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Some conceptual questions about somatic gene therapy and their relevance for an ethical evaluation

Sigrid Graumann, 1999

In: Nordgren, Anders (ed.): Gene Therapy – Ethical, Legal, and Social Perspectives (Acta Universitatis Upsaliensis. Studies in Bioethics and Research Ethics 4), Uppsala, pp. 67-77

Right from the beginning the development of molecular biology has been accompanied by the idea of making man himself the object of molecular genetic research:

"The highest level of application of molecular biology would be the direct control of nucleotid sequences in human chromosoms associated with the possibility to identify, select and integrate the desired genes which appear in an existing population in great variety." [ 1 ]

Ever since genetic manipulation of mammal cells has been made possible, researchers have discussed a medical application of gene transfer technology on human beings. In the beginning public opinions tended to be rather sceptical towards plans concerning genetic manipulation of human cells.

"Considering that nuclear energy threatens global catastrophe and that many other technological advances visibly damage the quality of life, who would wish to have scientists tampering with man's inner nature." [ 2 ]

In addition to their success modern technology brought along a general insecurity of the public concerning its destructive potential. However, even more relevant than this was that critics have placed genetic therapy in a historical context of fantasies of the improvement of man triggered by old as well as new eugenics. That is why a clear cut division between somatic gene therapy and germ line therapy has been decisive for the development of a concept of genetic therapy which has become publicly legitimised. Somatic gene therapy means that not all the cells of an organism are the target of genetic manipulation, but merely the pathologically relevant cells of specific tissue or organs. This means that genetic manipulations will not be passed on to descendants and that there is therefore no reason to fear modern technologies could serve for a genetic improvement of mankind. The concept of germ line therapy, however, is related to the idea of a direct manipulation of the germ cells of an organism, or all cells and this implies those germ cells as well which carry technically caused genetic manipulations and will thus be passed on to following generations.

"The two issues - somatic cell gene therapy and germ line therapy - had to be distinguished and separated for purposes of debate and public policy considerations." [ 3 ]

In addition to this, a clear therapeutic orientation was significant for a legitimizable concept of gene therapy. Friedmann, who played an important role in the development of this concept, said:

"The term gene therapy was adopted to distinguish itself from the ominous, germ-line perceptions of the term human genetic engineering." [ 4 ]

Subsequently, it has been stated in general that there are no considerable objections against somatic gene therapy with a clear therapeutic aim. The following ethical discussion restrains to the conditions of the clinical practice of somatic gene therapy [ 5 ] - and that means it restrains first of all to the assessment of chances and risks.

The concept of a likewise understood somatic gene therapy which had gotten rid of its historical burden, for many euphoric critics became the object of hopes and promises to be able to offer therapies against genetically caused diseases, which formely could not or only insufficiently have been cured, by now being able to target their genetic basis. A revolution of traditional medicine was proclaimed. I would, however, argue, that the primary question would have to be, whether there is a possibility after all to realise this concept in accordance with its formulated goals. This is the first point where in my opinion basic doubts are justified.

Generally, risks have to be taken into consideration. The general rule for the legitimisation of a therapy or a clinical trial demands, that the anticipated benefits for the involved patients have to overrule the risks. The presumption here is that the benefits as well as the risks can be determined. This is the second point where in my opinion basic doubts are justified.

The following reflection of the concept of somatic gene therapy will clarify this doubts.

Development and modification of the concept of somatic gene therapy

The original ideal concept of genetic therapy is to treat patients suffering from monogenetically caused hereditary diseases with a transfer of intact gene sequences on to the pathogenetically relevant cells and to thereby provide them with a causal, specific treatment that has relatively few side effects.

"One approach of gene therapy would involve specific removal from the genome of a mutant gene sequence and its replacement with a normal functional gene." [ 6 ]

In order to realise this idea it would have to be possible to implant the intact gene at exactly the same place as the defect gene in the genome of the target cell. This would theoretically guarantee that the therapeutic gene is exprimated correctly by its according regulating environment. This means, that the gene product would have to be produced in the right cell, at the right moment in the right amount and in the right relation to other proteins. This, however, is exactly what cannot be achieved with the transfer systems which are currently available for somatic therapy. The transfer gene integrates somewhere in the genome or is exprimated extrachromosomally. Therefore the effects of the gene transfer cannot be predicted with certainty.

This is the reason why in the first clinical tests only those diseases could be treated which were caused by the defect of a gene which did not necessarily have to be specifically regulated in order to achieve a therapeutic effect. Anderson, who performed the first clinical test in the field of gene therapy in 1990, said:

"Early attempts in gene therapy will almost certainly be done with genes for enzymes that have a simple, 'always on' type of regulation." [ 7 ]

Among these simple diseases are e.g. ADA-deficiency, cystic fibrosis and hypercholesterolaemia, which became the objects of the first clinical trials in the field of gene therapy of hereditary diseases.

Today, the great majority of clinical minutes is not about the treatment of monogenic hereditary diseases as was expected at first, but about the treatment of cancer and other acquired diseases which are regulated by environmental factors and a greater number of genes. All of the diverse strategies made use of in clinical tests in the field of gene therapy concerning the treatment of cancer aim at a reduction of the tumour mass and not at all at the genetic defects which possibly can cause cancer. In this respect they do not differ in principle from conventional approaches in cancer treatment like the surgical removal of tumours, chemotherapy and ray treatment. These concepts are not at all in accordance with the original idea of a specific gene correction or with the intention to triumph over diseases by targeting their genetic roots.

Gene therapy in the context of bio-medical research

The 'Panel to Assess the NIH Investment in Research on Gene Therapy' in the United States asserted in its report published in December 1995 that up to now not a single successful clinical test has been made. Nevertheless somatic gene therapy is still associated with a special quality of medical progress:

"Somatic gene therapy is a logical and natural progression in the application of fundamental biomedical science to medicine and offers extraordinary potential, in the long-term, for the management and correction of human disease, including inherited and acquired disorders, cancer, and AIDS." [ 8 ]

The trust in future success, which is formulated here despite the fact that basic technical problems remain unresolved, can hardly be understood on a basis of established facts, but rather has to be regarded in a context of a Bacon-like optimism concerning progress: Scientific medicine, that is bio-medicine, is, according to Bacon's ideal associated with the notion of reliability, efficiency and success. The self-image of scientific medicine gains its belief that it will be able to provide the best suited method in the fight against man's morbidity and mortality through participation in modern science research programs. Scientific methods are associated with the notion of exact and realistic documentation of phenomena, especially as long as the following three methodological rules are obeyed:

1. The abstraction of the singular concrete case to the ideal circumstances, the reduction of the research object to its methodologically relevant features.

2. The carrying out of controlled experiments. Only few specific features of the object are observed and measured under controlled circumstances.

3. The formalised generalisation.

The goal of experimental scientific work is to gain control of the object of research. The methodological directive in doing so is to split the object into smaller and smaller empirically definable units in order to reconstruct it according to its smallest analysed units. The starting point for the development of the research program in the field of scientific medicine was made by the experimental physiologist Bernards (1813-1877).

"Consequently, the physiologist and the physician, as well as the physicist and the chemist who find themselves confronted with a complex question have to split up the whole of the problem again and again into simpler and better defined aspects." [ 9 ]

In the course of progress, the research program went from a macro to a micro level, from the level of organs to that of tissues, to the cells and finally to the DNA. Human genetics and especially gene therapy thus represent the temporary final point within the logic of the research program of scientific medicine, which Bernard had formulated already in the 19th century.

Questions concerning risks and methodical reductionism

A practical and theoretical simplification of reality is the prerequisite for a control of biological phenomena. Scientific formation of cognition assumes a reduction of complexity and always leads to reductionist interpretations in so far as certain aspects which are considered to be of major importance are placed in the centre and others become marginalised. This way of finding a way to deal with the phenomena is achieved by paying the price of a loss of reality which opens space for cognitive insights at the same time as it narrows down perspectives. A widening of cognition can be asserted in terms of the success of modern science. The narrowing of cognition caused by a loss of insight due to a selective perspective which is part of the approach has been criticised widely. On the one hand criticism was directed against incalculable risks brought about by modern science and technology, on the other hand it was directed against the incapability to describe complex phenomena adequately. [ 10 ]

Gene therapy and the central genetic dogma

The development of somatic gene therapy as well as the major part of the entire genetic research is guided by three theoretical presumptions which can be called the central genetic dogma according to Francis Crick (1966):

The first theoretical presumption is that the genotype represents a sophisticated chemical program, which controls all physiological processes including the development of an organism. The phenotype consequently represents the realisation of the genetic program.

The second theoretical presumption can be described as the one-dimensionality of genes. The sequence hypothesis, which Francis Crick formulated in 1957, assumes "that the peculiarity of a piece of nucleic acid is expressed only by the base sequence and that this sequence is a simple code for the amino acid of a specific protein." [ 11 ]

The third theoretical presumption is that the relationship between genotype and phenotype is a hierarchical one. This means that the flow of direction of information is from the DNA via the RNA to the protein.

Thus it is assumed that a mutation which can be found in a genome corresponds with a precisely relatable effect within the organism and that a technically caused genetic change would have to lead to a precisely predictable effect. If then a gene is transferred to certain cells of the body in the course of a somatic gene therapy treatment, the achievement of a precisely predictable therapeutic effect would have to be possible - assuming that the basic methodical problems are solvable. Prerequisite for such a success, however, is that the theoretical presumptions are correct.

The dispute of paradigms in the field of genetics

The central genetic dogma can be regarded in accordance with Thomas Kuhn as part of the leading paradigm of genetic research, which has to be accepted by the scientific community unquestioned and on the basis of which ordinary scientific puzzle solving is carried out. According to Kuhn scientific progress proceeds in successive stages. The prescientific stage, which is characteristic of a relatively uncoordinated researching of individual scientists is followed by an ordinary scientific stage in which a research-guiding paradigm is developed. A paradigm consists of general theoretical assumptions and rules as well as of techniques necessary for their application, which are accepted by the scientific community for a specific field of science. Ordinary research is practised by those scientists who operate within a paradigm. They have to adopt an uncritical attitude towards the paradigm. Their task is to do ordinary research within the realm of accepted means given by the paradigm - which would in this case be the moleculargenetic resort of methods. The humane genome project would represent a striking example for ordinary scientific puzzle solving.

At the ordinary scientific stage it occurs again and again that empirical data appear which question the dominant paradigm. However, this alone does not suffice to render the dominant paradigm obsolete. It is only when such anomalies accumulate and alternative paradigms become formulated that ordinary research finds itself in a crisis, which could lead to a revolutionary stage and to the establishment of a new paradigm. [ 12 ]

Voices have been raised which consider genetic research to be in such a stage of crisis. I do not want to decide at this moment whether they are right in proclaiming that the genetic paradigm reaches its own end. [ 13 ] On the contrary, I rather doubt that because there are solely theoretically alternatives and no methodologically to the leading paradigm. However, I would like to present some empirical arguments in favour of this thesis and like to make use of them for my own purposes:

Empirical arguments against the validity of the central genetic dogma

According to the central genetic dogma all regulation processes of organisms and cells which means the regulation of the development of organisms and the regulation of metabolic processes must be determined by the genes. But this is inconsistent with the popular understanding of metabolic processes as control circuit systems. [ 14 ] Accordingly regulative processes are envisioned as an interaction of gene, gene product and environment. E.g., the blood insulin concentration has to vary according to the blood sugar concentration. This means that the insulin-gene has to respond somehow to the environmental information 'sugar-concentration'. This contradicts the genetic dogma.

The genetic dogma contains the idea that ontogenesis proceeds in programatically regulated, additive and hierarchically structured sequences of developmental steps. However, the complicated and in this case necessary spatial and temporal co-ordination of the individual steps of development and differentiation cannot be explained satisfactorily hereby. [ 15 ]

The newer state of knowledge in genetics shoes that the regulation of gene expression is not restricted to the level of the DNA. There are regulation mechanisms which are put up in front of the level of the DNA like DNA-imprinting. [ 16 ] And there are regulation mechanisms which succeed the transcription on the level of the RNA like m-RNA-splicing and m-RNA-editing. [ 17 ] We know DNA-sequences which deliver different gene products by these mechanisms. [ 18 ] This means that there are regulation processes which cause alterations of the gene products beyond the DNA and therefore they are unlikely determined by the DNA alone.

Besides that, we know physiological functions in the organisms which can be reached by different genetic path ways. [ 19 ] Such examples can show that the DNA is not simply active but rather reactive on the necessities of life processes.

In order to describe phenomenons like metabolic processes, the development of the organisms and the gene expression in their complexity, researchers today often draw back on explanation-models based on system theories:

One relatively simple alternative model concerning the regulation of metabolic processes and ontogenesis is derived from cybernetic control circuit models. A regulative network which is comprised of individual regulative units could be completed by other regulative elements on the level of DNA, RNA or gene product. By this means, cascade control units and feed back loops could be integrated as well. [ 20 ]

In the meantime more far reaching alternatives based on complex system theories gained acceptance in the formulation of biological theory. These alternative approaches consider interactive epigenetic networks to be the key to an understanding of physiological and ontogenetical regulative processes instead of the genom itself. Ontogenesis is in this case understood as a historical and not as a programmatic process, which is controlled by genetic and epigenetic interactions on all levels of organisation. Thus the phenotype represents the result of interactions between multiple factors, of which genes only represent one category. [ 21 ]

I don't agree with the opinion, that these explanations-models based on complex system theories can compensate for the reductionist deficits characteristic of the empirical-analytical methods of modern science. However, due to their adoption of a new perspective, that is, due to an analysis of the whole instead of particular elements only, these models deliver us with an important widening of the understanding of biological phenomena.

Can gene therapy be considered a sensible goal of modern medicine?

If these alternative models of biological regulative processes prove to be of a higher validity and are thereby closer to empirical reality than the old genetic paradigm which has become doubtful, this would imply that the effects a natural genetic change or a technical genetic manipulation have on the phenotype are not exactly predictable. I do not argue that it is impossible to achieve desired effects at all, but simply that such cannot be predicted on a secure basis. Gene therapy tests would then be trial and error tests with a relatively undefined result and not as it was hoped calculated corrections of genetic deficiencies. It may be the case, that somatic gene therapy could enrich modern medicine with some new methods of treatment, but it could never, as was often assumed bring about a revolution of scientific medicine. In addition to this, are not only the positive effects not exactly predictable, but also the risks of gene therapy cannot be calculated satisfactorily.

Implications for the ethical discussion

This perception is of particular relevance for the ethical evaluation of somatic gene therapy.

On the one hand, those ethical arguments in favour of the novelty of therapeutically actions connected with somatic gene therapy loose their validity. The utility of gene transfer techniques in clinical practice will not be so huge and revolutionary as it has been assumed so far. In this respect, a policy of research which concentrates on the development of somatic gene therapy appears to be highly questionable, especially taking into consideration the limitedness of resources. Particularly as the development of alternative and maybe more successful therapeutic approaches becomes neglected thereby.

On the other hand, those ethical arguments objecting somatic gene therapy by assuming that gene therapy cannot be restricted on therapeutically purposes for individual patients loose their validity as well. If the above mentioned thesis is true it will never be possible to achieve exactly calculated effects in humans. This means that both hopes and fears about total genetic control by gene therapy or genetic enhancement are extremely unrealistic.

As follows, we should concentrate on the assessment of chances and risks of somatic gene therapy by taking into account the uncertainty of the achievable goals and by taking the biological risks of gene transfer in humans more seriously.

Because of the methodological problems and the uncertainty of the theoretical basis of gene therapy we cannot state today that the anticipated benefits for the involved patients are overruling the risks. This means that up to now the general rule for the legitimisation of therapies or clinical trial cannot be fulfilled. We do not know what exactly the scientific progress will bring for the future. We can assume that it will not provide us with a revolution of medicine by overcoming genetic diseases. We can rather hope that it will offer some additional symptomatic but nevertheless useful therapeutically options. And we know that it should be decisive to assess the risks of gene transfer carefully before introducing somatic gene therapy into (experimental) clinical practice.

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