Understanding the human mind in biological terms has emerged as the central challenge for science in the 21st century. We want to understand the biological nature of perception, learning, memory, thought, consciousness and the limits of free will. That biologists would be in a position to explore these mental processes was unthinkable even a few decades ago. Until the middle of the 20th century, when I began my career as a neuroscientist, the idea that mind, the most complex set of processes in the universe, might yield its deepest secrets to biological analysis and perhaps do this on the molecular level could not be entertained seriously.
The dramatic achievements of biology during the past 50 years have now made this possible. The discovery of the structure of DNA by James Watson and Francis Crick in 1953 revolutionized biology, giving it an intellectual framework for understanding how information from the genes controls the functioning of the cell. That discovery led to a basic understanding of how genes are regulated, how they give rise to the proteins that determine the functioning of cells, and how development turns genes and proteins on and off to establish the body plan of an organism. With these extraordinary accomplishments behind it, biology assumed a central position in the constellation of sciences, in parallel with physics and chemistry.
Imbued with new knowledge and confidence, biology turned its attention to its loftiest goal: understanding the biological nature of the human mind. This effort, long considered to be prescientific, is already in full swing. Indeed, when intellectual historians look back on the last two decades of the 20th century, they are likely to comment on the surprising fact that the most valuable insights into the human mind to emerge during this period did not come from the disciplines traditionally concerned with mind--philosophy, psychology or psychoanalysis. Instead they came from a merger of these disciplines with the biology of the brain, a new synthesis energized recently by dramatic achievements in molecular biology.
Mind Is Brain
The result has been a new science of mind, a science that uses the power of molecular biology to examine the great remaining mysteries of life. This new science is based on five principles. First, mind and brain are inseparable. The brain is a complex biological organ of great computational capability that constructs our sensory experiences, regulates our thoughts and emotions, and controls our actions. The brain is responsible not only for relatively simple motor behaviors, such as running and eating, but also for the complex acts that we consider quintessentially human, such as thinking, speaking and creating works of art. Looked at from this perspective, mind is a set of operations carried out by the brain, much as walking is a set of operations carried out by the legs, except dramatically more complex.
Second, each mental function in the brain--from the simplest reflex to the most creative acts in language, music and art--is carried out by specialized neural circuits in different regions of the brain. This is why it is preferable to use the term "biology of mind" to refer to the set of mental operations carried out by these specialized neural circuits rather than "biology of the mind," which connotes a place and implies a single brain location that carries out all mental operations.
Third, all of these circuits are made up of the same elementary signaling units, the nerve cells. Fourth, the neural circuits use specific molecules to generate signals within and between nerve cells. Finally, these specific signaling molecules have been conserved--retained, as it were--through millions of years of evolution. Some of them were present in the cells of our most ancient ancestors and can be found today in our most distant and primitive evolutionary relatives: single-celled organisms such as bacteria and yeast and simple multicellular organisms such as worms, flies and snails. These creatures use the same molecules to organize maneuvering through their environment that we use to govern our daily lives and adjust to our environment.
Thus, we gain from the new science of mind not only insights into ourselves--how we perceive, learn, remember, feel and act--but also a new perspective of ourselves in the context of biological evolution. It makes us appreciate that the human mind evolved from molecules used by our ancestors and that the extraordinary conservation of the molecular mechanisms that regulate lifes various processes also applies to our mental life.
Because of its broad implications for individual and social well-being, there is now a general consensus in the scientific community that the biology of mind will be to the 21st century what the biology of the gene was to the 20th century.
A Systems Approach
As we enter the 21st century, the new science of mind faces remarkable challenges. Researchers of memory storage, including my colleagues and me, are only standing at the foothills of a great mountain range. We have learned about the cellular and molecular mechanisms of memory storage, but now we must progress to the systems properties of memory. For example, which neural circuits are critical for which kinds of memory? How does the brain encode internal representations of a face, scene, melody or experience?
To develop an approach that relates neural systems to complex cognitive functions, we must focus on neural circuits, discerning how patterns of activity in different circuits merge to form a coherent representation. To learn how we perceive and recall complex experiences, we must determine how neural networks are organized and how attention and awareness shape and reconfigure neural activity in those networks. To accomplish these goals, biology must focus more on human beings and on nonhuman primates using imaging techniques that can resolve the activity of individual neurons and neuronal networks.
What Is Attention?
These reflections have led me to wonder what scientific questions I would pursue were I to start anew. I have two requirements for selecting such a research problem. First, it must allow me to participate in opening a new area of research that will occupy me for a long time. (I like long-term commitments, not brief romances.) Second, the problem must lie at the intersection of two or more disciplines. Based on these criteria, three sets of questions appeal to me.
What is this spotlight of attention? How does it trigger the neural circuitry of spatial memory to encode information? Moreover, what modulatory brain systems turn on when an animal pays attention, and how are they activated? How does attention enable me to embark on "mental time travel" to the little apartment in Vienna where I grew up? To investigate these matters, we ought to extend our studies of memory beyond laboratory animals to human beings.
The second question is, How do unconscious and conscious mental processes relate to one another in people? The notion that we are unaware of much of our mental life--an idea that German physician and physicist Hermann von Helmholtz proposed in 1860--lies at the core of psychoanalysis. Only through understanding such issues can we address, in biologically meaningful terms, Sigmund Freuds theories proposed in 1899 about conscious and unconscious conflicts and memory. To Helmholtzs notion, Freud added the important observation that by paying attention, we can access some of our unconscious mental processes--ones that would otherwise go unnoticed.
Seen from this perspective--a view that most neural scientists now hold--most of our mental life is unconscious. And we become aware of many otherwise inaccessible brain processes only through words and images. So, in principle, we should be able to use brain-imaging techniques to connect psychoanalytic processes with brain anatomy and neural functioning. Such a bridge might enable us to learn how disease states alter unconscious processes and how psychotherapy might help reconfigure them. Unconscious psychic processes play such a large role in our lives; perhaps biology can help us learn about them.
Another example involves male courtship in the fruit fly Drosophila. A key protein, called Fruitless, governs this instinctive behavior, and Fruitless is expressed differently in male and female flies. Ebru Demir and Barry J. Dickson, neuroscientists at the Research Institute of Molecular Pathology in Vienna, have made the remarkable discovery that when female flies express the male form of this protein, they mount and direct courtship toward other female flies--or toward males genetically engineered to produce a characteristic female odor, or pheromone. Dickson also found that for Drosophila to grow the neural circuitry for courtship and sexual preference, the Fruitless gene must be present and active during the flys early development. (If scientists add this gene later, instead, then it does not have the same effect.)
Still a third example comes from Giacomo Rizzolatti, a neuroscientist at the University of Parma in Italy. He discovered that certain neurons in the premotor cortex become active when a monkey carries out a specific action with its hand, such as putting a peanut in its mouth. Remarkably, the same neurons respond when a monkey watches another monkey (or even a person) put food in its mouth. Rizzolatti calls these cells "mirror neurons," suggesting that they offer insight into imitation, identification, empathy and possibly the ability to mime vocalization--all unconscious mental processes intrinsic to human interaction. Vilayanur S. Ramachandran, a neuroscientist at the University of California, San Diego, has found evidence of comparable neurons in the premotor cortex of humans.
Mental States Are Brain States
Reflecting on just these three research strands, I can see whole new areas of biology opening up, providing a sense of what makes us social, communicative beings. An ambitious undertaking of this kind might not only reveal what enables members of a cohesive group to recognize one another but also give us insight into tribalism, which so often promotes fear, hatred and intolerance of outsiders.
Since the 1980s the path toward merging mind and brain research has become clearer. As a result, psychiatry has taken on a new role, both stimulating and benefiting from biological thought. During the past few years, even members of the psychoanalytic community have taken on a keen interest in the biology of mind, acknowledging that every mental state is a brain state, that all mental disorders involve disorders of brain function. Treatments work when they alter the brains structure and functioning.
To give a sense of how attitudes among researchers have changed in recent years, when in 1962 I turned from studying the hippocampus in the mammalian brain to studying simple forms of learning in the sea slug Aplysia, I encountered many negative reactions. At the time, there was a strong sense among brain scientists that mammalian brains differed radically from those of lower vertebrates, such as fish and frogs--and were incomparably more complex than invertebrate brains. The fact that Nobel Prizewinning neuroscientists, such as the late Alan Hodgkin, Andrew F. Huxley of the University of Cambridge and the late Bernard Katz, discovered the fundamental principles of signaling in the human nervous system by probing the neural axons of squids and the synapses joining nerves and muscles in frogs seemed to these mammalian chauvinists an exception. Of course all nerve cells are similar, they conceded, but neural circuitry and behavior differ markedly in vertebrates and invertebrates.
Of Flies and Men
This schism persisted until molecular biologists revealed the amazing continuity--throughout evolution, from lower to higher organisms--of the genes and proteins governing all neural systems. Even then, disputes arose as to whether the cellular and molecular mechanisms of learning and memory revealed in simple animal studies would generalize to more complex animals. Neuroscientists argued about whether elementary forms of learning such as sensitization and habituation gave rise to forms of memory that would be useful to study. The ethologists, who study animal behavior in natural settings, emphasized the generality of these simple forms of memory, whereas the behaviorists highlighted associative forms of learning, such as classical and operant conditioning, which are clearly more complex.
The disagreements were eventually resolved in two ways. First, Seymour Benzer, a biologist at Caltech, proved that cyclic AMP, which is important for short-term sensitization in Aplysia, plays a critical role in more complex forms of learning, such as classical conditioning, in a more complex animal--namely, Drosophila. Second, the regulatory protein CREB, first identified in my laboratory in Aplysia, proved to be a key molecular component in switching from short- to long-term memory in many forms of learning and types of organisms, ranging from snails to flies, to mice and to people. Evidently, learning and memory, as well as synaptic and neuronal plasticity, or ability to change, involve a family of processes that vary in molecular subtleties but share various components and a common logic. In most cases, these discussions proved beneficial for science, sharpening questions and moving research forward. To me, the most important facet of the debates was the sense that we were progressing in the right direction.
These debates influenced my views, as did my psychiatric training and psychoanalytic interests, which lie at the very core of my scientific thinking. Together they shaped my perspective on mind and behavior, establishing overarching ideas that influenced nearly every aspect of my research and fueled my interest in conscious and unconscious memory.
Passion and Bold Discoveries
Few experiences excite and stimulate the imagination more than discovering something new, no matter how modest. A new finding allows someone to see for the first time a small piece of natures puzzle. Becoming absorbed in a problem, I find it helpful to develop a comprehensive perspective by learning what previous scientists thought about it. I want to know not only which lines of thought proved productive but also where and why other lines proved unproductive. And so Freud, as well as other early researchers in learning and memory--such as the classic psychologists William James, Edward Thorndike, Ivan Pavlov, B. F. Skinner and Ulric Neisser of Cornell University--all strongly influenced my thought. Their thinking, and even the unproductive paths they followed, provided a rich cultural background for my later work. Thus, my initial aspirations in psychoanalysis were hardly a detour. Rather they became the educational bedrock of all that I have tried to learn.
It is important to be bold. One should tackle difficult problems, especially those that initially appear messy and unstructured. One should not fear trying new things, such as moving from one field to another or working at the boundaries of disciplines--where the most interesting problems often emerge. Most good scientists never hesitate to ask questions, explore unfamiliar terrain, follow their instincts or learn new science along the way. Nothing stimulates self-education more than pursuing a new area of research.
Defining a problem, or a set of interrelated problems, with a long trajectory is also critical for success. Early on I stumbled fortunately onto an interesting problem while studying the hippocampus and memory and then switched decisively to investigate learning in a simple animal. Both problems had enough intellectual sweep and scope to carry me through many experimental failures and disappointments.
As a result, I did not share the midcareer malaise of some colleagues who grew bored with their science and turned to other things. Rather I thrived on testing new ideas. My friend and colleague Richard Axel, a fellow neuroscientist at Columbia University who received the Nobel Prize in 2004 for his remarkable discovery that there are 1,000 different receptors for smell, often speaks about the addictive quality of reviewing in ones mind new and interesting findings. Unless Richard sees new data coming along, he becomes despondent--a feeling many of us share. Such is the constructive side of addiction, one that I have experienced in pursuit of my own lifelong passion--namely, to understand the cellular and molecular basis of mind.