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HUMAN LYMPHOID CELL LINES : POTENTIAL HAZARDS TO LABORATORY WORKERS
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predicted by our unified theory of growth and disease.1-3 Theory also indicates potential complications (see below) that need to be borne in mind when such associations are tested. Genes that predispose to diseases with reproducible agepatterns are expected to code for polypeptide components of complex recognition molecules.1-3 These molecules serve to identify cells in the feedback system that controls and coordinates growth: they are synthesised both in the central controlling cells and in the cells of the tissue whose growth is homoeostatically regulated. We call the recognition molecules in the central part of the controlling system mitotic control proteins (M.C.P.S), and those in the controlled, or target tissue, tissue coding factors (T.C.F.S). Each distinctive target tissue is characterised by a specific T.C.F., and the element in the central system that controls its growth has a specific mz.c.P. Some or all of the genes that code for the protein component of a given T.c.F. also code for the protein component of the cognate M.c.p. Hence, mutual recognition along both the efferent and afferent pathways of growth-control exploits the identity of the protein components of related M.c.p.s and T.C.F.s. (Non-protein constituents probably distinguish M.c.p.s from T.C.F.S.) Cell-borne T.C.F.s and the cellular M.C.P.S carried by thymus-dependent small lymphocytes comprise histocompatibility antigens, conventional tissue-specific antigens, and many subtler determinants that distinguish, for example, one small section of epidermis from another, and a left tissue from its right counterpart. 1-3 Our theory predicts, therefore, that correlations should be found between predisposition to age-dependent disease, and M.C.P.-T.C.F. proteins, which, in man, include the major HL-A histocompatibility antigens.1-3 The observations of Dr. Zervas and his colleagues confirm these predictions. Now to the complications. Many diseases that appear by ordinary clinical criteria to be more or less homogeneous, probably consist of a complex of two or more genetically distinctive entities. 2, 4-7 There is little doubt that Hodgkin’s disease belongs to this category : three distinct groups can be distinguished, each with a characteristic sex and age distribution.2,4,5,7 Because the genetic predisposition of each group should differ, in at least one respect, from that for the other two, we can understand why Dr. Zervas and his colleagues failed to find the HL-A5 antigen in 100% of their patients with Hodgkin’s disease. This kind of complication might also help to explain why Walford et al.8 found correlations between the HL-A2 and Merritt antigens on the one hand, and acute childhood leukxmia on the other, whereas other investigators did not. Acute childhood 1eukaemia probably consists of at least four genetically distinctive diseases, and, in general, their relative and absolute proportions can be expected to differ from one population to another.2 When a disease consists of more than one genetically distinctive type, each with its characteristic sex and age distributions, then age-at-onset can often help to assess the type when clinical and histopathological differences are inconclusive. It follows from our theory that if antisera could be developed in sufficient numbers and specificity to identify all the relevant components of M.c.p.s and T.c.F.s associated Burch, P. R. J., Burwell, R. G. Q. Rev. Biol. 1965, 40, 252. Burch, P. R. J. An Inquiry Concerning Growth, Disease and Ageing. Edinburgh, 1968. 3. Burch, P. R. J. Nature, 1970, 225, 512. 4. MacMahon, B. Cancer Res. 1966, 26, 1189. 5. Cole, P., MacMahon, B., Aisenberg, A. Lancet, 1968, ii, 1371. 6. Burch, P. R. J., Milunsky, A. ibid. 1969, i, 554. 7. Burch, P. R. J. ibid. 1970, i, 469. 8. Walford, R. L., Finkelstein, S., Neerhout, R., Konrad, P., Shanbrom, E. Nature, 1970, 225, 461. 1. 2.
with a given disease, then should become possible. General Infirmary, Leeds 1.
entirely objective diagnosis P. R. J. BURCH.
HUMAN LYMPHOID CELL LINES : POTENTIAL HAZARDS TO LABORATORY WORKERS SiR,łThe recent report of Choi and Bloom1 is likely to stimulate many investigators to employ their techniques of establishing and cloning these predominantly diploid human lymphoid cell lines. Choi and Bloom established such lines from comparatively small numbers of peripheralblood leucocytes from normal subjects by exposing the leucocytes to cell-free lysates derived from a lymphoid cell line established from a patient with infectious mononucleosis or by co-cultivation with a minor population of cells of that line. The Henles have reviewed the evidence which implicates the Epstein-Barr (E.B.) virus as the astiological agent in both infectious mononucleosis and Burkitt’s lymphoma.2 An xtiological role in Burkitt’s lymphoma is further supported by the evidence of E.B. virus nucleic acid homology in a " virus-free" line of Burkitt tumour cells.3 It seems reasonable to assume, as a working hypothesis, that all established human lymphoid cell lines, including those derived from " normal" subjects 4,5 and those derived by exposure to lysates from virus-free " cell lines, represent viral transformants. One can therefore raise the question of the potential hazard to laboratory workers presented by the widespread use of cell lines which may have the potential for vegetative replication of an infectious agent implicated in the pathogenesis of a naturally occurring human neoplasm. Although this agent may be ubiquitous in manone must consider the potential risk to particularly susceptible subjects, especially in view of the enormous numbers of a specific virus to which an individual may be exposed under conditions of cell culture. There is the further possibility of the inadvertent in-vitro selection for variants with enhanced oncogenic or other pathogenic properties, especially in experiments employing mutagens. As a minimum precaution, we suggest that laboratory workers employ vertical laminar-flow hoods when handling such cultures.’ In the United States, such hoods have recently become commerciallv available from at least eight different manufacturers.8 Pathology Department, GEORGE M. MARTIN University of Washington, BARBARA R. SCHWARTZ Seattle, Washington 98105, MARY ANN DERR. U.S.A. "
VENEREAL DISEASE
SiR,łIwould support on every count the views of Dr. Jefferiss (Sept. 26, p. 673) regarding the need to maintain extended hours for v.D. clinics. Over and above the personal problems there are also epidemiological considerations. The V.D. service in this country should miss no opportunity to provide high standards of control over the spread 1. Choi, K. W., Bloom, A. D. Nature, 1970, 227, 171. 2. Henle, G., Henle, W. Hosp. Pract. 1970, 5, 33. 3. Zur Hausen, H., Schulte-Holthausen, H. Nature, 1970, 227, 245. 4. Moore, G. E., Minowada, J. In Vitro, 1969, 4, 100. 5. Broder, S. W., Glade, P. R., Hirschhorn, K. Blood, 1970, 35, 539. 6. Gerber, P., Birch, S. M. Proc. natn. Acad. Sci. U.S.A. 1967, 58, 478. 7. McDade, J. J., Sabel, F. L., Akers, R. L., Walker, R. J. Appl. Microbiol. 1968, 16, 1086. Barbetto, M. S., Taylor, L. A. ibid. p. 1225. Staat, R. H., Beakley, J. W. ibid. p. 1478. Coriell, L. L., McGarrity, G. J. ibid. p. 1895. 8. Baker Company, Inc., Biddleford, Maine; Bioquest, Cockeysville, Md.; S. Blickman, Inc., Weehawken, N.J.; Envirco, Inc., Albuquerque, N.M.; Pure Aire Corporation of America, Van Nuys,
Calif.; Stainless Equipment Co., Englewood, Colo.; Henry Tromner, Inc., Philadelphia, Pa.; and Westinghouse Electric Corp., Grand Rapids, Michigan.
predicted by our unified theory of growth and disease.1-3 Theory also indicates potential complications (see below) that need to be borne in mind when such associations are tested. Genes that predispose to diseases with reproducible agepatterns are expected to code for polypeptide components of complex recognition molecules.1-3 These molecules serve to identify cells in the feedback system that controls and coordinates growth: they are synthesised both in the central controlling cells and in the cells of the tissue whose growth is homoeostatically regulated. We call the recognition molecules in the central part of the controlling system mitotic control proteins (M.C.P.S), and those in the controlled, or target tissue, tissue coding factors (T.C.F.S). Each distinctive target tissue is characterised by a specific T.C.F., and the element in the central system that controls its growth has a specific mz.c.P. Some or all of the genes that code for the protein component of a given T.c.F. also code for the protein component of the cognate M.c.p. Hence, mutual recognition along both the efferent and afferent pathways of growth-control exploits the identity of the protein components of related M.c.p.s and T.C.F.s. (Non-protein constituents probably distinguish M.c.p.s from T.C.F.S.) Cell-borne T.C.F.s and the cellular M.C.P.S carried by thymus-dependent small lymphocytes comprise histocompatibility antigens, conventional tissue-specific antigens, and many subtler determinants that distinguish, for example, one small section of epidermis from another, and a left tissue from its right counterpart. 1-3 Our theory predicts, therefore, that correlations should be found between predisposition to age-dependent disease, and M.C.P.-T.C.F. proteins, which, in man, include the major HL-A histocompatibility antigens.1-3 The observations of Dr. Zervas and his colleagues confirm these predictions. Now to the complications. Many diseases that appear by ordinary clinical criteria to be more or less homogeneous, probably consist of a complex of two or more genetically distinctive entities. 2, 4-7 There is little doubt that Hodgkin’s disease belongs to this category : three distinct groups can be distinguished, each with a characteristic sex and age distribution.2,4,5,7 Because the genetic predisposition of each group should differ, in at least one respect, from that for the other two, we can understand why Dr. Zervas and his colleagues failed to find the HL-A5 antigen in 100% of their patients with Hodgkin’s disease. This kind of complication might also help to explain why Walford et al.8 found correlations between the HL-A2 and Merritt antigens on the one hand, and acute childhood leukxmia on the other, whereas other investigators did not. Acute childhood 1eukaemia probably consists of at least four genetically distinctive diseases, and, in general, their relative and absolute proportions can be expected to differ from one population to another.2 When a disease consists of more than one genetically distinctive type, each with its characteristic sex and age distributions, then age-at-onset can often help to assess the type when clinical and histopathological differences are inconclusive. It follows from our theory that if antisera could be developed in sufficient numbers and specificity to identify all the relevant components of M.c.p.s and T.c.F.s associated Burch, P. R. J., Burwell, R. G. Q. Rev. Biol. 1965, 40, 252. Burch, P. R. J. An Inquiry Concerning Growth, Disease and Ageing. Edinburgh, 1968. 3. Burch, P. R. J. Nature, 1970, 225, 512. 4. MacMahon, B. Cancer Res. 1966, 26, 1189. 5. Cole, P., MacMahon, B., Aisenberg, A. Lancet, 1968, ii, 1371. 6. Burch, P. R. J., Milunsky, A. ibid. 1969, i, 554. 7. Burch, P. R. J. ibid. 1970, i, 469. 8. Walford, R. L., Finkelstein, S., Neerhout, R., Konrad, P., Shanbrom, E. Nature, 1970, 225, 461. 1. 2.
with a given disease, then should become possible. General Infirmary, Leeds 1.
entirely objective diagnosis P. R. J. BURCH.
HUMAN LYMPHOID CELL LINES : POTENTIAL HAZARDS TO LABORATORY WORKERS SiR,łThe recent report of Choi and Bloom1 is likely to stimulate many investigators to employ their techniques of establishing and cloning these predominantly diploid human lymphoid cell lines. Choi and Bloom established such lines from comparatively small numbers of peripheralblood leucocytes from normal subjects by exposing the leucocytes to cell-free lysates derived from a lymphoid cell line established from a patient with infectious mononucleosis or by co-cultivation with a minor population of cells of that line. The Henles have reviewed the evidence which implicates the Epstein-Barr (E.B.) virus as the astiological agent in both infectious mononucleosis and Burkitt’s lymphoma.2 An xtiological role in Burkitt’s lymphoma is further supported by the evidence of E.B. virus nucleic acid homology in a " virus-free" line of Burkitt tumour cells.3 It seems reasonable to assume, as a working hypothesis, that all established human lymphoid cell lines, including those derived from " normal" subjects 4,5 and those derived by exposure to lysates from virus-free " cell lines, represent viral transformants. One can therefore raise the question of the potential hazard to laboratory workers presented by the widespread use of cell lines which may have the potential for vegetative replication of an infectious agent implicated in the pathogenesis of a naturally occurring human neoplasm. Although this agent may be ubiquitous in manone must consider the potential risk to particularly susceptible subjects, especially in view of the enormous numbers of a specific virus to which an individual may be exposed under conditions of cell culture. There is the further possibility of the inadvertent in-vitro selection for variants with enhanced oncogenic or other pathogenic properties, especially in experiments employing mutagens. As a minimum precaution, we suggest that laboratory workers employ vertical laminar-flow hoods when handling such cultures.’ In the United States, such hoods have recently become commerciallv available from at least eight different manufacturers.8 Pathology Department, GEORGE M. MARTIN University of Washington, BARBARA R. SCHWARTZ Seattle, Washington 98105, MARY ANN DERR. U.S.A. "
VENEREAL DISEASE
SiR,łIwould support on every count the views of Dr. Jefferiss (Sept. 26, p. 673) regarding the need to maintain extended hours for v.D. clinics. Over and above the personal problems there are also epidemiological considerations. The V.D. service in this country should miss no opportunity to provide high standards of control over the spread 1. Choi, K. W., Bloom, A. D. Nature, 1970, 227, 171. 2. Henle, G., Henle, W. Hosp. Pract. 1970, 5, 33. 3. Zur Hausen, H., Schulte-Holthausen, H. Nature, 1970, 227, 245. 4. Moore, G. E., Minowada, J. In Vitro, 1969, 4, 100. 5. Broder, S. W., Glade, P. R., Hirschhorn, K. Blood, 1970, 35, 539. 6. Gerber, P., Birch, S. M. Proc. natn. Acad. Sci. U.S.A. 1967, 58, 478. 7. McDade, J. J., Sabel, F. L., Akers, R. L., Walker, R. J. Appl. Microbiol. 1968, 16, 1086. Barbetto, M. S., Taylor, L. A. ibid. p. 1225. Staat, R. H., Beakley, J. W. ibid. p. 1478. Coriell, L. L., McGarrity, G. J. ibid. p. 1895. 8. Baker Company, Inc., Biddleford, Maine; Bioquest, Cockeysville, Md.; S. Blickman, Inc., Weehawken, N.J.; Envirco, Inc., Albuquerque, N.M.; Pure Aire Corporation of America, Van Nuys,
Calif.; Stainless Equipment Co., Englewood, Colo.; Henry Tromner, Inc., Philadelphia, Pa.; and Westinghouse Electric Corp., Grand Rapids, Michigan.