As diverse opinions are held about the significance of systemic influences in cancer, the subject needs some reconsideration. What are “systemic influences”? In the literature on cancer this preliminary question is usually ignored, presumably because it is thought that the answer is self-evident. With this view I do not agree. I think one must begin by forming a general conception about the nature of systemic influences. What are they like in the normal body? What is their position in bacteriological immunity, about which knowledge is more advanced than in cancer? Ideas derived from a discussion of these two questions ought to provide a useful base for approaching the problem as it concerns malignancy.

In the normal body the systemic influences which the plasma exerts upon the tissues form a complex system presenting three aspects, the chemical, the chemico-physical, and the vitalistic. For example, sometimes it may be said that the plasma's activity is due to a special chemical substance, such as a hormone; sometimes the predominant factor is due to the balance of its colloidal constituents; and not infrequently its action can only be attributed to those properties of living matter which cannot be reproduced in the chemical or the physical laboratory. These three aspects of systemic influences are not independent factors but have to be correlated; and the essential difficulty of the subject is to assign to each of them its appropriate significance.

In natural immunity and resistance towards bacteria, these normal systemic influences are in possession of the field and it is upon their activities that the fate of the bacterial intruders largely depends. Where the immunity is non-specific, as in the inability of saprophytes to grow in living tissues, the defensive factor bears a prominently vitalistic aspect. The mechanism of bacterial destruction seems largely to depend on the circumstance that the bacteria find themselves in a living animal environment where they cannot remain in the resting stage; they must endeavour to grow but they perish in the attempt because the medium is unsuitable.

What is the nature of “alexin” as a natural defensive mechanism? The idea that it is a special chemical substance secreted by some cells of the body must be abandoned. In vitro, it is a property due to the chemico-physical lability and colloidal complexity of fresh serum, in virtue of which the serum promotes interactions which would not take place in a more stable medium. In vivo, the plasma possesses similar chemico-physical properties in a more complex and more effective form, supplemented by its vitalistic capacities as living material. For these properties of the circulating plasma the term “alexin” is not appropriate.

As regards specific manifestations of natural immunity, how is one to explain the selective action of normal systemic influences on bacteria which are pathogenic for some species of animals but not for others? Selection naturally suggests special chemical attributes of the plasma; but species immunity has not been identified with the presence of distinctive chemical substances and it is not likely that it ever will be. One has to fall back on the chemico-physical attributes of the plasma which constitute its general “make up,” as characteristic of a particular species. And these attributes must be regarded not as a system in stable equilibrium but as a dynamic system involving an ordered sequence of reactions.

The most important feature of true natural immunity is that, when the bacteria have been disposed of, the condition of the plasma remains as it was before their intrusion. Its activities have not been due to antibodies, in the accepted serological sense, and the destroyed bacteria have not behaved as antigens.

In most of the literature on acquired immunity the chemical conception stands out very conspicuously. Bacterial protein behaves as an antigen and stimulates certain cells of the host to secrete an antibody; that is regarded as the basis of immunity. After allowing for the operation of chemico-physical laws, the predominant feature remains that an immunological reaction is essentially the interplay between two chemical entities, an antibody (agglutinin, lysin, tropin, etc.), and its corresponding antigen. This conception is considered preferable to the much less concrete ideas of interactions between systemic influences and living bacterial protoplasm.

Whilst appreciating the value of precise chemical data, I consider that this view of acquired immunity is one-sided and inadequate. Systemic influences (other than serological antibodies) cannot be left out of account in the conception of interactions between living bacteria and the living animal body. One needs a scheme which will help to correlate natural with acquired systemic influences, to bridge the gap between specific and non-specific factors, and to modify the conception of an antibody as a special chemical entity, specially secreted by certain cells in response to the stimulus of a foreign protein. Within such a scheme, as I have endeavoured to show, an explanation may be found for what may be called the routine production of antibodies by antigens.

Coming now to cancer, one must first insist on the commonsense view that the transplantation of grafts is a special and relatively unimportant line of experiment which, whatever interests it may possess in other respects, does not help to explain either established autogenous cancer or the genesis of cancer. In these grafting experiments certain systemic influences emerge which cannot be explained as due to the production of antibodies by antigens. This is to be expected, on the analogy of similar manifestations of antibacterial systemic influences. But neither natural nor acquired systemic resistance to the taking of a graft involves anything which may be regarded as a new kind of systemic influence peculiar to cancer.

In the case of established autogenous cancer there does seem to be a new kind of systemic influence which is directly attributable to the disease. This influence, as is found by animal experiment and by observation on human malignancy, inhibits, or tends to inhibit, the creation of a second and independent malignant growth in the same animal body. Apparently products of the existing cancer pass into the circulation and cause other tissues to lose their susceptibility to influences which might ultimately have produced a malignant variant. The mechanism of this inhibitory action is obscure and is probably more complex than the chemical influence of a particular cancerous product upon normal cells. Whatever may be the right explanation, the observed facts indicate that it is something new, which is created by the cancerous condition; they afford no proof whatever that, before the cancer existed, there were in the circulation special systemic influences which were favourable or unfavourable to the genesis of cancer.

The idea that there are systemic influences concerned with the genesis of cancer has assumed many forms and is often expressed ambiguously. Does it mean that normal cells have a “natural tendency” to malignancy and will actually become malignant if freed from systemic control? I do not accept this “natural tendency”; unrestrained growth does not suffice to explain the origin of cancer. What is meant by “systemic control”? My view is that such control regulates normal cells and that cancer cells are independent of it; I do not agree that there is a special kind of antimalignant systemic control which may destroy the fully fledged cancer cell. What is the nature of “susceptibility” to the change into the cancerous condition? I regard it as essentially a cellular property, not as a humoral or systemic influence, though I admit that irritant material which gains access to the circulation may increase the susceptibility of particular cells. What is meant by “resistance” (either local or systemic) to cancer? Owing to the recuperative powers of the animal body, local disturbances of metabolism are often corrected and there is a return to the normal condition; some of these disturbances, if left uncorrected, might have led to cancer and the fact that they have been corrected may, if one likes, be called resistance to the genesis of cancer. It is also known that true cancerous foci or metastases may remain quiescent for a considerable time. But I do not agree that such quiescence has been shown to be attributable to a specific kind of antimalignant “resistance” (either local or systemic).

Whilst there is no satisfactory evidence, either direct or indirect, of a systemic influence which causes cancer, systemic influences are so complex and obscure that this possibility cannot be definitely excluded. But there does not seem to be any cogent reason for dissenting from the view that the production of the malignant variant is due to its local environment.

Young normal rats are put on vitamin A-free diet and, after development of pronounced xerophthalmic symptoms, inoculated by mouth and by subcutaneous injection with Breslau bacilli (paratyphoid). The course of infection and bacteriological autopsy findings show a marked decrease in the resistance of these animals to this infection as compared with the findings in rats on adequate diet.

The experiments do not show any change in the mechanism of infection in pronounced vitamin A deficiency.

1. The average number of guinea-pigs born in albino litters is 3·000 as against 3·097 in the case of the mixed group, but the difference between the mean values is not statistically significant. Hence, it will be seen that there is little or no relationship between the colour of guinea-pigs and the number of their progeny.

2. It may be said that there is a relationship between fertility and the period of the year. There is a tendency for fewer litters to be born during the quarter, January to March, and likewise for the fertility to be lowest during this period, as the mean number of births per litter is 2·65 for albino guineapigs and 2·67 for the mixed class, both values being significantly below the mean for the whole period.

3. The mean weight of the albino guinea-pigs at birth is 81·2 ± 0·36 grm., the corresponding value for the cream, cream and white class is 82·6 ± 0·43, but the difference is of no statistical importance. Hence we conclude that the weight of a guinea-pig at birth is not affected by its colour. Once again attention is centred on the January–March quarter as the most unfavourable period, since there is a tendency for guinea-pigs of either colour born in these months to be below the normal weight.

4. When allowance was made for the effects of selection on our data, there was no material difference between the rates of growth for the two types of guinea-pigs and, furthermore, the period of the year at which littering occurred exercised no apparent influence.

5. The rate of mortality during the first thirteen days of life amongst albino guinea-pigs is 5·58 per 1000 per day, and amongst cream, cream and white guinea-pigs 4·73 per 1000 per day, but the difference probably represents nothing fundamental because, when the mortality is studied according to the size of the litter, the rates are sometimes in the reverse direction.

6. Finally, there is, in the present data, nothing to suggest that albino guinea-pigs are as regards fertility, growth and mortality, significantly different from cream, cream and white guinea-pigs.

Good results were obtained by Ferry, Pryer and Fisher (1925) in the treatment of cases of scarlatina with concentrated antitoxin, obtained from horses treated with toxin of scarlatina derived from streptococci. This antitoxin was supplied commercially by Parke, Davis and Co. It has been used in the present investigation.

1. A study has been made of natural agglutination as exemplified by the reactions of the serum of nine animal species with a variety of bacteria.

2. End-titres are recorded, and the fact is noted that sera of different animal species show an order of agglutinating activity which is almost constant for all organisms used. Ox, pig and horse sera give consistently strong reactions, while specimens from rabbit, guinea-pig and rat react weakly or not at all. Sheep, human and cat sera occupy an intermediate position. Variations are noted, however, with different individual specimens of serum from the same species.

3. Organisms of the series tested can also be grouped in order according to their apparent susceptibility to agglutination by normal sera.

4. The serum of young animals is found to be deficient in the agglutinating principle.

5. The agglutinating effect shows a thermolability intermediate between that of complement and the immune agglutinins. Complete inactivation occurs as a rule after exposure to 60° C.–65° C. for half-an-hour. For certain strains the serum principle is inactivated at much lower temperatures.

6. Lability curves show marked irregularity. In certain cases a zone of relative inactivation is produced at a temperature of 55° C.

7. The natural agglutinating substance is found to be present in greater degree in the carbonic acid insoluble fraction of serum than in the carbonic acid soluble fraction. In this respect it differs from the immune agglutinins, which are chiefly located in the carbonic acid soluble moiety.

8. The agglutinating principle for each organism can be absorbed completely by the homologous strain, when a variable lowering of the end-titre for other unrelated organisms results. A similar lowering of activity for these organisms may be produced by treating the serum with non-specific physical absorbents. Charcoal and Kieselguhr were used to demonstrate this.

9. By the technique of double absorption it can be shown that agglutination depends on non-specific and specific factors and it is concluded that normal serum agglutinates bacteria in virtue of a twofold mechanism:

(a) A non-specific effect reacting in varying degree with all organisms and removable by treatment with a finely divided absorbent.

(b) A series of specific effects reacting as true “natural antibodies.” These specific antibody-like principles exist for a wide variety of organisms. Absorption of any one organism removes the homologous effect leaving the remainder quantitatively unimpaired.

10. The question of bacterial variation and receptor analysis in relation to the natural agglutinins is being studied and will be reported on at a later date.

1. Beriberi occurring on a white-flour staple is similar to that occurring on a rice staple.

2. Under the difficult climatic conditions of North Newfoundland and Labrador, families are obliged to buy food stores in November or December to last until the following May or June. When poverty prevents a sufficient variety of foodstuffs, and calories are the foremost consideration, white flour with few extras forms the main dietary, and beriberi tends to occur in April, May or June. It occurs in families who have grown few vegetables and shot little game.

3. The disease attacks more men than women, and very rarely children between the ages of infancy and puberty. The age and sex incidences of beriberi are difficult of explanation and differ in different countries.

4. Infantile beriberi probably occurs in Newfoundland and Labrador, but is largely unrecognised.

5. The main cause of beriberi is vitamin B1 deficiency, but the diets of patients suffering from beriberi are deficient in other respects.

6. It is suggested that the infrequency of wet beriberi in Newfoundland may be due to the fact that wheat flour has a higher protein content than polished rice.

7. Since poverty and deficiency disease are rigidly associated, prevention is an economic rather than a medical problem.

8. Severe scurvy and rickets are not often met.

9. Functional hemeralopia or night-blindness occurs mainly during the summer among men. It occurs on a diet deficient in vitamin A, and is rapidly curable by vitamin A containing foods, a fact well known to the Newfound landers. The disease may occur in men taking a deficient diet for less than one month. Other evidences of vitamin A deficiency are lacking.

10. Tuberculosis, severe dental caries, functional stomach complaints and constipation are common. Gastric and duodenal ulcer, diabetes and obesity are rare.

1. Two preparations of bacteriophage were used for the treatment of a number of cases of acute bacillary dysentery.

2. The types of B. dysenteriae encountered in 60 cases of acute bacillary dysentery are described. In the 60 cases investigated the causal bacillus was bacteriophagable with the standard bacteriophage in vitro in 48.

3. The cases are tabulated and no dramatic results due to the bacteriophage treatment are demonstrated.

4. Treatment of the bacteriophage with hydrochloric acid, in a concentration similar to that of the gastric juice, for 60 minutes did not alter the virulence of the bacteriophage.

5. It is shown that 25 per cent, autoclaved intestinal mucus in normal saline, and human blood serum, not inactivated, compare unfavourably with laboratory broth as a medium for bacteriophage action.

6. The results of giving bacteriophage by mouth to normal individuals, and to dysentery patients are described and discussed.