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ERYTHROPOIETIC FACTORS
794 National Health Insurance, leaving private practice untouched. Mr. Dickson Wright did not believe that the proposed system of social security was inevitable, and thought it should be fought against ; a new Parliament The meeting was necessary to deal with the’ matter. gave its consent to nine points which had been tabled by the council : 1. That the administrative structure, both centrally and be modified to ensure that the medical a more direct responsibility for advice and administration through nominees chosen by representative bodies of the profession. That the scheme should not apply to the whole population, and that the general-practitioner service particularly should be " provided " only for those below a certain income limit. That contributions under a social security insurance scheme allotted to the health services should be devoted entirely to the financing of the general-practitioner service, and that the hospital and consultant services should be provided for by general taxation. That the regions for hospital administration should be large enough to provide a complete service for all purposes, and that no existing local authority is in a position to provide such a complete service. " direction " of members of the That there should be no but-that they should be free to practise in profession, places of their own choice. An adequate supply of doctors should be obtained for areas sparsely staffed by offering special inducements. That the security of the voluntary hospitals should be ensured. That tendencies towards the conversion of the profession into a whole-time salaried service should be resisted. That control of the profession by the Civil Service and the local authorities was not in the interests of the people. That the facilities of health centres should be available for all practitioners in the district. Turning to the Goodenough report, the President said
locally, should profession had
2.
_
3.
4.
5.
6. 7.
8. 9.
the council disliked the suggestion that financial pressure should be applied to compel medical schools to comply with proposals such as admission of women to all schools, reform of the curriculum, and so on. The council, he said, strongly contested the suggestion that a university degree should be the. only qualification for the profession. It was the duty of the College to maintain a portal of entry which was entirely under the control of the profession and independent of any subsidised body like a university. The Royal Colleges exerted an influence in the Empire such as no university could have. The council also objected to the principle that all medical schools should be large ; many men did far better in small classes than they would do in a class of a hundred students. At the end the meeting studied the plans for reconstructing the College on the present site. ERYTHROPOIETIC
IT is
FACTORS
long time since Wilkinson in this country and Castle in America showed that the factor responsible for normal red-cell formation, whose absence causes pernicious anaemia, is formed by interaction of an " intrinsic factor," hsemopoietin, secreted in the gastric juice, with an " extrinsic factor " brought in with the food. Considerable research by workers in several countries has given us highly purified materials representing these factors, but we still do not know exactly what they are. a
The work of Jacobson,2 on the other hand, has revealed that the argentaffine cells, found mainly in the cardia and the pylorus, are practically absent in pernicious anaemia and sprue, but present in other macrocytic anaemias which do not respond to liver treatment. These cells were shown to contain a pterin, probably uropterin, a particularly interesting observation, since many workers3 have reported haemopoietic responses after the administration of xanthopterin (synonymous with uropterin) to jrats and monkeys. Xanthopterin has alsoI) been found in liver extracts.4 Wright and Welch further showed that there is an increase in the formation of folic acid when rat liver slices are incubated with synthetic xanthopterin. They therefore suggest - that xanthopterin enters the folic molecule in this way. There is no rise in folic-acid production, as Totter and his colleagues6 have demonstrated, when chicken liver slices are substituted for rat liver, which may be the reason why O’Dell and Hogan failed to obtain a hsemopoietic response from xanthopterin administration to milk-anaemic chicks. In the monkey, however, a consistent response to xanthopterin is obtained. Haemo. poietin has been concentrated in fractions from the pressjuice of hogs’ stomachs according to the technique of Klein and Wilkinson 8 it had been separated from pepsin as early as 1933, but no further progress was made in determining its nature. Agren9 has published experiments showing that in the purification of preparations from pyloric mucosa the hsemopoietic activity and the aminopolypeptidase activity run parallel, and he therefore suggests that hsemopoietin and the enzyme aminopolypeptidase may be identical. This suggestion awaits confirmation. With regard to the extrinsic factor, it was early noted that sources of this factor, such as beef muscle, milk, eggs, yeast and wheat germ, were also sources of the vitamin-B complex, and that chemical procedures that’ removed the extrinsic factor also tended to remove the that vitamin B vitamin-B complex. Theand extrinsic factor might be connected was strengthened by the finding that some cases of pernicious anaemia. could be treated, partially at least, with yeast autolysates like ’Marmite.’ The next step was to test individual members of the B complex. Riboflavin and nicotinic acid have been excluded and now Castle and co-workers" have shown that all the identified members of the B complex are inactive : extrinsic factor is not thiamine, ,
possibility
pyridoxine,
pantothenic acid,
biotin, xanthopterin,
folic acid, choline or inositol. Nevertheless Castle, in the belief that there are depths of vitamin B yet unplumbed, thinks it is still " reasonable to continue to regard the extrinsic factor as a thermostable component of the vitamin-B complex as yet unidentified." No better fortune has attended the investigations into the nature of the " liver principle," found in the liver and produced by the interaction of intrinsic and extrinsic factors. The material is rather easier to handle and has been greatly purified, especially by Dakin and West" and by Wilkinson.3.2 The latter prepared material 18 mg. of which was sufficient to initiate a reticulocyte response and rapid remission in a patient with pernicious anemia. Yet recent electrophoretic studies 13 indicate that even these products are still mixtures of clinically active and inactive materials. ’
-
The intrinsic factor was at first thought to be produced by the glands in the pylorus and the first part of the duodenum, possibly Brunner’s glands ; but although this is almost certainly true for the pig it is doubtful in man, since in pernicious ansemia the main anatomical change is an atrophy of the glands in the fundus and body of the stomach, the pylorus being relatively unaffected. The latest report by Cox1 has confirmed his predecessors’. 1.
Cox, A. J. Amer. J. Path. 1943, 19, 491.
2. Jacobson, W. J. Path. Bact. 1939, 49, 1. 3. Tschesche, R., Wolf, H. T. Z. physiol. Chem. 1936, 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
244, 1; 1937, 248, 34. Jacobson, B. M., Subbarow, Y. J. clin. Invest. 1937, 16, 573. Mazza, F. P., Penati, F. Arch. Scienze biol. 1937-38, 23, 443. Wright, L. D., Welch, A. D. Science, 1943, 98, 179. Totter, J. R., Mims, V., Day, P. L. Ibid, 1944, 100, 223. O’Dell, B. L., Hogan, A. G. J. biol. Chem. 1943, 149, 323. Klein, L. J., Wilkinson, J. F. Biochem. J. 1933, 27, 600. Agren, G. Nature, Lond. Sept. 30, 1944, p. 430. Castle, W. B. et al. Science, 1944, 100, 81. Dakin, H. D., West, R. J. biol. Chem. 1935, 109, 481. Wilkinson, J. F. Lancet, 1936, i, 354. West. R., Moore, D. H. Trans. Ass. Amer. Phys. 1942, 57, 253.
locally, should profession had
2.
_
3.
4.
5.
6. 7.
8. 9.
the council disliked the suggestion that financial pressure should be applied to compel medical schools to comply with proposals such as admission of women to all schools, reform of the curriculum, and so on. The council, he said, strongly contested the suggestion that a university degree should be the. only qualification for the profession. It was the duty of the College to maintain a portal of entry which was entirely under the control of the profession and independent of any subsidised body like a university. The Royal Colleges exerted an influence in the Empire such as no university could have. The council also objected to the principle that all medical schools should be large ; many men did far better in small classes than they would do in a class of a hundred students. At the end the meeting studied the plans for reconstructing the College on the present site. ERYTHROPOIETIC
IT is
FACTORS
long time since Wilkinson in this country and Castle in America showed that the factor responsible for normal red-cell formation, whose absence causes pernicious anaemia, is formed by interaction of an " intrinsic factor," hsemopoietin, secreted in the gastric juice, with an " extrinsic factor " brought in with the food. Considerable research by workers in several countries has given us highly purified materials representing these factors, but we still do not know exactly what they are. a
The work of Jacobson,2 on the other hand, has revealed that the argentaffine cells, found mainly in the cardia and the pylorus, are practically absent in pernicious anaemia and sprue, but present in other macrocytic anaemias which do not respond to liver treatment. These cells were shown to contain a pterin, probably uropterin, a particularly interesting observation, since many workers3 have reported haemopoietic responses after the administration of xanthopterin (synonymous with uropterin) to jrats and monkeys. Xanthopterin has alsoI) been found in liver extracts.4 Wright and Welch further showed that there is an increase in the formation of folic acid when rat liver slices are incubated with synthetic xanthopterin. They therefore suggest - that xanthopterin enters the folic molecule in this way. There is no rise in folic-acid production, as Totter and his colleagues6 have demonstrated, when chicken liver slices are substituted for rat liver, which may be the reason why O’Dell and Hogan failed to obtain a hsemopoietic response from xanthopterin administration to milk-anaemic chicks. In the monkey, however, a consistent response to xanthopterin is obtained. Haemo. poietin has been concentrated in fractions from the pressjuice of hogs’ stomachs according to the technique of Klein and Wilkinson 8 it had been separated from pepsin as early as 1933, but no further progress was made in determining its nature. Agren9 has published experiments showing that in the purification of preparations from pyloric mucosa the hsemopoietic activity and the aminopolypeptidase activity run parallel, and he therefore suggests that hsemopoietin and the enzyme aminopolypeptidase may be identical. This suggestion awaits confirmation. With regard to the extrinsic factor, it was early noted that sources of this factor, such as beef muscle, milk, eggs, yeast and wheat germ, were also sources of the vitamin-B complex, and that chemical procedures that’ removed the extrinsic factor also tended to remove the that vitamin B vitamin-B complex. Theand extrinsic factor might be connected was strengthened by the finding that some cases of pernicious anaemia. could be treated, partially at least, with yeast autolysates like ’Marmite.’ The next step was to test individual members of the B complex. Riboflavin and nicotinic acid have been excluded and now Castle and co-workers" have shown that all the identified members of the B complex are inactive : extrinsic factor is not thiamine, ,
possibility
pyridoxine,
pantothenic acid,
biotin, xanthopterin,
folic acid, choline or inositol. Nevertheless Castle, in the belief that there are depths of vitamin B yet unplumbed, thinks it is still " reasonable to continue to regard the extrinsic factor as a thermostable component of the vitamin-B complex as yet unidentified." No better fortune has attended the investigations into the nature of the " liver principle," found in the liver and produced by the interaction of intrinsic and extrinsic factors. The material is rather easier to handle and has been greatly purified, especially by Dakin and West" and by Wilkinson.3.2 The latter prepared material 18 mg. of which was sufficient to initiate a reticulocyte response and rapid remission in a patient with pernicious anemia. Yet recent electrophoretic studies 13 indicate that even these products are still mixtures of clinically active and inactive materials. ’
-
The intrinsic factor was at first thought to be produced by the glands in the pylorus and the first part of the duodenum, possibly Brunner’s glands ; but although this is almost certainly true for the pig it is doubtful in man, since in pernicious ansemia the main anatomical change is an atrophy of the glands in the fundus and body of the stomach, the pylorus being relatively unaffected. The latest report by Cox1 has confirmed his predecessors’. 1.
Cox, A. J. Amer. J. Path. 1943, 19, 491.
2. Jacobson, W. J. Path. Bact. 1939, 49, 1. 3. Tschesche, R., Wolf, H. T. Z. physiol. Chem. 1936, 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
244, 1; 1937, 248, 34. Jacobson, B. M., Subbarow, Y. J. clin. Invest. 1937, 16, 573. Mazza, F. P., Penati, F. Arch. Scienze biol. 1937-38, 23, 443. Wright, L. D., Welch, A. D. Science, 1943, 98, 179. Totter, J. R., Mims, V., Day, P. L. Ibid, 1944, 100, 223. O’Dell, B. L., Hogan, A. G. J. biol. Chem. 1943, 149, 323. Klein, L. J., Wilkinson, J. F. Biochem. J. 1933, 27, 600. Agren, G. Nature, Lond. Sept. 30, 1944, p. 430. Castle, W. B. et al. Science, 1944, 100, 81. Dakin, H. D., West, R. J. biol. Chem. 1935, 109, 481. Wilkinson, J. F. Lancet, 1936, i, 354. West. R., Moore, D. H. Trans. Ass. Amer. Phys. 1942, 57, 253.