Andreas Hochwagen joins Whitehead Fellows program

CAMBRIDGE, Mass. (May 15, 2006) — Cell division is a tricky process, one that’s driven by some pretty heavy back-end calculus. If anything goes wrong in the equation, the resulting daughter cells can be plagued by genetic mistakes that lead to birth defects or cancer. Fortunately, our cells have installed surveillance mechanisms that guard against this. New Whitehead Fellow Andreas Hochwagen, who begins his Whitehead appointment on May 15, is determined to discover exactly how our cells guide this essential biological process.

“This is such an important aspect of basic biology,” says Hochwagen. “Understanding the mechanisms of cell division will provide us with tremendous insight into other health conditions and biological functions.”

Hochwagen, who received his PhD this year from MIT, comes to Whitehead from the laboratory of Angelika Amon, a former Whitehead Fellow who is now an Associate Professor of Biology at MIT and a Howard Hughes Medical Institute Investigator. While working in her lab, Hochwagen published a paper last fall in the journal Cell demonstrating that a widely used drug may be meddling with meiosis, the process by which gametes, i.e., egg and sperm cells, are created.

With the exception of gametes, all cell’s in our body contain two sets of chromosomes, one from our father, one from our mother. Gametes, however, contain only one copy of each chromosome. Only a small population of cells in our body, called germ cells, are able, through meiosis, to produce egg and sperm cells. This requires many additional steps, which in turn increases the likelihood of error.

“Meiosis requires lots of breaking up and reshuffling of the chromosomes,” says Hochwagen. “It can get very messy.”

Luckily, our cells constantly monitor the integrity of DNA. If mistakes are found, the cells repair these mistakes prior to further division. These mechanisms are called “checkpoints.”

Early in Hochwagen’s graduate work, he decided that yeast would be the perfect testbed for understanding how these checkpoints work. While yeast cells are obviously not in the business of creating sperm and eggs, they still undergo meiosis when they reproduce.

As Hochwagen was screening these cells to find genes and proteins that acted as checkpoints, one item jumped out: A key protein involved in safeguarding meiotic cell division also is a target for rapamycin, a widely used immunosuppressant drug given to transplant recipients.

Hochwagen then created a population of mutant yeast cells with no ability to repair damaged DNA. “As a result, as soon as DNA damage occurred, a strong checkpoint response was triggered in the cells preventing any further division,” he says.

Next, he treated those mutant cells with rapamycin, and the result was unsettling. Within an hour of treatment, the cells began to divide again, passing on all DNA mistakes to the subsequent generations. Clearly, something in rapamycin either overrode the checkpoint response, or disabled it altogether. This suggests that patients taking rapamycin may lack an essential component for curbing the effects of DNA damage that occurs during meiosis.

“This is pretty scary, because many people who take this drug take it for life,” says Hochwagen. “This could result in lower fertility, or in birth defects such as Downs syndrome.”

At Whitehead, Hochwagen plans to follow up on these results and to delve into the deeper question of how cells repair genetic damage. “The process of repairing broken DNA is huge,” he points out. “The cell needs to scan the entire genome for the correct base pairs that can fix the break. Scientists really aren’t very clear on how this all works. With yeast, we’re now in a position where we can address these questions.”

“I admire Andreas’ creativity, his scientific acumen and productivity, and his ability to find his own way at this early juncture in his career,” says Whitehead Director David Page.

“I’m delighted to see Andreas join the Whitehead Fellows program,” says Angelika Amon. “His scientific instincts are exemplary, and I have no doubt he’ll make great contributions to the Institute.”

Whitehead Fellows are postdoctoral researchers of exceptional promise who are given the space, resources and support needed to start and run their own labs, without traditional faculty responsibilities. Hochwagen, who came to the U.S. in 2000 from Austria, will join four other current Whitehead Fellows: Thijn Brummelkamp, Fernando Camargo, Hui Ge, and Paul Wiggins.