101 THEORY DRIVE: The Discovery of Memory

Los Angeles Times

Sunday, August 19, 2007

By Terry McDermott, Times Staff Writer

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.

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.”

—

________________________________________

Los Angeles Times

Monday, August 20, 2007

By Terry McDermott, Times staff writer

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.

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.

—

________________________________________

Los Angeles Times

Tuesday, August 21, 2007

By Terry McDermott, Times Staff Writer

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.”

---

Los Angeles Times

Wednesday, August 22, 2007

By Terry McDermott, Times Staff Writer

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

Adisquieting 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.

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