By William J. Cromie

Gazette Staff

Mark Ptashne, who showed that humans and yeast have a lot in common, has won the 1997 Albert Lasker Award for medical research.

Lasker Awards are the most prestigious awards in medical research given in the United States. Many recipients go on to win Nobel Prizes.

Ptashne, the Herchel Smith Professor of Molecular Biology, will receive $25,000, an inscribed statuette, and a citation highlighting his 30 years of work on understanding how genes work.

Officials of the Albert and Mary Lasker Foundation will present awards tomorrow at a luncheon in New York City. Along with Ptashne, Victor McKusick of Johns Hopkins University will be honored as the founder of medical genetics, a new field that has led to the mapping of thousands of genes. A third Lasker Award will go to Alfred Sommer, also of Johns Hopkins, for his discovery that vitamin A supplements can prevent blindness and life-threatening infections in children.

"The award covers two phases of work that I've been doing at Harvard for decades," Ptashne says. "First, my colleagues and I showed how genes are switched on and off in a simple virus that grows in bacteria. Then we demonstrated that essentially the same mechanism works in yeast and higher organisms, including humans."

The occasion also marks Ptashne's departure from Harvard. He will leave shortly to take an appointment as Ludwig Professor of Molecular Biology at Memorial Sloan-Kettering Cancer Center in New York City.

A Key Discovery

Ptashne came to Harvard from Reed College in Portland, Ore., in 1961. He became a Junior Fellow in the Society of Fellows in 1965.

Two years later, Ptashne isolated a curious protein from a virus that infects bacteria. The protein, called "lambda repressor," controls genes in bacteria that the virus invades and uses to reproduce itself. Ptashne and Nancy Hopkins, now at M.I.T., found that the protein works by attaching to a specific site on DNA, the material of which genes are made.

For this achievement, Ptashne shared Harvard's 1968 Ledlie Award with Walter Gilbert, now Carl M. Loeb University Professor. In 1971, Ptashne went from lecturer to professor in a single promotion.

Ptashne then collaborated with other researchers, including Stephen Harrison and Thomas Maniatis, to find out how the protein was able to do what it did. Harrison is now professor of biochemistry and molecular biology; Maniatis was named last week as the first Thomas H. Lee Professor of Molecular and Cellular Biology.

"We determined that the proteins that regulate genes work like keys that fit specific locks, or chemical sequences, on DNA," Ptashne explains. "After this binding occurs, the protein key must also interact with other binding proteins to turn the gene on or off."

The Key Fits Many Locks

By the 1980s, Ptashne and his laboratory team began experiments to determine whether genes are controlled in the same way in higher animals. They started with yeast. That doesn't sound like a big leap up the evolutionary ladder. However, yeast, like humans but unlike bacteria, have their genes neatly folded and packed into nuclei at the center of their cells. It's possible to change these genes in the laboratory the way they might be changed in natural situations, such as during reproduction and development.

"We didn't know if a whole new principle was needed to explain how genes are activated in such organisms," Ptashne recalled. "We were delighted to find that proteins like lambda repressor do the same thing in yeast as they do in bacteria, that is, bind to specific DNA sites, interact with other binding proteins, then turn genes on or off."

The same type of experiments were done with fruit flies, plants, and human cells, and the same mechanism worked every time.

"This mechanism explains gene activation throughout nature," Ptashne comments. "It's astonishing the extent to which the molecules found in bacteria and yeast are the same or similar to those in humans. Things could have happened differently, but once evolution got the process right, there was no point in changing it."

These results make it clear that many genetic diseases stem from key molecules not locking onto DNA properly. They include developmental disorders that lead to dwarfism and mental retardation.

Human cells can harbor cancer-causing genes which may be turned on, via lock-and-key proteins, by chemicals, radiation, or other signals from the environment. Other genes, which protect cells against the uncontrolled growth that characterizes cancer, are sometimes repressed by such proteins. Included are tumors of the breast, brain, and eye.

The fact that these findings led to a new understanding of cancer was recognized by the General Motors Cancer Research Foundation when it awarded Ptashne its Sloan Prize in 1990.

Leaving Harvard

In 1986, Ptashne wrote A Genetic Switch to explain how gene regulation works. Now in its second edition, the book is still popular among students and researchers worldwide. Many of the latter, who worked as students or postdoctoral fellows in Ptashne's lab, are now prominent scientists at the Medical School, M.I.T., the University of California at Berkeley and at San Francisco, and other research institutions.

A gift of $2.5 million from a British biochemist and philanthropist established the Herchel Smith professorship in molecular biology, to which Ptashne was appointed in 1993. Ptashne has invited Smith to visit his lab, but he has yet to meet his reclusive benefactor.

Although Ptashne thinks of Harvard as "a wonderful place, with colleagues and an atmosphere that are the best in the world," research support and outside interests have motivated him to leave.

"It's gotten more and more difficult to support a research laboratory with grants," he says. "You become like a politician; when you get funds, the only thing you can think about is how to get the grant renewed. It got to the point where it was not clear that I could work here with the peace of mind and freedom that suits my style. Sloan-Kettering Cancer Center has accumulated a large amount of money to spend on basic research, and they seem determined to promote first-rate science."

Ptashne, 57, also is drawn to New York City by interests in music and art, and the fact that he married a New York attorney, Lucy Gordon, three years ago.

The violin is one of Ptashne's passions. He studied at the New England Conservatory of Music in Boston, and he looks forward to studying and playing in New York.

With the reduced pressure to raise money for his laboratory, Ptashne intends to continue basic research on lowly animals, research that he expects will produce high dividends in medical knowledge.

"The emphasis on defining the entire human genome makes basic work on simple organisms more significant than it ever was," he says. "When we look in human genes, we find the same, or similar, molecules as in bacteria, yeast, worms, and fruit flies. And we can carry out experiments that allow us to change these molecules, something we cannot, of course, do with humans. Paradoxically, what we learn from such experiments represents progress in better understanding human development and disease."