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Biology 202
2001 Third Web Report
On Serendip

The Modern Day Brain Transplant:

An End to Parkinsonism or the Beginning of a Greater Debate?

Huma Q. Rana

It sometimes begins with a feeling of lethargy, being "down in the dumps," or shakiness (1). Maybe it begins with a twitch of the pinky finger that was not there before. Speech becomes more difficult and softer to the level of a whisper; this is often accompanied by irritability. Movements become rigid, unsteady and slow (2). A tremor develops, with trembling of the hands, arms, legs, jaw, and face. Later, walking is often only accomplished through short and shuffling steps, intermixed with a loss of balance and instability (3). These symptoms usually progress until the person is incapacitated and unable to do simple tasks such as brushing their teeth, buttoning clothing, or turning newspaper pages (1).

This is a description of a person living with Parkinson's disease. According to the Parkinson's Disease Foundation, there are one million people living with Parkinson's nationwide (1). Several public figures have also revealed their private struggles with Parkinson's including Michael J. Fox, Muhammad Ali, Janet Reno and Billy Graham (1). As evidenced by the names listed, Parkinson's strikes an array of people, it is generally a late onset disorder, however, in some cases, such as with Michael J. Fox, Parkinson's has a "young onset".

Parkinson's disease is a disorder that results from the depletion of the neurotransmitter dopamine. The basal ganglia is the part of the brain responsible for movement. When 80% of the dopamine-secreting cells in a specific part of the basal ganglia, the substantia nigra, are lost Parkinson's symptoms develop (4). The cause for the neuropathology of Parkinson's is still unknown. Two possible causes of Parkinson's that have been researched include environmental factors such as toxins and defective genes (5).

Treatments for the disease vary widely. The standard treatment is to prescribe levodopa (L-dopa) (4), the precursor of dopamine to patients. This is given because dopamine itself does not cross the blood-brain barrier. The levodopa is converted to dopamine inside the brain and is effective in improving the severity of symptoms dramatically. Unfortunately, long-term usage of levodopa causes a myriad of side effects, such as head bobbing, grimacing, abnormal movements of the trunk and limbs (2). With time, the side effects of levodopa become more dramatic than the original Parkinson's and the thus outweigh the benefits of giving the drug. Other treatments include a brain "pacemaker," deep brain stimulation with electrodes, and pallidotomy (destroying a portion of the globus pallidus in the brain). The research on neural transplantation as a method of treating Parkinsonism has recently been at the forefront of the media (5).

These neural cell transplants are not the brain transplants of 1950s horror movies nor is cell therapy a new concept. For decades researches have been implanting fetal neural tissue as a possible answer to illnesses such as diabetes, Alzheimer's, and Huntington's diseases (2). In the 1980s, successes in reducing Parkinson's symptoms in animals by transplanting fetal cells inspired researchers to do human clinical trials (6). However, due to an eight-year ban on this type of research by Presidents Reagan and Bush, the research was suspended, but resumed in 1993 with the coming of the Clinton administration (6).

The rationale behind fetal tissue transplants is that isolating and transplanting fetal dopamine-producing neurons into the putamen and caudate nucleus will cause these neurons to establish connections with other parts of the brain and will replace the cells originally lost. In theory, these new cells would begin to produce their own dopamine and increase the level of dopamine in the system bringing it back to normal (2). The brain tissue is usually obtained from immature fetuses whose mothers have undergone elective abortion. Tissues from the appropriate region are then transplanted into the Parkinson patient. The surgery relies on the plasticity of the brain, meaning its ability to change and reconnect using the new cells. But whether this is the cure for Parkinson's disease is still debated.

The results of the most recent fetal tissue transplants for Parkinson's were recently released to the media. The first randomized, controlled, double-blind study in this field involved three neuroscience centers in the USA. Human embryonic mesencephalic tissue containing dopamine neurons, obtained from 7-8 week old aborted embryos were transplanted into the brains of 20 patients with Parkinson's. Twenty other Parkinson's patients underwent sham surgery meaning a hole was drilled through the cranium, but the dura was not penetrated and no cells were transplanted (7), (8). According to the researchers' article in the New England Journal of Medicine, "The findings of this study showed that human embryonic dopamine-neuron transplants survive in patients with severe Parkinson's disease and result in some clinical benefit in younger but not older patients" (8). As evidenced by the careful language and subtleties of the above quote, the results of the study were mixed.

Thirty-three patients in total received transplants and survived for three years after surgery; the control group got the transplants as well after the final assessments were made (8). Some improvement did occur in the 19-surviving members of the original transplantation group of 20. There was 28 percent improvement over baseline in total UPDRS scores (a comprehensive inventory of symptoms and signs of Parkinson's disease). There was a 38% improvement in younger patients and a 14% improvement in older patients. (8). However, for some the improvement came at a price, five of thirty-three patients (15%) developed dyskinesias or abnormal movements 2-3 years after implantation (7). The dyskinesias involved uncontrollable writhing, joint flexing, chewing, and other movements (9). The five affected patients were 60 years or older at the time of the surgery (8).Therefore, 15% of the patients were worse off after the surgery than they were before it.

According to Curt Freed, the principal investigator of the study, by the second year 15% of patients had recurrent dyskinesias even after reducing levodopa treatment which indicated that the transplants had produced an excess of dopamine in the patients. This may have been caused by continued outgrowth from the transplant that led to the relative excess of dopamine. Four of the five patients who had the dyskinesia were rendered disabled by the side effects (7). Paul Green, a neurobiologist at Columbia University commented on the grave side effects, "It has made me reluctant to proceed with this line of research in a clinical setting (7)." The findings led the researchers to question the plasticity of older brains. They feel these older brains must be less malleable since Parkinsonism did not improve in the older patients during the first year after transplantation (8). However, researchers in Sweden and UK who have had more success with transplantation say the technique of the recent study needs to be examined and surgeries need to be done with a protocol (7). These averse side effects were not reported in trials done by other centers which have recruited 3-4 times as many patients as were included in the current study. Stephen Dunnett of the University of Cardiff, UK, was critical of the new study's protocol, which he blames for the dyskinesias. He expressed concern over the use of "unvalidated techniques." (7) The latest study used a frontal approach to deliver cultured cells from two donor embryos while previous researchers had used a parietal approach and injected fresh cells from three to four donors per side. Furthermore, this study did not use immunosuppressants after the surgery (7). It is quite possible that problems with technique and the numerous differences from the protocol could have resulted in the dyskinesia observed (7).

Despite the obvious setbacks, Freed's study showed that transplants of embryonic dopamine neurons survive in the putamen of patients with Parkinson's disease regardless of age (8). The fact that human dopamine cells transplanted to another human suffering Parkinson's can survive and may be able to produce some symptomatic relief should be celebrated and is enough to compel more study. Only through further study can inadequate relief of symptoms and side effects from cell loss be determined and corrected (10).

Not all agree that further research should be done. The results of the latest study have caused a media uproar. The New York Times has reported the conclusion of the study as a failure (10). Pro-lifers were already up in arms about the surgery, because it involved using cells from aborted fetuses, but then the mixed results of the surgery did not help (9). Republican Senator Sam Brownback of Kansas commented on the surgery, "Not only are you destroying one human being [the fetus], you may be destroying two (9)." Further controversy erupted due to the ethics of performing sham surgeries on the control group (9).

I would argue that the distinction between the ethical debate over abortion of human fetuses and the need for research should be recognized. The linkage between abortion and cell transplantation in humans is not necessary or even desirable for transplantation. There are three common reasons for this. Firstly, to develop a major medical treatment that relies on the event or availability of aborted human fetal donor tissue is undesirable and impractical for researchers anyway (11). Next, human fetal tissues can increase infection risks to patients receiving transplants. Finally, the technique for coordinating and handling aborted human fetal brain tissue is quite difficult and may not provide enough surviving dopamine cells for patients to recover form the disease (11).

An alternative option is that transplantation surgery does not have to be limited to the use of cells from aborted fetuses; other investigated cell sources include neural stem cells, animal cells, and cells made from cancer tumors (12). With the recent isolation of human neural stem cell, there is new hope for neural cell transplants without causing an abortion controversy (12). Neural stem cells are immature cells that can differentiate into all the cell types of the brain (12). In a study using mice at the National Institute of Neurological Disorders and Stroke (NINDS), it was found that the stem cells would travel throughout the brain producing proteins that were deficient and replenishing cells that were destroyed by disease (13).

Another recent clinical trial which used animal cells released its results in March 2001. Fetal porcine cells were used instead of cells from human fetuses. The study conducted by Genzyme Corporation and Diacrin Incorporation, implanted fetal pig cells into the brains of 10 patients and did sham surgery on the other 8 Parkinson's patients. Though a preliminary study had showed promising results, this treatment/placebo trial showed no difference between the two groups 18 months later (14), (15). Although the use of porcine cells eliminates the abortion controversy, it raises other concerns such as cross-species infection common in xenotransplantation (15). This once again shows that most scientific advances come at a cost.

Aside from the abortion issue, further controversy erupted due to the ethics of performing sham surgeries on the control group (9). The inclusion of the sham control group had sparked considerable debate because it involved drilling holes into the skulls of patients to account for any possible placebo effects of the surgery. Dr Ruth Maklin of the Albert Einstein College of Medicine in New York has voiced her opposition to such surgeries in the New England Journal of Medicine. "Performing a surgical procedure that has no expected benefit other than the placebo effect violates the ethical and regulatory principal that the risk of harm to subjects must be minimized in the conduct of research," said Dr Maklin (16). The patients in the control group were offered the opportunity to undergo surgery after the final assessments had been made. Regardless of this, Maklin's feelings are echoed by numerous others who also believe that it was unethical to expose patients to such a potentially harmful intervention. Although patients were not directly harmed by the sham surgery, they did undergo a serious and painful surgery and were exposed to developing infection since no antibiotics were used in the experiment.

As stated earlier, fourteen of the twenty members of the control group did undergo the transplantation surgery. However, this is yet another fault of the study because by giving both of the groups the surgery, the researchers have barred any possible long-term comparisons between the two groups (7). This is a significant setback to the research because improvement in patients tends to occur more than a year after transplantation. Although, I lack expertise in neurobiological research, it seems from the comments of the European researchers, and from the oversight of giving the placebo group the treatment, that this particular experiment was ill-conceived or at the very least ill-planned. There were some obvious flaws with the study, such as not adhering to protocols and taking the final assessment too early, that could have been prevented.

Despite the setbacks in the field of neural transplants, research into the plausibility of alleviating or even reversing Parkinsonism is necessary. As the American population ages and the elderly outnumber the young, the horrors of Parkinson's will have an even more profound affect upon society. Though treatments with L-Dopa can help, there is a need for a treatment with sustained benefits for Parkinson's patients. The possibility of reversing a neurodegenerative disease that has been awakened by neural cell transplants is astounding. The plasticity and mechanisms of the brain are still complex and therefore incremental results such as those seen in the latest neural transplants are a welcome addition to scientists, patients, and the public (17). In general, I believe that this research is extremely beneficial to society, in that it leads to a greater understanding of the brain and its pliancy. There is no easy answer to the debates caused by Parkinson's research. However, the problem of Parkinsonism is not desisting and there is an obvious need for more clinical trials and for perfecting the technique of neural transplants. Until this type of surgery reaches the mainstream, Parkinson's patients are left with no choice but to buy time by using ineffective medications, pallidotomy, or deep brain stimulation. Furthermore, only through more clinical trials of neural cell transplants will scientists be able to elucidate the limitations that age puts on the plasticity of the brain.

Although I am personally a proponent of further research in this realm, there are many people who would disagree with using neural transplants as a cure for Parkinsonism. Furthermore, the more I research and ponder the issue, the less definite I become and the less I adhere to the staunch feelings I report above. More than anything else, this type of research, undeniably and without fail raises questions. In her paper on the use of stem cells, Lisa Cahill, a professor of theology, sees the use of stem cells as a classic moral dilemma which is: does the end justify the means [abortions, sham surgery, and negative side effects] (18)? However, neither the end nor the means can be isolated from their context and ramifications on society as a whole. Would sacrificing embryos lead to a general disrespect for life and an increase in abortion (18)? Would prohibiting research endanger scientific inquiry and result in callousness and neglect towards those who suffer from serious illnesses (18)?

These issues lead us to an even broader idea and to evaluating the value that our society puts on medicine. Are we too reliant on modern day medicine to cure all of our ailments? Should we look towards advancements in biotechnology to solve age-old human problems like aging, suffering, and death? By doing this type of research into Parkinson's disease, Alzheimer's disease, and various other diseases are we in fact trying to suppress that which makes us human? Isn't this type of research a quest for immortality? In fact, the media has proclaimed research into the use of fetal and stem cells as a fountain of youth. In light of the latest findings published in the New England Journal of Medicine, the head of Do No Harm: Coalition of Americans for Research Ethics, Dr. David Prentice, remarked, "This is one area of research where there is plenty of evidence that it might have unexpected and unfortunate results. We've all heard that fetal stem cells might be the Fountain of Youth. I say that the water is poisoned." (19) Dr. Prentice believes that researchers are eager to press ahead just for the sake of discovery although there has been considerable evidence that they should rethink this field of study (19).

When one hears the horror stories associated with these surgeries, it is difficult not to agree. For example, in 1996, a 52-year old man traveled to China to have fetal tissue transplanted into his brain (20). Twenty-three months after surgery, he died suddenly. The autopsy showed that the transplanted tissues had survived, but had not grown into neurons. The cells had grown wildly, differentiating into hair shafts, skin, cartilage, and bone that studded his ventricular system. His body had also launched an immune attack against the fetal tissue graft (20). The reality of the situation is that there are dangerous and debilitating side effects to these surgeries, that they can in fact wreak havoc on human lives. Furthermore, many argue that by the large-scale public financing of stem cell research, we perpetuate the notion that biomedical techniques are an unbounded and unassailable force for good and are the answers to all of our problems.

Opponents of this research claim that scientists are "playing God" by conducting this type of work. In my opinion, who decides where the line between medicine and "playing God" is drawn? There is no clear demarcation and one could argue that the first time a human rubbed an herb on a scrape or stuck a leaf on a bleeding wound was the first step towards "playing God." The only difference now is that our technology has become more sophisticated. However, part of me agrees with Dr. Prentice. We, as humans, are imperfect. We are meant to get sick, to age, and to eventually die. However, as a diabetic, I cannot help but find hope in this type of research. There is promise in the idea of no longer suffering, of being physically flawless, or at the least just being as healthy as the "normal" population. I assume that it is this same type of reasoning that propels Parkinson's patients and scientists to search relentlessly for a cure.

It is unfortunate but perhaps necessary, that the research in Parkinson's is being hampered by the ethical concerns raised by abortion and sham surgery. To me, the line of research into neural cell transplants does not represent the end of Parkinson's disease, but it certainly does seem to provide promise in finding a cure for the disease. One could consider it to be the beginning of the end, but even that is debatable. Most importantly, this research makes us question our values. It broadens our horizons; it makes us wonder what we are, what we can be, and finally what we should be. Many in the scientific community respond to attacks on their inconclusive research by saying that the nature of scientific inquiry is to investigate the journey and not a sure destination. I think I agree with that sentiment and for me that reasoning seems like enough to justify this medical research.

WWW Sources

1) Food and Drug Administration. , Web Page on Parkinson's Disease.

2)Life Extension Foundation Web Page, Fetal Neural Transplants in Parkinson's.

3) Pace, Brian & Richard M. Glass. "Parkinson Disease." JAMA, The Journal of the American Medical Association, Vol. 284, Issue 15. (October 18, 2000). p2012. JAMA, *

4)Parkinson Action , Routes to a cure.

5)Thirteen Online , What's Being Done in Parkinson's Research?

6)Parkinson's Action , Library of information of PD.

7) Weber, Wim & James Butcher. "Doubt over cell therapy for Parkinson's disease." The Lancet Vol. 257, Issue 9259. (March 17, 2001) p. 859. The Lancet , *

8) Freed, Curt, et al. "Transplantation of Embryonic Dopamine Neurons for Severe Parkinson's Disease." The New England Journal of Medicine Vol. 344, Issue 10 (March 8, 2001). The New England Journal of Medicine , *

9)Time Magazine, The Parkinson's Experiment: This one had everything: aborted fetuses, sham surgery, desperate patients-and then it went awry.

10) U.S. Newswire , Parkinson's Action Network Urges Aggressive Pursuit of Research in Cell Transplantation.

11)Harvard Neuroscience Institute, Fetal Nerve Cell Transplantation: Advances in the Treatment of Parkinson's Disease.

12) "Rebuilding the Brain." Business Week. Issue 3615 (Feb. 8, 1999) p 78. Business Week , *

13)NINDS, National Institute of Neurological Disorders and Strokes at NIH.

14) "New Setback Reported in Treatment for Parkinson's Disease in U.S." Xinhua News Agency (March 19, 2001). Xinhua News Service , *

15) Friedrich, M.J. "Fetal Pig Neural Cells for Parkinson Disease." JAMA, Journal of American Medical Association Vol. 282, No. 23. (December 15, 1999). JAMA, *

16) NEJM, Sounding Board of the New England Journal of Medicine.

17) Editorial. "Cell Therapy for Parkinsons's Disease." New England Journal of Medicine Vol. 344, No. 10. (March 8, 2001). The New England Journal of Medicine , *

18) Cahill, Lisa Sowle. " Stem Cells: A Bioethical Balancing Act: The moral issues are not limited to the safety of embryos." America Vol 184, No.10. (March 26, 2001). *

19) Editorial. " Analysis: Fetal research hit from within." United Press International. March 15. 2001. UPI-United Press International *

20) McGovern, Celeste. " Neurology: Fatal outcome of fetal tissue transplant for Parkinson's patient." Alberta Report Vol 26, No. 43. (December 6, 1999). Alberta Report, newsmagazine , *

* Sources can be located online, but require registration of a username and password on the site or via Infotrac.

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