Manipulating Human Genes: How Significant are Species Boundaries?

Department of Anatomy and Structural Biology, University of Otago

Professor D Gareth Jones [I am grateful to Elizabeth Anderson and Dr Kerry Galvin for their assistance with the preparation of this article.]

Transgenic animals, species and genes

Humans have been manipulating genes indirectly via animal breeding and domestication for thousands of years. Over the past 200 years selective breeding has changed the genetic constitution of farm animals to the point where they are no longer recognisable. For example, the modern Holstein-Friesian looks nothing like the European bison, and the large white pig is quite unlike the wild boar. Similar breeding in the laboratory has used naturally occurring mutations to produce mouse models of Duchenne muscular dystrophy.

A transgenic organism is one that expresses genetic information not normally found in that species. It has been genetically modified in some way. The process involves microinjecting a gene into a single-celled embryo so that the gene is incorporated into its DNA. The genetic change is then passed from one generation to the next. Unfortunately, the success rate of this technique is low, and it is still something of a hit-and-miss affair. Despite this, the production of transgenic animals is a far more precise method of modifying animals than naturally occurring mutations. However, it also introduces novel genetic combinations, with whatever dangers may accompany such novelty.

Laboratory animals have had inserted into them genes thought to be responsible for human cancers. Transgenic mice were first produced in 1982, and farm animals shortly afterwards in 1985. Sheep have been genetically modified to produce proteins used to treat human blood clotting disorders. Everything from silkworms to fruit flies has been modified genetically, with rats and mice extensively used in the laboratory. From a scientific perspective, transgenic animals are now viewed as essential research tools. Nevertheless, they are artificial constructions, and they force us to consider the nature of species and species boundaries.

Of the different concepts of species, two stand out. According to one view, species have their own unchanging essence, so that each is sharply delineated from all others. This is the traditional essentialist view, emphasising species integrity. For an essentialist the production of transgenic animals will be problematic because a clear boundary has been crossed. An alternative view is that species are populations that are reproductively isolated from one another. This is the more flexible contemporary scientific view. This population-based concept acknowledges the movement of genes across species boundaries. However, it does not follow from the fact that it happens that crossing species boundaries is of no consequence, since one can argue that the species concept needs to be maintained as a cultural category.

In discussing the transfer of genes between species it is important to be clear about what this means biologically and physiologically. The genetic code is essentially universal, in that all cells from all species usually contain much the same genetic information. This similarity points to the numerous genetic linkages between humans and all other life forms on the earth. When we turn to genomes (the complete DNA sequence of an organism) and compare them between species (such as humans, mice and chimpanzees), we find that the gene repertoire is very similar among mammals.

In other words, genes cross the species barrier all the time, calling into question the significance of this barrier. A protein like insulin is made up of 150 amino acids, of which only five differ between humans and pigs. Hence, if the DNA sequence of the pig gene is altered to make a human protein, what has been produced? Can the resulting protein be described as a pig gene or a human gene, and in what sense does it matter? Perhaps it would be better to refer to it simply as a piece of DNA.

Despite the similarities, there are also important differences between humans and other species, and between individual humans. Most of the genetic differences between individuals are of little relevance, but others might fall at a critical spot in the gene, leading to a particular disease, say. Thus moving genes from one individual to another, and from one species to another, may have major consequences. Enormous care is required to ensure safety, and to achieve what one sets out to achieve. But in light of the above it would be surprising if profound human barriers were being breached. While this conclusion does not justify inserting genes (human or non-human) into other organisms, it does remove a major concern.

Xenotransplantation: the broader scientific context

The insertion of human genes into other organisms should be placed in the broader context of transplanting human tissues into other animals. This is xenotransplantation, the transfer of tissues or organs between different species. Xenotransplantation is a relatively common procedure in the biological and medical sciences, and while differing in significant respects from the transfer of genes, there are also many similarities.

Animals into which human material is grafted are used as model systems for studies on a diverse range of subjects, including brain development, drug actions and human diseases. Many studies have focused on the grafting of human nervous tissue into rat brains, as a prelude to neural transplantation into patients with Parkinson's and Huntington's diseases. Human tissue has also been grafted into the rat spinal cord in an attempt to develop treatments for human patients with spinal cord injuries. Xenotransplantation of human tissue into animals has not raised undue concern in terms of breaching species barriers.

Human genes in other organisms

The ever-increasing gap between the supply and demand of cadaveric organs [Organs derived from dead people.] for transplantation has been a major impetus behind the search for alternative organ sources. One option is to genetically modify animals so that their organs will be more suitable for transplantation into humans. This is vigorously pursued because the transplantation of unmodified animal organs into humans results in overwhelming rejection of the organ.

The pig is the donor animal of choice for xenotransplantation. When a pig organ is transplanted into a human, rejection by the immune system destroys the organ within hours or even minutes. The insertion of human genes into the pig's genetic material could be one way to inhibit this immune response and thus overcome rejection. In discussing ethical concerns, the Nuffield Council of Bioethics concluded that the use of transgenic pigs in this way is ethically acceptable. The reason given was that, since the genetic modification requires the transfer of very few human genes, it would not destroy the integrity of either species. Currently, the scientific techniques require further refinement, and the wide-ranging concerns elicited by xenotransplantation have yet to be satisfactorily addressed.

Human genes have also been inserted into animals in order to generate livestock that produce large quantities of therapeutic proteins in their milk. These animals are then 'milked', and the proteins are purified and used to treat human diseases. The proteins in question are difficult to make in sufficient quantities in other ways, or are derived from human blood products that are limited and expensive and also carry the risk of infection. Mice, rabbits, pigs, goats, sheep and cows have been genetically modified with human genes to produce pharmaceutical products in their milk. Proteins manufactured in the mammary glands of sheep and goats are currently undergoing clinical trials in the United Kingdom and the United States. These include alpha-1-antitrypsin for the treatment of cystic fibrosis and emphysema, and antithrombin as an anti-blood clotting agent for patients undergoing surgery.

Most human diseases have no naturally occurring animal models, and many of the animal models that do exist are very imprecise imitations of human conditions. Transgenic technology offers a way to create animal models which precisely mimic many human diseases. For example, there are now rats and mice exhibiting human cancers, and cardiovascular, autoimmune and neurological diseases.

Two specific examples of diseases with transgenic rodent counterparts are heart disease and Alzheimer's disease. One target of cardiovascular researchers is the protein ApoE. This is involved in cholesterol transport, and the three human isoforms are associated with atherosclerosis and Alzheimer's. Mice with the human isoforms inserted into their genome develop high cholesterol levels and atherosclerotic plaques that are exacerbated by a high fat diet. This is similar to the human condition, indicating that the inserted genes behave similarly in the animal model. Another example is a mouse model that carries the human gene for an Alzheimer β-amyloid protein. It exhibits high concentrations of the mutant protein and develops significant amyloid plaques and memory deficits, akin to human Alzheimer's sufferers.

These transgenic animal models were produced in the 1990s and are readily available for purchase and use. They provide an important tool for understanding disease processes, and for testing potential treatments before moving into clinical trials.

Blurring species boundaries: xenotransplantation and gene transfer

In clinical terms the transplantation of a kidney can be compared ethically to the use of dialysis equipment, since the therapeutic goals are comparable, regardless of whether the kidney comes from a human or pig. On the other hand, the transplantation of neural cells from one species to another may potentially affect personality and have implications for the nature of the patients' humanity. Is this type of procedure substantially different from other standard treatments, such as neurosurgery, which are generally regarded as ethical when carried out for good, therapeutic reasons?

It is difficult to see how the ethical issues associated with xenotransplantation would be different from human-to-human transplantation undertaken in the neural area. A neuron's significance stems from its functions and from the connections and circuits of which it is a part, not its origin. There may be no significant difference between neurons from a human, a pig or a rat, so at the cellular level the differences between species - even rats and humans - are minimal. A small population of rat or pig cells in a human would not threaten the humanness of the individual concerned. Neither would a whole organ like a kidney or heart. But what about genes?

Do genes take us to a different level from the one we have encountered with organs and cells? Is it meaningful to refer to human genes and pig genes in isolation of the context within which they are found? A gene by itself will rarely be the only cause of a particular condition or trait, let alone the basis of distinctive species characteristics. The connection between a gene and an individual scoring highly on an IQ test, for example, or having an aggressive personality is very indirect. In other words, the complexity of what makes us human beings is rivalled only by the complexity of our genetic (and environmental) make-up. Consequently, it is highly unlikely that the movement of a small number of genes will influence the essential characteristics of humans or other species.

Ethical arguments against transgenesis

In what sense, then, might transgenesis be regarded as objectionable? One reason would be if it is considered intrinsically wrong to deliberately alter genetic sequences. This objection can only be sustained if genetic sequences are inherently fixed and therefore should never be altered. This means they should not be altered therapeutically within human beings, and they should not be altered by inserting human genes in other organisms (or vice versa). This argument only holds if one accepts the essentialist concept of species.

The problem with this viewpoint is that any form of genetic selection modifies genetic sequences. Natural selection and the selective breeding of animals do this. The only difference with transgenic animals is that the process is much more rapid. Deliberate sequence alteration is common to all three processes, all of which would have to be rejected if genetic alteration is regarded as inherently unethical. And yet natural selection is a natural process, and the selective breeding of animals is not usually regarded as unethical.

It could be argued that humans should not interfere with Nature, even if the interference is aimed at accomplishing something that occurs in Nature. The directions of human control could be viewed as detrimental to animals and plants and to the balance of the ecosphere. It is in this context that one can question whether it is ethical to allow mice to carry the burden of non-mouse genes. Since this probably will not benefit the mouse, can it be justified? This consideration has nothing to do with crossing species barriers, but rather with animal welfare issues.

Animal welfare

The issues here include any undue suffering of transgenic animals, and animal wastage in the production of transgenics. Valid as such issues are, they are the same as for any other area of animal experimentation.

Some have argued further that when human genes are inserted into animals, the latter are being used as mere instruments for human benefit and interests. This is seen as an infringement of animal 'integrity'. The issues are similar to those encountered in debates on xenotransplantation, where some have concluded that xenotransplantation can be morally justified because human beings possess capacities and abilities that confer on them more moral value than animals.

One fundamental question in this debate is whether an attitude of exploitation underlies the development of transgenic technology. Answers to this question vary, and depend on the conclusions one reaches regarding animal rights and the balance between animal suffering and human benefit. In terms of human benefit, transgenic animals undeniably constitute a valuable research tool for pursuing knowledge and have the potential to increase understanding of human diseases.

It is reasonable to conclude that considerable care should be taken to ensure that any genetic modification is not detrimental to the animal's welfare. One way of diminishing the possibility of exploitation is to insist that those who wish to use transgenic animals justify their position scientifically, ethically and clinically.

Playing God

But should we be indulging in any genetic sequence manipulation? Should we be 'playing God'? For this objection to have any force, we are back at the essentialist nature of species. Either species are of ongoing significance, or they are not. If they are not, the 'playing God' objection loses much of its force.

The criticism that a procedure is akin to 'playing God' tends to reflect hostility towards the procedure rather than presenting a clear rationale of how it transgresses divine boundaries. The most one tends to elicit from uses of the phrase is that current human and animal forms are divinely ordained and should not be modified in any manner, leaving in limbo the numerous uses made of domestication, breeding of farm animals, vaccines, antibiotics, and surgery. Are these examples of illicitly 'playing God'?

Christians contend that humans are made in God's image, and so function in some respects like God. Emphasis is usually placed on creativity and inquisitiveness, and on exercising responsible control over the created order. Within this context, scientists are seen as functioning as God's images, probing into the created world, attempting to understand it and then re-direct it as his stewards. Within the medical sphere the desire is to exercise at least limited control over human disease. One means of accomplishing this may be via studies with transgenic animals.

In these terms, 'playing God' takes on a different hue from the usual negative one. It can be regarded as part of what God-like creatures do. This may sound dangerous, but there are still limits and constraints on what we as humans may do. There are connotations of fulfilling a God-given mandate to serve and care for others, as well as to care for animals and plants on which humans are dependent. Playing God also acknowledges that humans are to participate in the process of transforming the world, by sustaining, restoring and improving what has been temporarily entrusted to us. Inevitably there are dangers due to pride and arrogance, but there are also dangers due to sloth and lethargy. While the former are frequently highlighted, the latter are all too often ignored.

When seen in this light, playing God opens the door to the insertion of human genes into other organisms. This does not mandate it, but it does allow the possibility of reaching a decision on scientific and ethical merits.

The special nature of human beings

In Christian terms there may still be the objection that human beings are completely separate from other animal species, and that mixing genes is a violation of this separation. The distance between the species is being minimised and as a result the status of human beings is threatened. The Christian tradition, with its roots in the book of Genesis, has emphasised 'kinds' rather than' species'. Unfortunately these two are sometimes merged, making the distinction far more specific than the writers of the biblical account probably intended. However, if we consider the large divisions suggested by kinds, what we get are major rough distinctions.

In these terms, human beings are to be seen as separate from other animals in that they are capable of having a special relationship to God. But this special relationship rests far less on biology than on an awareness of God, of the importance of community, and of a responsibility for looking after the remainder of God's creation. While a biological base cannot be totally ignored, neither should it be unduly elevated. The status of humans in the Christian tradition is not gene-centred. If this is the case, it renders the debate on the insertion of human genes into other organisms as a matter to be decided on other grounds. This is where a balanced judgement based on accurate science, careful ethical analysis, and an appreciation of a range of cultural issues comes in to play.

It is unlikely we will emerge with a definite right or wrong answer. What we do have is a broad framework for initiating debate.

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