The sea slug Aplysia californica is not unlike an eggplant. It is big--up to a foot long and six pounds--and bruise-purple from gorging on seaweed. Harass one, and it will emit "a very fine purplish-red fluid," as Charles Darwin found long ago, "which stains the water for the space of a foot around." Hardly a jewel of the sea.
Yet neuroscientist Eric R. Kandel looked at the slug 50 years ago and saw a gemlike formal simplicity, which he used to help build the foundations of modern neuroscience. With Aplysia, Kandel revealed that we learn not by altering neurons but by strengthening or building new synapses, or connections, between them--a breakthrough of a lifetime. Then he went on to elucidate the most intricate and basic mechanisms underlying this vital process, including how this synaptic remodeling embodies the concept now known as gene expression; that is, it occurs because genes, along with shaping our bodies and coloring our hair, constantly alter our brains by responding to experience.
These discoveries, for which Kandel shared the 2000 Nobel Prize in Physiology or Medicine with Arvid Carlsson of Goeteborg University in Sweden and Paul Greengard of the Rockefeller University, provide a central structure in neuroscience's "connectionist" view of the brain as a highly plastic organ defined by interlaced connections among neurons and brain regions. To use the phrasing of New York University's Joseph E. LeDoux--one of a generation of neuroscientists whom Kandel profoundly influenced--Kandel first made clear that "you are your synapses."
If Kandel's career helped to define the foundations of neuroscience in the 20th (and 21st) century, his life in turn reflects some of the past century's most essential forces. A psychiatrist before he was a neuroscientist, Kandel came to his new discipline because he wanted more testable, physical explanations of human behavior than psychiatry in the 1950s could provide. And he came to the country he now calls home, the U.S., while fleeing the Nazis and the great upheaval that was World War II. The power of his own recollections of this era helped to forge his fascination with memory. To decipher memory's making, he decided, was to strive to decipher one's essence and identity.
"We are who we are," Kandel points out, "because of what we have learned and what we remember." He has shown not merely that this is true but also how it happens.
An Unexpected Journey
Some would argue that reducing memory to mechanism dilutes its magic. Kandel, however--as fond of Proust as of Pavlov and intensely humanistic--makes no apologies for insisting that even our deepest thoughts and emotions rise from mechanistic biology. In his office at Columbia University--a room large and impressive yet comfortable, with a sitting area facing views of the Hudson River and coffee kindly offered to a visitor--he laughs and says, "Of course, the mind is a product of the brain! How could it not be?"
Yet Kandel is hardly a cold reductionist. For starters, he is gracious, warm and funny. And he wears no blinders. Born in Vienna in 1929, he grew up--first there, then in New York City after his family fled--loving literature, music, history and science. He is intrigued by memory's mechanisms and its shaping of character and culture. His interest in psychiatry, for instance, stems partly from his admiration of Sigmund Freud's elegant writings and partly from his pained fascination with the swings in individual and social psychology that convulsed mid-20th-century Europe. And his interest in memory rises from the power of his own childhood recollections, particularly that of the night on which the ugliest part of the 20th century intruded into a happy home.
Kandel related this tale to me in his office, and it appears at greater length in his memoir In Search of Memory. It is November 9, 1938, two days after Eric's ninth birthday, and the boy is steering a treasured new birthday gift, "a beautiful, shiny blue car," around his parents' Vienna apartment. It is early evening. Kandel's father is due home from running the family's toy store. A thunderous pounding on the door interrupts Eric's play. The Nazi police have come to roust out this Jewish family. They order his mother to pack some things and leave the apartment. When the family returns after a few days--reunited, incredibly, with Eric's father, who won his release from captivity because he had fought for the Austrians in World War I--they find the apartment ransacked. All the family's valuables, including Eric's new toy, have been taken. "One humiliating and frightening year" later, Kandel and his brother fled to the U.S., to be joined later by their parents.
Those memories would prove the most vivid of Kandel's life. To their power, Kandel writes, "I cannot help but link my later interest in mind--in how people behave, the unpredictability of motivation, and the persistence of memory." And so fascism's intrusion inspired some of neuroscience's most elegant, innovative and influential work.
Kandel graduated from a public high school in New York and then attended Harvard University, where he developed an interest in psychoanalysis that led him to enter New York University Medical School in 1952. There, in a second-year neuroanatomy course, a seemingly prosaic assignment to build a model of a brain out of clay fired his interest in the brain as mind. "Nothing I ever did," Kandel tells me half a century later, "provoked my understanding of the brain as much as building that model did." He soon began studying the brain in earnest, first in the Columbia laboratory of electrophysiology pioneer Harry Grundfest during elective semesters in medical school and then, having earned his M.D., at the National Institute of Mental Health. After working there on memory in mammalian brains, he decided to focus on the neural dynamics of a much simpler animal: the sea snail Aplysia.
A Path Revisited
"Reductionism," Kandel notes, "is not a philosophy but a method." Yet in the early 1960s, when he decided to focus on memory mechanisms in Aplysia, many of the authorities he consulted doubted that such a simple animal could illuminate a process as labyrinthine as human memory. Kandel had already tried to study memory in the monkey hippocampus and found its complexity confounding. He had a hunch that the simpler Aplysia could reveal the kind of "elementary forms of learning," as he puts it, "common to all animals." Certainly Aplysia is elementary. The strange, squishy beast has only 20,000 neurons, many big enough to see with the naked eye and easy to probe and monitor with electrodes and sensors.
Kandel's 45 years of work on Aplysia make for an epic tale, full of great brainstorms and bulldog tenacity. But at its center is a simple set of conditioning and sensitization experiments.
His first step was to establish a basic sea-slug reflex: touch Aplysia near its gill, on its back, and the slug will retract the gill. Kandel then added, just before the gill touch, a light shock to the animal's tail. After a few repetitions the slug would retract the gill at the tail shock alone.
Behaviorally, such association was nothing new; it was Pavlov redux. Unlike Pavlov, however, Kandel was watching more than the animal's behavior: he sought to understand its neural circuitry. Over several years (with many different slugs and colleagues), he identified and monitored the precise synaptic circuits, dynamics, signaling mechanisms and, finally, even the genes and gene actions that such tasks engaged. One of his first great discoveries was that although the slugs varied in how quickly they absorbed their lessons, they all learned by using the same 30-neuron circuit. This finding produced the central insight about the synaptic nature of memory. For if this learning always involved the same neurons, then the differences in what and how fast various animals learned must lie in the connections between neurons. Subsequent investigations confirmed and elaborated on this idea.
This discovery was only the first of many that Kandel made with Aplysia. He soon found, for instance, that although short-term memory is created by strengthening existing synapses, long-term memory requires the creation of new synapses. He then identified, confirmed or refined the understanding of the roles that several key neurotransmitters play in creating these signals. And since the 1990s he has been distinguishing ever smaller elements in the "cascades" of genetic expression--genes creating messengers that activate other genes that build the proteins that activate or control yet other genes--that create these synapses. All this work showed, wrote Kandel in a recent essay on reductionism in art and science, that "genes are not simply the determinants of behavior--they are also servants of the environment."
These insights into gene-environment interaction and memory's synaptic nature remain the core of Kandel's work. They also drive a bold campaign he has undertaken to remake psychiatry, the specialty he trained in and left for neuroscience. It is time, he has announced in prominent journal articles and many talks, to transform the "interpretive healing art" of psychiatry into "a modern discipline based on molecular biology." Psychiatry's aging interpretive framework, he argues, must be reworked to incorporate what we have learned about the biological bases of memory and emotion.
For someone who admires Freud as much as Kandel does, this campaign carries some historical irony. Kandel's discovery and proof that memory is synaptic confirmed a notion first offered by the great Spanish neuroscientist Santiago Ramón y Cajal, who held a view of the mind quite different from that of Freud. In 1894 Ramón y Cajal suggested that memory is stored not in neurons (his discovery of which would win him a Nobel Prize in 1906) but in the growth of new connections between them. But because he lacked the tools needed to explore synaptic change, he could not pursue his synaptic hypothesis of memory. Into that evidentiary vacuum walked Freud, who offered the mytho-literary-metaphorical model of memory and psychodynamics that would dominate psychological theory for most of the 20th century. Meanwhile Ramón y Cajal's synaptic model of learning lay dormant--that is, until Kandel proved it in the 1960s. When Kandel presses his psychiatric colleagues to get biological, he is not just urging them to modernize; he is calling them back to a path they once abandoned to follow Freud.
Yet integrating psychiatry's path with that of neuroscience is a big job, and psychiatrists sharing Kandel's agenda admit they are only beginning to merge biology and interpretation. "We're trying," says Stuart Yudofsky, a former Kandel protégé at Columbia who now directs clinical psychiatry at the Baylor College of Medicine. "But I don't think any of us has got to where we want to." Nevertheless, a new Kandelian psychiatry, if you will, is already taking shape and stands to accelerate rapidly in the years to come.
The most direct potential lies in drug design. Today's psychiatric drugs may improve on yesterday's, but they are still crude. For instance, because SSRI (selective serotonin reuptake inhibitor) antidepressants alter serotonin availability everywhere rather than only at mood-crucial receptors, they have unwanted effects on sexual function and make some people dizzy, sleepless or fatigued. SSRIs also ignore genetic variation among people, so they leave some patients unchanged. Even those who find relief may have to try several different SSRIs before hitting on one that works.
What is needed is a variety of drugs that aim precisely at the chains of gene expression that cause mental distress. Researchers are now identifying key gene variants associated with disorders that include schizophrenia, bipolar disorder, anxiety disorder and depression. With some luck and more hard work, such research could facilitate the production of psychiatric drugs that can alter specific gene-environment interactions, manipulating, for instance, the chain of gene expression through which a particular variant in the serotonin transporter gene--the "short" allele--is known to make people vulnerable to depression. Such drugs would work more effectively and with fewer side effects than today's medications.
Talk therapy will change, too--it already has. Recent studies have shown, for instance, that counseling can change brain chemistry in some patients just as effectively as drug therapy can [see "The Best Medicine?" by Hal Arkowitz and Scott O. Lilienfeld, on page 80]. Talk therapy, for instance, creates marked, measurable reductions in activity in a brain area called the right caudate nucleus in obsessive-compulsive patients, and it returns serotonin levels as well as sleep patterns to normal in some people with depression. Such therapy-driven changes seem to arrive through different avenues than changes tied to medication do. A 2004 study showed that effective psychotherapy in depressed patients causes metabolic changes primarily in the brain's "thinking" areas, such as the forebrain, whereas SSRIs most strongly affect "nonthinking" subcortical areas. This finding jibes perfectly with Kandelian insights into the two-way nature of gene-environment interaction: psychotherapy, being a change in one's environment that engages the conscious mind, works from the top of the environmentgene expression loop, whereas drugs work from the bottom.
Some psychiatrists are altering their approach accordingly. Glen Gabbard, a psychoanalyst and professor of psychiatry at Baylor, argues that the bottom-up dynamics addressed by drugs are associated with what we might call basic temperament, whereas the top-down processes accessible by counseling relate more to learned behavior. With "a general tendency toward despondency or passivity, you're probably going to have better luck with drugs," Gabbard says. "But drugs aren't going to change someone's tendency to, say, demonize others or fail to listen. That requires therapy. You have to choose your battles."
A Change of Mind
Meanwhile the connectionist theory of mind that Kandel helped to create has already led the rest of us to see ourselves differently. Our humor reflects this change, as jokes about Freudian slips give way to quips about psychochemistry. "He must be off his meds" may express an unfortunate stigma about mental illness, but as a replacement for cracks about Oedipal hostilities it denotes a significant shift. We see the mind in ever more mechanistic terms, replacing tales of conflicted psyches and warring inner selves with stories of errant messengers and deaf receptors. This vision is arguably a more hopeful take on human nature. It sees us neither as preprogrammed genetic machines nor as impossibly conflicted inner selves but as malleable networks that we can alter and heal.
Kandel's snails, meanwhile, foot-long and luridly purple, are still yielding secrets. Over the past five years, for instance, a team in Kandel's lab has discovered that a protein called CPEB plays a key role in Aplysia's long-term memory retention by taking a form distinctly like that of a prion, the strange, proteinlike structure that causes spongiform brain diseases such as mad cow. It is the first time anyone has shown that a prionlike protein plays a role in normal physiology. Kandel is now investigating just how CPEB aids memory and whether it might be manipulated to improve memory.
He is also investigating the role that certain genes called Grp and stathmin play in how mice construct memories and process ideas about fear and safety. And with mice Kandel is finally returning to his study of the hippocampus and the larger dynamics of brain-wide neurocircuitry that were simply beyond reach when he tried to study them in monkeys 45 years ago. "The big excitement now," he says, "is on the systems level. With something like Aplysia, you can take a molecular question and drive it into the ground. But it's not a cosmic animal. It doesn't have awareness or think great thoughts. But mice, in their own way, they do."
Kandel can expand his mission, of course, only because he and others have defined many of the molecular and cellular fundamentals underlying these wider brain functions.
If he is indebted to his own early success, so is the rest of neuroscience. Jack Barchas, chair of psychiatry at Weill Cornell Medical College and himself a groundbreaking researcher of endorphins and other stress-related hormones, says, "Eric has changed the landscape again and again. It started when he had the balls to see how fear is created in Aplysia and say, 'Ladies and gentlemen, this is not just a scared little snail. This is humanity. This is anxiety. This snail is anxious.'
"That alone changed everything. But Eric's real genius has been having the courage to change and develop and keep asking new questions. We in science are always climbing a slippery rope. Every once in a while somebody ties a knot in it that lets everybody stand on and keep going. Eric's tied a bunch of those."