- Email: [email protected]
THE ROYAL SOCIETY
1344
MEDICAL SOCIETIES THE ROYAL SOCIETY EXPERIMENTAL PRODUCTION OF MALIGNANT TUMOURS
AT a meeting of the Royal Society held on June 15th, with Sir GOWLAND HOPKINS, the president, in the chair, Dr. J. A. MURRAY opened a discussion in a survey which was published in our issue of last week.
The Chemistry of Carcinogenic Agents Dr. J. W. CooK then spoke of the production of cancer by pure chemical compounds. He agreed with Dr. Murray that the results offered no explanation of the mechanism of tumour production. Chronic irritation was an unsuitable term for the effects of carcinogenic agents on the skin. Many irritating constituents of coal-tar had no effect at all in a carcinogenic application. The essential chemical feature of carcinogenic agents was a carbon ring structure consisting of four or five aromatic rings. Compounds varied greatly in carcinogenic potency, and the were not entirely due to solubility variations. The most powerful was benzpyrene. The parent substance was benzanthracene, which had little cancer-producing power, though additions to its molecule produced many carcinogenic hydrocarbons. Negative results were obtained with 15 other derivatives and all except two of the hydrocarbons having five benzene rings. Cancer production, therefore, seemed to depend on a particular type of molecular arrangement. Subcutaneous tumours had also been obtained by injection of these substances, and one mouse tumour had reached its sixty-seventh generation. Dibenzanthracene tumours had also A number of naturally been obtained in fowls. substances contained the essential molecular occurring arrangement-e.g., vitamin D, the cardiac poisons, and the ovarian hormone. In the carcinogenic hydrocarbons all the rings were aromatic. The process of breakdown of cholesterin into the female hormone involved aromatisation of one ring, and an extension of the process to cancer-producing substances could easily be imagined. A correlation between carcinogenic and oestrogenic compounds had been shown in the 1, 2, 5, 6 dibenzanthracene ring system. Even more suggestive was the conversion of bile-acid substances into hydrocarbons of the benzanthracene group. The fate of the stearols and bile acids in the body might prove of great
differentiations
importance. The Problems of
agents.
.
Carcinogenesis by cell-free extracts was immediate and specific, thus differing from the other form of transmission. Moreover it could give rise to antibodies and, so far, was limited to fowls and to growths of mesoblastic origin. It had never been conclusively demonstrated in mammals. Experimentally it behaved like a virus and was more easily effected in young than aged birds, although spontaneous tumours were commoner in the old bird and behaved like mammalian cancer. The factor probably had a complex form, one part being of fowl origin and the other a virus. There was an apparent contradiction between fowl and mammalian tumours, and this contradiction had not yet been resolved. Those who so confidently denied the possibility of a virus took a narrow view. Normal animal cells might contain non-pathogenic viruses capable of transformation into pathogenic viruses in certain circumstances, just as bacteria might change their character. An injection of fowl-virus into the blood stream had no effect, but if a haemorrhage followed, a tumour would develop at its site. A better explanation than either- mutation or virus was the metabolic change in malignant cells which rendered them less-dependent on oxygen than normal cells. The oxygen supply was probably one of the devices whereby tissue control was integrated. The solution of the ultimate cause might not improve diagnosis or treatment, and the difficulties of explanation had tended to obscure the great advances that had been made. There was no greater mystery in cancer than in any other disease of cell life. It began as a local disease and in that stage could be cured and was being cured in a great majority of cases. If there were extraneous factors it must be possible to avoid them if they were known, and then cancer would be a preventable disease. Filtrable Fowl Tumours
Dr. C. H. ANDREwES said that filtrable fowl tumours formed a valuable line of attack on cancer as a whole ;
Carcinogenesis
Dr. W. CRAMER said that the normal cell
in man produced it in experimental animals, and, measured in biological time, the period required was much the same. The long period required for carcinogenesis explained the age-incidence of cancer ; it was more difficult to produce in the aged than in the young, and the age-incidence was not, therefore, due to any change in the host. The development of malignancy was undoubtedly influenced by susceptibility, probably inherited, in the host. The change known as chronic irritation might act by inducing the cells themselves to produce carcinogenic
was
always subject to stimuli from without. Malignancy was the negation of the integration between stimulus and reaction. From this derived the transplantability of malignant tissue ; the malignant cell
dominated the connective tissue reaction and so was able to establish itself. In the rare cases of spontaneous regression and under the influence of radium the connective tissue regained its dominance. The change was due to something within the cell which could not be separated from it. Transplantation was simply tissue culture in vivo. The change was probably in the nucleus. Carcinogenesis presented two problems : the nature of the change and the manner in which it was induced ; the latter was practically solved, but the former was still quite unknown. The agents which produced cancer
it was not possible to regard them as quite different from mammalian or other fowl tumours. All fowl tumours sooner or later proved to be filtrable. The filtrable agents could be neutralised by specific antibodies from tumour-bearing or immunised birds. Serological studies had thrown interesting light on the problem. The agents behaved in most respects like viruses, but one tumour appeared in a flock while no others were found, or others of quite a different type appeared. Serologists could point out that the body did not produce both an agent and an antibody to it. Moreover, the antibodies behaved just like other virus antibodies. Serologically, therefore, the agents seemed to be actually viruses and not something produced by the host. The necessary postulation of multiple viruses was a difficulty. This problem could be studied from the serological
1345 of view, but the answer was indefinite. In fowls all the viruses seemed to be the same, but pheasant sera were much more specific. Bacteria also had specific and group antibodies. The virus antibodies were neither identical nor entirely distinct and either finding might be stressed in building a theory. Goats could yield antifowl antibodies, and these neutralised fowl tumour extracts but were heat-labile. This seemed a strong argument for the fowl origin of the filtrable agent, but further observations showed that the characteristic might not be permanent. The association between the virus and the protein was probably closer than in any other virus, and might determine the specificity. The viruses which caused tumours were’ not to be distinguished from those causing infections.
point
FOWL TUMOURS FROM TAR PRODUCTS
Dr. P. R. PEACOCK said that the relationship between avian and mammalian tumours must be solved before speculations as to the cause of tumours were profitable. An interesting method of study was the application of carcinogenic agents to fowls. There was no difficulty in producing fowl tumours by tar products. One such tumour had been propagated through 11 generations without ever becoming filtrable. Dr. Peacock gave an account of his experiments in this connexion. In 139 birds he had succeeded in producing 32 tumours, 14 of which metastasised widely. A number of the growths had proved transplantable by an injection of finely ground suspensions-not guaranteed cell-free, but such as would not usually reproduce a mammalian tumour. None, however, had become filtrable yet. The growths were exactly comparable with mammalian growths and paralleled the spontaneous fowl tumours which had eventually become filtrable. Prof. J. MCINTOSH confirmed the importance of Dr. Peacock’ss investigations and described facts which had come to light in the course of his work along these lines. Some 30 different kinds of Rous tumour had been obtained and their pleomorphism needed explana’,ion, as did their relationship with mammalian tur_ours. He had injected normal and Rous-immune fowls with tar in lard ; some had survived for a year. Tumours had been found in just over 50 per cent. of the birds injected. The breast muscle injected did not always bear a tumour, but showed local cell reaction in addition to the marked cell proliferation always found in some other organ. The tumours might resemble the Rous sarcoma or be fibro-endotheliomatous, leucoblastic, or angeio-endotheliomatous. Some birds showed leukaemia after tarring. The Rous-immune birds never developed a Rous tumour, but showed fibroor angeio-endotheliomatous growths and leuksemia. One tumour had been transmitted for six or eight passages and others for less ; the older one was filtrable and corresponded with the Rous type. A spontaneous tumour had never been found in the 5000 birds used ; the tar must act as a carcinogenic agent. The extraordinary pleomorphism had been found associated with a leuksemic virus. These results indicated a number of possible explanations. The filtrable leukaemia along with a filtrable Rous type of tumour in tar-treated birds might be explained as the result of tar stimulation activating the tissues, which were then acted on by a virus widely distributed in the fowl world. The second explanation was a pleomorphism in the virus, which could have an affinity with any mesoblastic tissue. The third and perhaps the simplest was the acceptance of some form of specific factor in addition
to
a
virus, determining which cell should be attacked. ground had yet to be covered before, the
Much
between fowl and mammalian tumours would be cleared up. Dr. W. E. GYE said he had found no cross-relationship between leukaemia and tumours. One of the puzzles of the cancer problem was the remarkable variation in the rate of growth of apparently similar tumours. The slow-growing tumours contained an inhibitory factor, which had been demonstrated by J. B. Murphy. There was a quantitative relationship between the rate of growth and the inhibitory factor. The rate of progress in this work depended on looking inside a cell rather than at its morphology.
relationship
Conclusion Prof. A. E. BOYCOTT did not think Dr. Murray’s. three hypotheses were alternative. A gene mutation might explain why a cancer cell was different from a normal cell, but could not explain the cause of cancer. The growth of a cancer cell was different from that of normal cells, but it had its own code of growth and histology and stuck to it for ever and ever. Surely its cells must differ genetically from those of the host. The gene mutation theory was the most useful explanation of this fact. The two other hypotheses might be made two stages of the same hypothesis to explain the production of this change. A great variety of physical and chemical agents had carcinogenic power. The problem was : did they act on normal cells directly or did they all cause the production of some carcinogenic agent in the tissues ? There was very little convincing evidence,, for an extraneous virus. Fowls never caught tumours from one another, and a virus that stood all the knocking about that this agent could stand must be a remarkable one. The antigenic argument could be carried too far. Protein compounds were different from the original protein. antigenically If " normal " viruses occurred in " normal " cells they were perhaps better called by some other name than " virus."
ROYAL SOCIETY OF MEDICINE SECTION OF OBSTETRICS AND GYNÆCOLOGY AT a meeting of this section on June 16th, with Mr. J. P. HEDLEY, the president, in the chair, a
discussion took
place
on
Uterine Inertia Mr. A. C. H. BELL, speaking of inertia in the first stage of labour, said that its scientific treatment could not be established on a sure footing until its cause was known. Among the predisposing causes in text-books were overdistension of the uterus given in association with weak pains, premature rupture of membranes, and malpresentations such as the persistent occipito-posterior. In regard to this last, non-rotation of the occiput was probably a result of the inertia, not the cause of it. The part played by hormones was uncertain, though it was known that extract of posterior pituitary lobe stimulated contraction of uterine muscle. Possibly fear, resulting in the liberation of adrenaline, might inhibit uterine contraction. There was little evidence to support the idea that fibrosis was a cause of rigid cervix. The clinical evidence was strong that inertia usually occurred in women undergoing their first confinement, especially those who were nervous. He had recentlycollected the available facts concerning 49 cases of severe inertia which occurred among 4500 consecutive.
MEDICAL SOCIETIES THE ROYAL SOCIETY EXPERIMENTAL PRODUCTION OF MALIGNANT TUMOURS
AT a meeting of the Royal Society held on June 15th, with Sir GOWLAND HOPKINS, the president, in the chair, Dr. J. A. MURRAY opened a discussion in a survey which was published in our issue of last week.
The Chemistry of Carcinogenic Agents Dr. J. W. CooK then spoke of the production of cancer by pure chemical compounds. He agreed with Dr. Murray that the results offered no explanation of the mechanism of tumour production. Chronic irritation was an unsuitable term for the effects of carcinogenic agents on the skin. Many irritating constituents of coal-tar had no effect at all in a carcinogenic application. The essential chemical feature of carcinogenic agents was a carbon ring structure consisting of four or five aromatic rings. Compounds varied greatly in carcinogenic potency, and the were not entirely due to solubility variations. The most powerful was benzpyrene. The parent substance was benzanthracene, which had little cancer-producing power, though additions to its molecule produced many carcinogenic hydrocarbons. Negative results were obtained with 15 other derivatives and all except two of the hydrocarbons having five benzene rings. Cancer production, therefore, seemed to depend on a particular type of molecular arrangement. Subcutaneous tumours had also been obtained by injection of these substances, and one mouse tumour had reached its sixty-seventh generation. Dibenzanthracene tumours had also A number of naturally been obtained in fowls. substances contained the essential molecular occurring arrangement-e.g., vitamin D, the cardiac poisons, and the ovarian hormone. In the carcinogenic hydrocarbons all the rings were aromatic. The process of breakdown of cholesterin into the female hormone involved aromatisation of one ring, and an extension of the process to cancer-producing substances could easily be imagined. A correlation between carcinogenic and oestrogenic compounds had been shown in the 1, 2, 5, 6 dibenzanthracene ring system. Even more suggestive was the conversion of bile-acid substances into hydrocarbons of the benzanthracene group. The fate of the stearols and bile acids in the body might prove of great
differentiations
importance. The Problems of
agents.
.
Carcinogenesis by cell-free extracts was immediate and specific, thus differing from the other form of transmission. Moreover it could give rise to antibodies and, so far, was limited to fowls and to growths of mesoblastic origin. It had never been conclusively demonstrated in mammals. Experimentally it behaved like a virus and was more easily effected in young than aged birds, although spontaneous tumours were commoner in the old bird and behaved like mammalian cancer. The factor probably had a complex form, one part being of fowl origin and the other a virus. There was an apparent contradiction between fowl and mammalian tumours, and this contradiction had not yet been resolved. Those who so confidently denied the possibility of a virus took a narrow view. Normal animal cells might contain non-pathogenic viruses capable of transformation into pathogenic viruses in certain circumstances, just as bacteria might change their character. An injection of fowl-virus into the blood stream had no effect, but if a haemorrhage followed, a tumour would develop at its site. A better explanation than either- mutation or virus was the metabolic change in malignant cells which rendered them less-dependent on oxygen than normal cells. The oxygen supply was probably one of the devices whereby tissue control was integrated. The solution of the ultimate cause might not improve diagnosis or treatment, and the difficulties of explanation had tended to obscure the great advances that had been made. There was no greater mystery in cancer than in any other disease of cell life. It began as a local disease and in that stage could be cured and was being cured in a great majority of cases. If there were extraneous factors it must be possible to avoid them if they were known, and then cancer would be a preventable disease. Filtrable Fowl Tumours
Dr. C. H. ANDREwES said that filtrable fowl tumours formed a valuable line of attack on cancer as a whole ;
Carcinogenesis
Dr. W. CRAMER said that the normal cell
in man produced it in experimental animals, and, measured in biological time, the period required was much the same. The long period required for carcinogenesis explained the age-incidence of cancer ; it was more difficult to produce in the aged than in the young, and the age-incidence was not, therefore, due to any change in the host. The development of malignancy was undoubtedly influenced by susceptibility, probably inherited, in the host. The change known as chronic irritation might act by inducing the cells themselves to produce carcinogenic
was
always subject to stimuli from without. Malignancy was the negation of the integration between stimulus and reaction. From this derived the transplantability of malignant tissue ; the malignant cell
dominated the connective tissue reaction and so was able to establish itself. In the rare cases of spontaneous regression and under the influence of radium the connective tissue regained its dominance. The change was due to something within the cell which could not be separated from it. Transplantation was simply tissue culture in vivo. The change was probably in the nucleus. Carcinogenesis presented two problems : the nature of the change and the manner in which it was induced ; the latter was practically solved, but the former was still quite unknown. The agents which produced cancer
it was not possible to regard them as quite different from mammalian or other fowl tumours. All fowl tumours sooner or later proved to be filtrable. The filtrable agents could be neutralised by specific antibodies from tumour-bearing or immunised birds. Serological studies had thrown interesting light on the problem. The agents behaved in most respects like viruses, but one tumour appeared in a flock while no others were found, or others of quite a different type appeared. Serologists could point out that the body did not produce both an agent and an antibody to it. Moreover, the antibodies behaved just like other virus antibodies. Serologically, therefore, the agents seemed to be actually viruses and not something produced by the host. The necessary postulation of multiple viruses was a difficulty. This problem could be studied from the serological
1345 of view, but the answer was indefinite. In fowls all the viruses seemed to be the same, but pheasant sera were much more specific. Bacteria also had specific and group antibodies. The virus antibodies were neither identical nor entirely distinct and either finding might be stressed in building a theory. Goats could yield antifowl antibodies, and these neutralised fowl tumour extracts but were heat-labile. This seemed a strong argument for the fowl origin of the filtrable agent, but further observations showed that the characteristic might not be permanent. The association between the virus and the protein was probably closer than in any other virus, and might determine the specificity. The viruses which caused tumours were’ not to be distinguished from those causing infections.
point
FOWL TUMOURS FROM TAR PRODUCTS
Dr. P. R. PEACOCK said that the relationship between avian and mammalian tumours must be solved before speculations as to the cause of tumours were profitable. An interesting method of study was the application of carcinogenic agents to fowls. There was no difficulty in producing fowl tumours by tar products. One such tumour had been propagated through 11 generations without ever becoming filtrable. Dr. Peacock gave an account of his experiments in this connexion. In 139 birds he had succeeded in producing 32 tumours, 14 of which metastasised widely. A number of the growths had proved transplantable by an injection of finely ground suspensions-not guaranteed cell-free, but such as would not usually reproduce a mammalian tumour. None, however, had become filtrable yet. The growths were exactly comparable with mammalian growths and paralleled the spontaneous fowl tumours which had eventually become filtrable. Prof. J. MCINTOSH confirmed the importance of Dr. Peacock’ss investigations and described facts which had come to light in the course of his work along these lines. Some 30 different kinds of Rous tumour had been obtained and their pleomorphism needed explana’,ion, as did their relationship with mammalian tur_ours. He had injected normal and Rous-immune fowls with tar in lard ; some had survived for a year. Tumours had been found in just over 50 per cent. of the birds injected. The breast muscle injected did not always bear a tumour, but showed local cell reaction in addition to the marked cell proliferation always found in some other organ. The tumours might resemble the Rous sarcoma or be fibro-endotheliomatous, leucoblastic, or angeio-endotheliomatous. Some birds showed leukaemia after tarring. The Rous-immune birds never developed a Rous tumour, but showed fibroor angeio-endotheliomatous growths and leuksemia. One tumour had been transmitted for six or eight passages and others for less ; the older one was filtrable and corresponded with the Rous type. A spontaneous tumour had never been found in the 5000 birds used ; the tar must act as a carcinogenic agent. The extraordinary pleomorphism had been found associated with a leuksemic virus. These results indicated a number of possible explanations. The filtrable leukaemia along with a filtrable Rous type of tumour in tar-treated birds might be explained as the result of tar stimulation activating the tissues, which were then acted on by a virus widely distributed in the fowl world. The second explanation was a pleomorphism in the virus, which could have an affinity with any mesoblastic tissue. The third and perhaps the simplest was the acceptance of some form of specific factor in addition
to
a
virus, determining which cell should be attacked. ground had yet to be covered before, the
Much
between fowl and mammalian tumours would be cleared up. Dr. W. E. GYE said he had found no cross-relationship between leukaemia and tumours. One of the puzzles of the cancer problem was the remarkable variation in the rate of growth of apparently similar tumours. The slow-growing tumours contained an inhibitory factor, which had been demonstrated by J. B. Murphy. There was a quantitative relationship between the rate of growth and the inhibitory factor. The rate of progress in this work depended on looking inside a cell rather than at its morphology.
relationship
Conclusion Prof. A. E. BOYCOTT did not think Dr. Murray’s. three hypotheses were alternative. A gene mutation might explain why a cancer cell was different from a normal cell, but could not explain the cause of cancer. The growth of a cancer cell was different from that of normal cells, but it had its own code of growth and histology and stuck to it for ever and ever. Surely its cells must differ genetically from those of the host. The gene mutation theory was the most useful explanation of this fact. The two other hypotheses might be made two stages of the same hypothesis to explain the production of this change. A great variety of physical and chemical agents had carcinogenic power. The problem was : did they act on normal cells directly or did they all cause the production of some carcinogenic agent in the tissues ? There was very little convincing evidence,, for an extraneous virus. Fowls never caught tumours from one another, and a virus that stood all the knocking about that this agent could stand must be a remarkable one. The antigenic argument could be carried too far. Protein compounds were different from the original protein. antigenically If " normal " viruses occurred in " normal " cells they were perhaps better called by some other name than " virus."
ROYAL SOCIETY OF MEDICINE SECTION OF OBSTETRICS AND GYNÆCOLOGY AT a meeting of this section on June 16th, with Mr. J. P. HEDLEY, the president, in the chair, a
discussion took
place
on
Uterine Inertia Mr. A. C. H. BELL, speaking of inertia in the first stage of labour, said that its scientific treatment could not be established on a sure footing until its cause was known. Among the predisposing causes in text-books were overdistension of the uterus given in association with weak pains, premature rupture of membranes, and malpresentations such as the persistent occipito-posterior. In regard to this last, non-rotation of the occiput was probably a result of the inertia, not the cause of it. The part played by hormones was uncertain, though it was known that extract of posterior pituitary lobe stimulated contraction of uterine muscle. Possibly fear, resulting in the liberation of adrenaline, might inhibit uterine contraction. There was little evidence to support the idea that fibrosis was a cause of rigid cervix. The clinical evidence was strong that inertia usually occurred in women undergoing their first confinement, especially those who were nervous. He had recentlycollected the available facts concerning 49 cases of severe inertia which occurred among 4500 consecutive.