September 7, 1999
SCIENTIST AT WORK / Dr. Joe Z. Tsien
Of Smart Mice and an Even Smarter Man
Related Article
Scientist Creates Smarter Mouse (Sep. 2, 1999)
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By NICHOLAS WADE
RINCETON, N.J. -- A certain amount of
disorder has broken out around Dr. Joe Z. Tsien, the
biologist who announced last week that he had created a
smarter strain of mouse by genetically altering a gene
for memory.
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Laura Pedrick for The New York Times
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Dr. Joe Z. Tsien with a supersmart mouse he genetically engineered in a conference room at Princeton University. The research may shed light on human intelligence.
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Patients call seeking help. Individuals of
enhanced imaginations warn that the mice may escape
and take over the planet. Television crews patrol the
halls. His voice-mail box has overflowed.
But Dr. Tsien, seemingly the only scientist on the
Princeton campus who, on a warm summer day, is
wearing a tie, ignores the chaos and a phone that rings
every couple of minutes. In soft tones he describes the
remarkable journey that has led him from Wuxi, a small
town near Shanghai, to the position of having made a
significant, maybe decisive, contribution to understanding the nature of memory and intelligence.
Dr. Tsien (pronounced chee-YEN) says he did not
begin to consider the wider implications of his work until
just before his article was published. He engineered his
smarter mice for purely academic reasons, to address
and perhaps solve the question of how memories are laid
down in the brain.
But the mice turned out to be smarter
as well as having better memories, lending an unexpected new dimension to the experiment.
Although many arguments with psychologists doubtless lie ahead, Dr. Tsien believes that learning, memory
and intelligence are all intimately related because, as his
smarter mice demonstrate, "a common unifying mechanism underlies them all."
And because mice and people use the same basic
mechanism of memory, the smarter mice could well
shed much light on the nature of human intelligence.
Dr. Tsien's result, as he is the first to note, rests on
knowledge and techniques developed by other scientists.
He describes his experiment as "obvious" -- at least in
retrospect. His achievement lies in the fact that, in a
highly competitive field of biology, he was the first to
conceive of the experiment and to see that it could be
decisive.
He also carried it out in a particularly convincing way. "Extremely nicely done," was the verdict of Dr.
Eric R. Kandel, a leading biologist at Columbia University and the former laboratory chief of Dr. Tsien.
The idea that led to the smarter mice was no lucky
break. Rather, it was a feat for which Dr. Tsien had been
preparing intensively for many years, including seven
years of postdoctoral education.
In Wuxi, where his
father was a clerk and his mother an accountant, he was
the only person to enter college from his high school, one
attached to a fabric plant. But the college was a good one,
the East China Normal University in Shanghai, and he
decided to do doctoral studies in the United States.
"In 1986, China was still very closed, so we really had
no idea about the United States," Dr. Tsien says in
describing how he picked a college. He chose the University of Minnesota because it offered to waive the application fee, which he could not afford, and because the
Chinese characters for Minnesota translated invitingly to
"clean air blue sky."
Having recovered from the surprise of finding the
clean-air-blue-sky state so cold, he developed an interest
in neurophysiology and the instruments then available
for monitoring the electrical signals transmitted by brain
cells. "I got fascinated by seeing a nerve cell fire. They
are talking -- what does that mean?" he says.
A long apprenticeship was necessary before he could
begin to parse that language. He did his Ph.D. thesis with
Dr. Lester R. Drewes of the University of Minnesota,
helping him conduct studies under a Defense Department grant on how the warfare agent sarin blocks the
transmission of nervous signals.
Receiving his Ph.D. in 1990, he was accepted as a
postdoctoral student by Dr. Kandel's
laboratory.
There he worked on identifying genes that are active in rats'
brains during memory formation.
"I
got a more systematic education in
neuroscience. I got to see how a big
lab operates," Dr. Tsien said.
He then moved to another leading
neuroscience laboratory, that of Dr.
Susumu Tonegawa at the Massachusetts Institute of Technology. Dr.
Tonegawa won the Nobel Prize in
Physiology or Medicine in 1987 for
research on the genetic control of the
immune system, and later switched
to the study of learning.
In Dr. Tonegawa's lab, Dr. Tsien
worked with so-called knock-out
mice, animals from which a gene has
been deleted.
The idea is to learn
what a gene does by excising it and
seeing what defects the mouse develops. He became interested in the
brain cell component, known as the
NMDA receptor, suspected of being
central to the memory mechanism.
The receptor consists of parts made
by several genes, the chief part being
specified by a gene called NR1.
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Princeton University
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A mouse whose memory was enhanced through genetic manipulation took a learning test recently in a laboratory at Princeton University.
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Using advanced genetic techniques, he decided to create a mouse
lacking the NR1 gene in the cells of
its forebrain.
Creating the mouse
took two and a half years and, for a
postdoctoral student, was a substantial risk. If the experiment failed,
there would be no result worth publishing.
In the end, he was able to knock out
the gene in just the cells of the hippocampus, a brain module dedicated to
learning and much studied by neuroscientists. "I think a god looked on
me very kindly," he said, referring to
the element of luck in creating such a
valuable research tool.
The mice lacking the NR1 gene in
the hippocampus indeed did not remember as well, suggesting the
NMDA receptor is important in laying down memories. But the experiment, published in December 1996,
was regarded by other experts as
less than fully conclusive, because
the absence of the NR1 gene could
have caused general brain damage
not specific to memory.
Dr. Tonegawa became very interested in the mouse, as did Dr. Kandel, because Dr. Tsien had made it
with a technique developed in Dr.
Kandel's laboratory. The two lab
chiefs were also interested in receiving due credit, and discussions ensued between them that were stressful for him, Dr. Tsien recalls.
However, he now had sufficient
credentials to set up his own laboratory. "After working with these two
powerful people, I wanted to be
free," Dr. Tsien says. Two years ago
he was appointed an assistant professor at Princeton and was able to
set up his own lab. He began to think
about how he might try to improve a
mouse's memory, rather than sabotage it, because such an experiment
would run far less risk of being criticized as nonspecific.
The focus of his thinking was the
anatomy of the NMDA receptor. The
intricate biological device is shaped
like a cylinder or doughnut embedded in the outer wall of certain brain
cells.
Usually its central channel is
firmly closed. But when the nerve
cell receives signals from two other
nerve cells at the same time, the
NMDA channel springs open, allowing a current to flow into the cell.
This current generates a long-lasting
change within the cell, making it
much more responsive the next time
that either of the two other nerve
cells is active alone.
This property of the NMDA receptor -- opening when two signals arrive simultaneously -- has long been
suspected to be the basic mechanism
of memory, because it is a way for
the brain to make an association
between two events. The exact degree of simultaneity turns out to be
very important. In young mice, two
signals can arrive as much as one-tenth of a second apart for their
coincidence to change the nerve cell.
In older animals, the NMDA receptor allows a much narrower window
of time for an association to register.
Another known fact about the receptor was that its composition
changed with the age of the animal.
Its main component is the gene product of NR1, which Dr. Tsien had
knocked out in his memory-deficient
mice. But the NR1 component works
with any of four different partners,
which modulate its activity in different ways.
Two of the partners, known
as NR2A and NR2B, are particularly
important in cells of the forebrain.
As animals age, there is a switch
from NR2B to NR2A as the preferred
partner for NR1.
Abilities in many animals decline
after sexual maturity.
Song birds
cannot learn new songs. The human
mind becomes less flexible at learning new languages. "I am always
stuck with my Chinese accent, but if
I had come to the United States 12
years earlier I would have learned
perfect American," Dr. Tsien says
by way of personal example.
As he contemplated these various
pieces of information, Dr. Tsien said,
it seemed clear that they were related. The natural switch with age of
NR1's partner must underlie the increasingly stringent requirement for
two signals to arrive simultaneously,
and the narrowed window of time
must be the reason why older people
find it harder to make associations.
But no one had specifically stated
the idea in those terms, as far as Dr.
Tsien knew. And certainly no one had
done the obvious experiment, which
was to engineer mice in which the
NR2B gene was artificially put into
hyperdrive to see if their memories
improved.
So Dr. Tsien took a copy of the
mouse NR2B gene and linked it to a
special piece of DNA, called a promoter, that is active only in cells of
the mouse forebrain.
He injected this
genetic fragment into fertilized
mouse eggs, where it added itself to
the mouse's normal complement of
genes. Because of the promoter, the
NR2B gene was active in cells of the
forebrain, adding its product to that
produced by the mouse's own NR2B
gene.
With all the extra NR2B being produced in the mice's brain cells, the
NMDA receptors underwent a subtle
but significant change. Instead of
staying open for 100 thousandths of a
second, as they do in normal mice,
the receptor's interval increased to
250 thousandths of a second.
That minute biophysical change,
Dr. Tsien says, is what underlies the
superior learning skills of the mice.
The essence of smartness is an extra
150 thousandths of a second.
Credit for a discovery is often disputed, particularly when the finding
is important.
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| Dabbling with
genes, he built a better mouse.
| |
| |
Dr. Tonegawa told
reporter for The Star-Ledger of Newark, that Dr. Tsien may have started
developing the smarter mice while
at the Massachusetts Institute of
Technology and accused him of being uncollegial. If the mice were developed in Dr. Tonegawa's lab, M.I.T.
would have rights to them and Dr.
Tonegawa could exercise a lab
chief's claim to a share of the academic credit.
Dr. Tsien said he was "totally surprised" by Dr. Tonegawa's remarks.
His smarter mice experiment was
conceived and executed entirely at
Princeton, he said. Other scientists
have patented the NR2B gene but
Princeton has filed for a "use patent," the right to use the gene in
ways suggested by Dr. Tsien's work.
Dr. Tonegawa, who was traveling
in Japan last week, did not respond to
a request made through his secretary for an interview.
Dr. J. David Litster, M.I.T.'s vice
president for research and the official in charge of disputes over scientific conduct, said that M.I.T. "is not
endorsing Tonegawa's claims, certainly not until we know what they
are. If it's a dispute between Tonegawa and a former postdoc over
credit I don't really think we ought to
get involved in that."
Meanwhile Dr. Tsien is waiting to
see how the implications of his
smarter mice are received by his
peers in the neuroscience community and by the public. "To the scientific community this is a small step for
a man," he says. "The fundamental
question is, 'Is this a giant step for
mankind?' "
What does he think? "I don't
know," Dr. Tsien replies.
