What is fetal tissue transplantation?

Indications and Procedures

Advances in technology sometimes catapult a society into ethical arenas that are not yet circumscribed by laws and clear moral boundaries. Fetal tissue transplantation is one of these advances. It is a technology that carries the hope of curing a diverse array of severe, often tragic, ailments but one that raises many difficult questions. Tissues from aborted fetuses have been shown in experimental trials to be an excellent source of replacement tissue for patients whose diseases have destroyed their own vital tissues. Parkinson’s, Huntington’s, and Alzheimer’s diseases (in which regions of the brain deteriorate) or juvenile-onset diabetes mellitus (in which insulin-secreting cells of the pancreas degenerate) theoretically could be cured with suitable tissue replacement.

The two sources of tissue used in transplantations, donations from adult cadavers and from aborted fetuses, differ significantly in their suitability. Tissues from cadavers have the severe disadvantage of being immunologically rejected when grafted into anyone who is not an identical twin. The body’s surveillance system that protects against infection is designed to attack and destroy any cells that carry molecular markers identifying them as foreign. Patients receiving tissue transplants from other individuals, therefore, will tolerate the tissue graft only if their immune systems are first suppressed with a battery of potent drugs, leaving the patient dangerously unarmed against infection.

Other disadvantages of cadaveric tissues are cell death due to extended postmortem interval (time between individual’s death and collection of the tissue) and poor integration into the recipient organ. Porcine xenografts into patients with Parkinson’s disease have also been attempted, but they were unsuccessful because of the rejection of the majority of transplanted cells despite aggressive immunosuppression. Taken together, allografts, a transplanted tissue or organ from a genetically different member of the same species, are generally much better tolerated than are xenografts, a transplanted tissue or organ obtained from a member of a species different from that of the recipient. In contrast, isografts, which utilize tissue from a genetically identical twin, are not rejected. Of note is that transplant rejection decreases with the recipient’s age, possibly due to immunosenescence and the increased effectiveness of immunosuppressive drugs.

Fetal tissues, however, do not induce a full-scale immune response when transplanted. This is particularly true when cells are transplanted into an organ such as the brain, which is considered an immunologically privileged site along with other locations in the body, such as the anterior chamber of the eye, testis, renal tubule, and uterus. At these sites, the immune response to antigens is reduced and/or not destructive to the transplanted tissue. Nevertheless, transplanted fetal tissues do attract lymphocytes (a type of white blood cell of the immune system) and other immune cells, but the role of this process in graft survival and function is not well understood.

Other properties add to the suitability of fetal tissue for transplantation. Because it is not yet fully differentiated, fetal tissue is said to be very plastic in its abilities to adapt to new locations. Moreover, once placed in a patient, it secretes factors that promote its own growth and those of the new blood vessels at the site. Tissue from an adult source does not have these properties and consequently is slow-growing and poorly vascularized. Though growth factors can be added along with the graft, adult tissue is less responsive to these hormones than is fetal tissue.

It is the source of fetal tissue that has fired such debate over its use for transplantation. Though there has been general acceptance of using tissue from spontaneous abortions or from ectopic pregnancies which, because of their location outside the womb, endanger the life of the mother and must be terminated, these sources are not well suited to transplantation. Spontaneous abortions rarely produce viable tissue, since in most cases the
fetus has died two to three weeks before it is expelled. In addition, there are usually major genetic defects in the aborted fetus. In ectopic pregnancies as well, more than 50 percent of the fetuses are genetically abnormal, and most resolve themselves in spontaneous
abortion outside a clinic setting. These types of abortions are almost always accompanied by a sense of tragic loss felt by the parents. Many researchers find it unacceptable to request permission from these parents to transplant tissue from the lost fetus.

The alternative source of fetal tissue is elected abortions. One-and-a-half million of these abortions occur in the United States every year. The debate over the ethical correctness of elected abortions has left a cloud of confusion over the issue of using this tissue for transplantation.

When an elective abortion is performed in a clinic, the tissue is removed by suction through a narrow tube. Normally, the tissue would be thrown away. If it is to be used for transplantation, written permission must be obtained from the woman after the abortion is completed. No discussion of transplantation is to take place prior to the abortion, and no alteration in the abortion procedure, except to keep the tissue sterile during collection, is to be made. The donor may not be paid for the tissue, and both the donor and the recipient of the tissue must remain anonymous to each other.

Once collected, the tissue is searched through to locate suitable tissue for transplantation. Although the size of the transplanted tissue varies depending on the type of cell replacement, often only a small block of tissue is used, about eight cubic millimeters (the size of a thin slice of pencil eraser). The tissue is screened for infectious diseases such as hepatitis B and Human immunodeficiency virus (HIV). Tissue that is collected is washed a number of times in a sterile solution to ensure that there is no bacterial contamination, and then it is maintained in a sterile, buffered salt solution until it is used. To increase the amount of usable tissue, the tissue may be grown in culture on a nutritive medium under carefully controlled conditions of humidity (95 percent), temperature (37 degrees Celsius), and gas (5 percent carbon dioxide in air) to stimulate normal growing conditions. Preservation of the tissue for long-term storage has been made possible by the highly refined technique of freezing the tissue in liquid nitrogen (cryostorage). Fetal tissue has been kept for as long as ten months in this manner before being used successfully in transplantation. Although the technique should provide methods of maintaining tissue indefinitely, not all types of cells contained in such tissues
survive cryopreservation well. For example, despite many attempts to optimize storage conditions, fetal neurons are severely harmed by freezing.

The actual transplantation of the tissue is usually relatively quick and in some cases relatively noninvasive. Often the tissue is injected into the patient as a suspension of individual cells. This permits the use of a small-bore tube called a cannula to deliver the cells to the target organ, thereby avoiding large surgical incisions. Because of modern stereotaxic imaging equipment such as computed tomography (CT) scanning and ultrasound, the physician is able to determine with extreme precision exactly where the cells are to be delivered and can visualize the position of the transplant cannula as the cells are injected. In this way, an entire region of an organ can be seeded with fetal cells. Often the patient is under only a local anesthetic. This aspect of the surgery is especially important when fetal cells are being inserted into the brain, since the physicians can then monitor the patient’s ability to speak and move, to ensure that no major damage to the brain is occurring. Usually, antibiotics are given on the day of the transplantation procedure and for two additional days to avoid infection. Although the procedure is relatively safe and recovery
is quick—patients often go home in less than three days—transplantation into the central nervous system (CNS) carries risk of hemorrhage (bleeding) and blood clot formation that can damage neurons in the affected area.

Fetal tissue transplantation is still considered an experimental procedure, and further trials are needed to fine-tune the techniques. For example, the precise age of fetal tissue that would be most effective in various cases is uncertain, though it is generally agreed that tissue from a first-trimester fetus is optimal, and six to eight weeks of gestation is most suitable for grafts into brains of Parkinson’s sufferers. Often it is not known which patients would respond best to the therapy, but in case of neurotransplantation in Parkinson’s disease patients, those with good response to levodopa (L-dopa), a precursor of dopamine, benefit the most. Researchers are also uncertain about whether immunosuppressive drugs should be administered. In animal trials using mice, rats, and monkeys, fetal tissue allografts, but not xenografts, have been well tolerated in the absence of immunosuppression. In humans as well, fetal tissue appears to be readily accepted, with no signs of rejection, and in one study, patients did better without immunosuppression. Some surgeons, however, unwilling to risk tissue rejection, routinely give the transplant patient immunosuppressive drugs, such as cyclosporine and prednisone.

Uses and Complications

The major focus for fetal tissue transplantation has been the treatment of patients with Parkinson’s disease, and results have been encouraging. The disease is caused by a deterioration of dopamine-producing regions of the midbrain, the substantia nigra, so named because of the presence of pigmented neurons, which secrete dopamine, in the putamen and caudate nucleus of the basal ganglia. There these neurons send their processes (projecting parts). There is an accompanying loss of motor control causing slowness of movement (bradykinesia), tremors, rigidity, and finally paralysis. Death is most typically a result of accompanying illnesses, such as infections, or caused by the loss of balance and falls. The key drug used to treat the disorder, L-dopa, produces side effects that cause unrelenting and uncontrolled movement of the limbs (dyskinesias) and hallucinations, and the drug loses its effectiveness over time. Advanced patients, who are no longer taking the medication, often remain in a “frozen” state.

A number of patients who have received fetal tissue transplants have shown remarkable improvement and diminished requirements for drug treatment. The first case in the United States to be treated was a man with a twenty-year history of parkinsonian symptoms. He had frequent freezing spells, could not walk without a cane, and suffered from chronic constipation. He also was unable to whistle, a beloved hobby of his. He was operated on by Curt R. Freed and his associates in 1988. Following the operation, initial improvement was slow, but within a year, he was walking without a cane, his speed of movement had considerably improved, and his constipation had resolved itself. He also had regained his ability to whistle. Even after four years, improvements continued. Such results have occurred with many parkinsonian patients receiving fetal tissue transplants.

Beneficial effects of transplants have also been obtained in patients with induced Parkinson-like symptoms. In 1982, some intravenous drug users developed Parkinson-like symptoms after using a homemade preparation of “synthetic heroin” that was contaminated with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). MPTP destroys dopamine-secreting cells of the substantia nigra. Two of these patients received fetal tissue transplants in Sweden. Within a year after their operation, they were able to walk with a normal gait, resume chores, and be virtually free of their previously uncontrollable movements.

Because no patient with Parkinson’s disease or with Parkinson-like symptoms has yet been cured by a fetal tissue transplant, some have considered the results of such experiments to be disappointing. The expectation of complete cures from a technique that is still in its early experimental phase, however, is overly optimistic. Many patients themselves are encouraged, and many have resumed driving and the other tasks of normal daily life. Altogether, more than two hundred patients with Parkinson’s disease have received fetal tissue transplants worldwide. It is important to note that fetal tissue transplants are not stem cell transplants, or grafts of tissue produced from stem cells. Coincidentally, fetal tissue usually contains some stem cells, but the transplant effects are thought to be mostly mediated by the mature or maturing cells in the donor tissue (dopamine neurons or pancreatic beta cells, for example).

That transplanted fetal brain tissue can replace damaged brain tissue to any extent has opened the doors of hope for many diseases. For example, Huntington’s disease, a genetic disorder that destroys a different set of neurons but in the same region as that affected by parkinsonism, brings a slow death to those carrying the dominant trait. Its severe dementia and uncontrollable jerking and writhing that steadily progress have had no treatment and no cure. In animal studies in which fetal brain tissue was transplanted into rats with symptoms mimicking Huntington’s disease, results have been encouraging enough to warrant human trials, and one human trial, reported by a surgeon in Mexico, has shown limited success. Another such study is ongoing in France. Researchers are hopeful, though less optimistic, that Alzheimer’s disease, a form of dementia that is characterized by neuronal death within the brain, also may be treatable with fetal tissue transplants. Because the destruction is so widespread, however, it is difficult to determine where the transplants should be placed.

Type 1 insulin-dependent diabetes, often called juvenile-onset diabetes, also has been treated with fetal tissue transplants. More than a million people in the United States suffer from this disease caused by the destruction of pancreatic beta cells, the insulin-secreting cells that regulate sugar metabolism. Though the disease can be controlled with regular insulin shots, the long-term effects of diabetes can lead to blindness, premature
aging, and renal and circulatory problems. After animal tests showed a complete reversal of the disease when fetal pancreatic tissue was transplanted into diabetic rats, human trials were initiated with great expectations. Though complete success has not been achieved, the sixteen diabetic patients who were given fetal pancreatic tissue transplants by Kevin Lafferty between 1987 and 1992 all showed significant drops in the amount of insulin needed to manage their disease. The transplanted tissue continued to pump out insulin.

An unusual variation of such procedures has been to transplant fetal tissue into fetuses diagnosed with severe metabolic diseases. It is more effective to treat the condition while the fetus is still in the womb than to wait until after birth, when damage from the disease may already be extensive. Fetuses with Hurler’s syndrome and similar “storage” diseases have been treated in this way. Hurler’s syndrome is a lethal condition in which tissues become clogged with stored mucopolysaccharides, long-chain sugars that the body is unable to break down because it lacks the appropriate enzyme. One of the fetuses to receive this treatment was the child of a couple who had lost two children to the disease. With the transplanted tissue, the child lived and by one year of age was producing therapeutic levels of the enzyme. It has been estimated that there are at least 155 other genetic disorders that could be similarly treated by fetal tissue transplants in utero.

The list of ailments that fetal tissue transplants may alleviate includes some of the major concerns of modern medicine. In addition to those already mentioned are macular degeneration, sickle cell disease, thalassemias, metabolic disorders, immune deficiencies, myelin disorders, and spinal cord injuries. In interpreting the value of these applications, however, it is important to separate the politics of abortion from the medical issue of fetal tissue transplantation.

Perspective and Prospects

Though controversy surrounds the use of fetal tissue for transplantation, such controversy has not included all facets of fetal tissue research. Indeed, fetal cells were used in the 1950s to develop the Salk polio
vaccine and later the vaccine against rubella (German measles). With the scourge of Acquired immunodeficiency syndrome (AIDS), in the 1990s fetal cells were first used to help design treatments against the AIDS virus. Even the early attempts at fetal tissue transplantation occurred quietly. Reports date as far back as 1928, when Italian surgeons attempted unsuccessfully to cure a patient with diabetes using fetal pancreatic tissue, a procedure repeated, again unsuccessfully, in the United States in 1939. In 1959, American physicians tried to cure leukemia with fetal tissue transplants, but again without success.

The first real indicator that such techniques might work came in 1968, when fetal liver cells were used to treat a patient with DiGeorge syndrome. The success of this procedure resulted in its becoming the accepted treatment for this usually fatal genetic disorder, which results from a deletion of a part of chromosome 22. Because many of the DiGeorge patients are athymic (fail to develop a thymus), they lack T cells, making them immunodeficient. Because the fetal liver supports hematopoiesis (the production of blood cells, including immune cells) during development, fetal liver cells have some value in the treatment of immunodeficiency. However, fetal thymus transplantation can promote more complete immune system reconstitution and is now used as a treatment in athymic patients.

Because suitable fetal tissues are often very difficult to obtain, recently the focus on donor cells for transplantation has shifted toward stem cell-derived cells. Stem cells can be relatively easily expanded in numbers in culture and have the potential to generate a large supply of different cell types for transplantation, thereby averting some of the issues that have decelerated the field of fetal transplantation. Donor cells differentiated from one’s own stem cells could be used in an autograft and thereby circumvent both immunological and ethical issues. Studies to explore the potential of such technologies are ongoing. Thus the next chapter in the fetal tissue transplantation story may involve the fast-evolving fields of stem cell research and regenerative medicine.

It was not until 1987 that ethical issues over fetal tissue transplants truly surfaced in the United States. Debate was precipitated when the director of the
National Institutes of Health (NIH) submitted a request to the Department of Health and Human Services to transplant fetal tissue into patients with Parkinson’s disease. Rather than receiving approval, the request was tabled, pending a thorough study of the issue by an NIH panel on fetal tissue transplantation. The panel made a detailed report on the ethical, legal, and scientific implications of fetal tissue transplantation, concluding that it was acceptable public policy. Despite the report, however, the Secretary of Health and Human Services instituted a ban against the use of government funds for transplanting fetal tissue derived from elective abortions. While in effect, the ban influenced private funding as well. Physicians who performed fetal tissue transplants, unable to obtain grant money, were forced to charge their patients—a bill that could reach as high as forty thousand dollars per transplant. President Bill Clinton’s lifting of the ban in 1993, on
his third day in office, paved the way for research advances, including isolating and propagating human stem cells. The opposition of Clinton’s successor, George W. Bush, to the use of fetal tissue and stem cells for scientific purposes led to several legislative battles and cast some doubts on the future of this field. President Barack Obama restored the use of government funds for stem cell research upon taking office in 2009.

The debates over fetal tissue transplantation are far from over. Though a strict set of guidelines are in place concerning the procurement of fetal tissue, ensuring that the needs never influence decisions concerning abortion, other issues have not been addressed. Some ask whether a fetal tissue bank should be established and, if so, whether it should be government-funded to avoid commercialization. As technology continues to create increasingly complicated ethical issues, society’s responsibility increases, as does its need to be scientifically informed.

Bibliography

Barker, Roger A., et al. "The Long-Term Safety and Efficacy of Bilateral Transplantation of Human Fetal Striatal Tissue in Patients with Mild to Moderate Huntington's Disease." Journal of Neurology 84, no. 6 (June 2013): 657–665.

Beardsley, Tim. “Aborting Research.” Scientific American 267, no. 2 (August, 1992): 17–18.

Beauchamp, Tom, and James F. Childress. Principles of Biomedical Ethics. 6th ed. New York: Oxford University Press, 2009.

Begley, Sharon. “From Human Embryos, Hope for ’Spare Parts.’” Newsweek, November 16, 1998, 73.

Brundin, Patrik, and C. Warren Olanow, eds. Restorative Therapies in Parkinson’s Disease. New York: Springer, 2006.

Clinical Trials. http://www.clinicaltrials.gov.

“Fetal Cell Study Shows Promise for Parkinson’s.” Los Angeles Times, April 22, 1999, p. 29.

Freed, Curt R., Robert Breeze, and Neil Rosenberg. “Transplantation of Human Fetal Dopamine Cells for Parkinson’s Disease.” Archives of Neurology 47, no. 5 (May 1, 1990): 505–512.

Freed, Curt R., and Simon LeVay. Healing the Brain: A Doctor’s Controversial Quest for a Cell Therapy to Cure Parkinson’s Disease. New York: Times Books/Henry Holt, 2002.

Holland, Suzanne, Karen Lebacqz, and Laurie Zoloth, eds. The Human Embryonic Stem Cell Debate: Science, Ethics, and Public Policy. Cambridge, Mass.: MIT Press, 2001.

Lindvall, Olle, Patrik Brundin, and Håkan Widner. “Grafts of Fetal Dopamine Neurons Survive and Improve Motor Function in Parkinson’s Disease.” Science 247 (February 2, 1990): 574–577.

Marshak, Daniel R., Richard L. Gardner, and David Gottlieb, eds. Stem Cell Biology. Cold Springs Harbor, N.Y.: Cold Springs Harbor Press, 2002.

Millán-Guerrero, Rebeca. "Role of Neural Stem Cells in Parkinson's Disease." Current Signal Transduction Therapy 6, no. 3 (September 2011): 337–340.

Seledtsova, G., et al. "Delayed Results of Transplantation of Fetal Neurogenic Tissue in Patients with Consequences of Spinal Cord Trauma." Bulletin of Experimental Biology & Medicine 149, no. 4 (April 2010): 530–533.

Singer, Peter, et al., eds. Embryo Experimentation. New York: Cambridge University Press, 1993.

U.S. Congress. Senate. Committee on Labor and Human Resources. Finding Medical Cures: The Promise of Fetal Tissue Transplantation Research. 102d Congress, 1st session, 1992. Senate Report 1902.

Wade, Nicholas. “Primordial Cells Fuel Debate on Ethics.” The New York Times, November 10, 1998, p. 1.