Hope

Against all odds, she is raising hopes in Alzheimer's research
Dr. Karen Hsiao Ashe's quest for answers has broken new ground.

Maura Lerner, Star Tribune

In the fall of 2004, a research assistant sheepishly approached Dr. Karen Hsiao Ashe about a problem with one of her experiments.
It involved a group of mice that had been bred to become forgetful, like people with Alzheimer's. Only this time, the mice had surprised them.
"Something very funny has happened," the assistant told her. "These animals are getting better."
Ashe, a University of Minnesota neurologist, was astonished. "Something must have gone wrong," she said. Actually, it was a breakthrough in disguise. The experiment turned out to be the first scientific evidence that memory loss could be reversed in an advanced stage of Alzheimer's disease. And it helped seal Ashe's reputation as one of the leading scientists in her field. Her groundbreaking work, colleagues say, is raising hope that it may be possible to halt the destruction of memory in people suffering from Alzheimer's.
In the past six months, Ashe, 51, has been showered with honors --including the $250,000 MetLife Foundation Award for Alzheimer's research and the Potamkin Prize, known as the "Nobel Prize of neurology." And just last week, three of her discoveries were named among the 12 most important advances in Alzheimer's research in the past three years, in a survey of experts by the prestigious journal Nature Medicine. Of the top three studies, two were from her lab.
For the publicity-shy scientist, the attention is unnerving. "I'm really happiest when I'm looking at data and making discoveries," said Ashe, who grew up in Arden Hills, the daughter of scientists who emigrated from China. At the same time, she's eager to translate her good fortune into something that will help patients. So in addition to her research, she is heading the new Center for Memory Research and Care at the university to help speed new treatments from lab to bedside.
For 14 years, Ashe has been quietly making her mark at the university where her father, C.C. Hsiao, spent his career as a professor of aerospace engineering.
Ashe, who is married to a neurologist and has three children, said she chose to study Alzheimer's "because it robs people of what makes [them] human: Their thoughts, their memories, their feelings." She has bucked animal-rights activists and skeptics in her quest.
"She's a brilliant scientist, but she's a very careful scientist," said Dr. Deborah Powell, dean of the University of Minnesota Medical School.
"She waits until she has something major to say and then she says it."
Ashe is best known for developing the "forgetful mice" used worldwide to study memory loss. Now, she has shed new light on the cause of Alzheimer's, which affects more than 4 million elderly Americans.
She discovered, among other things, that memory loss can be caused by a poisonous type of protein, which she named "A-beta star," found in the brains of her lab mice. And she found that even forgetful mice begin to recover when another type of protein, known as tau, is cut off.
Her discoveries could lead to new treatments, she believes. But it will take years to get there.
Ashe, who graduated from both Harvard and MIT, says she knew at age 3 that she wanted to be a scientist. "I just can't remember wanting to be anything but a scientist," she said. "I just wanted to discover new things about how the universe worked."
Maybe it was a combination of genes -- both of her parents have Ph.D.s -- and the games she played as a toddler, counting peas on her plate. "She was a very inquisitive and creative child," said her mother, Joyce Hsiao, a biochemist. "I thought every child was like that. We were not really teaching her; we thought we were just playing games with music and science and numbers."
Ashe's parents came to the United States as graduate students in the late 1940s and decided to stay after the Communist revolution in China, settling in Minnesota.
Karen, the eldest of four children, laughingly calls herself "one of those extremely over-achieving Asian-Americans, first generation." An accomplished pianist, she won a citywide music competition as a teenager, even sewing the dress she wore. After graduating from St. Paul Academy, she skipped her freshman year of college and entered Harvard as a sophomore.
By 1982, she had earned an M.D. and a Ph.D. and before long landed a job studying brain disorders with Dr. Stanley Prusiner, the University of California scientist who went on to win the Nobel Prize for discovering the cause of mad cow disease.
Ashe was fascinated by what made brain cells go awry. She turned her attention to Alzheimer's when she joined the Minnesota faculty in 1992.
Like most scientists, she believed Alzheimer's was caused by sticky clumps of molecules, known as plaques and tangles, in the brain. But she wanted to see how they affected behavior. For that, she needed a living model.
So she set out, through genetic engineering, to design a mouse that had both the brain defects and memory loss of Alzheimer's. It was tougher than she expected. And it almost undermined her career.
For two years, she didn't publish a thing, which didn't exactly impress her colleagues. When she came up for tenure -- a lifetime appointment -- her own mentors lined up against her.
But Dr. Shelley Chou, then dean of the medical school, realized that she was getting close on the forgetful mouse. He took a leap of faith and gave her tenure, Ashe recalled.
By 1996, she had created her first Alzheimer's mouse, Tg 2576, and made breeding pairs available for free to academic scientists. Today, hundreds of thousands of descendents of those first mice have been used in experiments around the world.
In 1999, a few of them made news when animal-rights activists broke into Ashe's university lab and "liberated" 50 to 100 of her research mice. But it wasn't much of a setback; the mice were only a part of her total population and had been separated from the main colony because they were infected with mites. Most of her work was untouched. The lab beefed up security afterward.
The real breakthroughs have come in the last few years. They've shown that memory loss isn't caused by plaques and tangles in the brain; the culprits are elsewhere. Ashe believes she has found one of them and is closing in on another.
Her work, experts agree, could change the way scientists look at Alzheimer's.
Ultimately, Ashe hopes they'll be able to detect the disease early enough to make a difference, maybe through a blood test. It may only be partly reversible once it has begun, she said, but "I believe that it's preventable."

Maura Lerner • 612-673-7384

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