We Are Our Brains

by D. F. Swaab

  The transplant of fetal dopamine cells into the brains of Parkinson’s patients did produce some positive results. The patients were able to cut down their L-dopa medication, and their movement disorders were slightly reduced. But it is still very far from a true cure, and the results vary. Moreover, both the effects and the side effects resemble those of L-dopa. In around 15 percent of cases, abnormal movements (dyskinesia) arise as a complication of the transplant, but the same applies to patients taking L-dopa. Placebo-controlled studies were also carried out in which, in a blind trial, 50 percent of patients underwent the operation but didn’t receive a transplant. Two years later there was no longer any appreciable difference in terms of movement disorders between the transplanted patients and those who underwent a fake operation. So all in all, the results are not convincing (see chapter 16).

  A second brain disorder that has led to the experimental transplant of fetal brain tissue is Huntington’s disease, an inherited condition that causes movement problems and in which brain cells in the striatum waste away. At a later stage, dementia ensues. The mutation that causes the disease is so rare that in all South African patients the disease can be traced back to a single sailor who arrived at the Cape of Good Hope on Jan van Riebeeck’s ship in 1652. The first transplants of fetal striatum tissue have been given to Huntington’s patients, and monitoring in a multicenter study is showing clinical improvements. Studies of patients who have since died show that the transplants contain living cells that integrate in the network of brain cells. One transplant, however, grew too fast, causing neurological problems. So, here, too, optimism needs to be tempered.

  Fetal retinal tissue transplants are being used to treat blindness caused by nerve cell degeneration, like retinitis pigmentosa and macular degeneration. The results are encouraging.

  If transplants of fetal brain tissue become truly successful in the future, ultimately enabling brain defects to be effectively repaired using this technique, we will face an important question. After all, many of our characteristics, including our personality, are determined by the development of brain structures in the womb. If fetal donor tissue is implanted in your brain, what characteristics might you acquire from the donor? These will depend on the area of the fetal brain used and the place where it’s implanted. Yet even taking this into account, it’s difficult to predict what these transplanted characteristics might be. When this technique becomes effective and is applied to higher brain structures, like the cortex, you might wonder to what extent you’re in fact compiling a new person. How much transplanted tissue would it take before a recipient should add the donor’s surname to his or her own? It will get even more interesting if we manage to transplant brain tissue from other species. Because of the scarcity of human fetal brain tissue, fetal brain tissue from pigs has been transplanted into the brains of Parkinson’s patients, who were then given medication to prevent rejection. So far these operations haven’t been successful: Only a few pig cells survived. But if xenotransplantations of this kind ever work in the future, might not human recipients find themselves endowed with the friendliness and intelligence of pigs?

  FIGURE 24. In Parkinson’s disease, the dopamine-producing black pigmented cells in the substantia nigra (SN) die, and can therefore no longer control the motor area, the striatum (P = putamen, CN = caudate nucleus).

  GENE THERAPY

  Medication in the form of a piece of DNA …

  In gene therapy, pieces of DNA containing the code for a particular protein (a gene) are inserted into a cell. The cell then starts to produce medicine in the form of the gene product, that is, a new protein. Brain researchers had thought that it would take an extremely long time before this new therapy, which until recently was still only being used experimentally in cultured cells and laboratory animals, could be applied in a clinical setting to treat disorders of the nervous system. But gene therapy is already being tested on patients with eye disorders and Alzheimer’s disease.

  In recent years, the research group led by Mark Tuszynski in San Diego has been the first to apply gene therapy to the treatment of Alzheimer’s. They are getting cells to produce nerve growth factor (NGF) as a possible medicine, targeting an area of the brain that’s important for memory, the nucleus basalis of Meynert (NBM, fig. 25). The cells of the NBM, which is located at the base of the brain, make sure that the chemical messenger acetylcholine—important for memory—is produced throughout the cerebral cortex. NBM cells become somewhat less active with aging, much less active in the case of Alzheimer’s. Tuszynski first showed that he could restore NBM neuron activity in aged rhesus monkeys using NGF gene therapy. He did this by removing some skin cells (fibroblasts) and culturing them outside the body. He then inserted the NGF gene in these cells and transplanted them into the brains of old monkeys, close to the NBM. The skin cells were shown to produce NGF in the monkeys for at least a year and to restore the activity of NBM cells.

  The same procedure was adopted with Alzheimer’s patients. For the first stage of the new therapy, eight Alzheimer’s patients were selected who were at such an early stage of the disease that they could still understand the experiment and give formal consent. In this phase 1 study, intended to show how a new therapy is tolerated, patients’ fibroblasts were removed, cultured, and genetically engineered to produce NGF. This was done using a virus as a vehicle. The virus had been disabled in such a way that it could still penetrate the cell, along with the NGF gene, but no longer multiply and thus cause disease. The NGF-producing skin cells were then injected into the region of the NBM in an operation involving stereotactic surgery. (This technology—dubbed “cerebral GPS” by the Dutch doctor Bert Keizer—shows very precisely where the tip of the needle is located in the brain.)

  In the case of the first two patients, the operations were far from successful. As is customary in stereotactic brain surgery, the patients weren’t anesthetized. Although tranquilized, they moved when the cells were injected. Subsequent bleeding in the brain caused paralysis on one side. One patient went on to recover from the paralysis, but the other died five months later of lung embolisms and heart failure, a complication that had nothing to do with the operation or the gene therapy. In subsequent operations, the cells were injected under general anesthesia, preventing any movement. PET scans showed that the cerebral cortex became more active after the procedure. It has been claimed that the memories of Alzheimer’s patients who received gene therapy deteriorated only half as rapidly as those who weren’t given this treatment. But this was a phase 1 study, so it lacked good controls. The brain of the patient who died after five months showed a robustly stimulating effect on the NBM neurons, giving hope that gene therapy can work.

  It will take a while, though, before the effects and side effects of this therapy are known. Previously, three Alzheimer’s patients in Sweden had also been given NGF—in their case it was infused into their brain cavities with a miniature pump. But the experiment was stopped because the treatment had little effect on memory function while causing serious side effects in the form of chronic pain and weight loss. We can only hope that the NGF now being produced by the cells that Tuszynski injected into the brain tissue will stay in place better, eliminating the side effects. (We found that sensitivity to NGF was greatly reduced in the NBM of Alzheimer’s patients. Whether this will prove problematic isn’t yet clear.) The next step that Tuszynski will take is to inject NGF directly into the brain with the aid of another virus, which may prove a more effective technique.

  In late 2009 it was reported that in France gene therapy had been used to cure two boys of the fatal brain disease adrenoleukodystrophy (ALD). People with this rare hereditary condition lack the ALD protein that breaks down fatty acids. The latter build up in the myelin sheath, the protective layer that coats nerve fibers in the brain. As a result the nerves lose function, causing progressive physical and mental disability. The disease was brought to international attention by the movie Lorenzo’s Oil, in which the father of a boy with ALD
tries to cure him with a mixture of oils (a method that ultimately proves unsuccessful). In the French study, an intact ALD gene was inserted into stem cells taken from the boys’ bone marrow using a lentivirus (a stable virus form) as a carrier molecule, after which the modified cells were replaced in the bone marrow. Exactly how the engineered cells prevent the defects in the brain is unclear, but the two seven-year-old boys in question have been doing well for two years now.

  Many laboratories are now working on gene therapy for a wide range of diseases. In our laboratory, Joost Verhaagen is using it to repair damage to adult spinal cords. The day when patients can be cured of spinal cord injuries and brain infarcts is still far away, but the first favorable results with laboratory animals already show the potential effectiveness of such therapy. Experiments are being carried out to repair damaged nerve fibers by implanting cells engineered to produce growth factor at the site of spinal cord injuries. At the same time, proteins that block the regrowth of nerve fibers in the damaged spinal cord are inhibited. New advances have been made in the latter area: Promising animal experiments have prompted Martin Schwab of Zurich to set up a clinical study using antibodies to neutralize a protein that inhibits such regrowth in recent spinal cord injuries.

  FIGURE 25. The basal nuclei—the nucleus basalis of Meynert (NBM), the diagonal band of Broca (DBB), and the septum—are the source of the chemical messenger acetylcholine in the cortex and hippocampus. This chemical messenger is important for memory (see also fig. 33).

  Gene therapy for disorders of the nervous system is most advanced in the field of ophthalmology. Children with Leber’s disease—a hereditary condition caused by a genetic mutation—are born with poor sight and go completely blind in adulthood. Experimental gene therapy on dogs proved effective against this disease. A phase 1 study was then carried out on three young adult patients whose retinas were seriously affected to determine whether treatment involving insertion of a piece of DNA coding for the missing protein was safe. The new therapy caused no serious side effects. Moreover, one patient’s sight improved remarkably; he regained the ability to detect and avoid objects in poor light. The next step will be to treat children with Leber’s disease at a stage when their retinas are still reasonably intact. Monkeys with red-green color blindness have already been cured using gene therapy. Measurable results were achieved within five weeks, and within eighteen months they could distinguish all colors.

  The first clinical studies involving gene therapy for the blind and for patients with dementia herald an entirely new era of potential treatment for human brain disorders. In its very early days, gene therapy sometimes proved shockingly disappointing. One young patient died, while others developed leukemia. But gene therapy is now reemerging as a promising form of treatment.

  SPONTANEOUS REPAIR OF BRAIN DAMAGE

  Brain damage can sometimes spontaneously repair to some degree. But don’t reproach someone unfortunate enough not to recover from brain damage that they didn’t try hard enough to get well!

  It was previously thought that brain tissue, once lost, could never be regenerated and that the functional improvements that can occur after a stroke are simply due to reduced swelling and, to a limited extent, to functions being taken over by other regions of the brain. People who suffer trauma and go into a coma can come out of it within a matter of days or weeks or progress to a vegetative state also known as coma vigil, in which they are awake without being conscious. Coma vigil can herald improvement, but some patients remain in this state permanently without making any further progress (see chapter 7). After three months in a vegetative state a patient is thought to have no chance of recovery. Yet people occasionally do come out of a vegetative state after a very long period. An exceptional case is that of Terry Wallis, who went into a coma after a car accident and then progressed to a minimally conscious state from which he awoke nineteen years later. He had occasionally responded to external stimuli by nodding and grunting, but he couldn’t communicate his thoughts and feelings. Yet nine years after the accident he started to speak the occasional word, and after nineteen years he fully regained the power of speech. He was also able to count and to move his limbs. However, he remained severely handicapped, unable to walk or to feed himself. He was also unaware of the passage of time; he didn’t know that his daughter—a baby at the time of the accident—had become a stripper or that his wife had had three children by another man. You might wonder whether this constitutes a worthwhile existence and whether Terry, described by the media as “a modern Lazarus,” is himself happy about this “miracle,” but his case is truly special from a medical point of view. His recovery is attributed to the fact that new axons—nerve fibers that create connections between different brain regions—formed in his brain. Over a period of eighteen months, MRI scans showed an increase in the volume of nerve fibers at the rear of the cortex as well as in those connecting the various cortical regions. Increased activity was also detected in a part of the parietal lobe called the precuneus, which is important to our consciousness of our surroundings and of ourselves. This area, which doesn’t function in patients in a vegetative state or coma or suffering from dementia—or during sleep, as a matter of fact—remains active when the brain is in a minimally conscious state. It was during the period when these activity changes were registered that Wallis regained consciousness. An increase was subsequently measured in the fibers of his cerebellum, at a time when his motor functions had improved strikingly. What distinguishes the few patients who are able to emerge from a vegetative state or a minimally conscious state after such a long period is still a mystery. But their existence does overturn the long-held view that recovery is impossible in such cases.

  The story of Jill Bolte Taylor caused a media sensation. She was a brain researcher at Harvard who, at the age of thirty-seven, suffered a massive stroke in her sleep. She woke up with a pounding pain behind her left eye, and when her left arm became paralyzed she realized what was happening. With huge difficulty she telephoned a colleague to try to ask for help. She thought she was speaking clearly but in fact could only utter unintelligible sounds. Luckily the colleague, realizing that something was terribly wrong, called 911. Trying to communicate at a moment like that must be nightmarish. A doctor friend of mine realized that he was having a stroke and called his GP. The GP listened briefly to the incomprehensible sounds at the other end of the line, decided that it must be a prank caller, and promptly hung up. At that moment my friend’s wife came home with the groceries, and he called out to her. Annoyed, she yelled back, “How often do I have to tell you to wait until I’m in the same room before you talk to me! I can’t hear a word you’re saying out here!” and went on unpacking the groceries. Luckily he recovered spontaneously from the damage caused by his stroke and has fully regained the power of speech. The situation in which Jill Bolte Taylor found herself was very different. Two and a half weeks after the cerebral hemorrhage, surgeons removed a golf ball–sized blood clot from her brain. She was left unable to walk, talk, read, or write and could remember nothing of her former life. With her mother’s help, she gradually learned how to function again. It took her eight years to recover fully. She has written a bestseller about that period in which she describes how she used her willpower and her knowledge of the anatomy of the brain to consciously stimulate the damaged brain circuits and get them working again. This is pseudoscientific mumbo jumbo, but it proved immensely popular with the general public. “I truly believe that as a patient you’re responsible for your own recovery,” she said with great conviction. Of course it’s important to do your utmost to regain health after a cerebral hemorrhage or stroke. But the danger of Taylor’s enthusiastic but unscientific pronouncements is that they can be used to reproach those unfortunate patients who don’t recover from such injuries for failing to work sufficiently hard on their recovery. When I first began studying to be a doctor, my father placed the power of medicine in perspective. “There are two kinds of maladies,” he said. “One kind
goes away by itself, and the other kind you can’t do anything about anyway.”

  12

  The Brain and Sports

  NEUROPORNOGRAPHY: BOXING

  In various civilized countries, this form of inflicting deliberate neurological damage on one another has been banned for decades.

  Witnessing aggression sparks aggression. Measures have rightly been taken to restrict excessively violent computer games. So it doesn’t make sense that certain forms of primitive aggression, like boxing, are still permitted. You can watch boxers inflicting permanent brain damage on one another on prime-time television, yet no one seems to get very upset about it. As the audience howls encouragement in the background, you see (repeatedly and in close-up) detailed footage of the onset of neurological damage: an unsteady gait, impaired speech, eyes flicking left and right, an occasional classic epileptic fit, reduced consciousness after being knocked down, unconsciousness after being knocked out, and occasionally coma and death. It’s more or less a complete course in neurology, in fact. Since the Second World War, around four hundred boxers have died from injuries incurred under the supervision of the various boxing unions. It’s incredible that the most revolting examples of this neuropornography are shown on television, even at times when young children might still be watching.

  In boxing, long-term brain damage from repeated blows to the head is much more common than acute damage. In 1928, the term punch-drunk was coined for boxers who stood unsteadily, moved slowly, and developed behavioral disorders, varying degrees of dementia, or Parkinson’s disease. This was replaced by dementia pugilistica, and now the neutral term chronic traumatic brain damage is used to describe the condition suffered by 40 to 80 percent of professional boxers. Around 17 percent of professional boxers have Parkinson’s. Muhammad Ali, formerly the world’s greatest boxer and fastest talker, has become a shuffling Parkinson’s patient with a mask-like face who struggles to form a sentence.