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My father’s wish for me to become a doctor got me as far as the medical course in Oxford. This course had the peculiarity that all students were required to do an extra year between preclinical and clinical studies devoted to pure, laboratory-based science. The more academically inclined students were encouraged to spend a further three years to get a Ph.D. degree. By doing so, I became acquainted with W. Maxwell Cowan, M.D., Ph.D.,* then a clinical-stage medical student from South Africa, who was my personal tutor and laboratory team leader. So began my career in neuroanatomical research, and my father was satisﬁed, despite my having side-stepped the world of swaying stethoscopes.
I was Max Cowan’s ﬁrst (and only) graduate student in Oxford from 1960 to 1963. No sooner had I peered down a microscope and seen nerve cells, no sooner had I traced the strange and beautiful curves of the brain’s hippocampus, than I was hooked on the sheer beauty of this mysterious structure. Our main interest was in studying how the different bundles of nerve ﬁbers were arranged in the brain. Although, after his move to the United States in the 1960s, Max was to be the pioneer of tracing nerve ﬁbers by using radioactive substances as “labels,” the tracing method during the Oxford days involved cutting nerve ﬁbers and then seeing what happened downstream from the cut. The power of this method had been demonstrated by the greatly respected senior scientist who headed our department, Sir Wilfrid Le Gros Clark, in his classic studies of how nerve ﬁbers reach the cortex.
In the 1960s, using the electron microscope was just becoming technically feasible. Light microscopes had produced a magniﬁcation of a thousand; now, it was possible to work at a million times magniﬁcation. We saw more and more previously unseen forms in all their elegance. In New York City, one of the scientists leading the advance of the new technology, Sandy Palay, M.D., had just obtained the ﬁrst pictures that showed the structure of synapses. It became possible to study these microscopic gaps between nerve cells. It was Max who encouraged me to take up this new and exciting tool, and it was the coincidence of these inﬂuences that led me to the discovery that, after injury, new synapses form in the adult brain. I called this occurrence “plasticity,” by which I simply meant the ability to respond positively to change; the term has disseminated more widely through the ﬁeld of neuroscience than I ever could have dreamed. Although I did not realize it at the time, this idea was to set the direction for the rest of my professional life.
Discovering that the Brain can Repair Itself
The germ of this idea came during a late-evening conversation with Max as we left the Department of Human Anatomy. More than ﬁve years of struggle were to ensue, however, before it became accepted, because the wider implication of plasticity, as I used the term, was that one day repair of brain and spinal cord injuries might be possible.
The hypothesis that new synapses can form in the adult brain rested on a simple observation. Nerve cells communicate with each other by way of ﬁbers that travel through the brain from one cell to another. When a nerve ﬁber reaches its destination, it communicates with the target nerve cell by making a synapse. When nerve ﬁbers are severed, these synaptic connections degenerate and are lost. The severed ﬁbers do not regrow. Connections, and therefore the functions they carry out, are not restored. All this was known. My new observation was that within the ﬁrst few days after an injury the lost synapses are, in fact, replaced —not by regrowth of the original cut ﬁbers, but by a sprouting from local, undamaged nerve ﬁbers located in the area which has lost its connections, and that area thereby acquires new contacts. The brain ﬁlls in the defect like wet sand ﬁlling in a hole. The new connections formed in this way are not normal, but they do result in a rapid and complete restitution of the original numbers of synapses.
The idea that synapses can form after injury in the adult brain was indeed new, but why was it resisted so ﬁercely? The attacks came on two fronts. One was a technical objection, which Max was the ﬁrst to raise: Maybe the observed effect was simply due to shrinkage, which compacted the same number of synapses into a smaller space and gave the illusion of there being an increase. The other was moral: To overturn the medical profession’s long-standing pessimistic predictions about the failure of recovery after brain or spinal cord injury might unsettle patients, who needed to come to terms with their disability and not be given false hope. In 1976, when I was invited to speak at a prestigious Royal Society of London gathering, assembled before the great gold mace that King Charles II had granted the Society, my chairman (a well-known but now deceased academic, who I do not intend to name) took the step —unique in my experience—of intervening to say that before allowing questions he wanted to point out this presentation was very dangerous.
“What would I do,” he asked “if a mother came to me and said, ‘My little Willie’s got brain damage. Can you repair it?’ ” In the years since then, I have often reﬂected on the absurd implication that, to prevent raising people’s hopes, all medical research would have to be conducted in complete secrecy.
In retrospect, though, I regard it as a tribute that an idea could arouse such ﬁerce opposition. It was opening a scientiﬁc door and giving hope. True, even all these years later we have still not gone through that door, and the hope is still only a hope, but I like to think that others will one day walk through the door.
“Plasticity” Finds its Second Instance
My career depended more than once on the coincidence of being in the right place at the right time. Another such coincidence was the eminent endocrinologist Geoffrey Harris’s moving with his research team to become head of my department in Oxford in 1962. This afﬁliation put me in touch with quite different ideas about the brain. Harris’s team wanted to know how the brain controlled the reproductive system. Harris himself was famous for his demonstration that the brain controls the endocrine system by producing hormones in a part of the brain next to the pituitary gland that then travel down nerve ﬁbers and are carried by blood vessels to the pituitary gland. Here was a difference between the sexes. Only the female brain could initiate the surge of hormones needed to induce the discharge of a ripe egg from the ovary, although it was known, also, that this sexual difference could be permanently overridden during a brief period of postnatal development by a single exposure of the brain to testosterone.
Over lunchtime games of bridge with my new colleague, Keith Brown-Grant, we discussed how to investigate the anatomy of those areas of the female brain involved in triggering the surge of pituitary hormones that is required to initiate ovulation. By applying the method of quantitative assessment of synapses that I had developed in studying the response to injury, I now showed that this functional difference between male and female brains was associated with a difference in the connections between synapses—a difference not determined by the genetic sex of the animal, but one that could be converted to the pattern of the opposite sex simply by supplying or withdrawing estrogen during the critical period.
These observations demonstrated two crucial premises of plasticity. First, synaptic connections could be changed; second, the change in synaptic connections led to changes in function. The concept of plasticity had found another example, but what continued to excite and attract me, and does to this day, was the hope that by understanding more about plasticity we might learn how to get people out of wheelchairs.
Repairing the Damaged Spinal Cord
In the early 1970s, the idea of spinal cord repair received a great impetus. Canadian neurologist Albert J. Aguayo, M.D., demonstrated the accuracy of the late 19th century prediction by Spanish brain research pioneer Santiago Ramón y Cajal that pieces of tissue taken from nerves of the limbs and transplanted into the brain and spinal cord could restore growth of cut nerve ﬁbers and, to a degree, connectivity and function. The tissue in which nerve cells are embedded consists of cells called glia. There are different types of glial cells. The specialized type of glial cells responsible for the regrowth of nerve ﬁbers observed by Aguayo are called Schwann cells.
Aguayo’s studies directed attention to the idea of transplanting glial cells. Until that time, glial cells had been the Cinderella of the brain. Nerve cells made connections, had electrical impulses, and, in Cajal’s phrase, were noble. They did the thinking. No matter that glial cells precede nerve cells in development (and may give rise to nerve cells). No matter that glial cells outnumber nerve cells by several orders of magnitude, a preponderance still more marked in both relative and absolute terms in primates and reaching its peak in humans.
Putting the spotlight on glia was a historic turning point in the search for plasticity. In terms of the anatomy of the brain, for example, my team demonstrated the universal presence of a kind of railroad tracks in the brain: very ﬁne threadlike processes made up of the glial cells called astrocytes that permeate the bundles of nerve ﬁbers and accompany nerve ﬁbers on their travels through the brain and spinal cord.
Before this time, a widely held view was that we are born with a ﬁxed complement of nerve cells, and that our lives must be directed towards preserving them and avoiding things that precipitate their untimely loss. But from the late 1960s onwards, a new technique, involving the use of radioactive precursors of DNA, led to a sensitive method of detecting the formation of new nerve cells. With this technique it has become increasingly clear that new nerve cells are actually formed throughout adult life.
A new aspect of plasticity had been revealed, and this formation of new nerve cells was expressed to its maximum in the olfactory system, where, in the lining of the upper nasal passages, the nerve cells that make possible our sense of smell can be totally replaced within a month after loss by injury. When the nerve cells are replaced, they grow ﬁbers that extend through minute holes in the base of the skull to reach the brain, make synaptic contacts there, and restore the sense of smell. In 1985, I used the electron microscope to demonstrate that there is a unique arrangement of glial cells at the point where the olfactory nerves enter the brain. Might not these glial cells from the olfactory system be a means to transfer the capacity for regeneration to other nerve ﬁbers in the brain and spinal cord? This idea is now being widely investigated.
My research team has shown that transplantation of olfactory glial cells, after they have been removed and grown in a culture, can restore severed connections in the spinal tract of rats, restoring functions such as breathing and climbing. Severing nerve ﬁbers also tangles up the railroad tracks—the ﬁne astrocytic threads that guide axons. Although it remains to be proved, I believe that the transplanted olfactory glial cells of a type called ensheathing cells can work by reconstituting the ﬁne astrocytic threads that have been tangled. This process restores the pathways needed to guide regrowing nerve ﬁbers across areas of injury and enable them to reach their original destinations.
In a life of research, there are a few magical moments. One of mine came in 1996 in the early hours of a mid-winter night in northwest London. The National Institute for Medical Research was deserted, but I was impatient to follow the behavior of rats that had received transplanted olfactory glial cells into the spot where we had made a tiny area of damage in their spinal cords. We had previously trained the rats to use their forepaw to retrieve pieces of Chinese noodle presented through a slit in the front of the cage. After the spinal injury, they never used the paw of the operated side. Now, with the transplanted olfactory cells in their severed spinal tract, I was watching their progress.
At the animal facility, I settled down to the testing regime: for each rat, 50 tries per paw per night. The calmness and quiet of the night is a blessing for studying behavior. The rats, comfortable as nocturnal animals, came forward eagerly for their favorite brand of noodles. After the ﬁrst few tries, one rat seemed to make a tentative movement of the neglected paw. I blinked and discounted it, but the hairs on the back of my neck began to rise. And then, after a few more ineffective tries, the paw came out again, tentatively, very little, and very slowly. There is a rapport between the tester and the trained rat. Each tries to please the other. This time, the rat paused and looked up at me with an expression that looked for all the world like amazement. At least, I know that I looked at the rat with amazement. Then, I tightened my grip on the noodle. At once, the rat tightened its grip and pulled the noodle forcibly away from me.
When the time comes to reﬂect on a life of research, this experience will be one of the moments that forever remain, the sense of “eureka” that at last, perhaps, I was seeing repair of injury to the spinal cord, that the long-sought goal might be achievable.
Since that time, we have discovered other situations in which transplanted olfactory glial cells induce growth of cut nerve ﬁbers. For example, they stimulate growth of cut nerve ﬁbers from the eye, and serve as bridges for ingrowth of nerve ﬁbers when injuries have pulled them out of the spinal cord. Both transplanted olfactory glial cells and Schwann cells can induce elongation of cut nerve ﬁbers, but only olfactory glial cells have the additional crucial property of opening up the interface between astrocytes and nerve ﬁbers in order to allow the regrowing nerve ﬁbers to re-enter the brain and spinal cord and thus restore connections and functions.
Obtaining glial cells from the nasal lining opens up the possibility of using grafts from a person’s own nose to repair damage to the spinal cord. Other cells might be found to have such properties; ways of improving the results will surely be found; and, in general, the approach will be made increasingly practical. But the results so far are positive to the point that now there is no backing away from the idea that repair is possible.
As important and heartening as these results surely are, the discoveries also offer a clue to one of the enduring mysteries of the brain: If structure is the basis of function, how can functional plasticity be coaxed from a system that is incapable of repairing itself structurally? Just asking that question makes us realize that the concept of plasticity is in its infancy. What we have seen is the tip of a distant iceberg, whose vastness we cannot judge. Still, with this widened perspective, I would like to take the rest of this article to ponder where the idea of plasticity could lead us.
What is the Brain for?
It is surprising how rarely any scientist even asks: What is the function of the brain? What is its purpose? The reason is not hard to guess. It is easier to study the part than the whole. We can study seeing, hearing, or movement; we have techniques to record impulses, detect patterns of activity, and stimulate speciﬁc bundles of nerve ﬁbers. But these approaches, in effect, pull apart bits of a larger whole of which they are only components. What is the function of the whole? I would like to suggest one straightforward starting point. The brain is the main organ of evolution. It is the brain of one animal that pits itself against another in the ﬁght for survival, and nowhere is this more true than in the human animal.
How does the brain function in the ﬁght for survival? The usual answers might include acuity of vision, hearing, smell, control of muscles, movement, skills. But this gives short shrift to the distinctive functions of the human brain, reducing it to a brainless force. And where human beings are involved, sheer force rarely wins the battle. The real survival skills are cunning, deception, planning, prediction, imagination. All of these skills include, and are based on, memory, concept formation, ﬂexibility, adaptability. These are precisely the functions I would include under the concept of plasticity.
Plasticity implies, above all, not having to react the same way a second time. In functional terms it implies the ability to learn, record, and analyze. Plasticity is the ability to go round the insuperable obstacle, not through it; to dodge and outwit; to be unpredictable to an opponent; to offer new ideas that recruit allies; and, when the outcome is positive, to beneﬁt from experience by doing it even better the next time. Plasticity in this sense encompasses imagination. And what is imagination if not to think what has never been thought, to hear what has never been heard, to see what has never been seen, and—for humans— to convey this imagination to others through what we call the creative arts? By imagining what does not exist, man has pushed back boundaries through exploration. Maybe there is another way from Spain to the Indies, by sailing west instead of east? Maybe we can put a man on the moon? It is the leap of imagination by which man is continually conquering new environments and passing to new generations an ever-increasing knowledge that brings with it power to prevail.
“Tell me where is fancy bred? Or in the heart or in the head?”
—William Shakespeare, The Merchant of Venice, Act III, Scene 2
Where in the brain does imagination lie? That question has the potential to transform our entire view of the brain. Start with the concept of “localization of function,” which means that different functions are located in different parts of the brain. Thus, the back of the cortex has the function of vision, the cerebellum has the function of balance, and so on. But here we run into a serious limitation.
The human visual cortex (depending a bit on exactly where its ever-shifting boundaries are drawn) is about the size of the palm of your hand. Yet, our visual acuity is much inferior to that of the eagle, whose whole brain is scarcely bigger than a bean. So what does the huge human visual cortex do? The cerebellum is the organ of dance, helping maintain posture and poise as we move. The human cerebellum is about as big as a child’s ﬁst. But we have great difﬁculty catching a common houseﬂy, whose poise, balance, movement—and ability to anticipate, evade, and outwit our fastest snatches—reside in a brain the size of a pinpoint. When it comes to ﬂying, its David of a brain is more than a match for our Goliath of a brain. So what is the justiﬁcation for our vast cerebellum?
Faced with these questions, we are a bit like Stone Age man confronted with a computer: We do not know the logic of the construction. I suggest that an important step is to look at overall function. If the purpose of the brain is adaptability, and humans have the largest brain with the widest adaptability, then we should look in the brain for a logic of construction that enables change, learning, and memory. The holistic concept that unites these functions is ﬂexibility, and ﬂexibility is unlikely to reside in one speciﬁc area of the brain. It is more likely to be distributed throughout all the brain’s systems, but particularly those systems such as vision, hearing, speech, and movement where plasticity is most required. How will we know when we are seeing this ﬂexibility? The simple answer has to be: when a system gives a variable response instead of a ﬁxed one. Of course, variable responses are something that scientists hate and try to eliminate.
Let us return to the question of structure. A basic concept is that the structure of the brain, the way it is put together, underlies its function. Therefore, we should be looking in every area of the brain to see whether structure is ﬁxed or variable. Where we see the greatest adaptability and imagination—plasticity of function—we would expect to see the greatest plasticity of structure; where we see little ﬂexibility, we would expect to encounter little plasticity. But, in the end, we would expect to see at least some structural plasticity everywhere.
Ideas that Stall Progress
On the face of it, this seems such a reasonable idea that we must ask why it has been so little investigated. To begin with, I think, there are technical limitations. The ﬁrst is that the study of anatomy, or structure, is largely the study of dead tissue. Anatomy shows only the connections ﬁxed forever in a museum specimen or on a microscope slide, frozen at a moment of time, the moment of death. I remember my anatomy teacher, Sir Wilfrid Le Gros Clark, who was also an anthropologist, holding up a human bone and saying: “It could have come out of an ancient Egyptian tomb. It is a ﬁxed, unchangeable object and can be preserved for centuries. But during life, the same bone in the body is forever changing. Its constituents are replaced totally every six weeks. And if a patient is put to bed and kept inactive, the bones start to weaken and lose mass within days.” If that applies to bone, how much more so to brain?
A second technical limitation could lie in the nature of electrophysiologic recording, which is used to track brain functions. Virtually anything will disturb the trace. To obtain meaningful traces, the human subject or animal must be isolated and kept under conditions sheltering it from any disturbing input. There was an experiment in which the Mexican physiologist, Hernandez-Peon, and his team were recording from the auditory system of a cat. The experiment was long, so the experimenters decided to stop for lunch and opened a tin of sardines. As soon as the smell escaped from the tin, the cat’s response to the auditory signals ceased. Even in the anesthetized cat, a system to all appearances stable, and so much under the experimenters’ control, the brain was simply hiding its own inner programs, which were prepared to spring into activity just when the brain seemed so completely helpless.
But a third and perhaps most formidable barrier to studying plasticity is not technical but conceptual. We have come to regard the assembly and development of the brain as occurring during embryonic life and then ceasing at birth or at least during childhood. We know that many genes are involved in assembling the brain and spinal cord and are required to direct the correct pattern of connectivity, but so far little attention has been paid to their possible role in adult plasticity.
Furthermore, we now have a weight of opinion that the adult brain is ﬁlled with inhibitory molecules that actually prevent growth of nerve ﬁbers. But what could possibly be the adaptive value of such a system? Is it not more likely, in fact, that we are seeing only part of the implication of the experimental data? Maybe these so-called inhibitory molecules are guidance molecules, which, like trafﬁc lights, can be red or green and function not to prevent trafﬁc ﬂow but to regulate and therefore facilitate it?
To understand the function of a molecule we have to know where it is distributed. The brain has the most complex structure of any known biological object. More genes are used to assemble it than all of the body’s other systems combined. The molecules that these genes use to determine how the brain is put together are not swirling around at random but have a dynamic localization considerably more complex than that of the nerve ﬁber pathways themselves. If we ignore this structure and treat the brain as a kind of bowl of porridge, it is unlikely we will unlock its secrets.
Maybe the failure of regeneration in the adult brain and spinal cord, which condemns patients to incurable disability, is not a result of a sea of inhibitory molecules poured in by a malign Providence but a kind of side effect of an essential protective mechanism. Maybe, too, the purpose of that mechanism is not to frustrate repair by tearing up the astrocytic railroad tracks, but to re-deploy them for the essential emergency requirement for sealing off the injury and preventing the nervous system from being subjected to further damage.
How entrenched the inhibitory theory has become was made clear to me when I reported that transplantation of olfactory glial cells induces cut nerve ﬁbers to regrow to their destinations in the spinal cord. “How do they ﬁnd the correct termination?” I was asked in puzzlement—and no little skepticism. But why assume that the regeneration of nerve ﬁbers in the damaged adult spinal cord would naturally be random or disorganized? After all, in all situations that we know where nerve ﬁbers grow, they show precise regulation, rigidly orchestrated by a hierarchy of genes, honed to perfection by the ﬁerce evolutionary struggle for efﬁciency. There is no evidence that these controls are absent or cannot be re-activated in the adult. The nerve ﬁbers of the spinal cord are programmed to go to their speciﬁc targets during development. Where else should they go when they regenerate in the adult?
If We were More Optimistic…
All scientiﬁc inquiry rests on the premise that we do not know the answer we seek. Theories are the tools for advancing knowledge, but the established theory, the one that claims to know the answer, is the enemy of advance. Advance is aided by encouraging novel and opposite theories, not by suppressing them.
If we regard genetic signaling as simply a prenatal, developmental process, and reinforce it with the idea of a postnatal development of inhibition, we are driven inexorably to the view that development ceases at birth, that repair of damage is actively prevented, and the period from birth until death is no more than a lifetime of progressive degeneration. But this idea is demonstrably untrue. The newborn baby cannot talk or walk; it has not composed music, made drawings, written poems, read books, learned languages, created weapons of mass destruction, or made love on the beaches of remote tropical islands. Life is more than a prolonged prelude to death; it is a process of development, expansion, exploration, achievement, and creation. The events of our lives are the wellspring of our social evolution, the key to the future of the human race. This process cannot be carried out by a structure frozen in monumental, self-inﬂicted inhibition—condemned from birth to a state of slow, terminal decay.
For the newborn baby, plasticity lies ahead, not behind. What is important is what is not yet known. I like to tell students that the best answer they can ever give to a question is “I don’t know.” Search begins in ignorance. Failure to recognize ignorance, persuading ourselves that we know the answer, prevents progress. The system that brain scientists study is far more complex than can ever be envisaged in our philosophy. Without humility and without a sense of humor, the search will be a grim struggle indeed.
Where Might We Go?
Plasticity is the essential difference between the human and animal brain. With it, the human brain created our civilization and will create our future. The difference between the past and the future is that the future can be changed. If our research leads us to understand more about plasticity, we will truly be studying what makes us human. And the value of our research will ultimately be measured not by some abstract intellectual or aesthetic standard but by its effect on the quality of human life.
If we are to understand what makes the human brain human, we must look at functions that are unique to it and different from other species. The mechanistic view of the brain as a machine for seeing, hearing, and producing movement does nothing to explain the human brain’s huge size. These functions help to further only a reactive, or responsive, mode of function. What makes the human brain different is that it can be proactive; it can think, imagine, communicate, and record. In a word, the over-arching characteristic of our species is to do what has never been done.
In looking at these higher functions, we can begin to think about some of those basic and infuriatingly simple questions that non-neuroscientists somehow expect us to be able to answer and to which we have so few answers: Where lies our unique and individual personality? Our self-awareness? Our consciousness? What makes me me, and not you? These are, after all, inquiries about the ultimate expression of plasticity.
*Cowan, who was vice president and chief scientific officer of the Howard Hughes Medical Institute, was vice-chairman of the Dana Alliance for Brain Initiatives from its founding in 1992 until his death in 2002.