The Decline and Fall of Latin (and the Rise of English)

S C I E N C E A N D E T H I C S
NOVEMBER 1999

Holy Grail or Pandora's Box?

Evaluating Human Embryonic Stem Cell Research

By M. Therese Lysaught

Research on human embryonic stem cells has numerous potential medical applications, but should it be pursued at the risk of imperiling our collective moral soul and social infrastructure?

magine yourself, 12 years from now, sitting in your doctor's office. The doctor has just informed you that you have a serious, debilitating disease. Treatment options are limited. Describing these options and following the canons of informed consent, your physician neutrally adds a caveat about one: the therapy is derived from human embryos. You must make a choice. What would you do?
A hypothetical scenario? Maybe not. Although floating in legal limbo and ensnared in an ethical quagmire, human embryonic stem (ES) cell research will most likely continue. Flourishing in the private sector, it may soon gain further momentum from an influx of federal money.

    It has been a tumultuous 12 months since November 1998, when two research groups independently announced that they had achieved a major technical breakthrough: They had isolated human stem cells from embryonic tissues, cultivated the cells in laboratories for several months, and shown that these cells could develop into all three basic layers of cells in the human embryo. Because these cells, under the right conditions, can potentially "differentiate" (develop) into nearly every type of cell and tissue in the human body, they hold great promise for applications in medicine as well as for research into human development.
    Hearing the news, the biological research community buzzed with excitement. Harold Varmus, director of the National Institutes of Health (NIH), was quoted as saying that human ES cell research "had the potential to revolutionize the practice of medicine and improve the quality and length of life." At the same time, ethical and moral critiques resounded. The central concern expressed was that the techniques by which the stem cells were derived involved the destruction of human embryos, depriving them of their potential to develop into full human beings. A related concern is whether this research would open one more door by which some might tinker with human life, possibly in some grand experiment in eugenics. Will the efforts at pursuing the holy grail of regenerative medicine open up a Pandoras box of undesirable moral and social consequences?

    The quest

    Interest in embryonic stem cells dates back to at least 1981, when they were first cultured successfully from mouse embryos. Since then, ES cells have been isolated from various other animals, including sheep, hamsters, pigs, cows, rabbits, mink, rhesus monkeys, and marmosets. But culturing human ES cells proved difficult: Once isolated, they refused to stay undifferentiated, seemingly driven to spontaneously differentiate and form primitive structures. The first publicly anowledged attempt to isolate and culture ES cells from human embryos in vitro was published in 1994. That attempt was unsuccessful.

From the moment it was announced, human ES cell research has found itself fighting a war on two fronts: the legal and the ethical.

    Given these difficulties, biologists were especially impressed when, on November 6, 1998, James Thomson and his research team at the University of Wisconsin, Madison, reported in Science that they had successfully maintained human ES cells in laboratory culture for a number of months. The cells were derived from "spare," week-old embryos produced by in vitro fertilization at a fertility clinic, after obtaining consent from the gamete contributors. Thomson's group further showed that the ES cells could differentiate into a variety of tissue types--including the gut lining, muscle, cartilage, bone, and neural epithelium--representing derivatives of all three basic layers of the mammalian embryo.
    Four days later, the work of John Gearhart and his group at Johns Hopkins University was published in the Proceedings of the National Academy of Sciences, announcing that they had isolated and grown similar stem cells in culture. Their work differed from Thomson's in two significant ways. First, Gearhart's group isolated what are called primordial germ (PG) or embryonic germ (EG) cells, which are precursors of sperm and egg cells. Second, the cells were obtained not from embryos made in vitro but from aborted fetuses that were 5--9 weeks old. Tests showed that these cells had a number of characteristics typical of stem cells and could further develop into the three embryonic germ layers.
    Excitement about these reports was sparked by the many ways in which the cells could be useful. Researchers could now design experiments to determine how human embryonic cells differentiate into various types of tissues, leading to the development of the human body. Moreover, because ES cells are capable of giving rise to nearly every type of cell in the human body, a wide range of clinical applications has been predicted. Consider some of these:

ES or EG cells may be coaxed to differentiate into nerve or brain cells, and the latter could then be used to treat neurological disorders--including Alzheimer's and Parkinson's diseases--for which no viable therapy currently exists.
Likewise, if ES cells were transformed into heart muscle cells, the latter may be used to replace damaged tissue in the hearts of those who have suffered heart attacks or congestive heart failure.
lOr ES cells may be used to produce pancreatic islet cells in culture, and these may then be injected into the pancreas of a diabetic to manufacture insulin, reducing or eliminating the need for daily injections.
Some cell lines (derived from ES cells) might be used to grow entire organs for replacement, providing a ready supply of organs and tissues, reducing the need to depend on organ donation.
Other cell lines may be developed for use as human tissue banks against which pharmaceuticals and other chemicals could be tested for toxicity and effectiveness.
Some scientists have thought of making genetic alterations to ES cells, with the purpose of growing tissues with specific characteristics and using these tissues to compensate for defective ones.
Others envision genetic engineering of whole embryos.
Additional possibilities include the treatment of spinal cord injury, stroke, burns, arthritis, muscular dystrophy, kidney disease, liver disease, and macular degeneration (which causes blindness).

    It is clear, however, that for any of these applications to come to fruition, much research remains to be done. At this time, scientists have yet to discover how to direct the cells to become particular types of tissues. The process of generating organs (or even parts of organs) is a lot more complex. When researchers injected ES cells into mature mice, the result was a tumor called a teratoma. Thus, special techniques will need to be developed and various tests performed before ES cells are allowed for therapeutic use in humans.

    Legal and ethical battles

    From the moment it was announced, human ES cell research has found itself fighting a war on two fronts: the legal and the ethical. Clearly, the ethical debate centers on the destruction of human embryos and, relatedly, the destruction of human fetuses. For many, this in and of itself raises insurmountable moral barriers. Such research represents one more step toward transforming human beings into biological products to be mined and exploited as raw materials so that some may benefit and a few may hugely profit.

    The legal dispute focuses on funding. A mere two weeks before Thomson's article appeared, Congress passed Public Law 105--277, the Omnibus Consolidated and Emergency Supplemental Appropriations Act (OCESAA). This legislation allocated funds for fiscal year 1999, including money to support the National Institutes of Health (NIH). As with similar bills passed since 1995, OCESAA included an appropriations rider banning the use of federal funds to pay for "research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero."
    The impetus for this restriction was the 1994 Report of the Human Embryo Research Panel. In this report, an advisory panel to the director of the NIH recommended lifting the de facto funding ban on embryo research that had been in place sin 1980, arguing that some embryo research could be justified. Actually, except for 9 states that ban such research entirely and 16 that ban the sale of parts of human embryos, it is not illegal in other parts of the United States to conduct research on human embryos. The congressional ban applies to NIH funding for human embryo research but leaves open the possibility of funding by private sources. Consequently, Thomson's and Gearhart's projects were funded by a biotechnology company, Geron Corporation of Menlo Park, California.
    With the congressional ban in effect, the NIH could not fund research in which human embryos would be destroyed. But the ban did not specify that NIH money could not be used for research on stem cells that were purchased from a private source such as Geron. Recognizing this loophole, Harriet Rabb, general counsel for the Department of Health and Human Services, sent Varmus a memo on January 15, 1999. In this memo, Rabb opined that the congressional ban "would not apply to research utilizing human pluripotent stem cells because such cells are not a human embryo." In other words, there is a difference between conducting research that destroys an embryo and conducting research with products derived from a destroyed embryo.
    Many, however, found this distinction to be sophistry. In February, 70 members of the House of Representatives protested Rabb's decision in a letter to Secretary of Health and Human Services Donna Shalala. Clearly, they maintained, such a distinction violates both the letter and the spirit of the law. Since Thomson's method requires the destruction of embryos prepared in vitro, human ES cell research cannot be separated, conceptually or morally, from the initial act. Researchers using human ES cells, in other words, would be complicit, cooperating with evil after the fact.
    In June, the National Bioethics Advisory Commission (NBAC) concurred in part with the representatives. This panel of experts was inaugurated by President Clinton in 1995 to advise the National Science and Technology Council on ethical matters pertaining to research in the United States. It is morally inconsistent, NBAC held, to allow scientists to conduct research on cells that they legally could not derive. Nonetheless, contrary to the elected officials, NBAC concluded that federally funded scientists should be allowed to do both. While the NBAC statement will not change the legal context, it will undoubtedly influence the debate, as Congress heads back to session in the fall and considers whether to extend the appropriations rider another year.
    One option would render the legal impasse on federal funding moot: Researchers could employ Gearhart's method, which, although funded by Geron, would have been eligible for federal funding under existing law. One may recall that the Reagan administration had placed a moratorium on federal funding of fetal tissue research, following the 1988 report of another NIH advisory panel, the Human Fetal Tissue Transplant Research Panel. But this moratorium was lifted by President Clinton when he took office in 1992. Guidelines for the conduct of fetal tissue research were subsequently developed and implemented in 1993.

Who can claim ownership of human tissue, and can it be bought and sold? What are the social ramifications when we begin to see human biological material as having cash value--something that can be patented and traded?

    Thus, although fetal tissue research remains contentious, due to its inevitable connection with abortion, federal funding is permitted within certain guidelines. But advocates of human ES cell research raise two objections to this comomise. First, they maintain that deriving ES cells from fetuses is more difficult than deriving them from in vitro embryos. Moreover, it remains unclear whether the cells Gearhart derived from embryonic germ cells are equivalent to Thomson's embryonic stem cells.
    Others argue that permitting federal moneys to be used for deriving human ES cells would bring embryo research under federal oversight. Currently, embryo research is conducted in the private sector, beyond public control or purview. With the allied area of technological reproduction, it remains one of the least researched and regulated areas of biotechnology in the United States.
    Even if the legal challenges are resolved, a number of ethical issues will remain. For instance, fostering practices based on Thomson's and Gearhart's methods could pose intrinsic conflicts of interest for those who own and run fertility clinics. If embryos and aborted fetuses become commodities to be sold to researchers, might financial and commercial interests distract from the patients' best interests? If a profitable market develops for "leftover" embryos made in vitro, might there be an inducement to produce "extras"?
    Would women be prescribed excessive doses of fertility drugs so that they produce more eggs? Even current levels of these drugs present significant risks to the women who take them. Might clients feel subtly coerced into donating their embryos for research (rather than storing them or donating them to another infertile couple), to please the physician who either holds their happiness in his hands or has provided them with the child they always wanted?
    Behind these issues lurks the increasing specter of the commodification and commercialization of human tissue. Geron funded Thomson's and Gearhart's work and now holds an exclusive license on their techniques. But who can claim ownership of human tissue, and can it be bought and sold? What are the social ramifications when we begin to see human biological material as having cash value--something that can be patented and traded? What happens to our social philosophy when we begin to conceive of persons as parts? Who stands to profit from such research? Certainly not those who "donate" the tissue.
    Finally, one of the most troubling questions concerns the potential of human ES (or EG) cells themselves. Are they capable of developing into a human person? Or can the cells, under proper conditions, develop into a viable human embryo? While a number of scientific voices maintain that the answer is no, both Thomson's and Gearhart's initial articles suggest that cultured human ES and EG cells have embryonic characteristics. In addition, the animal data on such questions are ambiguous. If each of these cells is capable of growing into an embryo, then embryo destruction multiplies exponentially. Can medical advances be grounded in a systematic practice that destroys human life (or even potential human life)? Would such an internal conflict ultimately destroy medical practice from within?

    An alternative route

    The benefits of regenerative medicine are significant. But ought significant benefits be pursued at the risk of imperiling our collective moral soul and social infrastructure? An alternative approach would advance many of the benefits of human ES research, yet render most of the ethical questions moot: Obtain stem cells from adult humans or placentas instead of from embryos. Although difficult to locate and isolate, stem cells stock the human body--in the liver, bone marrow, brain, and so on--replenishing aging and damaged tissues.
    There are certain limitations to the use of stem cells isolated from the adult body. First, each group of stem cells in an adult can differentiate into a limited number of cell types but not the wide variety produced by ES cells. Second, scientists have not yet discovered the full range of stem cells present in the adult human body. Nonetheless, stem cells obtained from an adult offer important advantages over ES cells. They are closer to the endpoint of differentiated cells, making it easier and faster to transform them into the specific tissues desired. And because the cells would be derived from the patient's own body, the problems of immune rejection and donor shortage would be eliminated.

Harvesting Embryonic Stem Cells

    Examples point the way. In an April 1999 issue of Science, researchers at Osiris Therapeutics reported that they could take what are called "mesenchymal" stem cells from adult human bone marrow and convert them into bone, cartilage, fat, and bone marrow stroma cells (the last of which provide support for blood-forming cells). They also raised the possibility of converting these stem cells into heart muscle cells. Likewise, in May, Byron Peterson of the University of Pittsburgh Medical Center reported in Science that his group was able to convert bone marrow stem cells into functioning liver tissue.
    Several organizations, such as the National Childrens Leukemia Foundation (NCLF), are encouraging the use of stem cells obtained from human placentas and umbilical-cord blood, which are otherwise discarded after childbirth. According to NCLF, a number of children's lives have been saved after receiving treatment with stem cells obtained from those sources.
    In addition, two research groups--one led by Jonas Frisen at the Karolinska Institute of Stockholm and the other led by Arturo Alvarez-Buylla at Rockefeller University in New York--reported in Cell earlier this year that they had successfully isolated and transformed rat neural stem cells. While the two groups disagreed on the location of the neural stem cells, both succeeded in inducing the cells to produce the three main types (lineages) of brain cells.
    How might neural stem cells be useful? Angelo Vescovi of NeuroSpheres Ltd. in Calgary, Alberta, reported in Science (January 1999) that his team had transplanted neural stem cells from the central nervous systems of mice into a second group of mice, where they fulfilled the function of bone marrow stem cells, producing different types of blood cells. And Evan Snyder's group at Harvard Medical School reported in a June issue of the Proceedings of the National Academy of Sciences that they had successfully transplanted neural stem cells from an adult mouse into a neurologically impaired newborn mouse, with therapeutic success.
    In the final analysis, there is little doubt that stem cell research--both embryonic and adult--will continue. The legal issues will be resolved, one way or other. And if human ES cell research wins NIH funding, guidelines outlining proper procedures will be developed. But the moral and ethical issues will remain. And a decade from now, a multitude of patients may find themselves unwittingly dropped into the middle of our opening scenario. Will they have a choice?

M. Therese Lysaught is assistant professor in the Department of Religious Studies at the University of Dayton in Dayton, Ohio. She teaches bioethics at the university and has served on the Recombinant DNA Advisory Committee of the National Institutes of Health.