September 2, 1999
Scientist Creates Smarter Mouse: Work on Formation of Memory May Someday Help People
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By NICHOLAS WADE
n a major test of the brain's most
basic mechanism of learning, a scientist has created a smarter strain
of mice by manipulating a gene involved in memory formation. He believes his work lays the basis for
eventually doing the same in people,
whether in helping patients with
memory loss, in counteracting the
fading of memory in the elderly, or
even in making healthy individuals
smarter.
Other experts, while praising the
technical quality of the work, see its
first application as in treating patients rather than in enhancing intelligence.
Also, they say, although
there are reasons to believe that
mice and humans are similar in this
respect, the applicability of the work
to people remains to be established.
The mice were created in an experiment designed to assess how
memories are formed in the mammalian brain. The animals performed better than normal mice in
six different tests, a strong indication that the altered gene is indeed
involved in learning and memory
formation.
The finding, reported in today's
issue of Nature, also explains why
young animals learn better than older ones, because the manipulated
gene is one whose activity is known
to fade with age in mice, monkeys
and probably people, too.
The smarter mice were created by
a team of researchers led by Dr. Joe
Z. Tsien, a neurobiologist at Princeton University.
Dr. Eric R. Kandel, a leading brain
expert at Columbia University,
praised the quality of Dr. Tsien's
work, saying his new research
"seems really reliable and is very
nicely done."
For scientists, the importance of
Dr. Tsien's paper is that it goes a
considerable way toward proving a
longstanding idea, known as Hebbs's
rule, about how the brain forms the
neural associations that are the basis
of memory.
"This paper takes a big step forward to showing people had been on
the right track," said Dr. Charles
Stevens, a neurobiologist at the Salk
Institute.
For others, the interest of Dr.
Tsien's work lies in its possible application to people.
Though no one yet
knows whether the same manipulation would make people smarter, Dr.
Tsien said, the DNA sequence of the
mouse gene he manipulated is 98
percent identical to that of humans,
suggesting that altering it by drugs
or gene therapy might also make
people smarter.
"It is not a hypothetical question,"
he said. "It is time for people and the
public to begin to discuss these issues."
Dr. Tsien's work builds on the
work of many other biologists and
used known techniques for manipulating the genes of mice.
The gene
that he and his team altered is one
that makes part of a feature known
as the NMDA receptor. This structure is embedded in a nerve cell's
membrane and serves as a sort of
biological antenna to pick up signals
from other nerve cells.
In seeking to understand the basic
mechanism of memory, the forming
of an association between two events,
biologists have long focused on the
NMDA receptor because it needs two
separate signals to be triggered into
action.
To prove the role of the gene in
learning, Dr. Tsien decided to enhance its function by exploiting a
natural change that occurs over a
mouse's life span.
The NMDA receptor is composed
of a variety of subunits. One such
component, known as the NR2B subunit, is common in the young while
another kind, known as the NR2A
subunit, predominates later in life.
The juvenile form of subunit produces a much stronger effect in the
nerve cell, and this is believed to be
the reason why younger animals
learn more easily than older ones.
Working with colleagues at the
Massachusetts Institute of Technology and at Washington University in
St. Louis, Dr. Tsien created strains of
mice that had extra copies of the
gene that is the blueprint for making
the NR2B subunit. He also inserted a
DNA sequence just in front of the
extra genes that causes them to be
active only in the appropriate tissues, notably the forebrain and the
hippocampus, a brain module associated with spatial and other kinds of
memory.
Having generated these genetically altered mice, Dr. Tsien's team
first extracted neurons from the hippocampus and showed that the electrical change to be expected from
having extra copies of the NR2B
subunit -- a flow of calcium ions into
the neuron -- was indeed taking
place.
The biologists then performed six
different types of standard learning
tests on the mice, which exercised
different association areas of the
brain.
One test required remembering the location of a submerged platform hidden in milky water, another
the ability to recognize novel objects.
In all these tests the genetically
engineered mice performed consistently better than normal mice, Dr.
Tsien said, giving him reason to believe the animals had enhanced intelligence as well as better memory.
Dr. Kandel notes that Dr. Tsien
was not restoring the learning ability
of old mice but doing something even
more interesting: enhancing the natural abilities of young mice.
The experiment thus raises the question of
"whether intelligence is optimized
by the brain or could you push it even
further," Dr. Kandel said, adding,
"That you can improve a young animal's performance is interesting."
Dr. Tsien has named the new
strain of mice Doogie after the precocious character in the television
show, "Doogie Howser, M.D."
His experiment brings home that
the blueprint for the brain is written
in the genes and that, probably well
before society is ready to assess the
full implications, biologists believe
they now stand on the threshold of
being able to change fundamental
aspects of the brain's architecture.
"Our results suggest that genetic
enhancement of mental and cognitive attributes such as intelligence
and memory in mammals is feasible," Dr. Tsien and colleagues declared in their Nature article.
Other experts do not disagree with
this assessment but put greater emphasis on the complications that lie
ahead.
"One has to move with great caution and the realization that these
are very complicated processes,"
Dr. Kandel said. "Our understanding
of memory processes is quite shallow -- this is the beginning of the
beginning. What the bad consequences or limitations are we don't
really understand. But by and large
the thinking is probably on the right
track."
In principle, human intelligence
could be enhanced by altering people's genes, when reliable methods of
gene therapy are developed, or more
simply by developing drugs that
would change the activity of the
memory association gene, Dr. Tsien
said.
But none of these possibilities
could be explored, in his view, without wide public discussion and the
establishment of guidelines.
A more reserved approach was
taken by Dr. Kandel, who said the
first applications of Dr. Tsien's work
should be in the medical context of
helping those with memory loss. Dr.
Kandel described as "neurobiological cosmetics" the notion of enhancing normal intelligence, and also emphasized that intelligence was far
from being the only mental attribute
of importance.
Enhancing human intelligence, Dr.
Kandel said, "is a very slippery turf
from a moral point of view," putting
his thoughts this way:
"It's one thing to improve memory
in people with a memory deficit. But
to begin to mess around with normal
memory is tricky. I don't think we
want to emphasize in society that
intelligence is the only factor that
counts, because whatever allows
someone to be creative and effective
is probably not determined by the
activity of the NMDA receptor in the
hippocampus alone.
"I wouldn't want to come across
with some simplistic view that 'Take
this pill' and we could produce a
superior race."
Psychologists agree that both genetics and a person's environment
are important in shaping intelligence, though they differ, often in
politically polarized ways, on the relative importance of each.
Like Dr. Kandel, other brain biologists noted the problems in applying
Dr. Tsien's work to people.
Dr. Timothy Tully, a biologist at the Cold
Spring Harbor Laboratory on Long
Island, who has genetically enhanced
the memory of fruit flies, said the
altered receptor unit was a reasonable target for new drugs but that
these could fail to enhance human
intelligence for many reasons.
"Maybe the juvenile brain needs to
be maximally plastic but as the animal matures you don't want the
brain to be so plastic," Dr. Tully said.
Nature might have deliberately
arranged the tapering off of learning
ability with age, said Dr. Stevens of
the Salk Institute, so as to prevent
the brain's memory capacity from
becoming overloaded.
"It may be that learning things too
well is bad," Dr. Stevens said. "We
could be stuck learning things we
didn't want to learn and our hard
disks would be full of too much information."
The difficulty that older people
have in recalling things may be due
in part to the complexity of accessing an increasing store of information, he suggested.
Dr. Tsien, however, is skeptical of
the natural wisdom argument, noting
that nature does many things that
are not in the individual's best interest, such as letting people's bodies
run down and die.
He believes that
improving people's intelligence,
whether by drugs or genetic alteration, could have profound effects
throughout society.
"Civilization is based on our extraordinary human intelligence," Dr.
Tsien said.
"That is why our society
evolves and civilization evolves, and
if there is a way to enhance intelligence then it may not be surprising
to see a change in the evolution of
society."
