Spyros Artavanis-Tsakonas in the lab. Image: Samantha Apple
Spyros Artavanis-Tsakonas, professor of cell biology, emeritus, in the Blavatnik Institute at Harvard Medical School, has received a prestigious 2025 Canada Gairdner International Award. He is being recognized for his research on Notch, a cell signaling pathway involved in many biological processes and implicated in diseases ranging from cancer to neurodegenerative disorders. The pathway is highly conserved across species, including humans.
The Gairdner Awards, which celebrate scientists who have made seminal discoveries or contributions to biomedical research, were announced on April 11. Artavanis-Tsakonas is honored along with Iva Greenwald, professor of biological sciences at Columbia University, and Gary Struhl, the Herbert and Florence Irving Professor at the Zuckerman Institute and professor of genetics and development and neuroscience at Columbia. Artavanis-Tsakonas and Greenwald also won the 23rd Annual Wiley Prize in Biomedical Sciences for their work on Notch.
Through his decades of research in fruit flies and mice, Artavanis-Tsakonas has deciphered key aspects of the basic biology of Notch, including molecular details of the pathway, interactions of genes that control it, and its influence on embryonic development. Now, Artavanis-Tsakonas has turned his attention to Notch’s role in neurodegenerative diseases.
Driving development in fruit flies, fish, and humans
Notch was identified in the early 1900s as a mutation that causes notches in fruit fly wings. Over time, it became clear that Notch acts as a molecular communication system that affects many aspects of development. Notably, the system directs how cells become specialized to perform certain functions, and it is present in all multicellular animals.
“This pathway is highly conserved in evolution and is profoundly important for the development of animals, whether you’re a fruit fly, a fish, or a human,” Artavanis-Tsakonas said.
He first learned about Notch from a 1970 review paper that he read as a young scientist. The paper described Notch as the single most important gene for embryonic development in fruit flies — a powerful statement that intrigued him.
“That made a huge impression on me,” Artavanis-Tsakonas recalled. “I was inspired to work on Notch and went on to study it for my entire career.”
A breakthrough came in the mid-1980s, when Artavanis-Tsakonas and colleagues figured out how to clone the Notch gene location in fruit flies. This gave scientists the ability to explore the molecular biology and genetics of Notch, enabling them to dig into the pathway’s role in cell communication, development, and disease.
Artavanis-Tsakonas became especially interested in how Notch drives development in such diverse species and plays a role in such a vast array of cell functions.
“For me, how the same signaling pathway integrates in so many different ways to drive diverse developmental outcomes is one of the biggest questions in biology,” Artavanis-Tsakonas said.
One exciting moment in his research came after sequencing the Notch gene, when Artavanis-Tsakonas discovered that the gene encodes a receptor that spans the cell membrane. This positioning allows the receptor to transmit signals from the external environment to the cell interior, creating a pathway for Notch to communicate directly with nearby cells and exert influence on their development.
“The way cells control the Notch signal is extremely important for biology and pathology, so we have been essentially working to dissect the pathway by identifying its core components and defining its complex genetic architecture,” Artavanis-Tsakonas said.
Meanwhile, Greenwald discovered the Notch genes in the worm C. elegans and figured out how to clone them. She also identified components of the Notch pathway that are conserved across species. Later, Greenwald and Struhl used fruit flies to work out much of the biochemical mechanism that Notch uses to communicate with the nuclei of nearby cells and turn gene activity on and off.
In recent years, Artavanis-Tsakonas and colleagues have focused on identifying and studying the complex interplay among the hundreds of genes that can modulate Notch activity. To learn about this genetic circuitry, the Artavanis-Tsakonas lab built a map of interactions across the proteins they encode. Understanding this interplay can help scientists unravel how the Notch pathway controls cell fates during development.
“This has been quite interesting because it allows us to think about Notch within the whole system of a cell,” said Artavanis-Tsakonas. He added that Notch’s critical role in development means that overactive or underactive signaling often leads to disease.
As of late, Artavanis-Tsakonas, whose lab is now merged with the lab of David Van Vactor, professor of cell biology at HMS, has shifted to studying Notch within the context of neurodegeneration. In particular, he is focusing on genetic factors related to Notch that are involved in amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s, and spinal muscular atrophy.
Artavanis-Tsakonas considers his research to be curiosity driven and basic in nature. He added, however, that “basic biology is the mother of novel therapeutic approaches and part and parcel of developing new drugs.”
In the case of Notch, he noted, understanding the pathway’s role in various diseases could provide new avenues for developing therapies.
Over the years, Artavanis-Tsakonas estimates that the handful of labs studying Notch have multiplied to more than a hundred that work on the pathway in some way.
“Notch is involved in so many aspects of biology that you stumble upon it, whether you like it or not. It has become a genuine field in biology,” he said.
For him, Notch has proven an endlessly fascinating topic — one that has provided a rich groundwork for his decades-long career.
“My motivation is simple: To answer the next question. That’s it.”
