We Are Our Brains (33 page)

Parkinson's disease is characterized by the death of dopamine cells located in a part of the midbrain called substantia nigra, from the Latin for “black substance” (
fig. 24
). In autopsies the substantia nigra normally shows up as a black band shimmering through the brain tissue, caused by the dark pigmentation of the dopamine-producing neurons. When the dopamine cells die off, they can no longer innervate and control the motor area in the middle of the brain, the striatum. That is what causes the movement impairments typical of Parkinson's.

It would be logical to assume that one could cure Parkinson's by replacing the dead cells. In 1987, a Mexican doctor by the name of Ignacio Madrazo published an article in the renowned
New England
Journal of Medicine
in which he reported incredible improvements in patients with Parkinson's disease after tissue from their own adrenal gland (which contains dopamine cells) was transplanted into the caudate nucleus (
fig. 24
). His article sparked a wave of similar transplants, some two hundred in the space of two years. The operation, however, proved ineffective, and 20 percent of those who underwent it during the two-year period died. Autopsies showed that the transplanted tissue from the adrenal gland had not survived. Only scar tissue was found in the striatum of the patients. Dr. Madrazo's promising results were probably due to a combination of poor research and placebo effects (see
chapter 16
).

Since 1988, in an alternative to the patients' own adrenal tissue, dopamine cells from fetal brain tissue have been transplanted into the striatum of Parkinson's patients. In order to be effective, the tissue must come from six- to eight-week-old fetuses. In around 85 percent of patients operated upon, the transplanted material can be viewed using a PET scan. Indeed, dopamine cells that had been communicating with the host brain cells have still been found in the striatum of deceased patients sixteen years after the operation. However, the new dopamine cells sometimes showed signs of Parkinson's disease. That the condition can infect transplanted tissue might explain why patients who initially appeared to benefit from the procedure subsequently deteriorated. Moreover, tissue from four embryos is needed for a single transplant. That amount is hard to obtain, because the tissue comes from aborted fetuses whose use in a transplant requires maternal consent. As a result, a great deal of hope has been invested in an alternative source of transplant tissue—specifically, embryonic stem cells—from which dopamine neurons can be cultured. But these therapies are still very risky and have many drawbacks. One case has already emerged of a patient who developed a brain tumor four years after having stem cells injected into his cerebellum. Stem cells have the potential to grow into anything, including tumors.

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).

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.