12 results
Systemic Influences in Immunity and Cancer
- Arthur Eastwood
-
- Journal:
- Journal of Hygiene / Volume 30 / Issue 3 / August 1930
- Published online by Cambridge University Press:
- 15 May 2009, pp. 267-299
-
- Article
-
- You have access Access
- Export citation
-
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.
Bacterial Virulence and Immunity
- Arthur Eastwood
-
- Journal:
- Journal of Hygiene / Volume 26 / Issue 3 / August 1927
- Published online by Cambridge University Press:
- 15 May 2009, pp. 235-270
-
- Article
-
- You have access Access
- Export citation
-
Bacteriologists are not in a position to disregard the limitations recognised by the physiologists. Precise data which are not available from experiments are far from sufficient to explain the properties of living matter; they must be supplemented by vaguer conceptions about the functions of a cell, its internal organisation and its susceptibility to stimulative or inhibitory agencies—conceptions which cannot yet be translated into recognised chemical substances and physical properties. One must therefore start by recognising that bacterial virulence, being dependent on vital processes, cannot be fully explained in chemico-physical terms.
Combining Affinities in Bacterial Variation and Carcinogenesis
- Arthur Eastwood
-
- Journal:
- Journal of Hygiene / Volume 32 / Issue 3 / July 1932
- Published online by Cambridge University Press:
- 15 May 2009, pp. 301-331
-
- Article
-
- You have access Access
- Export citation
-
Although knowledge of principles determining variation is imperfect, some progress has been made and further help may be obtained from some of the newer conceptions about combining affinities regulating normal growth. There are reasons to believe that growth depends on a rhythmic cycle of synthesis, peculiar to living protein, whereby at each successive stage one particular “building stone” is selected for synthesis, with rejection of all others. There is also some evidence that the surface of a growing bacterium passes through periodic phases. Additional light on the activities of the bacterial surface is thrown by the new conception of enzymes which regards them not as fixed chemical entities but as chemico-physical “centres of activity.”
Some of the principles which are gradually coming to light in bacterial variation may ultimately be of assistance in the much more obscure problem of explaining the change from the normal mammalian cell to its malignant variant. I refer in particular to conceptions, which I have discussed in the preceding part of this article, about the mechanism of cellular growth and the nature of a cell's combining affinities.
The Capillary Endothelium in Relation to Antibodies
- Arthur Eastwood
-
- Journal:
- Journal of Hygiene / Volume 22 / Issue 3 / March 1924
- Published online by Cambridge University Press:
- 15 May 2009, pp. 355-387
-
- Article
-
- You have access Access
- Export citation
-
Pathologists and physiologists are agreed that the capillary endothelium is of high importance in the animal economy, though it is admitted that its functions are involved in much obscurity. With the immunologist, the primary difficulty is lack of physiological data which would enable him to start with the normal functions and to interpret abnormalities in the light of these. And it is obviously far from easy to plan experiments providing the sort of information the immunologist wants about the functions of endothelium as part of a living mechanism, in which parenchymatous cells, body fluids, and endothelial channels jointly participate.
Chemico-physical Stability and Cancer1
- Arthur Eastwood
-
- Journal:
- Journal of Hygiene / Volume 29 / Issue 2 / July 1929
- Published online by Cambridge University Press:
- 15 May 2009, pp. 117-131
-
- Article
-
- You have access Access
- Export citation
-
The prominence recently given to the Rous sarcoma has increased the confusion of hypotheses about malignancy. With a view to clarification, one may say that there are three simple hypotheses of outstanding importance, viz.: (1) the living virus hypothesis, which regards living viruses as the actual and effective cause of both the avian and the mammalian disease; (2) the autogenous enzyme hypothesis, which ascribes both diseases to the development within living cells of an ens malignitatis resembling an enzyme rather than a virus; and (3) the “chronic irritation” hypothesis, which explains mammalian malignancy on this principle and considers fowl sarcoma to be of a different nature.
A Note on Immunology and Malignant Disease.
- Arthur Eastwood
-
- Journal:
- Journal of Hygiene / Volume 24 / Issue 3-4 / December 1925
- Published online by Cambridge University Press:
- 15 May 2009, pp. 255-273
-
- Article
-
- You have access Access
- Export citation
-
The “chronic irritation” theory still retains its interest, though it has not yet provided a thoroughly satisfactory explanation of the origin of that stimulus to growth which causes normal tissue to become malignant. If employed with caution, ideas borrowed from bacteriological work on “transmissible autolysis” may be contributory in the search for the explanation which is desired.
It is important to maintain a careful distinction between the initiation and the continued propagation of the malignant variant.
It seems hazardous to assume that one can apply as immediately valid for cancer those ideas about the natural and acquired resistance of the host which are current in bacteriological literature. On the other hand, it is not suggested that such ideas should be discarded but rather that they should be regarded as suggesting alternative possibilities, none of which can be definitely excluded.
Analogies with immunological reactions to foreign protein (bacterial or animal) certainly suggest the possibility that the cure of cancer may be found in discovery of “the right antibody for the right antigen”; but it is not clear how far such analogies can be accepted as being entirely appropriate; still, owing to the likelihood that new kinds of antigens and antibodies will be discovered, continued search for these factors in cancer is of high importance.
In the present article, which is a sequel to a former discussion on stimulants to bacterial variation, I have considered whether the idea of a stimulus to the production of non-viable variants may be regarded as of immunological interest in relation to the therapeutic problem of cancer.
I have endeavoured to show that this idea is worth consideration, provided that its importance is not exaggerated and that it is correlated with better established data about the principles of immunity.
The Nature of Antibodies
- Arthur Eastwood
-
- Journal:
- Journal of Hygiene / Volume 33 / Issue 2 / April 1933
- Published online by Cambridge University Press:
- 15 May 2009, pp. 259-281
-
- Article
-
- You have access Access
- Export citation
-
It is best to begin with antibodies which conform to their original definition as new serological properties attributable to an antigenic stimulus.
Their origin is still disputed. They are often regarded as cellular secretions due to adsorption or ingestion of antigen. For my part, I consider that they are formed in the plasma by filtration through capillary endothelium which has adsorbed antigen.
The precise specificity which characterises many antibodies is difficult to explain. I have suggested that it may be due to an interplay of reactions between the dextro- and laevo-rotatory forms of particular combining affinities.
But antibodies are not always the exact counterparts of their antigens. I have discussed some of the possible reasons why animal idiosyncrasies may be responsible for irregular results. A defective yield may also be due to the antigen, which may be present in a masked condition.
It is often taken for granted that the characters of the antibodies found in the serum of an actively immunised animal are identical with those actually present in the animal's circulation. I have given reasons for thinking that this assumption is frequently erroneous.
Coming now to the more elastic conceptions of “antibodies,” which relate to properties not attributable to an antigenic stimulus, the part played by alexin in the circulation of the normal animal has first to be considered. It is not a distinctive chemical entity, nor is it simply a chemico-physical condition of the plasma; it is a complex of chemical and physical factors which defy analysis. The dual mechanism represented in vitro between alexin and “immune body” does not afford a true picture of alexin's activities in vivo.
The humoral factors in natural resistance are too complex to be regarded as a dual mechanism. The difference between susceptibility and resistance often depends on that precise sequence of events in the plasma's activities which is peculiar to the species or even to the individual.
Acquired immunity is a reconstruction of the normal mechanism, with the emergence of a definitely new property. It is not simply the introduction of a new antibody but involves also utilisation, with readjustment, of the complex biological conditions normally present. As a result of the antigenic stimulus: (1) antibodies may be formed which are the precise mirrors of their antigens; (2) by a similar but less precise mechanism, antibodies may arise which are not the exact counterpart of any particular antigen; (3) the antigenic stimulus may lead to complex humoral changes which are not identifiable as antibodies.
Current opinions on immunological principles, as expressed by well known authorities, exhibit divergencies which cannot be satisfactorily reconciled with each other. There is, however, general recognition that the present status of knowledge is highly deficient. Though the time is not yet ripe for anything like a finally satisfactory reconstruction of these principles, efforts in this direction are needed, with readjustment of the old ideas by the aid of hypotheses about what is going on in the living body.
Further Comments on the Causation of Malignant Disease1
- Arthur Eastwood
-
- Journal:
- Journal of Hygiene / Volume 28 / Issue 1 / August 1928
- Published online by Cambridge University Press:
- 15 May 2009, pp. 9-32
-
- Article
-
- You have access Access
- Export citation
-
Invisible infective agents may be divided into: (1) true, ultramicroscopic, living viruses, which do not arise de novo and, so far as is known, are not ubiquitous; (2) transmissible infective agents which arise de novo and are propagated through living cells, but are not themselves living organisms; (3) stimulants to variation which arise de novo, are not transmissible, and are not living organisms.
Class (1) is not represented in malignant disease. “Bacteriophage” is a representative of class (2); very probably the infective agent of fowl sarcoma comes under the same category, and possibly some important human diseases of doubtful aetiology. There is no satisfactory evidence that mammalian malignant disease is related to class (2); its causation, according to the “chronic irritation” theory, must be attributed to influences comprised within class (3).
The stimulants to variation in class (3) depend for their effectiveness upon the unstable energy of living matter. The changes which they produce are “biological” in the sense that they are changes of chemical constitution which could not be obtained without the aid of vital processes.
Regulation of normal growth in the animal body means regulation of the cell's facilities for obtaining energy. I think it is misleading to regard it as a forceful restraint (or stimulus) upon the cell's inherent capacity for unlimited growth.
The assumption, borrowed from “natural immunity” towards bacteria, that there is in the animal body a natural principle which destroys frequently occurring foci of incipient malignancy is also unsubstantiated and misleading.
During the latent period, certain cells, which subsequently grow into a neoplasm, lose their capacity to respond to inhibitory systemic influences. This change is brought about by local and not by systemic causes.
As regards the special class of tumour derived from cells which have been displaced in foetal life, long residence in an abnormal situation does not appear to be equivalent to the ordinary latent period; but it may have had the effect of increasing their susceptibility, so that, if exposed to chronic irritation, the cells would more readily lapse into the latent period predisposing to malignancy.
It is known that the various tissues of the animal body differ in their degree of susceptibility to the precancerous change. This is a cellular characteristic; so also is the difference in the susceptibility of one animal as compared with another. It is not a question of difference in a hypothetical humoral property of “systemic resistance.”
On the termination of the latent period by a fresh stimulus to proliferation, certain cells commence active growth and are incapable of responding to systemic inhibitory influences. These conditions seem sufficient for the origin of an innocent neoplasm. But something more is required to explain malignancy, because the malignant cell is essentially different from the cells in a benign tumour.
About the actual cause of the change to malignancy one can only offer conjectures. I have suggested a way in which the change may possibly be produced through the agency of the local endothelium and the autogenous formation of antibodies.
On taking a broad view, the change into the malignant variant is not something unique; equally remarkable changes are to be found in the properties of bacteria. In both cases the facts have to be accepted, at present, without satisfactory explanation of the conditions which gave rise to them. One finds with bacteria that degradation or “roughness” may be a phase preparatory to the acquirement of new properties, just as the degradation of cells in the latent period seems to be a requisite preparation for acquiring the new property of malignancy. But the actual steps involved in the change from a bacterial saprophyte to an invasive parasite are as difficult to understand as are the processes involved in the conversion of a normal animal cell into its malignant variant.
Throughout the study of cancer it is very desirable to maintain a clear distinction between cause and effect. For example, the enzymes peculiar to cancer are not the cause of cancer but the effect of the biological change which produced the cancerous cell.
Second Report on Bacteriological Aspects of the Meningococcus Carrier problem1
- Arthur Eastwood
-
- Journal:
- Journal of Hygiene / Volume 17 / Issue 2-3 / July 1918
- Published online by Cambridge University Press:
- 15 May 2009, pp. 63-123
-
- Article
-
- You have access Access
- Export citation
-
In my first report I showed that in the throats of persons not known to have been in contact with cases of cerebro-spinal fever organisms were frequently found which were indistinguishable from meningococci isolated from the cerebro-spinal fluid of persons suffering from that disease.
The Characteristics of Tubercle Bacilli in Human Bone and Joint Tuberculosis
- Arthur Eastwood, Fred Griffith
-
- Journal:
- Journal of Hygiene / Volume 15 / Issue 2 / January 1916
- Published online by Cambridge University Press:
- 15 May 2009, pp. 257-309
-
- Article
-
- You have access Access
- Export citation
-
The material on which this enquiry is based consisted of tuberculous tissue, pus, or fluid obtained from the sources specified in Table II, pp. 260–268.
Stimulants to Bacterial Variation
- Arthur Eastwood
-
- Journal:
- Journal of Hygiene / Volume 23 / Issue 3 / December 1924
- Published online by Cambridge University Press:
- 15 May 2009, pp. 317-346
-
- Article
-
- You have access Access
- Export citation
-
1. Immunity cannot be completely explained by antigen-antibody reactions, even if the term ‘antibodies’ be made sufficiently elastic to include various obscure properties which are exhibited, in vivo, in the actively immune animal. Various other factors have to be considered. One of these is the influence of stimuli upon the vital capacities of bacteria.
2. Transmissible bacterial autolysis appears to be due to a stimulus acting upon the growing bacterial cell and leading to the splitting off of a certain number of daughter-cells which are non-viable, and consequently undergo autolysis.
3. Transmissible autolysis is not due to a stimulus sui generis but is no more than a particular incident in the general phenomena of bacterial variation.
4. The secretions of bacteria in pure culture may stimulate, control, or retard their growth and may lead to the production of variants.
5. When introduced into the animal body, bacteria encounter stimulants of animal origin which may be either favourable or unfavourable to their growth and are to be distinguished from the stimulants attributable to the bacteria themselves.
6. One aspect of the differences between natural immunity and natural susceptibility may be interpreted as due to differences in the stimuli inherent in the particular animal species and to consequent differences in their effects upon the particular bacterial species.
7. Similarly, when no better explanation is available, the acquired immunity (active or passive) of a susceptible animal may be interpreted as a change of the animal's stimulant action from one which was favourable (or indifferent) to the growth of a bacterium to one which is adverse, i.e., a stimulant to the reproduction of daughter-cells which are non-viable in the animal body.
8. Leucocytes are one of the sources of material possessing two kinds of properties, viz., (a) stimulant action on the growth capacities of cells (both bacterial and animal) and (b) enzyme action on the constituents which living and dead cells possess in common. The older researches on the characters of leucocytic extracts were occupied with (b), though they may occasionally be linked up with (a), since there are some indications that their leucocytic material was also acting as „lytic substance.”
9. In some cases it must remain, for the present, an open question whether demonstrable antibacterial action is attributable to some more or less obscure enzymes or to what I have termed „stimuli.”
10. A stimulus may be a substance which is also an antibody, and its stimulative properties may be highly specific. But it would be absurd to assume that for each special kind of stimulative effect there is a special and chemically distinctive kind of stimulus. Both stimuli and antibodies usually possess a wide range of different combining affinities which cannot be explained on the „mosaic” theory that each different combination is due to the presence (in the stimulus or antibody) of a different chemical group.
11. A stimulus, as distinct from a food, causes the bacterial cell to function in a particular way but is not incorporated as part of the structure of the cell. This convenient distinction, however, does not imply that there is necessarily a sharp line of demarcation between a stimulus and a food.
Managed Care, Doctors, and Patients: Focusing on Relationships, Not Rights
- ROBYN S. SHAPIRO, KRISTEN A. TYM, DAN EASTWOOD, ARTHUR R. DERSE, JOHN P. KLEIN
-
- Journal:
- Cambridge Quarterly of Healthcare Ethics / Volume 12 / Issue 3 / July 2003
- Published online by Cambridge University Press:
- 01 July 2003, pp. 300-307
-
- Article
- Export citation
-
For over a decade, managed care has profoundly altered how healthcare is delivered in the United States. There have been concerns that the patient-physician relationship may be undermined by various aspects of managed care, such as restrictions on physician choice, productivity requirements that limit the time physicians may spend with patients, and the use of compensation formulas that reward physicians for healthcare dollars not spent. We have previously published data on the effects of managed care on the physician-patient relationship from the physician's perspective. In 1999, we collected data on the impact of managed care arrangements on the physician-patient relationship from the patient's perspective. This article discusses our collective findings.