3.1. The gene - that obscure object of desire

REGINE KOLLEK

What are genes?

Genetic engineering enables us to isolate and analyse the hereditary material from any living thing. Genes can be cut and pasted into the genetic material in the cells of any other organism which then expresses the new characteristics of the artificially transplanted genes. For instance, a gene from a flounder fish conferring resistance to cold has been transplanted into a tomato to make it frost-resistant. Cells, plants or animals modified in this way are termed transgenic.

This new-found ability to manipulate genetic material has great potential for commercial exploitation, since genes play a critical role in providing a blueprint for particular products or characteristics. The ability to patent individual genes is regarded as being vital to the exploitation of their commercial potential. But that is not as easy as it sounds, since the gene seems to be becoming an increasingly elusive and slippery entity to define.

What are genes

Johannsen introduced the concept of the gene as the carrier of hereditary material, in 1909. In the early 1940s, Beadle and Tatum postulated that each gene codes for one characteristic. Not long after, deoxyribonucleic acid (DNA) was identified as the complex molecule that acts as the vehicle for transmitting hereditary characteristics from one generation to the next. Genes were thought to consist of linear and continuous DNA segments coding for particular gene products. Genes were understood in two ways: in structural terms as DNA segments, and in functional terms in relation to the gene product, a protein, that they coded for.

This clear and simple model did not survive for long; over the last forty years the picture has become more complicated. It is now known that in addition to the structural genes identified initially, there are also regulatory genes which do not code for specific products but regulate and modify the action of structural genes. In addition, some genes, known as pseudogenes, are never actively translated into gene products, but are simply passed on passively to posterity. In the 1960s, repetitive sequences were recognized. The function of these short identical DNA sequences which recur frequently within the genome still remains a mystery. And in the 1970s it became apparent that even structural genes are not translated directly into products. Instead the active parts of the gene are separated by inactive chunks (introns) which are excised prior to translation.

Moreover, wandering DNA sequences known as transposons or 'jumping genes' have been found to have the ability to replicate themselves independently of the genome. If a transposon then 'jumps' to a different location in the genome, it can produce a different effect, such as changing the colour of maize.

The icing on the cake was the discovery that matching strands of the double helix making up the DNA molecule can code for different products. For example, one strand of a particular DNA molecule in the rat codes for a hormone produced in the brain, while the other strand codes for a chemical found in the heart. It had previously been believed that the sole function of the second strand of DNA was to ensure that the gene is correctly duplicated during cell division.

Thus the gene is now very hard to define. It cannot be conceived as a separate structural entity, since sequence overlaps can occur both on the same DNA strand and on the opposite one. It is not a continuous sequence and does not necessarily have a constant location in the chromosome. Nor does it have a unique and discrete function, since it may depend on the activity of one or more regulatory genes. Moreover, genes with the same function do not necessarily share the same structure, and genes with an identical structure do not always have the same function.

The gene, therefore, is not an easily identifiable and tangible object. It is more a mental construct which has been shaped by history and a great deal of intellectual effort. It is virtually impossible to develop a clear, empirical definition of a gene. This is why the gene concept is burdened at every turn with the ballast of myriad unresolved problems, which are often lost in the attempt to establish a universal definition, or are swept under the carpet by superficial textbook formulations.

From genotype to phenotype

The genotype refers to the structure of an organism's genetic information. The phenotype is the outward manifestation of the genotype (such as eye colour or tail length).

Scientists generally regard a gene as a known quantity when its DNA sequence has been decoded and the function of the gene product has been described. It is generally assumed that when such a gene is transplanted into a different organism it will perform the same function as in its parent organism or will not be active at all. But there is growing evidence that the relationship is not as simple as that, as the following example illustrates.

Since many life forms share early parts of their evolutionary history, similar or identical DNA sequences are often found among a wide variety of organisms. Many of these perform identical or similar functions in a range of different cells and organisms. However, this is not always the case. For example, the gene for a particular protein, called isomerase, occurs in bacteria, yeasts, insects and mammals. In spite of their broadly similar structural and biochemical properties, the proteins perform completely different functions in the various species. In the fruit fly isomerase is involved in vision, while in mammals it regulates the maturation of immune cells.

This example demonstrates that it is not just a gene's sequence which determines its properties, but that its location in its chromosomal, cellular, physiological and evolutionary context also plays a significant role. Position effects of this kind can influence the concentration of a gene product in the cell, or a gene's activation timeframe. It is know that structurally identical genes located on different chromosomes are capable of being triggered at different stages of embryo growths A particular gene's activity can also be determined by whether it is inherited through the mother or the fathers

According to Barbara McClintock, who first discovered jumping genes in maize, gene functioning is totally dependent on the environment in which they find themselves'. The functioning of a gene is determined not only by the structure, hut by the interplay of a large number of factors which need to maintain a specific relationship with each other. So it is only possible to make precise descriptions of the purpose of a specific DNA segment in a specific organism in relation to a specific constellation of biological and genetic factors.

Different concepts of the gene - different maxims for action

There is a trend in basic research and theoretical debate towards a partial dissolution of the traditional concept of the gene. However, this more fluid approach is not reflected by those concerned with the practical application of experimental findings. Here there are several different schools of thought which place varying emphases on different aspects of the relationship between genes and their environment. These varying perceptions can produce diverging responses to genetic engineering and the patenting of genes or transgenic organisms. The dominant viewpoints are:

(A) Genetic determinism

DNA is seen as carrying all the essential information that an organism needs to live fully. Less radical variants admit that the environment can play a part as well. But the fundamental starting point is that these environmental factors - like genes - can be considered in isolation and can have unambiguous and measurable effects. Because each contributing factor can be isolated and defined, manipulation of genes and organisms is seen as both logical and justifiable. From this standpoint, the organism is seen as a machine, and its physiology as little different from a series of industrial processes. Thus it follows that the patentability of genes and other genetic material is also both rational and acceptable.

One variation of this argument also accepts that hereditary material is the central component and control agency of the organism. However, a different value is attached to this fact than in the previous case. Since genes are the essence of life, it is seen as injurious to the integrity and dignity of the individual concerned to manipulate or patent its life source. While this and the previous view come to antagonistic conclusions about the legitimacy of genetic engineering and patenting, they both exaggerate the role of DNA in life processes, and sanctify it.

(B) The systems view

Genes are seen as an essential, but not the only, determining factor in the control of development processes. According to the developmental biologist H. F. Nihout, 'In a system in which every component and past history have come together at the right time and in the right proportions, it is difficult to assign control to any one variable, even though one may have a disproportionate effect.'

Nihout sees the control of development as being spread diffusely between gene products and structural elements of the surrounding tissues. Genes are passive material sources which a cell can call on when it has a need; they are not the control centre for the cell or organism. Nihout thus proposes a switch from a 'gene-centred' approach to an 'interacting components' model. Proponents of the systems approach see the development and maintenance of physiological functions as controlled by the whole organism, in an interconnected rather than hierarchical way.

From the viewpoint of the systems approach, the deliberate and targeted manipulation of complex traits is extemely difficult, given that it is almost impossible to predict the synergistic effects which could be triggered between different components. Nevertheless, this position does not exclude the possibility that functions could be corrected by trial and error in certain straightforward cases.

Arguments against the use of genes in isolation (which is the basis of their commercial exploitation) or against gene patenting do not arise from this perspective. From the systems perspective, such arguments arise less from ethical posturing than from the pragmatics of such undertakings.

(C) Scientific constructivism

The constructivist view starts from the assumption that scientific activity (the development of hypotheses and theories coupled with experimentation) is fundamentally an act of construction. The intellectual and material products of science are the direct result of the assumptions and/or methods used to produce them. Any role which is assigned to hereditary material is seen as an artificial construct determined not only by the inherent properties of the object of investigation, but also by the premisses and conditions required to undertake such investigation.

This means that the manipulation of genetic material has nothing to do with the 'essence' of an organism, and is consequently not subject to any moral qualification. 'Genes' are seen as creations of the human mind and represent scientific 'inventions' against whose patenting there can be no objection, at least not within the logic of this line of argument.

Positions along these lines are added to the scientific debate by Donna Haraway, amongst others. Her 'Manifesto for Cyborgs' only half-jokingly calls on women, in particular, to contribute to the cultural and material construction of their own bodies and not to leave the process entirely to male scientists.

Implications for the debate on gene patenting

All three attempts to explain the role of the gene are subject to ethical-moral and political pitfalls. Over-emphasizing the role of the gene creates the danger of genetic determinism, and some expressions of the radical rejection of genetic engineering are guilty of this. The systems approach inevitably raises the question of why genes should be treated differently from any other cell components. It suggests that genes should be given no more significance than any other substances isolated from plant or animal cells, and should therefore be freely available for patenting and manipulation. Adopting the constructivist approach makes the debate on whether genes have been 'found' or 'invented' unsustainable, since all phenomena emanating from scientific experimentation are perceived to he ultimately 'manufactured'.

What wisdom can we draw from this debate? Does the fact that the gene is so hard to pin down as a scientific object have any relevance for the patent debate? Is it not much more important to concentrate on the economic and social consequences that will flow from the extension of patent protection to genetic material and living organisms? While the last question is crucial to any political and ethical evaluation of regulatory regimes being drawn up for patents, the problem of defining the gene does raise some urgent and relevant questions. These relate primarily to the definition of the object or process which a patent is intended to protect.

The first step in the manufacture of transgenic cells or organisms is to select and isolate the DNA sequence whose coding information one intends to exploit and patent. The standard practice is not to use the structure as it exists in the organism, but to excise the introns and use only the area that codes for a particular protein. It is also general practice to use the gene of a single individual. However, not every gene is present in an identical form in different individuals. Gene sequences can vary somewhat without changing the characteristics of the derived gene product. These alternative forms of the same gene are known as alleles and occur at varying frequencies in different populations.

The so-called CTFR gene, whose mutation can lead to cystic fibrosis, for example, has more than 400 variants. Only very few are involved in causing the serious form of the illness. Alongside the variants that are found in those obviously suffering from the disease are others which do not have pathogenic effects. These are found in Northern, Central and Western Europe, and in varying frequencies in the USA.

As a rule, only a single variant is used to create a transgenic cell in order to synthesize larger quantities of the gene or gene product; this is registered as a prototype under the patenting procedure. Consequently, patent protection can apply only to this specific variant and not to any 'gene', however it is defined.

Different alleles can vary not only in terms of their structure, but also their effect on the organism. Some CTFR alleles may be able transmit improved resistance to cholera. Does a patent holder also inherit an automatic right to exploit such multiple properties of a gene or its alleles, even though the original patent application made no mention of them? Does the same scenario apply to other - as yet undiscovered - functions of the DNA sequence concerned, which might never come to light unless the sequence is implanted into a new host organism?

If every allele and every synthetic construction differs both structurally and functionally, then each patentable invention can only relate to a particular set of conditions within which a DNA sequence is made exploitable, and not to the DNA sequence itself. With this insight, the current trend towards awarding extremely broad patent protection for genes and their exploitation (see p. 89) is both dubious and absurd.

Until now, the debate within the scientific community over the patentability of genetically engineered products has paid scant attention to certain fundamental problems of definition. An explanation for this fact lies in the highly pragmatic nature of patent law procedures, which do not follow the logic of scientific argumentation but focus on the needs of the market and the commercial interests of inventors. Nevertheless, defining the object of the patent remains a problem which patent law will have great difficulty circumventing in the long term.

A framework of rules to resolve this issue will need to respect the interests not only of commercial users but also of scientists who fear that the patenting of genes will hinder their work. However, disputes over special interests must not take precedence over the principle that, however expressed, the new regime must not injure human dignity and must not denigrate other creatures as merely the servants of humankind's inventions.

References

1. Adelman, J.P., Bond, C.T. et al. (1987). 'Two mammalian genes transcribed from opposite strands of the same DNA locus', in: Science 235, 1514-1517.

2. Fischer, G., Wittman-Liebold et al. (1989). 'Cyclophilin and peptidylprolyl cis-trans isomerase are probably identical proteins', in: Nature 337, 476 478. Shieh, B.H., Stannes, M. et al. (1989) The ninA gene required for visual transduction in drosophila encodes a homologue of cyclosporin A-binding protein', in: Nature 338, 67-70. Takahashi, N., Hayano, T., Suzuki? M. (1989) 'Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin', in: Nature 337, 473-475.

3. Bonnerot, C., Grimber, G. et al. ( 1990) 'Patterns of expression of position-dependent integrated transgenes in mouse embryos', in: Proceedings of the National Academy of Sciences 87, 6331-6335.

4. Howlett, R. (1994) 'Taking stock in Stockholm', in: Nature 370, 178-179.

5. Quoted in Evelyn Fox Keller (1986). Love, power and learning (Liebe, Macht und Erkenntis), Hanser: Munich, p 179.

6. Nihout, H.F. (1990). 'Metaphors and the role of genes in development', in: BioEssays 12 (9), 441-446.

7. See, for example, Strohman, R. (1994). 'Epigenesis: the missing beat in biotechnology', in Bio/Technology 12, 156-164.

8. Haraway, D. (1985). 'A manifesto for Cyborgs: science, technology and socialist feminism in the 1980s'. In: Socialist Review 15 (2): 65-108.

9. D T., Schlr, et al. (1991). 'Gene mutation analysis in German cystic fibrosis patients' (Mutationsamalyse bei deutschen CF-patienten) in: Medizinische Genetik Vol 3, 24-26.

10. Rodman, D.M., Yamudio, S. (1990). 'The cystic fibrosis heterozygoteadvantage in surviving cholera?' in: Medical Hypotheses 36, 253-258. Gabriel, S.E., Brigman, K.N. et al. (1994) 'Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model', in: Science 266, 107-109.