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Man as an Experimental Animal

THE Twenty-Third Stephen Paget Memorial Lecture was delivered at the Physiology Lecture Theatre,UniversityCollege,London. W.C.1, on Tuesday, 4th November, 1954, by Sir Geoffrey Jefferson, C.B.E., F.R.S. It was entitled “Man as an Experimental Animal." The Rt. Hon. the Lord Hailey, G.C.S.I., G.C.M.G., G.C.I.E., President, was in the chair.

Lord Hailey remarked that he had heard many interesting lectures before the Society, and he was not going to stand between the audience and the lecturer by giving a long introduction to the speaker or his subject. He always approached a member of the Royal Society with reverence, and he was sure that they could not find anyone better qualified to speak to them. He was very interested in the title which Sir Geoffrey had chosen.   He did not expect that Sir Geoffrey's approach would be as crude as the person who commented that there had been a good deal of experiment by human beings on animals, and it was just about time that animals turned round and did some experiment­ing on human beings ! Lord Hailey added that he had been constantly "experimenting" on his “patients” with good results. Many engaged in administration were experimenting all the time—those drawing up different sets of consti­tutions, for example, for countries inAfricaand the like—with some queer results! But the audience wanted to hear the results not of social experiment but of scientific experiment on man, because man was at once the most amenable and the most irrational animal one could possibly choose for experiment.

Sir   Geoffrey  Jefferson   then   delivered  his Lecture.

 

Man as an Experimental Animal

By SIR GEOFFREY JEFFERSON, C.B.E., F.R.C.S. (Eng.), F.R.C.P. (Lond.), F.R.S.

 

We live in an age when the climate of opinion, when the air that so many breathe, is so heavy with news of experiment that the need to acclaim its virtues, much less to defend it, would be to speak in an outmoded idiom. The publicity given to scientific matters by our newspapers, by the radio and television, is so great that it is difficult to realize how hard our predecessors had to battle to make biological experiment acceptable. We commemorate in this yearly lecture that gentle soul, Stephen Paget, son of a great man and the brother of bishops. He would have been more successful in the Church, I fancy, than he was in Medicine, but I do not say that he would have been happier. He was a timid soul in a surgical sense, it seemed to me as the young man who came to have more than a slight acquaintance with him, but a most compassionate one. It was his love for his fellow-men and his grief at their sufferings that excited in him so ardent a resolve to further by all means in his power research into disease. That inevitably meant his support of experiment though not at his own hands. The Greek method of observation and Aristotelian logic might have been expected to have made the stronger appeal to his retiring and always literary mind. Undoubtedly his father's example and his admiration for his parent's character, so apparent in his editing of Sir James's autobio­graphy, inclined him towards action instead of contemplation. I have chosen for this lecture to speak of man as the subject of experiment; that would have appealed to Stephen Paget, and I can imagine his chuckling and saying “Excellent—let's see what sort of a mess you make of that one!" for he was a shrewd man and humorous.

 

It is only too apparent that all accidents and most diseases are in themselves experiments on human beings, but I do not flatter myself that I shall be able to escape from my duties by so convenient a side door. It is the essence of experiment that it is planned, timed and con­trolled, which accident and disease are not. Occasionally, it is true, a sudden flash of insight leads to a great discovery accidentally, as happened to Sir Alexander Fleming when he noticed the circles clear of bacteria around the spots of penicillin mould on his staphylococcus cultures. Or again the fluky discovery of the pancreatic origin of diabetes by Minkowski, when he noticed not only the great thirst of his pancreatectomized dog, but the great attraction to flies of its urine, voided as it played in the courtyard on a hot day. The attraction was the sugar in the urine, as was quickly discovered. You will understand the surprise of von Mering and Minkowski, because they were not looking for the then unknown cause of diabetes but were experimenting on fat absorption. On this subject of chance in medical research Sir Henry Dale has written with insight. In this category of accident must come the delightfully neat experiment carried out by an animal on a man. I refer, of course, to the ferret inoculated with a classical strain of influenza virus, a ferret that sneezed at Stuart-Harris and infected him. Stuart-Harris recorded with Wilson Smith (1936) the sharp attack of influenza that he thereupon suffered. This demonstration that the ferrets could inadvertently themselves experiment led to the immunization of laboratory workers engaged in similar experiments. We may recall here Sherrington's experience when, wondering what monkeys did when unobserved, he looked through the key-hole in his laboratory to meet the beady eye of a monkey equally curious about Sherrington's behaviour.

 

The most important element in experiment is not the virtuosity of its technical performance, great though that sometimes is, but what went before—the imaginative and often intuitive thinking which saw some problems as capable of answer if tackled in such and such a way. It is, that is to say, not, beyond a point, a question of "Know how" but, as Norbert Weiner has said, much more one of "Know what"—knowing what the experiments lead to in the widest sense. This is much more to the point in atomic physics than it is in physiology so perhaps it does not much concern us.

 

In the class of human experiments come those into the causation of yellow fever. It had been shown in 1881 by Carlos Finlay, a man with a Scot's father, a French mother, an American education and a Havanapractice, that the disease could be produced on volunteers by the bites of mosquitoes, or so he thought. He found that a person infected by only one mosquito recov­ered and was immune thereafter. Nine years later the Yellow Fever Commission, Walter Reed, James Carroll, H. Agramonte and Jesse Lazear, were sent to Cubaon duty with the U.S. Army in which yellow fever had broken out, and decided to repeat Finlay's experiments. None of Finlay's 90 human experimental subjects had suffered more than a sharp attack of yellow fever, but a tragedy was to follow amongst the personnel of the Yellow-fever Commission. Dr. Lazear whilst collecting blood from yellow-fever patients was bitten by a mosquito (which was identified afterwards as Aedes aegypti) which he deliberately allowed to feed on his hand so as to make of himself an experiment. Five days later Dr. Lazear had a chill and on the eleventh he was dead. Lazear had already success­fully infected his colleague, James Carroll, and a soldier volunteer by mosquito bites. They both recovered. It is interesting to read the history of this discovery as it appeared to the workers at that time. Even then they felt that the evidence failed to be absolutely conclusive, and it was probably only the great reduction in the incidence of yellow fever after Gorgas had instituted vigorous anti-mosquito methods of paraffining of stagnant water that conviction was reached.

 

Infective Hepatitis

 

Nowhere has man been used so successfully as his own guinea-pig as in research into infective hepatitis and its differentiation from that other viral disease, serum hepatitis. It will be recol­lected that a very bothersome but rarely fatal disease characterized by fever and malaise quickly followed by jaundice was formerly believed to be due to infection of the biliary tract from the gut, hence the name given to it in my young days, "catarrhal jaundice." It is only really important when large numbers of men come together as in armies. Outbreaks occurred in Napoleon's Army inEgyptand it was preva­lent in British troops in World War I, whilst it broke out again in all nationalities in the recent War. In recent years views on the cause of "catarrhal jaundice" have undergone com­plete revision. It is now recognized as a trans­missible viral disease and that knowledge has come as a result of human experiment. Voigt (1942) was the first to report it as a virus infec­tion, having succeeded in giving the disease to healthy volunteers by feeding to them samples of the duodenal contents obtained by tube aspiration from a man ill with the malady. Others quickly confirmed this observation, showing the infectious agent to be present in the blood and in the stools, and succeeded in trans­mitting the disease to many volunteers either by injecting fractions of a patient's serum or giving small quantities of his faeces in food. The infective agent proved to be capable of passing bacteria-tight filters and is well accepted to-day as a virus. The object of these researches on man was first to establish beyond doubt the fact that the disease was infectious and viral in origin, that the jaundice was due to damage to liver cells and had nothing primarily to do with the bile-ducts. After that it was most desirable to discover the common routes of infection, the period of greatest infectivity, the incubation period, which is very long, and the degree of immunity that followed an attack. The upshot was that it was found that infective hepatitis was most easily transmitted only during the most acute stage, that the disease is ordinarily acquired by the mouth and possibly by the respiratory tract. Arising out of this discovery came another, the nature of serum hepatitis. The solution of this problem was so neat and the conclusions so clear that the disease has virtually disappeared. But it could break out again in War when great numbers of men are living in conditions that make infections easily transmissible. It had long been observed that some persons became jaundiced and ill after blood transfusions. Once it became known that there was such a thing as viral hepatic disease and that it was relatively common, it needed but a short step to arrive at the conclusion that serum jaundice was most probably due to contaminated syringes or blood donors. The jaundice seen sometimes in the days of the salvarsan treatment of syphilis had been thought generally to be due to the toxic effects of arsenic on the liver. There were dissenters from this view and it now seems practically certain that the effect was of virus origin. There is, too, the obvious risk that in blood or plasma transfusions the donor might have the virus in his blood. For this reason donors are now not accepted within at least a year after the attack if they have had jaundice. These viruses are not only highly infective in minute quantities but also resistant to sterilization. Heating human serum to 60° C for 10 hours will usually inactivate the virus, but like so many other viruses it is much more difficult to destroy than are bacteria.

 

Man's use of man for the spread of his knowledge of yellow fever and particularly of infective hepatitis stemmed from two different causes. In the first place the experiments of Finlay and the Yellow Fever Commission were directed to discover whether the disease was due to a bacillus (B. icteroides) or to the bites of contaminated mosquitoes and if the latter, which variety? Their researches settled this problem beyond doubt with the result that a determined onslaught on and eventual elimination of the mosquito Aedes aegypti (especially well illus­trated in the work of Gorgas during the building of thePanama Canal) led to the near suppression of the disease. It was found to be transmissible to monkeys and especially to mice. This was not true of infective hepatitis in which man remains by far the most susceptible and, be it said, convenient animal. The experiments were reasonably safe because, annoying and temporarily disabling though the disease is, it is rarely fatal.

 

Hormones

 

Exactly how to classify a fascinating domestic experiment I do not know. Dr. George Oliver, a physician ofHarrogate, was the author of an important book on blood-pressure. He invented a blood-pressure apparatus and for a long time his was the standard work. Motivated purely by curiosity but wondering about possible causes of high blood-pressure, he got suprarenal glands from the butcher's, pounded them up and injected some of the extract into his young son's arm.   He observed the almost   immediate changes in the circulation that ensued. Dale has told the story of Oliver's visit to Schafer's laboratory atUniversityCollegewhere the latter was taking tracings of blood-pressure.  Schafer was sceptical and reluctant to interrupt his own work to test an observation by a provincial doctor, especially perhaps one who was in a practice in a fashionable spa. Here he was wrong. The doctor had been a distinguished student ofUniversityCollege, taking most of the prizes. He was persuaded to try the experi­ment when, to his astonishment and no doubt to Dr.Oliver's delight, the blood-pressure soared. Dr. Oliver had made the first unmis­takable demonstration of the internal secretion of a ductless gland, in short, of a hormone. Although the fame of the discovery and the refinements of the demonstration of its action were made by Schafer on animals, and its sympathomimetic qualities were elaborated by others, the discovery is owned by George Oliver and the obedient volunteer in his household. G. R. Murray has, I suppose, priority in the practical respect in hormonal treatment because it was in 1891, three years earlier, that he had treated his myxocdema patient, the 46-year old “Mrs. S.”, by bi-weekly injections of a glycerine extract of thyroid gland.   Murray, who was one of my teachers and later a personal friend and counsellor, made plain the tentative nature of the treatment and recounted it in these words: "The experimental nature of the treatment was explained, and the patient, realizing the other­wise hopeless outlook, promptly consented to this trial."   Within three months there was a remarkable, an undeniable improvement both in her appearance and in her well-being. She lived to be 74 years old. The active principle of the thyroid was not isolated until Edward Calvin Kendall succeeded in producing "thy­roxine" in pure crystalline form on Christmas Day, 1914.   Adrenaline, on the other hand, had been isolated by J. Takamine and by Thomas Bell Aldrich independently of one another in 1901.   Furthermore, the quick-acting nature of adrenaline made its effects demonstrable to Oliver and Schafer within 30 sees, of injecting it. Proof was immediate.

 

Digestion

 

Accident furnished us with one of the best, certainly the most famous examples of man's experiment on man. The incident was that of the 19-year old French Canadian trapper, Alexis St. Martin, who had been the victim on 6th June, 1822, of a stomach wound caused by the accidental discharge of a shot-gun at a range of 2 or 3 feet. This led to a permanent gastric fistula with prolapse of the mucous membrane of a portion of the fundus.   Dr. William Beaumont, stationed at the lonely out-post of Michilimackinac in northern Michigan, a block-house built by the British in 1780, saw him 20 minutes after the accident and first tried unsuccessfully to induce the fistula below the left breast to close by dres­sings. When this failed he contrived a plug made of lint tied with string. He pushed it through into the stomach and then pulled the string tight and fixed it to the dressings.   It needed renewal but it worked very well. He came slowly to realize the unique opportunity that confronted him and began a series of observations on the temperature (which was always 100° F) and on the movements of the stomach during digestion.   He further demon­strated that there was little secretion of gastric juice except in response to the ingestion of food. It is strange to us to-day to realize that before this opportunity arose to test the gastric juice it had been thought by Spallanzani to be neutral, though others, notably Prout in 1824, identified with certainty free hydrochloric acid in it.Beaumontwas deeply interested in but puzzled by the composition of the gastric juice.   He had pushed in gauze bags on strings and saw meat and fibre digested, but something more happened than he could mimic by immersing food-stuffs in weak acids.   He thereupon enlisted the help of the chemists.   The first that he tried was Prof. Dunglison (1798-1869) of theUniversityofVirginia.   Dunglison was an Englishman. Thomas Jefferson's favourite physician, and an accomplished man who had arrived atCharlottesvillein 1824.   He was the most help­ful ofBeaumont's chemical friends, but when he too found difficulty in accounting fully for the digestive qualities of the gastric secretion by its analysisBeaumontturned elsewhere.   Benjamin Silliman (1779-1864) ofYaleUniversitywas the obvious choice, because he was regarded asAmerica's best chemist.   Silliman had been a lawyer, but when a chair of chemistry and natural history was instituted at Yale and when it was discovered that there were no outstanding chemists in the country, Silliman was offered the post.   The understanding was that he would be given time to learn his subject.   This he did to such effect that he became in a few years an accomplished chemist.   Silliman was most inter­ested inBeaumont's question and full of .hope that he could help.   But in August, 1833, he wrote: "I regret that I cannot contribute something important to our previous knowledge —there is much in physiology that eludes the scrutiny of chemistry"; many, both proximate and ultimate, laws of the Creator, were, he feared, incomprehensible. However, he did not abandon hope, counselling the dispatch of some of the juice to Berzelius inStockholm. Silliman had just received the sixth volume of Berzelius' great work on chemistry. A man like that could surely tellBeaumontwhat he wanted to know. He was sent a pint of gastric juice, painstakingly collected. There were agonizing delays, agoniz­ing becauseBeaumont's book was on the point of publication, the famous "Observations and Experiments on the Gastric Juice" (Plattsburg). It was published in December, 1833. The crucial analysis by Berzelius had not arrived in time. It was fortunate thatBeaumonthad not dallied, for it was not until July, 1834, that the long awaited answer came. Berzelius had him­self failed. The specimen had taken four months to arrive inSwedenbut it had not decomposed. Berzelius reduced the sample of gastric juice that he had been sent to 3-^ gms. of ash by evaporation and then could make nothing of it. The answer thatBeaumontlonged for came 3 years after the publication of his book, for in 1836 a young man of 26. Theodor Schwann, who was later to play so important a part in the establishment of the cellular structure of animal tissue, identified pepsin.Beaumont's experi­ments are so well-known a medical classic that 'they need not be further discussed. But we may pause for a moment, as others have before us. to marvel at the coincidence of opportunity and a genius for observation, which converted what might have been no more than the sordid sequel to an accident into an epochal series of discov­eries. Time, opportunity, the man and a prepared mind here so creatively met together, a fact made plainer if we are reminded that several other cases of gastric fistula had already been reported inEurope. Very truly did the New York Evening Post write on 5th September, 1933 : " It seemed as if nothing short of a miracle could have enabled man to view the internal operations and test the power of the juices provided by nature to carry on the animal economy ; and yet it has been done and the previous knowledge has been revealed without the aid of a miracle although by a process little short of one. . . ." An interesting footnote to this story is that St. Martin outlivedBeaumontby 28 years and died at the age of 81. Osier tried to get the specimen but the family refused both bribes and blandishments.

Medicine as well as surgery must at times be experimental in its therapy.  A difficult experi­mental field is in the treatment of diseases which have no animal counterpart—an example is pernicious anaemia, for which George R. Minot and William P. Murphy proclaimed a cure in 1926 by the giving of liver extract. Much work has since been done with the end of isolating the active principle, which is now found to be a complex organic compound containing cobalt. Equally we should remember James Lind's discovery that scurvy could be cured or prevented by the use of lemon juice, though nearly two centuries would pass before the fundamental constituent. Vitamin C, would be discovered. I cannot hope to mention all the examples that could be quoted, others no doubt will have their preferences, and I must accept that.

 

experiments on the brain

I must pass now from these fields of history to ask a question. There must surely be some branches of research in which man is the pre-eminently suitable, in fact the only possible, subject. All have to do with the nervous system and especially those concerned with sensation, with pain and with thinking. Psychiatry is for instance essentially a field for human investiga­tion and experiment. Animal investigation has followed and not preceded human experiment. I must take you back to the first operation for a brain tumour on 25th November, 1884. We are close indeed on its 70th anniversary. The descrip­tions of this affair in the medicalj press are well known: less familiar are the discussions in The Times to which the operation gave rise. Someone signing himself " F.R.S." led off on 16th Decem­ber with a long letter describing in vivid terms what had happened. It seemed to him to be a wonderful opportunity to make a telling reply to the Bishop of Oxford and John Ruskin who had just spoken strongly against whatwas so curiously called " vivisection." The point, I need hardly remind you, about the famous operation was that the situation where the tumour lay had been localized to the upper part of the motor area by a comparison between the patient's symptoms and signs on the one hand and, on the other, the maps of cortical localization which resulted from the animal experimentation of the Germans, Fritsch and Hitzig. and more still, by those of David Ferrier. The writer to The Times, " F.R.S.", had a picturesque literary style, which you can savour from the following extract from a very long letter descriptive of the steps of the logical application of experimentally verified facts " While the Bishop of Oxford and Professor Ruskin were, on somewhat intangible grounds denouncing vivisection at Oxford last Tuesday afternoon, there sat at a window of the Hospital for Epilepsy and Paralysis in Regent's Park in an invalid chair, propped up with pillows, pale and careworn but with a hopeful smile on his face, a man who could have spoken a really pertinent word upon the subject and told the Right Rev. Prelate and great art critic that he owed his life, and his wife and children their rescue from bereavement and penury, to some of these experiments on living animals which they so soundly condemned." The Bishop of Oxford replied'on I9(h December that " if a perfect knowledge of the secrets of the human frame is desired in the interests of mankind, let mankind be the victims."

These letters led to a shower of further letters, five on Christmas Day, mostly in support of " F.R.S." " F.R.S." had to add a further note on 26th December saying that the poor man was dead (of infection). In a long leader on 27th December The Times took the view that in spite of the eventual fatality Godlec's experimental operation had been fully justified and that the gateway to cerebral surgery had been opened. This was an important pronouncement and true. Do I need to add that on 26th December there wui a letter from James Whitson, assistant \urgcon to the Glasgow Royal Infirmary, saying that this was not the first operation on the brain for a tumour, that a Scotsman. William MacEwen, had got there first '.' Whitson was quite correct. Then letters had to vie for place with news of Mr. Gladstone's 75th birthday, letters on " The Mate of the business at nisi prius" and scandal­ised objections to undraped figures in Alfred Steven's designs for the decorations of the dome of St. Paul's, designs that had the weighty commendation of Sir Frederick (later Lord) Lcighion and Mr. (later Sir) E. J. Poynler—men whose artisiic rating was nearly as high then as thai of Velasquez and Raphael. So we see that remarkable experiment come and go to lead us much more in the fulness of time than The Lancet had lugubriously prophesied for it in its leader on lOih November, 1883. The Lancet's review held lhai acceptance of the laboratory discoveries was not unanimous and that the facts themselves were somewhat confusing (as indeed they were). The writer proceeded : " But it must be con­fessed that the aid localization has afforded to ireatment has been small and practically confined to cases of surgical interference. Even of these cases there are very few—scarcely more than could be counted on the fingers on one hand— m which the power of localizing cerebral disease can be said to have been the means of saving a life that would have been lost without it."

The  leader concluded  with  these  minatory words : "If Dr.Ferrier's suggestions meet with much practical response, it is to be feared that cerebral localization will soon have more deaths to answer for than lives to boast of." These lines were evidently written by either a physician or a pessimist ;  the author could, of course, have been both.   We see, then, that these experiments on man had the mixed reception that we should have expected at that date.   It required the courage of a man like Sir Victor Horsley and, after him, Harvey Cushing to silence opposition and to win the confidence of the world.   All operations are of their nature experimental, the statistical results are broadly known and from them the general impersonal risks can be calcu­lated.   In some, what concerns us most is danger to life itself, in others fatality can be almost excluded and the experimental side depends on the success that can be expected, the relief that can be anticipated in the individual instances. No statistics have so personal a message.   If it comes to that, all medical treatment is also experimental. As ProfessorPickeringhas pointed out, the prescription even of rest in bed for two or three weeks or of a bottle of cough mixture are experiments, the results of which deserve closer observation and quantitative analysis than they get.

sensation

I mentioned just now that man was the only suitable animal for experiments on sensation and on pain. It was by regarding closely the stages of sensory and motor recovery after nerve suture that what we call generally " sensation " was broken down into a number of components (light touch, the recognition of pain, pressure, temperature, localization of the point touched and so forth). It seemed to Henry Head, who was deeply interested in this subject, that he would appreciate the whole thing better if he had some nerves cut in his own left arm. This was done by Dean and Sherren of theLondonHospitalin 1904. Head chose what he thought were purely cutaneous nerves and came to some wrong conclusions by that mistake, as J. S. B. Stopford pointed out. His other mistakes in interpretation have been pilloried by F. M. R. Walshe. The correctness or otherwise of Head's results is beside the present point, which is, that he decided to turn himself into his own experi­mental animal. Wilfred Trotter and Morriston Davies followed suit shortly after and arrived at conclusions that have stood much better the test of time. Since then the personal experiment has ■ been applied by other research workers.

A constant problem for the neuro-surgeon is the pain of malignant invasion of the skeletal tissues in various forms, especially in cancer of the uterus and prostate.   How to help these sufferers to whom peace cannot sufficiently be brought by morphia ?   Foerster in  Rreslau divided the posterior or sensory roots of the spinal  nerves without giving much relief to patients with pain of any origin—relief, that is, commensurate with the disadvantages of dener-vating large areas of skin and muscle.   As a by-product Foerster was able to plot the nerve . supply of the different dermatomes of man in as definite a way as is possible with something a trifle individually variable.   By stimulating the distal ends of the nerves he showed for the first time the vaso-dilatation of the vessels of the skin of the relevant spinal segment.   One has the feeling in reading his reports (as one had in conversation  with   him)  that   Foersler  was basically an experimental physiologist rather than a therapeutist and that he chose his cases sometimes with a view to filling in a missing space in his collection of facts.  A much better piece of physiology was already on the way when Foerster was doing these operations—the operation of cordotomy. However Foerster had had a part in that as well, having persuaded Tietze to do, and successfully, the operation known now as cordotomy. A fortunate chance fell to Spiller inPhiladelphia, who observed that a colouredpatient in his Hospital was numb to pain and temperature up to a level on his trunk, without paralysis.    The sense of touch and pressure was retained. This patient had tubercu­losis and shortly died. At the post-mortem two very small tuberculous nodules were found symmetrically placed in the spinal cord in the situation of the spino-thalamic tracts.   There had been other suggestive evidence, notably that of Tiirck of Vienna, suggesting that these fibres were responsible for the transmission of pain. Spiller at once saw the possibility of turning the misfortune of his patient to the good of others. He persuaded a surgeon, Martin, to divide this part of the spinal cord in another person with unbearable pain.   The result was so great a success that the operation has since'become a standard one. The optimum sites of the partial spinal sections have been worked out in recent years with great diligence by J. C. White ofBoston, plotting the effect of limited sections of the cord under local anaesthesia.   No approach to the operation which is not of an experimental 'nature is likely to be long successful.   More recently still Talairach and David inParishave tried the effects of destruction of the chief nuclei for the reception of pain in the brain itself by

destroying them by electro-coagulation. These are essentially human experiments of a high order and involve the use of the Horsley-Clark stereo­tactic apparatus to which we shall shortly come back. Experimental vertical sections of the human spinal cord to relieve pain in the upper limbs were made by Donald Armour inLondonand Tracy Putnam inNew York. They have been used by the French for pelvic cancers also. But these, though highly experimental in the case of man, were no more than applications of some animal experiments by Brown-Sequard long ago, experiments that led Brown-Sequard to some quite wrong conclusions about sensation since he equated " sensation " with " pain " and little else.

Other revelatory experiments on pain in man are those on visceral pain. Such were the old observations of Lennander that crushing and burning the intestine and gall bladder were quite painless, whereas traction on the mesentery was not. John Morley investigated the agonizing shoulder tip pain experienced by some patients with general peritonitis or chemical peritoneal inflammation such as follows the perforation of a gastric or duodenal ulcer. He scrubbed the under surfaces of the diaphragm with gauze and abolished the referred pain by experimental novocaine block of the nerves supplying the shoulder tip area. Along the same line were the experiments pursued by Hurst and others of having patients or medical students swallow inflatable bags. F. H. Bentley and Smithwick, using that technique, showed that the pain of duodenal distension was abolish by section of the splanchnic nerves. The res of important researches by several investigat ; was to show that distension, tension and traction were the chief causes of visceral pain, the peripheral reference of which had been so acutely observed at the bed-side by James Mackenzie of Burnley 50 years ago. and more cogently by Sir Thomas Lewis. No one indeed worked with more whole­hearted zeal in observation on the character and reference of pain in human beings than Sir Thomas Lewis—the defender as it were of " clinical science," a term invented, so appro­priately to-day, by Stephen Paget's father. He accepted no interpretation of symptoms that he could not experimentally verify on the living subject. This one sentence gives no idea of the years he spent on painstaking work; his observa­tions on the pains of angina pectoris and of other visceral and limb pains are classical. No less were those of Kellgren. who explored the pains arising in muscles, fasciae and the ligaments of joints by injecting small amounts of hypertonic saline into these structures and observing the site, often at a distance, of the severe but tem­porary pain that followed. Usually Kellgren was his own or Lewis's test animal. He has told that he had more than 1000 painful injections of one sort or another to find their effect. None of this work could have been done on animals, since the whole point was the description of the character of the pain, its situation in relation to the position of the causal agent and its relation­ship to the nature of the stimulus.

researches on headache

No better example of experiment on man could be found than in the researches into the causes of headache by the planned production of pain in the head. Notable researches have been those of G. W. Pickering, D. W. C. Northfield, and H. G. Wolff and Bronson Ray and other collaborators, though many besides have added their quotas.  These all confirmed the ancient observation that the brain itself is quite insensi­tive but they added something new.   It was that the stimulation of the cerebral blood-vessels and some of the brain's coverings by direct or indirect means led to referred pain somewhere on the head's surface but according to the site of the stimulation. It was shown that the violent but short-lived headache that follows histamine injection is accompanied by dilatation of the cerebral vessels and by a pronounced increase in the amplitude of their pulsations.   It was further shown by Pickering and Hess that there the intensity of the headache corresponds with the degree of pulsation, being most severe when pulsation was greatest. This relationship between a sort of slackness of the central vascular system and headache was confirmed by another series of observations that had results that were surprising to many. It was demonstrated that the surest way to give a person a headache was to lower the intracranial pressure by draining off ccrebro-spinal fluid. On the contrary, raising the pressure by lumbar injection of saline into a normal person, even to five times and more the normal, as I have done myself, does not cause headache.   Evidently, then, the headache of a brain tumour or abscess or blood-clot is not due to raised pressure alone, for some pressures experimentally reached were far above those registered by most brain tumours. It is generally agreed that tumour headache is caused by distortion of normal intracranial relationship and is due either to traction on dura! septa or to drag on vessels and on the sensory cranial nerves, of which, of course, the trigeminal has the widest supply. Some of the human experiments were daring, such as those of Ray and Wolff, who introduced inflatable rubber balloons into the third and into the lateral ventricles of conscious patients and charted the sites of their induced headaches. The common headache of mankind, migraine and pseudo-migraine, is due to dilation of the vessels in the scalp, bone and dura mater. The cerebrospinal fluid pressure is never high in these cases, and most relief can be obtained by the use of vasoconstrictors of the ergotamine group which, it has been shown, have more effect on the extra-cranial arteries than on those inside the dura. Limitations of time do not allow of a wide discussion of researches on this commonest of the pains to which mankind is heir. Enough has been said to make plain how much these workers have done to clarify a subject that was full of confu­sion and of conjecture until experimental recourse was made to the right animal—man himself.

stimulation of the cerebral cortex

Present day views on epilepsy have been derived almost entirely from experiments on man. The great protagonists have been first Victor Horsley, then Ottfrid Foerster and Krause. who got only so far. Much more fruitfully have worked Wilder Penfield and Herbert Jasper and their co-workers in the Montreal Neurological Institute. The new observations take origin not only from electrical stimulation of the surface of the brain, even of its less exposed parts in conscious patients, but also from direct recordings of electrical potentials from the exposed brain surface, in the search for damaged areas such as could be regarded as the " discharging lesions " in Hughlings Jackson's phrase or their synonym " epileptogenic foci." The discovery and excision of these areas has led to many cures. Cortical stimulations to map out the site of the motor area is now a common­place of neurosurgery and has been employed by myself and by too long a list of neuro­surgeons for them to be named. It was early used by Victor Horsley, as he reported in 1888, and again in 1909, to mark out the exact piece of brain that needed removal in focal epileptic attacks or the wild involuntary movements of a man's arm. That was a straightforward piece of physiology, the application of Ferrier's work and the much more acute observations of Sherrington, which had, to be sure, not yet seen its final fruition with the anthropoids. More exciting were the two cases published in 1909 by Harvey Cushing on sensations resulting from stimulations of the post-Rolandic area in man. Operating under local anaesthesia he established the sensory function of the human post-central strip. Penfield, since that day 46 years ago. has greatly extended these observations on both the motor and sensory and other responsive areas of the brain. His maps of the excitable .cortex will eventually, it is to be hoped, supplant those of the cat and monkey so much more beloved of physiologists because they have been their laboratory familiars. Ferrier many years ago said that all parts of the cortex would prove to be excitable, but he could not demonstrate excita­bility himself except from restricted areas of the brain. The greater part was unresponsive. Ferrier's prophesy was long unfulfilled and only recently has come closer to confirmation. Thus we now know that responses must be looked for not only in movements of the limbs or in sensa­tions or in flashes of light or sounds or odours, but in two other directions. The first is in the autonomic or visceral changes that may be the replies to stimulation of some areas (changes in heart rate, respiration, blood-pressure, intes­tinal movements, etc.). This work has mainly been done on animals. The second and much the more exciting, even dramatic, discovery was made by Penfield—that stimulations of the temporal lobe in human beings may evoke experiences, pictures in the mind. An example may be given of the response of a woman of 32 who had epileptic fits of a minor sort. Each remark corresponds to a separate stimulus : " I hear singing," " Yes, it is ' White Christ­mas.There is an orchestra too . . . yes, a choir." " That is different, a voice—talking— a man." " Yes. I have heard it before ... a man's voice talking."' " Yes, about the same as before." " There is that sound again—like a radio programme—a man talking." She said that it was a play. Results of a similar kind or the evocation of a familiar scene, a moment or two only in life, well-accepted by the patient, in no way frightening but all with a considerable content and depth of experience, have been obtained from other cases. But it is by no means anybody's brain that will yield such vivid experiences: confirmatory results by others must still be made. Something very like that can occur spontaneously in patients with temporal'lobe tumours. The upshot of this and other work that cannot be pursued now is that a seizure pattern has emerged recognizable as coming from one or other temporal lobe. It is very much to the point that these seizures, previously labelled psycho-motor fits, are often caused by extensive scars from damage, perhaps at birth. The excision of the scar and of anterior parts of the pathological temporal lobe has led tcr the cessation of or great diminution in the frequency and severity of the attacks in a proportion claimed to be as high as 2 out of

3 cases. Murray Falconer has now had some success in improving not only the fits but the behaviour of delinquent children and young adults subject to this kind of seizure. Experiments carried out on man in the laudable attempt to relieve him of epilepsy have in many ways helped greatly in our interpretation of the brain's integration and of its mechanisms. It marks a major advance in man's understanding of him­self.

The advance has been assisted by the explora­tions of frontal lobe physiology. Our new knowledge has come about again from two sources—first, major excisions of the frontal lobes of which 1 myself reported the first 8 European examples in 1937 and again 75 examples in 1942. Going still further Krynauw inJohannesburgreported in 1950 the first cases of removal of a cerebral hemisphere from children already hemiplegic and suffering from fits that started in the paralyzed limbs. It was found that the mental state of these children was often improved by the loss of the half of the brain's cortex, the remaining healthy half being no longer disturbed by the flow of disturbing impulses from the abnormal parts. This was much the same conclusion as I had reached myself from the lobectomies for brain tumour. Close on the heels of that came the rising popularity of pre-frontal lobotomy and its modifications for mental disorders, which we owed to the inspiration of Egas Moniz (1936). All this is very much in the field of human experiment and'is much too large a subject to be discussed profitably now. Equally experi­mental in their way were the introduction of the malarial treatment of general paralysis (Wagner-Jauregg -1917) and the insulin (Sakal 1927), metrazol (Meduna 1937) and electric-shock therapy (Carletti and Kalinowsky 1937) of the psychoses.

conclusion

Logical deductions on the place that man best occupies as an experimental animal should follow even from this incomplete review. Plainly it would be unthinkable that he should be used widely in experiment on the propagation of dangerous infections. Such use as has been made in that field was so very properly in the discovery of the epidemiology of transmissible diseases and in immunizing man against them. There, naturally, Jenner's" famous experiments come at once to mind. For most of the viral diseases our present armamentaria of antibiotics are disappointing failures. With nothing to abort them they are dangerous playthings for human application. Sir Howard Fiorey pointed out in his brilliant Stephen Paget Lecture on the history of the development of penicillin that it would have been utterly impossible to discover its potentialities without animal experiments, so small were the-quantities of the mould avail­able and so wide the range and dangerous the infections to be tested in the days when it was first necessary to prove penicillin's usefulness. As Fiorey further pointed out some moulds other than penicillin on first testing with cul­tures proved to be as powerful as penicillin and 10 have an even wider antibacterial spectrum. Yei animal experiment saved man from disaster by revealing that many were most dangerous to life. That illustrated another point, the useless-ness of man as a test subject for the toxicity of drugs and for the biological assay of synthetic hormones. Man is much too rare, too expensive, altogether too valuable an animal to be used on ihe scale necessary for this indispensable work. Mention might be made at this point of John Hunter's famous experiment when he inoculated himself with what he thought was gonorrhoea, but, unfortunately, the patient had a hard chancre so that he developed syphilis as well. Penicillin would quickly have cured Hunter of both these diseases had he not lived 150 years too soon.

It seems then in the end that man is only useful as a test subject for those affections or diseases to which he alone is subject or in which his subjec­tive responses to experiment are essential to the experiment itself. This is most true of the nervous system and already his ready acceptance of himself in this experimental role has led to the illumination of many a dark corner. I am convinced that no surgeon is quite as conscious of the truly experimental nature of his work and of the opportunities it affords for physiological observations as the neuro-surgeon.

Man himself has been the real hero of this discourse, man. the inventor, whose curiosity and imagination have led him to these adventures, and man, often the doctor, the patient and courageous subject in this search for knowledge.

REFERENCES Dale, Sir H. H.   " An autumn gleaning."London, 1954.

Havens, W. P., and Paul, i. R. " Viral and rickettsial infections of man." Ed. by T. M. Rivers.Phila­delphia, 1952.

Lewis, Sir T.   " Pain."  London, 1942.

Myer, J. S. " Life and letters of Dr. William Beaumont."St. Louis, 1912.

Truby, A. E. " Memoir of Waller Reed : the yellow fever episode."   1943.

.Professor Henry Barcroft, F.R.S.. proposing a vote of thanks, recalled the cartoon that showed a mother stork pushing a baby stork in a pram and the child stork by her side asking : " Did a man bring it ? " Although the Research Defence Society was primarily interested in animal experiments, this was only because of their value in the general science of promoting the welfare of man. " Man as an Experimental Animal " was a subject in which they had a particular interest. He expressed the sincere thanks of members, who would look forward with pleasure to reading the Lecture in Conquest.

Dr. 0. G. Edholm, seconding, remarked that sometimes one felt that thanks to a lecturer were given grudgingly. To-night it was so easy to thank Sir Geoffrey with sincerity. Not only had the form and content of his address been delightful, but he had given a lesson in the art of lecturing. Many of the experiments to which he had referred were familiar, but he had shown them in a new light.

There was no doubt that man would experi­ment with man, as he experimented with animals, and it was right that the Research Defence Society should take an interest in man as an experimental animal as well as in all the other animals with which it was concerned.

Lord Hailey. putting the vote of thanks, which was carried with acclamation, remarked that he had not realized the extent to which " experiments " were being carried on by the medical profession in treatment. He would now feel that, by allowing medical men to " experiment " upon him, he would be a little more useful to mankind than he thought he could be.

 


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