1281 water, oxygen, and
Points of View
deficient. The
iously living things competing for existence-parasites (viruses,
THE DIRECTION OF MEDICAL RESEARCH*
THOMAS MCKEOWN
Department of Social Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TJ ANY critic of medicine is likely to find himself linked with others whose views have nothing in common with his own, except perhaps that they may be said to be in some sense "against the current"t. There is no other common ground between Rothschild (resources should be diverted to applied research),Laing (schizophrenia is a disorder of the psychiatrist’s mind rather than of the patient’s), Illich (medicine does more harm than good), and Pappworth (some clinical procedures are unethical), names which have been bracketed with my own as "marauders" whose "flak" is said to be directed at medical research workers.’ The criticisms referred to collectively are all different, and if they are considered worth attention they should be examined separately. I shall here try to clarify my own ideas about the direction of medical research, in the hope that any further controversy related to them will at least be restricted to points of difference. The most fundamental issue confronting medical research is evaluation of two approaches to the control of disease, one through knowledge of disease origins, the other through an understanding of disease mechanisms. And as both are needed, what is wanted is a decision about the distribution of effort between them and, if possible, recognition of the kinds of problems with which each is likely to be rewarding. Although the evidence on these basic questions is far from complete, there are two sources to which we can look for enlightenment: a concept of the determinants of health and disease; and an examination of reasons for past changes in health, particularly the transformation which has occurred since the 18th century. DETERMINANTS OF HEALTH AND DISEASE
1. Until the past 300 years-about one ten-thousandth of his existence-man, like other living things, was exposed to rigorous natural selection, the large majority of individuals conceived having died before or, more often, after birth without reproducing. Man is therefore well adapted to the environment in which he evolved, that of the nomadic period. 2. Only a small part of the burden of disease is determined irreversibly at fertilisation by abnormalities of genes or chromosomes. Most diseases, probably including the common ones, are due to adverse environmental influences on people whose genes make disease more or less likely but not inevitable. 3. The adverse influences are of two kinds, deficiencies and hazards. Of the four essentials for life-food, * Some of the issues referred to in this paper were discussed in the Osler Lecture, McGill University, April 18, 1979.
† The
title of a collection of essays in the history of ideas. Berlin I. London: Hogarth Press, 1979.
food has been serhazards are from other
heat--only common
bacteria, protozoans, helminths, and arthro-
pods) and predators, particularly human predators. 4. Under the conditions of evolution, basic requirements for health were provision of food and protection from hazards presented by other living things. Changes in the environment from the conditions under which evolved create new hazards, from exposure to influences to which the genes are not adapted.
man
HEALTH IN THE PAST
Against the background of these conclusions man’s health history can be divided into three periods. The Nomadic Period
almost the whole of his existence man lived as to his environment but with a short life. The main cause of sickness and early death was food deficiency, operating directly through disease and starvation, or indirectly through competition for resources which resulted in injury and death (from hunting, infanticide, tribal wars, &c.). Early man’s experience of infectious disease is an open question. Living mainly in tropical and subtropical areas he no doubt suffered from vector-borne diseases, but with thinly spread populations infection was relatively less important than in the later periods.
During
a
nomad, well adapted
The Agricultural Period
The
Agricultural Revolution 10 000 years ago an improvement in food supplies which led to a decline of mortality and increase of numbers. The expanded populations created the conditions required by many microorganisms and infection became the predominant cause of death. However, population growth was unrestrained, and numbers increased to the point where food supplies again became marginal. Hence the causes of sickness and death in the agricultural period resembled those in the nomadic period in that food deficiency was still critical, but differed in that microorganisms rather than man himself presented the main threat from other living things. This change resulted from the expansion and aggregation of populations-a departure
brought
from the conditions under which aggravated by defective hygiene.
man
evolved-and
was
The Transitional Period
developed countries the past three centuries have improvement in health and a change in the nature of the predominant health problems, from infecIn
seen a vast
tions to non-communicable diseases. The chief reason for the decline of infectious diseases was elimination of the conditions that had made them predominant--deficient food, uncontrolled population growth, and poor hygiene. Immunisation and treatment contributed little to the reduction of infectious deaths before 1935, and over the whole period since cause of death was first registered (1838 in England and Wales) they have been less important than the other influences.
1282 This interpretation has provoked the reply that it underestimates the contribution of clinical medicine to the decline of mortality and treatment of morbidity,2-4 and also, remarkably, that it overlooks the significance of the pastoral or samaritan role of the doctor.s (On the contrary, the value of the pastoral role increases with inability to reverse the course of established disease.) I have attempted recently to make a fuller and, I hope, more balanced appraisal of medical achievement, and the conclusions concerning the infections can be indicated by reference to tuberculosis, the disease in which treatment has made the greatest contribution. "Effective clinical intervention came late in the history of tuberculosis and over the whole period the effect was small in relation to that of other influences. But although the problems presented by tuberculosis in the mid twentieth century were smaller than in the early nineteenth, it was still a common and often fatal disease with a high level of associated morbidity. In two of its forms, tuberculous meningitis and miliary tuberculosis, it was invariably fatal. The challenge to medical science was to increase the rate of decline of mortality and, if possible, finally remove the threat of a disease which had been a leading cause of death for at least two centuries. In this it was outstandingly successful, and it would be as unreasonable to underestimate this achievement as to overlook the fact that it was preceded, and probably necessarily proceeded, by modification of the conditions-low resistance from malnutrition and heavy exposure from overcrowding-that had made tuberculosis so formidable".6 The conclusion which seems inescapable is that with
due regard for the invaluable contribution which immunisation and therapy have made in some diseases, we owe the decline of the infections essentially to control of the conditions which led to them, rather than to knowledge of their mechanisms applied through clinical practice. HEALTH IN THE FUTURE
One of the most important issues concerning the future of man’s health is the extent to which control of non-communicable diseases will also be achieved by modification of their origins. In principle this seems possible,for few of them, and probably no "common diseases", are determined irreversibly at fertilisation. But it is already evident that many of the adverse environmental influences are much less tractable than those that led to the predominance of the infections. However, -when setting goals for medical research we cannot focus attention exclusively on non-communicable diseases. In the world today there is a mix of health problems, both within countries and between countries, as diseases that were predominant in the past exist sideby-side with those that will be more significant in the future. I suggest that the residual problems can be divided broadly into four classes, distinguished according to the feasibility and means of their control: relatively intractable; preventable, associated with poverty; preventable, associated with affluence; potentially preventable, not clearly related to poverty or affluence.
Relatively Intractable The diseases in this class comprise those determined at fertilisation-mainly the single-gene disorders and chromosomal aberrations-and also congenital abnormalities (such as most types of mental subnormality and
determined, in which the environmental influences are prenatal. Inclusion of the latter is admittedly arguable, but it seems unlikely that the in-
malformations)
not so
fluences which lead to most of them will be identified and controlled within the forseeable future. In designating these diseases as relatively intractable, I am not suggesting that they offer no scope for prevention and treatment. The prevention of rhesus haemolytic disease is a remarkable example of an advance made possible by a combination of genetic and clinical knowledge. The identification and abortion of a fetus affected by Down disease is another solution of an apparently intractable problem. Equally impressive in a quite different way is the immense technical accomplishment which restores a child with a patent ductus arteriosus or atrial septal defect to a life of normal duration and
quality. I conclude that with the possible exception of some determined in utero, the diseases in this class are unlikely to be controlled by modification of their origins, and must be tackled through knowledge of their mechanisms. This indeed is the field which uniquely requires the traditional laboratory and clinical approach, and the more successful postnatal measures are in dealing with preventable conditions, the more important the residual congenital problems will be seen to be.
Preventable, Associated with Poverty In the.world as a whole the predominant health problems are still those associated with poverty. The grounds for this conclusion are the large differences in health indices (such as death-rates and expectations of life) between continents, between countries, and between social classes within the same country. The social-class differences are greatest for infective and parasitic diseases of the respiratory system, but are also quite marked for malignant neoplasms, diseases of the nervous system and sense organs, diseases of the digestive system, diseases of the genitourinary system, and accidents, poisonings, and violence. Of course advance will be accelerated by medical knowledge. Nevertheless for the solution of the problems of poverty in the future, as in the past, we must rely mainly on elimination of the ill effects of poverty, particularly malnutrition, defective hygiene, and excessive numbers. At this point it should also be said that the future threat from infectious diseases is by no means restricted to developing countries. Their rapid decline has led to some complacency, and it is widely assumed that serious infections will not reappear, or that if they do they can be controlled. On an evolutionary time scale three centuries is a trivial period, and it would be foolish indeed to believe that man’s relation to microorganisms has been finally stabilised. Attention has recently been drawn to the risk of further pandemics from airborne infections,’-for example, from new strains of influenza-A virus arising as zoonoses.8 It is evident that the infections still require a prominent position in medical
research. Preventable, Associated with Affluence In
lems
developed countries the predominant health probare no longer attributable to food deficiency or
1283
hazards from other living things; they are due to profound changes from the conditions of life under which man evolved., Many of these changes are in respect of behaviour facilitated by afHuence-smoking, consumption of excessive or refined food, lack of exercise, &c. Although the effect of such influences cannot be measured exactly, during the past century one of them (smoking) appears to have halved theb increase in expectation of life of adult males who smoke.6 Will ill health of this type be controlled mainly by modification of behaviour or by clinical measures based on knowledge of disease mechanisms? Of course both possibilities should be investigated, but it is surely remarkable if we look to medical intervention for solution of a problem such as cancer of the lung, a disease which can be largely prevented by creating an environment in which young people are not encouraged-by
viewpoint, by advertisement, by example-to begin to smoke. The pessimistic view that habits cannot be changed comes from adopting too short a time scale. They do change, and quite rapidly; after all it is not long since our ancestors were practising infanticide, spitting on floors, tipping chamber pots into the street, and producing large numbers of children without regard for the consequences. Shakespeare realised that change may not be visible when we
are
close to it:
Ah yet doth beauty like a dial-hand, Steal from his figure, and no pace perceived. Sonnets, 104.
Potentially Preventable, not Clearly Related to Poverty oraffluence There remains a heterogeneous class of diseases which do not fit into the preceding categories. There is no reason to believe they are established at fertilisation; but they have not declined with advances in standards of living and they do not appear to be determined by behaviour. Nevertheless many diseases in this class are obviously related to changes from the conditions under which man evolved. Some of them, such as industrial diseases and accidents, could be dealt with largely by control of their origins; with others the change required (for example, to low-density populations in the case of the common cold) would be unacceptable, and they must be approached through knowledge of their mechanisms. In still others (multiple sclerosis, rheumatoid arthritis, most cases of renal disease, a minority of cancers) not enough is known to indicate which is the more promising approach and the prudent course is to investigate both origins and mechanisms. CONCLUSIONS
Diseases
be divided broadly into two categories, the according possibility of their prevention by manipulation of environmental (i.e., non-genetic) influences. Those in the first category cannot be controlled in this way, because they are due to abnormalities of genes or chromosomes, or if they are not, because the influences which lead to them are prenatal and likely to be inaccessible. Most of these conditions are present at birth, although some are not recognised until later and others can
to
’
manifested until late life. Diseases of this type be thought of as the price to be paid for the advantages which accrue from the intricate exchange of genes at fertilisation, or from the protected environment provided by a period of intrauterine life. The solution of such problems depends on prevention of the conception or birth of those affected, or on treatment, as in the case of cardiac malformations or, in late life, an arthritic hip. By definition all other diseases are due to postnatal influences which in principle might be controlled. During almost the whole of his existence man was well adapted to his environment, and the chief cause of sickness and early death was food deficiency, operating directly through disease and starvation, or indirectly through competition for resources. But since the end of the nomadic period ill health has been due largely to exposure to influences to which the genes are not adapted. The Agricultural Revolution led to the predominance of the infections, and their decline during the past 300 years resulted mainly from removal of the conditions which had made them predominant-insufficient food, defective hygiene, and unrestricted population growth. Most non-communicable diseases which are now prominent in developed countries are due to further changes in conditions of life, particularly in respect of behaviour made possible by affluence. Nothing in this analysis suggests that we can dispense with empirical investigations. There is no intuitive or metaphysical faculty which will lead to the solution of problems such as mental subnormality and rheumatoid arthritis; nor are they likely to be resolved in the forseeable future by fortuitous changes in ways of life, such as those which initiated the decline of the infections. (This is not to say that postnatal diseases are not attributable mainly to changes in ways of life.) What is in question is not the value of medical research9, but the kinds of research which are likely to be rewarding with different classes of disease problems. are not
can
Historians recognise that scientific progress has often been retarded by psychological blocks, by inadequate conceptualisation of problems for whose solution the evidence was already available. (The delay for more than 1000 years in applying knowledge of optics to the study of the eye is a remarkable example.) The dominance of a mechanistic approach to disease since the 17th century has led us to overlook the enormous contribution from modification of disease origins in the past, and to underestimate its potential in the future. If we had been thinking of disease origins as well as mechanisms, would it have taken quite so long to suspect the importance of smoking, refinement of food, and lack of exercise in repiratory, intestinal, and cardiovascular disease? Even the very preliminary analysis attempted here is sufficient to indicate some problems with which only a mechanistic approach is likely to be successful, and others in which a search for origins will be more reward-
ing. While emphasising the importance of disease origins, I hope I have left no doubt about my recognition of the need for continued investigation of disease mechanisms. At the risk that it will be considered an act of supererogation, I will summarise the grounds for this view. 1. It is unthinkable that man, who is keenly interested in the nature of the world in which he lives and the
1284
of the space beyond it, should not have an greater interest in his own body and the diseases which affect it. 2. Whatever doubts one may have about the possibility of eliminating many diseases through knowledge of their mechanisms in the foreseeable future, in the light of past experience of the unpredictability of scientific progress it would be foolish to set limits on what may one day be possible. 3. There is one class of medical problems, and that arguably the most difficult (referred to above as relatively intractable), in which only a mechanistic approach is likely to succeed. 4. The control of diseases which are in principle preventable may be delayed, in some cases indefinitely, for a number of reasons: because the influences are largely unknown (as is the case at this time in breast cancer and multiple sclerosis); because they are multiple, and hence difficult to dissociate (as in coronary-artery disease) ; because they are costly to eliminate (as in many accidents and occupational hazards); because their control involves changes in behaviour which people are reluctant to accept (as in cancer of the lung and contents
equal
or
Better Perinatal Health MATERNAL DISEASE, INFECTION, TRAUMA, RHESUS ISOIMMUNISATION
MARGARET M. KERR JOHN MACVICAR Department of Obstetrics and Gynœcology, University of Leicester; and Department of Pœdiatrics, Queen Mother’s Hospital, Glasgow
hypertension has a substantial impact on perinatal mortality and morbidity. In Britain the effects of other maternal diseases, of rhesus isoimmunisation, of fetal birth trauma, and even of perinatal infection are slight by comparison (table I). These hazards are not the same in all parts of the world. For instance, rhesus MATERNAL
isoimmunisation varies
even
from
one
part of a country
another, depending on the number of women who are rhesus negative. It is commonest in those of Caucasian
to
descent. The incidence of fetal death and morbidity due to birth trauma will be determined by the availability and skills of attendant services, and deaths due to infection vary according to the prevalence of a particular infection-in Ethiopia, for example, 8% of perinatal deaths are due to congenital syphilis. Amniotic-fluid infections seem to be common in certain parts of the United States and Africa: in the U.S.A. they account for 17% of all perinatal deaths, in Africa up to 31%.2 MATERNAL DISEASE
Hypertensive disorders are the most frequently encountered complication of pregnancy. The effect on fetal growth and maturity is related to the degree of hypertension.3 In mild hypertension intensive antenatal care produces good results, whereas the benefit of hypotensive agents in more severe cases is not fully evaluated.4,5 The usual view is that, in a patient who was normotensive at the beginning of pregnancy, a blood-
cirrhosis of the liver); because they are technically complex (as in malaria and schistosomiasis). So long as the deleterious influences are not eliminated there will be a need for continued treatment of diseases and disabilities which are in principle avoidable. Indeed, some of the greatest successes of clinical medicine, based on a knowledge of disease mechanisms, are from treatment of conditions such as accidents which, ideally, should not occur. REFERENCES
1. Paton W. Ends, means and achievements in medical research. Lancet 1979; ii: 512-18. 2. Lever AF. Medicine under challenge. Lancet 1977; i: 352-55. 3. Beeson PB. McKeown’s The Role of Medicine: a clinician’s reaction. Milbank Mem Fnd QR 1977; 55: 365-71. 4. Dollery C. The end of an age of optimism. The Rock Carling Fellowship, London: Nuffield Provincial Hospitals Trust, 1978; 14-20. 5. McDermott W. Medicine: the public good and one’s own. Perspec Biol Med
1978; 21: 167-87. 6. McKeown T. The role of medicine: dream, mirage or nemesis? 2nd ed. Oxford: Blackwells, 1979. 7. Fiennes R. Zoonoses and the origins and ecology of human diseases. London: Academic Press, 1978. 8. Beveridge WIB. The origin of influenza pandemics, WHO Chron 1975; 29: 471-73. 9. Editorial. Academic medicine—threatened institution. Lancet 1979: ii: 677-78.
140/90 mm Hg or more indicates a hypertensive disorder requiring admission to hospital. This figure may be misleading in some instances. If a patient’s initial blood-pressure was unusually low, a rise of 30 mm Hg in the systolic or 15 mm Hg in the diastolic may be more informative. There would be much sense in applying this criterion universally since there are racial differences in the level of "normal" blood-pressure as well as in the incidence of hypertensive disorders during pregnancy.6’ Patients with hypertensive disorders which predate a pregnancy should be thoroughly assessed as early in pregnancy as possible. The clinician will have to decide whether to prescribe hypotensive agents throughout the pregnancy. He will need to keep a careful watch for superimposed pre-eclampsia, which will increase perinatal loss and usually necessitates induction of labour before term. Hypotensive therapy late in pregnancy should be regarded merely as a means of "buying time" to increase fetal maturity at delivery. Delivery of the fetus remains the only real cure for hypertensive disorders arising in pregnancy.
pressure of
Diabetes mellitus.-The high perinatal mortality previously in diabetic pregnancies has fallen from 40% to as low as 5% in some centres.8,9 Close cooperation between obstetrician, diabetic physician, and poediatrician, with scrupulous attention to antenatal care, insulin requirements, and timing and mode of delivery are vital. If the incidence of unexplained stillbirths is to be reduced we should also be seeking to identify patients with unrecognised abnormal glucose tolerance. Even in the best-run units the paediatrician may still be presented with a fragile baby, deceptively large for dates. The diabetic’s baby should always be regarded as preterm. Irrespective of birth condition these infants must be admitted to the special-care unit and observed for respiratory difficulty, hypoglycxmia, and
seen
hyperbilirubinoemia. Thyroid disease.-Pregnancy is seldom encountered in unthyroid disease. In a woman well controlled with antithyroid drugs the placental transfer of these agents will present little risk to the fetus. Neonatal thyrotoxicosis should
controlled
sought even when the mother has been on treatment. Fetal hypothyroidism is not always related to maternal disease (it be
Points of View
deficient. The
iously living things competing for existence-parasites (viruses,
THE DIRECTION OF MEDICAL RESEARCH*
THOMAS MCKEOWN
Department of Social Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TJ ANY critic of medicine is likely to find himself linked with others whose views have nothing in common with his own, except perhaps that they may be said to be in some sense "against the current"t. There is no other common ground between Rothschild (resources should be diverted to applied research),Laing (schizophrenia is a disorder of the psychiatrist’s mind rather than of the patient’s), Illich (medicine does more harm than good), and Pappworth (some clinical procedures are unethical), names which have been bracketed with my own as "marauders" whose "flak" is said to be directed at medical research workers.’ The criticisms referred to collectively are all different, and if they are considered worth attention they should be examined separately. I shall here try to clarify my own ideas about the direction of medical research, in the hope that any further controversy related to them will at least be restricted to points of difference. The most fundamental issue confronting medical research is evaluation of two approaches to the control of disease, one through knowledge of disease origins, the other through an understanding of disease mechanisms. And as both are needed, what is wanted is a decision about the distribution of effort between them and, if possible, recognition of the kinds of problems with which each is likely to be rewarding. Although the evidence on these basic questions is far from complete, there are two sources to which we can look for enlightenment: a concept of the determinants of health and disease; and an examination of reasons for past changes in health, particularly the transformation which has occurred since the 18th century. DETERMINANTS OF HEALTH AND DISEASE
1. Until the past 300 years-about one ten-thousandth of his existence-man, like other living things, was exposed to rigorous natural selection, the large majority of individuals conceived having died before or, more often, after birth without reproducing. Man is therefore well adapted to the environment in which he evolved, that of the nomadic period. 2. Only a small part of the burden of disease is determined irreversibly at fertilisation by abnormalities of genes or chromosomes. Most diseases, probably including the common ones, are due to adverse environmental influences on people whose genes make disease more or less likely but not inevitable. 3. The adverse influences are of two kinds, deficiencies and hazards. Of the four essentials for life-food, * Some of the issues referred to in this paper were discussed in the Osler Lecture, McGill University, April 18, 1979.
† The
title of a collection of essays in the history of ideas. Berlin I. London: Hogarth Press, 1979.
food has been serhazards are from other
heat--only common
bacteria, protozoans, helminths, and arthro-
pods) and predators, particularly human predators. 4. Under the conditions of evolution, basic requirements for health were provision of food and protection from hazards presented by other living things. Changes in the environment from the conditions under which evolved create new hazards, from exposure to influences to which the genes are not adapted.
man
HEALTH IN THE PAST
Against the background of these conclusions man’s health history can be divided into three periods. The Nomadic Period
almost the whole of his existence man lived as to his environment but with a short life. The main cause of sickness and early death was food deficiency, operating directly through disease and starvation, or indirectly through competition for resources which resulted in injury and death (from hunting, infanticide, tribal wars, &c.). Early man’s experience of infectious disease is an open question. Living mainly in tropical and subtropical areas he no doubt suffered from vector-borne diseases, but with thinly spread populations infection was relatively less important than in the later periods.
During
a
nomad, well adapted
The Agricultural Period
The
Agricultural Revolution 10 000 years ago an improvement in food supplies which led to a decline of mortality and increase of numbers. The expanded populations created the conditions required by many microorganisms and infection became the predominant cause of death. However, population growth was unrestrained, and numbers increased to the point where food supplies again became marginal. Hence the causes of sickness and death in the agricultural period resembled those in the nomadic period in that food deficiency was still critical, but differed in that microorganisms rather than man himself presented the main threat from other living things. This change resulted from the expansion and aggregation of populations-a departure
brought
from the conditions under which aggravated by defective hygiene.
man
evolved-and
was
The Transitional Period
developed countries the past three centuries have improvement in health and a change in the nature of the predominant health problems, from infecIn
seen a vast
tions to non-communicable diseases. The chief reason for the decline of infectious diseases was elimination of the conditions that had made them predominant--deficient food, uncontrolled population growth, and poor hygiene. Immunisation and treatment contributed little to the reduction of infectious deaths before 1935, and over the whole period since cause of death was first registered (1838 in England and Wales) they have been less important than the other influences.
1282 This interpretation has provoked the reply that it underestimates the contribution of clinical medicine to the decline of mortality and treatment of morbidity,2-4 and also, remarkably, that it overlooks the significance of the pastoral or samaritan role of the doctor.s (On the contrary, the value of the pastoral role increases with inability to reverse the course of established disease.) I have attempted recently to make a fuller and, I hope, more balanced appraisal of medical achievement, and the conclusions concerning the infections can be indicated by reference to tuberculosis, the disease in which treatment has made the greatest contribution. "Effective clinical intervention came late in the history of tuberculosis and over the whole period the effect was small in relation to that of other influences. But although the problems presented by tuberculosis in the mid twentieth century were smaller than in the early nineteenth, it was still a common and often fatal disease with a high level of associated morbidity. In two of its forms, tuberculous meningitis and miliary tuberculosis, it was invariably fatal. The challenge to medical science was to increase the rate of decline of mortality and, if possible, finally remove the threat of a disease which had been a leading cause of death for at least two centuries. In this it was outstandingly successful, and it would be as unreasonable to underestimate this achievement as to overlook the fact that it was preceded, and probably necessarily proceeded, by modification of the conditions-low resistance from malnutrition and heavy exposure from overcrowding-that had made tuberculosis so formidable".6 The conclusion which seems inescapable is that with
due regard for the invaluable contribution which immunisation and therapy have made in some diseases, we owe the decline of the infections essentially to control of the conditions which led to them, rather than to knowledge of their mechanisms applied through clinical practice. HEALTH IN THE FUTURE
One of the most important issues concerning the future of man’s health is the extent to which control of non-communicable diseases will also be achieved by modification of their origins. In principle this seems possible,for few of them, and probably no "common diseases", are determined irreversibly at fertilisation. But it is already evident that many of the adverse environmental influences are much less tractable than those that led to the predominance of the infections. However, -when setting goals for medical research we cannot focus attention exclusively on non-communicable diseases. In the world today there is a mix of health problems, both within countries and between countries, as diseases that were predominant in the past exist sideby-side with those that will be more significant in the future. I suggest that the residual problems can be divided broadly into four classes, distinguished according to the feasibility and means of their control: relatively intractable; preventable, associated with poverty; preventable, associated with affluence; potentially preventable, not clearly related to poverty or affluence.
Relatively Intractable The diseases in this class comprise those determined at fertilisation-mainly the single-gene disorders and chromosomal aberrations-and also congenital abnormalities (such as most types of mental subnormality and
determined, in which the environmental influences are prenatal. Inclusion of the latter is admittedly arguable, but it seems unlikely that the in-
malformations)
not so
fluences which lead to most of them will be identified and controlled within the forseeable future. In designating these diseases as relatively intractable, I am not suggesting that they offer no scope for prevention and treatment. The prevention of rhesus haemolytic disease is a remarkable example of an advance made possible by a combination of genetic and clinical knowledge. The identification and abortion of a fetus affected by Down disease is another solution of an apparently intractable problem. Equally impressive in a quite different way is the immense technical accomplishment which restores a child with a patent ductus arteriosus or atrial septal defect to a life of normal duration and
quality. I conclude that with the possible exception of some determined in utero, the diseases in this class are unlikely to be controlled by modification of their origins, and must be tackled through knowledge of their mechanisms. This indeed is the field which uniquely requires the traditional laboratory and clinical approach, and the more successful postnatal measures are in dealing with preventable conditions, the more important the residual congenital problems will be seen to be.
Preventable, Associated with Poverty In the.world as a whole the predominant health problems are still those associated with poverty. The grounds for this conclusion are the large differences in health indices (such as death-rates and expectations of life) between continents, between countries, and between social classes within the same country. The social-class differences are greatest for infective and parasitic diseases of the respiratory system, but are also quite marked for malignant neoplasms, diseases of the nervous system and sense organs, diseases of the digestive system, diseases of the genitourinary system, and accidents, poisonings, and violence. Of course advance will be accelerated by medical knowledge. Nevertheless for the solution of the problems of poverty in the future, as in the past, we must rely mainly on elimination of the ill effects of poverty, particularly malnutrition, defective hygiene, and excessive numbers. At this point it should also be said that the future threat from infectious diseases is by no means restricted to developing countries. Their rapid decline has led to some complacency, and it is widely assumed that serious infections will not reappear, or that if they do they can be controlled. On an evolutionary time scale three centuries is a trivial period, and it would be foolish indeed to believe that man’s relation to microorganisms has been finally stabilised. Attention has recently been drawn to the risk of further pandemics from airborne infections,’-for example, from new strains of influenza-A virus arising as zoonoses.8 It is evident that the infections still require a prominent position in medical
research. Preventable, Associated with Affluence In
lems
developed countries the predominant health probare no longer attributable to food deficiency or
1283
hazards from other living things; they are due to profound changes from the conditions of life under which man evolved., Many of these changes are in respect of behaviour facilitated by afHuence-smoking, consumption of excessive or refined food, lack of exercise, &c. Although the effect of such influences cannot be measured exactly, during the past century one of them (smoking) appears to have halved theb increase in expectation of life of adult males who smoke.6 Will ill health of this type be controlled mainly by modification of behaviour or by clinical measures based on knowledge of disease mechanisms? Of course both possibilities should be investigated, but it is surely remarkable if we look to medical intervention for solution of a problem such as cancer of the lung, a disease which can be largely prevented by creating an environment in which young people are not encouraged-by
viewpoint, by advertisement, by example-to begin to smoke. The pessimistic view that habits cannot be changed comes from adopting too short a time scale. They do change, and quite rapidly; after all it is not long since our ancestors were practising infanticide, spitting on floors, tipping chamber pots into the street, and producing large numbers of children without regard for the consequences. Shakespeare realised that change may not be visible when we
are
close to it:
Ah yet doth beauty like a dial-hand, Steal from his figure, and no pace perceived. Sonnets, 104.
Potentially Preventable, not Clearly Related to Poverty oraffluence There remains a heterogeneous class of diseases which do not fit into the preceding categories. There is no reason to believe they are established at fertilisation; but they have not declined with advances in standards of living and they do not appear to be determined by behaviour. Nevertheless many diseases in this class are obviously related to changes from the conditions under which man evolved. Some of them, such as industrial diseases and accidents, could be dealt with largely by control of their origins; with others the change required (for example, to low-density populations in the case of the common cold) would be unacceptable, and they must be approached through knowledge of their mechanisms. In still others (multiple sclerosis, rheumatoid arthritis, most cases of renal disease, a minority of cancers) not enough is known to indicate which is the more promising approach and the prudent course is to investigate both origins and mechanisms. CONCLUSIONS
Diseases
be divided broadly into two categories, the according possibility of their prevention by manipulation of environmental (i.e., non-genetic) influences. Those in the first category cannot be controlled in this way, because they are due to abnormalities of genes or chromosomes, or if they are not, because the influences which lead to them are prenatal and likely to be inaccessible. Most of these conditions are present at birth, although some are not recognised until later and others can
to
’
manifested until late life. Diseases of this type be thought of as the price to be paid for the advantages which accrue from the intricate exchange of genes at fertilisation, or from the protected environment provided by a period of intrauterine life. The solution of such problems depends on prevention of the conception or birth of those affected, or on treatment, as in the case of cardiac malformations or, in late life, an arthritic hip. By definition all other diseases are due to postnatal influences which in principle might be controlled. During almost the whole of his existence man was well adapted to his environment, and the chief cause of sickness and early death was food deficiency, operating directly through disease and starvation, or indirectly through competition for resources. But since the end of the nomadic period ill health has been due largely to exposure to influences to which the genes are not adapted. The Agricultural Revolution led to the predominance of the infections, and their decline during the past 300 years resulted mainly from removal of the conditions which had made them predominant-insufficient food, defective hygiene, and unrestricted population growth. Most non-communicable diseases which are now prominent in developed countries are due to further changes in conditions of life, particularly in respect of behaviour made possible by affluence. Nothing in this analysis suggests that we can dispense with empirical investigations. There is no intuitive or metaphysical faculty which will lead to the solution of problems such as mental subnormality and rheumatoid arthritis; nor are they likely to be resolved in the forseeable future by fortuitous changes in ways of life, such as those which initiated the decline of the infections. (This is not to say that postnatal diseases are not attributable mainly to changes in ways of life.) What is in question is not the value of medical research9, but the kinds of research which are likely to be rewarding with different classes of disease problems. are not
can
Historians recognise that scientific progress has often been retarded by psychological blocks, by inadequate conceptualisation of problems for whose solution the evidence was already available. (The delay for more than 1000 years in applying knowledge of optics to the study of the eye is a remarkable example.) The dominance of a mechanistic approach to disease since the 17th century has led us to overlook the enormous contribution from modification of disease origins in the past, and to underestimate its potential in the future. If we had been thinking of disease origins as well as mechanisms, would it have taken quite so long to suspect the importance of smoking, refinement of food, and lack of exercise in repiratory, intestinal, and cardiovascular disease? Even the very preliminary analysis attempted here is sufficient to indicate some problems with which only a mechanistic approach is likely to be successful, and others in which a search for origins will be more reward-
ing. While emphasising the importance of disease origins, I hope I have left no doubt about my recognition of the need for continued investigation of disease mechanisms. At the risk that it will be considered an act of supererogation, I will summarise the grounds for this view. 1. It is unthinkable that man, who is keenly interested in the nature of the world in which he lives and the
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of the space beyond it, should not have an greater interest in his own body and the diseases which affect it. 2. Whatever doubts one may have about the possibility of eliminating many diseases through knowledge of their mechanisms in the foreseeable future, in the light of past experience of the unpredictability of scientific progress it would be foolish to set limits on what may one day be possible. 3. There is one class of medical problems, and that arguably the most difficult (referred to above as relatively intractable), in which only a mechanistic approach is likely to succeed. 4. The control of diseases which are in principle preventable may be delayed, in some cases indefinitely, for a number of reasons: because the influences are largely unknown (as is the case at this time in breast cancer and multiple sclerosis); because they are multiple, and hence difficult to dissociate (as in coronary-artery disease) ; because they are costly to eliminate (as in many accidents and occupational hazards); because their control involves changes in behaviour which people are reluctant to accept (as in cancer of the lung and contents
equal
or
Better Perinatal Health MATERNAL DISEASE, INFECTION, TRAUMA, RHESUS ISOIMMUNISATION
MARGARET M. KERR JOHN MACVICAR Department of Obstetrics and Gynœcology, University of Leicester; and Department of Pœdiatrics, Queen Mother’s Hospital, Glasgow
hypertension has a substantial impact on perinatal mortality and morbidity. In Britain the effects of other maternal diseases, of rhesus isoimmunisation, of fetal birth trauma, and even of perinatal infection are slight by comparison (table I). These hazards are not the same in all parts of the world. For instance, rhesus MATERNAL
isoimmunisation varies
even
from
one
part of a country
another, depending on the number of women who are rhesus negative. It is commonest in those of Caucasian
to
descent. The incidence of fetal death and morbidity due to birth trauma will be determined by the availability and skills of attendant services, and deaths due to infection vary according to the prevalence of a particular infection-in Ethiopia, for example, 8% of perinatal deaths are due to congenital syphilis. Amniotic-fluid infections seem to be common in certain parts of the United States and Africa: in the U.S.A. they account for 17% of all perinatal deaths, in Africa up to 31%.2 MATERNAL DISEASE
Hypertensive disorders are the most frequently encountered complication of pregnancy. The effect on fetal growth and maturity is related to the degree of hypertension.3 In mild hypertension intensive antenatal care produces good results, whereas the benefit of hypotensive agents in more severe cases is not fully evaluated.4,5 The usual view is that, in a patient who was normotensive at the beginning of pregnancy, a blood-
cirrhosis of the liver); because they are technically complex (as in malaria and schistosomiasis). So long as the deleterious influences are not eliminated there will be a need for continued treatment of diseases and disabilities which are in principle avoidable. Indeed, some of the greatest successes of clinical medicine, based on a knowledge of disease mechanisms, are from treatment of conditions such as accidents which, ideally, should not occur. REFERENCES
1. Paton W. Ends, means and achievements in medical research. Lancet 1979; ii: 512-18. 2. Lever AF. Medicine under challenge. Lancet 1977; i: 352-55. 3. Beeson PB. McKeown’s The Role of Medicine: a clinician’s reaction. Milbank Mem Fnd QR 1977; 55: 365-71. 4. Dollery C. The end of an age of optimism. The Rock Carling Fellowship, London: Nuffield Provincial Hospitals Trust, 1978; 14-20. 5. McDermott W. Medicine: the public good and one’s own. Perspec Biol Med
1978; 21: 167-87. 6. McKeown T. The role of medicine: dream, mirage or nemesis? 2nd ed. Oxford: Blackwells, 1979. 7. Fiennes R. Zoonoses and the origins and ecology of human diseases. London: Academic Press, 1978. 8. Beveridge WIB. The origin of influenza pandemics, WHO Chron 1975; 29: 471-73. 9. Editorial. Academic medicine—threatened institution. Lancet 1979: ii: 677-78.
140/90 mm Hg or more indicates a hypertensive disorder requiring admission to hospital. This figure may be misleading in some instances. If a patient’s initial blood-pressure was unusually low, a rise of 30 mm Hg in the systolic or 15 mm Hg in the diastolic may be more informative. There would be much sense in applying this criterion universally since there are racial differences in the level of "normal" blood-pressure as well as in the incidence of hypertensive disorders during pregnancy.6’ Patients with hypertensive disorders which predate a pregnancy should be thoroughly assessed as early in pregnancy as possible. The clinician will have to decide whether to prescribe hypotensive agents throughout the pregnancy. He will need to keep a careful watch for superimposed pre-eclampsia, which will increase perinatal loss and usually necessitates induction of labour before term. Hypotensive therapy late in pregnancy should be regarded merely as a means of "buying time" to increase fetal maturity at delivery. Delivery of the fetus remains the only real cure for hypertensive disorders arising in pregnancy.
pressure of
Diabetes mellitus.-The high perinatal mortality previously in diabetic pregnancies has fallen from 40% to as low as 5% in some centres.8,9 Close cooperation between obstetrician, diabetic physician, and poediatrician, with scrupulous attention to antenatal care, insulin requirements, and timing and mode of delivery are vital. If the incidence of unexplained stillbirths is to be reduced we should also be seeking to identify patients with unrecognised abnormal glucose tolerance. Even in the best-run units the paediatrician may still be presented with a fragile baby, deceptively large for dates. The diabetic’s baby should always be regarded as preterm. Irrespective of birth condition these infants must be admitted to the special-care unit and observed for respiratory difficulty, hypoglycxmia, and
seen
hyperbilirubinoemia. Thyroid disease.-Pregnancy is seldom encountered in unthyroid disease. In a woman well controlled with antithyroid drugs the placental transfer of these agents will present little risk to the fetus. Neonatal thyrotoxicosis should
controlled
sought even when the mother has been on treatment. Fetal hypothyroidism is not always related to maternal disease (it be
