The effect of research on curative medicine
Henry H. Dale
c.b.e., f.r.s., director of the National Institute for Medical Research
In his Hunterain Oration of 1927, Lord Moynihan, finding analogy in the ideals of the "war to end war," voiced the hope that, armed with the knowledge given by Lister's work, "surgery may one day help to end surgery." All medical research has the same ultimate ideal—the creation of such a body of exact knowledge that mankind may have the means of preventing its physical afflications. But, again to quote from the same eloquent address, "ideals are not so much for capture as for pursuit." Whatever the future may achieve in prevention, medicine is still largely the healing art, and an important part of its task, during any time that we can forsee, will still be the relief of suffering, by measures which attack the causes or alleviate the symptoms of disease. It may be worth our while, then, to consider some of the effects of the experimental method on therapeutics.
Looking back over the comparatively short period of some thirty years which has elapsed since my own student days, I get the impression of a remarkable change. At the close of the last century, the new knowledge that experiment had given was only beginning to make its way into the therapeutic aspect of medicine. Treatment was still largely dependent on the administration of drugs, the use of which was based on tradition and empirical observation. I would not for that reason include them all in a hasty or general disparagement. Some of the old remedies hold their own to-day, and with increasing value as experiment has shown the manner of their action and provided a rational basis for their use. I can mention some examples later, in another connexion. There were many others, however which were given without any real conviction of their value; the most that a weary scepticism expected of them was that they should not obstruct a tendency to cure by natural process. In striking contrast to this pessimism with regard to much of the older therapeutics was the clear conviction concerning the value of the few remedial agents, which had already then come into general medicine through the work of the research laboratories. The physician who had known myxcedema as an incurable condition, before Horsley's work and Murray's clinical application of it, did not give thyroid gland to such a case with the feeling that it might do good, and that it would in any case be harmless. He gave it with a knowledge of its practically certain efficacy. The physician in the isolation hospital, who had had the heartbreaking experience of trying to cope with diphtheria in the days before antitoxin, did not give antitoxin with the feeling that it was, at least, harmless; he gave it with the knowledge that, if the case had come early under treatment, the antitoxin would almost certainly effect a cure.
These were early examples of therapeutic agents, the remedial action of which had not been discovered by chance observation, like that of the older medicines, but had been arrived at by logical process of experiment. Since those days the number has grown with a steady acceleration. The example of insulin is already almost too familiar; but it has become so because of the dramatic contrast which it has effected in the outlook of the sufferer from diabetes. Going back to my student days again, I retain a vivid memory of the attitude to diabetes of the great physician in whose wards I studied. Faced with a severe case of this condition, he called the students aside, and said to them, "I hate to have a case of diabetes in my wards. We can do nothing for it. The best thing that could have happened to this poor fellow would have been that his disease had not been discovered. His life would have been shorter, but less miserable." Could any physician say that now? Can anyone, doctor or layman, who has had contact with a severe case of diabetes, then and now, seriously doubt the enormous change which insulin has effected ? Nobody with knowledge has ever represented insulin as curing diabetes, or diminishing the frequency of its occurrence.
On the contrary, the spread of knowledge of what insulin can do for the diabetic individual would be expected to make doctors more alert in the diagnosis of diabetes, and sufferers more ready to seek advice. And, since a death certificate often records more than the immediate cause of death, it was to be expected that the Registrar-General's returns of the causes of death, compiled from such certificates, would eventually show some increase in the apparent total death-rate from diabetes. The true effect of insulin, on the other hand, in giving many years of practically normal life to the diabetic, is seen in the recorded shift of the apparent "mortality" from diabetes, from the earlier to the later years of life. The patient, kept in practically normal health by its regular use, remains diabetic; all that insulin has given him is a long span of vigorous life, in place of a few years, at most, of weakness, misery and deprivation. Has anyone so convinced himself that insulin is useless and harmful, that he would hinder its use? Let him explain his views and make clear his cruel intention to the many who have been diabetic before insulin, and are now living active and useful lives with its aid. I catch sight, in my audience, of one who is in that position. I should like to know what Dr. Lawrence would say to anybody who would wish to deprive him of insulin, and to put him back to the condition and the prospect from which insulin came just in time to rescue him.
Consider the case of a remedy of an entirely different kind - a chemical substance, produced by artificial synthesis and chosen, after laborious trial of many, as the one supremely efficient in attacking the infective microbe of syphilis. Its discovery would have been unthinkable without experiments on animals artificially infected. All the modern effort to control this scourge of human folly, and to save the innocent from the danger of its contact, would be crippled if salvarsan and its derivatives were no longer to be had. I could multiply examples of the new and potent remedies which the experimental method has given to medicine, but let these suffice for the moment. I want to emphasise the effect of research, not only in producing new remedies, but in putting old ones to their proper use. Let me give a few examples.
Ipecacuanha is a drug of respectable antiquity. Nobody knows who discovered, in South America where it was native, its curative action in dysentery, or how long its value has been known. What we do know is that it was brought to Europe in the 17th century, as a secret remedy for dysentery, and that the secret was sold, by its enterprising possessor, for a large sum to the King of France. Ipecacuanha is not only, in one form or another, still in use for its original purpose; experimental research has enormously enhanced its value in two different ways. Unaided clinical observation had applied the name "dysentery" to conditions entirely different in their causation. When research had shown that there is a dysentery, which is almost confined to the tropics, caused by infection of the bowel with an amoeba, and a more widely spread group of dysenteries due to bacteria, it was found that ipecacuanha exerted its effect only on the amoebic dysentery, and was useless in the bacillary diseases, for which other suitable remedies were found. Again, a difficulty in administering ipecacuanha effectively had been the nausea and vomiting which it caused. When chemists had isolated the chief alkaloids of the drug, and these were found to be strongly emetic, it seemed a bright idea to prepare an "emetine-free ipecacuanha" for treating dysentery; and this was actually made and used for that purpose for a good many years. Then experimental research, in which the Treasurer of this Society, Sir Leonard Rogers, was prominently concerned, showed that the curative action of ipecacuanha in dysentery was entirely due to the alkaloids which had been removed. And now the full value of the old, traditional use of ipecacuanha in dysentery has been obtained, amoebic dysentery being treated by the alkaloid emetine, given by such methods, or in such forms, as to minimise its nauseating action.
The case of ipecacuanha illustrates in another way the course that investigation may take. To anyone who knows the facts, it is unthinkable that, without experiments on animals, we should have obtained the clear knowledge now available concerning the parasites causing the different dysenteries. At the appropriate stage this method of experiment was essential. In due course, however, it led to a process of cultivating the dysentery amoeba artificially outside the human or animal body. My colleagues, Dobell and Laidlaw, at the National Institute for Medical Research, have so perfected the process that this artificial growth of the amoeba on a dead medium can be continued indefinitely; and the efficacy of the ipecacuanha alkaloids, in stopping the growth of this cause of tropical dysentery, can now be demonstrated very beautifully in a test-tube. Think what that may mean for further progress. New substances, likely to have a curative action on amoebic dysentery, can now be given a first trial without the use of experimental animals, other then the amoeba themselves. Compare the position which has thus developed, under the intelligent use of experiment, with that in which a really valuable drug, ipecacuanha, was for centuries used indiscriminately to treat a group of human diseases, on only one of which it had any effect, and was, in the end, deprived of its only valuable constituents to avoid a minor inconvenience of their action. Can anyone seriously face this possibility, that some valuable new remedy might similarly find its true use, only after centuries of confusion and misapplication, at an uncounted cost of human pain and sickness unrelieved or aggravated?
This is not the only instance I could quote of a traditional drug of real potency and value, the use of which, in course of time, degenerated into the administration of an extract containing none of the true activity, until experimental research had identified the active constituents. I want to call your attention more especially, however, to a particular need for the method of direct experiment, in giving precision and safety to the use of many really active remedies. In the case of the potent vegetable drugs it is often possible, when once the active constituent has been identified, to determine the activity of a sample by an ordinary chemical analysis. When the methods were first found, however, of producing nature's own remedies against certain infections, by rendering a horse artificially immune against the corresponding bacterial poison, and separating from its blood the serum containing the natural antidote, a new problem of standardisation presented itself. Such an antidotal substance could not be chemically distinguished from the constituents of an ordinary serum; it could only be recognised and estimated by its power of combining with the bacterial poison so as to render it harmless; and this neutralisation, again, could only be demonstrated by injecting the mixture into a susceptible small animal. On these lines methods have developed by which the activity of some of these important new remedies can be measured, as accurately as that of some of the older drugs can be measured by chemical analysis. The first of these natural antidotes, to which such biological methods of measurement and standardisation were successfully applied, were the antitoxins against diphtheria and tetanus. Doses of these remedies came to be indicated, not in minims, ounces, or pints, but in units of accurately measured activity.
A new system of dosage, necessitating animal experiment for its indication, thus came into being with the advent of a new class of remedies, and the success of their application has been very largely dependent upon it. As soon as a method has become available for thus measuring the activity, of a serum with accuracy, it has risen to a new order of therapeutic usefulness.
There are still cases, unfortunatelv, in which the antidotal power of a serum, though it can be shown to exist, cannot yet be measured with any approach to accuracy. For want of such methods. of measurement the practical value of the serum is seriously compromised. The physician using it, instead of giving a dose of known activity, adjusted to the severity of the infection which he is treating, must be content with a rough and vague indication of its strength, or even with none at all—merely injecting as much as he conveniently can, in the hope that it will turn the scale in favour of his patient's recovery. Each new clinical use of such an unstandardised remedy is not merely an experiment on man; it is a bad experiment, without adequate data, the result of which will make little contribution to the general body of life-saving knowledge.
Where accurate methods for biologically measuring the activity of one of these natural antidotes already exist, it is accordingly a duty, imperative on those concerned in its production, to see that those methods are regularly applied, with skill and care; where adequate methods have not yet been found, it is equally a duty of those with opportunity to press on with research from which such methods may result.
This direct, biological method of measuring the curative action of a remedy was first used, as I have said, for these natural antidotes, the immune sera. It soon appeared, however, that there were others of the new, natural remedies, which required to have their activity measured by biological methods, because their active constutuents could not be chemically recognised or determined. One of these had a special interest for me, because I had some concern with the investigations which led to its introduction into practical use. There is a part of that mysterious little organ called the pituitary body, lying at the base of the brain, which yields several highly potent substances—substances which, we must suppose, are always being naturally added to the blood in minute quantities, to maintain certain functions of the healthy body. I happened, in the course of experiments, to observe the action of one of these, which very powerfully stimulates the muscular wall of the womb to contraction. It is probably for this effect that the extract of the pituitary body has found its most extensive practical use, either in mercifully accelarating the process of childbirth, or ensuring a firm contraction of the womb when the labour is ended. But a potent natural remedy of this kind must be given in properly adjusted dosage, if its action is to be certain and safe. It is a remedy of emergency, and its use can be negatively dangerous if the preparation is weak or inactive, and positively dangerous if it is unexpectedly strong. Yet, until recently, this potent extract had no recognised standard for its activity. No suitable doses had been determined for its use under varying conditions; nor would any indications of dosage have had any meaning, when the strength of the extract itself could vary over a wide range.
My former colleague, Dr. Burn, and I, some eight years ago, obtained samples of the different makes of the extract then supplied for use by doctors in this country, and measured their activities by a direct, biological test. We found that the strongest of them was no less than eighty times as strong as the weakest; yet all were being used by medical men as though they were equivalent. Nobody will ever know how often the life of mother or child was jeopardised, or even lost, under those conditions, because an almost inactive sample failed to produce the direly needed action, or because another, of enormously greater potency, produced it in dangerous excess. Now all that is changed, because the law has prescribed a standard, and has insisted that this extract shall be physiologically tested and labelled in units of strength. The doctor now knows that a unit means the same amount of activity, whatever preparation he uses; and it has been possible to establish the fact that a dose of two units is safe and adequate for one purpose, and of ten units for another.
I have already mentioned the case of insulin. There could not be a more striking example of this necessity for animal experiment in the direct, biological measurement and standardisation of the activity of a natural, potent remedy. Without animal experiments we should not have known of the existence of insulin. Without animal experiment it could not have been, and cannot yet be, prepared and tested, so that it can be safely and effectively used in the treatment of human diabetes. There is no other remedy with which such absolute precision in dosage is needed. The sufferer from diabetes, for lack of natural insulin in his system, has excess of sugar in his blood. The exactly right dose of insulin, repeated at proper intervals, will bring the sugar to within practically normal limits. Too small a dose will leave him with the symptoms of diabetes; too large a dose will so empty his blood of its natural sugar as to produce alarming and even dangerous symptoms of a different kind. We still know far too little about the chemical nature of insulin to be able to measure it, or even to detect it, by a chemical test. The only way of indicating the strength of an insulin solution is in physiologically determined units. When the strength has thus been correctly determined and indicated, the doctor can adjust the dose to the particular patient's need with a remarkable accuracy, and the patient can go on, day after day, for a long period, taking the same dose, so long as the units in the solutions which he uses have been accurately measured.
What would happen if these animal tests were inadequately done, or omitted altogether? The question has been answered by actual experience. The obligation to standardise accurately by animal tests had not been adequately met in the case of a particular make of foreign insulin, which appeared for a short time in this country. Reports immediately began to come in from doctors whose patients had relapsed into diabetes because one batch was too weak, and from doctors whose patients had suffered from dangerous symptoms because another batch was too strong. Samples of these batches were immediately tested at the National Institute for Medical Research, and it was found that one, indeed, was about forty per cent, weaker, and the other about sixty per cent, stronger than the indications on their respective labels. Fortunately the controlling authority had power to deal -with the situation promptly, and no more of such inadequately standardised insulin has been distributed here. But, if so much trouble could arise from a failure to carry out the available tests efficiently, you may imagine what would be the state of affairs if they were not carried out at all. Without accurate control of its activity by regular tests on animals, insulin could never have come into practical use. If this method of control were now made impossible, the use of insulin would have to be abandoned in practical medicine. I ask again, whether anybody is so confident in his opinions, so firm in his prejudice, that he is willing to put such abandonment as a practical proposal to the sufferers from diabetes, to their relatives and their friends.
I mentioned remedies of another type which research has given to medicine—salvarsan and its derivatives, now the recognised and indispensable specifics for syphilis. These substances are artificially made by the chemist, and if they could be made perfectly pure there would be no need to test them by other than chemical methods. Unfortunately their nature is such, that slight and undetected changes in the process of their preparation may render them dangerously poisonous, on the one hand, or weak in curative action on the other; and such defects, with their varying dangers to the patient and to the community, cannot be detected by any chemical test. Before the war these remedies were made entirely in Germany, where the necessity of controlling their quality by an animal test was recognised from the first. When the outbreak of war cut off the supply, the health of the army and the nation demanded their immediate production in England, where the details of the intricate process of their manufacture had to be worked out anew. To my then newly formed department under the Medical Research Council fell the task of improvising tests, to ensure that the materials so made were safe and effective. For fifteen years from that date some of my colleagues gave a large part of their time and skill to the routine control of the quality of every batch of these potentially dangerous remedies, and to perfecting the methods of testing them on small animals, by which that control could be made effective. In every country in which they are made and sold to-day, such a regular biological control is recognised as absolutely necessary. To put an end to the use of animals for these tests would have the result, that these substances would become too dangerous and variable to be used at all, and that the chief weapon would be struck from the hands of those who are fighting a foul disease.
I have mentioned incidentally the effect of the law, in ensuring the proper application, to some of the remedies of which I have been speaking, of the tests on animals which alone make them safe and effective in use. I should explain briefly this legal mechanism of control. The Therapeutic Substances Act of 1925 set up an Authority, centred for England in the Ministry of Health, to prescribe standards and tests for the strength, quality and purity of those potent remedies which cannot be tested by chemical methods. When standards are prescribed, somebody has to be responsible for preparing them and keeping them; and when tests in relation to those standards are made obligatory, somebody must be responsible for the control examinations, made to ensure that the required tests are being properly carried out. These obligations were accepted, by the Medical Research Council, for the National Institute for Medical Research. A department of that Institute is regularly engaged in investigations connected with the preparation and maintenance of the standards which have already been defined, with the improvement of the methods of applying them, and with the search for new methods of standardising remedies which still need such control.
The claims on the services of this department are not limited to our own country. A valuable activity of the Health Organisation of the League of Nations, has been the promotion of international agreements on standards of this kind ; and the National Institute at Hampstead, in addition to its responsibility for British Standards, has been asked to take charge of the world standards for certain important remedies. We had the task, for example, of making the first international standard for insulin, which we still keep, and distribute all over the world as required. Whereas, at one time, there was danger that different standards might arise in different countries, it is now assured that the unit of insulin means the same amount of activity, wherever in the world the insulin is made and used.
I spoke of research with a view to improving the methods of testing these substances. One kind of improvement, let me say, which we always have in view, is the discovery of a test for any of these substances which will enable us to measure its activity without using living animals at all. We would much rather use chemical indicators in test-tubes, always provided that they will give an equally good guarantee of the safety and effectiveness of a remedy which is to be used in treating the human patient; we would gladly spare the lives of mice, but not at the expense of the lives of men.
You will understand that the provision of official standards, and the control of their proper application, can only be undertaken by some central body, acting on behalf of the Government. The Government provides the standards, and the inspection, to ensure that the food you buy is correctly weighed, that the cloth you buy is correctly measured, and that the units of gas and electricity supplied to your houses are correctly determined. With the Therapeutic Substances Act it assumed an analogous responsibility with regard to the correct measurement of the strength of these potent remedies; and, in taking such powers, the Government accepted the obligation for the necessary expenditure. A few months ago, a member of Parliament sought leave to introduce a Bill to prevent the expenditure of public money on experiments involving the use of living animals. If he had been able to persuade the House to pass his Bill, the Government, having accepted this duty of control over some of the most important medicines now used, would have been deprived of the power of fulfilling its obligation.
Lord Knutsford, in writing to me about this lecture, suggested that the meeting would like to hear an account of the work of the National Institute for Medical Research. I have not time even to attempt a description of all the items of research there in progress, and I have, perhaps, dwelt too long on one minor aspect of the Institute's activities. To make the results of research available for safe and effective practical use is an important task, and one which, in itself, often entails further research of an exacting kind. But the main aim of research, the main objective of a Research Institute, must always be the further advance of knowledge into the unknown. Let me briefly mention one other field of research which is engaging a large share of the interest of workers in the National Institute, and in other centres of medical research, at the present time. Since the work of Pasteur, Koch, and their followers revealed the part played by bacteria in the causation of infectious diseases, a large share of medical investigation has been given to these minute vegetable organisms, which can be seen with the microscope, and can usually be cultivated artificially on suitable materials. More recently, microscopic infecting organisms of animal nature have been identified, especially as causes of certain diseases of the tropics. There has remained, however, a large group, including some of the most deadly infections of men and animals, of which the infecting agents are so minute that they will pass freely through filters fine enough to retain all known bacteria, and that the highest available, or even theoretically possible, powers of the microscope will not enable the human eye to detect them. In such a case it is easy to show that the infective agent exists, and that it multiplies with enormous rapidity in the body of its victim. The further study, however, of these viruses, as they have come to be called, is beset with extraordinary difficulties. The ordinary methods of bacteriology are of little value for the study of organisms which can neither be seen nor be cultivated artificially.
New methods are urgently needed, which will do for the study of the viruses what the methods created by Pasteur and Koch did for that of the visible bacteria ; and the discovery of such methods claims all the patience, the ingenuity, the scientific experience and discipline, the self-sacrificing labour and devotion, of distinguished investigators in all parts of the world. The Roll of Honour of those who have themselves fallen victims to the object of their quest is already a sadly long one. On the success of such work depends the real advance of knowledge, concerning diseases as familiar as measles, mumps, chicken-pox, smallpox, the so-called sleepy sickness, yellow fever, influenza, and even our persistent enemy the common cold ; and, among the diseases of domestic animals, foot-and-mouth disease, cattle-plague, dog-distemper, hydrophobia, and many others. And what I should like you to realise is, that since the viruses causing these diseases can neither be seen with a microscope nor cultivated outside the living body, to prevent their study and investigation by the method of experiment on living animals would be to prevent their study altogether. The presence of such a virus can only be demonstrated, the quantity of it can only be measured, by experimental inoculation into a living animal.
A hope of everybody concerned in such work, and a principal object of his investigation, is the discovery of methods for displaying the virus by some use of the microscope, and for cultivating it on some kind of lifeless medium, so that its nature may be brought under closer study, without recourse at every stage to animal experiment. Hopeful progress in that direction is being made, and at an increasing rate in recent years. At present, however, the abandonment of experiments on animals would mean the practically complete cessation of the study of these deadly diseases, with all that it might give of life-saving knowledge, for man and for the animals themselves. Man's fruitful, conservative, and purposeful experiments would cease, but nature's vast and destructive ones would continue.