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Past Winner
2004 NSERC Doctoral Prize

Marie Evangelista

Cell Biology

Queen's University

It was seeing sexual impotence in yeast that gave Marie Evangelista the first hint that something was up with a gene called Bni1.

This intimate insight led the recent Queen's University Ph.D. recipient to the discovery of a protein that's key to how cells get their shape and divide, and earned her a 2004 NSERC Doctoral Prize – one of Canada's premier awards for new doctoral graduates.

The finding has implications for areas from understanding how bacteria hijack and steer human cells, to how cancer cells spread.

Eukaryotic cells (those with a nucleus), whether yeast or human, have an internal skeleton made up of molecules of actin linked together in long chains, or filaments. For decades, cell biologists have known that the actin filaments are arranged in two ways depending on their function: branched, similar to a tree, or bundled together like a group of wires.

In the late 1990s, researchers discovered a protein complex, Arp2/3, that controls the assembly of branched actin structures.

"But how actin bundles are generated in living cells remained a mystery," says Dr. Evangelista.

Many molecular biologists, including Dr. Evangelista and her supervisor and close collaborator Dr. Charlie Boone, assumed that Arp2/3 also regulated the creation of actin bundles. The question was how? She hypothesized that its activity was regulated by another gene, Bni1. Using yeast, the simplest eukaryote, Dr. Evangelista deleted the Bni1 gene to see what would happen.

"If you knock out Bni1 in yeast, the yeast no longer form mating projections, so they can't change shape to mate," says Dr. Evangelista from San Francisco where she's a postdoctoral researcher at Genentech Inc. "But there are a lot of molecules that control how actin filaments are arranged. We didn't know at what level of organization Bni1 was working."

It turns out Bni1 is the central actor.

After four years of doctoral work laboriously searching for the molecular pathway joining Arp2/3, Bni1 and actin, Dr. Evangelista decided to test yeast-derived Bni1 protein directly with actin molecules. Finally, she was able to add her purified Bni1 and actin proteins together.

"I didn't think anything would happen," recalls Dr. Evangelista. But when she tested the mixture, she found that in the presence of Bni1 protein, actin filaments could form at a much faster rate than without Bni1.

She called over Dr. Boone. "We were kind of in awe. We just sat there. We knew right away that this was a big finding. I think I looked at him and said, 'I guess I can graduate pretty soon, this is my ticket," says Dr. Evangelista.

The results were published to acclaim in Science in 2002, in collaboration with Drs. David Pruyne and Anthony Bretscher from Cornell University, and Dr. Sally Zigmond from the University of Pennsylvania.

Since then other researchers have demonstrated that Bni1 plays the same role in mammalian cells. Just this year, researchers determined the protein's crystal structure, paving the way for unraveling its detailed amino acid sequence.

Dr. Evangelista says that given Bni1's central role in regulating the formation of actin bundles, it's important for understanding any process that involves cell polarity and movement.

"Normally cells are kept immobile by regulating the actin cytoskeleton," she says. "When there's deregulation of this then you can have things like cancer in which cells gain the ability to metastasize, or become motile."

At Genentech, Dr. Evangelista is trying to unravel another molecular pathway, this one related to a genetic abnormality that leaves embryos with hedgehog-like heads. As to what she'll discover, says Dr. Evangelista: "You really never know where it's going to lead you."