Scientific American Mind, Oct/Nov 2007:
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 aplysia 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 show 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 and bodies by responding to experience.
These discoveries, for which Kandel shared the 2000 Nobel Prize in Medicine and Physiology with Arvid Carlsson of the University of Göteberg 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. Kandel first made clear, to use the phrasing of New York University’s Joseph LeDoux, one of a generation of neuroscientists whom Kandel profoundly influenced, that “you are your synapses.”
If Kandel’s career helped define the foundations of 20th (and 21st) century neuroscience, 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 1950s psychiatry 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 that era helped forge his fascination with memory. To decipher memory's making, he decided, was to help decipher one’s essence and identity.
“We are who we are,” as 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 most 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 is scarcely blindered. Born in Vienna in the 1930s, he grew up—first there, then in New York after his family fled—loving literature, music, history and science. He finds fascinating both memory’s mechanisms and its shaping of character and culture. His interest in psychiatry, for instance, stems from admiration of Sigmund Freud’s elegant writings and also from his own 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 (see Further Reading). 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 a few things and leave the apartment. When the family returns after a few days—reunited, incredibly, with Eric’s father, who won 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, the KandelsKandel and his brother flee fled to the U.S., to be joined a year later by their parents.
Those memories would prove the most starkly stamped of Kandel’s life. To their power, writes Kandel, “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, powerful and influential work.
In America Kandel graduated from a public high school in New York City 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 told me a half-century later, “provoked my understanding of the brain as much as building that model did.” He soon began studying the brain in earnest, first at the Columbia University lab of electrophysiology pioneer Harry Grundfest during elective semesters in medical school, and then, after getting his M.D., at the National Institute of Mental Health. After doing some nice work 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.” But in the early 1960s, when Kandel decided to focus on simple 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 sort of “elementary forms of learning,” as he puts it, “[that] are 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 makes 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 genetic 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 this idea in detail.
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 roles that several key neurotransmitters played 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, as he put it 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 both 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 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 Roman y Cajal, who held a view of the mind quite different from that of Freud. In 1894 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, Cajal’s synaptic model of learning lay dormant—that is, until Kandel proved it out 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 integrate biology and interpretation. “We're trying,” says Stuart Yudofsy, a former Kandel protégé at Columbia who now directs clinical psychiatry at Baylor College of Medicine. “But I don't think any of us has got to where we want to.” Yet a new, Kandelian psychiatry, if you will, is already taking shape and stands to accelerate greatly 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 sleepy. SSRIs also ignore genetic variation among people, so they leave some patients unchanged while making others suicidal. Even those who find relief may have to try several different SSRIs before hitting upon one that works.
What is needed is drugs that aim precisely at the chains of gene expression that cause mental distress. Researchers are now identifying key gene variants associated with disorders including schizophrenia, bipolar disorder, anxiety disorder and depression. With some luck and more hard work, such research could produce 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 transport gene—the “ss” allele—is known to make people vulnerable to depression. Such drugs would work far more effectively and with far fewer side effects than today's medications.
Talk therapy will change too—already has. Recent studies have shown, for instance, that talk therapy can change brain chemistry in some patients just as effectively as drug therapy can [see “Facts and Fictions in Mental Health,” by Hal Arkowitz and Scott O. Lilienfeld, on page TK]. 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 depressives. Such therapy-driven changes seem to arrive through different avenues than do changes tied to medication. 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 jibes perfectly with Kandelian insights into the two-way nature of gene-environment interaction: psychotherapy, being a change in environment that engages the conscious mind, works from the top of the environment-gene 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 College of Medicine, argues that the bottom-up dynamics addressed by drugs are associated with what we might call basic temperament, while the top-down processes accessible by counseling relate more to learned behavior. “A general tendency toward despondency or passivity, you're probably going to have better luck with drugs,“ says Gabbard. “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 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 expresses 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 not as preprogrammed genetic machines or 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 a prion, the strange, protein-like structures that cause spongiform brain diseases such as mad cow. It is the first time anyone showed a prion playing a role in normal physiology. Kandel is now investigating just how this prionlike protein aids memory and whether it might be manipulated to improve memory.
He is also investigating the role that certain genes called Grp and stahmin play in how mice construct memories and other mental models of fear and safety. And with mice he 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 in New York City 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 stands on and keep going. Eric’s tied a bunch of those.”
In Search of Memory: The Emergence of a New Science of Mind. Eric Kandel., Norton, 2006.
Psychiatry, Psychoanalysis, and the New Biology of Mind. Eric Kandel,. American Psychiatric Publishing, Inc., 2005.
Eric Kandel Research Laboratory Web site: http://www.erickandel.org