In Search of Memory: The Emergence of a New Science of Mind (30 page)

Before long, the remarkable tools and molecular insights that had been used to dissect gene and protein function in bacteria, yeast, and non-neuronal cells were eagerly seized upon by neuroscientists, especially by me, to study the brain. I had no experience with any of these methods—it was all night science for me. But even at night I understood the power of molecular biology.

T
hree events conspired to transform my plan to apply molecular biology to the study of memory from night science to day science. The first was my move in 1974 to Columbia University’s College of Physicians and Surgeons to replace my mentor Harry Grundfest, who was retiring. Columbia was attractive to me because it was a great university with a wonderful tradition in scientific medicine and was particularly strong in neurology and psychiatry. Founded as King’s College in 1754, it was the fifth oldest college in the United States and the first to grant a medical degree. The decisive factor was that Denise was on the faculty of the College of Physicians and Surgeons and we had bought our house in Riverdale because it was convenient to the campus. My move from NYU to Columbia therefore shortened my commute dramatically and made it possible for both of us to have independent careers yet participate in a common faculty.

Moving to Columbia led to the second event, my collaboration with Richard Axel (figure 18–1). Just as Grundfest had been my mentor in the first stage of my biological career, spurring me to study brain functions at the cellular level, and Jimmy Schwartz had been my guide in the second stage, exploring the biochemistry of short-term memory, Richard Axel would prove to be the collaborator who guided me into the third stage of my biological career, one centered on the dialogue between a neuron’s genes and its synapses in the formation of long-term memory.

18–1
Richard Axel (b. 1946) and I became friends during our early years at Columbia University. Through our scientific interactions, I learned molecular biology and Richard began to work on the nervous system. In 2004 Richard and his colleague Linda Buck (b. 1947), who had been his postdoctoral fellow, won the Nobel Prize in Physiology or Medicine for their classic work on the sense of smell. (From Eric Kandel’s personal collection.)

Richard and I met in 1977 at a tenure committee meeting. At the end of the meeting, he walked up to me and said, “I’m getting tired of all of this gene cloning. I want to do something on the nervous system. We should talk and maybe do something on the molecular biology of walking.” This proposal was nowhere near as naïve and grandiose as my proposal to Harry Grundfest that I study the biological basis of the ego, superego, and id. Nevertheless, I felt obliged to tell Richard that as of the moment, walking was probably out of the reach of molecular biology. Perhaps a simple behavior in
Aplysia
, such as gill withdrawal, inking, or egg laying, might be more tractable.

As I got to know Richard, I quickly appreciated how remarkably interesting, intelligent, and generous he is. In his book on the origins of cancer, Robert Weinberg gives an excellent description of Richard’s curiosity and his incisive intellect:

Richard’s glasses have actually always been gold-rimmed, but otherwise the description is right on target. Besides having added the “Axel syndrome” to the annals of academic discomfort, Richard had made important contributions to recombinant DNA technology. He had developed a general method of transferring any gene into any cell in tissue culture. The method, called co-transfection, is widely used both by scientists in their research and by the pharmaceutical industry in generating drugs.

Richard was also an opera addict, and soon after we became friends, we went to the opera together on a number of occasions, always without tickets. The first time we went, we caught a performance of Wagner’s
Walküre
. Richard insisted that we enter the opera house through the lower entrance that connects to the garage. The usher who collected tickets at this entrance recognized Richard immediately and let us in. We went into the orchestra and stood in the back until the lights were dimmed. Then another usher who had recognized Richard as we entered came to us and pointed to two empty seats. Richard slipped him money, the exact amount of which he refused to reveal to me. The performance was marvelous, but periodically I would break out in a cold sweat as I worried about reading a headline in the next day’s
New York Times
: “Two Columbia Professors Discovered Sneaking into the Metropolitan Opera.”

Shortly after we began our collaboration, Richard asked the people in his laboratory, “Does anyone want to learn neurobiology?” Only Richard Scheller stepped forward, and he became our joint postdoctoral student. Scheller proved a most fortunate addition—creative and bold, as his volunteering to explore the brain indicated. Scheller also knew a great deal about genetic engineering; he had contributed important technical innovations while still a graduate student, and he was generous in helping me learn molecular biology.

When Irving Kupfermann and I were investigating the behavioral function of various cells and cell clusters in
Aplysia
, we had found two symmetrical clusters of neurons, each containing about two hundred identical cells, which we called bag cells. Irving found that the bag cells release a hormone that initiates egg laying, an instinctive, fixed pattern of complex behavior.
Aplysia’s
eggs are packaged in long gelatinous strings, each of which contains a million or more eggs. In response to the egg-laying hormone, the animal extrudes an egg string from an opening in its reproductive system, which is located near its head. As it does so, its heart rate increases and it breathes more rapidly. It then grabs the emerging egg string with its mouth and waves its head back and forth to draw the string out of the reproductive duct, kneads the egg string into a ball, and deposits it on a rock or an alga.

Scheller succeeded in isolating the gene that controls egg laying and showed that it encodes a peptide hormone, or short string of amino acids, that is expressed in the bag cells. He synthesized the peptide hormone, injected it into
Aplysia
, and watched as it set off the animal’s whole egg-laying ritual. This was an extraordinary accomplishment for its day because it showed that a single short string of amino acids could trigger a complex sequence of behavioral actions. My work with Axel and with Scheller on the molecular biology of a complex behavior—egg laying—sparked both men’s long-term interest in neurobiology and fueled my desire to move even further into the maze of molecular biology.

Our studies of learning and memory in the early 1970s had linked cellular neurobiology to learning in a simple behavior. My studies with Scheller and Axel, beginning in the late 1970s, convinced me, as they did Axel, that molecular biology, brain biology, and psychology could be merged to create a new molecular science of behavior. We spelled this conviction out in the introduction to our first paper on the molecular biology of egg laying: “We describe a useful experimental system in
Aplysia
for examining the structure, expression, and modulation of genes that code for a peptide hormone of known behavioral function.”

This shared project exposed me to the technique of recombinant DNA, which became crucial to my subsequent work on long-term memory. In addition, my collaboration with Axel laid the foundation for an important scientific and personal friendship. I therefore was delighted and not at all surprised when I learned on October 10, 2004, four years after I was recognized by the Nobel Prize committee, that Richard and one of his former postdoctoral fellows, Linda Buck, had been awarded the Nobel Prize in Physiology or Medicine for their extraordinary work in molecular neurobiology. Together, Richard and Linda made the astonishing discovery that there are about a thousand different receptors for smell in the nose of a mouse. This vast array of receptors—completely unpredicted—explains why we can detect thousands of specific odorants and indicates that a significant aspect of the brain’s analysis of odors is carried out by receptors in the nose. Richard and Linda then used these receptors in independent studies to demonstrate the precision of connections between neurons in the olfactory system.

The third and final event that promoted my goal of learning molecular biology and using it to study memory occurred in 1983, when Donald Fredrickson, the newly appointed president of the Howard Hughes Medical Institute, asked Schwartz, Axel, and me to form the nucleus of a group devoted to this new science of mind—molecular cognition. Each group of scientists the medical institute supports at universities and other research institutions around the country is named by its location. We thus became the Howard Hughes Medical Institute at Columbia.

Howard Hughes was a creative and eccentric industrialist who also produced movies and designed and raced airplanes. He inherited from his father a major interest in the Hughes Tool Company and used it to build a large business empire. Within the tool company he established an aircraft division, the Hughes Aircraft Company, which became a major defense contractor. In 1953 he gave the aircraft company in its entirety to the Howard Hughes Medical Institute, a medical research organization that he had just founded. By 1984, eight years after Hughes’s death, the institute had become the largest private supporter of biomedical research in the United States. By 2004 the institute’s endowment had risen to over $11 billion, and it supported 350 investigators in numerous universities in the United States. About 100 of those scientists belonged to the National Academy of Sciences, and 10 had Nobel Prizes.

The motto of the Howard Hughes Medical Institute is “People, not projects.” It believes that science flourishes when outstanding researchers are provided both the resources and the intellectual flexibility to carry out bold, cutting-edge work. In 1983 the institute started three new initiatives—in neural science, in genetics, and in metabolic regulation. I was invited to be senior investigator of the neural science initiative, an opportunity that had an extraordinary impact on my career, as it did on Axel’s.

The newly formed institute gave us the chance to recruit Tom Jessell and Gary Struhl from Harvard and to ask Steven Siegelbaum, who was about to leave Columbia, to remain. These were marvelous additions to the Hughes group at Columbia and to the Center for Neurobiology and Behavior. Jessell rapidly emerged as the leading scientist working on the development of the vertebrate nervous system. In a brilliant series of studies, he pinpointed the genes that endow different nerve cells in the spinal cord with their identity (the same cells that Sherrington and Eccles had studied). He went on to show that those genes also control the outgrowth of the axon and the formation of synapses. Siegelbaum brought his remarkable insights into ion channels to bear on how channels control the excitability of nerve cells and the strength of synaptic connections and how these are modulated by activity and by various modulatory neurotransmitters. Struhl developed an imaginative genetic approach in
Drosophila
to explore how the fruit fly develops its body form.

WITH THE TOOLS OF MOLECULAR BIOLOGY AND THE SUPPORT
of the Howard Hughes Medical Institute in hand, we could now address questions about genes and memory. Since 1961 my experimental strategy had been to trap a simple form of memory in the smallest possible neural population and to use multiple microelectrodes to track the activity of participating cells. We could record signals from single sensory and motor cells for several hours in the intact animal, which was more than adequate for the study of short-term memory. But for long-term memory we needed to be able to record for one or more days. This required a new approach, so I turned to tissue cultures of the sensory and motor cells.

One cannot simply remove sensory and motor cells from adult animals and grow them, because adult cells do not survive well in culture. Instead, cells must be taken from the nervous system of very young animals and provided with an environment in which they can grow into adult cells. The crucial advance toward this goal was made by Arnold Kriegstein, an M.D.-Ph.D. student. Just before our lab moved to Columbia, Kriegstein succeeded in rearing
Aplysia
in the laboratory from the embryonic stage of the egg mass to adulthood, a feat that had eluded biologists for almost a century.