The Idea That Scandalized Brain Science

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.

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.

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.

“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.

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.

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.

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.

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*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.