-Caveat Lector-
N.Y. Times
September 7, 1999
SCIENTIST AT WORK / Dr. Joe Z. Tsien
Of Smart Mice and an Even Smarter Man
By NICHOLAS WADE
PRINCETON, 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.
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.
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.
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.
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.
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