Unravelling the workings of the brain

This essay was written by Geoff Raisman and was first published in the 2000 Mill Hill Essays.

Not so many years ago I used to visit an old lady. Over her long life, she had brought up a family. She had witnessed the call-up of her father, her husband, her brothers, and her nephews to two world wars, and welcomed their return. All through, she had enjoyed a long and healthy life. She had been spared the interventions of the medical profession. She had never spent a day in bed. She had never taken a meal in bed. She had never not washed and dressed herself.

Now the ruins of two world wars have been replaced by new buildings, and the next generation faces its problems, no less than those before. But for the old lady, the family and friends she knew were all gone. Each time I saw her she seemed to be drifting further and further away. And, bringing to mind all the dire reports of how many nerve cells we lose every day, I imagined the person I knew would also with them slowly disappear. It seemed so.

But I was wrong. There would be wonderful moments, sitting in a chair while nut brown autumn sunshine streamed through the window, when it was as if a cloud passed away from her lined face, and there shone through the eager face and sparkling eyes of a little girl of long ago, unchanged by time.

And I wondered at this mystery. If the brain is for each of us the seat of our personality, and if nerve cells are continually being lost as we get older, how does the soul manage to scamper like a refugee from building to building of a blitzed city, sheltering in the cellars, undiminished, always ready to emerge unexpectedly, still fighting and alive amid the ever increasing pile of ruins that was once its happy home? The Blitz destroyed many buildings. But it did not destroy London.

And this is a mystery. For we are used to thinking that this bit of the brain moves the hand, and this the foot. That the back of the brain is used for seeing, and the side for hearing, a bit here for speech, another piece for memory. And ever more sophisticated machinery enables us to probe deeper and deeper, and to say, this bit in here is the place for emotions, this bit for intuition, this almond-shaped piece is used for fear. So that one day we will put together all the jigsaw pieces for every kind of thing we can conceive. And yet, when the map is complete, where in that map will we find George, or Mary? A bundle of machinery that moves and sees and speaks and hears and fears may be a Frankenstein, but it is still not a human being. How will we know which piece makes you into you, and me into me?

The mind, that unique thing that makes each person an individual, still eludes us, mocking our simple ideas. We are more than the sum of the parts. Because we are all different. For we, like the old lady, can take in the experiences of a century, and the inevitable blows of fate, and still maintain ourselves, our own unique identity, endure, flourish, and grow in the face of overwhelming change. Things may change and change, but we are still the same person. The captaincy of the brain is to steer the ship of our lives through calm and storm, through fair weather and through foul, to endure, to learn, and to grow. The brain enables us to rise above circumstance. What the brain enables us to do is to manage change. How?

It was already known that the brain consists of millions and millions of the microscopic little grey cells that Hercule Poirot used to solve murder mysteries. It was already known that these nerve cells are connected by tiny fibres, only the largest of which could be seen by the microscopes then available, and that these fibres carry minute electrical signals, like a vast telephone exchange, throbbing with every movement of the body, with the heart-beat, and with breathing, never silent. But how do all these uncountable numbers of separate nerve cells maintain their separate identities, and how is this ocean of electrical activity able to control our bodies? What is the mysterious language of the brain? If we could put some enchanted sea shell to our ears, and listen to it, what words would we hear?

The key to this problem came from observing the effect of drugs. Since ever human records began, every culture on earth has known that drugs, like alcohol, or nicotine, affect the brain, sleep, dreams, the senses, the emotions, the movements of the body, breathing, and the very beating of our hearts. Drugs can change our perception of the world, can change our personalities. Gradually, with the work of pioneers like Sir Henry Dale, the Institute’s first director, drugs were being divided into classes. Some, for example, increased the heart rate, others slowed it. Yet others, like the venom of snakes and scorpions, or the paralysing South American arrow poison, curare, blocked the nerve impulses needed to move our muscles. But what was the relationship between the effects of the slow, heavy drugs and the mercurial, flickering electrical signals of the brain? How could drugs have such profound and long lasting effects?

For some time, scientists had been toying with the idea that the nerve cells of the brain were not in direct continuity with each other. Rather, they speculated that there must exist a minute gap between nerve cells. What they proposed was that when the electrical signal gets to the end of the nerve fibre it stops, because there is a gap. This gap, or rather this hypothetical gap, was called a synapse. It was hypothetical because no one had yet been able to see this gap, it was too small. Nonetheless, Dale and his collaborators were convinced that drugs must have their action by enhancing or blocking communication between nerve cells. They proposed that once it reaches the synapse, the electrical signal induces the release of a tiny puff of a transmitter chemical which then stimulates the nerve cell on the other side of the synaptic gap. In other words, the communication between each of the myriad of individual nerve cells does not consist of electricity alone, it is a combination of an electrical signal followed by a chemical signal. Drugs, they suggested, act by interfering with, perhaps mimicking, these natural chemical signalling systems of the brain.

These supposed chemical signals were called transmitters because they transmitted messages, the words of the unknown language. And every moment of our lives, unceasingly, day and night, from birth to death, every single one of our millions of nerve cells is assailed by tens to hundreds of thousands of these messages. It was a brave theory. Especially brave considering synapses were too small to be seen, and the transmission of impulses from one nerve cell to another takes only a thousandth of a second. The theory could only be proved if a transmitter chemical could be identified, and if it could be shown that it was indeed released during synaptic transmission. But that was a tall order. How could such a minute amount of a chemical transmitter ever be collected, let alone identified?

Here Wilhelm Feldberg , a brilliant young German Jewish refugee, provided Dale with the key, a special drug called eserine. Eserine was known to increase certain forms of nervous activity. Dale had proposed that if synaptic transmission lasted only for a thousandth of a second, the transmitter substance must be rapidly broken down in the body. Otherwise, the transmission would continue, and not be brief. Feldberg considered that the drug eserine had its effect by preventing the breakdown of a transmitter. Therefore, they argued, if they applied this drug during transmission, the breakdown of the transmitter would be prevented, and this would allow the transmitter to accumulate, and build up to levels where it might be detected. Even so, the amount of transmitter was not enough to be detected by test tube chemistry. Like the traces of odourless poison gas in a Victorian coal mine, only a living thing, like a canary, was sensitive enough to warn the miners of its presence. Similarly, only a living system was sensitive enough to detect the presence of the synaptic transmitter. The system Feldberg introduced was the contraction of the muscles of the Hungarian leech.

Dale and Feldberg’s experiments were a brilliant success. Using eserine they were able to preserve enough of a transmitter to detect a substance that made the Hungarian leech contract. They collected the substance, identified it as acetylcholine, and showed that when this substance was applied to synapses, it mimicked natural transmission. This little team, working in the cramped laboratories of the first National Institute for Medical Research, tucked amongst the winding, narrow streets on the tree shaded flanks of Hampstead Heath, had identified the first natural nervous transmitter. It was clear now that synapses indeed existed, and that nerve cells ‘speak’ to each other by initiating electrical impulses which are converted to minute puffs of chemicals. They went on to show that acetylcholine is used by nerve fibres to drive the movements of our limbs. It is the substance which converts the electrical signals in our nerves into the movements of our muscles. It is the substance which steadies the rapid beating of our hearts. The first word in the mysterious language of the brain had been decoded.

We know from everyday experience that the brain is not simply a passive recipient of information. Forgetting is not only a passive process of things slipping away. It is also an active one. The brain helps us to live with the past not only by remembering things we need or like, but, at least as important, by blotting out the disturbing memories of things we find unpleasant. The brain examines what it sees and decides what it wishes to accept, and what to reject. And if something doesn’t seem to fit, it can re-interpret it in the light of past experiences, a powerful and a dangerous facility, and one that was explored by an ingenious series of experiments in the laboratories of Mike Gaze and Mike Keating.

It was the hippy era. Young men in the U.S. forces, and students throughout the universities of the world were experimenting with drugs that changed their perception of the world. And in the rather splendidly placed new laboratories under the high roof of the National Institute for Medical Research at Mill Hill, Gaze used electrical recording to show that if impressions coming from the outer world become too disturbing, the brain can respond by modifying itself. Nerve fibres arising from the back of the eye form a pathway that sends an image of the world to the brain. That image fits with what we expect. Things that fall to the ground are seen as going downwards, and aeroplanes taking off are seen as rising. Gaze examined what happened if these orderly nervous pathways become disturbed. What would happen, for example, if the image of a thing falling down were to become rotated so that it now appears to be going up? The image is now nonsensical. How does the brain deal with it? Gaze showed that the brain is able to cope with this. It knows the object is really falling to the ground, so it simply readjusts the pattern of connections so as it make it appear that things go in the expected direction – in our example, down instead of up. When confronted with apparent nonsense, the brain readjusts itself so as to make sense of it.

Have you ever considered how strange it is that we have two eyes and not one? Dealing with this situation provides a challenge for the brain. When we look at a single object, the two separate eyes form two separate images of the same thing, and transfer these two images to the brain. Fortunately, the two images are normally in register with each other, and so only one object is seen. But what would happen if something were to disturb the system, and the two images are now no longer perfectly in register with each other? Keating’s work showed that, under these circumstances, the nervous connections within the brain readjust themselves so that the two images overlap perfectly. Although there are two images, the brain realises this is nonsense, and only records them as a single object. Here again is a clear example of how the connections in the brain change so as to adapt the brain to the realities of the world outside.

Nor is the brain simply a recipient of messages. The brain remembers what it has been told. And it does not simply remember, but profits from its experiences, and does better next time. Unlike the old dog, the brain can learn new tricks. But how is this achieved? To be able to handle, or rather to master information in this way requires the brain to retain an image of the past. Put another way, the synapses, like a tape recorder, remember the messages they have heard. But how do they do it?

During a seminal visit to the laboratory of Terje Lomo in Oslo, Tim Bliss, then a student at the Institute, was trying to understand how a synapse could learn. At this time neurosurgeons in Canada had shown that one part of the brain, called the hippocampus, is required for human memory. Examining this part of the brain, Bliss and his collaborators showed that when a nervous pathway leading to the hippocampus is stimulated by an electrical input, it ‘remembers’ the input for many hours. During this time any further stimulation of this pathway results in a much stronger response. In other words, the brain behaves like any other bodily function, the more we use any particular pathway, the stronger that pathway becomes. This remains to this day the best indication of how the brain is able to learn and remember. In fact there is now evidence that synapses in the brain behave like muscles, the more they are used, the bigger they grow.

The work of Gaze, Keating and Bliss had shown some of the ways the brain adapts to changes and challenges in the environment. But that master function of the brain, the ability to survive damage to itself, was still a mystery. In the end, the solution was as obvious as it was simple. If the brain is not to be destroyed, then it must be capable of re-building itself.

My own introduction to this problem arose from a very simple observation. Using the electron microscope, we were able to see that when an area of the brain suffers damage, the immediate response of the surviving tissue is to clear away the debris and replace all the lost synapses by an equal number of new ones. Looking back it seems almost inconceivable that such a simple observation could possibly have met with as much scepticism, opposition, and derision as at that time it did. For centuries it had been observed that brain damage does not repair itself. Therefore, people argued, the connections of the brain must be fixed. Once they have been formed, they are present for life, and if parts of the brain are disconnected by damage, as unfortunately commonly occurs in stroke, they remain disconnected. Holding such a view, it was customary to advise patients that it was impossible to repair brain or spinal cord injuries. And having given this gloomy advice, it was therefore unsettling to be faced with direct electron microscopic evidence that new connections do form after injury.

And of course the observation did indeed raise many puzzling questions: If the damaged adult brain is capable of forming new synapses, why do the brain and spinal cord not repair themselves after injury? Why are spinal injured patients confined to wheel chairs? Why does the spinal cord not repair itself like, say, a broken bone, or even a nerve in the arm? But the most intriguing question of all was: ‘What can we do about it? It was a practical matter: How might it be possible to induce repair in a system which did not repair itself?

In fact the nerve cells in the brain and spinal cord are outnumbered some ten to one by another, smaller, spidery type of cells, called glial cells. Glial cells do not convey electrical signals; they do not release puffs of transmitters across synapses. Instead, they are woven like many coloured threads into a carpet. As a baby’s brain grows, the unrolling of that carpet provides the pathways enabling the growing nerve fibres to find their way through the intricate maze of corridors. There are many distinct types of glial cells, so that the carpet has subtly changing designs and colours in different regions.

What might be the reason for the differences in glial cells in the different regions? And how might this knowledge contribute to the problem of how to repair injuries to the brain and spinal cord? Whereas nerve fibres in the brain and spinal cord cannot repair themselves, nerve fibres in the nerves of the limbs have the power to regrow after they have been cut. It had long been suggested that this power of repair may be due to the special types of glial cells present in limb nerves, and that if these cells could be transplanted into brain injuries, they might induce repair there too. Early experiments showed that transplantation of these cells into the brain can encourage nerve fibre growth. But so far it has not been possible to obtain a satisfactory repair of a human injury using this approach.

So we sought alternative sources of reparative cells. One source looked especially promising, the part of the brain concerned with the sense of smell. This part of the brain evolved millions of years ago. It was present in our most ancient ancestors. It is present today in fish, amphibia, reptiles, birds and mammals. Recent research has shown that it retains an extraordinary and primitive property, the capacity for self-renewal. Unlike the rest of the brain, where we have only one set of nerve cells to last all our lives, the nerve cells concerned with the sense of smell have only a short life of some weeks. And as each generation of cells die they are continually replaced by newly-formed cells. These new nerve cells must all grow connections with the rest of the brain. This, therefore, is the one part of the brain where nerve fibres are in a state of continual growth throughout life. We speculated that, in order to support this continual growth of nerve fibres, the glial cells of this part of the brain must also retain a primordial vigour for repair, a youthful capacity which has been lost in the later evolution of the rest of the brain. Could these special glial cells provide a source for the reparative powers we sought? A young chinese colleague and I took samples of the specialised glial cells from the part of the brain concerned with the sense of smell, and studied the effects of transplanting them into minute areas of damage in the spinal cord. Our observations showed that these special glial cells induce rapid regrowth of the damaged spinal nerve fibres, and return of lost functions. It is as if these special cells roll out a red carpet so enticing that even damaged nerve fibres are persuaded to grow along it. If this procedure can be transferred to practical application, we hope it may one day be the basis for getting paralysed people out of wheel chairs.

This is a glimpse of the history of research into the nervous system at the Institute, a record of some of the things that have happened here. But a record of the past is a record, a list of things, no more than that. History is more than a record. A record becomes history when it tells us not only about where we have come from, but, far more important, about where we are going. History is a beginning, not an ending.

In the fifty years since its move to Mill Hill the shiny copper roof of the Institute has turned a hoary green with age. We have identified many of the words in the language of the brain. I hope I have been able to give you some clues to the questions I asked at the beginning of this account. I hope you can begin to glimpse some of the many intricate and fascinating ways that, over a century of havoc, the old lady’s brain enabled her to preserve inside, like Alice in Wonderland, the eager, bright-eyed little girl of long ago. And, like Alice’s glimpse of a wonderful garden through the keyhole, we too have had a glimpse of how, one day, we will be able to help those whose injuries are so grievous that they cannot even stand up.

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