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Bacteriophage and Epidemiology
277
Meanwhile the place of bacteriophage in Nature has isoniazid) ; and they produced no significant change remained rather obscure. What are the origins of of in the blood-pressure. Only high concentrations isoniazid inhibited the activity of isolated intestine- specific bacteriophages ? Why should almost every again an interesting observation, for constipation may serological type of bacterium apparently have a With the exception of a occur in treated patients. corresponding specific bacteriophage waiting to attack definite bronchiolytic action by the isopropyl deriva- it ? Has bacteriophage any function at all in the natural history of bacteria ? Elsewhere in our present tive on cholinergically induced bronchial spasm in the issue Dr. L. F; HEWITT proposes answers to these was little evidence of parasympathetic there guineapig, RUBIN et al.14 acute questions. It is, as he says, a common observation toxicity, activity. Investigating showed that for mice and dogs the therapeutic ratio that bacteriophages which are specific to one seroThe animals succumbed, after logical type of organism can often be adapted to lyse was generously wide. excitement and convulsions, to death by respiratory organisms of a different type, on which at first they have no effect. But now he reports that bacteriophages can failure. It seems more than likely that this was the be adapted to attack not only a different serological result of a direct stimulation of the central nervous now that P’AN et aU8 have demonstype but also a different species ; for he has found that system, especially trated that barbiturates give protection against these staphylococcus bacteriophage can be made to act on toxic effects. The changes which may follow longdiphtheria bacilli. If this interaction between different continued treatment are possibly of greater imporspecies turns out to be a general phenomenon, the tance. Animals so treated lose appetite and weight, problem of the origin of a variety of specific bacteriobecome ataxic, and have convulsions ; jaundice, with phages will disappear ; for we need postulate only the existence of a single bacteriophage, or small group of of the liver and has also fatty degeneration kidneys, But these results have followed bacteriophages, to understand how by adaptation the developed. alarming whole multitude of specific bacteriophages may be doses higher than those generally given therapeutically, though the margin is not great. More encouragingly, evolved. From this Dr. HEWITT goes on to suggest they are reversible in most cases as soon as the drug that bacteriophages play an important part in Nature is withdrawn. in controlling the evolution of bacteria and their In man the side-effects recorded include constipation, difficulty in starting micturition, virulence, and hence the spread of epidemics. A twitching of the extremities, exaggerated reflexes, specific bacteriophage, by lysing all the organisms in a headache, vertigo, drowsiness, dryness of the mouth, susceptible culture except the few mutants which are eosinophilia, and slight anaemia. These have seldom resistant, exerts a potent selective action. The resistant mutants often have quite different characters been of serious consequence, but, as there now seems from the parent strain, and in a single subculture the to be a tendency to give larger doses of the drug, and as further derivatives are coming into use, an even properties of a strain may therefore be entirely altered : for example, a completely avirulent diphcloser watch must be kept for these danger-signals. theria strain can become virulent and toxigenic. When they are observed, details should be sent to the Committee on Therapy of the American Trudeau The intervention of the bacteriophage may thus be Society, as requested by Dr. D. T. Carr in a letter in said to speed up, very greatly, the slow processes of our
natural selection.
last issue.
Bacteriophage
and
Epidemiology
MANY years ago, when TWORT described a transmissible agent which attacked staphylococci,19 and u HERELLE extended the study of Bacteriophagum intestinale, the hope arose that a virus of this kind might be used against bacterial infections. In treating patients, it was thought, bacteriophage might eliminate the invading bacteria, and in preventive medicine it might, for example, get rid of the cholera vibrios in a contaminated well. But these hopes were frustrated. In the first place bacteriophages were found to be highly specific and to attack closely related strains : which meant that an extremely large number of haeteriophages would be needed to cope with the variety of pathogens encountered in Nature. Secondly, it was discovered that bacteriophage added to’ a culture does not lyse all the bacteria present : a few resistant organisms survive and multiply, and the new culture which grows out consists of organisms resistant to the bacteriophage. For these reasons bacteriophage ii(,A-er proved itself as a therapeutic or preventive agent. and its use has been confined mainly to the laboratory,where the specificity of its action has been a great asset. As bacteriophages will attack only related strains, closely they are widely used for typing bacteria responsible for infections.
only
18. Pan. S.Y., Markaroglu, L., Reilly, J. 19. Twort, F. W. Lancet, 1915, ii, 1241.
Ibid, 66, 100.
Quite a high proportion of bacteria usually carry a latent bacteriophage, which does not seem to do them any harm but is capable of lysing other strains with which it comes in contact. Thus cultivation together of a phage-carrying strain and a susceptible strain can result in modification of the susceptible strain through selection of the resistant mutants which survive the action of the phage. This has been demonstrated in mixed cultures in the and a similar process might presumably occur in infected patients. As it must be comparatively rare for a patient to be infected with two strains of the same bacterial species-one carrying phage and the other susceptible to its action-the possible modification of strains in this way has not seemed very important. But if, as Dr. HEWITT claims, coccus bacteriophages can be readily adapted to lyse diphtheria bacilli, a new significance will be attached to the coincident infection of a patient with two different species of bacteria. The bacteriophage from one species, if it is adapted during the infective the other, could modify its properties to attack process the of resistant mutants. The infective selection by the next patient would then be to on agent passed different from the primary infection. and. if the resistant mutant selected to differ conthe in the nature of the infection siderably, change might be dramatic. The plagues which have in the past suddenly flared up and devastated large popu-
laboratory,
staphylo-
happened
278
lations may have originated in some such selective process ; and bacteriophage, instead of being regarded as a mere academic toy, must be suspected of possibly very sinister activities in epidemiology. Such speculation apart, Dr. HEwrrr’s evidence suggests that it has had, and still has, an important r6le in bacterial evolution.
Annotations OVERCROWDING IN PRISON THERE can be worse things in prison than iron bars, and sleeping three to a cell is probably one of them. In its seventh report the Select Committee on Estimates1 deplores that 4500 men in our prisons are sleeping in this overcrowded way. The reason is not far to seek, for the prison population has now risen to over 25,000 men and women-twice as many as before the war. It is ironical that this increase is in part due to the Criminal Justice Act of 1948, which, with the aim of reforming people and not merely deterring them from crime, permits longer sentences. The additional responsibilities which the Act imposes have unfortunately fallen on the prison organisation at a time when it still has not made good war-time deficiencies in accommodation and staff, and the problems of overcrowding are aggravated by those of understaffing. Not only are there too many prisoners but there are too few warders. As a result the prisoners spend long hours of boredom and near idleness in their cells while the warders habitually put in overtime. The committee dislikes both the short working week of the prisonerssometimes as short as 22 hours-and the long working week of the warders ; it thinks that overtime in the long run is neither economical nor efficient. Much of the indiscipline, everyone agrees, is due to a comparatively small group of prisoners. The worst prisoners are not usually the worst criminals, and the committee urges the Prison Commissioners to give high priority to building a separate prison or prisons where these psychopathic trouble-makers could be not only segregated but also studied and treated. Overcrowding brings problems of health as well as discipline, and the committee is especially concerned at the increased risk of infection, particularly of tuberculosis. Some arrangements have been made to examine prisoners by mass-radiography units ; but the initiative is left to the senior medical officer in each prison, and the committee recommends that the Director of Prison Medical Services should approach the Ministry of Health to ensure that prisoners get their fair share of the services of these units. The prison medical service, like the other branches, is understaffed. Instead of 52 full-time doctors, it has only 42 : and few recruits come forward, for the salaries are unattractive. The committee particularly regrets that it is no longer possible to produce a medical and psychiatric report of each boy and girl who passes through the borstal allocation centre, and urges an early return to this pre-war custom. MYXOMATOSIS AND RABBITS IN the past fifteen months an artificially induced epizoötic has killed many millions of rabbits in Australia, thus demonstrating for the first time that a pathogenic agent can he successfully put to work against a mammalian pe",t.2 Myxoma virus, which may be related to the pox group of viruses, has a species of Brazilian rabbit as its natural host. and it was first recognised in laboratory animals by Dr. H. B. Aragão, who also suggested its u-e in biological control. The work started by Sir Charles Martin in 1933 at Cambridge showed that ..
"
1. H.M. Stationery Office. 1952. 2. Ratcliffe, F. N., Myers, K.,
Nature. Lond. 1952. 170,
7.
Pp. 216, 9s. Fennessy, B. V., Calaby, J. H.
the disease was highly pathogenic for wild and domestic rabbits, but was harmless for all domestic animals and for most of the native fauna of Australia, as well as for the imported European hare. Fears that the virus might be the cause of serious infections in man have also proved unfounded. Myxoma virus thus combines extreme virulence for one animal pest with almost complete avirulence for most other creatures, and it was therefore an ideal pathogen to use in attempts at biological control. Field trials carried out before the late war in semi-arid pastoral areas were inconclusive, but they did show that the virus was transmitted among rabbits by the stickfast flea, whose limited mobility made it a poor vector. Some of the many ecological difficulties were soon encountered ; for example, it was impossible to establish and spread the disease where foxes were lying in wait to pick off the first generations of lazy infected rabbits. After the war the Commonwealth Scientific and Industrial Research Organisation decided to re-examine the possibilities of controlling the increasingly serious rabbit menace with myxoma virus, and between May and November, 1950, the virus was released The immediate seven times in the Murray valley. results were disappointing, for the disease had no appreciable effect on the numbers of rabbits. In December, however, the disease suddenly flared up at one of the infected places, and soon reports came from many other areas, including a place on the Darling river nearly 400 miles from the nearest known point of infection. The wide dispersal of the virus and the intense local spread produced a remarkable epizootic within the next two or three months, and it was thought that mosquitoes, moving under their own power or carried by high-level winds, were responsible. Nothing else could explain the isolated outbreaks along the southern margins of the epidemic area in Victoria and in South Australia, nor an isolated outbreak almost in the centre of the continent. In the new year the epizootic gained moinentum, and by February, 1951, an area of 1000 square miles The disease spread at remarkable speed was involved. the rabbit population and killed 90% of them. through River courses, creeks, and swamps were most heavily involved, suggesting once again that water-breeding vectors were essential to spread. In such a large area, however, geographical conditions varied enormously; in the Murray valley, for example, only those rabbits within a few hundred yards of the water’s edge were killed, whereas in south-east Queensland the disease was unbounded, and it was possible to drive for a day or more through country that had previously been swarming with rabbits and see only a few isolated survivors. When the trials began it was known that myxoma virus could be transmitted by two species of fiea and but little was known by several species of about their performance in the field. It was found that transmission was almost certainly mechanical and that any blood-sucking arthropod was a potential vector. The epidemiology of the disease, and hence its practical value in biological control, is largely influenced by the ecology and habits of vectors, the strength of their preference for rabbit blood, and the length of time for which they are about in great numbers. In such a vast and varied area it was likely that different vectors would have local predominance ; in the Murray valley. for example, Culex amrulzrostris was a principal vector. whereas on the Victorian coast and the off-shore island-4e(le.q catiiptorhytichus was the most important. During the winter months of 1951 the disease continued to smoulder, and ectoparasites may have ensured the persistence which was necessary to the success of the scheme. In the summer of 1951-52 a closer study was made of the various vectors, and Anopheles annulipes,
mosquito,
Meanwhile the place of bacteriophage in Nature has isoniazid) ; and they produced no significant change remained rather obscure. What are the origins of of in the blood-pressure. Only high concentrations isoniazid inhibited the activity of isolated intestine- specific bacteriophages ? Why should almost every again an interesting observation, for constipation may serological type of bacterium apparently have a With the exception of a occur in treated patients. corresponding specific bacteriophage waiting to attack definite bronchiolytic action by the isopropyl deriva- it ? Has bacteriophage any function at all in the natural history of bacteria ? Elsewhere in our present tive on cholinergically induced bronchial spasm in the issue Dr. L. F; HEWITT proposes answers to these was little evidence of parasympathetic there guineapig, RUBIN et al.14 acute questions. It is, as he says, a common observation toxicity, activity. Investigating showed that for mice and dogs the therapeutic ratio that bacteriophages which are specific to one seroThe animals succumbed, after logical type of organism can often be adapted to lyse was generously wide. excitement and convulsions, to death by respiratory organisms of a different type, on which at first they have no effect. But now he reports that bacteriophages can failure. It seems more than likely that this was the be adapted to attack not only a different serological result of a direct stimulation of the central nervous now that P’AN et aU8 have demonstype but also a different species ; for he has found that system, especially trated that barbiturates give protection against these staphylococcus bacteriophage can be made to act on toxic effects. The changes which may follow longdiphtheria bacilli. If this interaction between different continued treatment are possibly of greater imporspecies turns out to be a general phenomenon, the tance. Animals so treated lose appetite and weight, problem of the origin of a variety of specific bacteriobecome ataxic, and have convulsions ; jaundice, with phages will disappear ; for we need postulate only the existence of a single bacteriophage, or small group of of the liver and has also fatty degeneration kidneys, But these results have followed bacteriophages, to understand how by adaptation the developed. alarming whole multitude of specific bacteriophages may be doses higher than those generally given therapeutically, though the margin is not great. More encouragingly, evolved. From this Dr. HEWITT goes on to suggest they are reversible in most cases as soon as the drug that bacteriophages play an important part in Nature is withdrawn. in controlling the evolution of bacteria and their In man the side-effects recorded include constipation, difficulty in starting micturition, virulence, and hence the spread of epidemics. A twitching of the extremities, exaggerated reflexes, specific bacteriophage, by lysing all the organisms in a headache, vertigo, drowsiness, dryness of the mouth, susceptible culture except the few mutants which are eosinophilia, and slight anaemia. These have seldom resistant, exerts a potent selective action. The resistant mutants often have quite different characters been of serious consequence, but, as there now seems from the parent strain, and in a single subculture the to be a tendency to give larger doses of the drug, and as further derivatives are coming into use, an even properties of a strain may therefore be entirely altered : for example, a completely avirulent diphcloser watch must be kept for these danger-signals. theria strain can become virulent and toxigenic. When they are observed, details should be sent to the Committee on Therapy of the American Trudeau The intervention of the bacteriophage may thus be Society, as requested by Dr. D. T. Carr in a letter in said to speed up, very greatly, the slow processes of our
natural selection.
last issue.
Bacteriophage
and
Epidemiology
MANY years ago, when TWORT described a transmissible agent which attacked staphylococci,19 and u HERELLE extended the study of Bacteriophagum intestinale, the hope arose that a virus of this kind might be used against bacterial infections. In treating patients, it was thought, bacteriophage might eliminate the invading bacteria, and in preventive medicine it might, for example, get rid of the cholera vibrios in a contaminated well. But these hopes were frustrated. In the first place bacteriophages were found to be highly specific and to attack closely related strains : which meant that an extremely large number of haeteriophages would be needed to cope with the variety of pathogens encountered in Nature. Secondly, it was discovered that bacteriophage added to’ a culture does not lyse all the bacteria present : a few resistant organisms survive and multiply, and the new culture which grows out consists of organisms resistant to the bacteriophage. For these reasons bacteriophage ii(,A-er proved itself as a therapeutic or preventive agent. and its use has been confined mainly to the laboratory,where the specificity of its action has been a great asset. As bacteriophages will attack only related strains, closely they are widely used for typing bacteria responsible for infections.
only
18. Pan. S.Y., Markaroglu, L., Reilly, J. 19. Twort, F. W. Lancet, 1915, ii, 1241.
Ibid, 66, 100.
Quite a high proportion of bacteria usually carry a latent bacteriophage, which does not seem to do them any harm but is capable of lysing other strains with which it comes in contact. Thus cultivation together of a phage-carrying strain and a susceptible strain can result in modification of the susceptible strain through selection of the resistant mutants which survive the action of the phage. This has been demonstrated in mixed cultures in the and a similar process might presumably occur in infected patients. As it must be comparatively rare for a patient to be infected with two strains of the same bacterial species-one carrying phage and the other susceptible to its action-the possible modification of strains in this way has not seemed very important. But if, as Dr. HEWITT claims, coccus bacteriophages can be readily adapted to lyse diphtheria bacilli, a new significance will be attached to the coincident infection of a patient with two different species of bacteria. The bacteriophage from one species, if it is adapted during the infective the other, could modify its properties to attack process the of resistant mutants. The infective selection by the next patient would then be to on agent passed different from the primary infection. and. if the resistant mutant selected to differ conthe in the nature of the infection siderably, change might be dramatic. The plagues which have in the past suddenly flared up and devastated large popu-
laboratory,
staphylo-
happened
278
lations may have originated in some such selective process ; and bacteriophage, instead of being regarded as a mere academic toy, must be suspected of possibly very sinister activities in epidemiology. Such speculation apart, Dr. HEwrrr’s evidence suggests that it has had, and still has, an important r6le in bacterial evolution.
Annotations OVERCROWDING IN PRISON THERE can be worse things in prison than iron bars, and sleeping three to a cell is probably one of them. In its seventh report the Select Committee on Estimates1 deplores that 4500 men in our prisons are sleeping in this overcrowded way. The reason is not far to seek, for the prison population has now risen to over 25,000 men and women-twice as many as before the war. It is ironical that this increase is in part due to the Criminal Justice Act of 1948, which, with the aim of reforming people and not merely deterring them from crime, permits longer sentences. The additional responsibilities which the Act imposes have unfortunately fallen on the prison organisation at a time when it still has not made good war-time deficiencies in accommodation and staff, and the problems of overcrowding are aggravated by those of understaffing. Not only are there too many prisoners but there are too few warders. As a result the prisoners spend long hours of boredom and near idleness in their cells while the warders habitually put in overtime. The committee dislikes both the short working week of the prisonerssometimes as short as 22 hours-and the long working week of the warders ; it thinks that overtime in the long run is neither economical nor efficient. Much of the indiscipline, everyone agrees, is due to a comparatively small group of prisoners. The worst prisoners are not usually the worst criminals, and the committee urges the Prison Commissioners to give high priority to building a separate prison or prisons where these psychopathic trouble-makers could be not only segregated but also studied and treated. Overcrowding brings problems of health as well as discipline, and the committee is especially concerned at the increased risk of infection, particularly of tuberculosis. Some arrangements have been made to examine prisoners by mass-radiography units ; but the initiative is left to the senior medical officer in each prison, and the committee recommends that the Director of Prison Medical Services should approach the Ministry of Health to ensure that prisoners get their fair share of the services of these units. The prison medical service, like the other branches, is understaffed. Instead of 52 full-time doctors, it has only 42 : and few recruits come forward, for the salaries are unattractive. The committee particularly regrets that it is no longer possible to produce a medical and psychiatric report of each boy and girl who passes through the borstal allocation centre, and urges an early return to this pre-war custom. MYXOMATOSIS AND RABBITS IN the past fifteen months an artificially induced epizoötic has killed many millions of rabbits in Australia, thus demonstrating for the first time that a pathogenic agent can he successfully put to work against a mammalian pe",t.2 Myxoma virus, which may be related to the pox group of viruses, has a species of Brazilian rabbit as its natural host. and it was first recognised in laboratory animals by Dr. H. B. Aragão, who also suggested its u-e in biological control. The work started by Sir Charles Martin in 1933 at Cambridge showed that ..
"
1. H.M. Stationery Office. 1952. 2. Ratcliffe, F. N., Myers, K.,
Nature. Lond. 1952. 170,
7.
Pp. 216, 9s. Fennessy, B. V., Calaby, J. H.
the disease was highly pathogenic for wild and domestic rabbits, but was harmless for all domestic animals and for most of the native fauna of Australia, as well as for the imported European hare. Fears that the virus might be the cause of serious infections in man have also proved unfounded. Myxoma virus thus combines extreme virulence for one animal pest with almost complete avirulence for most other creatures, and it was therefore an ideal pathogen to use in attempts at biological control. Field trials carried out before the late war in semi-arid pastoral areas were inconclusive, but they did show that the virus was transmitted among rabbits by the stickfast flea, whose limited mobility made it a poor vector. Some of the many ecological difficulties were soon encountered ; for example, it was impossible to establish and spread the disease where foxes were lying in wait to pick off the first generations of lazy infected rabbits. After the war the Commonwealth Scientific and Industrial Research Organisation decided to re-examine the possibilities of controlling the increasingly serious rabbit menace with myxoma virus, and between May and November, 1950, the virus was released The immediate seven times in the Murray valley. results were disappointing, for the disease had no appreciable effect on the numbers of rabbits. In December, however, the disease suddenly flared up at one of the infected places, and soon reports came from many other areas, including a place on the Darling river nearly 400 miles from the nearest known point of infection. The wide dispersal of the virus and the intense local spread produced a remarkable epizootic within the next two or three months, and it was thought that mosquitoes, moving under their own power or carried by high-level winds, were responsible. Nothing else could explain the isolated outbreaks along the southern margins of the epidemic area in Victoria and in South Australia, nor an isolated outbreak almost in the centre of the continent. In the new year the epizootic gained moinentum, and by February, 1951, an area of 1000 square miles The disease spread at remarkable speed was involved. the rabbit population and killed 90% of them. through River courses, creeks, and swamps were most heavily involved, suggesting once again that water-breeding vectors were essential to spread. In such a large area, however, geographical conditions varied enormously; in the Murray valley, for example, only those rabbits within a few hundred yards of the water’s edge were killed, whereas in south-east Queensland the disease was unbounded, and it was possible to drive for a day or more through country that had previously been swarming with rabbits and see only a few isolated survivors. When the trials began it was known that myxoma virus could be transmitted by two species of fiea and but little was known by several species of about their performance in the field. It was found that transmission was almost certainly mechanical and that any blood-sucking arthropod was a potential vector. The epidemiology of the disease, and hence its practical value in biological control, is largely influenced by the ecology and habits of vectors, the strength of their preference for rabbit blood, and the length of time for which they are about in great numbers. In such a vast and varied area it was likely that different vectors would have local predominance ; in the Murray valley. for example, Culex amrulzrostris was a principal vector. whereas on the Victorian coast and the off-shore island-4e(le.q catiiptorhytichus was the most important. During the winter months of 1951 the disease continued to smoulder, and ectoparasites may have ensured the persistence which was necessary to the success of the scheme. In the summer of 1951-52 a closer study was made of the various vectors, and Anopheles annulipes,
mosquito,