From:
 The New York Times
 April 24, 2007 Tuesday
 Section F; Column 2; Science Desk; Pg. 2

HEADLINE: On the Trail of Parkinson's, Through Yeast Cells

By CLAUDIA DREIFUS
CAMBRIDGE, Mass.

 Short of a Nobel Prize, there are few scientific honors that the biologist
Susan L. Lindquist has not won.

     Among other accolades, she is a Howard Hughes Medical Investigator, a
member of the National Academies of Science and the American Academy of Arts and
Sciences, and the 2006 recipient of the Sigma Xi William Procter Prize for
Scientific Achievement.

   It has all come her way because of her imaginative research into how proteins
function. Dr. Lindquist, the former director of the Whitehead Institute for
Biomedical Research at the Massachusetts Institute of Technology, studies how
molecular proteins change shape in cell division. The process, called protein
folding, can-- when it goes wrong -- lead to diseases like Alzheimer's and
Parkinson's.

     Last June, Dr. Lindquist and a group of colleagues published a paper in the
journal Science reporting new clues about how Parkinson's develops and how it
might be treated.

     ''Afterward, we received many calls here from people with Parkinson's,''
she recalled in her office at M.I.T.

     ''It was heartbreaking,'' said Dr. Lindquist, 57, who is a founder of
FoldRx Pharmaceuticals, a startup biotechnology company seeking to develop drugs
to fight Parkinson's. ''We are still many, many years away from a drug. I hated
telling people that.''  Q. Your research specialty is a cellular function called
protein folding. What exactly is that?  A. The DNA that is within every cell has
the task of coding the proteins that carry out a cell's activities. DNA is made
up of the long molecular strings, sort of like a cassette tape containing the
code for a symphony. When that tape, the DNA, is plugged into the cell, it
instructs the proteins in how to carry out their different functions.

     But these proteins, which begin as long strings, have to fold into very
specific shapes to do their job. Cells are crowded places, and millions of
proteins have to fold into them perfectly. If a protein doesn't fold up just
right, terrible things can happen.

     Cystic fibrosis -- that's a loss of function disease caused by a protein
not folding correctly. Parkinson's, Alzheimer's, Huntington's disease and some
types of cancers are diseases of protein misfolding. With them, the misfolded
proteins accumulate inside the cell, interact with things they shouldn't and
send off the wrong chemical signals. That's what I've been studying lately.   Q.
Have you found a key to Parkinson's disease?  A. I think we found a pathway,
rather than a key.

     We had this idea. We took the gene from a human brain cell that was
malfunctioning and was thought to be a cause of Parkinson's. We inserted it into
a yeast cell. The yeast died. Next, we did a very broad genetic analysis and
asked, ''Which genes can save that cell from the Parkinson's protein?'' We took
5,000 different genes and we tested them one by one. From that, we found several
genes, and one that is particularly strong, that express a protein that can save
yeast cells from the Parkinson's gene.

     To take the experiment further, we collaborated with some other labs.
Together, we took this gene and put it into the brains of nematodes that were
engineered to express a human Parkinson's gene. Sure enough, it saved their
neurons from dying. We tried the same thing with fruit flies and then with rat
embryonic neurons. The anti-Parkinson's gene saved them, too. Later, we screened
through some 150,000 chemical compounds to see if we could find a substance that
saved yeast from Parkinson's. And we did.   Q. Why start your experiment with
yeast, of all things?  A. (Laughs) I know. Even people in my laboratory thought
we were crazy to try to study neurodegenerative diseases with a yeast cell. It's
not a neuron. But I thought we might be looking at a very general problem in the
way proteins were being managed in a cell. And yeasts are easy to study because
they are such simple cells.

     As biology has moved forward, we've come to realize that the same rules
apply to all living things. If there's a defect in basic cell biology, it might
be shared by other cells. So we can learn a lot about complicated organisms from
studying very simple cells like yeast.   Q. Did always you want to be a
biologist?  A. When I was young, I thought I'd become a nurse or a social
worker. Those were the jobs open to women. In college in the late 1960s, there
was a lot of hard-core prejudice against women doing science. That's still
somewhat true, though the prejudicial attitudes are more submerged now. Today,
about 50 percent of the graduate biology students at the prestigious
institutions are female. Yet, only 10 to 15 percent of the professors are.

     When I was young, it didn't seem like the world was open to me. When I got
to graduate school, Harvard, there were 1 or 2 women professors among the 65 in
the biological sciences department. You could not look at that and think you had
a chance.

     Sometimes, the bias freed me to take risks. Once early in my career, I
wanted to change my research focus from fruit flies to yeast. As you can see,
I've long been interested in exploiting the special properties of yeast. Someone
very senior advised me: ''Don't change your specialty. You'll never get
tenure.'' Well, I didn't think I was going to get tenure anyway. So I made the
switch. It led to a big leap in my research.   Q. Lawrence Summers, in his
notorious speech, suggested that female scientists might be hindered in their
careers because of motherhood. As the mother of two, would you agree?  A. Oh,
having children is a lot of work. But one's circuits are also recharged by them.
I do believe that coming home to them, watching them grow, has helped my
science. Kids change your thought patterns around. That's good for your brain.
Q. You give lectures to younger women scientists about career building. What do
you advise?  A. I talk about the personal aspects. I tell them if they want to
have a family, they'd better pick a partner who's going to support their work.

     Another thing, they have to make mindful financial choices.

     For example, when I had my two children, I was at the University of
Chicago. I saw how a lot of my female colleagues, as soon as they got tenure,
bought houses in the suburbs, which ate up their money and spare time. My
husband and I stayed in our Hyde Park apartment, which was near the lab. We used
my salary to hire a really good nanny. I always put my resources into things
that kept me from falling apart and helped my kids.  Q. How did you find a
supportive life partner?  A. I put a lot of careful thought into this. I had an
earlier marriage which didn't work out. When I started dating again, I knew I
wanted children. So I consciously looked for a man who'd be a great partner for
that.

     I tried blind dates, I went to parties I had no interest in. Eventually, I
met my husband at a party that some students gave for their favorite professors.
He taught medieval French literature. I had wanted a nonscientist. I have a lot
of nonscientific interests and I wanted my partner to be someone who brought
different intellectual content to my life.  Q. Is this an exciting time to be a
biologist?  A. Unbelievable. I have to tell you that the sheer intellectual joy
of finding out how life works is really cool. This is the greatest intellectual
revolution, and it is happening right now, and I'm lucky enough to be in the
middle of it.

URL: http://www.nytimes.com

GRAPHIC: Photo: IN THE LAB -- Susan Lindquist and her team tested 5,000 genes to
find a few that express a protein capable of saving a yeast cell from the
Parkinson's gene. (Photo by Robert Spencer for The New York Times)


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