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Pre-symptomatic diagnostics: benefits, pitfalls and comments

Do we really need to read the crystal ball of genetics to predict our future health?

Sandro Rusconi, scientific director NFP37 program 'somatic gene therapy'


The news of the scientific publishing of the human genome sequence has hit the media in recent weeks. Where is genomics taking us? What has been done and what can/should /cannot/should not be done? These are the questions that many of us have. In this chapter I endeavour to explain some of the implications for predictive medicine, hoping, if not to give final answers, at least to raise more precise questions.

Heredity: the good news and the bad news

Everybody can agree on the fact that eye colour and similar physical traits are inherited. Of course not only positive physical factors but also defects (such as low stature, bone deformations et cetera) are also visibly inheritable. In addition to these physical disadvantages many metabolic disorders such as thalassemias, phenylketonuria, haemophilia are also passed on to future generations. More complex traits such as musical talent or other artistic pre-dispositions are dependent on heredity and on environmental conditions. Finally, the pre-disposition towards complex mental or behavioural disorders such as schizophrenia, manic depression and drug-addiction may also be located in our genetic background. Therefore, there is essentially no human or animal characteristics that does not depend (weakly or strongly and in a simple or more complex manner) on genetic layout.
Classical genetics has identified over 4000 inheritable disorders that are apparently caused by a single gene defect. Of about 1000 thereof the scientific community has clearly identified the corresponding gene defect and 80% of those genes have been molecularly isolated and analysed. One hopes that for the remaining 3000 the almost complete genome sequence may be of assistance in identifying candidate genes. Besides those 'monogenic' disorders there exist hundreds of 'polygenic' disorders. This means that their emergence and strength does not depend on the status of a single gene but on anything between two and twenty genes or more. This makes genetic analysis by conventional means almost impossible and also represents a very arduous challenge for molecular genetics. Finally, some disorders (such as many cardiovascular disorders or many forms of cancer) are not necessarily directly caused by a hereditary genetic alteration, but genetic layout can play a role in accelerating or slowing the emergence of these conditions.


In medicine a diagnosis is the identification of a disorder on the basis of symptoms or of any correlation such as environmental pre-requisites. A precise diagnosis is fundamental to effective medical practice. These deductions can become under some circumstances predictive. Predictive diagnosis can prevent the emergence of problems. If you are red-haired and have some freckles you are predisposed to hypersensitivity to heavy sun-exposure, and with appropriate behaviour you can conduct a healthy life without exposing yourself to the excessive risk of skin cancer. Unfortunately there are relatively few examples that allow predictive diagnosis based on the physical properties of an individual. Due to this lack of predictability, we are exposed to a large number of risks without having the faintest idea. But since many of those pre-dispositions are encoded in our genetic layout modern medical genetics offers a new possibility in this respect. Recent studies have established that between one quarter and one third of the eight percent of women that develop breast cancer are genetically predisposed to a higher risk of this disorder. Similarly, there are genetic pre-dispositions to a higher risk of prostate cancer and colon cancer. Undoubtedly there are hereditary risks for early onset of rheumatoid arthritis, different forms of allergies (including those to drugs), different types of cardiovascular failure, early onset of Alzheimer. In some circumstances many of the genes whose status seem to play a key role in determining the risk level have been isolated and characterised, while for other conditions research is still at the level of hypothesis. So we go from the absolute certitude of predicting that somebody will develop a chorea Huntington (a deadly neuro-degenerative disorder) to the measurable increase of risk of breast cancer, to the still heavily disputed pre-dispositions to behavioural, neurological and psychological conditions such as depression, schizophrenia and epilepsy.
What makes this field interesting and preoccupying at the same time is that molecular genetics allows one in some instances to quantitatively determine the risk long before the appearance of any symptoms i.e. when the individual is not yet a real 'patient'. So we go from the notion of 'patient' to the notion of 'customer'. The doctor has changed into a sort of oracle of 'good news-bad news' of events that are remote in time.

Benefits of Pre-Symptomatic Diagnosis

Talents and pharmacology

If we accept the notion that the analysis of heredity patterns may soon reveal the pre-disposition to particular physical or intellectual talents, then we can imagine that this information, if properly managed, could be of supplemental assistance in making appropriate career choices.. Obviously, the inheritance of talents will never be totally quantifiable, and their unfolding also depends strongly on the environment. However knowedge of one's own 'hardware' in objective terms may help in shaping the proper career orientation. As we shall see below this could be a double-edged sword.
Knowledge of individual intolerance, hyper-reactivity or unresponsiveness to common drugs (from aspirin to anti depressant) may be the major bonus of predictive genetics. In the US more than 10'000 people per year die or become severely ill just by correctly taking prescription drugs. The number of those hyper-reacting people outweighs the toll taken by those who get sick by errors in auto-medication. This is due to the simple statistical notion that for every drug there is an intrinsic fraction of patients where the side effects will be of major concern. A predictive diagnosis would be extremely useful in increasing the safety and efficacy of our pharmacopoeia.

Curable disorders (examples)

The majority of tumours can be effectively treated or even cured if diagnosed precociously. The same applies to several degenerative disorders at the cardiovascular and neurological level. In addition the emergence of some of these disorders can be slowed by appropriate diet or physical exercise. Therefore, a preliminary knowledge of individual pre-dispositions could motivate the patient to act properly in terms of prevention: a) more stringently control diet and exercise; (b) voluntarily attend for more frequent and specific check-ups. It is therefore of major benefit to be able to pre-symptomatically diagnose pre-disposition to, for example, colon cancer, breast cancer, prostate cancer, polycystic kidney, Parkinson's, etc.

Incurable disorders

There are many diseases that are still practically incurable or poorly treatable such as Alzheimer's, Huntington, cystic fibrosis, etc. As the case of many of these disorders the necessary knowledge permits a predictive diagnosis. How good the prediction, depends largely on the type of disorder. It ranges from the certainty of developing Huntington's disorder to variable percents of increased risk of developing different forms of cancers or for the onset of Alzheimer. Is there any benefit from diagnosing these disorders precociously? Paradoxically, the answer is 'yes'. In the case of e.g. Huntington's disorder, a neurodegenerative disorder that effects people starting from the age of 30 to 40 (depending on the genetic configuration) the prediction is essentially 100% reliable on the presence of a defective allele which is dominant for the emergence of the disorder. The chance of inheriting the defective gene is 50% and there is no effective cure. Imagine a family where the father of two sons is effected by this disease. If the analysis would show that neither has inherited the culprit mutation, then this knowledge could provide enormous relief. If one of them or both bear the defect, then the situation becomes more complicated. This is a problem that can only be solved by professional genetic counsellors. I believe that no a priori rules can be drawn up for such a situation and only a case-by-case analysis would indicate or contra-indicate the predictive analysis.

Potential misuses and pitfalls of pre-symptomatic diagnosis

Use/misuse by life / health insurance companies

One potential scenario that is undoubtedly very negative is the concrete possibility that life and health insurance companies might exert pressure to obtain personal data that would assist them in formulating customised insurance premia. Obviously such access is largely dependent on the legal framework and if there is a battle to conduct to prevent unwanted leakage, this must be fought at the legislative level.

Use/misuse by employers

Employers may have a double interest in obtaining genetic data on employees. On one hand they might find it advantageous to screen for presence or lack of specific hereditary qualities and weaknesses with a view to better management of the career profile of employees, be they new or of long standing. On the other hand the knowledge of a predisposed health status could be very advantageous for the planning of long term jobs (see the arguments in favour of selected knowledge transfer to health or life insurance companies).

Use/misuse by the individual

I think nobody can claim to be indifferent when confronted with objective data on one's own disadvantageous genetic pre-dispositions. Therefore awareness of this personal 'bad news' can be take only two forms: positive or negative, there is no 'neutral'. People who have a generally positive attitude are only minimally impressed by an objective knowledge of their own weakness of any kind. In fact their character makes them try to balance these negative aspects with compensating behaviour. On the other hand, people who have the tendency to develop negative attitudes cannot be directly confronted with objective bad news concerning their health: therefore,, if administered, this information must be accompanied by very skilled professional coaching. Some could end up on a fatalistic or even a masochistic path which could strongly exacerbate the risk of disease through psycho-somatic reinforcement. Therefore information transfer to the 'patient' is also a very delicate matter that can only be solved by a consensus among professionals on the best guidelines to adopt in terms of what to say, how to say it and how to follow up the effects of this information transfer.

Use/misuse for military or strategic applications

A detailed knowledge of behavioural pre-dispositions could also be exploited for military purposes, where specific skills are strongly required. Obviously use of this knowledge would largely depend on its reliability and superiority over conventional training/selection procedures which so far have been extremely efficacious in the military sector. However a much more frightening application can be envisaged based on complex genetic traits: so-called ethnically-oriented weapons. In fact, although gene patterns vary among individuals genetic traits exist that are shared by the vast majority of the members of an ethnic group (it is sufficient to consider somatic traits to understand this concept). So, very much as dark complexion and black hair characterises Mediterranean populations, there are widespread enzyme defects in this population as there are in specific Asian or African populations. These ethnic biochemical traits can be more precisely assessed with the emerging structural and functional genomic technologies. This means that widespread characteristics that can in principle be used in medicine to prevent over-reaction to specific drugs can also become targets for ethnically-oriented drugs or viruses. This is a realistic fear since unmistakable signs exist that this type of research is indeed being conducted in several countries. It is exceedingly crude because it can transform racial discrimination into a bio-chemically based genocide.


Are we prepared to digest the philosophical/metaphysical problem of 'predestination'?
The fulfilment of genetically imprinted pre-dispositions ultimately depends on environmental and behavioural conditions, and for each one there is always a specific level of uncertainty about the final outcome. In spite of this, knowledge of these physiological and psychological inclinations gives us the impression that we have a better grasp on our future. Are we really ready for the disclosure of this type of information? Perhaps our society is still too primitive in its structure to successfully manage this kind of knowledge. Perhaps it prefers to rely on astrological practices to predict an individual's future. These practices have the merit of being totally arbitrary and as such being credible only 'a posteriori'. Yes, one needs a high degree of maturity to benefit from objective knowledge about the future while avoiding all the drawbacks of improper speculation. 'Maturity' for a society means appropriate legislation and proper cultural and social consensus. When considering the psychotic reactions of our society to the recent events from mad cows to the GMO food, one has the impression that neither of those is currently in place as regards gene technology. Therefore, a substantial auto-educational process must be accomplished before we are ready to intrepidly read the crystal ball of genetic pre-dispositions without being frightened of it.
Technology is like any of the medicines that we are using every day. We know that a pill can cause side effects. The secret lies in the dosage so as to maximise the beneficial and minimise the unwanted effects. This is the real challenge.

© Copyright Agency BATS: Contact Legal Advisor: Advokatur Prudentia-Law Date of publishing: 2001-10-17

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