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Biology 202
2001 Second Web Report
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The Modern Day Brain Transplant: An End to Parkinsonism?

Huma Q. Rana

It sometimes begins with a feeling of lethargy, being "down in the dumps," or shakiness (1). Or 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 simples 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 an "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 which have been researched include environmental factors, including toxins, or 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, usage of long-term 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 Parkinson's, diabetes, 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 the 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 (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).

The findings led 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 needs to be examined and surgeries need to be done with a protocol (7). It is quite possible that problems with technique could result in the dyskinesia seen in the most recent study (7). Furthermore, the 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 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 fixed (10).

Unfortunately, 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 say that the distinction between the ethical debate over abortion of human fetuses and the need for research 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 which were destroyed by disease (13).

Another recent clinical trial released its results in March 2001. However, 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 placebo/sham 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.

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 (16). I believe that this research is extremely beneficial to society, in that it leads to a greater understanding of the brain and its pliancy. 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.

Unfortunately, the research in Parkinson's is being hampered by the ethical concerns raised by abortion and sham surgery. There is no easy answer to these issues; 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. To me, though the line of research into neural cell transplants does not represent the end of Parkinson's disease, it does seem to be the beginning of the end.

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) 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 , *

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

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