麻豆传媒

REMEMBER the screaming headlines of 1988: 鈥淏rain graft cure for Parkinson鈥檚 disease鈥�? Surgeons in Mexico, in Sweden and in Britain had transplanted brain tissue from aborted fetuses into the brains of people with Parkinson鈥檚 disease, and some had made claims of spectacular recovery. Six years on, Parkinson鈥檚 disease remains as incurable as ever. But results from a steadily growing pool of transplant patients 鈥� the worldwide tally now stands at over 200 鈥� suggest that fetal grafts may have a place in slowing the progress of the disease in people who would otherwise face a bleak future.

It is no longer a question of whether grafts can work, but of whether this costly, complex and controversial procedure should be made available as a treatment to many more patients. Uncertainties abound. Might researchers end up perfecting their techniques only to find that doctors and health service managers lack the resources to implement them? Could a greatly increased demand for fetal tissue be met from existing supplies? Alternatively, might developments in cell culture and genetic engineering mean that future transplant programmes could dispense with fetal brain tissue altogether?

Time will tell. Right now, researchers are focusing on a more basic question: do brain grafts of fetal tissue work well enough to justify expanding current programmes? Since the late 1980s many countries 鈥� including Britain and the US 鈥� have had guidelines that allow fetal tissue to be used for transplants within certain ethical limits.

The concept is simple enough. Brain cells that die in adulthood, whether through disease or injury, are irreplaceable in the normal course of events. Fetal brains, obtained from abortion clinics, are a potential source of healthy, immature cells. Two decades of research on laboratory rats confirm that such cells can grow and make connections when implanted into adult brains. Yet still nobody knows for certain what makes a graft successful in a human patient.

The hope is that grafted fetal cells can arrest or alleviate the effects of degenerative brain conditions such as Parkinson鈥檚 disease, Alzheimer鈥檚 disease or Huntington鈥檚 disease. And the results so far suggest that in the case of Parkinson鈥檚 disease at least, they can 鈥� up to a point.

Symptoms include rigidity or trembling in the limbs, difficulty controlling voluntary movements, and a shuffling or stumbling gait. Grafts will probably not help those whose disease is so advanced that they are wheelchair-bound or have difficulty swallowing. But case studies of less severely affected patients show that many find it easier to live with their disease as a result of a transplant (see 鈥淭he story of Patient 7鈥�).

Less clear is what these encouraging results mean for the quality of life of the millions with Parkinson鈥檚 disease round the world. 鈥淲e now have good evidence that grafts can survive and have functional effects,鈥� says Olle Lindvall, who leads the Swedish team based at the University Hospital in Lund. 鈥淏ut the functional improvements are incomplete. The challenge is to find out if it is possible to obtain more complete recovery.鈥�

His British colleague Niall Quinn of the Institute of Neurology in London is equally circumspect. 鈥淚 think clinical use is still some years away,鈥� he says. 鈥淣one of us are kidding ourselves that this is going to be a cure 鈥� at present the main question is just how much you can achieve with grafting.鈥� Both are careful to describe their collaborative series of operations as an experimental programme.

Others use more optimistic terms. Curt Freed of the University of Colorado School of Medicine in Denver, who has carried out at least 21 grafts since 1988, is prepared to call what he is doing treatment. People who wish to register as patients in the programme start with two weeks of video recording at home. The Colorado team then uses the recordings to assess each patient鈥檚 suitability. The situation is complicated by the fact that in the US patients are responsible for their medical bills 鈥� and the cost of surgery is $40 000. While some patients have paid this in full, others have successfully claimed reimbursement from their medical insurers for 鈥渢herapy of indeterminate value鈥�.

The Colorado team stresses the risks of the operation, including brain haemorrhages and death. Nevertheless, Freed says that so far the surgery has helped most patients. 鈥淔or those who have no alternative, I believe it is a therapy,鈥� he says.

Differences in outlook are only to be expected. New surgical techniques, unlike new drugs treatments, need only the approval of local ethical committees as opposed to national regulatory authorities. As a result, there are almost as many grafting techniques and evaluation methods as there are patients with fetal brain grafts. The varied nature and unpredictability of Parkinson鈥檚 disease doesn鈥檛 help much either. On the face of it, the disease is the obvious choice for a grafting programme. It involves a loss of cells in one tiny region of the brain, the substantia nigra. Because the disease leaves such a selective trail of destruction, it should be a relatively straightforward matter to replace the missing cells and evaluate the benefits or otherwise of the graft.

In reality, things are far more complex. The immediate cause of the symptoms seems to be the disappearance of the neurotransmitter dopamine from a structure called the striatum, where it is normally released by fibres coming from the substantia nigra. Since the 1960s, drugs have been available that boost the amount of dopamine in the brain, and these have given a new lease of life to most Parkinson鈥檚 patients. But after a few years of treatment, many of them start to experience what are known as 鈥渙n-off鈥� effects: unpredictable swings between relatively normal function with a tendency to overactivity, and virtual immobility.

This is where fetal transplant programmes could held (see Diagram). Yet assessing their effectiveness on such patients is tricky. Each patient鈥檚 physical capabilities can vary from hour to hour and day to day and each study typically involves fewer than five patients. And it is virtually impossible to weigh up the relative merits of different transplant programmes unless everyone is measuring the same thing. Yes, brain scans from positron emission tomography (PET) can theoretically measure how much dopamine is produced in the brain, and hence how well the graft is surviving. But PET is itself an experimental procedure. While some scans appear to show unambiguously that grafts are surviving, researchers occasionally dispute one another鈥檚 scans.

What鈥檚 more, in most drugs trials, patients don鈥檛 know whether they are taking the drug or a placebo. But similar protocols are harder to apply with transplants. 鈥淭he patient and I both know he鈥檚 got a graft, so in that sense the experiment is not controlled,鈥� concedes Lindvall.

Sardonic eye

Ira Shoulson, a neurologist at the University of Rochester in New York state, is working on new drug treatments for Parkinson鈥檚 disease. He regards the state of play in the transplant field with a somewhat sardonic eye. 鈥淭here are only two problems with basic research in transplantation 鈥� there鈥檚 not enough of it, and the same rigour is not applied in the clinical situation as it is in drug trials. There鈥檚 a genuine effort to help people 鈥� that鈥檚 important, but it鈥檚 insufficient by itself, which is why we [in drugs research] have standards.鈥�

Researchers in Europe are now addressing this problem collectively. In 1989, NECTAR (the Network of European CNS Transplantation and Restoration) was set up. It has laid down standards so studies can be compared, including criteria for accepting patients into a study, standard assessment procedures before and after the operation, and ethical constraints on the way tissue is obtained. Membership of NECTAR is voluntary, but any researcher joining must agree to abide by its standards. The details of the operation are left up to the researchers themselves. Earlier this year, NECTAR set up a register of patients, which will pool all the data from those with transplants, and from those who join future programmes included in the network.

Meanwhile in the US, the National Institutes of Health have decided to start with a clean slate. From 1988 until 1993, research into fetal tissue transplantation was possible in the US only with private funding. Under the Reagan and Bush administrations, there was a moratorium on state funding for all such research, in deference to pro-life voters. In January this year, a year after the moratorium was lifted by the Democrats, the NIH awarded a $4.5 million grant to Freed鈥檚 team in Denver to fund the first control-led clinical trial of fetal grafting, which will be free to patients.

After several months of initial testing, 20 patients will receive grafts of fetal tissue, while a further 20 will undergo 鈥渟ham operations鈥� 鈥� the surgeon, Robert Breeze, will drill a hole in their skulls, but leave the brain untouched. Neither the patients nor the doctors assessing them will know who had the real transplants. Results comparing the progress of the two groups in the periods before and after the operation should be announced in about three years.

In principle, a double-blind trial of this type is long overdue. It is normally regarded as essential to clinical studies in order to avoid bias on the part of the experimenter, placebo effects and so on. However, the NIH-funded trial has not been a cause of general rejoicing in the field. In fact, as the journal Science reported in February, it is widely regarded as premature. 鈥淣o one yet has an ideal procedure,鈥� says Lindvall. 鈥淲hen someone does, then it will be time for a controlled trial.鈥� The approach to this ideal, he believes, can best be made through small-scale studies.

Researchers fear, too, that if the Colorado study produces negative or inconclusive results, that will be the end of the story as far as research funding is concerned. That disturbs American researchers in particular. John Sladek of the Chicago Medical School, one of the first scientists to work on neural transplants in the US, criticised the NIH for putting all their eggs in one basket. 鈥淲e鈥檙e worried about what will happen if that basket falls apart,鈥� he told Science. Others have raised eyebrows at the propriety of subjecting patients to sham surgery. However, Freed鈥檚 grant will cover the costs of transplants for all the control patients once the study is complete.

The European transplant community is equally concerned. Lindvall鈥檚 colleague H氓kan Widner wrote to Science to express the concern of NECTAR members that 鈥渙nly one neural transplantation procedure from a single centre is to be assessed. Since transplantation techniques are still at an early stage of development, the optimal methods of tissue procurement, graft preparation and implantation are not yet established. Consequently the results of any single trial must be considered with great caution.鈥�

The big technical problem faced by all surgeons is the poor survival of the cells in the graft. Between 5 and 10 per cent seems to be the most that anyone can expect. Lindvall鈥檚 group is trying to boost the number of surviving cells by using several fetuses for each patient 鈥� as many as six for each side of the brain, in some cases. And to ensure the grafted cells are spread through as much of the target area in the striatum as possible, they place five to seven grafts on each side. They prepare the fresh tissue as a dissociated suspension of cells and immediately inject it using a fine needle.

Freed鈥檚 team, which has also reported good results, adopted the 鈥渕ultiple injection鈥� approach at an early stage. But in other respects his techniques are quite different. He used only one or two fetal brains per patient; and prepared the tissue by extruding it into fine 鈥渘oodles鈥�, which he then kept alive in culture for several days. This was to monitor the quality of the cells before cutting them into small pieces and injecting them. While Lindvall鈥檚 team always uses drugs that suppress the patient鈥檚 immune system, Freed gave no such drugs to 6 out of 12 patients, and found no difference in their improvement.

Researchers assume that the more cells survive, grow and produce dopamine, the better recoyery will be. Some PET scans also seem to show that recovery is at least partly related to the amount of dopamine produced by the graft. Laboratory experiments on rats, however, suggest that the graft does not simply act as a pump, dishing out dopamine indiscriminately. It is at least as important for cells in the graft to send their fibres out into the brain and make direct connections with the cells of the host. Even then, the rats, like their human counterparts, only seem to make a partial recovery and no one knows why.

The details of how grafts interact with the brains of their human hosts are equally vague. Postmortem studies would help, but happily for them rather few transplant patients have died. The largest group of patients to come to postmortem consists of 5 of the 55 patients operated on by the late Edward Hitchcock, professor of neurosurgery at the University of Birmingham between 1988 and 1993.

But these findings have little relevance to the work of other groups. Hitchcock鈥檚 surgical technique was very different and he used fetal tissue taken at a much later stage of pregnancy, 12 to 18 weeks as opposed to 6 to 9 weeks.

Embarrassing episode

One reason for what might seem to be excessive circumspection among the scientists is the memory of an embarrassing episode with many parallels to the fetal transplant story. In 1987, Ignacio Madrazo and his colleagues from the La Raza Medical Centre in Mexico produced impressive videos of a Parkinson鈥檚 disease patient who had apparently made a miraculous recovery from his previously incapacitated state. He had been given a brain implant consisting of cells from his own adrenal gland, part of which produces some dopamine.

Despite the fact that there was very little evidence from research on animals that the technique was effective, several neurologists at American hospitals set up adrenal grafting programmes almost immediately. None was able to claim any more than slight and transient improvements, and adrenal grafting has now virtually disappeared.

It seems unlikely that fetal grafting will suffer the same fate because positive results continue to emerge from more and more meticulously conducted research programmes. The next few years should bring some definite answers about the safety and efficacy of grafting in Parkinson鈥檚 disease. Which is just as well. Researchers at the forefront of this field may see the clinical application of their work as a distant prospect. But as increasingly reliable reports of successful grafting operations accumulate, more and more patients will be joining the queue 鈥� and more and more surgeons will be ready to oblige.

The story of Patient 7

IN a field where standards are highly variable, a Swedish team based at Lund in Sweden is regarded as a mdoel of scientific rigour. In the 1970s, Anders Bj枚rklund鈥檚 pioneering experiments on laboratory rats established that grafts taken from the brains of rat fetuses could survive, grow and integrate with cells in the brain of an adult 鈥� and could reverse the effects of a form of Parkinson鈥檚 disease produced in the laboratory.

In 1987, Bj枚rklund鈥檚 colleague, Olle Lindvall, performed some of the world鈥檚 first grafting operations on human patients. By 1989, he had carried out six such operations, four on victims of Parkinson鈥檚 disease, and two on people who had developed severe symptoms of a Parkinson鈥檚-like disease after injecting themselves with a synthetic drug containing the poison MPTP. No one was cured, but four of the six recovered a measure of independence and mobility that had seemed lost.

At this point, Niall Quinn of the Institute of Neurology in London, who had worked with the Swedes on the assessment of their patients, felt the time was right for some of his own patients to join the grafting programme. But he had to be very selective. 鈥淢any patients are keen to clutch at straws, but aren鈥檛 suitable for some reason,鈥� says Quinn. 鈥淥thers are suitable but have ethical or other objections. The ideal is someone who鈥檚 relatively young, physically fit, with good home support, who鈥檚 tried all the available drugs and is still not doing very well. They鈥檝e got to be prepared to keep daily charts and visit the clinic frequently for tests. Trial subjects are really very special people.鈥�

鈥淧atient 7鈥� was the first to fit the bill. He was 45, and had been diagnosed as having Parkinson鈥檚 disease five years previously. Drugs which had worked well for the first three years or so were becoming less effective, and he had just taken medical retirement from a job in the computer department of a large company. He had started to consult Quinn after losing faith in the 鈥渒eep taking the tablets鈥� approach of the neurologist in his local hospital. Most importantly, he was highly motivated to do something about his condition.

鈥淚鈥檇 ask him [Quinn] about transplants at the time they were in the news, but he said 鈥極h, no, you don鈥檛 want to get involved in those,鈥� 鈥榬ecalls Patient 7. 鈥淭hen a few months later, he asked me if I wanted to join the Swedish programme. I decided that if I said no I鈥檇 always regret it.鈥� He immediately embarked on a series of tests to establish the extent of his disability, with and without drugs, in the year before the operation.

Patient 7 is the first of a total of six British and Swedish patients whose operations are designed to discover whether maximising the distribution of the grafted cells in the target brain area can lead to greater improvement. Each patient will have grafts implanted to a minimum of five sites in the striatum on each side of the brain, in two operations spaced several months apart.

Each operation requires a large amount of fetal tissue to ensure that enough of the right kind of cells are transplanted. The women involved have to consent to the procedure, and the Swedish team aims to carry out the grafting operation within hours of the abortion. Ethical guidelines require that the timing of abortions cannot be dictated by the needs of the transplant programme.

These constraints presented considerable logistical problems 鈥� and frustration for Patient 7. He was first told to be ready to fly to Sweden in the spring of 1992 鈥� but it wasn鈥檛 until a year later that the call finally came.

In the event his operation went very smoothly. It involved having a metal frame bolted to his skull (鈥渨hile they were fixing it they put thumbscrews in my ears, the most excruciating part of the whole thing鈥�), followed by a CT scan, which was then used to guide the precise insertion of the grafts into his brain through a hole in his skull. 鈥淚 walked in and lay down on the table, they bolted the frame down, and the rest of it was a bit hazy. I heard the drill, but it was someone else, not really me.鈥�

In the two months after the operation, Patient 7 felt he was 鈥渞emarkably better. Things like putting my jacket on, doing up buttons, getting tablets out of the dispenser, all became much easier.鈥� This was followed by a few months鈥� decline, but since then he has enjoyed a steady improvement. 鈥淚鈥檓 not as good as I was in July and August, but I鈥檓 much better than before the operation. I now find I鈥檓 safe to drive most of the time, whereas before I could only drive in my best periods.鈥� And for someone who works with computers, a valuable benefit of the operation is that he can once more use a keyboard without holding down the keys for too long, and he can double-click with the mouse.

These impressions are backed up by batteries of standard tests which confirm that his arms and hands are now more mobile, and he has fewer 鈥渙n-off鈥� episodes. And brain scans taken at the Hammersmith Hospital in London reveal that the grafts are surviving and producing dopamine, the neurotransmitter lacking in people with Parkinson鈥檚 disease.

But Patient 7 still has Parkinson鈥檚 disease. 鈥淢y speech annoys me most,鈥� he says, 鈥渋t鈥檚 fast, quiet and indistinct. My walking has got worse, and I鈥檝e got dystonia [a contraction of the muscles that forces him to walk on the side of his foot].鈥�

In September, Patient 7 returned to Lund for his second graft. He came back in high spirits. 鈥淚t remains to be seen whether the current state is maintained,鈥� he told 麻豆传媒 on his return. 鈥淚f it is, then I will be worrying the life out of the neurologists to let me reduce my drugs to zero. The only remaining cloud on the horizon is my walking.鈥�

For over five years, Patient 7 has effectively been a member of the Anglo-Swedish research team (literally 鈥� he helps with the computer analysis of the results). But he doesn鈥檛 think transplantation could be offered to patients routinely. 鈥淚 would have been miserable if I hadn鈥檛 done it. But there鈥檚 so much involved, so much waiting, it could never be a widespread thing. I鈥檇 like to say it would be but I don鈥檛 think it will.鈥�