Genesis of Eden

Genesis Home

Aborting Research Scientific American Aug 92

Although this article is now six years old and refers to the previous US administration it raises significant ethical issues.

Fetal cell transplants in the U.S. are stalled by opposition

At the First International Congress of the Cell Transplant Society held recently in Pittsburgh, 13 papers were delivered during a special session on transplanting tissue obtained from fetuses. Their results inspired increasing confidence that those vigorous cells can enhance life for people with a number of disabling diseases. But only one presentation was by U.S. researchers-and it was based on sheep. The balance were by workers from China, japan, Russia, Hungary, Singapore, Sweden and Yugoslavia. The paucity of reports by U.S. scientists was mute testimony to the effects of a 1988 federal moratorium on funding for studies on fetal cell transplantation that use tissue obtained from voluntarily aborted fetuses. The Bush administration has continued to enforce the ban even though a specially convened expert panel recommended that the research should proceed provided safeguards were put in place to prevent it from encouraging abortion. In addition, the ban has discouraged private funding for the work and had a limiting effect on most investigative efforts into fetal development, says D. Eugene Redmond, jr., a fetal transplantation researcher at Yale University.

Poll: Fetal Cell Experiments Should Continue

A majority of the U.S. public does not agree with attempts by the antiabortion lobby and the Bush administration to hold back research on fetal tissue transplantation. A poll by Louis Hards and Associates found that 74 percent of those surveyed believe experiments should continue, including 55 percent of those who oppose abortion. The survey of 1,255 adults was conducted in June. Here are the results:

Do you believe that research in this field should continue or not?

    Total (percent)  Antiabortion  Proabortion
 Yes, should continue:  74  55  87
 No, should not continue: 22 42 9
 Not sure: 4 3 3

Allowing fetal cell research using aborted fetuses should be forbidden because it will encourage more abortions.

    Total (percent)  Antiabortion  Proabortion
 Agree: 33 60 17
 Disagree: 64 37 81
Not sure: 3 3 2

The use of aborted fetuses for research should be allowed if the alternative source-chiefly miscarriages-is inadequate In volume and quality.

    Total (percent)  Antiabortion  Proabortion
 Agree: 61 33 79
 Disagree: 33 61 17
Not sure: 6 6 5

The standoff has now escalated into a full-blown political confrontation. President Bush vetoed a congressional effort to overturn the ban in late June, and an attempt to override the veto failed to succeed. Opponents of the admiriistration's position-among them the American Medical Association, the Association of American Medical Colleges, the Association of Biotechnology Companies, the juvenile Diabetes Foundation and several foundations on Parkinson's disease-emphasize that their support for research on fetal cell transplantation does not imply any particular view on abortion. "What we are talking about has nothing to do with abortion," insists Sara King, research director of the juvenile Diabetes Foundation. Assistant Secretary for Health James 0. Mason has accused critics of exaggerating the potential of fetal cell trans plantation. Yet although the techniques are still experimental and involve small numbers of patients, the clear consensus of researchers is that the results with Parldnson's disease, at least, are encouraging. And scientists are optimistic that the findings have broader application. Fetal cells not only thrive in a host, they also can develop into specialized forms and secrete substances that nurture surrounding tissue. In addition, some fetal cells seem less likely than other cells to trigger an immune reaction. These properties could make fetal cells uniquely valuable for treating diseases in which tissue degenerates. Parkinson's disease, for example, slowly deprives its victims of the power of movement by destroying cells in a small region of the brain. Most of the 100 or more [email protected] patients worldwide who have had fetal brain cells implanted are reported to show signs of improvement, according to Anders Bjbrklund, a Swedish pioneer in the field. Bjbrklund readily agrees that the technique must be refined. Thirty-four months after transplantation, positron emission tomography scans indicated that ordy 5 to 10 percent of the cells he and his colleagues implanted into one group of four patients appeared to have survived. Even so, three of the four patients show improved mobility, Bjbrklund says. Similarly, Robert E. Breeze, who has performed fetal tissue transplants in Parkinsonian patients with Curt R. Freed of the University of Colorado, says seven of eight patients are improved, one dramatically. Breeze and Freed support their research with private funds and patient fees. Parkinson's is not the only disease that might be treatable with fetal tissue. Several researchers at Pittsburgh reported progress using pancreatic tissue grafts to reduce diabetics' reliance on insulin. Using fetal tissue could eliminate some of the problems encountered in obtaining tissue from adult cadavers. The one U.S. researcher who has achieved promising results treating diabetics with fetal pancreatic tissue, Kevin J. Lafferty of the University of Colorado, discontinued the work when the ban came into effect in 1988. Another disease that might one day be treatable with fetal tissue is muscular dystrophy, according to Terrence A. Partridge of Charing Cross and Westminster Medical School, London. And Paul R. Sanberg of the University of South Florida implants rat fetal tissue in rat brains that have chemically been damaged to cause symptoms resembling those of Huntington's disease, another devastating neurodegenerative disorder. Sanberg says his treatment can restore normal levels of activity. Deane B. Jacques of the Hospital of the Good Samaritan in Los Angeles, who plans to use private funds to treat Parkinsonian patients, hopes within a few years to experiment with treating patients disabled by cerebral palsy and stroke in the same way. The encouraging results serve ordy to rankle further the handful of U.S. scientists who have proceeded despite the ban. J. William Langston of the Califomia Parkinson's Foundation in San Jose, who has sent brain-damaged patients to Sweden where Bj6rklund's colleague Stig Rehncrona implants fetal cells, worries that the administration's ban is eroding the quality of fetal transplantation research by forcing it to go outside the peer-review system of the National histitutes of Health. Breeze argues that the ban slows progress toward determining the best age for transplanted tissue and impedes efforts to determine where precisely such tissue should be placed.

Other countries have moved ahead by taking measures to assure that the research does not encourage abortion, either by inspiring altruism in potential donors or creating a market for fetuses. In England, where Edward R. Hitchcock of the University of Birmingham has performed several dozen fetal transplants in Parkinsonian patients, apparently with beneficial results, women who have already decided to have an abortion are asked if they are wimng to donate fetal tissue for medical research. Donors are not told what disease is being studied, in order to avoid evoking sympathy on their part. Ironically, such safeguards parallel those proposed by the U.S. review committee in 1988. it insisted that financial inducements should be illegal and that women should not be able to donate fetal tissue for named beneficiaries. In addition, the conunittee said women should be asked to donate only after they had made a firm decision to have an abortion. Among those voting with the 17-4 majority on the committee was Bernadine Healy, who is now director of the National Institutes of Health. Otis Bowen, who as secretary of health under President Reagan enacted what was then seen as a temporary ban, said recently that he thought the goverm-nent should have permitted federal support of the research once it received the advice. But the present administration stffl contends that such guarantees might not work. "It's very unlikely [donors] wffl not know the humanitarian effect of donating tissue," said Assistant Secretary Mason at a recent press conference in Washington.

"This may well be part of their decision about whether or not to have an abortion." (Mason also admitted there are no data to support that view.) In an attempt to defuse mounting opposition, the administration announced in May that it would spend $3 million to establish "banks" of fetal tissue from "spontaneous abortions"-miscarriages-and from ectopic pregnancies, in which a fetus develops outside the uterus and has to be removed to save the mother. Mason said transplantation research using tissue from the proposed banks would not be "encouraging or justifying elective abortions,' and Healy declared the approach to be "feasible." But the researchers knowledgeable about fetal development protest that the proposed banks are irnpractical. "As far as I know, there is not anybody who is involved who believes this is a reasonable proposal," Redmond says. Redmond points out that researchers have avoided tissue from miscarriages and ectopic pregnancies for good reasons: tissue for transplantation should be kept in sterile controlled conditions, and its developmental stage must be known. That is possible in a medical facility, but fetuses spontaneously aborted are likely to become infected. Indeed, a high proportion of miscarriages occurs because of infection or some genetic abnormality. Moreover, "tissue from thousands of miscarriages would have to be collected and cryopreserved, and subsequent pathological, cytogenetic and rriicrobiological studies would have to be done in order to obtain the 3.58 fetuses per year that might be usable" in a large hospital, Redmond maintains. "It sirnply would never work." Nor would using fetuses obtained from an ectopic pregnancy, which is a surgical emergency: delaying the procedure to get informed consent and to assemble a team to preserve the tissue would be unetwcal and dangerous, Redmond says. And tissue from ectopic pregnancies is often nonviable because it has a poor blood supply. Healy has suggested that soon it wfll be possible to culture fetal cells in the laboratory. If so, cells from a single ectopic pregnancy might then be used to treat hundreds of patients. And many investigators are worldng on ways to implant animal cells into patients without triggering immune reactions. But those techniques are not yet available. In the meantime, according to Breeze, the administration's position is "greatly" hindering progress toward treatments that could relieve enormous suffering. -Tim Beardsley

Into the Moral Maze: Abortion and Gene Therapy NS 10 Oct 98 3

WHEN scientists speak their minds, they often open up a can of worms. Take the case of French Anderson, a gene therapy pioneer who plans to extend the technique to fetuses in the womb. Recently he suggested to a government panel in the US, the Recombinant DNA Advisory Committee, that the technique to cure a fatal blood disease called alpha-thalassaemia might first be tried on fetuses already scheduled for abortion. There are reasons of a sort for considering this option (see p 5). Yet it is impossible to imagine Anderson escaping the firing line. Gene therapy already has its vocal critics: some say the technology lies on the slippery slope to eugenics, others object claiming the book is still open on whether gene therapy is safe. Extending gene therapy to the womb is certain to inflame those arguments-and throwing in the issue of abortion is like adding explosive to the fire. Let's not forget that the US is a country where the procedure of abortion itself is constantly under emotional, legal and political attack. Given this climate, it sounds like courting disaster to even voice these ideas, especially when in utero gene therapy trials on humans are years away. But Anderson's concerns are, and should be, focused on the condition he hopes to treat. At its worst, alpha-thalassaemia can kill the fetus and threaten the life of the mother. As in many such deadly conditions, the mother can only choose between a rock and a hard place. So giving doctors and parents another option seems like a worthy goal. To that end, his team is undertaking the long task of developing better and safer ways to deliver healthy genes into the womb and of testing them in animals. Explaining his plans, however, and seeking input from and the approval of the government and the public at large will be a far more daunting job. The discussion that will follow can hardly be expected to be friendly. And decisions about how to implement the technology may be as difficult as the one expectant parents already face when they discover their fetus carries a deadly disease or life-threatening condition. In such a situations, there are no right answers. At best, people arrive at decisions they can live with after knowing all the facts and speaking frankly. Anderson is brave to set the right example by laying some of the most controversial issues on the table from the start.

The Greater Good NS 10 Oct 98 5

CONTROVERSIAL plans to treat unborn children with gene therapy have been given an even more contentious twist. Under a proposal presented to a US government panel late last month, this therapy would initially be tested on fetuses destined for abortion. Earlier this year, French Anderson of the University of Southern California in Los Angeles announced that he was seeking approval for fetal gene therapy (This Week, 27 June, p 12). He is still developing the techniques and will not be ready to start trials for at least three years. "We wanted to leave time for lots of public and private discussions," he says. Anderson pioneered human gene therapy in 1990, when he treated children with a hereditary disorder called severe combined immune deficiency (SCID), caused by the lack of an enzyme vital for the development of the immune system. At a meeting of the National Institutes of Health Recombinant DNA Advisory Committee (RAC) on 24 September, Anderson described how fetuses with SCID would be given healthy copies of the gene for the enzyme. He also outlined plans for in utero treatment of an inherited blood disease called alphathalassaemia, caused by a defect in the gene for part of the oxygen-carrying molecule haemoglobin. One concern is that a fetus's small size means the therapeutic gene has a a greater chance of invading reproductive tissue and introducing genetic changes that will be passed down the generations. But the committee had particular concerns about alpha-thalassaemia, says Claudia Mickleson, biosafety officer at the Massachusetts Institute of Technology and chair of the RAC. We each carry four copies of the gene that is defective in people with alpha-thalassaemia. In the worst cases all four copies are damaged and fetuses die in the womb or shortly after birth. The mother can also develop a life-threatening condition called pre-eclampsia, which involves high blood pressure and fluid retention. "If the therapy was inefficient, the fetus would still die, but its extended life span could increase the mother's risk," says Mickleson. Anderson is now suggesting his team could get round this dilemma by asking women who had already decided to abort their fetus to take part in the first trial. Some RAC members agree that this avoids the ethical problems of a partial cure but, as Anderson admits, it has difficulties of its own. After aborting the fetus, the researchers might discover that they had managed to cure the condition. "The parents and researchers will have this guilt that I'm not sure it's possible to emotionally prepare for," says Anderson. The only solace, he says, is that the family would then be able to attempt another pregnancy knowing there was a treatment if the next fetus inherited the disorder. At least one RAC member is deeply troubled by Anderson's proposal. Louise Markert, a paediatric immunologist at Duke University Medical Center in Durham, North Carolina, says: "Is it morally right to experiment on the fetus when it can give no consent and there is no way for it to benefit from the therapy?" Nevertheless, she applauds Anderson for having the courage to initiate such a controversial debate. "We're in the early stages and we'll visit these issues again and again," predicts Mickleson. Philip Cohen, San Francisco

Culturing New Life Sci Am Jun 98 9

Human embryonic germ cells cells (centre) grow on "feeder" cells .

Many killer diseases involve irreversible degeneration of some crucial cell type or tissue: islet cells of the pancreas in diabetes, neurons of the brain in Parkinson's disease, Huntington's disease and other neurological conditions. Researchers have long dreamed of culturing in the laboratory human cells that could colonize and regenerate failing tissue. But biology has been uncooperative. Cancer cells readily grow in a bottle, but healthy, normal ones soon stop propagating outside the body. Recent discoveries point to a solution. Investigators have been able to identify and culture for many months rare "stem cells" from various crucial tissues. These cells, when implanted in the appropriate type of tissue, can regenerate the range of cells normally found there. Stem cells have been discovered in the nervous system, muscle, cartilage and bone and probably exist in pancreatic islet cells and the liver. More remarkable still, unpublished work has convinced moneyed entrepreneurs that special cells derived originally from a fetus could produce a wide variety of tissue-specific cells. A type of human stem cell found in bone marrow, which gives rise to the full range of cells in blood, has been known since Irving L. Weissman of Stanford University discovered it in 1991. A cancer patient whose marrow has been destroyed by high doses of radiation or chemotherapy can be saved by a transplant of bone marrow-derived cells. Stem cells in the transplant establish lineages of all the cells in blood. Researchers have, however, been surprised to learn that stem cells exist in tissues such as the brain, where they can give rise to all three of the common cell types found there: astrocytes, oligodendrocytes and neurons. The discovery "contradicts what is in the textbooks," says Ronald D. G. McKay of the National Institute of Neurological Disorders and Stroke. McKay reports that he has demonstrated that central nervous system stem cells grown in his laboratory can engraft in mouse brains and alleviate behavioral abnormalities in animals getieticilly engineered to mimic features of Parkillson's disease. Pancreatic islet and liver stem cells were likewise not widely expected to exist in adults, but the evidence for them is "strong," Weissman says. Although they may constitute only one in every few thousand tissue cells, stem cells can be isolated through specific molecules they display on their surfaces. One way to make use of stem cells would thus be to extract them from a tissue sample given by the patient or a donor, then multiply them in the laboratory. Several companies are studying this approach. SyStemix in Palo Alto, Calif., a division of Swiss pharmaceutical giant Novartis, is testing its technique for isolating blood-producing stem cells from bone marrow as a means to improve conventional bone marrow transplantation. Such cells taken from a donor can also bring about in a patient immune system tolerance of any of the donor's cells, Weissman notes, suggesting a future for them in preventing rejection of transplants. He has established a company, StemCells, Inc., now part of CytoTherapeutics in Lincoln, R.I., which aims to establish solid-organ stem-cell lines. Osiris Therapeutics in Baltimore, which Novartis partly owns, is testing patient-derived mesenchymal stemcell preparations for regenerating injured cartilage and other types of tissue. Yet growing tissue-specific stem cells from donors or patients has a potentially worrisome disadvantage, says Thomas B. Okarma of Geron in Menlo Park, Calif. Blood-producing stem cells have to divide rapidly in order to reengraft a patient's bone marrow successfully. With each division, structures at the end of the chromosomes known as telomeres shorten slightly. As a consequence, the reengrafting cells age prematurely, perhaps limiting their growth potential. Geron therefore plans to derive tissue-specific stem and other cells from a different source: nonaging cells called embryonic germ cells. These ultimately versatile cells can, Okarma believes, be cultured indefinitely and can give rise to every cell type found iii the body. They are similar to what in animals are called embryonic stem cells. Mouse embryonic stem cells are extracted from live, very early stage embryos. When injected into a developing embryo, they populate and develop into all tissue types. Scientists in the U.S. cannot use the same technique to isolate human embryonic stem cells because of legal restrictions (an institution that allowed such work would most likely lose all federal funding). But John D. Gearhart, a professor of gynecology and obstetrics at Johns Hopkins University, has employed a different approach to establish human cell lines that seem to have characteristics of embryonic stem cells. Gearhart knew that in mice, gonad-precursor cells in the developing fetus behave like true embryonic stem cells. He and postdoctoral fellow Michael Shamblott therefore established embryonic germ-cell lines from human gonad-precursor cells, which they took from aborted fetuses. Gearhart is now testing whether the cells can indeed develop into a full range of human cell types-by implanting them in mice that have no functioning immune system, where they give rise to tumors. For now, Gearhart will say only that he has seen "several cell types" forming in the tumors and that he aims to publish full details within months. But if Gearhart's cell lines, or others', make cells from all tissue types, they could become a long-lived source for human tissue cells and stem cells. Several Investigators have in the past year or so shown that animal embryonic stem cells can be induced to develop into tissue-specific cells by bioengineering techniques. Loren J. Field and his associates at Indiana University, for example, have made heart muscle cells from mouse embryonic stem cells by adding to them specific DNA sequences. The resulting cells engraft in a developing heart. McKay has been able to create central nervous system stem cells from mouse embryonic stem cells. "Human embryonic stem cells would have profound implications for the treatment of human disease," notes James A. Thomson of the University of Wisconsin. Okarma says Geron plans to develop techniques to convert Gearhart's cells into medically useful types. Because embryonic germ cells do not age, it should be possible to alter their immunologic characteristics with genetic engineering. Doctors treating a patient in need of new neural tissue, for example, might then convert banked cells that match the patient's into neural precursors and place them in the patient's brain. (Fetal tissue is sometimes used now, but the supply is limited.) If an exact match is needed, a technique known as nuclear transfer could even be used to create tissue that is immunologically identical to the patient's own, Okarma speculates. Geron also has a keen interest in telomerase, an enzyme that prevents the telomeres at the ends of chromosomes from getting shorter each time a cell divides. Geron scientists showed earlier this year that when human cells that normally do not express telomerase have the gene artificially activated, they divide in culture indefinitely. Okarma says Geron researchers plan to investigate whether telomerase can allow tissue-specific stem cells to be cultured indefinitely. Isolating and culturing stem cells is still an exacting task. Moreover, stringent safety testing would be needed before physicians could introduce modified cells into a patient, because they could conceivably become cancerous. But the broad, long-term potential of stem-cell therapy is becoming apparent. In the meantime, companies such as Geron hope human stem cells will assist drug-development efforts. Stem cells could even bring to fruition the long-sought promise of gene therapy. The technique has yet to become a practical mode of treatment, because it has proved difficult to get active therapeutic genes into mature cells. But if therapeutic genes could be introduced into just a few stem cells, they could be cultured and then deployed in quantity. How long before stem cells are in widespread medical use? Thomson declines to be specific. But he estimates that "we'll know how to make specific cell types within five years." -Tim Beardsley in Washington, D C