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NIDDK's Hennighausen Wins von Humboldt Award

By Anna Maria Gillis

The award came out of the blue. NIDDK's Dr. Lothar Hennighausen had no idea he was a candidate. He didn't even know the man who nominated him for an Alexander von Humboldt Research Award. But thanks to Dr. Axel Ullrich, a researcher at the Max Planck Institute for Biochemistry in Martinsried, Hennighausen is off to Germany for a sabbatical beginning in July.

Ullrich, who will be Hennighausen's host, nominated the chief of NIDDK's Laboratory of Genetics and Physiology for the award last year. Sponsored by Germany's Alexander von Humboldt Foundation, the awards recognize approximately 150 foreign scholars each year for their accomplishments. The award, which is given in all disciplines of science, engineering and humanities, is named for the 18th-century German naturalist and explorer.

NIDDK's Dr. Lothar Hennighausen leaves next month
for a sabbatical in Germany.

Hennighausen says it is "an honor to be singled out by Ullrich," an expert on breast cancer, who led the group at Genentech that developed Herceptin, the first recombinant drug to combat breast cancer. Ullrich also cloned the human insulin gene and the insulin receptor, and he made pioneering studies on the way different molecular signaling pathways "talk" to each other.

These areas interest Hennighausen, who, with his colleagues, determined key signaling pathways that control mammary gland formation. Mammary tissue, which is relatively new in evolutionary terms, gets its cue to take shape from a signaling pathway called Jak2-Stat5 that is activated by the hormone prolactin. It is one of the many variants of Jak-Stat pathways that rely on the interaction of Jak and Stat proteins to activate genes. Jak2 is a tyrosine kinase, an enzyme that adds phosphates to the amino acid tyrosine in other proteins. In the case of Stat5 molecules, once they are phosphorlyated by Jak-2 and paired with another phosphorlyated Stat5 protein, they travel to the nucleus to activate genetic programs that cause milk-secreting cells in the mammary gland to grow and differentiate.

Understanding the signaling pathways that drive mammary tissue changes "provides a unique opportunity to develop molecular interventions and prevention for breast cancer," says Hennighausen.

Given that he'll be free to study whatever he wants, Hennighausen has decided to tackle something ambitious. "I want to design small molecules that will disrupt the Jak-Stat pathway."

To activate the genes governing mammary tissue production, "you need a dimer of Stat5," adds Hennighausen, who wants the small molecule he creates to prevent such pairings. He hopes that collaboration with Ullrich, who has formed a company that makes tyrosine kinase inhibitors, will give him a good start.

However, the goal of this exercise is not only to make a therapeutic drug. If it is successful, it also might make research requiring mouse models easier and far less expensive. It can take years and cost tens of thousands of dollars to create mice that lack a gene to make a particular protein. "Ideally, we would like to use pharmacogenetics to inactivate proteins," says Hennighausen. If a pharmacological approach worked, scientists "could simulate a knockout, but not go through the creation of a traditional gene knockout mouse."

Hennighausen acknowledges that "it's risky to fool around with new ideas," and sometimes the day-to-day demands of administering a lab make it hard to find the time. He's looking forward to a year where he can try a different focus. "It's good to learn something new and be a student again."

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