[tt] LA Times: Chasing Memory (four parts)

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Chasing Memory (four parts)
By Terry McDermott, Times Staff Writer
7.8.19-22

One man's epic quest for understanding
http://www.latimes.com/news/science/la-na-memoryfirst19aug19,0,5585770.story

(BEGIN TEXT OF INFOBOX)
Glossary of terms
Adenosine: A molecule that exists throughout mammalian biology. In
the brain, it appears to perform a specific function in the memory
process -- erasure.
Ampakines: A class of drugs designed to enhance communication
between brain cells. The drugs, still in development, are
envisioned to enhance almost all cognitive activities.
Axon: A fiber that extends from a neuron and sends signals to other
fibers called dendrites. Axons and dendrites meet at the synapse.
Dendrite: A fiber that extends in bunches from a neuron. Dendrites
receive signals from another sort of fiber called an axon.
Dendrites and axons meet at the synapse.
Dentate gyrus: Part of the hippocampus; Lynch Lab found that sharp
waves, an electrical rhythm, originated here. The lab hypothesized
that the waves were a means by which the brain erased things it did
not want to put into long-term memory.
Integrin: One of the most common types of molecules in mammalian
biology, integrins tie things into place. For example, they cause
blood cells to clot, allowing wounds to heal. Lynch Lab
hypothesized that integrins solidified LTP, locking molecular
changes into place.
LTP, or long-term potentiation: The strengthening of connections
between brain cells that occurs once they have communicated, making
subsequent communication more efficient. The communication consists
of electrochemical exchanges between two neurons at the synapse,
which is where they meet.
Neuron: The most common type of cell in the brain (numbering in the
hundreds of millions); LTP occurs between two neurons.
Sharp waves: A naturally occurring brain rhythm that originates in
the hippocampus and seems to erase LTP -- or to cause forgetting.
Spine: The point on a dendrite where it contacts an axon.
Synapse: The point at which two neurons communicate in the brain.
It is actually not a structure but a gap of about 20 nanometers
(20-billionths of a meter) across which one neuron sends chemical
signals to the other. The chemicals set off cascades of events
inside the receiving neuron. There are estimated to be 100 trillion
to 10 quadrillion synapses in a human brain, allowing for immense
memory capacity.
(END)

Gary Lynch has spent decades trying to understand how the brain
processes new information so that we can recall it later.

The first time I spoke with the neuroscientist Gary Lynch, the
conversation went something like this:
Me: I'm interested in spending time in a laboratory like yours,
where the principal focus is the study of memory. I'd like to
explain how memory functions and fails, and why, and use the work
in the lab as a means to illustrate how we know what we know.
Lynch: You'd be welcome to come here. This would actually be a
propitious time to be in the lab.
Me: Why's that?
Lynch: Because we're about to nail this mother to the door.
______________________________________________________________

FOR THE RECORD:
"Chasing memory": The glossary accompanying the Aug . 19 memory
article in Section A defined genes as "strings of amino acids that
make up an organism's genome, a sort of blueprint from which the
organism is built. Individual genes are strings of amino acids;
each string contains instructions for building a particular
protein." The definition should have said: "Genes: strings of DNA
that form a blueprint from which the organism is built. Each gene
contains instructions for building a particular protein." --
______________________________________________________________

Lynch is a neuroscientist at UC Irvine, where he has spent 37 years
trying to uncover the biochemical mechanisms of memory.
He has, for almost the length of his career, been trying to answer
essentially a single pair of questions: What happens in the brain
when a human being encounters a new experience so that he or she
can recall it at will tonight, tomorrow, in 2025? And what goes
wrong when we can't remember?
This second question has in the last several years taken on great
weight.
We are on the verge of a dementia pandemic. It is estimated that by
2040, 100 million people worldwide will suffer from Alzheimer's
disease, Huntington's, Parkinson's or some other form of dementia.
Science has been able to do precious little to combat these
diseases, in large part because the understanding of the underlying
cognitive processes has been meager. Thousands of scientists have
spent countless years seeking and largely failing to unearth the
secrets within the human brain.
Medical advances have allowed more and more people to live longer
but have been unable to relieve longevity of its principal bane --
the breakdown of mental processes, especially memory. When memory
loss occurs, it seldom fails to impress upon its victims and those
who know them the extent to which our memories constitute our
selves.
That breakdowns occur is not surprising. Consider: You're 50 years
old. What's your time in the 100-yard dash? How does that compare
to the 18-year-old you? Why would your brain be exempt from
declining in analogous ways? It isn't. So much goes wrong so often
that many malfunctions are considered ordinary and are often
referred to collectively as normal cognitive decline.
Before that first conversation with Lynch, I already knew that he
had been an often polarizing figure in his field, that he had a
reputation for being pugnacious, and that he had been uncannily
right about a lot of things over a very long time.
In the subsequent two years, I spent a great deal of time in his
lab. I spoke with the other scientists who worked there and
observed their experiments; I read papers they and others
published; I learned how to perform some of the most rudimentary
tasks of their basic experiments. But what I did mostly was talk to
Lynch. Or, more to the point, listen as Lynch explained mammalian
biology and brain science.
Listening to Lynch often entailed following swooping, exhilarating
flights over time and intellectual terrain. Bear with me, he
sometimes said, this might not seem connected to what we've been
talking about, but it will circle back. Ten, 20 or 30 minutes
later, often after side trips to ancient Rome or Yankee Stadium or
Bismarck's Germany, it did.
Lynch almost always spoke in such a way that his huge ambition,
self-regard and lack of pretense were vividly displayed. He was
unreserved, witty, juvenile, insightful and learned in ways that
were surprising. He was as apt to quote Cormac McCarthy as Gregor
Mendel. He made on-the-fly references to, among many other things,
left- handed relief pitchers, Moses, British naval history, the
stock market, Kaiser Wilhelm II, Maxwell's equations, the ur-city
of Ur, Darwin, Dylan, Kant, Chomsky, Bush, Titian, field theory,
drag-racing, his father's perpetual habit of calling him --
intentionally -- by the wrong name, his career as a gas jockey at
an all-night service station, Pickett's charge at Gettysburg,
Caesar crossing the Rubicon, and the search for the historical
Jesus.
Christine Gall, Lynch's frequent collaborator and longtime
significant other, said: "Gary just has more RAM than other people.
He can access lateral information that most people can't. It isn't
like he has to think and remind himself. It's right there. He has
access to it. To have that available to inform you, to make the
next cognitive leap -- that's his strength."
That leaping ability has earned Lynch as much trouble as reward. He
never shies from proclamation based on his intuitions, nor from
criticizing those not privy to his insight. "That is what amazes
me," he said. "People will walk in who are very sensible and
intelligent biologists and tell you, 'Memory is this.' And you go,
'How in the hell could it possibly be that? I didn't think it was
that when I was back at Our Lady of Fatima Grade School. I mean, I
didn't think it was that when I was working at the all-night gas
station. For crying out loud!' "
One result of this perhaps excessive straightforwardness has been a
constant war with the neuroscience establishment, with university
administrators and colleagues at Irvine. But whatever his
difficulties, Lynch has slogged along, making hard progress
documented in more than 550 published papers, some of which are
considered classic and are among the most frequently cited works in
all of neuroscience.
As a corollary to his basic research, Lynch has sought ways to
counter the various afflictions that erode the brain's abilities.
Working with chemist Gary Rogers, he invented a new class of drugs
called ampakines, which, if they worked, would not only improve
memory, but would make the brain perform better in numerous other
ways. Drugs of this sort, called cognitive enhancers or, more
simply, smart pills, have been the Holy Grail of brain research for
a century.
Like much contemporary drug research, ampakine development has been
slow going, but by the time I met Lynch, versions of his drugs were
being considered by the Food and Drug Administration for a series
of clinical trials, which should largely determine whether their
substantial promise could be fulfilled. Success would be a signal
moment in neuroscience history.
By chance, the ampakine drug trials would get underway at the same
time the memory research in his lab seemed headed toward its own
finale. Lynch had a sense that answers he had spent a career
chasing were at hand.
He was alternately eager at the opportunity and despondent at the
likelihood of failure. He knew, as every research scientist does,
that almost everything almost always goes wrong. If, over time,
science can be viewed as the steady extinction of ignorance, in the
near term, on most days, ignorance wins hands down.
"If you're good, if you're any good at all, you put yourself in a
situation where reality could come around and -- WHACK! -- knock
you down. That's what you really are afraid of. If you don't have
that, you're not playing science," Lynch said.
He was definitely playing science now. With the drug research and
the fast-approaching end to his torturous journey in what he once
characterized as a gulag of unyielding biology, he had a rare
opportunity -- a shot on goal, he called it.
"Come to the lab," he said. "This could get interesting."

Lynch Lab

Save for lynch, Lynch Lab was empty just before New Year's 2005.
Much to Lynch's chagrin, everyone was vacationing.
The lab had just developed a new technique that he thought would
allow researchers to visualize the physical trace of memories, and
in doing so resolve long-standing, fundamental debates in
neuroscience.
This new technique promised to answer conclusively what had been
supposition, and to answer it in such a way that you would
literally see the result. And people went on vacation?
Most of the space in Lynch Lab was taken up by two parallel ranks
of standard lab benches, complete with faucets, hoses, beakers,
stocks of chemicals, pipettes, scales, reference books and
undergraduates. Lynch and the lab's senior scientists had offices
on the perimeter, but most of the experimental work was done out on
the benches.
Lynch could almost always be found in his office, writing or
reading, and chewing on a cigar if he had one or a plastic
cafeteria fork if he didn't. No matter whose name was on them,
almost all of the journal papers that issued from the lab were
written by him.
He has an open, almost guileless face, so helplessly expressive
that your first impulse is to invite him to a poker game. The years
have begun to accumulate, however, cutting deep lines. He is about
6 feet tall, rail-thin but for the beginnings of a belly, with
tangled, graying hair that has relaxed considerably from its
Charlie Manson heyday. He usually dresses in high-quality,
untucked, casual clothes -- Klein, Boss and Zegna shirts and jeans
and well-worn chukka boots.
His corner office is spare and clean -- a large glass-top,
metal-frame desk; a dual-monitor Mac workstation; a few potted
plants along broad, undraped windows. He has a telephone on his
desk, but it is often unplugged. He sometimes goes for weeks
without reading e-mail. The only decorations on the walls are a
single small plaque honoring him because his papers were so often
cited by other scientists, and a pair of large abstract paintings
of brain interiors, which are mostly purple and surprisingly
pleasant.
Except for a congregation of Starbucks decaf cups, he is
fastidious. There is almost never more than a single pen and a pad
of paper on the desktop; he keeps a spray bottle of glass cleaner
handy to scrub it, which he does religiously. He usually has a
bottle of whiskey and a brace of glasses stowed among the plants.
Before serving, he scrubs the glasses with the same care he applies
to the desk.
The duties of a university scientist leading his own lab are
manifold. Foremost, the existence of the lab depends on his ability
to fund it. He is an employee of the university, but also a profit
center. He must attract grants, from which the university takes a
significant cut, to pay the basic expenses of his laboratory:
salaries, equipment, supplies.
The overwhelming majority of grant money comes from the federal
government, most through the National Institutes of Health. The
competition for money is intense and often leaves normally placid
scientists swearing like deckhands. Lynch, whose lab has been
funded mostly by the federal government at around $1 million per
year for decades, was no exception.
In part because of the constant threat of extinction, neuroscience
labs -- even those that don't have Lynch in them -- are not the
happiest places. There is tension and fear and jealousy and a
near-constant sense that careers are about to be made or, more
commonly, missed. Such fraught situations call for careful,
considered management.
Due to a lack of interest, or possibly ability, which can be the
same thing, Lynch seemed to run his lab like a man on a midnight
beer run, running pell-mell down the aisle, throwing things, many
of them unhealthful, into the cart and hoping there would be enough
for everybody when he got back to the house.
Which is to say, although it was obvious to him, it wasn't always
clear to others what Lynch was up to.
In addition to providing money, the lead scientist, in the academic
world called the principal investigator, is the intellectual leader
of the team. Lynch did very few experiments himself, but designed,
assigned or approved virtually all of what everyone else did. He
would hate to admit it, but he was a dictator.

The 'free-ride guy'

The youngest son in a disintegrating Irish Catholic working-class
family in Wilmington, Del., Lynch earned scholarships to Catholic
high school, then -- "always a free-ride guy" -- the University of
Delaware.
The ride ended abruptly when he was kicked out for partying. He
worked odd jobs until he was readmitted. Because Lynch's main
interest in college was to have a good time, something had to
change. When he came back, he changed majors from engineering to
psychology for, he said, two reasons -- engineering students spent
weekends building electric circuits and, as important, there were
very few girls among them. Lynch chose psychology, he said, because
there were plenty of girls and no weekend work.
Lynch, in spite of his professed laziness, excelled and earned a
graduate scholarship to Princeton, where he quickly determined he
was much more interested in mucking around inside the head than
standing outside it and asking questions.
He earned his doctorate in psychology in 1968, just three years
after enrolling. Soon after, he received a job offer from UC
Irvine. The university was so new it hadn't yet graduated its first
class.
The offer was to teach in the psychobiology department. Lynch had
not completed a single college course in biology. (Too many
details, he said.) He had never been to California. But one of the
first of those now ubiquitous lists of the best universities had
been recently published. UC Berkeley ranked No. 1 in the world.
"The thrill I felt was -- it's the people's university," said
Lynch. "That's a public university. Oxford, Cambridge are down
here; Harvard's down here; Princeton's down here. The best
university in the world is a public university. I thought, 'Man, we
are so on the right track.' That inspired me. . . . I thought,
'This is it; this is finally it.' In the face of people working on
great things together in the sunshine, in the eternal summer of
California, privilege falls away. What could be more beautiful?"
Irvine then was not far removed from its ranch-land past. There
were cattle grazing on the hills above the campus and cowboys
chasing them. Almost overnight, the university became a center of
brain research.
Neuroscience, too, was young, and there was a sense broadly shared
that the human brain, one of the great frontiers of science, was
about to be colonized -- although from what direction or by whose
army was unclear. Biologists, chemists, anatomists, psychologists,
mathematicians, even philosophers and physicists, all suddenly
calling themselves neuroscientists, plunged into the field. No one
knew where they were going, and no one wanted to be left behind.
Memory as a subject of inquiry and wonder is as old, perhaps, as
man. The ancient Greeks variously proposed that memory and other
mental processes were a function of the heart, the lungs or the
brain, which eventually became the agreed-upon site. Beyond locale,
however, little was learned about the processes of mental activity
for the next 2,000 years.
Although the great Spanish anatomist Santiago Ramon y Cajal
proposed in the late 19th century that the brain was composed of
tiny cells called neurons and that memory might be stored at
connections between neurons, there were plenty of scientists who
thought the whole mental apparatus too ineffable, too mysterious a
subject to yield to laboratory examination.
The seminal event in the modern history of memory research occurred
by accident in 1953. In an effort to stop horrific epileptic
seizures afflicting a young Connecticut man, a neurosurgeon named
William Scoville removed a portion of the man's brain. The surgery
stopped the seizures but rendered the man, known in the literature
as H.M., incapable of forming new memories. His memory of events
before the surgery was uninhibited.
A main portion of the brain that Scoville removed was a temporal
lobe structure called the hippocampus. The fact that H.M. could no
longer form memories but could recall older ones suggested strongly
that the hippocampus was crucial to making but not storing memory.
It immediately made the hippocampus the central focus of memory
research, a position it had maintained when Lynch, just 26, arrived
in Irvine in 1969.
Lynch was wild-eyed, bushy-haired and bearded, a man of his time --
a bit too fully, perhaps. It was the '60s, it was Southern
California, land of eternal light and endless good times. Lynch
lived in a party pad on Balboa Island.
By every account, including his own, Lynch ate badly, drank heavily
and slept hardly at all. There were days he seemed to consume more
cigars than calories.
"Gary doesn't sleep," said Michel Baudry, a 10-year veteran of
Lynch's lab. "He's incredible. I don't know how he survives."
Another researcher, Kevin Lee, recalled that for a period in the
1970s, the only things he ever saw Lynch eat came out of a vending
machine, a single vending machine. His main meal consisted of
salted peanuts mixed into soft drinks.
"You know, Gar," Lee recalled telling him, "you might think about
diversifying your diet. Nothing radical, but hey, man, try a new
machine. Have some chips."
Lynch's diet was of a piece with his extreme work habits, which
typically included seven days a week of 12-hour or longer shifts in
the lab, often followed by monumental bouts in the nearest bar.
Given 400 square feet of lab space and $900 to equip it, Lynch
quickly made discoveries having to do with the brain's ability to
repair some damage to itself after injury. It had generally been
thought that the brain was static, that it did not produce new
cells or structures after it reached maturity. Lynch and others
began to wonder whether the brain did not possess more
malleability, what was called plasticity.
In 1973, just as Lynch was expanding his investigation of brain
plasticity, a pair of scientists in Europe discovered that when
they stimulated the hippocampus with electric current intended to
simulate brain activity, connections between hippocampal cells were
strengthened and, more important, those strengthened connections
could be retained indefinitely. They called the phenomenon
long-term potentiation (LTP).
The combination of brief stimulation and long-lasting effect
matched the key characteristics scientists had long associated with
memory. Lynch and others wondered whether LTP was the biochemical
process underlying memory. A global race was on to prove it.
Thirty-two years later, Lynch hoped he was near the end of it.

'A strange place'

Lynch lab has been staffed over the years by a succession of
visiting scientists, grad students, postdoctoral researchers, dope
peddlers, English majors and whoever else was swept up in Lynch's
often irresistible aura.
All of the inhabitants have been very bright, some brilliant. A
number have gone on to chair university departments, to found
successful companies or to publish distinguished papers, but when
they were in the Lynch Lab, there wasn't much to recommend them to
civil society. Any hint of future distinction was obscured by the
chain-gang grind of life in the lab.
Lynch's extraordinary drive and ability to make every person feel
that he or she was working on the single most important experiment
in neuroscience history was the oxygen the lab lived on. Especially
in the early years -- a period Lynch called "the boy lab" because
of its testosterone-driven internal competitions -- the lab was a
woolly place, not far removed in its culture from a Neanderthal
cave. The guy with the biggest club generally got his way. Lynch,
while not at all physically imposing, had a ferocious temper and
never left a shadow of a doubt about his willingness to swing
whatever was at hand. The history of the place was littered with
battered telephones and drywall with holes suspiciously the size of
baseball bats and fists.
"That's part and parcel of the fire that burns in him," said Lee,
who now chairs the neuroscience department at the University of
Virginia. "The phone on the wall? It just looked like a baseball
sometimes."
"He never really hurt anybody physically but himself. Although
there were people with emotional scars, I can tell you," said John
Larson, now of the University of Illinois at Chicago.
Lynch said: "That lab was a strange, strange place. A lot of weird,
weird, different kinds of people. The dean would look at it and
say, 'That's a strange damn place.' I'd answer: 'Have you looked at
me?' "
Amy Arai, a native of Japan, recalled the culture shock she felt
when she joined the lab in the 1980s. "In Japan, everything is very
formal. Scientists wear jackets and ties to work every day. Here in
Irvine, nobody did that," she said. "I had a hard time even
locating Gary. . . . I wandered around looking for him. There were
lots of people wandering around, including one particularly scruffy
guy I saw in the hallways, shirt always untucked and dirty. I'd
sort of hold my breath when I passed him in the hall. I thought he
was a janitor."
One day, weeks after arriving, Arai was summoned to Lynch's office,
which was removed from the rest of the faculty offices in a
double-wide trailer next to a parking lot. Arai walked in and found
the trailer empty except for the "janitor," who was sitting behind
a desk smoking a cigar. It was Lynch.
Baudry, a Frenchman, toured labs in the United States for five
weeks in 1978, then went back to Paris and told his professors he
was going to join Lynch. Baudry recalled the reaction of
Jean-Pierre Changeux, the rising star of French neuroscience: "He
looked at me. He said, 'You're crazy. Gary Lynch? The hippie of
neurobiology?' I said, 'I'll take my chance.' I went to Gary's lab,
and it really was something different in its ambience. All these
wild people. The contrast with Paris -- fields, cows around the
campus. I thought, I have to give this a shot. It really was the
Wild West. And Gary really was this wild person."
Lynch still draws an off-kilter collection of researchers. His
latest lab -- the "girl lab," as he described it -- included a grad
student who wasn't officially assigned to the lab, a postdoc who
ended up there by virtue of being kicked out of her original
department, and a preternaturally talented undergrad who was
hanging out only long enough to decide which med-school scholarship
to accept. The senior scientists, except for one man who never left
his private office, were three women, who seemed to speak with one
another as seldom as possible.
Work was assigned largely by Lynch's judgment of who could do what.
If an undergrad was able, he would find himself in the middle of
crucial experiments.
The lab has changed locations and varied in size over time --
anywhere from three dozen people to as few as six or seven. In
January 2005, there were around a dozen regular members, with
students floating in and out.
Much of the work was some variation of two basic LTP experiments.
One involved isolating single neurons, which, using high-powered
microscopes, were identified, then pinched with a clamp to hold
them in place. This was exceptionally tedious. Researchers could go
entire days without successfully clamping a single cell.
The other experiment entailed placing a thin slice of a rat's
hippocampus in a nutrient bath in which it stayed alive for hours,
then imposing one of a variety of conditions on the slice --
usually, infusing it with chemicals known to inhibit or incite
certain molecular reactions -- then stimulating the slice with a
precisely timed, placed and quantified electric impulse and
measuring what happened to that impulse.
What the scientists were trying to find out by blocking or inviting
the action of certain molecules was what role they played in LTP.
Theoretically, you could determine all of the principal agents by
this process of elimination.
In practice, people spent extraordinary amounts of time -- hours at
a sitting, days or weeks in succession -- staring at graphical
renderings of the results on computer screens. It was not work
filled with obvious drama or even, except for making the occasional
note in a lab journal, movement. The lab was quiet -- no music; no
telephones; low conversations, when there were any at all.
Lynch lived in dread of being scooped on discoveries. The residents
of the lab did not gush in praise of his patience. He strode among
the benches several times a day to see how much progress was -- or,
more usually, was not -- being made.
Lynch talked often about hating the day-to-day process of science,
the actual experiments. He could hardly bear to wait for them to be
done to prove what he suspected to be true.
One day, explaining his distaste, Lynch said, "There is so damned
much housekeeping. The problem is, biology is a very horizontal
science. You have this result over here, that one over there. None
of it lines up."
His lack of enthusiasm for working on the bench meant that he
needed others who were both capable and willing to do it. No wonder
he was unhappy about the rash of holiday vacations.

'Shadow land'

The person lynch was most unhappy with was Eniko Kramar, a postdoc
neurophysiologist who was running the crucial experiment Lynch
expected to prove his basic theory of memory encoding. Kramar could
hardly be regarded as a slacker. She typically worked longer and
harder than anyone in the lab, excepting Lynch.
Having come relatively late to neuroscience, she was approaching a
point in her career where she needed to make discoveries, then move
on to lead her own lab, or remain locked in subordinate roles. She
had become, like Lynch, a virtual scientific monk, paring away
other activities in her life until all that remained was the lab.
Unlike Lynch, she had actually had a wide range of outside
interests -- family, friendships, athletics.
Although it seemed to her at times that the more she did, the more
Lynch demanded, they were in important respects a good team. He was
a synthesizer. She was a pointillist, a technically minded bench
scientist who took care to not extrapolate beyond the results on
her screen. She sometimes found even those suspect, wondering if
some mistake hadn't deceived her into false optimism.
When Kramar returned from her brief Christmas holiday, she plunged
back into the experiment, which she had been planning since the
previous summer. It involved using a novel staining technique that
would let the researchers actually see changes in neurons.
A key part of Lynch's conception of LTP, and thus memory, was that
the process initiated a micro-scale remodeling of the interior
skeleton of cells at synapses.
It is generally agreed that memory is somehow built out of networks
of brain cells called neurons. How those networks get built is the
central question of memory research.
Researchers have established that when you experience a sensation
in the outside world -- perhaps seeing, smelling or touching
something -- the sensation is translated by the sensory organs into
an electrical signal that is routed to neurons in the brain, where,
if the signal is strong enough within individual neurons, it causes
chemicals called neurotransmitters to be released onto neighboring
cells.
Neurons are not physically connected to one another. There are tiny
spaces called synapses between them. The neurotransmitters travel
across the synapses. Think of the neurotransmitters as keys. On the
surface of the neighboring neurons are molecules that receive the
neurotransmitters. These are called receptors. Think of the
receptors as locks. When neurotransmitters attach to receptors on
the surface of a receiving cell, when the key opens the lock,
channels open into the cell.
It is because the neurons are not physically connected that
communication between them is never certain. You never know whether
a key is going to find a lock. This is thought to be why any
cognitive activity, including memory, is approximate. Sometimes the
connections are made; other times they are not.
The LTP hypothesis can be summarized by saying: After two neurons
have successfully made contact once -- that is, after the
neurotransmitters have attached to receptors -- the next time the
original cell releases its neurotransmitters, there is a much
greater chance the neighboring cell will receive them. There is a
greater chance a key will find a lock.
Lynch's longtime goal was to figure out why. The general outline of
his hypothesis was this: Once a neurotransmitter attaches to a
receptor, opening a channel into the cell, calcium pours through
the channel, setting off a chemical cascade inside. The end result
of that cascade is an interior reorganization of the cell.
A key molecule involved in the interior remodeling is called actin,
which is a structural protein used throughout mammalian biology to
build internal cell scaffolds. In the same way the outside of a
house reflects the shape of the frame beneath it, when an internal
cell scaffold is altered, the exterior of its cell is changed too.
In this case, Lynch thought a portion of the cell would become
squatter, with more surface area. The greater surface area provides
space for more receptors. The greater the number of receptors, the
greater the chance of a neurotransmitter finding one and making a
connection between the two cells.
The lab had recently developed a method in which the actin scaffold
proteins could be labeled with a dye. The labeling would occur only
after the actin changed shape; in lab terminology this was referred
to as polymerized actin.
The idea of Kramar's experiment was that after inducing LTP with
the usual electric stimulus, portions of the cells would
restructure, creating polymerized actin. Because the actin was
stained, you could actually see it under a microscope. If you could
see it, it would mean Lynch had been correct in proposing that the
whole physical remodeling, the actin polymerization, was the end
result of LTP.
That reorganization, in turn, strengthened the connection between
cells; networks of those neurons with strengthened connections
constituted the underpinning of memory.
When Lynch had originally proposed this sort of rapid structural
change at synapses, many in the field were skeptical. Eventually,
most researchers came around to the view that some sort of
structural change occurred, but it was taken more as a matter of
faith. Even many who believed the structural rebuilding occurred
thought newly synthesized proteins from the cell nucleus had to be
sent to the synapse to do it, and they spent an awful lot of time
looking for those proteins.
Lynch thought it would take too long for the proteins to be
manufactured in the cell nucleus; events were already underway, and
the material needed to complete the job was on hand.
Imagine a construction crew framing a building. If the protein
synthesis believers were right, the carpenters would have to call a
warehouse every time they needed a nail. Lynch proposed that the
crew had the nails right there in their belts. This experiment was
intended to provide proof.
"We're in the penumbra, the shadow land," Lynch said. "And now
comes the moment of moments."


Trials, and a series of errors, in the brain lab
http://www.latimes.com/news/science/la-na-memorysecond20aug20,0,7063203.story

Gary Lynchs UC Irvine research team struggles to understand how
memories are made. It is crucial to treating age-related declines.


The myth of modern science, that it proceeds carefully, rationally,
incrementally, building bit by bit from rock-solid foundations to
impregnable fortresses of fact, comes unraveled in contemporary
neuroscience. Fortresses, entire kingdoms of neuroscience have been
built on what turn out to be frail premises that get swept away
entirely when the next new thing comes along.
A few years ago, a huge amount of effort was spent researching the
then-thought marvelous qualities of a humble molecule called nitric
oxide. This molecule, better-known in the broader world as the key
element in laughing gas, was celebrated as a vital actor in human
memory and cognition.
Science Magazine, as if honoring a rock star or president, put the
thing on its cover and declared it Molecule of the Year.
______________________________________________________________

FOR THE RECORD:
Chasing memory: An article in Monday's Section A about UC Irvine
neuroscientist Gary Lynch's research into memory said nitric oxide
was a key element in laughing gas. It is not; nitrous oxide is what
makes up laughing gas.
______________________________________________________________

By the end of the next year, nitric oxide had fallen off the end of
the Earth. Little of what had been claimed on its behalf turned out
to be true. This was but one example in a long, sad tradition of a
science, as if gripped by mass hysteria, going off the deep end and
pretending it knew how to swim.
There was no guarantee, neuroscientist Gary Lynch liked to say,
that something was important just because you happened to study it.
"You always imagine those animals out in a herd, the wildebeests --
they're running along, and a lion jumps up and takes out this guy
named Clyde," Lynch said. And the world proceeds as if Clyde never
happened. "They don't talk about Clyde anymore. It's just not good
form to talk about him."
Lynch, who runs a lab at UC Irvine, has spent three decades
studying a phenomenon known within neuroscience as long-term
potentiation, or LTP, which can be very loosely defined as a
process in which electrical stimulation strengthens connections
between brain cells. Lynch had taken up the study of LTP because it
had characteristics strikingly similar to human learning and
memory. It seemed to take place in parts of the brain where memory
was thought to occur, and like memory, it occurred in an instant
and could last a lifetime.
The practical reality of memory -- that human beings, from very
young ages on, learn and store information -- had been established
and studied for millenniums. How it happened, however, remained a
dark continent yet to be mapped.
When people, even scientists, talked about memory, they likened it
to objects or concepts in everyday life. They talked about filing
cabinets, and photographs, and videotape replays. They almost never
talked about what memories really, physically were. Why? They
didn't know. LTP seemed an excellent candidate to be that physical,
molecular underpinning of memory.
Beyond the pure scientific intrigue of it, memory research has
grown more important as medical advances allow more people to live
into old age. With longevity has come an epidemic of memory failure
among the aged. Alzheimer's disease and other forms of crippling
dementia threaten to make living longer less a blessing than a
curse.
Things can go radically wrong inside an old brain, and unless you
understood how the physical processes of memory worked, Lynch
thought, you'd never be able to fix it when it broke.
Brain scientists generally agreed that networks of neurons somehow
wired together in the brain were fundamental elements of memory.
LTP was hypothesized as the means by which that wiring occurred.
Lynch had bet his career that he could work out the details of LTP,
and that what he found would matter -- that it would turn out to be
something beyond "an interesting little bit of biology." There were
too many similarities between LTP and memory, he thought. The gods
were unpredictable, he said, but seldom that cruel.
LTP had been discovered in 1973 not as a naturally occurring
phenomenon, but in the artificial and arbitrary conditions of a
laboratory experiment. Because of this, not everyone was convinced
LTP had significance outside the lab. As one of Lynch's rivals,
Nobel laureate Eric Kandel of Columbia University, said: "You know
what LTP is? It's an artificial way of stimulating your brain. Who
knows if this is what happens in learning and memory?"
That no one had figured out LTP was due largely to the inherent
complexity of brain biology. Seth Grant, a neuroscientist at the
Sanger Institute outside London, has counted more than 1,000
proteins thought to be involved in memory. If even half of that
number actually were involved, isolating and understanding the
behavior of each would be a Herculean undertaking.
Lynch was more prosaic. "It's a bitch and two-thirds," he said.
"And stupid too."
Other scientists had moved on. "The boys," as Lynch routinely
referred to the neuroscience establishment, turned en masse to the
exploration of what genes might be involved. That they were able to
find such genes almost at will was read by gene proponents as a
reason to stay and look for more. To Lynch, it made no sense. "It's
like trying to understand a computer by studying it a transistor at
a time. Not only will it take forever, it will never work. You'll
never get there unless you understand the programming."
"I asked myself: 'Why am I following you down this alley?' So I
didn't."
Lynch instead rode out the LTP bet. In January 2005, after decades
of studying and teasing out its details, he was in the midst of an
experiment to determine once and for all whether LTP was a mere
laboratory curiosity or the real thing -- the means by which
neurons were wired together to form memories. Lynch, in other
words, was about to find out whether he was a candidate to stand
Nobel shoulder to Nobel shoulder with Kandel. The alternative? He
was Clyde.
Lynch had long ago proposed that the end result of LTP was a
micro-scale physical remodeling of neurons that allowed them to
communicate better with one another. The lab had just developed a
new technique that Lynch thought would allow researchers to
visualize this remodeling, in fact, to see the physical trace of
memories.
This new technique promised to answer conclusively what had been
supposition, and to answer it in such a way you would literally see
the result.
Neuroscience comprises many distinct disciplines, or tribes, as
Lynch called them, ranging from mathematicians to evolutionary
biologists. Eniko Kramar, a senior scientist in the lab, was
actually going to run the experiment. Kramar was a
neurophysiologist, meaning she studied the function of brain cells.
Physiologists, generally, can be thought of as engineers. They're
practical people, interested in how stuff works.
At the moment, the stuff in question was synapses in a rat brain.
Most brain research labs used animals in their work, the main
reason being the lack of human subjects willing to have their
brains dissected. Lynch Lab used rats almost exclusively.
Other labs used mice or simpler creatures -- fruit flies and sea
slugs. Genes that performed certain known functions in fruit flies
did the same or similar work in humans; the genes were conserved,
scientists say -- natural selection winners passed up the
evolutionary chain. Use of these animal models is a daily
expression of unquestioned trust in evolution as a central fact of
human history. Even as debates might rage in broader society over
the idea that human beings are descended from apes, there was a
strong conclusion in biology labs that human antecedents go back
way past the apes to the flies and beyond.
Still, Lynch wondered about the practicality of studying memory in
nonmammals that, in human terms, didn't have any. "Memory is an
emergent phenomenon," he said. "Steam is an emergent phenomenon. If
you want to study steam, you better study hot water. You ain't
going to get steam out of mud."
Visualizing success
Kramar's experiment began with the death of a rat, which she
accomplished using a small guillotine. It took her less than five
minutes to decapitate -- or, as she put it, sacrifice -- the
animal, cut open its skull, remove the brain and separate the
hippocampus, a portion of the temporal lobe thought to be involved
in memory, from the rest of its cortex. She then sliced the
hippocampus, which in a rat is about the size of a clipping from a
thick thumbnail, into five very thin sections.
The slices were transferred to a small, circular Plexiglas chamber
centered on a workbench under a microscope. The chamber was fed by
separate lines carrying a nutrient-rich warm liquid and oxygen,
which together kept the brain alive and in some sense functioning.
The top of the chamber had cutouts that allowed electric probes to
be placed into the brain slices, one for stimulating and one for
recording. The stimulating electrode could be set to deliver
currents of precise timing and duration. Lynch and colleagues had
discovered decades before that LTP was optimized when initiated by
electric currents that mimicked a naturally occurring rhythm within
the human nervous system known as theta rhythm. This coincidence --
that the best way to obtain LTP in the lab was to mimic actual
real-world biology -- had, more than anything, convinced Lynch that
LTP was real.
"That day -- the day we found theta -- our mouths fell open," said
John Larson, who worked with Lynch on the discovery.
Kramar's chamber was situated on a table equipped with shock
absorbers to prevent the rumble of a truck or car outside from
disturbing the queasy equilibrium of the experiment. Because the
electrical measurements needed to be precise, any equipment that
might interfere with them was grounded, and connections were
shielded with aluminum foil to prevent stray signals from
intervening.
With all the foil and electrical tape and ground wires, the whole
apparatus, which the scientists referred to as a rig, had a kind of
jerry-built, Rube Goldberg quality.
After the slice was stimulated to mimic the theta rhythm, the
current would pass along previously identified pathways, setting
off biochemical reactions. The recording electrode measured the
current as it exited the slice. The data were fed automatically
into a computer program that translated and graphed the results. If
LTP occurred -- that is, if more neurons were wired together --
more current would move through the slice after the stimulation
than before.
Then, by using chemicals to block the actions of different
molecules within the brain slice, the scientists could tell whether
those molecules were essential to LTP. By laborious process of
elimination, they ought to be able to unveil the entire process.
The essential parts of that process would be the fundamental
building blocks of memory. They had done a great deal of the work
already, identifying what they thought were the key steps. They
hoped their new visualization technique would allow them to
actually see some of those steps.
Kramar was an exacting person, naturally fastidious in setting up
the experiment. She knew what was at stake. She didn't need Lynch
leaning over her shoulder to tell her this was important. Theirs
was a fraught relationship. In one important way they were
complementary. Lynch was given to big-picture conceptualization,
while Kramar lived at the level of the brush stroke. Their
temperaments were so utterly different as to be nearly opposed.
Kramar punched a key on her computer, initiated the electric pulse
and waited. The recording electrode was picking up interference
from elsewhere, overwhelming the readings. Kramar tried, patiently
at first, to isolate and banish the interference. She spent hours
looking, but never found the source. The brain tissue died in the
chamber.
The day's work ended before it ever got underway. Lynch wouldn't be
happy and Kramar knew it, but she was more upset that she had
killed a rat to no good end.
The seemingly random interference was the kind of thing that drove
the scientists crazy. It wasn't enough that they were opposed, they
felt, every step of the way by the complexity of the biology. They
had to fight their way to even get to the biology. Kramar had run
slices in other experiments in this rig for months without anything
like this ever happening.
"You do the same thing every day for a year, and then one day, for
no reason at all, you can't do it," she said. "It makes no sense,
but you just have to come back and do it again."
The next day, the interference was gone, a ghost vanished. Kramar
ran the experiment, stimulating the slices, taking her readings,
then infusing the slices with a dye that would stain only the
portions of the neurons that had been changed in the experiment.
They would show whether Lynch's hypothesized remodeling had
occurred.
Afterward, she packed the slices on ice and took them to a nearby
lab, where they would be prepped and mounted on slides.
Two days later, Kramar, with her own and Lynch's great
anticipation, got the mounted brain slices back. They were
worthless. Either the experiment had failed to produce any effect
on the slices -- unlikely -- or the slices had been improperly
mounted. She would have to start over.
Lynch said: "You're always surprised or horrified or pleased or
something. It's not what you expected. It's always a bunch of
crap."
A whimper, not a bang
The next day, Lynch said: "Several years ago, I sent a student out
and said, 'Your job is to find out what the boys know about
assembly.' That's what grad students are for. They're the cannon
fodder of science. You throw them at problems that have no chance
of being solved. One day, the student came back and said a new
thing -- integrins."
Integrins tie cells down to a particular place. They fix, for
example, blood cells into place so that a cut will clot. Think of
them as a kind of cellular thread that stitches cells into place.
As is typical in biology, molecules that perform a specific
function in one place often perform some variation of the same
function elsewhere. So Lynch presumed with integrins. He made them
a key part of his investigation, and the lab had since reported
that integrins in the brain fastened neurons in place, locking in
the changes LTP created.
"The only thing that keeps the neurons in your brain from rolling
out your nose is the fact that they're stuck together at adhesion
junctions. The adhesion junctions are actually the synapses," Lynch
said. "It's the boring biology of wound-healing, of blood platelets
clotting. . . . That's what I love about it, you know. It's like
the T.S. Eliot thing -- when it's all over it'll be a whimper, it
won't be a bang. It won't be a magic protein, it won't be a special
gene. It won't be any of that crap. It'll be watching a cell crawl
across the dish."
Just then, Ted Yanagihara, a gifted undergrad who was working with
Kramar, poked his head inside Lynch's office. It was a mark of the
meritocratic nature of the lab that Yanagihara, just a kid, really,
was entrusted with such work.
"Bad news," he said. "I have a result, and it's not a good result."
Kramar, in addition to the visualization experiment, was working
with Yanagihara trying to gather further evidence that integrin
molecules were one of the building blocks of LTP. They used
chemicals, called antibodies, to stop integrins from having any
effect. If they did, they hypothesized, they would block the final
stage of LTP.
Kramar was doing one version of this test in her slice experiments.
Yanagihara was doing another working with single cells. Everybody
was on edge. Some days the methods failed and they couldn't gather
results. On days their methods worked, the data were wrong or
confusing. Sometimes the integrins were blocked, sometimes they
weren't. This continued for two weeks.
Said Lynch: "That's the trouble with biology: There are just too
damned many variables."
"It's a wonder anything ever gets done," Yanagihara said.
Lynch said: "If you want clean results, go be a physicist."
Lynch accepted the repeated failures with surprising equanimity.
He'd been through worse droughts before. One experiment in the
early 1980s took two years. It had turned an entire cohort of grad
students into a contemporary legion of the damned, but the legion
kept marching and eventually the experiment succeeded.
Lynch amused himself. He had been shopping for a new car, his first
since a 1987 Ford Mustang that was now falling apart, day by day,
piece by piece, in the parking lot. Lynch had been a drag-racer as
a kid, and cars, along with single-malt Scotch whiskey and good
books, were among the very few possessions he cared much about.
He wanted a brand-new Chevrolet Corvette convertible, a formidable
machine, but he couldn't find the model he wanted nearby. While
everything was falling apart in the lab, he found a dealership in
San Jose that had it. He hopped a flight, wrote a check and drove
the car home that night.
Kramar took the setbacks more personally. By the end of the month,
she was exhausted and did the unthinkable -- she took a weekend
off. "I thought, I'm not even going to show my face. When I get
like that, I have to back away from everything. I went out and
bought books, then sat home and read them."
The mood in the lab had grown very dark. One day, Yanagihara said
to Kramar: "This is a nervous moment."
Kramar replied: "You're nervous? It's my career at stake."
She laughed dryly; no one laughed along. The integrins were a
crucial part of the hypothesis, and apart from what would be the
acute embarrassment of having to retract previously published
conclusions, Lynch had no alternative explanation. His entire
research program would be a shambles.
It was remarkable that so much could go so wrong all at once. Some
days the electric probes were too noisy to produce reliable
results. One day a computer melted, smoke rising from its innards.
Programs crashed. A day's work was halted when a grad student
couldn't make it to the lab.
"The answer is sitting there waiting for you, and you can't do
anything about it because your graduate student got his car
impounded," Lynch said, then went off on a long rant about the
torture of academic biology. "If I never go to another meeting, get
involved in another symposium, I'll be happy. I don't care if I
ever train another graduate student. Don't get me wrong. I'm
pleased with the way they've turned out. Lots of them have gone on
to do interesting things. But I want to be done. Done. Over."
There was an occasional ray of hope.
Yanagihara one day, finally, working with the brains of young rats,
got his experiment to work right, and found the result he was
expecting to find. "If we get it tomorrow in middle-aged rats, it's
great," he said.
"If you see a garbage can flying out of the lab onto the hedge,
you'll know we didn't," Kramar said.
The next day, the trash cans remained inside, but only because
nobody had the energy to throw them out the window. The experiment
had failed again.
terry.mcdermott at latimes.com
______________________________________________________________

Breakthroughs, and new crises, in the lab
http://www.latimes.com/news/science/la-na-memorythird21aug21,0,5918024.story

As Gary Lynchs team starts piecing together the story of memory,
his health prompts him to look into his own brain.


Lynch Lab sits between a toll road and the UC Irvine main campus,
in an office park of indistinguishable low-rise, beige-on-beige
stucco buildings. Neuroscientist Gary Lynch had moved his lab and
office -- for a while, just a desk in a hallway -- numerous times
during his Irvine career, often as the result of some feud or
slight. He ended up in the office park largely because everybody --
including him -- concluded all parties would be better-served if
there were physical distance between Lynch and his university
peers.
The lab is at 101 Theory Drive, a developer's idea of a scientific
street name that Lynch found presumptuous.
It is a mark of the difficulty of life sciences -- biology and its
many descendants -- that to call something a theory is to honor,
not slight it. Theory, evolutionary biologist P.Z. Myers has
written, is what scientists aspire to. Lynch, for all of his
bombast, was respectful of the intellectual protocols of his
science.
"I would have called it Hypothesis Drive," he said.
The hypothesis is the fundamental organizing principle in
scientific research. Its "if this, then that" structure underlies
almost all scientific experiments. The work in Lynch's lab has been
driven by a single overriding hypothesis Lynch first published in
1980.
Lynch proposed that the fundamental act by which a memory was
encoded involved a nearly instantaneous physical restructuring of
portions of brain cells, called neurons. That restructuring allowed
neurons to be built into small networks. Each small network would
be a memory, he thought.
Lynch's research focused on a particular area of the brain, a
structure called the hippocampus, long thought to be involved in
memory. Most neurons in the hippocampus have roughly triangular
bodies. Slender fiber extensions called dendrites sprout from the
top and bottom. The branches coming out of the top are called
apical dendrites. Those coming from the bottom are called basal
dendrites.
Also coming out of the bottom is a single larger extension called
an axon. All along their lengths, the dendrites are marked by
microscopic nubs called spines, thousands of them per dendrite. The
axons of one neuron extend to meet the dendritic spines of other
neurons. These dendrite-axon junctions are the synapses.
Lynch proposed that the dendritic spines at these junctions changed
shape during a process known as long-term potentiation (LTP), which
resulted in the strengthening of the bond between a dendrite and an
axon. The remodeled dendrites, he said, were the base elements of
memory.
Lynch acknowledged that the details of the biochemical interactions
that caused the shape change were complex and not well-understood
-- at the time he originally proposed it, in fact, not understood
at all.
But the crux of the hypothesis was that human interaction with the
environment -- a glimpse of blue ocean, the touch of a silk scarf
-- resulted in an actual physical change in cells in the brain, and
that those changes were the underpinning of memory.
Two notable properties of memory are its vast size and that it can
be made in a moment, yet last essentially forever. Any attempt to
describe the physical components of memory had to account for those
properties.
There are about 100 billion neurons in the human brain. Each neuron
has dozens of dendrites, and each dendrite has thousands of
potential synapses. So the synapses offered immense storage
capacity. But how could storage be so long-lasting? "For me it was
really, really obvious it had to be structural, but beyond that,
what could I tell you?" Lynch said.
Aside from the pure scientific achievement of understanding the
proposed memory mechanism, the value to ordinary people has become
more apparent almost every day since Lynch proposed it.
We are in the midst of a brain failure epidemic. Worldwide, it is
estimated that by 2040, more than 100 million people will suffer
some form of dementia. The physical mechanisms of memory break, and
do so with frightening frequency. Lynch was fond of saying that you
had no hope of fixing it if you hadn't first figured out how it was
supposed to work.
To understand why it can take so long to figure out, imagine a vast
pile of broken plates. A hypothesis is what someone, after
surveying the pile, might say about putting the pieces back
together.
If the hypothesis holds for a while, survives challenge and
criticism, much of it improbably hostile, it might eventually come
to some rough, general acceptance and be joined to other hypotheses
to form something more far-reaching. Neuroscientists habitually use
a particular word to categorize such a body of thought -- or
collected wisdom -- in a part of their science. They don't, as a
layperson might, refer to it as a theory. Instead, they call it a
story.
Lynch was perilously close to believing he knew the story of human
memory -- why it exists, how it works, how it fails.
Eric Kandel, a Nobel laureate for his own memory research and a
competitor, said of Lynch's work, "The current view of LTP is Gary
Lynch's view" meaning that much of what was known about the process
was what Lynch had discovered.
"He was the first person to fully appreciate the significance of
LTP as a physiological phenomenon -- very prescient," said Richard
Morris of the University of Edinburgh.
At the time it was published, Lynch's hypothesis was a lonely view.
By January 2005, after he and others around the world had spent
decades collecting evidence, the hypothesis was widely shared but
by no means proven.
Lynch and his colleagues then embarked on a series of experiments
intended to prove or disprove his hypothesis once and for all. And,
as if to taunt Lynch, almost everything the lab did for a month
didn't work. Computers crashed, fundamental experiments backfired,
grad students went AWOL. The whole research program seemed
imperiled. The lab was not a happy place.
Middle-aged aging
What brain scientists love about the hippocampus, apart from its
presumed significance, is that it is largely a good neighborhood in
which to work. It is, compared with much of the rest of the brain,
orderly, neatly layered and segregated. It is well-mapped; its
regions named with straightforward simplicity -- CA1, CA3, etc. If
you chose to poke around there, you generally knew what you were
poking.
There is a place in the hippocampus, however, where the naming
scheme as well as all ideas about the function of the thing ran
aground. The place is called, in an appropriately Middle Earthian
way, the mossy fibers.
"It's the strangest connection in the brain -- the strangest thing
in the mammalian brain -- right in the middle of the memory
structure," Lynch said. "There's no hypothesis as to why these
things are sitting in the middle of the memory structure."
"These things" are very long, faintly furry axons extending from
neurons in an area of the hippocampus known as the dentate gyrus.
That they are there bugged Lynch to no end. Here sat something
dead-center in the thing he had studied for decades, and he was
utterly perplexed by it. Clues were gathering, however.
Laura Colgin, a postdoc in the lab, was intrigued by weak electric
pulses that apparently originated in the same area as the mossy
fibers. Other researchers had reported similar low-frequency waves
occurring elsewhere in the brain during sleep and periods of
wakeful rest. They called them sharp waves. No one knew what the
sharp waves did until Colgin discovered that in the right
circumstances, they seemed to erase LTP. In other words, if LTP was
the mechanism for memory, sharp waves could be a mechanism for
forgetting.
As counterintuitive as it seemed, the idea that there might be an
active forgetting mechanism made sense. No one remembered or would
want to remember everything. There had to be a way to get rid of
stuff.
"The brain is set up to detect patterns and causality, even when
they don't exist," Lynch said. Because the brain does this, Lynch
thought, it would be useful for the brain to have a way to rid
itself of patterns that turned out to be misleading.
"The assumption that contiguity means causality probably flows from
LTP, and controlling it provides a good excuse for the erasure
process," Lynch said.
Say, for example, you scratched your nose at the same time a dog
barked. The brain might read the fact that these two events
occurred at the same time as evidence they were related. There was
a need to rid yourself of these sorts of false associations.
While Eniko Kramar was leading the troubled effort to validate
Lynch's broader LTP hypothesis, Colgin's sharp wave research
prompted Lynch to begin a broader investigation of ordinary,
non-disease-related memory decline, which had been documented in
the psychology literature for decades. The general consensus of
that research was that memory started to decline not long after
humans reached physical maturity. You peaked at about 20 years of
age. After that, in terms of your ability to remember new things,
it was a long, slow, steady slide. Some studies indicated the rate
of decline was pretty much a straight line. You lost as much
ability to memorize between the ages of 20 and 30 as you did
between 50 and 60.
To neuroscientists, forgetfulness was largely seen as a behavioral
curiosity, and was not much studied as a biological phenomenon.
When it was, it was generally regarded less as a process itself
than as the failure of the memory process.
In Lynch's work, it was clear that LTP was greatly diminished in
elderly rats, but there were no experimental data to support the
notion of middle-aged decline. If LTP were the underpinning of
memory, and memory began declining in middle age, then LTP's
decline should mirror that of memory.
Lynch decided to do a more systematic search. He assigned the
project to a young graduate student, Chris Rex, who was a student
of Lynch's collaborator, Christine Gall. Rex had come to Lynch Lab
to learn physiology, and never left. He fell in love, he said, with
the direct contact to the biology that he felt doing physiology
experiments. "It's more like having a conversation where the
challenge is really asking the right questions," he said.
Lynch had a vague idea that one reason no one had ever found LTP
decline in middle-aged animals was that everyone had looked in the
wrong places. That they did so was largely a matter of convenience.
The apical dendrites are more numerous and easier to study, so most
research focused there.
Lynch sent Rex off into the basal dendrites of middle-aged rats,
where -- wonder of wonders -- Rex found distinct failure of LTP.
Since Colgin's discovery that forgetting could be the result not of
a failure but of an active process, Lynch had begun formulating a
broader view of LTP. He began to see it as the result of an
exquisitely balanced set of inputs. Some of the inputs encouraged
LTP. Others inhibited it. Such systems are common in mammalian
biology. They can fail from either direction -- too little
incitement or too much inhibition. Maybe the failure of memory was
simply the result of this mechanism getting slightly out of kilter.
It could be as simple, Lynch thought, as too much of one protein or
too little of another.
Lynch had known since the early 1990s that too much of a molecule
called adenosine outside a neuron interfered with LTP. He suggested
Rex administer a drug known to block adenosine to brain slices of
middle-aged rats where LTP was inhibited.
After a couple of weeks of false starts, including another computer
crash and some difficulty administering the drug, Rex decided to
wait until after LTP was induced to block the adenosine. Everybody
else in the lab thought that was a weird idea that would never
work. Lynch shook his head. "Crazy kid," he said.
At 1 a.m. on a Saturday in February 2005, Rex erased the LTP
deficit. It was completely, utterly gone. Full LTP was restored. In
brain science, even many successful experiments have vague results
that could be read in various ways. Seldom is anything this
clear-cut.
"It should never have worked," Lynch said.
Rex, a second-year grad student, grinned and shrugged his
shoulders. "Pretty lucky," he said.
The result was astonishing. What Rex seemed to have discovered was
a major cause -- if not the major cause -- of one of the most
persistent, widespread real-world effects of aging: forgetfulness.
And it seemed to be caused mainly by too much of a single molecule,
adenosine.
After weeks of repeated failures on almost every other front, Lynch
was ecstatic. "You mean this crap actually works?" he said. "You
don't expect to see a result this black-and-white. You expect
ambiguity. Aging does not occur uniformly even across a single
neuron. It's an instant default explanation for memory loss. It's
getting to the point where we might have to start believing we were
right."
A good rain
Rex's long-shot success dislodged some karmic plug in the LTP
universe. Things started to work throughout the lab.
Kramar had struggled for weeks with the experiment that was
intended to definitively validate Lynch's hypothesis that the
dendrites of neurons were physically reorganized during LTP. She
had endured a weird barrage of difficulties: problems with her
experimental apparatus, outdated chemical reagents, improperly
prepared specimens.
Suddenly, the difficulties all disappeared. The experiment started
working precisely as planned, and her results were almost too good
to be true.
"The data are perfect," Lynch said.
Kramar, still shaken by the preceding bleak weeks, spent hours
alone in the imaging room, studying her results; she was afraid to
believe what she was seeing. She produced stunning images showing
the cellular reorganization Lynch had hypothesized as the end stage
of LTP, the step that locked a memory in.
She did a series of experiments to block LTP, and the cellular
reorganization disappeared. She incorporated Rex's adenosine
findings. The results were clear-cut. Adenosine blocked the
reorganization. Take it away, and the process worked perfectly. She
blocked the integrins, the molecules that stitched everything else
into place. The LTP disappeared. Every crank of the wheel churned
out another supporting result.
After decades of struggle, all of the pieces were falling into
place. Lynch's long-standing hypothesis was being borne out to the
smallest detail. He could hardly believe it.
"I have to say, I'm flabbergasted," Lynch said. "I genuinely
believe that what we're staring at is the exact thing that occurs
in adult mammals as they lay down memories. The exact thing. That's
it. That's what I wanted. I wanted to see the thing itself. . . .
It's just colossal. It's a very hard thing to believe."
The mundane nature of the molecules involved made the findings more
convincing, Lynch thought. No divine intervention, no magic gene --
"just another lift from the parts bin," as he termed it.
"You give up grandeur, but in return you get confidence," he said.
One morning, not long after, Lynch woke up and could barely get out
of bed. He had no balance. He couldn't walk down the hall. Within
the week, he developed an acute respiratory infection. He had an
attack of gout. Another unrelated ancient ailment -- caused by a
chronic spinal condition -- recurred. It was like a perverse
illustration of his constant complaint that you never knew what was
about to go wrong.
The lack of balance was thought to be the result of a viral
infection of the inner ear; his doctor sent him to get an MRI to
rule out problems deeper inside.
Each image of a typical MRI shows a very thin slice of whatever
body part is being examined. A brain MRI produces in digital form
what you would get if you were able to take a very large kitchen
mandoline and work your way down, slice by slice, from the top of a
skull to the bottom. The resulting stack presents a digital photo
album of the inside of the head. After the exam, Lynch asked for
copies of the images.
He left the clinic that day with a CD-ROM containing the interior
images of his head in the pocket of his black cotton jacket. He
hopped in his brand-new cobalt-blue 400-horse Chevrolet Corvette
convertible and headed toward Irvine.
Lynch is a torque man. He drives very fast, especially in the lower
gears, where the experience of speed is visceral. Unless he's on
the freeway, he seldom gets out of third gear. Of course, in the
Corvette, third gear can mean flying 100 mph down a blind alley,
giggling like a schoolgirl.
Lynch took the CD-ROM back to his lab, where he fed the images into
a computer program that allowed him to scroll from top to bottom --
like riding the Magic School Bus with Ms. Frizzle -- through his
brain. Upon first sight of his own brain, Lynch began to make some
not altogether happy noises. There were low whistles, smacked lips
and much muttering. He shook his head a couple of times. He grew
uncharacteristically somber.
MRIs, as useful as they can be, remain crude tools. They allow one
to see larger structures inside the body. Unfortunately, the work
of the brain occurs mainly at the micro scale. The MRI would give
Lynch a flyover from 35,000 feet; what he really wanted was to blow
down through the anatomical weeds, low to the ground in first gear
in the Vette.
Even so, the MRI revealed cause for concern. The human brain
contains in each hemisphere large cavities -- literal holes in the
head -- called ventricles, where cerebrospinal fluid is produced.
The ventricles in Lynch's brain were enlarged. This in itself came
as no great surprise. Ventricle enlargement often accompanies
aging. The crucial questions were how much expansion and from what
cause.
As he sat in his office, looking at his brain blown up to quadruple
scale on his giant Mac monitor, he exhaled, shook his head,
pointed, and said, "Boy howdy. That doesn't look very good."
Lynch and a company he co-founded were that very month trying to
get Federal Drug Administration approval to begin testing the drugs
he had invented, called ampakines, in humans. The ampakines were
intended to help alleviate a wide variety of brain malfunctions.
He slumped back in his chair and said, "You better hope we come up
with something on them ampakines. Normal or not, you don't want
this."
Despite the siege of illnesses, Lynch continued going to the lab
every day. One Friday, he realized he had forgotten to submit to
the National Institutes of Health crucial data supporting his
request for renewed funding. The data were long past due. Lynch was
stricken.
That afternoon, everybody in the lab gathered to celebrate the
incredible run of good fortune. Somebody dug out three bottles of
Sierra Nevada Pale Ale and divided it up among a dozen or so
people. With no drinking glasses at hand, they poured the beer into
test tubes and tiny chemical beakers.
Lynch, standing in the middle of the celebration, raised his
beaker:
"We do adenosine, Eni's integrin experiments. We ran the table. We
ran the table. Then I realize: I forgot my grant. I forgot to send
the supplemental material. I'm a chronic screw-up. I promise you,
I'm the only neuroscientist in history who forgot his grant. This
is a screw-up of biblical proportions. Even I have to say it --
that's a screw-up. This grant is cursed."
Lynch stood there, swaying back and forth. His face, expressive
even when becalmed, now seemed about to stretch beyond the bones
beneath it. His jaw worked slowly from side to side, his grin
shifting with it. He leaned on a lab bench for support, to keep
standing.
He stood with his little beaker of beer and grinned. He stood there
like that, grinning and quiet and swaying, for a long time.
"It doesn't matter," he said. "I can barely walk a straight line,
and I blew my grant. I'm a chronic screw-up. Who cares? I have this
beautiful science raining down all around me."
______________________________________________________________

Success and rejection
http://www.latimes.com/news/science/la-na-memoryfourth22aug22,0,1347800.story

Gary Lynch expects his brain lab's work to bring 'all the tribes of
neuroscience to the same campfire.' Instead, he meets resistance.

Reflecting in the spring of 2005 on his lab's recent successes,
which he regarded as a culmination of decades of work, UC Irvine
neuroscientist Gary Lynch said: "This will be a moment when all the
tribes of neuroscience come to the same campfire."
He was wrong. There was no reaction. Nothing. Initially, he
couldn't even get a short paper on a crucial visualization
experiment published. Lynch envisioned the experiment as a grand
confirmation of his notion that a change in the physical structure
of brain cells at the connections between them was responsible for
the encoding and persistence of memory.
It had taken 20 years to acquire the tools to execute, and when
Eniko Kramar, a senior scientist in Lynch's lab, produced a series
of spectacular microscopic photographs depicting where and how the
change occurred, Lynch awaited the triumphal acclamation of the
lab's success.
The tribes were not at the same campfire. Many apparently hadn't
yet learned that fire had been discovered.
When a paper is submitted to a scientific journal, the journal
editors send it for review to panels of scientists. Peer review is
the backbone of contemporary scientific legitimacy and lauded by
everyone involved. It is also an opportunity for mischief and
misunderstanding.
Lynch's history of antagonizing his peers sometimes made peer
review more a gantlet than a critique. Richard Thompson of USC, a
renowned neuropsychologist, said he had more than once nominated
Lynch to membership in the prestigious National Academy of
Sciences, but was told by other members Lynch would not be elected
so long as they lived.
"There's a reason for his paranoia. There are a lot of people out
there who don't like him. Gary doesn't suffer fools gladly,"
Thompson said, then paused for a moment. He chuckled and said: "And
there are a lot of fools in the world."
The reviews on Kramar's paper seemed not to even acknowledge its
main point -- that the lab had for the first time demonstrated the
physical reorganization of cells that occurred in the final stage
of long-term potentiation, or LTP, which Lynch believed was the
biochemical process underlying memory.
One reviewer, in recommending against publication, complained that
the scientists had only looked at a specific set of synapses, which
was inexplicable as criticism. They looked there because that's
where they were doing the experiment, that was where the condition
they were examining existed. It was as if a traffic engineer,
having proposed adding carpool lanes to the San Diego Freeway, was
asked why he hadn't examined four-way stop signs in Barstow.
Lynch was irate, and for a couple of days everybody avoided him.
Then one morning, he was at his desk, smirking like a boy with the
key to the cookie jar.
What happened? I asked.
"I can't tell you," he said, his grin growing.
But, of course, it was Lynch; he had to tell. He pointed at his
computer monitor on which was displayed information on a company
called Memory Pharmaceuticals, founded by Nobel laureate Eric
Kandel, and a competitor of Lynch's biotech company, Cortex
Pharmaceuticals.
"I'm shorting Eric's stock," Lynch said and cackled.
Kandel was the god king of contemporary neuroscience. He won the
Nobel Prize in 2000 for investigations of synaptic activity that
occurred during reflex learning in sea snails. He had also almost
single-handedly made the study of protein synthesis a major focus
of neuroscience.
Lynch thought the emphasis was wrongheaded, but there was little he
could do. Kandel, for his part, had nothing but nice things to say
about Lynch. He barely acknowledged they were competitors, despite
the fact that the two had led opposing armies in a 1990s war over
where at the synapse the crucial actions of LTP occurred.
Lynch turned out to be right and won that battle, but he lost the
war. Kandel received the Nobel Prize; Lynch went to ground.
For reasons not entirely clear even to Lynch, he retreated to his
Irvine lab. He focused on his research, continued to publish
voluminously, but largely absented himself from the numerous
academic conferences and symposiums at which neuroscience findings
were presented and debated and, not insignificantly, reputations
made and maintained. He declined to meet with visiting researchers
and fought with administrators and colleagues.
"It got to be very hard for me to keep playing with the boys," he
said.
Few things are more punishing to an ambitious man than to be right
and unappreciated. The latest fight over the Kramar paper was but
one more slight. In the end, Lynch reacted as he had before: He
complained bitterly then went back to work.
One of the things he devoted time to was the development of a
family of drugs, called ampakines, intended to enhance LTP.
Ampakines had followed a tortuous path, but finally in the spring
of 2005, Cortex, the small biotech firm in Irvine that licensed
them, had a viable drug candidate ready for federally mandated
human trials. The drug, called CX717, had sailed through Phase I
safety trials, and Cortex was now applying to the Food and Drug
Administration to conduct separate Phase II trials for its effects
on sleep deprivation, Alzheimer's disease and attention-deficit
hyperactivity disorder (ADHD).
The trials could be do-or-die events for Cortex.
That CX717 was to be tested in such a variety of diseases was in
part a business strategy to give Cortex as many chances at success
as possible. The strategy also reflected Lynch's belief that LTP
was a fundamental brain process. Whatever the cause of many
neurological diseases, poor communication between neurons was
almost always one of the results.
The first CX717 results from a small sleep-deprivation trial came
back in May. They were better than could have been hoped. The only
drawback to the trial was its size -- just 16 men, who were
deprived of a night's sleep, then given the drug and tested.
Without the drug and without sleep, their test scores fell off the
chart. With the drug and without sleep, they tested the same as
they had when well-rested, and had none of the jitters commonly
associated with stimulants.
It was a clear win for the company. Its stock sank.
"Try to lift the species out of the puddle of its own crap and what
do you get?" Lynch joked. The other trials had yet to get underway,
and there was too much going on to brood. The lab's incredible run
of success in nailing down details of the biochemical processes
underlying memory and forgetfulness, begun that March, continued
through the spring and summer.
Lynch began experimenting with more potent versions of the
ampakines. Julie Lauterborn, working in the lab of Christine Gall,
Lynch's longtime significant other and collaborator, had earlier
discovered that some ampakine variants increased production within
the brain of compounds known as neurotrophins.
These molecules, in particular one known as brain-derived
neurotrophic factor, or BDNF, were essential to the maintenance of
brain function. So many claims had been made for BDNF over the
years that Lynch tended to disregard them. He mocked it, referring
to BDNF as the "big-deal growth factor."
"That's the story -- everything that's wrong with the brain, BDNF
will fix it," Lynch said. "To me, it was ludicrous."
But when Kramar in his lab confirmed other reports that BDNF played
a crucial role in the LTP process, Lynch began to examine the
interaction between ampakines and BDNF.
He was astonished to learn that particular ampakines could be used
almost as a switch to turn on BDNF production and thereby boost
LTP.
There had been a long history of attempts to somehow get more BDNF
delivered to the brain. A company in San Diego had gone so far as
to drill holes in heads and pump BDNF directly in. To have found a
simple, apparently painless and yet powerful means to turn on BDNF
production would be like discovering a magic potion.
Lynch was convinced that many neurological diseases -- Alzheimer's,
Huntington's, Parkinson's -- were in part caused by the normal wear
and tear that accompanied aging.
Brain cells, unlike most of the cells in the body -- or most of the
cells in most of living creatures in all the known world -- were
more or less permanent. They did not die and get replaced by new
cells. They lived, for a century if their host did, and accumulated
all the damage anything that old might expect.
The combination of aging and specific diseases, some of them
genetic in origin, led to mental difficulties -- memory loss among
them, Lynch thought. Ampakines were supposed to help ameliorate
many brain diseases by bulldozing through the problems the diseases
created, compensating for aging. The drugs wouldn't cure the
diseases, but would relieve the most debilitating symptoms.

Tools of the trade

The direction of science is largely determined by the tools
available to pursue it. Problems arise when a tool dictates
direction -- an illustration of the axiom that if you only have a
hammer, every problem looks like a nail.
Grant-makers and journal editors demand that you use the popular
tools to gain their approval. Tenure committees make decisions
based on grants and publications. In very short order, research
becomes normative. Interlopers are shunned, and risk-taking is
constrained.
"If you've got a method that lets you look at something, then the
answer must be what that method allows you to see," Lynch said.
In Lynch's view, an unsightly number of neuroscientists have been
swinging hammers at a problem -- memory -- that didn't look to him
like a nail. The field was enthralled by the tools of molecular
biology and their ability to manipulate genes in experimental
animals.
It was routine to reverse-engineer laboratory mice or rats --
knocking genes in or out of the animals -- so that they had or
lacked certain qualities. In this way, the animals could mimic
specific disease states. There were rats with Huntington's disease,
Alzheimer's, Parkinson's.
One problem in using the animals for neuroscience was the
complexity of the human brain, which in many of its actions was
redundant. If one gene was knocked out, eliminating the protein
that gene manufactured, other genes might make compensating
proteins. It was often impossible to delineate precisely what
caused what.
"They're nowhere near knowing what the machine is, so they can't
know what the machine produces," Lynch said. "It's like a 747
crash-landed in the jungle. The monkeys are crawling all over it,
having a hell of a time trying to figure out what it is."
Lynch realized he suddenly possessed new tools of his own: Whatever
the fate of the unpublished Kramar paper (which was eventually
published), the method it described to visualize the late stage of
LTP was an important new laboratory tool; and the ampakines
themselves were a tool that could probe the inner workings of LTP.
The outline of Lynch's LTP hypothesis was this: When you
experienced a sensation in the outside world -- seeing, smelling or
touching something -- the sensation was translated by the sensory
organs into an electrical signal that was routed to the brain,
where it caused the brain cells, or neurons, that received the
stimulus to release chemicals to neighboring neurons. A cascade of
chemical events inside those neighboring neurons resulted in their
interior reorganization. That reorganization strengthened the
connection between cells at the points where they meet, called the
synapses. Networks of those neurons with strengthened connections
constituted the underpinning of memory.
In a normal LTP experiment, a slice of a rat's brain was subjected
to a precisely timed and measured electrical stimulus, mimicking
the electrical signal produced by a real-world sensory stimulus.
The experimenter measured the strength of the electric signal as it
traveled through the slice. If a larger-than-usual signal exited
the slice, that meant LTP had occurred and connections between the
neurons in the slice had been strengthened. All you really needed
for these experiments were a microscope, a chemical catalog and a
pair of electrodes. That didn't mean they were easy, just that the
tools to do them were straightforward.
Using her visualization method and the ampakines, Kramar examined
the BDNF-LTP interaction. Over the course of months, what emerged
was a picture that was at once immensely complicated and impossibly
elegant.
"Endogenous BDNF does everything they said. It's all true. It's all
true," Lynch said. "But I was too lazy to read the papers
carefully."
BDNF, Lynch now thought, was crucial to the physical restructuring
inside a neuron during LTP. In essence, it was on the "on" switch.
Lynch thought another molecule, adenosine, was the "off" switch. A
fine balance of the two was needed for the brain to work. Through
the fall, Lynch and company elaborated on this line of thinking.
Chris Rex, a grad student who had discovered LTP deficits in
middle-aged rats, set up an experiment to see what would happen if
he used ampakines to instigate BDNF production in the same rats.
It worked. The ampakine turned on the BDNF, and the BDNF promoted
LTP. The age-related deficit disappeared. As Lynch put it later:
"Middle-aged aging cured."
Lynch, at Gall's persistent urging, began to reintegrate himself
into the wider world of science. He accepted invitations to speak
at a few conferences.
The progress was not without drama, some of it self-inflicted.
Lynch continued his war with the university administration.
Finally, feeling he wasn't being treated with sufficient respect,
he shut down his lab at 101 Theory Drive, dispersing his
researchers to Gall's lab. Some of the scientists were by then --
or would soon be -- gone for good. Ted Yanagihara went to med
school in New York. Laura Colgin left on a postdoc to Europe. The
lab's computer expert left for private industry.
Lynch's health teetered between bad and calamitous. He showed up at
a conference in Vancouver fevered and shot full of antibiotics. He
gave his lecture, listened to others and made small talk, all the
while looking to be on the verge of collapse. "Just to have one
damned thing that works," he said.
His various maladies never seemed to go away. The problems he'd had
with balance didn't completely resolve. His neurologist held to the
initial diagnosis -- a viral infection. Lynch suspected something
more serious but never pursued another diagnosis. "I put that into
the 'Forget About It' file," he said. "Don't have time to worry
about it."
Through it all, he continued to publish. In a universe where most
papers are written in a combination of dense chemical symbolism and
genre jargon, Lynch's work stood out for its sometimes whimsical,
often literary tone. Some examples: "Consolidation: A View From the
Synapse," "Long-Term Potentiation in the Eocene," "Spandrels of the
Night?" and "Ampakines and the Three-Fold Path to Cognitive
Enhancement."
Not that this endeared Lynch to everyone in the field. In addition
to the Kramar paper, he began to have others rejected at a rate he
had never experienced. Said Lynch: "Uneducated reviewers to the
left, pygmies to right, but on came the army of science."
The army's accumulating evidence was producing a rich portrait of
the LTP process that seemed to Lynch to have far-reaching
implications. LTP seemed to be a fundamental brain process, perhaps
the fundamental brain process.

The end of the artifact

A disquieting aspect of LTP research had long been that Lynch, his
colleagues and thousands of other scientists had devoted decades of
research to it, attempting to describe its details, yet all the
while there was no assurance it had anything to do with memory.
They hoped it did. Some believed it did. None of them knew.
Kandel, the godfather himself, said he was far from convinced LTP
had real-world significance. Lynch, in the early years of LTP
research, seldom used the word memory to describe its relevance. He
said it was a presumed "substrate of behavioral plasticity," a
phrase nearly perfect in its obfuscation.
The great final task for Lynch would be linking LTP unequivocally
to learning and memory. There was a chance he had spent 30 years
chasing a mere curiosity, "an interesting little piece of biology,"
as he put it.
This worried Lynch; it scared the hell out of him.
Lynch determined he might be able to use the new visualization
method to do an experiment that could show without question that
LTP was memory.
The visualization technique involved staining structural molecules
inside neurons so that their reorganization could be seen. The
reorganization occurred only on the extensions of the neurons known
as dendritic spines. If particular spines had no reorganization,
the dye would wash right through without sticking. It would only
stick to the spines where LTP had occurred.
Lynch's lab had introduced and used the technique in normal LTP
bench experiments. Lynch wanted to try it in actual animals. Rats
would be trained in a new task, something that would be encoded
into memory. Then the dye would be injected into the rat's brain.
If it worked, the staining pattern would illuminate a neural trace
of memory. This was not a modest undertaking. Scientists for more
than a century had been trying to find such traces, often referred
to as engrams.
For a time in the mid-20th century, the search had been a furious
chase. It had since been all but abandoned as a sort of pipe dream.
His goal, Lynch said, was to see "spines encode memory in real rats
after real learning . . . maps of memory encoding sites in the
brain. . . . The crowd goes wild!!!"
The crowd, such as it was, would need patience. It took nearly half
a year to get the experiment up and running.
By fall, the lab had demonstrated that the technique could work in
a rat learning to navigate a new environment. The next test would
be to compare the brains of rats that had been allowed to roam free
with rats kept in cages. Presumably, the roaming rats would have
learned and remembered something of their environment and converted
this learning into memories that would have caused more spines to
restructure.
After the roaming period, the rats would be sacrificed and the
brains of the roaming and the caged rats examined. If successful,
it would confirm that the method worked in living animals, and the
team could proceed to do specific learning and memory experiments.
Lynch thought that might take a few days. Days turned to weeks,
weeks to months.
Given that Lynch had been at this for three decades, a few months
hardly mattered, unless you were living them.
Then, on a Saturday evening in early spring, Kramar was at the
microscope when she saw it -- an actual trace of an actual memory.
She started screaming.
"Gary was in the bathroom. I was so excited I almost ran in there
to get him," Kramar said.
Now that he knew the method worked, Lynch gathered the group the
next Monday to prepare for the final push. He had decided the rats
would learn pairs of odors such as lemon-orange and
strawberry-peppermint.
"The olfactory advantage is that we understand where odor memory is
encoded. We know a priori that if the animal learns, it has to be
here. In the visual cortex, you don't know where to start," he
said.
Vadim Fedulov, a graduate student, was assigned to run the rats in
a maze in the odor-learning experiment. He had been in the lab for
just a couple months. Lynch had agreed to take him on when it
looked as if he might be tossed out of grad school altogether. He
was young, very bright, somewhat unpredictable and not punctual at
all. He was, in other words, a typical Lynch recruit.
One morning not long after, before the markets opened, Cortex
announced the results of a clinical trial in which the ampakine
CX717 had been given to adults diagnosed with ADHD. The results
were an unqualified success. The drug reduced ADHD symptoms across
the board, almost equal to existing medications -- mainly
stimulants -- without any of their deleterious side effects.
ADHD affects an estimated 4% of children in the United States. More
than 30 million prescriptions are written for the disorder
annually.
Cortex stock doubled in value over the next week. Chief Executive
Roger Stoll announced the company was in negotiations with at least
eight big pharmaceutical companies that wanted to license CX717.
Such a deal, Stoll said, would be worth immediately as much as $30
million to the company and eventually several hundred million
dollars.
Lynch was ecstatic. It was the first big public demonstration of
the power of the ampakines. This was a day he had waited 15 years
for.
"It's immensely gratifying. It really is," he said. "It validates
the principle that you can treat neurological diseases by
increasing cortical communication."
Lynch, feeling magnanimous, patched up his relationship with the
university and moved back to 101 Theory. Kramar received a job
offer from an Irvine biotech company. Although she hated the
timing, in tears, she took the job.
Danielle Simmons took over her role in the engram search. Fedulov
built his T-maze -- which was outfitted with sliding doors and
flashing lights and apertures through which he inserted cotton
swabs soaked in various scents -- and began running rats.
Lynch was scheduled to speak at a pharmaceutical conference in San
Francisco. He prepared to be welcomed as a conquering hero.
Two days before the conference, the FDA called Cortex and said it
had found unspecified problems in preclinical results -- that is,
lab tests on animals -- with CX717. It ordered an immediate halt to
all human trials.
Monday morning, as Lynch was scheduled to speak, the clinical hold
was announced. Lynch had a bronchial infection and was loaded with
antibiotics and steroids; his plane was two hours late because of
bad weather. Cortex stock fell 60%. The subject of Lynch's talk was
the failure of translation from preclinical lab work to clinical
trials in memory drugs.
Irony wasn't quite strong enough to describe the circumstances.
Lynch had no objection to the FDA's action, even though he thought
the hold would be resolved painlessly. "They're doing what they
have to do," he said. "We're putting stuff in people's brains, and
they should be careful."
Lynch returned to Irvine, the lab and the odor-learning experiment.
Fedulov had trained three rats and was ready to inject the dye and
have the brains prepared for examination. Two of the rats, for
reasons unknown, died from the injections. The sole remaining rat
was sacrificed, its brain sliced and set on slides. Fedulov had the
slides at 101 Theory. Lynch wanted to look at them at Gall Lab,
where Lauterborn, an expert microscopist, could read and photograph
the images. He called Fedulov and asked that he bring the slides.
Tracey Shors, a neuropsychologist from Rutgers who early in her
career had written a much-discussed paper casting a skeptical eye
toward the role of LTP in memory, happened to be on the UCI campus.
She and Lynch were old friends and met to discuss their various
researches. Lynch told her about the afternoon's prospects; she was
interested, but skeptical. Bring me an engram, she said. Bring me
an engram.
Lynch went to lunch, just about dying from anxiety. When he
returned, Fedulov was nowhere to be found. There was Lynch, the big
experimental result waiting -- no rat brains, no scientists.
"You'd think I was trying to launch the space shuttle," he said.
Lynch called Fedulov on his cell. He'd come and gone and left the
slides in a refrigerator, neglecting to tell anyone. To further
darken the atmosphere, a short paper Lynch had written describing
the preliminary results of this work had come back from a journal
editor, declined with scathing reviews.
Fedulov finally showed up, retrieved the slides and mounted the
first in the microscope. One of the great difficulties in finding
the markings of memory, assuming you even knew what they looked
like, was knowing where to look. The brain, at the nano-scale, was
a very big place. Even a rat has hundreds of billions of synapses.
USC neuropsychologist Thompson has estimated that the human brain,
with as many as 10 quadrillion synapses, is capable of more
distinct neural patterns -- memories -- than there are atoms in the
universe. The reason Lynch had chosen an odor-learning exercise for
this experiment was because the olfactory cortex was the simplest
system to navigate.
Lauterborn searched through the slides, found the olfactory cortex
and moved aside to let Lynch take a look. He immediately began
oohing and ahhing. "Oh. Oh. Yes, yes, they could." He continued to
scan across the slides. "Yes, yes, yes, YES. I'm almost convinced.
Almost."
Lauterborn took digital photographs of the slides through the
computer and brought up the images for more-detailed examination.
The slides were a guided tour through the brain from the olfactory
bulb to the cortex to the hippocampus, to the region thought to
control emotion, the amygdala.
Lynch scanned across the brain regions. "That's gorgeous. . . .
That's the way the world's supposed to be. Look at that. . . . All
this time, that is the picture I wanted to see. Right there."
The following week they replicated the experiment with four more
rats.
Lynch was again at the microscope. The image on the monitor showed
a vast gray field of brain matter. The gray was lighted up here and
there sparsely, but intensely.
"You see 'em. You see 'em. Look at them," he said. He traced on a
piece of paper the path from the nose to the point on the image in
the olfactory cortex being viewed. "It's a direct connection
between the olfactory cortex and the hippocampus [the memory center
of the brain]. Four synapses from the nose to the hippocampus."
Back at the microscope, he followed the path through to the
hippocampus and murmured, "Vadim, Vadim, I'm going to make you
famous. . . . That's it. That is the first demonstration that LTP
is engaged in memory."
Is memory? I asked.
"Is memory," he said. "It couldn't have been much better. All those
years, all those arguments -- it's all gone."
He went back to the microscope. After a minute or so of further
scanning and examination, he shouted, "You see that, boys and
girls? Science works."

A theory of a lot

One day not long after, Arvid Carlsson, a Nobel laureate
pharmacologist from Sweden, visited. Lynch briefed him on the
engram experiments. Carlsson was enthralled.
"To me, it seems so absolutely surprising and convincing," he said.
"It makes so much sense. It seems to be a fundamental discovery."
The approbation of a learned and widely respected old hand like
Carlsson was gratifying to Lynch, but to a surprising extent he had
moved beyond needing it. The science had yielded. All he wanted now
was more.
As the results continued to come in, he got it. An unrelenting
problem in memory research for decades had been determining the
location of long-term memory storage. "One of the darkest areas of
research," Alcino J. Silva of UCLA called it. "We know nothing
about it, literally nothing."
Researchers almost unanimously agreed that the hippocampus played a
fundamental role in acquiring new memories, but they seemed to be
moved later to the cortex for storage. If that were true, who or
what moved it?
Because Lynch Lab could now see actual memory traces, the
scientists were able to plot them onto brain maps. The maps showed
how complicated a phenomenon even a simple memory was and the
degree to which a single memory trace was distributed across brain
regions. When the rats learned new smells, the trace of the
learning landed in the olfactory bulb, then in the cortex, the
hippocampus, the amygdala.
In a single stroke, Lynch's LTP research seemed to have yielded a
realistic hypothesis for long-term storage. The memory wasn't moved
from the hippocampus but was encoded simultaneously in both the
hippocampus and the cortex. Presumably, a signal could later be
sent from the hippocampus to keep or discard that particular
memory.
Last October, the FDA lifted its hold on ampakine clinical trials,
but it imposed a dose limit for patients, and the trials didn't
restart until the limits were lifted this July. In the meantime,
other researchers around the globe began experimenting with
ampakines in a variety of indications, ranging from breathing
disorders to mental retardation.
Rex and Lulu Chen, a new graduate student, devised an alternative
means for the visualization experiments. The new method was easier
to execute and produced stunning, unambiguous, easily replicable
results. Publication of their work early this year provided the
validation Lynch had anticipated almost two years earlier.
Offers -- pleas, even -- to collaborate rained in from around the
globe. There was talk with the National Institutes of Health about
setting up an engram project, a sort of national memory- mapping
program to extend Lynch's work.
Lynch took gleeful satisfaction in the way in which the lab's
methods -- described disdainfully as producing results that were
"simply not credible" and contradictory to "all the assembled cell
biological knowledge" a year before -- suddenly seemed poised to
become standard practice in dozens of labs.
While declaring almost daily that he was about to quit the whole
enterprise, Lynch couldn't help himself. The experiments seemed to
provide interesting insights into Huntington's, retardation and,
out of left field, menopause. Kramar, bored with the pace of work
in private industry, returned to the lab. Hypotheses were being
born by the dozen, and Lynch began planning the next expeditions
onto the reedy shores of the unknown.
Lynch had in his career tried hard, he thought, even if no one
shared the opinion, to remain modest, shying from big ideas and
theories. He had thought it vain to suppose he could formulate an
overarching explanation of memory and cognition. Now he was greedy.
He wanted to shake the entire apparatus and demand all its secrets
fall to the ground.
A physicist, when grandiose, will talk about forming a TOE -- a
Theory of Everything. Lynch wasn't ready quite for that. This was
still biology, after all. He would settle for a TOAL -- Theory of a
Lot.
"I need to solidify the breakthrough -- get my arms around how big
the thing is, how much of brain biology can be folded into it," he
said.
The brain, he thought, represented a devil's bargain. You get
memory storage almost beyond measure, but because that memory
required more or less permanent neurons, you could not routinely
replace them with new cells. If neurons broke, and they do, you
were stuck with the results. As he so bluntly put it: You get
stupid. And, because the brain controls so much of what the body
does, when neurons fail you lose much more than memory.
"The evolutionary idea of stability as the cost of memory
fascinates me," Lynch said. "And maybe, at the end, there lies the
answer for how to get my broken-down brain going again."
Most of the work by this time was being done in Gall's lab, a few
hundred yards away from 101 Theory, where, some days, Lynch worked
alone.
It seemed fitting, somehow. There he sat at the end of the great,
long chase, often sick as a dog, the entry locked, the clamorous
tribes of the neurosciences a low hum in the distance; no phone, no
e-mail, not even a name on the door to betray his presence. The
only way you would know he was there at all was the blue Corvette
out front. And, of course, the science, which, no matter the
circumstance, difficulty or hour, had poured out for 30 years like
water from the well. And poured still.

terry.mcdermott at latimes.com