs, approved for treating H.I.V.: zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC). Eventually, these were joined by a new generation of drugs known as protease inhibitors.

Because of its potential side effects, notably numbness, burning sensations and loss of fat in the feet, legs or hands, the drug is now used primarily in poor countries, where it is cheap and widely available.

Stavudine earned tens of millions of dollars for Yale each year — more than the total amount for all its other licensed medicines combined. It also made millions for Dr. Prusoff, who became a vocal supporter of a campaign initiated by Doctors Without Borders to persuade Bristol-Meyers to lower the drug’s price in sub-Saharan Africa, where AIDS was rampant.

In March 2001, the company announced that it was reducing the price of the drug in Africa to 15 cents for a daily dose, from $2.23, and removing barriers to the sale of generic equivalents there.

“We weren’t doing this to make money,” Dr. Prusoff told the Yale School of Medicine Chronicle. “We were interested in developing a compound that would be a benefit to society.”
William Herman Prusoff, known as Bill, was born on June 25, 1920, in Brooklyn. His parents, Jewish immigrants from Russia, ran a small grocery.

He earned a degree in chemistry from the University of Miami in 1941. Rejected by the Army because of his poor vision, he spent World War II inspecting fuses at a munitions factory in Memphis and, as a health inspector, checking the water supply and the kitchens in Miami Beach hotels where pilots were billeted.

Urged by his parents, he applied to medical school, without success. He later enjoyed recalling that Yale deemed him so unqualified that it refunded his application fee in a gesture of pity.

Instead, he earned a doctorate in chemistry from Columbia in 1949 and then taught pharmacology in Cleveland at Western Reserve University (now Case Western Reserve) before joining the pharmacology department at Yale in 1953.

Dr. Prusoff used some of his patent money to create the William H. Prusoff Foundation, which supported numerous programs, including the Yale Initiative for the Interdisciplinary Study of Anti-Semitism. He also endowed lectureships in virology and pharmacology at Yale and several scientific prizes.

In addition to his son, Alvin, of Fairfield, Conn., he is survived by a daughter, Laura, of Ortahisar, Turkey, and three grandchildren.

Thursday, April 7, 2011

Baruch Blumberg, Who Discovered and Tackled Hepatitis B, Dies at 85

Dr. Baruch S. Blumberg, the Nobel Prize-winning biochemist and medical anthropologist who discovered the hepatitis B virus, showed that it could cause liver cancer and then helped develop a powerful vaccine to fight it, saving millions of lives, died Tuesday in Moffett Field, Calif. He was 85 and lived in Philadelphia.

His family said he died, apparently of a heart attack, shortly after giving a keynote speech at a NASA conference at the Ames Research Center in Moffett Field, which is in the San Francisco Bay area. Dr. Blumberg had long been associated with a NASA project to hunt for micro-organisms in space.

Dr. Blumberg’s prize-winning virology and epidemiology work began in the 1960s at the Fox Chase Cancer Center in Philadelphia and took him and his colleagues on field trips around the world, from Japan to Africa.

The work led to the discovery of the hepatitis B virus in 1967, the first test for hepatitis B in the blood supply and the development in 1969 of the hepatitis B vaccine — the first “cancer vaccine.” Dr. Irving Millman, a colleague at the research center, was its co-creator.

Dr. Blumberg’s discoveries have been compared to those of Jonas Salk, the developer of the polio vaccine. He shared the Nobel Prize in Physiology or Medicine in 1976 with D. Carleton Gajdusek for their work on the origins and spread of infectious viral diseases. (Dr. Gajdusek had discovered the cause of the kuru, or “trembling disease,” prevalent in New Guinea.)

Almost 20 years later, after decades of hepatitis B-related studies and a global search for medicinal plants to treat hepatic infections, Dr. Blumberg began what he called his second career. In 1999 he became the founding director of the National Aeronautics and Space Administration’s Astrobiology Institute.

The institute’s mission was to oversee research teams in the development of life-detecting devices for planetary rovers and asteroid fly-bys, and to scrutinize life forms in “extreme” environments on Earth, like the ocean bottom and the geothermal cauldrons that produce geysers. He joined several expeditions himself.

To these seemingly disparate endeavors — investigating disease-causing organisms and postulating alien or primordial life forms — Dr. Blumberg contributed a broadened understanding of the evolutionary phenomenon called polymorphism, in which a species can adapt to an environment through changes in appearances and functions.

From his base in Philadelphia, Dr. Blumberg began investigating viruses with a study of yellow jaundice, so named because of the characteristic vivid yellowing of the eyes and skin. As early as 1940, medical researchers had determined that there were two different forms of virus-induced jaundice, one that is transmitted as an intestinal infection, and the other spread mainly by blood transfusions.

Scientific field trips to pinpoint the agent responsible for blood-borne jaundice were conducted by Dr. Blumberg and his colleagues in the Philippines, India, Japan, Canada, Scandinavia, Australia and Africa. Ultimately it was blood serum from an infected Australian aborigine that yielded the so-called Australian antigen, a protein found on the surface of the hepatitis B virus.

After he and Dr. Millman developed the hepatitis vaccine, they struggled to interest a pharmaceutical company to help develop and produce it.

“Vaccines are not an attractive product for pharmaceutical companies in that they are often used once or only a few times and they ordinarily do not generate as much income as a medication for a chronic disease that must be used for many years,” Dr. Blumberg wrote in an autobiographical essay for the Nobel committee.

Moreover, he said, the medical research community in the early 1970s remained skeptical about the claim that a virus had been identified and a vaccine developed.

Ultimately he and Dr. Millman signed an agreement with Merck & Company, whose vaccine laboratories were near Philadelphia.

Dr. Blumberg’s discoveries are credited with saving millions of patients from ever developing liver cancer. But in his scientific autobiography, “Hepatitis B: The Hunt for a Killer Virus” (Princeton University Press, 2002), he observed ruefully that hepatic disease was still killing 1.5 million people a year worldwide — despite the widespread availability of the vaccines he helped develop — and that 350 million were chronically infected.

Still, he was hopeful. “Life — and death — are full of surprises,” he wrote, “and while it may be tempting fate to be too optimistic, it appears likely that within the next few decades this virus will be effectively controlled.” (There is still no vaccine for the blood-borne hepatitis C, one of the five known hepatitis viruses.)

Dr. Blumberg’s traced his fascination with inherited variations in susceptibility to disease to the volunteer service he did during medical school at an isolated mining town in northern Surinam, where he delivered babies, performed clinical services and undertook the first malaria survey done in that region.

He was particularly interested in the sugar plantation workers who had been imported from several continents.

“Hindus from India, Javanese, Africans (including the Djukas, descendants of rebelled slaves who resided in autonomous kingdoms in the interior), Chinese, and a smattering of Jews descended from 17th century migrants to the country from Brazil, lived side by side,” Dr. Blumberg wrote in his Nobel essay. “Their responses to the many infectious agents in the environment were very different.”

He wrote his first scientific paper based on these studies and would revisit the tropics repeatedly. “Nature operates in bold and dramatic manner in the tropics,” he wrote.

By the late 1990s Dr. Blumberg was immersed in astrobiology, as NASA called the new science. Appointed by the NASA administrator, Dan Goldin, to lead the Astrobiology Institute, Dr. Blumberg and his team were asked to address three profound questions: How does life begin and evolve? Does life exist elsewhere in the universe? And what is life’s future on Earth and beyond?

As in his disease studies, Dr. Blumberg sought collaborations with specialists in a variety of fields, including physics, chemistry, geology, paleontology and oceanography as well as biology and medicine that would “help us to recognize biospheres that might be different from our own.”

While urging the development of instrumentation for astrobiological space probes, Dr. Blumberg recommended equal efforts in the study of earthly “extremophiles,” the organisms that somehow thrive in extreme temperatures, pressures and chemical conditions.

In fissures in the deep ocean floor, Dr. Blumberg said, are extremophiles that might resemble the earliest life forms on Earth or other planets. He described Earth as “a place of extremes” during the first few hundred million years of its 4.5-billion-year existence, given to radical climate fluctuations, from searing heat to immobilizing cold, amid constant meteorite bombardments and catastrophic volcanic eruptions.

He speculated that life might have started on Earth at geothermal sites, either underground or in the sea. The NASA venture — since diminished by administrative changes and financing cutbacks — was welcomed by those who advocate a search for extraterrestrial intelligence, known as SETI, and call the science “exobiology.” Dr. Blumberg joined the board of the SETI Institute in Mountain View, Calif.

But in an interview with The New York Times in 2002, he said he would be “very surprised if we found something in space, that it would look like E.T.”

“If we found something more like a virus or a bacteria,” he said, “that would be astounding enough.”

Baruch Samuel Blumberg (Barry to his friends) was born in New York City on July 28, 1925, the second of three children of Meyer Blumberg, a lawyer, and Ida Blumberg. After attending the Yeshiva of Flatbush in Brooklyn, he went to Far Rockaway High School in Queens (whose graduates also include the Nobel physicists Richard Feynman and Burton Richter).

His undergraduate studies at Union College in Schenectady, N.Y., were interrupted by World War II, when he served as a Navy deck officer on landing ships. Returning to Union College, he completed a bachelor’s degree in physics, enrolled in graduate studies of mathematics at Columbia and transferred to Columbia’s College of Physicians and Surgeons, earning his M.D. there in 1951.

Dr. Blumberg served a clinical fellowship at Columbia Presbyterian Medical Center, went to Oxford University’s Balliol College for a doctorate in biochemistry, and returned to the United States in 1957 to join the National Institutes of Health, where he headed the Geographic Medicine and Genetics Section until 1964.

Most of his research afterward was conducted at the Fox Chase Cancer Center. Dr. Blumberg was also on the faculty of the University of Pennsylvania and its School of Medicine as a professor of medicine, medical genetics and medical anthropology.

Dr. Blumberg married Jean Liebesman, an artist, in 1954. She survives him, as do two daughters, Anne Blumberg of Boston and Jane Blumberg of Oxford, England; two sons, George, of Oxford, and Noah, of Chevy Chase, Md.; and nine grandchildren.

Dr. Blumberg saw his Nobel as more than an act of recognition. He said it helped draw renewed attention to his work with enormously beneficial consequences. After receiving the prize, he said, he was invited to China. “I spoke before several thousand people,” he told The Times in 2002. “I provided them with a copy of the patent, and now I’m told that it helped to change the direction of what they were doing and led to the saving of a lot of lives.”

Saving lives, he said, was the whole point of his career. “Well, it is something I always wanted to do,” he said. “This is what drew me to medicine. There is, in Jewish thought, this idea that if you save a single life, you save the whole world, and that affected me.”