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COMMONWEALTH SCHOOLS
405
Letters
to
the Editor
COMMONWEALTH SCHOOLS SIR,-Dr. Rabindran’s suggestion (Aug. 10) that those going to developing countries should have orientation courses is excellent. I believe that in Ghana this has been arranged not only for expatriates but also for those returning after acquiring a higher diploma. I think, however, that he mistakes the intention of the Stoke school. This aims at a supervised practical course which will give an opportunity for those who have to take a National Health Service post to acquire recommendations in this country which will help them to get posts of reasonable educational value. Had this course been called a preliminary Membership course I suspect there would have been no shortage of applicants. It is regrettable that courses in higher medicine or surgery or in the basic sciences are misnamed by overseas " graduates Membership or " Fellowship " or " Primary " courses. It is more unfortunate that they and their overseas sponsors believe that these courses are a substitute for, rather than a supplement to, good responsible clinical experience. All would agree on the personal advantages that British diplomas confer. It is less certain that the mass export of diplomas to developing countries is of value to them in solving their health problems. "
New Cross Hospital,
Wolverhampton.
P. W. HUTTON.
EFFECTS OF THALIDOMIDE ON HUMAN LEUCOCYTE CULTURES
SIR,-On the hypothesis that the teratogenic action of thalidomide depends on its inhibitory effect on growing tissues, or more specifically, as suggested by Hunter,! that this compound has direct antimitotic properties, Back et al. have tested its chemotherapeutic effect on malignant growth. Their results of such experiments with one type of adenocarcinoma and one type of leukaemia in mice were entirely negative. Roath et al. 34 studied the effect of thalidomide and some of its derivatives on in-vitro cultures of human leucocytes initiated by the addition of phytohemagglutinin (P.H.A.). They observed a strong inhibitory effect on the transformation of the lymphocytes into " blast " cells, amounting to about 50% of the cells at a concentration of 3 ilg. of thalidomide per ml. of the culture medium. Since this " blast " formation of the lymphocytes has been interpreted56 as the first of a series of changes leading to a general mitotic activity and the growth of the culture, the observations of Roath et al. 34 may seem to support Hunter’s2 explanation of an antimitotic property of thalidomide. Because some of our recent results from work with human leucocyte cultures are relevant to this discussion, we should like to introduce them here. In our investigation, which is primarily concerned with the improvement and standardisation of P.H.A.-stimulated humancultures for use in screening tests of drugs, thalidomide has been tested on 30 leucocyte cultures from 11 different individuals. Concentrations varied from 10 to 200 g. per ml. In 3 of the cultures no cells in mitosis were observed. In all
leucocytes
1. 2. 3 4. 5. 6.
Hunter, T. A. A. Lancet, 1962, ii, 400. Back, A., Bichel, J., Hejgaard, J. J. ibid. 1963, i, 1271. Roath, S., Elves, M. W., Israels, M. C. G. ibid. 1962, ii, 812. Roath, S., Elves, M. W., Israels, M. C. G. ibid. 1963, i, 249. Nowell, P. C. Exp. Cell Res. 1960, 19, 267. Elves, M. W., Wilkinson, J. F. Nature, Lond. 1962, 194, 1257.
the rest the mitotic index did not differ significantly from that of the matched control cultures. But some reservation should be made with respect to the fact that, with the present methodological error of this test, amounting to ±30%, comparisons are rather unreliable. As regards the possibility that thalidomide may be unstable at physiological pH,’’ 7 cultures from 3 individuals were given additional doses on the second and third days. Although the final concentrations of thalidomide in these cultures reached a value of 150 g. per ml., no significant changes of their mitotic indices were observed.
Thus these experimental data do not indicate that thalidomide possesses any general antimitotic properties. Moreover, the " blast"cell transformation mentioned above 34 does not appear to be a change which is necessary to prepare the cells for the following mitoses, since it can be inhibited without any significant influence on the mitotic activity. The variation of several cell and culture properties, such as thalidomide sensitivity, between cells derived from different individuals needs further clarification. Our results are so far suggestive, only, of a variation in which genetical determinants play a significant part. These problems are at present being investigated in this laboratory on cell cultures derived from twins. So far we have not found any reported data on man, but recent investigations by Hagenindicate that the susceptibility to the teratogenic action of thalidomide in mice is genetically determined. This investigation was supported in part by a grant from the Swedish Cancer Society Institute for Medical Genetics, University of Uppsala, Sweden.
KERSTIN LINDAHL-KIESSLING JAN A. BÖÖK.
A GENETIC THEORY OF INFLAMMATORY POLYARTHRITIS
SIR,-Mr. and Mrs. Maynard Smith (Aug. 17) and Dr. Burch (June 8) should reconsider the concept of somatic mutation before leading us into academic algebraic argument. Mutation in the de Vries sense of the word is a sudden, rare, genetic change manifest after sexual reproduction, such as that which produced the ancon sheep. Leaving sex out of it, presumably somatic mutation means a sudden rare change in a somatic cell population which may give rise to a new clone of cells. The concept tacitly assumes that somatic cells in general breed or divide true except for the rare event of a mutation. A little thought shows this assumption to be nonsense. When many zygotes divide they go through one-, two-, three-, four-, and five-celled stages and not through one-, two-, four-, eight-, and sixteen-celled stages. Change is occurring at each cell division. When a basal skin cell divides it may give rise to another basal cell and a prickle cell. The two clones of cellsbasal cells and prickle cells-do not arise from sudden rare changes, but by a common and continuing process. It is also known that yeasts and fungi can produce new clones by continuous processes without mutation. Never since 1902 has Boveri’s somatic mutation theory adequately described the facts of the cancer problem. Why now try and drag it in to describe other diseases ? "-The difficulty lies, not in the new ideas, but in escaping from the old ones ..." The old idea is that when a cell divides the two daughter cells are genetically identical. This is manifestly untrue. A skin cell of Mrs. Jones will certainly give rise to two daughter cells which are still Mrs. Jones’s skin cells; but, as far as the genetics of clones is concerned, some variation may occur at every cell division.
With regard to the problem of polyarthritis, anyone with some experience of the disease knows that clinical 7. 8.
Williams, R. T. Lancet, 1963, i, 723. Hagen, E. O. ibid. p. 501.
Letters
to
the Editor
COMMONWEALTH SCHOOLS SIR,-Dr. Rabindran’s suggestion (Aug. 10) that those going to developing countries should have orientation courses is excellent. I believe that in Ghana this has been arranged not only for expatriates but also for those returning after acquiring a higher diploma. I think, however, that he mistakes the intention of the Stoke school. This aims at a supervised practical course which will give an opportunity for those who have to take a National Health Service post to acquire recommendations in this country which will help them to get posts of reasonable educational value. Had this course been called a preliminary Membership course I suspect there would have been no shortage of applicants. It is regrettable that courses in higher medicine or surgery or in the basic sciences are misnamed by overseas " graduates Membership or " Fellowship " or " Primary " courses. It is more unfortunate that they and their overseas sponsors believe that these courses are a substitute for, rather than a supplement to, good responsible clinical experience. All would agree on the personal advantages that British diplomas confer. It is less certain that the mass export of diplomas to developing countries is of value to them in solving their health problems. "
New Cross Hospital,
Wolverhampton.
P. W. HUTTON.
EFFECTS OF THALIDOMIDE ON HUMAN LEUCOCYTE CULTURES
SIR,-On the hypothesis that the teratogenic action of thalidomide depends on its inhibitory effect on growing tissues, or more specifically, as suggested by Hunter,! that this compound has direct antimitotic properties, Back et al. have tested its chemotherapeutic effect on malignant growth. Their results of such experiments with one type of adenocarcinoma and one type of leukaemia in mice were entirely negative. Roath et al. 34 studied the effect of thalidomide and some of its derivatives on in-vitro cultures of human leucocytes initiated by the addition of phytohemagglutinin (P.H.A.). They observed a strong inhibitory effect on the transformation of the lymphocytes into " blast " cells, amounting to about 50% of the cells at a concentration of 3 ilg. of thalidomide per ml. of the culture medium. Since this " blast " formation of the lymphocytes has been interpreted56 as the first of a series of changes leading to a general mitotic activity and the growth of the culture, the observations of Roath et al. 34 may seem to support Hunter’s2 explanation of an antimitotic property of thalidomide. Because some of our recent results from work with human leucocyte cultures are relevant to this discussion, we should like to introduce them here. In our investigation, which is primarily concerned with the improvement and standardisation of P.H.A.-stimulated humancultures for use in screening tests of drugs, thalidomide has been tested on 30 leucocyte cultures from 11 different individuals. Concentrations varied from 10 to 200 g. per ml. In 3 of the cultures no cells in mitosis were observed. In all
leucocytes
1. 2. 3 4. 5. 6.
Hunter, T. A. A. Lancet, 1962, ii, 400. Back, A., Bichel, J., Hejgaard, J. J. ibid. 1963, i, 1271. Roath, S., Elves, M. W., Israels, M. C. G. ibid. 1962, ii, 812. Roath, S., Elves, M. W., Israels, M. C. G. ibid. 1963, i, 249. Nowell, P. C. Exp. Cell Res. 1960, 19, 267. Elves, M. W., Wilkinson, J. F. Nature, Lond. 1962, 194, 1257.
the rest the mitotic index did not differ significantly from that of the matched control cultures. But some reservation should be made with respect to the fact that, with the present methodological error of this test, amounting to ±30%, comparisons are rather unreliable. As regards the possibility that thalidomide may be unstable at physiological pH,’’ 7 cultures from 3 individuals were given additional doses on the second and third days. Although the final concentrations of thalidomide in these cultures reached a value of 150 g. per ml., no significant changes of their mitotic indices were observed.
Thus these experimental data do not indicate that thalidomide possesses any general antimitotic properties. Moreover, the " blast"cell transformation mentioned above 34 does not appear to be a change which is necessary to prepare the cells for the following mitoses, since it can be inhibited without any significant influence on the mitotic activity. The variation of several cell and culture properties, such as thalidomide sensitivity, between cells derived from different individuals needs further clarification. Our results are so far suggestive, only, of a variation in which genetical determinants play a significant part. These problems are at present being investigated in this laboratory on cell cultures derived from twins. So far we have not found any reported data on man, but recent investigations by Hagenindicate that the susceptibility to the teratogenic action of thalidomide in mice is genetically determined. This investigation was supported in part by a grant from the Swedish Cancer Society Institute for Medical Genetics, University of Uppsala, Sweden.
KERSTIN LINDAHL-KIESSLING JAN A. BÖÖK.
A GENETIC THEORY OF INFLAMMATORY POLYARTHRITIS
SIR,-Mr. and Mrs. Maynard Smith (Aug. 17) and Dr. Burch (June 8) should reconsider the concept of somatic mutation before leading us into academic algebraic argument. Mutation in the de Vries sense of the word is a sudden, rare, genetic change manifest after sexual reproduction, such as that which produced the ancon sheep. Leaving sex out of it, presumably somatic mutation means a sudden rare change in a somatic cell population which may give rise to a new clone of cells. The concept tacitly assumes that somatic cells in general breed or divide true except for the rare event of a mutation. A little thought shows this assumption to be nonsense. When many zygotes divide they go through one-, two-, three-, four-, and five-celled stages and not through one-, two-, four-, eight-, and sixteen-celled stages. Change is occurring at each cell division. When a basal skin cell divides it may give rise to another basal cell and a prickle cell. The two clones of cellsbasal cells and prickle cells-do not arise from sudden rare changes, but by a common and continuing process. It is also known that yeasts and fungi can produce new clones by continuous processes without mutation. Never since 1902 has Boveri’s somatic mutation theory adequately described the facts of the cancer problem. Why now try and drag it in to describe other diseases ? "-The difficulty lies, not in the new ideas, but in escaping from the old ones ..." The old idea is that when a cell divides the two daughter cells are genetically identical. This is manifestly untrue. A skin cell of Mrs. Jones will certainly give rise to two daughter cells which are still Mrs. Jones’s skin cells; but, as far as the genetics of clones is concerned, some variation may occur at every cell division.
With regard to the problem of polyarthritis, anyone with some experience of the disease knows that clinical 7. 8.
Williams, R. T. Lancet, 1963, i, 723. Hagen, E. O. ibid. p. 501.