There was never any mistaking the path that Roeland Nusse's career would follow. As early as his high school years in Amsterdam, when a particularly engaging teacher introduced him to the still young field of molecular biology, Nusse knew that was the career for him.
Research experience in labs at the University of Amsterdam and the Netherlands Cancer Institute when he was an undergraduate further whet his appetite. His time in the University of Amsterdam lab of Piet Borst made a particularly strong impression. Using what today's scientists might consider primitive tools, the lab made groundbreaking discoveries, such as the discovery of introns in genes. "This was all before recombinant DNA, but you could still smell the excitement in the field," said Nusse. There, Nusse worked with a postdoctoral fellow who also went on to make his mark, Richard Flavell. Flavell (Yale University School of Medicine) is also currently an HHMI investigator.
In the mid-1970s, Nusse returned to both the University of Amsterdam and the Netherlands Cancer Institute to conduct his doctoral studies. At that time researchers were homing in on retroviruses as a cause of cancer, and Nusse focused his studies on a virus known to cause mammary tumors in mice.
Nusse next joined Harold Varmus's lab at the University of California, San Francisco as a postdoctoral fellow, bringing him into the forefront of cancer research in one of the most-heralded labs in the world. Varmus was among the leading proponents of retroviruses as a tumor-causing mechanism, and, together with colleague J. Michael Bishop, he had shown that a virus that causes tumors in chickens does so by altering the activity of a gene already present in normal chicken DNA. "I was very inspired by what Varmus was doing," said Nusse.
It was in Varmus's lab, in 1982, that Nusse discovered the Wnt1 gene, which was activated in breast cancer in the mouse. It later turned out to be the first member of the Wnt gene family, which now has 19 members. It was a lucky find, he says, as it has been determined by his lab that Wnt1 plays important roles in embryonic development, cell differentiation, and tissue regeneration. Subsequent work in many labs has shown that Wnt signaling is implicated in many forms of human cancer, as well. "We cloned this gene and at the time we had no clue that it would turn out to be so important," he said.
At the Netherlands Cancer Institute, where he returned as a staff scientist after his work in the Varmus lab, Nusse and his colleagues discovered that fruit flies possess a gene with similar origins and functions to the gene they had found in mice. By linking the fruit fly gene to the gene they had found in mice, Nusse showed that there was a genetic connection between normal development and cancer.
In 1990, Nusse returned to the Bay Area, taking a position in the department of developmental biology at Stanford University and becoming an HHMI investigator.
Being able to study the gene in Drosophila expanded the kinds of studies that Nusse and his colleagues at Stanford could undertake, thanks to the genetic tools and extensive data available to fruit fly geneticists. In 1996, Nusse, working with another HHMI investigator, Jeremy Nathans (Johns Hopkins University School of Medicine), identified frizzleds as receptors for wingless and other Wnt genes. Nusse's lab has also found a role for a Wnt gene in immunity in the fruit fly.
Since his initial discovery, Nusse and his lab have continued to focus on Wnt signaling. Signaling factors such as Wnt help direct embryonic cells into their specialized roles, and in adults, Wnt helps control the pace of stem cell division. "The bottom line is, almost every cell in the embryo may become a target," of Wnt signaling, said Nusse.
By studying the cells that give rise to limbs in the mouse embryo, Nusse found that Wnt encourages cells to keep dividing, while actively preventing them from differentiating into more mature cell types.
Less is known about Wnt's role in adult tissue. It is thought that the gene may also act in this dual fashion, especially in response to damage, he said.
Nusse's lab has identified Wnt proteins and Wnt signaling in the brains of mice where novel neurons have formed, suggesting a contribution to neurogenesis. The proteins and signaling have also been found in the bone marrow, accompanying the formation of new blood cells. In a series of experiments in the adult mouse, Nusse and his colleagues used naphthalene to selectively destroy Clara cells, which are known to be important for detoxification of lung cells. As the cells regenerated, the researchers were able to observe and elucidate the Wnt mechanism in Clara cell regeneration.
Two Wnt genes were expressed after the injury and only when the tissue was impaired. That suggests that injured Clara cells—and possibly other types of cells, though it is not currently known—can send signals that activate Wnt transcription, according to Nusse.
Nusse had long-suspected that Wnt proteins could be a powerful tool for manipulating stem cells in vitro, but the ability to harness that power eluded Nusse for a quarter-century—until 2002, when he discovered how to purify the proteins in an active form. His lab is now using the purified proteins as growth factors to directly manipulate stem cells.
"I'm very excited about the work we're doing with neural stem cells," said Nusse. "Some day, we may see that the mechanisms we're working on will help cure Parkinson's disease."