The Persistence of Memory

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The following year, as a postdoc in cancer specialist Ed Harlow's laboratory at the Massachusetts General Hospital Cancer Center, she stumbled on an odd protein. Tsai had been charged with identifying enzymes known as cyclin-dependent kinases, which typically play a role in cell division. Her task was to discern their function by analyzing and tracking cancer cells as they multiplied in petri dishes. But one of the molecules, CDK5, wasn't behaving like the rest: it didn't appear to be doing much of anything. "I became very intrigued by this particular kinase, simply because it wasn't entirely easy to work with," she recalls. "It was very peculiar."

The molecule wasn't relevant to her assignment, because it played no role in cell division--so it would have been easy to forget about it and move on. But not for Tsai. "I didn't want to just give up and say, 'Oh, this thing, it doesn't matter,'" she says. "I decided to give it one last shot."

Since CDK5 was dormant in the cancer cells, Tsai changed the medium. She pulled together a variety of tissue and organ samples, again checking to see whether CDK5 might be active. In most, it did nothing. Yet it was active in the brain. "That actually was the first time I seriously looked at the brain and started to discover all these fascinating things about the brain," she says. Her days as a cancer researcher were coming to a close. CDK5 was leading her to a new calling.

While recounting her discovery of CDK5, Tsai laughs and says, "I was extremely lucky." But the torrent of papers that followed this one finding had more to do with pure determination.

First, she found that the protein doesn't act alone. To become active, CDK5 needs to bind with a protein she called p35, which is active only in the brain. To find out what this combo was up to, Tsai, then at Harvard Medical School's pathology department, genetically modified mice so they couldn't express p35. She and her colleagues shut down the gene that produced p35, halting CDK5's activity, too. In these mice, she says, "we found an extremely intriguing defect in brain development." The animals were prone to seizures, and in certain parts of their brains, their neurons were arranged differently from those in healthy mice. Without p35, and the associated activity of CDK5, their brains just didn't develop properly.

Yet she soon learned that CDK5 wasn't purely benevolent. As her group continued studying it, they noticed an odd, truncated version of that partner, p35. This molecule, dubbed p25, kept turning up in diseased or damaged brains in mice--and in tissue samples from deceased Alzheimer's patients. "We found that this particular protein was more associated with neurotoxic conditions," she says.

The p25 also drove the activity of CDK5, so Tsai developed a group of mice that overexpressed the new molecule when the antibiotic doxycycline was removed from their diet. This allowed her to crank up the activity of CDK5 instead of shutting it down. And when she did so, the mice developed Alzheimer's-like effects in just a few weeks. Learning and cognition suffered, neurons died in massive numbers, and the tangled beta-amyloid fibers typically found in the tissue of deceased Alzheimer's patients turned up in their brains too. Though Tsai had already shown that CDK5 is critical for proper brain development and function, the experiment proved that too much of the protein can be seriously detrimental. "When this [p25] is produced," she says, "it drives CDK5 to the dark side. It makes it toxic to cells."