Caltech Biologist Will Share Nobel Prize : Science: Research sheds light on how genes control development of embryos.

TIMES MEDICAL WRITER

A Caltech biologist who was the first to explain how genes control the development of organs during the early growth of an embryo will share the 1995 Nobel Prize in physiology and medicine with researchers from Princeton University and Germany who followed up on his pioneering discovery.

Edward B. Lewis, 77, of Caltech, Eric F. Wieschaus, 48, of Princeton and Christiane Nuesslein-Volhard, 52, of the Max Planck Institute for Developmental Biology in Tubingen, Germany, received the award for explaining how an essentially shapeless fertilized egg develops into an organism with a front and back, head and feet and right and left sides.

Their discoveries "really set the agenda" for what has become perhaps the hottest area of research in biology--how genes determine the ultimate shape of humans, according to molecular biologist Ian Duncan of Washington University in St. Louis. "There has been a revolution in developmental biology that is directly attributable to their work."

Although all three worked with fruit flies, they "have achieved a breakthrough that will help explain congenital malformations in man" as well, according to the Nobel citation released Monday in Stockholm. "It is likely that mutations [in the genes they discovered] are responsible for some of the early, spontaneous abortions in [humans] and for some of the about 40% of the congenital malformations that develop due to unknown reasons."

The three winners expressed surprise and excitement at the announcement of the prize.

Lewis, who is in Ascona, Switzerland, to deliver a scientific lecture today, said he was just getting out of a taxicab and still suffering from jet lag when he learned of the award. "As you can imagine, I'm overwhelmed. It's quite a shock," he said in a statement released by Caltech. "It's very nice, but actually what is more exciting is the science. . . . It's much more exciting to get these discoveries than to win prizes."

Wieschaus said he was awakened Monday morning by a phone call from a man with a Swedish accent. "I thought he probably had a wrong number," he told a press conference. "Maybe he did, but they are not going to take it back."

Nuesslein-Volhard celebrated the announcement Monday with champagne, buttered pretzels and bouquets from her colleagues. "I am already smiling like crazy," she told reporters. "At the moment, I feel like I am in an extraordinary state." She is the first German woman to win a Nobel Prize.

The three will share a $1-million prize to be awarded in Stockholm on Dec. 10.

Lewis is one of the true fathers of developmental biology. He began his studies just after World War II by using radiation to destroy genes in the common fruit fly. The fly is prized as an experimental animal because of its short life cycle, only nine days.

Lewis and his colleagues would expose the flies to radiation, then sort through the thousands of offspring to identify unusual mutants, mating them with each other to preserve each new genetic variation. One group of bizarre mutations, called homeotic mutations, led to the appearance of normal body parts in abnormal places.

Lewis, for example, found flies that grew a second set of wings behind their normal pair. Others eventually identified mutants that grew legs on normally legless portions of the abdomen or even on the head in place of their antennae.

Examining such mutations, Lewis discovered a cluster of genes on the third chromosome that he called bithorax because it seemed to double a thoracic segment. Knocking out the genes in the cluster one at a time with radiation, he discovered that each controlled development of a different segment of the fly's body and that the genes were lined up along the chromosome in the same order as the parts of the fly's body that they control.

Genes at the beginning of the cluster switched on the development of the thorax; those in the middle controlled development in the upper abdomen; those at the end of the cluster controlled the lower end of the abdomen.

Researchers have subsequently found that virtually identical genes carrying the blueprints for body composition exist in all animal species. "One of the most striking things that has come out of molecular analysis of these genes" is that a broad variety of animals use the same genes to control the mechanism by which one gets to "a highly sophisticated adult animal from a small egg," said molecular biologist David Hogness of Stanford University.

"I think this is one of the best awards that the Nobel committee has made," he said.

Nuesslein-Volhard and Wieschaus, working together at the European Molecular Biology Laboratory in Heidelberg in the 1980s, extended Lewis' work, searching for mutations that control earlier stages of development. Eventually, they identified the genes that cause the fertilized egg of the fruit fly to develop into an ordered pattern of segments that controlled the overall shape of the fly. The genes previously found by Lewis regulated the ultimate anatomical fate of each segment.

"Taken together, what their work describes is a genetic program that leads to the differentiation of cells, generating an organism with different segments and organs," said Mel Simon, chair of Caltech's division of biology.

Although Lewis is now formally retired, "he still comes in every day, and works evenings and weekends too," said Susan Celniker, a senior research associate at Caltech who has worked with him for 12 years. "He works harder than most graduate students."

And his work is still on the cutting edge of developmental biology, added Simon. "We hope we can get another 10 to 15 years out of him."

Times staff writer Mary Williams Walsh contributed to this story from Berlin.

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The Winners in Medicine

Two Americans and a German shared this year's Nobel Prize for their pioneering discoveries about the genes that control the formation of body parts in a developing embryo. Those genes transform a shapeless egg into a well-defined fetus that has a head and feet, left and right sides and distinct organs. The discoveries should provide insight into congenital malformations in human embryos.

* Name: Edward B. Lewis

* Age: 77

* Country: U.S.

* Institution: Caltech

* Fact: Twenty-third Caltech faculty member or alumnus to receive Nobel.

****

* Name: Eric F. Wieschaus

* Age: 48

* Country: U.S.

* Institution: Princeton University, N.J.

* Fact: Wieschaus was left out when the other two won the prestigious Lasker Award for the same research in 1991.

****

* Name: Christiane Nuesslein-Volhard

* Age: 52

* Country: Germany

* Institution: Max Planck Institute for Developmental Biology, Tubingen

* Fact: First German woman to win a Nobel.

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