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New creations?

In the past three decades, researchers have been able to make many mammalian cells grow as cell lines in culture. These cell lines have been essential to the growth of modern cell biology, and have had many therapeutic spin-offs, such as the production of diagnostic monoclonal antibodies. The use of cell lines is even supported by many animal rights campaigners, as they have spared some animals from being used in research.

In the last few years, a special kind of cell line derived from early embryonic cells has also been developed. These cells, called embryonic stem cells (ES cells), are derived from preimplantation blastocysts and can be subjected to genetic manipulation. A major practical application of ES cells is to allow the selecting out of desired genetic variations. Cells carrying the altered gene(s) can then be injected into a blastocyst of the same species to genetically engineer an animal with a desired trait, such as early tumor formation. (A slightly different technique was used to create the famous patented Harvard "Oncomouse.") The animals made will be intraspecies chimeras, but their progeny will not be because only a single egg or sperm cell is used. Some of these reproductive cells will be genetically derived from ES cells of the chimeric animal. In this way a new genetic strain of animals is made.

ES cells could also be injected into a blastocyst of another species to create a transspecies chimera. New species can also be created by simply mixing very early (preblastocyst) embryonic cells from two different species. The most publicized example of such a cross-species chimera was the "geep," formed by mixing the embryonic cells of a goat and a sheep. While most of the research with ES cells has been done in mice and farm animals, researchers have developed similar cell lines from human embryonic tumor cells.

Given the effects of dds research on the animals involved, and the potential implications of future research, is it ethical for research using ES cells or chimeras to proceed?

In medicine, scientific research, and agriculture, the use of ES cell lines presents definite advantages in breeding, limited clonal reproduction, and the development of new animal strains. Research on ES cells is a very rapidly developing new technology, and since it involves changing life-forms themselves, respect and caution are required of any researcher. Considering the wide genetic variation occurring naturally, new animal strains should not be thought of as unique, artificial forms of life. Nor has past experience with recombinant DNA indicated any inherent danger in mixing genes from different species. A first question to address, then, is whether the benefits to our knowledge and technological advances are worth the harms to the animals.

Many human genetic diseases are untreatable, and even if the gene(s) involved are known it can take many years to understand the cause. Some animals have been made using ES cells to be laboratory models of human disease, and will substantially advance the research leading to cures. Animals have also been made to be sensitive for drug testing, and if cloned animals are used this can greatly reduce the number of animals-as well as the time-required for such tests, prior to clinical trials. ES cells are also being used for basic research into gene expression and development, which, while having fewer immediate benefits, will have broader long-term benefits in agriculture and medicine.

An important objection to this research is that we should not deliberately create diseased animals. if we begin from the premise that it is wrong to make diseased animals, unless there is some perceived benefit to other animals or humans, the central research question is how much scientific benefit can be reasonably expected to come from the creation of these animals. Here we have to weight not only benefits and harms, but also uncertain benefits with certain harms, namely, the suffering of diseased animals. Although the prospective benefits suggest that we should assess the ethics of proposed research on a case-by-case basis, this assessment should be guided by a limit that created animals should not suffer beyond the falling thresholds acceptable for vivisection.

Some current research using ES cell lines raises questions about whether animals are being used without any clear sense of what benefits are expected. For example, some research has used ES cell lines to test the effects of blind mutations to multiple genes, with the principal goal seeming to be to maximize the number of mutated genes per animal. Researchers then analyze the animals that survive this process in a manner analogous to that in which mutated yeast and bacterial cells are used to study gene mutations. While this approach may increase the pace of research, it may be unethical in that it imposes more pain on animals than is caused by vivisection upon known animal varieties. Moreover, if we do not know what genes we are mutating or the effects of a given mutation, how will it be possible to determine whether the research in question is potentially beneficial or ethical? In general, there needs to be a more thorough examination of the ethical limits of breeding mutated, transgenic, and chimeric animals for both research and agriculture.

Research involving potential human ES cells is more dubious. Skills in human embryo manipulation are improving, and several babies have been born following preimplantation genetic biopsy; at the pace at which embryo manipulation advances, it may not be long before there are practical uses for ES cell lines. In addition to research on the roles of genes in development, some research might be extrapolated for use in corrective germline therapy. This would be ethical, however, only when we have first achieved precision with research on animals.

Moreover, such research should be deferred until society has come to a consensus on the time and developmental limits of human embryo experimentation. If we are prepared to justify some human embryo experiments for their scientific or medical benefit, then research on embryos involving ES cell lines could also be reviewed by regulatory authorities. The criteria here might be the extent to which research is directed toward developing therapy to treat the symptoms or the causes of some genetic diseases. Scientists have come to accept regulation upon their work. The control of the use of some development in genetic manipulation, such as the temporary ban during the 1970s and current controls on human gene therapy and human embryo examination, show that limits can be placed. These examples illustrate that, if the legal-ethical debate catches up with the science, common fears of a slippery slope need not be so great.

Darryl Macer is foreign professor in the Institute of Biological Sciences, University of Tsukuba, Japan, and a bioethics consultant to the Department of Scientific and Industrial Research and the Ministry for the Environment, New Zealand.

COMMENTARY:

by Roger A. Balk

This case is problematic in the way it links together events and processes that are distantly if at all related. Growing cell lines in culture and developing embryonic stem cells are related only to the extent that both make use of cell cultures. A major question that may be raised by the creation of transgenic animals is the kind of potential moral threat this activity represents.

The case suggests that the creation of a transspecies chimera is a major problem in and of itself. At the risk of trivializing the discussion, we could observe that this is nothing more than the creation of another jackass, and while mule drivers may be a special breed, neither they nor their charges are commonly regarded as a new species. Of course, to many, and not just animal rightists, the question of a species barrier is a significant point for moral and ethical concern, and to this matter we will return in due course.

The fact is that embryonic stem (ES) cell research is a very exciting technological development for those engaged in transgenic animal research. It introduces DNA by viral transduction or transfection into embryonic stem cell lines. The process involves isolating inner mass cells from a blastocyst and maintaining them in culture as pluripotent ES cells. ES cells are selected in which the incoming DNA recombines with homologous chromosomal sequences to create a mutation in the target gene. These cells are transferred into a recipient blastocyst and germ-line chimeras are generated. The chimeras are founders of lines that carry the selected mutation. The process as a whole is called homologous gene targeting.

There is tremendous potential use for homologous gene targeting in developing therapies for human genetic disorders. Targeting mouse homologs of these genes would produce animal models of specific human diseases. It may also be possible to propagate other stem cells in vitro just as it is possible to propagate ES cells-such as the recent isolation of mouse bone-marrow stem cells that retain their ability to regenerate the entire blood cell population. When it becomes possible to identify and propagate the corresponding human bone-marrow stem cells, the cells of someone suffering from a severe hemoglobinopathy could be targeted with sequences of normal globin genes to correct the genetic defect. Moreover, the fact that this process can occur in vitro suggests that a potential replacement for animal models may exist in this technology.

A process with this kind of potential cannot be regarded as benign, and the question of what ethical and social controls should be placed on its development and use is a very real one.

While the creation of cross-species chimeras may get news headlines, it is not really very newsworthy. It does not in itself represent a change in species. A goat with a few sheep genes is still a goat. The major challenge presented by such mutants would appear only if it were decided to wipe out all the sheep and goats in the world except for the offspring of this combination. The future of this population based upon a single animal source could be threatened, since it lacked the genetic variation that is the basis for survival in terms of Darwinian evolution. To replace the cumulative wisdom of natural selection for human purposes by interfering in massive ways with the future of germ lines is worrisome, to say the least. As it might be applied to commercial agriculture, the technology will require careful scrutiny and undoubted regulation. To my mind, the issue of intervention, not that of the sanctity of species (a dubious biological notion at best), is the real cause for concern. The appropriate response is to limit specific human designs strictly, rather than outlaw a very promising technology.

The speed at which developments are taking place in this one area of biotechnology poses a genuine problem even for those who are active participants in these changes. For those of us who must come by our understanding of these events at second hand, it is downright daunting. The series of experiments that enable these new techniques to be developed are abstruse to the nonspecialist; often a whole new field is there before anyone is actually aware of its presence. Even more depressing is the poor record of the regulatory process in the United States in coping with these issues. When we add to this the fact that no ethical or social impact review is a part of the patenting process, it is easy to form the view that the whole undertaking has gotten out of hand.

This case presents no ethical challenges to the technique of ES cell research. The problem will arise when a specific proposal is made to target cells that control, say, some aspect of human behavior. The question is how we as a society are going to get wind of these developments, and what means we are going to devise for controlling the problems that grow out of them.

Roger A. Balk is a member of the Animal Care Committee at McGill University, Montreal, Quebec, and chairman of its subcommittee on ethics.

COMMENTARY

by Benjamin Freedman and Marie-Claude Goulet

Revenons a nos moutons. - Maitre Pantelin

Is this form of research ethical? The question has been asked a thousand times before, on topics from AIDS to zoonosis. It will, in the future, be asked ten thousand times more. We know the canonical form the answer must take: "It is ethical, provided... " And we know how to fill the hole left by the ellipsis: The trusty, rusty old bioethical tool kit is unpacked. Risks, benefits, liberties, all are arrayed on the bench, and forced into the approximately fitting slot of autonomy, beneficence, and so on. The approach has served us well before, on many questions, and. no doubt will in the future as well. But the activity in question-transspecies manipulation-is different.

We are not, in the most relevant sense, talking of transspecies research. Research is a preliminary to a change in practice, and the ethics of research is the ethics of a means. But transspecies manipulation is, recursively, the change itself-, research into doing it does it. (And new organisms do tend to take on a life of their own.)

It makes no sense, then, to talk of this as research; but even if it did, it would make no sense to use the old research ethics vocabulary in this context. The conscious, calculated modification of organisms to achieve a genetic complement unknown (and commonly unachievable) in nature, represents a new departure in human capacity, and a new stage in the history of this world over which we have claimed regnance. Before trying to parse the ethics of this practice, we need to choose an appropriate attitude for reflection. The attitude that must be rejected is one of business as usual. The appropriate emotion is awe.

John Mendeloff has noted features of reasoning common to bioethical commissions.[1] Areas of common agreement are sought-in particular, legitimating analogies: old, accepted practices that appear to be relevantly similar to the novel issue in question. A limited agenda is set, confining the question within narrow limits. The adoption of a legitimating analogy implies that no novel ethical concern is raised; the narrow agenda excludes all slippery slope arguments. Yet transspecies manipulation is of its essence a new departure, and our current fumbling attempts are ushering in a new era of biological (and biologistic) history. The standard maneuvers of commissions-"muddling through," in Mendeloff's phrase-so useful in seeking a consensus view, are peculiarly inapt for transspecies manipulation.

We can trace the malignant influence of these habits of thought within the numerous documents that have been issued through the standard consultative process, even when the genetic manipulation of human somatic cells is under practical consideration. (Unnoticed by most commissions, even current proposals for human somatic cell genetic intervention bear a transspecies component, in their functional incorporation of noncoding regulatory sequences drawn from mice or viruses.) The (Australian) National Health and Medical Research Council report on somatic cell gene manipulation sees it as ethically comparable to "many drugs" (p. 15), or "conventional treatments" or "drugs and vaccines" (p. 16), or "cancer chemotherapy" (p. 18)-very much business as usual. The statement on gene therapy issued by the European Medical Research Councils in February 1988 states, "Insertion of genetic material into somatic cells and their subsequent transplantation is not fundamentally different from any form of organ transplantation or blood transfusion."(!)

Undeniably, somatic genetic manipulation shares some features in common with other forms of treatment. The creation of chimeric forms of life has its own legitimating analogies, for example, selective breeding, cross-pollination, and the deliberate induction of mutagenesis. But both forms of genetic manipulation are in other respects strikingly new departures: planned maneuvers, in principle irreversible, that effect alterations of individual or species at the biological lowest common denominator, the molecular genetic level. That level of change is plenipotent. While dramatic changes in organisms or progeny can be induced chemically, surgically, by controlling the environment, or controlling breeding, the potential of these agents of change remains a subset of the prospects opened up through genetic manipulation, which in principle permits all possible biological changes to be actualized.

Of course, it will be responded, current molecular biologic and embryologic manipulative techniques are primitive, clumsy. Their current and imminent use will be restricted to the benign (correction of lethal single-gene defects in newborns, induction of more efficient strains of cattle and grain, for example), and to the occasional side-show ("geeps").

The objection utterly misses our point, which is not concerned with the use of transspecies manipulation but with its meaning and import. Future generations will look back at our geeps and see in them the muted harbinger of all that was to come. Future cartoonists will draw geeps as emblematic of prehistory, as Gary Larson, in The Far Side, draws wheels hewn of stone. The current induction of transspecies change is a cusp, and one that seems to us closer to an unimaginable future than to a comfortably familiar past.

As is often the case, though, it is easier to be critical than constructive. Transspecies manipulation is not business as usual; but what approach would be better? We will need to canvass our traditions, religious and cultural as well as ethical, for clues; and we may find, as we had discovered in reading traditional jewish sources, that genetics and speculation are central to some concepts of creation.[2] We will need to entertain and explore new principles of reasoning, too. An ethics of changing-changing of species as well as of individuals-is one possible arena for consideration, with departures from a natural baseline themselves requiring justification, independent of such familiar grounds of ethical critique as risk. (Further problems are in turn suggested, as choosing a benchmark for change from a world in random as well as purposeful flux.) Inquiry should be above all wide ranging; in the dictionary of ethics, the entry under "wicked" should read "seriously lacking in imagination."

We are not suggesting that transspecies manipulation be banned, nor are we prepared to say how it should be controlled. We are simply wondering how we should think about it. All that we are certain of is how this inquiry should start: with somber awe.

References

1. John Mendeloff, "Politics and Bioethical Commissions: `Muddling Through' and the "Slippery Slope,'" Journal of Health Politics, Policy and Law 10, no. 1 (1985): 81-92.

2. Benjamin Freedman, "Leviticus and DNA: A Very Old Look at a Very New Problem," Journal of Religious Ethics 8, no. 1 (1980).

Benjamin Freedman is professor of medicine and Philosophy at the McGill Centre for Medicine, Ethics and Law and clinical ethicist, Jewish General Hospital of Montreal; Marie-Claude Goulet has a Master's degree in molecular biology from the Universite de Montreal and is entering her third year at the National Program, Faculty of Law, McGill University.
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Title Annotation:Case Studies; research using embryonic stem cells derived from animal and human sources: comments on the ethics involved
Author:Macer, Darryl; Balk, Roger A.; Freedman, Benjamin; Goulet, Marie-Claude
Publication:The Hastings Center Report
Date:Jan 1, 1991
Words:3123
Previous Article:Autonomy and the common weal.
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