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Clonal Ageing
656
copper stores, and inorganic-iron preparations all contain traces of copper that are more than sufficient. So CARTWRIGHT, citing the dictum that " all unnecessary therapy should be avoided," advises against the administration of copper to patients. (It is just possible that some patients with sprue or the nephrotic syndrome may not absorb enough copper, but this is unproved.) Cobalt is known to have a definite effect on erythropoiesis, apart from the fact that it is present in the molecule of vitamin B12. Cobalt-deficiency anaemia is recognised in ruminants, but this anaemia is now known to be due to deficiency of vitamin B12. Administration of cobalt in relatively large amounts causes true polycythæmia in some animals and birds, with hyperplasia of red-cell-forming tissues, but this seems to be a toxic rather than a physiological effect. CARTWRIGHT points out that in man 5 µg. of cobalt is all that is needed daily, and probably much less suffices ; clinical deficiency of cobalt per se has never been recognised. There is good evidence that administration of cobalt over a long period raises the h.emoglobin level in anaemia secondary to infection, malignant disease, and renal disease ; this action is probably pharmacological, and there are many unpleasant side-effects. CARTWRIGHT does not think that there is any proof that cobalt aids the absorption of iron, and he is not convinced of its value in aplastic anaemia and chronic haemolytic anaemia. (But Dr. FOUNTAIN and Dr. DALES5 have lately described in these columns a case of pure red-cell aplasia in which other measures had failed and complete recovery followed administration of cobalt.) MUELLER and WILL6 have examined the relations between vitamin B12, folic acid, and ascorbic acid in megaloblastic anaemia. They agree that vitamin B12 and folic acid act as catalysts in the formation of nucleic acid, and that ascorbic acid has an indirect effect on folic-acid metabolism. It has to be also assumed that vitamin B12 is in some way connected with folic-acid metabolism, since deficiency of vitamin B12 causes a conditioned deficiency of folic acid. Folic acid, they consider, produces temporary remission in pernicious anaemia by a mass-action effect, mobilising the depleted vitamin-B12 store and thus paving the way for a worse relapse with aggravation of neurological disturbances. MuELLER and WILL point out that vitamin B12 can be bound and utilised locally by erythropoietic cells and will cause them to mature, whereas folic acid has no such direct action. Folic acid acts at some other point in the biochemical synthesis of nucleoprotein ; megaloblastic anaemia of pregnancy, for example, may be a conditioned deficiency of folinic acid co-enzyme. Our therapeutic use of vitamin B12 is influenced by the fact that intrinsic factor, secreted in man in the upper part of the stomach, is essential for its absorption from the small intestine. SCHILLING7 estimates the daily of vitamin requirement B12 at less than 1 µg. ; for we therapy usually give ten times this amount, by8 intramuscular injection or as nasal " snuff." VILTER does not recommend the combinations of B,with intrinsic factor that can be given orally ; they are not equally effective in all patients and are relatively
expensive. 5. Fountain, J. R., Dales, M. Lancet, March 12, 1955, p. 541. 6. Mueller, J. F., Will, J. J. Amer. J. clin. Nutr. 1955, 3, 30. 7. Schilling, R. F. Ibid, p. 45. 8. Vilter, R. W. Ibid, p. 72.
This symposium closely supports with scientific evidence what is generally regarded as good clinical practice-namely, to treat iron-deficiency anæmias with simple iron preparations that include no added trace metals, vitamin-B complex, and so on, and to give ascorbic acid with the iron ; to treat pernicious anaemia with vitamin B12’ and the megaloblastic anaemias of pregnancy and steatorrhoea with folic acid ; and never to give folic acid to patients with
proved
or
suspected pernicious
anaemia.
Clonal Ageing THREE impressive lectures on the genetics of paramecium were recently delivered at University College, London, by Prof. TRACY SONNEBORN, of the University of Indiana. Although their subject was specialised, they included much to interest medical as well as general biologists. Among much important new information on ciliate genetics, SONNEBORN gave a convincing experimental analysis of the reason why stocks of paramecium invariably deteriorate unless they are sexually renewed. This organism shows very well the phenomenon of " clonal ageing"; and SONNEBORN’S work explains the process in this instance. Unfortunately for those who work on mammalian ageing, the reasons are probably peculiar to paramecium ; but they raise a great many points of fundamental importance in cytology. The so-called ageing of clones bulked large in the minds of biologists in the 1890s when they considered A clone senescence in higher organisms and man. all the cells comprises produced by simple asexual fission from a given sexually produced nucleus. A variety of strawberry or of Russell lupin provides a familiar example : the original plant was a hybrid produced by the fusion of two gametes and grown from seed, and all its descendants produced by cuttings or by division of the original root stock constitute a clone. All the asexually produced descendants of a protozoan which has just undergone one of its characteristic sexual processes-conjugation, autogamy, paedogamy, and so forth-make up a clone. So, in a different sense, do the cells of a metazoan body, for they all arise by simple fission from one sexually produced nucleus. It was early observed that while some protozoans could apparently be maintained indefinitely by simple fission alone, others soon lost vigour and died if they were not permitted to undergo periodic sexual phases. WEISMANN had held that the germ-plasm was immortal and the soma destin.ed to die ; might it not be that the ageing of the metazoan body, and the loss of vigour in clones, arose from the same source-the necessity for periodic sexual reorganisation as a condition of continued vigour ? MAUPAS propounded this idea ; and for many years a vigorous competition was conducted between protozoologists in seeing how many asexual generations of paramecium, eudorina, and similar creatures they could
In the course of this process much nonwritten about " potential immortality," but a great deal was learnt about protozoan reproduction and culture methods. It became evident that some clones deteriorate and others, including somatic cells such as fibroblasts in tissue-culture, do not. The results obtained by the gardeners were similarthere are plants which can be grown indefinitely from rear.
sense was
657 and others which lose thrift unless they are important tissue, senescence, or some other adverse periodically regrown from seed. The possibility that process such as malignancy, might well result from it. Furthermore we do not know exactly the extent to one important kind of body-cell might undergo loss or of more which somatic senescence can produce chromosomal vigour, progressively progressive inaccurate copying, the further it gets from the germ damage in germ cells. Parental-age effects are still the for Some remains in of most line, these, cytoplasmic factors gerontologist. plant familiar; but, clones deteriorate because they accumulate viruses ; appear to predominate, and the consequences are not others fail with striking unanimity after a given as a rule genetically fixed. The real importance of period, whole plantations being simultaneously affected Professor SONNEBORN’S work, as revealed in his A clonal lectures, lies in the information about the fine structure even when they are widely separated. of this kind (" June yellows " in straw- of intracellular physiology which he has obtained by degeneration berries) has lately been shown1 to be a true degenera- simple but highly ingenious methods. This approach tion of a particular genetic interest. Apart from this has proved brilliantly successful, not because paraexample, which is being investigated, the mechanisms mecium is a " good " organism, but because it has involved in the decay of any of the susceptible cell- been studied by a good biologist. Its intracellular lines have not hitherto been established. homoeostatic systems are at least as complex, it seems, The mechanism which SONNEBORN finds has been as the gross homceostatic mechanisms of man or suggested2 but has never previously been demons- dog. This is an alarming thought, but at least trated. When paramecium divides after a sexual Professor SONNEBORN has shown how they can be process, the new nucleus of each daughter cell divides approached. into two. One of these products, the micronucleus, which reaches the anterior end of the cell, has the Annotations normal diploid number of chromosomes, and is apparently concerned solely with conveying the FIRST-AID TREATMENT OF HEAD INJURIES genotype : it is, in other words, the " germ-plasm." The other portion, the macronucleus, controls the MANY of us have seen the unconscious motor-cyclist metabolism of the cell. It becomes highly polyploid, lying on the road while people gather round and warn and at subsequent cell divisions, while the micro- each other not to move him because ignorant manoeuvres nucleus divides evenly in the normal manner of might do harm. Thus the unfortunate victim lies in until an ambulance arrives with its staff trained nuclei, the macronucleus distributes its chromosomes ainhuddle first-aid. For what happens next we must turn to the at random to the daughter macronucleus arising from first-aid manuals, and we at once realise that these give it. Because of the enormous number of sets which it instruction which ignores modern knowledge regarding contains, every cell in the earlier divisions has a fair the causes of death after head injury : the grave dangers chance of getting its quota, but with the passage of of inhalation asphyxia in the unconscious patient have time more and more daughters receive an unbalanced not yet filtered into these manuals. set and a reduced physiological repertoire, and a After head injury vomiting is common, and the chromosome once lost cannot be restored from the inhalation of gastric juices may lead to death a few micronucleus except by sexual division-conjugation hours after the inhalation has taken place. Yet one or autogamy. In the later stages of clonal senescence first-aid manual advises for fracture of the skull: "Lay the patient on his back in all cases ... keep his head and even sexual division is affected and abnormal or nonviable products increase. SONNEBORN has shown that shoulders raised and support them on a pillow or a this is not due to the accumulation of mutations, since rolled-up blanket." Again in the first-aid treatment of : " Lay the patient on his back ..." These it can be prevented by periodic autogamy, even insensibility instructions are acted on throughout the country, even though this does not alter the genotype : it appears though they ignore the dangers of inhalation of blood to be due to injury inflicted upon the micronucleus and vomit. On the other hand a leaflet on the Early itself through the abnormal intracellular conditions Treatment of Head Injuries, lately published by the produced by the defective macronucleus. In ciliates advisory committee in neurology and neurosurgery to the germ-plasm has to live in the cell where the the North East Metropolitan Regional Hospital Board, declares : "the patient should be kept oi6 his side with processes of somatic maintenance are carried out, and a clear airway." This advice is intended for doctors it is therefore unusually exposed. This is probably a and nurses, but it is even more important that it should unique situation-it does not even apply in other be acted on before the patient reaches hospital, when ciliates-and the division of function between vegeperhaps blood is flowing into the pharynx from a tative and germinal nuclei is confined to this group. fractured base of skull. But it does not follow that this type of clonal ageing There are some hazards in encouraging first-aid workers has no bearing at all on senescence in higher animals. with regard to postural drainage of the throat and lungs, We do not know whether faulty copying and aneu- for multiple injuries may be present ; but this difficulty ploidy in somatic cells (which would be the rough is not insurmountable, and the present advice is so equivalent of macronuclear degeneration in para- dangerous when the patient is deeply unconscious that mecium) help to determine the life-span of metazoa.’ those concerned with first-aid instruction should review Somatic aneuploidy, though it has been described,3-5 the matter without delay. The first-aid worker could at is not a popular concept with cytologists ; it. is easily least be taught to listen to the patient’s breathing, and, simulated by bad technique.6 If it does occur in anyr if there is a death rattle " in the throat, to establish whatever the risks. In such cases it is
cuttings,
,
r
"
.
1. 2. 3. 4. 5.
McWhirter, G. In the press. Fauré-Frémiet, E. Rev. suisse Zool. 1953, 60, 426. Hsu, T. C., Pomerat, C. M. J. Morph. 1953, 93, 301. Tanaka, T. Cytologia, Tokyo, 1953, 18, 343. Sorokina, M. I. Bull. Acad. Sci. U.R.S.S. 1950, 6, 97. 6. Walker, B. E., Boothroyd, E. R. Genetics, 1953, 39, 210.
postural drainage essential that postural drainage
of the air passages be maintained in the ambulance, on the hospital trolley, and in the X-ray department as well as in the hospital bed, in the same way as with patients who have bulbar paralysis due, say, to poliomyelitis.
copper stores, and inorganic-iron preparations all contain traces of copper that are more than sufficient. So CARTWRIGHT, citing the dictum that " all unnecessary therapy should be avoided," advises against the administration of copper to patients. (It is just possible that some patients with sprue or the nephrotic syndrome may not absorb enough copper, but this is unproved.) Cobalt is known to have a definite effect on erythropoiesis, apart from the fact that it is present in the molecule of vitamin B12. Cobalt-deficiency anaemia is recognised in ruminants, but this anaemia is now known to be due to deficiency of vitamin B12. Administration of cobalt in relatively large amounts causes true polycythæmia in some animals and birds, with hyperplasia of red-cell-forming tissues, but this seems to be a toxic rather than a physiological effect. CARTWRIGHT points out that in man 5 µg. of cobalt is all that is needed daily, and probably much less suffices ; clinical deficiency of cobalt per se has never been recognised. There is good evidence that administration of cobalt over a long period raises the h.emoglobin level in anaemia secondary to infection, malignant disease, and renal disease ; this action is probably pharmacological, and there are many unpleasant side-effects. CARTWRIGHT does not think that there is any proof that cobalt aids the absorption of iron, and he is not convinced of its value in aplastic anaemia and chronic haemolytic anaemia. (But Dr. FOUNTAIN and Dr. DALES5 have lately described in these columns a case of pure red-cell aplasia in which other measures had failed and complete recovery followed administration of cobalt.) MUELLER and WILL6 have examined the relations between vitamin B12, folic acid, and ascorbic acid in megaloblastic anaemia. They agree that vitamin B12 and folic acid act as catalysts in the formation of nucleic acid, and that ascorbic acid has an indirect effect on folic-acid metabolism. It has to be also assumed that vitamin B12 is in some way connected with folic-acid metabolism, since deficiency of vitamin B12 causes a conditioned deficiency of folic acid. Folic acid, they consider, produces temporary remission in pernicious anaemia by a mass-action effect, mobilising the depleted vitamin-B12 store and thus paving the way for a worse relapse with aggravation of neurological disturbances. MuELLER and WILL point out that vitamin B12 can be bound and utilised locally by erythropoietic cells and will cause them to mature, whereas folic acid has no such direct action. Folic acid acts at some other point in the biochemical synthesis of nucleoprotein ; megaloblastic anaemia of pregnancy, for example, may be a conditioned deficiency of folinic acid co-enzyme. Our therapeutic use of vitamin B12 is influenced by the fact that intrinsic factor, secreted in man in the upper part of the stomach, is essential for its absorption from the small intestine. SCHILLING7 estimates the daily of vitamin requirement B12 at less than 1 µg. ; for we therapy usually give ten times this amount, by8 intramuscular injection or as nasal " snuff." VILTER does not recommend the combinations of B,with intrinsic factor that can be given orally ; they are not equally effective in all patients and are relatively
expensive. 5. Fountain, J. R., Dales, M. Lancet, March 12, 1955, p. 541. 6. Mueller, J. F., Will, J. J. Amer. J. clin. Nutr. 1955, 3, 30. 7. Schilling, R. F. Ibid, p. 45. 8. Vilter, R. W. Ibid, p. 72.
This symposium closely supports with scientific evidence what is generally regarded as good clinical practice-namely, to treat iron-deficiency anæmias with simple iron preparations that include no added trace metals, vitamin-B complex, and so on, and to give ascorbic acid with the iron ; to treat pernicious anaemia with vitamin B12’ and the megaloblastic anaemias of pregnancy and steatorrhoea with folic acid ; and never to give folic acid to patients with
proved
or
suspected pernicious
anaemia.
Clonal Ageing THREE impressive lectures on the genetics of paramecium were recently delivered at University College, London, by Prof. TRACY SONNEBORN, of the University of Indiana. Although their subject was specialised, they included much to interest medical as well as general biologists. Among much important new information on ciliate genetics, SONNEBORN gave a convincing experimental analysis of the reason why stocks of paramecium invariably deteriorate unless they are sexually renewed. This organism shows very well the phenomenon of " clonal ageing"; and SONNEBORN’S work explains the process in this instance. Unfortunately for those who work on mammalian ageing, the reasons are probably peculiar to paramecium ; but they raise a great many points of fundamental importance in cytology. The so-called ageing of clones bulked large in the minds of biologists in the 1890s when they considered A clone senescence in higher organisms and man. all the cells comprises produced by simple asexual fission from a given sexually produced nucleus. A variety of strawberry or of Russell lupin provides a familiar example : the original plant was a hybrid produced by the fusion of two gametes and grown from seed, and all its descendants produced by cuttings or by division of the original root stock constitute a clone. All the asexually produced descendants of a protozoan which has just undergone one of its characteristic sexual processes-conjugation, autogamy, paedogamy, and so forth-make up a clone. So, in a different sense, do the cells of a metazoan body, for they all arise by simple fission from one sexually produced nucleus. It was early observed that while some protozoans could apparently be maintained indefinitely by simple fission alone, others soon lost vigour and died if they were not permitted to undergo periodic sexual phases. WEISMANN had held that the germ-plasm was immortal and the soma destin.ed to die ; might it not be that the ageing of the metazoan body, and the loss of vigour in clones, arose from the same source-the necessity for periodic sexual reorganisation as a condition of continued vigour ? MAUPAS propounded this idea ; and for many years a vigorous competition was conducted between protozoologists in seeing how many asexual generations of paramecium, eudorina, and similar creatures they could
In the course of this process much nonwritten about " potential immortality," but a great deal was learnt about protozoan reproduction and culture methods. It became evident that some clones deteriorate and others, including somatic cells such as fibroblasts in tissue-culture, do not. The results obtained by the gardeners were similarthere are plants which can be grown indefinitely from rear.
sense was
657 and others which lose thrift unless they are important tissue, senescence, or some other adverse periodically regrown from seed. The possibility that process such as malignancy, might well result from it. Furthermore we do not know exactly the extent to one important kind of body-cell might undergo loss or of more which somatic senescence can produce chromosomal vigour, progressively progressive inaccurate copying, the further it gets from the germ damage in germ cells. Parental-age effects are still the for Some remains in of most line, these, cytoplasmic factors gerontologist. plant familiar; but, clones deteriorate because they accumulate viruses ; appear to predominate, and the consequences are not others fail with striking unanimity after a given as a rule genetically fixed. The real importance of period, whole plantations being simultaneously affected Professor SONNEBORN’S work, as revealed in his A clonal lectures, lies in the information about the fine structure even when they are widely separated. of this kind (" June yellows " in straw- of intracellular physiology which he has obtained by degeneration berries) has lately been shown1 to be a true degenera- simple but highly ingenious methods. This approach tion of a particular genetic interest. Apart from this has proved brilliantly successful, not because paraexample, which is being investigated, the mechanisms mecium is a " good " organism, but because it has involved in the decay of any of the susceptible cell- been studied by a good biologist. Its intracellular lines have not hitherto been established. homoeostatic systems are at least as complex, it seems, The mechanism which SONNEBORN finds has been as the gross homceostatic mechanisms of man or suggested2 but has never previously been demons- dog. This is an alarming thought, but at least trated. When paramecium divides after a sexual Professor SONNEBORN has shown how they can be process, the new nucleus of each daughter cell divides approached. into two. One of these products, the micronucleus, which reaches the anterior end of the cell, has the Annotations normal diploid number of chromosomes, and is apparently concerned solely with conveying the FIRST-AID TREATMENT OF HEAD INJURIES genotype : it is, in other words, the " germ-plasm." The other portion, the macronucleus, controls the MANY of us have seen the unconscious motor-cyclist metabolism of the cell. It becomes highly polyploid, lying on the road while people gather round and warn and at subsequent cell divisions, while the micro- each other not to move him because ignorant manoeuvres nucleus divides evenly in the normal manner of might do harm. Thus the unfortunate victim lies in until an ambulance arrives with its staff trained nuclei, the macronucleus distributes its chromosomes ainhuddle first-aid. For what happens next we must turn to the at random to the daughter macronucleus arising from first-aid manuals, and we at once realise that these give it. Because of the enormous number of sets which it instruction which ignores modern knowledge regarding contains, every cell in the earlier divisions has a fair the causes of death after head injury : the grave dangers chance of getting its quota, but with the passage of of inhalation asphyxia in the unconscious patient have time more and more daughters receive an unbalanced not yet filtered into these manuals. set and a reduced physiological repertoire, and a After head injury vomiting is common, and the chromosome once lost cannot be restored from the inhalation of gastric juices may lead to death a few micronucleus except by sexual division-conjugation hours after the inhalation has taken place. Yet one or autogamy. In the later stages of clonal senescence first-aid manual advises for fracture of the skull: "Lay the patient on his back in all cases ... keep his head and even sexual division is affected and abnormal or nonviable products increase. SONNEBORN has shown that shoulders raised and support them on a pillow or a this is not due to the accumulation of mutations, since rolled-up blanket." Again in the first-aid treatment of : " Lay the patient on his back ..." These it can be prevented by periodic autogamy, even insensibility instructions are acted on throughout the country, even though this does not alter the genotype : it appears though they ignore the dangers of inhalation of blood to be due to injury inflicted upon the micronucleus and vomit. On the other hand a leaflet on the Early itself through the abnormal intracellular conditions Treatment of Head Injuries, lately published by the produced by the defective macronucleus. In ciliates advisory committee in neurology and neurosurgery to the germ-plasm has to live in the cell where the the North East Metropolitan Regional Hospital Board, declares : "the patient should be kept oi6 his side with processes of somatic maintenance are carried out, and a clear airway." This advice is intended for doctors it is therefore unusually exposed. This is probably a and nurses, but it is even more important that it should unique situation-it does not even apply in other be acted on before the patient reaches hospital, when ciliates-and the division of function between vegeperhaps blood is flowing into the pharynx from a tative and germinal nuclei is confined to this group. fractured base of skull. But it does not follow that this type of clonal ageing There are some hazards in encouraging first-aid workers has no bearing at all on senescence in higher animals. with regard to postural drainage of the throat and lungs, We do not know whether faulty copying and aneu- for multiple injuries may be present ; but this difficulty ploidy in somatic cells (which would be the rough is not insurmountable, and the present advice is so equivalent of macronuclear degeneration in para- dangerous when the patient is deeply unconscious that mecium) help to determine the life-span of metazoa.’ those concerned with first-aid instruction should review Somatic aneuploidy, though it has been described,3-5 the matter without delay. The first-aid worker could at is not a popular concept with cytologists ; it. is easily least be taught to listen to the patient’s breathing, and, simulated by bad technique.6 If it does occur in anyr if there is a death rattle " in the throat, to establish whatever the risks. In such cases it is
cuttings,
,
r
"
.
1. 2. 3. 4. 5.
McWhirter, G. In the press. Fauré-Frémiet, E. Rev. suisse Zool. 1953, 60, 426. Hsu, T. C., Pomerat, C. M. J. Morph. 1953, 93, 301. Tanaka, T. Cytologia, Tokyo, 1953, 18, 343. Sorokina, M. I. Bull. Acad. Sci. U.R.S.S. 1950, 6, 97. 6. Walker, B. E., Boothroyd, E. R. Genetics, 1953, 39, 210.
postural drainage essential that postural drainage
of the air passages be maintained in the ambulance, on the hospital trolley, and in the X-ray department as well as in the hospital bed, in the same way as with patients who have bulbar paralysis due, say, to poliomyelitis.