From a fruit fly’s wings, they learned how bodies are built

The wingtips of a fruit fly are as round as a butter knife. But when a fruit fly carries a certain mutation, its wings form with irregular notches.

That mutation, linked to a gene on the fly’s X chromosome, was first noticed by geneticists more than a century ago. What no one realized then was this was a clue to one of the key mysteries of life: How do animals, including humans, develop from a single fertilized egg?

The answer involves a molecular messaging system called Notch signalling, after the fly wings, which cells use to co-ordinate the building of a body.

“If you have one cell that decides to become something and, as a consequence of that, the cell next door decides to become something else, these cells have to be talking to each other,” said Spyros Artavanis-Tsakonas, a professor emeritus of cell biology at Harvard Medical School in Boston, whose work was key to discovering how the system works.

Born in Greece, Dr. Artavanis-Tsakonas studied chemistry as an undergraduate. But when the opportunity arose in 1972 to do a PhD in molecular biology at Cambridge University in England, he was hooked.

Cambridge was then at the focal point of a scientific renaissance as biologists deployed new molecular tools to understand cell development and function. Surrounded by past and future Nobel Prize winners, Dr. Artavanis-Tsakonas said the experience was life-changing. “Even if you were a complete idiot, by osmosis you’d get something,” he said.

His training provided the impetus to take on the Notch gene during postdoctoral stints in Europe and the United States. By the 1980s when he was an assistant professor at Yale University, he and his colleagues had successfully cloned and then sequenced the gene, setting the stage for its further investigation.

A key insight from this work was that the gene carried instructions for making a protein that resides on the cell membrane. This was a sign that the protein was involved in exchanging information with other cells, a possibility that had also been discovered by Iva Greenwald.

A native of Brooklyn, Dr. Greenwald earned her PhD at MIT where she, too, became interested in how genes orchestrate development. But rather than working with fruit flies she was drawn to a simpler organism – the roundworm – as a basis for studying cellular processes.

This led her to a gene called lin-12 that performs the same function in roundworms as Notch does in fruit flies. While doing postdoctoral work at Cambridge she further discovered that some of its components were similar to those found in human cells. Here was an exciting hint that something more universal was at work.

“Just knowing if I kept working I might discover something else new and unexpected was thrilling,” Dr. Greenwald said.

Through the 1980s, Dr. Greenwald continued working on the idea that the lin-12 protein operated like a switch that could steer a cell’s fate based on the signal it received from a neighbouring cell. In this way, cells destined for different functions would know which path to take.

By 1991, she was at Princeton University and had teamed up with Gary Struhl, a developmental biologist and fellow New Yorker whose academic journey had similarly included time at MIT and Cambridge before he became a professor at Columbia University.

He was also her husband – Dr. Greenwald and Dr. Struhl had married only months before, but now they discovered they had a shared professional interest in establishing how the Notch/lin-12 system worked.

Aided by methods that Dr. Struhl had previously developed to study other genetic pathways in fruit flies, their collaboration led to the discovery of an elegant molecular pathway that would prove to be common to animal cells.

The pathway begins with the receptor that resides on the cell’s membrane. During communication, it can be latched onto and pulled by a counterpart structure on a neighbouring cell. This allows the receptor to be cut, triggering the release of an interior component that makes its way to the cell’s nucleus. There, it interacts with the cell’s DNA to promote particular genes, such as those that can determine the cell’s destiny.

Variants in the human version of Notch genes have been linked to forms of cancer and neurodegenerative disease. Researchers have also imitated the mechanism to create a synthetic version of Notch signalling for new therapies and for engineering new tissues.

Dr. Struhl said the applications opened up by the discovery underscore the values inherent in basic research, particularly involving organisms such as roundworms and fruit flies, which allow ideas about gene function to be tested.

“For me, the award represents the recognition and justification of these values,” he said.