Bioethics in Oncology, Genoma Project: Ethical Implications in Oncology

Paper presented at the IV Congress of Advances in Management of Malignancy

Contents:

Genetic diagnostics of cancer and bioethical implications...

Genetic therapy...

Bioethical implications of genetic therapy...

It is no accident that the term bioethics was coined by an oncologist, Van R. Potter, author of "Bioethics. Bridge to the Future", on whether it is right to persist with therapy at a terminal stage of the disease. In oncology, more than ever, the doctor is faced with difficult questions which go beyond the strictly health environment to raise basic issues concerning  the value of the life of the patient and his relationship with society. The costs of care, the suffering it leads to, the expectations it raises, the strain the patients family must go through ... inevitably lead to heart-rending decisions and dramatic alternatives. The breakthrough of gene therapy in the last few years have also  affected the field of oncology and, in particular, preventive strategies offered by DNA manipulation has raised further issues such as the responsibility of the scientific community to future generations, the violation of the identity of the human species, the uncontrollable consequences which might spring forth, all of which cannot possibly be exclusively entrusted to the "clan" of scientists but must be reflected upon and debated by society as whole. Before venturing on an examination of this issue it might be useful to outline the problem of cancer.

It is known that in this country cancer is responsible for some 23% of deaths compared with 12% of just 30 years ago. A superficial examination of the statistics, then, would seem to suggest massive progression of the disease. A closer examination of  the figures, however, shows that this may be explained by the fact that deaths from infections disease have almost disappeared and average life-span has, in fact, increased. In reality, cancer treatment has made some major progress over the last ten years rendering some tumours thought to be without hope up to only a short while ago actually curable. Survival  has been prolonged in many patients with serious types of cancer (in many cases by ten years or more) and new diagnostic techniques have enabled early disease to be identified and thus more easily managed.

It should be stressed, however, that the growth of diagnostic technique and cancer treament has led to an average increase in expenditure of 400% over the last 15 years together with a growth in overall health care expenditure which accounts for some 8% of GNP in Europe and 11% in the USA (while in developing countries this figure is still only 4%). At this rate expenditure  will reach 10% worldwide and 15% in the USA by the year 2000. It goes without saying that these spiralling costs cannot be unstained for long as the miracles of modern medicine progress much more rapidly than the financial resources available and the almost infinite needs of medical care, especially among the aged, have to face the reality of finite resources.

Some states in the USA have already faced up to this fact and recently the Ways and Means Committee of Oregon as its first act denied funds to an organ transplant programme (bone marrow, heart, liver, pancreas with the exception of kidney and cornea transplants which have a more favourable cost/benefit ratio), arguing that the choice was between extending basic medical care to cover 1500 persons without any assistance (including pregnant women and children from poor families) and financing 34 organ transplants. The Committee actually managed to refuse a bone marrow transplant to a child of seven with acute lymphoblastic leukaemia (later treated thanks to public subscription), provoking an outcry on a national scale. What emerged from this was the concept, shared by all at least in theory, that since resources are limited they must be used in the most rational way, and while  the choice of criteria may indeed be discussed but choices must be made. This undoubtedly ruthless premise is fundamental in approaching the question of diagnostic technology and cancer therapy which now concern an increasingly aging population and in the light of  the  breakthrough in knowledge of the human genome, 75% of which has been deciphered. This would suggest that by the end of the next decade it will be possible to identify all of most of the  5000 known genetic diseases with relatively simple laboratory tests. As always, however, advances in knowledge do require codes of behaviour to be adjusted and may raise ethical issues which are not easy to resolve.

 

Genetic diagnosis of cancer and its bioethical implications

 

This discovery was an important step in the fight against cancer since markers could be used in the  early diagnosis of  disease recurrence and metastasis as well as in the prognosis locating the sites of tumours and in monitoring response to  therapy.

The breakthroughs of biotechnology and, in particular, the Genome Project has, however, revolutionized the field of diagnostics making it possible to identify genes and those areas of DNA which regulate the predisposition to certain tumours. The most well known of these is the identification of anomalies in the gene XPF, p53 and in the FHIT gene situated on chromosome 3 which is  at the origin of many lung tumours, in particular, large and small epithelial cell lesions . Of particular interest are the social implications of this latest discovery in that the action of the genetic anomaly might manifest itself in the presence of environmental carcenogenic substances, especially those in  cigarette smoke. If, as is likely, this discovery leads to the wide spread use  of tests to diagnose this type of genetic anomaly it should be soon possible to carry out an awareness and information campaign on the risks of smoking aimed at "high risk" subjects who carry the genes.

The issue is however different  with diagnostic tests to identify potential cancers for which prophylaxis is impossible, for example, the identification of the oncogene Pml apparently linked to promyelocytic leukaemia, or even worse forms of cancer for which as yet no effective treatment exists. In these cases anyone who is diagnosed as having a predisposition to these diseases might interpret it as a death sentence, consequently provoking anxiety depression and psychosomatic illness. The impending large scale marketing and spreading of these diagnostic tests thus raises some vital ethical and moral questions such as whether it is right to diagnose at an early date the probability of a cancer for which there is little chance of treatment. We would not claim to offer a definitive opinion but it does seem worth mentioning the point of view expressed by Renato Dulbecco, Nobel Prize winner and coordinator of the Genome Project, "I do believe that it is always better to know than not to know. A person whose life is marked by a genetic error which we know will manifest itself at the age of forty, for example, ought to know what's going to happen at least so that he may organise his own existence." It is certainly easy to agree with this stance though it should be said that the availability of tests designed to identify a predisposition to cancer might contribute to aggravating the already problematic situation reported by the Bioethics Lay Council in 1992 this highlighted how the excessive  publicity by the mass media concerning diagnostic tests and in some cases by the lack of responsibility on the part of phisicians  (one only has to think of the sharp rise in the demand for a CT scan or Doppler after a simple bout of headache or vertigo) is one of the most serious problems now afflicting the health service in industrialised nations.

In the United States the market for diagnostic tests to ascertain the predisposition to cancer is already experienced  a boom and is becoming a "mania",  which further with the absolute lack of any regulation in this field has led to proliferation of numerous cancer-test laboratories The task of developing  norms should fall to the FDA, Federal Drug Administration, but their spokesmen have avoid any action declaring that, for the moment, there are no plans to regulate genetic tests which, they reaffirm, are made entirely with the free choice of the individual. This is certainly true but the problem is that the results of these tests limit themselves to a diagnosis of no practical use such as "in the next 20 years you have a 40 out of a 100 chance of getting breast cancer" and thus end up either needlessly terrifying the patient  or giving them false assurances.

Widespread use of pre-natal genetic  testing for potential cancer associated anomality such as the gene APC which gives a predisposes to familial polyposis and thus to cancer of the colon and rectum or the BRCAL gene which gives a predisposes  to breast cancer, pose  problems  to society as a whole which goes beyond the difficult choice of the parents. Negative eugenics removing every fetus marked with these  anomalies is impossible to propose (which it is worth remembering are not necessarily a death sentence). As regards rising health costs an assessment of just how much  a subject  marked by serious predisposition  will weigh in economic terms, thus draining enormous resources which could be better employed in other sectors of the health service. In this sense defining the cost/benefit ratio for the next ten years for a specific therapy or prophylaxis is indispensible. It is certainly a difficult calculation to make but it could lead to some important guidelines. This topic, which is already dramatic, becomes more so if we consider  in industrialised countries the emergence, along with the colossal and inefficient public health service, of a private health service based on private insurance whose numbers have already reached 800,000  Italy.

The emergence of reliable diagnostic tests based on chromosome analysis is upsetting the sector of personnel selection and many organisations including unions and pressure groups are now protesting, correctly in our opinion, against wide scale genetic investigation. We believe that just as it is not right to discriminate against  persons on racial or ideological grounds it is unjust to condemn people with a greater marked predisposition to cancer to unemployment or uninsurable status. Excluding candidates who are smokers is perplexing enough but expecting people to exhibit a  clean bill of genetic health ends up by dumping on society as a whole the costs of a risk which should fall to each enterprise. Many prestigious institutions such as the American Society for Human Genetics or the national action plan on breast cancer have raised their voices against this indiscriminate growth in pre-employment tests and have demanded that Congress intervene before it is too late. They echo the words of Francis Collins, head of the National Centre for Human Genome Research, stating that as noone can choose their genes none should be discriminated against on the basis of their genetic heritage.

An even more important discussion involves the question of life and health insurance. Insurance companies already request a medical examination before issuing a policy though this, until now, was designed to ascertain the current  state of health. The emergence of diagnostic tests capable of ascertaining the probability of future cancer onset has upset the whole situation and risks isolating individuals with  problematic genetic backgrounds . For their part most insurance companies stress that by basing the price of a policy on statistical figures, the isolation of those high risk subjects will  guarantee less costly policies which are more accessible to other individuals. It is clear that these positions are conflict  but they may be reconciled at least partly  if, as a recent proposal suggests, the state could intervene by partly covering insurance policies of subjects particularly at risk.

 

 

 

Genetic therapy

Research is now attempting to replace chemotherapy, wich is often poorly effective and weighed down by serious side effects with specific biological therapy. Among the many approaches  one of the most promising seeks to introduce into the cancer cell a gene capable of accelerating apoptosis. Apoptosis represents the main mechanism  for the  natural elimination of  cells in the course of physiological processes such as embryonal development and adult cell turnover, subserring out a homeostatic function, of autoregulation , maintaining a stable internal balance despite variations in external conditions and it is essential in numerous physiological processes such as the development and functioning of the immune system. Regulation of apoptosis depends on the participation of many genes some of which are already identified, and which correspond to two opposing classes: pro-apoptosis which act in favour of apoptosis and anti-apoptosis or survival genes, which oppose the former. Apoptosis is thus a balance of interacting antagonist forces. It is interesting to note that malignant transformation of the cell and the subsequent development of a tumour occur after a succession of gene mutations which are normally present in all cells, and which deregulate the programme of essential cell functions. Some of these have been identified as pro-apoptosis (c-myc, p53) or anti-apoptosis (bcl 2) genes and they are present in most tumours. This means that a situation may arise in which instead of dying due to apoptosis, the cells survive and while this may constitute a defence against the tumour, resistance to apoptosis may also lead to a cell population with an abnormally high survival potential which can contribute to tumour development. Regulation of apoptosis is thus an important aspect of cancergenesis. Thus, the importance of identifying and manipulating the processes which regulate this function is clear.

Genetic material which has been manipulated may be placed in tumour cells with the help of a virus. To work successfully the virus, itself manipulated through genetic engineering, must operate selectively to distinguish affected tumor cells from healthy cells and it must be sufficiently powerful to infect as many malignant cells as possible. Some time ago a protein, coded for by the oncogene Met was found to be produced in abnormal quantities by the cells of many tumours. As it is exposed in abundance on the surface of malignant cells this protein could be exploited to resolve the first problem, should a virus capable of recognising it be found. As regards the second requirement this may partly be resolved with the use of the feared HIV virus (modified in vitro and rendered incapable of replicating) to introduce exogenous outside genes into the cell. Unlike viruses studied earlier the HIV virus is the only one capable of invading cells which do not divide and it is precisely these cells which manage to elude conventional chemotherapeutic  drugs and causes  disease recurrences. Many have raised doubts as to the suitability of such a potentially dangerous  virus and "lighter" vectors have been suggested such as non-human lenti-viruses.

With this system definitive therapy may be possible for several tumours and attempts at introducing healthy genes to replace abnormal  genes have already been successfully performed in animals and, on a limited scale, in humans. Incomplete knowledge of the mechanisms which control the insertion of a new gene  however restricts a wider diffusion at present. In particular, the main stumbling block is the inability of genetic vectors, laboratory structures constructed on the basis of known viruses capable of carrying the gene, to reach the right point in a non deviding resting cell. This means that only rapidly proliferating cells, often in vitro cultures, may provide the target for  therapy. This problem has been brilliantly overcome by constructing a new genetic vector based on the aforementioned HIV virus, or AIDS virus. The idea is based on the acute observation, that the AIDS virus is able to enter resting cells and to maintain  a reserve of viruses capable of infecting other cells over a long period. This is exactly what the new vector does, maintaining the infective capacity of the original virus at though unlike the HIV virus, it is unable to replicate. It is actually relatively easy to place a gene in the vector and thus integrate it into a chromosome of the host cell. Like the HIV virus the shuttle-vector loaded with genetic information enters a resting cell, such as  nerve cells and thus makes it the target of potential therapy. In this way the principal limitation to available vectors which formerly could only infect active cells, has been overcome and the way is open to make organs  such as the liver, muscles, brain or resting bone marrow cells targets for therapy. Thus muscular dystrophy, Mediterranean Anaemia and many neurological diseases may be potential targets for gene therapy based on this type of vector. Cancer also falls within this category,  at least in those cases in which the genetic defect has been clearly identified. It is safe to say that many diseases which up to now are incurable will be eliminated by simply administering a vector loaded with healthy genes and provided with the right address of the cell to attack. Perhaps it is not the case to get too enthusiastic. A few years are still needed to design new therapies based on this vector and at least twenty (for safety reasons and to precisely align the "sights" developed to identify organs and cells in which parts of the genome are to be substituted) before this type of therapeutic technology forms a part of everyday medicine. The weapon is ready but the "magic bullet" essential in combatting the unseen enemy is still missing - could our mortal enemy the AIDS virus aid in eliminating itself and other diseases? It might seem a paradox although we do have an illustrious example in the smallpox virus, now  defeated thanks to the ingenious discovery of Jenner who used a close relative of the virus, vaccinia (cowpox virus), to combat the disease. Now, just as in the past, the  effort and intuition of the researcher form the basis for progress in medicine and biology.

Other biological therapy aims at strengthening the immunological defences of the organism. This type of approach has been studied in  rats, crossing animals resistant to lung cancer with animals genetically predisposed to cancer. A protective region of DNA has thus been discovered,  a "sentry" sequence designed to defend against lung tumour invasion, christened "Par 1" and located on  chromosome 11. Its action is not completely clear (there is probably a direct involvement  of a retinoic acid receptor) but it does provide the basis for the cloning of a gene which could provide the lung with genetic resistance, in particular in subjects with a hereditory predisposition to lung cancer.

New possibilities for the cure of lung cancer might derive from a therapeutic  vaccine. The term "vaccine" may lead to some confusion and it should be stressed that in the case of a tumour this type of vaccine would not actully prevent the disease but would combat the malignant growth already present. A cancer vaccine upon which the hopes of researchers lie, though still awaiting further experimentation, is constituted by the antibody  BEC2 and by genetically modified mycobacteria  BCG. So far, researchers have studied the vaccine on melanoma and small cell lung cancer: two forms of tumour in which chemotherapy can only hope to prolong the patient's life by 16 months, at the most. This vaccine however has given some encouraging results: at three years, six out of six patients whith lung cancer and 9 out of 14 patients with melanoma are still alive after  innoculation with such vaccines.

 

Bioethical implications in genetic therapy

DNA manipulation techniques, then, appear  set to provide us with more and more "intelligent" and selective remedies, new methods of cell manipulation and therapies which are no longer simply destructive but also "corrective" of the functional alterations of tumour cells. There are, however, serious questions which must be carefully examined  especially when genetic manipulation connected with cancer therapy involves germinal cells in which the correction made is transmitted to the subject's offspring.

In genetic therapy of somatic cells the extreme difficulty in controlling viral vectors designed to implant the nucleotide sequence leads to seriou risks (and thus the impossibility of controlling the ectopic manifestations of traits and the difficulty in predicting the consequences of the same sequence implanted  in portions of junk DNA). These risks increase exponentially when germinal cells are involved. In this field we cannot currently know how an alteration of the nucleotide sequence will affect the  phenotypic manifestation (or translation) of the patient's genome, we cannot foresee how such an alteration might evolve over time (and whether mutational phenomena will cause further gene anomalies) and we cannot predict how the  artificially altered  genome will be transmitted to offspring.

It must be said that  eugenetic aims in the human species associated with this technique, with the impossibility of controlling artificial evolutionary dynamics which may emerge, the impossibility of defining which traits to cultivate, the creation of a "clan" of "life engineers", the emergence of interests dictated by purely economic speculative motives...risks catastrophic consequences. In more general terms germinal genetic therapy highlights the responsibility that science has towards future generations and its reponsibility towards  ecological balance . This point is particularly delicate where DNA  is concerned, a structure which has been accumulating data for five billion years. Genetic manipulation violates the structure of DNA, without accurate knowledge of either the function of hexones (which constitute 95% of nucleotide structure) or the evolutionary principles of molecular genetics. This debate may widen further when the contrast  between the theory of pan-neutral evolution (natural evolution in function of polymorphism) and selection, the question of whether DNA may be considered hardware or software, the identification of saltatory genes as agents of intraspecies evolution are considered...

Putting aside this fascinating debate the dilemma of what to do to tackle cancer still remains, a disease which in the European Union alone strikes one million patients a year. Certainly research on recombinant DNA linked with the manufacture of new cancer drugs (Men 10755 or SCH 44342, for example) is fundamental and the risks of this research should not cause us to dismiss this field,  but rather should force us towards a new awareness. Let us not forget either that along with progress in genetic engineering, successes in radiation therapy and surgery in oncology have grown and it would be a mistake to consider them  outdated.

Even prevention seems to pall in the face of the miracles of genetic engineering. This is  however mistaken and much still can and must be done in this field which is relatively free from risks and which has  an optimum cost/benefit ratio, will also help to stem other diseases. The main problem hindering the spread of this concept is that still today cancer is still considered by the majority of the public to be a death sentence without appeal for  which nothing can be done. In actual fact much could be done if this attitude were to  change and if cancer became the subject of information and education in schools, places of work and doctors' surgeries.

In the USA alone it is hoped to save 200,000 people a year from cancer deaths by developing a network campaign  against smoking (responsible for  death from cancer of 75,000 people) on improving diet (20,000) and early diagnosis of  tumours  (105,000). Similar steps should be taken in this direction on the factors in  the environment which may cause tumours. It is worth mentioning the threats posed by radon gas (US research estimates it is responsible for 10% of lung cancers), asbestos, ionizing radiation and especially the risk from chemicals as 60,000 new chemical compounds are produced by industry and  released  the environment  each year (with annual production levels of at least 5,000 tons)  which, in 75% of cases, knowledge of their toxicity is either very limited or non  -existent (according to the US National Academy of science).