Applications and implications of the fundamental Genetics

Gonzalo Herranz. department de Bioética, Universidad de Navarra.
Intervention in First roundtable: Genetics fundamental. Present and future.
meeting International Bioethics Genetics and the human person.
Organised by the group de Bioética, Associação dos Médicos Católicos Portugueses.
Coimbra, 26 October 1989.

I would like to thank the group de Bioética de Coimbra and the association Portuguesa de Médicos Católicos for the invitation, sent to me through Prof. Amandio Tavares, to participate in this meeting to discuss the attractive and committed topic of Genetics and the human person. I accepted for two reasons: first, because I am sure that this is an opportunity, which I do not want to miss, to learn many things. The second is that, for any university student, visiting Coimbra is a gift. Besides, I am very attracted to Portugal: maybe it is the effect of some gene I received from my maternal grandfather, a minhoto by origin.

In the 20 minutes I have available to me, I will try to briefly touch on what seem to me to be the main implications of the fundamental Genetics for the individual and for society. I hope you will understand that, given the attention I have been paying in recent years to medical ethics, I will be referring equally to ethical issues and to technical and scientific details. I hope that this was the purpose of the organisers of the meeting when they invited me to address the topic.

1

The first point I want to make may seem commonplace, but it is of decisive importance: the new Genetics is serious, for it will place enormous power in our hands and a proportionate responsibility on our conscience.

The applications of technology Genetics are already giving us and will continue to give us marvellous new capabilities: some theoretical, contemplative, such as understanding the mechanisms and significance of biological inheritance and its disorders; others practical, manipulative, which will allow us to act on living beings, including man, and to dominate them with unprecedented power. It is too early to estimate the economic and anthropological impact of these applications, but it is certain that they will surpass anything we can dream of.

This power to penetrate deeply into the innermost depths of man and, in a certain sense, to modify him, will also modify our way of understanding and treating man. Among many other things, medicine will be decisively influenced by the new Genetics as it enters into the intense field of gravitation of the new . What we decide about its legitimate applications to the sick person will shape the roles and responsibilities of physicians.

Discussing the implications of Genetics, as we are doing today, and trying to weigh them up, is therefore not just a matter of indulging in a fashionable topic : it is an unavoidable and, given the way things are going, urgent obligation.

2

My second point is that there is no limit to the implications of the new Genetics born of recombinant DNA technology. To begin with, its field of application extends to all living beings and to many artificial in vitro systems: from the cloning of genes to the manipulation Genetics of micro-organisms; from the engineering of cultivated plants to the creation of transgenic animals. Once the necessary safety precautions have been taken and certain environmentalist prejudices have been overcome, the technology Genetics will make the farmer's and stockbreeder's work much safer and more productive in rich countries and, hopefully and hopefully, in poor ones too1,2.

His favourite object of study and intervention, however, will be the human being. The new Genetics will help us to know ourselves better, revealing aspects of our identity and our ancestry. Above all, it will help us to understand and diagnose many diseases, to prevent and treat them. Among the many and varied promises it will offer us, some will be too risky or aggressive and we will have to say: No, thank you.

3

There is no limit to the expansion of knowledge. Even before 1986, when Renato Dulbecco proposed sequencing the entire human genome3 , molecular Genetics was already on the crest of the wave. After that date, the Genetics cultivators have been living in a state of excited anticipation for which it is not easy to find a parallel. fill in Today, the laboratories of Genetics molecular are undoubtedly the most attractive for young scientists, eager to embark on what some say is the most promising adventure in the history of science: first the high-resolution gene mapping of human chromosomes and then the sequencing of the entire length of the genome. This is said to be an enormously ambitious business , with the dimensions of an epic, from which it is hoped to extract an incalculable amount of information to be able to intervene on human health and disease. For the moment, the "project Genome" is forcing the international academic community to ask itself a very important ethical and methodological problem: to decide between cooperation and competition. In its wake, the project will drag in its wake other complementary scientific adventures4,5.

4

There are no limits to the medical applications of the new Genetics. Let us look first at the diagnostic ones. The elegance and forethought with which new, ever finer and more efficient techniques are being designed is astonishing. Diagnostic technology at the DNA level is a rapidly expanding area .

It provides us, first of all, with a varied repertoire of techniques for investigating individuality Genetics. With far greater precision than the analysis of proteins, enzymes or cell markers, which are the product of the activity of our "expressed" genes, the individuality of each of us is more strongly marked by our "non-expressed" DNA, which does not manifest itself phenotypically and which can be identified by techniques aptly designated as genetic fingerprinting. This has been a great enrichment for forensic medicine. It is now possible to answer the following two questions with confidence in virtually all cases: To whom does a sample piece of human material belong, and is there any kinship between certain persons?6.

Perhaps the aspect of greatest medical interest lies in the ability of the new technology to detect genes responsible for autosomal dominant and recessive disorders, as well as X-linked disorders. The diagnostic data provided by the new technology can be applied at different levels: at the genetic committee , in prenatal or neonatal diagnosis, in the detection of affected subjects through family screening, in the identification of heterozygotes in the case of recessive diseases, etc.

Moreover, because this technology allows us to identify alterations in gene structure, we can understand more precisely the cause and pathophysiological mechanism of monogenic diseases. Of these, the most studied have, for many reasons, been haemoglobinopathies and thalassaemias. But much information is also accumulating on mutations in disorders of the coagulation cascade, collagen abnormalities, congenital disorders of amino acid metabolism or endocrine function, and lysosomal storage disorders7 .

It is inevitable that the social implications of the potential diagnosis of the new Genetics will raise enthusiasm and suspicion8,9. With this potential available, humanity will have to commit to some compromises. The gene technologist will have to put aside everything that means abuse of power of some men over others, that stigmatises or labels, that discriminates socially or economically, that deprives of rights or opportunities10,11. And he will reject the temptation to absolutise science, imposing eugenicist utopias or contributing to establish the tyranny of normality12,13. I think we have a great need, in our society today, to broaden our capacity to respect human beings damaged by disease Genetics, and to understand more fully the biological and social value of diversity, aware that "a society can be judged by the way it treats the most disadvantaged, the least loved, the insane "14.

5

But doctors are not satisfied with just diagnosing: they want to cure. Already today, many patients with genetic diseases are treated with a wide variety of remedies - dietary, pharmacological, surgical, educational - applied before or after birth. For many others, unfortunately, there is virtually no treatment at all. Both are potential targets of the new gene therapy, which offers, along with very attractive promises, risks that are not easy to calculate. Unfortunately, or fortunately, I don't know, things are moving more slowly in this field than in diagnostics15.

project to repair genetic defects, either by replacing altered genes with normal genes, or by incorporating the missing genes into organisms, has entered the experimental stage and, despite technical and administrative difficulties, is trying to take the first steps towards its application to humans. The efforts of the groups working in this field are directed towards gene therapy of somatic cells, as, for the time being, there is a very broad agreement to defer attempts to treat germline cells to a later stage8,16,17.

The technical difficulties of gene "surgery" are very great: the molecular basis of any therapeutic project must be precisely known; the therapeutic gene must be isolated and cloned under very well controlled conditions; the regulatory regions responsible for its correct quantitative expression must be defined; target cells must be identified, isolated and cultured; safe and efficient methods must be developed to introduce the gene into the correct place in the genome; procedures must be established to restore the treated cells to their correct place in the organism and to ensure their expansion and survival. And, before clinical applications can begin, unequivocal evidence must be available in experimental animals that the inserted gene functions properly and does not cause harmful effects in its new environment.

This seems an unattainable business , but there are also reasons for optimism. The procedures for inserting genes into cells are growing day by day: intranuclear microinjection, encapsulation in liposomes, transfection mediated by calcium phosphate, exhibition to pulsed electric fields, but, above all, transfection using retroviral vectors duly manipulated to avoid any undesired effects and to ensure the integration of the transferred gene into the host genome. This explains why group is working hard to intervene on haemoglobin defects, on adenine deaminase deficiency (manager of severe mixed immunodeficiency) and on hypoxanthine guanine phosphoribosyltransferase (Lesh-Nyhan syndrome)15.

The future is open. It holds promise as well as risks. Although, as I pointed out a moment ago, there is now a massive majority agreement to postpone the application of germline gene therapy in humans until there is extensive and positive experience with somatic cell therapy, some dissenting voices are calling for the ethical and legal aspects of the issue to be discussed now18.

6

I would now like to make reference letter another aspect of the implications of the new Genetics, an aspect that concerns us very directly, since I am not forgetting that we are in a university environment and under the sponsorship of the association of Catholic Doctors: the way to teach the new Genetics in the University and the way to disseminate it among the public. And to do both in the respect for man and for intelligence, so characteristic of Christian culture.

The group of work on the teaching of human Genetics in North American Medical Schools, while being of the opinion that there is no ideal procedure for teaching human Genetics , reached the agreement that students, at the end of their programs of study, should understand a certain issue of areas of knowledge, ranging from the structure of genes and chromosomes to pharmacogenetics to DNA polymorphisms to Genetics of behaviour. At the end of the list of knowledge areas listed was ethics19.

Probably no other area of medicine is more charged with ethical sense and responsibility than Genetics. We are all familiar with the genetics-ethics word game. But in the teaching of Genetics, ethics cannot be just another topic , which tends to be externalised and lost. It must intimately permeate the theory and applications of Genetics to man. At the end of their programs of study, young doctors and biologists should possess, as result of the ethical reflection to which they have been invited while becoming familiar with the knowledge of the Genetics, a certain issue of clear notions which I would like to comment on.

- One is that the individual who is affected by a genetic disorder is a sick human being who must be cured or at least cared for. He or she is not a useless pile of junk Genetics to be disposed of.

- Another is that the genetic patient enjoys the same rights as other patients. They cannot be discriminated against by virtue of their weakness. We must defend the right of everyone to have defects and for people to be able to live without being bothered or stigmatised for it20 . The new technology Genetics must never be an oracle that decides on people's life, reproduction or employment status.

- A third idea our graduates should possess: a keen awareness of both the limits of our knowledge and the strength of our respect for man. In other words, genetic diagnosis requires, in addition to due science, a strong sense of moral responsibility. For this reason, it is worth reviewing the ethical and social value of the "ethical neutrality" (nonjudgemental communication) that some consider to be the only morally worthy and, therefore, obligatory attitude of the clinical geneticist. One thing is the delicate respect that the doctor owes to the freedom of individuals or families; another is the "tactical" Withdrawal to hold and express one's own convictions.

- A refutation of the eugenicist mentality and the related fallacy that medical care for those afflicted by genetic defects not only absorbs a significant portion of health resources, but also overburdens humanity's pool of deleterious genes, is part of the Education due to our students and the general public. Everyone needs to be told that we doctors are not so powerful: that it is beyond the power of medicine both to damage the gene pool and to eradicate hereditary diseases.

- We are also obliged to persuade the general public that the new Genetics comes with moral and political implications. Legislation on the applications (agricultural, livestock, industrial, medical and social) of recombinant DNA will soon be necessary, and this is everyone's responsibility. Our fellow citizens must be informed of the magnitude of the values at stake and encouraged to participate responsibly in determining this aspect of society's destiny.

I am confident that meetings like this are an excellent means of awakening our responsibilities as men and as Christians. We have to assume the difficult and attractive attitude of being both promoters and judges of science. We can do so if we follow the committee which John Paul II gives us, in order to judge the achievements of science, in point 15 of Redemptor hominis: "The first concern relates to the essential and fundamental question: does this progress, whose author and author is man, make man's life on earth, in all its aspects, "more human"; does it make it more "worthy of man"? There can be no doubt that, in many respects, it does. However, this question is stubbornly raised again with regard to what is really essential: whether man, as man, in the context of this progress, really becomes better, that is to say, more spiritually mature, more aware of the dignity of his humanity, more manager, more open to others, particularly to the neediest and the weakest, more available to give and lend financial aid to all".

This is the critical sense for judging the new Genetics and its implications for the human person.

Notes

(1) Shell J. The impact of genetic engineering on plant breeding. In Weatherall D, Shelley JH, eds. Social consequences of genetic engineering. Amsterdam: Excerpta Medica. 1989:126-50.

(2) Winnacker E. Transgenic animals. Ibid: 151-74.

(3) Dulbecco R. A turning point in cancer research: sequencing the human genome. Science 1986:231:1055-6.

(4) McKusick VA. Mapping and sequencing the human genome. New Engl J Med 1989;320:910-5.

(5) Anonymous. Why sequencing the human genome? Nature 1988:331:465.

(6) King MC. Genetic testing of identity and relationship. Am J Hum Gen 1989;44:179-181.

(7) Antonarakis SE. Diagnosis of genetic disorders at the DNA level. New Engl J Med 1989;320:153-63.

(8) Roberts L. Ethical questions haunt new genetic technologies. Science 1989:243:1134-6.

(9) Lappé M. The limits of genetic Inquiry. Hastings Cent Rep 1987;17(4):5-10.

(10) Reiter J. Gentechnologie oder die manipulation des Lebens. Arzt Christ 1984;30:109-18.

(11) Catenhusen WM. Prospects and risks of genetic engineering. In Weatherall D, Shelley JH. Social consequences of genetic engineering. Amsterdam: Excerpta Medica. 1989:177-93.

(12) Hauerwas S. Suffering presence. Notre Dame: Univ Notre Dame Press. 1986:211-17.

(13) Fiedler LA. The tyranny of the normal. In: Murray TH, Caplan AL, eds. Which babies shall live? Clifton: Humana Press. 1985:151-9.

(14) Thomas L. Late night thoughts on listening to Mahler's Ninth Synphony. New York: Bantam Books. 1984: 100.

(15) Weatherall DJ. Gene therapy. Getting there slowly. Br Med J 1989;298:691-3

(16) Parlamento Europeu. Report on behalf of the Committee on Legal Affairs and Citizens' Rights on the ethical and legal problems of manipulation Genetics. Rapporteur: Mr Willi Rothley. Document A2-0327/88. European Parliament. 1988.

(17) Motulski AG. Impact of genetic manipulation on society and medicine. Science 1983;219:135-40.

(18) Glover JVC. Human genetic engineering. How far should we go? In Weatherall D, Shelley JH. Social consequences of genetic engineering. Amsterdam: Excerpta Medica. 1989:193-214.

(19) Graham JM, Rotter JI, Riccardi VM, et al. Report of the Task Force on Teaching Human Genetics in North American Medical schools. Am J Hum Genet 1989;44:161-5.

(20) Herranz G. Respect du patrimoine génétique. Communication a la première journée-debat de l'Association Mondiale des Amis de l'Enfance et le Conseil de l'Europe. Strasbourg, 10 April 1989 (in press).