Part 40

About the beginning of the twentieth century arose the new ‘Chemotherapeutic’ movement as it came to be called. This movement was initiated by the studies of natural Antibodies (p. 262) by Paul Ehrlich of Frankfurt (1854-1915). Antibodies are strongly antagonistic to the parasitic organism the toxin of which has elicited them, but, on the other hand, they are quite harmless to the animal body in which they reside. Here are ideal remedies provided by Nature herself. Ehrlich compared them to magic bullets, constrained by a charm to fly straight at their objective and to injure no other. No such perfect artificial drugs have yet been produced. The problem of Chemotherapy is rather how to poison the parasite as much as possible while poisoning the host as little as possible.

When Ehrlich began the study of Chemotherapy observers had long known that certain aniline dyes have a special affinity for certain cells or organisms. Indeed the affinity of certain of the dyes for certain bacteria had made possible the work of Koch on Tuberculosis and on other diseases. As far back as the seventies and eighties much work had been done on the subject, and the action of these dyes had interested a large variety of investigators. Ehrlich’s first results were on a protozoal parasite, which infests dogs. By injecting small doses of a certain aniline dye into the veins of the infected animal it was found possible to destroy the parasites while doing very little injury to the dog.

FIG. 133. THE ORGANISMS OF SYPHILIS IN A SMEAR FROM THE LOCAL INFECTION. Highly magnified. They are best seen by means of a special optical arrangement in which the outlines of the objects appear glistening white and the background black. The round objects are pus corpuscles, the two spiral objects the organisms of syphilis. ]

At this point Ehrlich turned aside from the aniline dyes to study the effects of much more toxic substances. He selected the compounds of arsenic for the purpose. After prolonged research, he obtained an arsenical derivative which proved very toxic to parasitic protozoa and little toxic to their animal hosts. When a vast number of experiments had been made, this substance was tried in 1910 in cases of human Syphilis. This disease had been shown by Fritz Schaudinn (1871-1906) in 1905 to be due to a protozoal parasite, the Spirochaeta pallida (Fig. 133). The results obtained by the new remedy were very satisfactory and a valuable specific was thus added to the medical armory. The drug became widely known as 606, since this is its number in the series of the arsenic derivatives with which Ehrlich had experimented. In the meantime others had been at work along lines suggested by the aniline experiments. Their investigations led in 1920 to the discovery of a specific against the deadly Sleeping Sickness or Negro Lethargy. This drug is known as Bayer 205 from the firm that prepared it and the number in the series of substances that were tested.

Since the first preparation of 606 and 205 some interesting facts have emerged concerning their action as well as the action of Quinine, Emetine, and other specific remedies. It has been found that the toxicity of these substances to the parasites against which they are aimed is much greater when the parasites are within the body than when the drugs are applied to the organisms outside the body. In other words, the drugs do something to the body, or the body does something to the drugs, that is inimical to the parasite. The nature of that something is still under discussion. In the case of Quinine it seems that the Quinine so affects the red blood corpuscles that the malarial parasites cannot enter them and so cannot go through their sexual cycle (Fig. 123). Thus the Quinine does not act as a direct poison but attacks the parasite in a much more subtle manner. In the case of other parasites the action of the specifics is more difficult to understand. It should be pointed out, however, that the chief victories of Chemotherapy have been in dealing with the protozoal rather than the bacterial diseases. A main task of future Medicine will be the discovery of means of eliciting antibodies against the various bacterial infections. For this there is more immediate hope from the use of remedies of vital origin than from those synthetically produced.

§ 21. Interpretation of Collective Medical Data.

The drawing of a deduction of scientific value from experience is by no means a simple process. In many sciences the investigator has the power to control experience; in other words he can experiment. But even the interpretation of experiment needs special precautions. The physical experimenter must, for instance, make sure that he has but one ‘variable’. Thus, if examining the effects of pressure on a gas, he must see that in raising or lowering pressure he is not altering temperature, or if recording the effects of temperature he must satisfy himself that he is eliminating those of pressure. In experiments upon living things the limitation of the field of action to one simple factor is often--perhaps always--impossible. The biological investigator is therefore accustomed to accompany his experiment with ‘controls.’ Thus, if he wishes to ascertain the effect on the growth of animals of feeding with milk that has been boiled, he must feed one series of animals on unboiled milk while he is experimenting with a series fed with the boiled milk. He must take steps to ensure that the two series are similar as regards age, strength, size, &c., and that the conditions under which they live are identical, except as regards the one factor the results of which he seeks to ascertain.

When the observer is dealing with human material, it is very seldom that he can either restrict the number of variables to one or secure an adequate series of controls. Physicians are habitually in a position in which action of some kind is demanded. They cannot await the conclusion of laboratory researches, which may extend over years, for the patient must be relieved at once or die. Being often unable to use those most reliable instruments of science, experiment or observation under control conditions, physicians have come to rely on what is called ‘a general experience of disease’.

One of the commonest fallacies of such general experience is assignment of causative relationship between two conditions, simply on the ground that they frequently occur in association. Thus it is a fact--and one to which attention has been drawn by medical observers--that rheumatic affections and red-headedness are often found together. But both conditions are common and it has not been satisfactorily demonstrated that the association of the two is any commoner than their frequency in the population at large would render probable. Such general experience is therefore very fallible and is incapable of scientific expression, though it is often very valuable and sometimes indeed entirely indispensable. To give such experience scientific expression, to place it in terms of the ‘primary qualities’ of the founders of modern Science (pp. 106-7), it is necessary to put it into statistical form. Statistical statement thus becomes of the highest importance for medical progress. Medical statistics, when prepared from proper material and drawn up with the requisite skill, are at once the most exact and the most generalized expression of medical experience.

FIG. 134. DIAGRAM ILLUSTRATING THE ALTERATION IN THE PERCENTAGE OF AGE-DISTRIBUTION OF THE POPULATION OF ENGLAND AND WALES FROM 1891 TO 1926. It will be observed that the people of England and Wales have been getting steadily older. ]

Statistical statements, however, vary greatly in their value and ease of interpretation. The simplest statistical statements with which the medical man has to deal are perhaps those which relate to surgical operations. The categories in which the patient may be placed are here limited; he may die, recover, improve, or get worse. If the operation is a quite simple one, and if the surgeon is perfectly honest, and also--which is rarer--quite unbiased, a small body of statistics may carry immediate conviction as to the value of an operation. Thus, Lister’s first results with amputation, as obtained under his antiseptic conditions, at once satisfy the mind, although the conclusions are based on only forty cases (p. 240). No surgeon at once both able and willing to appreciate these results would hesitate to adopt the new method.

The operation of amputation is, however, in a statistical sense, a particularly simple matter. The patient must either undergo the operation or not, and the proportion of cases in which the necessity is doubtful is very small. Further, he either recovers or dies--for the operation could hardly be in itself unsuccessful, nor the surgeon in doubt as to whether the patient had recovered or not. Many operations, however, are not of this order. They may be performed for conditions as to the exact nature of which the surgeon is uncertain, and for symptoms which may be only partially relieved. Thus, the removal of the appendix for Appendicitis may be most urgently necessary for the saving of life in one case and may be a matter of convenience for the relief of more or less indefinite symptoms in another. Further, what one surgeon calls appendicitis another may not. One surgeon may have every appendix that he removes submitted to skilled pathological examination before he accepts the case as one of appendicitis and places it among his statistics. Another may be quite content with naked-eye appearances of the nature of which he alone is witness, judge, and reporter. It is, therefore, clear that any collective statement as to the results of such an operation must be cautiously scrutinized before conclusions of the slightest scientific value can be drawn from them.

FIG. 135. DEATH-RATE FROM CANCER OF THE TONGUE. It will be observed that it is not a common cause of death till about 45 years of age, but that it then increases rapidly to fall again in both sexes in old age. These features are clearly related to various factors in the causation of the condition. One of these is certainly Syphilis, which is most frequently contracted between 20 and 30 and more often by men than women. The so-called ‘tertiary’ effects of this condition, some of which lead to Cancer of the Tongue, do not usually make themselves felt, however, for many years after infection. Contrast Fig. 136 and Fig. 137. ]

There is a common and rather foolish saying that ‘Statistics may be made to prove anything’. This is true, but it is true only in the sense that evidence may be made to prove anything. The matter turns on the questions, firstly whether the evidence is of a good or a bad order, and secondly whether the investigator is in a good or bad position to interpret the evidence. A statistical statement may be well or ill founded and well or ill interpreted, but statistical statement is, in fact, the only scientific method open to us for presenting long series of data. The conclusions to be drawn from those data, though sometimes evident and easily elicited, at other times demand specially skilled and specially trained interpreters. Moreover, to be of value to others, such interpreters must also be skilled in expression, so that the main body of those who have no statistical training may be in a position to understand the essential elements in their conclusions. In no medical department is literary power of greater importance than in that which deals with statistics. Thus has arisen the small but highly important class of medical statisticians. The rise of medical statistics into a vocation places the crown on Medicine as a science. It is not given to many medical men to be proficient in this department. But the duty lies on all medical men, and indeed on all citizens, to appreciate the value of this study and to seek to appraise its simpler and more established conclusions.

It is remarkable how frequently a straightforward statistical statement may remove a false impression, even when the impression is based on evidence not of a wholly unscientific character.

FIG. 136. DEATH-RATE FROM CANCER OF THE LIP. It will be observed that this curve resembles in form that of the death-rate from Cerebral Haemorrhage as shown in Fig. 137, but differs from that of the death-rate from Cancer of the Tongue as shown in Fig. 135. The chances of dying from Cancer of the Lip are negligible till middle age is past and then increase progressively throughout life. In the causation of Cancer of the Lip Syphilis is not an important factor. On the other hand the continuous irritation of pipe-smoking, which acts not at one age but throughout life, has to be considered as a causative element. Hence the resemblance to Fig. 137 rather than to Fig. 135. ]

FIG. 137. CHART OF DEATH-RATE FROM CEREBRAL HAEMORRHAGE AND ALLIED STATES. These conditions are extremely rare in the young, but among the commonest causes of death in later life. The liability to them increases progressively to extreme old age. This is explained by the fact that Cerebral Haemorrhage, etc. follows on the rupture of a blood-vessel in the brain and the rupture of the vessel is conditioned by the hardness and brittleness of its coat. The hardness of the arteries increases progressively in later life, whence the saying ‘a man is as old as his arteries’.

For example the increase in the incidence of deaths from Cancer has often been emphasized. But Cancer is a disease of advancing life. The age distribution of the death-rate from many forms of Cancer is closely parallel to that of certain other forms of senile disease (Figs. 136 and 137). Now the age constitution of the population of most civilized countries is altering in the sense that the proportion of the elderly and aged is constantly increasing (Fig. 134), so that some increase in the Cancer incidence must be expected. Moreover the appearance of some increase in the incidence of Cancer is due to improved diagnosis. How far there is a real increase, when these factors have been taken into account, is still somewhat doubtful. It must always be borne in mind that a relative decrease in the proportion of deaths from any cause must automatically increase the proportion of deaths from other causes.

Again, there is no doubt of the fall in the death-rate in England and Wales from ‘Phthisis,’ or pulmonary tuberculosis, during the last fifty or sixty years. There is also no doubt of the effect both of bad housing and of urban conditions in inducing a susceptibility to chest disease in general and to pulmonary tuberculosis in particular. Further, there is no doubt that the rural population suffers less from pulmonary tuberculosis than the town population. These matters of common medical knowledge have naturally led to the conclusion that the rise of the great towns has led to a great increase of pulmonary tuberculosis, and that this increase has been remedied by the improved housing and sanitary conditions of the last generation. A study of the statistical evidence, however, negatives this view. The rise in the proportion of deaths from pulmonary tuberculosis took place before the Industrial Revolution. Moreover, the proportion began to fall long before the campaign against tuberculosis could affect the issue. The history of pulmonary tuberculosis may, in fact, be regarded as that of an ‘epidemic’ outbreak, extending over about 100 years, of a disease which has always been endemic and remains so now that the epidemic is past.

FIG. 138. CURVE SHOWING PERCENTAGE OF DEATHS FROM PHTHISIS to total deaths from all causes in London over a period of 200 years. It will be seen that the percentage begins to rise definitely about 1730 and to fall definitely about 1830. This state of affairs may be pictured as an epidemic lasting about 100 years. ]

These points are well brought out in the accompanying diagram (Fig. 138). The fall in the proportion of deaths from Phthisis expressed there gives rise to further considerations. It might seem that the statement that the proportion of those who died from phthisis was diminishing left in itself no doubt that the disease was less prevalent than formerly. This, however, is not the case. Phthisis is more liable to affect those under forty-five years of age than those who are older. Now the proportion of the population that is under forty-five is steadily diminishing (Fig. 134). This is one of the results of the steadily diminishing general death-rate (Fig. 96, p. 196). Therefore the proportion of the more susceptible to the less susceptible is diminishing. It might have been the case (though it is not) that the ratio (more susceptibles)/(less susceptibles) was not only decreasing but was actually decreasing more rapidly than the ratio (total deaths)/(deaths from phthisis). Had this been so, the conclusion would have been justifiable that the fall in the proportion of deaths from the disease did not correspond to any decrease in its infectivity. In fact, however, the prolonged high mortality from phthisis and its later rate of fall do suggest the former prevalence of a more virulent type of the disease over a long period, in other words something of the nature of a prolonged epidemic.

This conclusion leads us to the conception of the nature of an epidemic. To gain some conception of the ideas involved in that word, we must glance back in history.

From the time of Hippocrates onward the subject of Epidemic outbursts of disease has drawn the attention of physicians. A writer in the Hippocratic Collection thought he could perceive an association of symptom-complexes with each other and with the weather. In the great work Epidemics, to which the name of the Father of Medicine is attached, such a view, known as that of ‘Epidemic Constitutions,’ is set forth. The view was revived by Sydenham in the seventeenth century and has given rise to a vast literature extending to our own time. In the eighteenth and nineteenth centuries the attempts of the investigators of vital statistics to place the leading events of life in a form capable of exact analysis (pp. 166-68) focused attention on the search for a mathematical expression for the rise and fall of epidemic diseases.

The first successful attempt to describe epidemics along these lines was made by William Farr (1807-1883), an official in the office of the Registrar-General in London, and one of the greatest of all epidemiological thinkers. His first publication on the subject was in 1840, and had reference to the recent outbreak of small-pox, in which more than 30,000 had died in England and Wales. It was his merit to observe that the successive decreases in the number of cases in successive equal periods during the decline of the epidemic correspond to the successive increases in the number of cases during successive equal periods of the rise of the epidemic. In other words, he observed that the rise and decline of an epidemic tend to be mathematically symmetrical.

Farr’s suggestion that epidemics are liable to follow the lines of regular mathematical rules drew little attention at the time, but in a later year it led to a most remarkable and striking prophecy. At the end of 1865 Cattle-plague broke out in England. Week by week the number of cases increased. In the fourth week of February 1866 the responsible Minister, in a speech in Parliament, gave a very gloomy account of the state of affairs, expressing the belief that the devastation would be far beyond what had yet been encountered. Farr, however, had been watching the returns, and had been applying his rule to them. He thereupon made a public pronouncement of his belief that at an early date the outbreak would reach its maximum and would then decline. The outbreak did, in fact, very closely follow the course which he had predicted by reasoned calculation. Farr even prophesied the number of cases that would occur week by week. His prophecy was near the truth.

During the years that followed Farr’s prediction his views were applied with success to a variety of epidemic conditions. The regular form of the development of the epidemic was found to apply in certain outbreaks of typhus, measles, and other conditions.

Farr’s law was more exactly expressed by him in 1868. It remained, however, simply a mathematical law, a rule of which the underlying cause was not apparent. It was soon observed that his law applied to many but by no means to all epidemics. Moreover, it was perceived that the actual figures which he gave for his epidemic of 1840 resembled those of certain other epidemics in that they could be fitted with greater or less exactness to a well-known mathematically described curve, known as the ‘normal curve of error’. We need not discuss the mathematical foundation of this curve, which is shown in two variants in Fig. 139. For our immediate purpose it is enough to observe that it rises gradually at first, but then more steeply, that the steepness decreases after a while, and then the curve begins to decline again, as it rose. We note that it is symmetrical.

FIG. 139. THE NORMAL CURVE OF ERROR, shown in two types made with the same formula but with different constants. This curve has been shown to be similar to that representing the incidence of cases in some Epidemics.