The significance of this first government-financed study using fetal tissue is that President Reagan had banned the use of taxpayer support for this type of experimentation in 1988. President Clinton lifted the ban in 1993, and President George W. Bush reinstated it in January 2001.Google Scholar

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The pertinent ethical regulations and guidelines can be found in the following: The Nuremberg Code, reprinted in Trials of War Criminals Before the Nuremberg Military Tribunals Under Control No. 102 (Washington, D.C.: U.S. Gov't Printing Office, 1949): At 181–82; Declaration of Helsinki, adopted by the 18th World Medical Assembly, 1964 and revised in 1975 and 1983; National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, DHEW Pub. No. (OS) 78–0012 (Washington, D.C.: U.S. Gov't Printing Office, 1978) [hereinafter cited as The Belmont Report]; World Health Organization, Proposed International Guidelines for Biomedical Research Involving Human Subjects (Geneva: CIOMS, 1982); Medical Research Council of Canada, Guidelines on Research Involving Human Subjects (Ottawa, Canada: Minister of Supply and Services, 1978).Google Scholar

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Stage I involves only one side of the body. Stage II involves both sides of the body, but does not impair walking. Stage III impairs both balance and walking. Stage IV markedly impairs balance or walking. Stage V results in complete immobility. For a more detailed analysis, see Family Caregiver Alliance, Fact Sheet: Parkinson's Disease (San Francisco: Family Caregiver Alliance, 2000), available at <http://www.caregiver.org/factsheets/parkinsons.html> (last revised August 2000).+(last+revised+August+2000).>Google Scholar

Dopamine is a neurotransmitter of some peripheral nerve fibers and many central neurons (e.g., in the substantia nigra, midbrain, ventral tegmental area, and hypothalamus). The amino acid tyrosine is taken up by dopaminergic neurons and converted by tyrosine hydroxylase to 3,4-dihydroxyphenylalanine (dopa), which is decarboxylated by aromatic-L-amino-acid decarboxylase to dopamine. After release, dopamine interacts with dopaminergic receptors, and its residue is actively pumped back (reuptake) into prejunctional neurons. Tyrosine hydroxylase and monoamine oxidase regulate dopamine levels in nerve terminals. Beers, M.H., Berkow, R., eds., The Merck Manual of Diagnosis and Therapy, 17th ed. (Whitehouse Station, New Jersey: Merck Research Laboratories, 1999): at 1360.Google Scholar

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For a more detailed analysis, See Prasad, K.N. et al.., “Efficacy of Grafted Immortalized Dopamine Neurons in an Animal Model of Parkinsonism: A Review,” Molecular Genetic Metabolism, 65 (1998): 1–9. In these experiments, researchers established immortalized dopamine neurons from fetal rat mesencephalon by inserting the large T-antigen (LTa) gene of the SV40 virus into the cells. A clone of the dopamine neuron (1RB3AN27) was isolated, characterized, and tested in 6-hydroxydopamine (6-OHDA)-lesioned rats (a model of Parkinson's disease). These cells divided with a doubling time of about twenty-six hours, expressed the LTa gene, and contained the tyrosine hydroxylase and dopamine transporter proteins and their receptive mRNAs, which became elevated upon differentiation. These cells were nontumorigenic and nonimmunogenic and improved the symptoms of neurological deficits (methamphetamine-induced rotation) in 6-OHDA-lesioned rats. The differentiated dopamine neurons were more effective than undifferentiated ones. These studies suggest that immortalized dopamine neurons generated in vitro by LTa gene insertion may be used in transplant therapy without the fear of tumor formation or rejection. See also Hauser, R.A. et al., “Long-Term Evaluation of Bilateral Fetal Nigral Transplantation in Parkinson's Disease,” Archives of Neurology, 56 (1999): 179-87. Hauser and colleagues concluded that fetal nigral tissue can be transplanted bilaterally into postcommissural putamen in patients with advanced Parkinson's disease safely and with little morbidity. Clinical improvement appears to be related to the survival and function of the transplanted fetal tissue. See also Piccini, P. et al., “Dopamine Release from Nigral Transplants Visualized In Vivo in a Parkinson's Patient,” Natural Neuroscience, 12 (1999): 1137-40. In a patient who had received a transplant in the right putamen ten years earlier, grafts restored both basal and drug-induced dopamine release to normal levels. This release was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Thus, despite an ongoing disease process, evidence indicates that grafted neurons can continue for a decade to store and release dopamine and give rise to substantial symptomatic relief. See also Honey, C., Gross, R.E. and Lozano, A.M., “New Developments in the Surgery for Parkinson's Disease,” Canadian Journal of Neurological Science, 26, no. 2 (Supp 1999): S45-S52.CrossRefGoogle Scholar

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Id. at 856. In addition, some researchers question whether transplantation of human fetal tissue is necessary for effective treatment of Parkinson's disease, or whether similar results could be produced with different types of cells. In fact, researchers are currently experimenting with as many as eighteen different ways of transplanting cells other than fetal cells. Two such methods involve cells derived from stem cells. Another involves retinal cells, which secrete dopamine and neurotropic factors. Recent evidence indicates that one or more of these new strategies may be useful clinically. For an example, see Phillips, , supra note 9, at 1118.Google Scholar

The stereotactic needle has a maximal outer diameter of 1.5 millimeters, which tapers to 0.9 millimeters at the tip. Multiple needle trajectories (six to eight per side) are used, and four tissue deposits are injected into each burr hole so that the deposits are separated by no more than 5 millimeters throughout the three-dimensional configuration of the target region. For a more detailed analysis of this procedure, see Kordower, et al., supra note 17, at 1118–24.Google Scholar

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In one large double-blind pharmacological study, patients assigned to the placebo group had 20 to 30 percent improvement in motor scores, and this improvement persisted throughout the six months of the trial. See Freeman, et al., supra note 4, at 989. See also Clark, P.I. and Leaverton, P.E., “Scientific and Ethical Issues in the Use of Placebo Controls in Clinical Trials,” Annual Review of Public Health, 15 (1994): 19–38; Olanow, C.W. et al., “The Effect of Deprenyl and Levodopa on the Progression of Parkinson's Disease,” Annals of Neurology, 38 (1995): 771-77; The Parkinson Study Group “Effects of Tocopherol and Deprenyl on the Progression of Disability in Early Parkinson's Disease,” N. Engl. J. Med., 328 (1993): 176-83. In both of these studies, significant improvement and deterioration were observed after the introduction and discontinuation, respectively, of placebos in patients with Parkinson's disease.Google Scholar

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Id. at 1106. To examine the placebo effect and researcher bias, Freeman et al. have documented a trial design consisting of thirty-six adults with advanced Parkinson's disease whose symptoms could not be adequately controlled using medical therapy. These patients voluntarily consented to undergo one of three study procedures: bilateral fetal nigral transplantation with tissue from one donor per side, bilateral transplantation with tissue from four donors per side, or bilateral placebo surgery. According to the trial protocol, patients in the control group undergo two placebo surgical procedures designed to provide an equivalent experience for the patients and their family members. Each placebo procedure includes the placement of a stereotactic frame, target localization on magnetic resonance imaging, the administration of general anesthesia with laryngeal-mask airway, and a skin incision with a particular burr hole that does not penetrate the inner cortex of the skull. There are no needle penetrations into the brain, and no fetal tissue is implanted. The duration of the surgical procedures and the perioperative care are identical in all groups. All patients receive low-dose cyclosporine for six months and continue to receive medical therapy. Patients are evaluated in an identical manner at three-month intervals. To maintain the blinding of investigators, the surgical and evaluation sites are at separate locations. The surgeon is the only member of the research team who is aware of an individual patient's group assignment. See Freeman, et al., supra note 4, at 988-91. For a more detailed analysis, See Freeman, T.B. et al., “Bilateral Fetal Nigral Transplantation into the Postcommissural Putamen in Parkinson's Disease,” Annals of Neurology, 38 (1995): 379–88. It should be noted that at the conclusion of the study, if fetal tissue transplantation is found to be safe and effective, subjects in the placebo group will be offered the better of the two transplantation procedures (with tissue from one donor per side or four donors per side). See Freeman, et al., supra note 4, at 989–90.CrossRefGoogle Scholar

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