Res Medica, Autumn 1969, Volume VI, Number 4 Page 1 of 6

Mutation Research and Human Welfare

Professor Charlotte AuerBach F.R.S. The Institute of Animal Genetics, Edinburgh

Abstract From an address to the Society in November 1968.

GENETICAL RADIATION DAMAGE Knowledge gained from mutation research can be put to various uses for the benefit of mankind. One of them is assessment of genetical hazards from ionizing radiations. Before the war, this meant almost exclusively X-rays used in diagnosis and therapy. H. J. Muller, who in 1927 discovered the mutagenic action of X-rays, almost at once entered upon a campaign against the reckless use of radiation in medical practice. Especially in the USA , it was fashionable for the G.P. to have in his surgery a fluoroscope with, usually, an unknown and, often, a very high output of radiation and to use it indiscriminately even where less dangerous methods of diagnosis were available. There was also a practice of temporarily sterilizing men by radiation; when these men later on became fertile again they produced children from sperm that had been heavily irradiated as spermatogonia. In women, similarly high X-ray doses were used to produce fertility by follicle rupture. Until the war, the medical profession took very little notice of Muller. This careless attitude changed when fall-out and nuclear accidents became a major concern. Nowadays many national and international organisations, in all of which geneticists play an important role, are engaged in monitoring the amount of radiation to which we are exposed, in assessing its genetical consequences and in fixing “permissible” levels of radiation.

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Res Medica, Autumn 1969, 6(4): 8-12 doi: 10.2218/resmedica.v6i4.861

AuerBach, C. Mutation Research and Human Welfare, Res Medica 1969, 6(4), pp. 8-12 doi: 10.2218/resmedica.v6i4.861 MUTATION RESEARCH AND

HUMAN WELFARE

Professor Charlotte AuerBach, F.R.S.

The Institute of Animal Genetics, Edinburgh.

From an address to the Society in November 1968

GENETICAL RADIATION DAMAGE radiation to which we are exposed, in assessing its genetical consequences and in fixing “per­ missible” levels of radiation. Knowledge gained from mutation research can be put to various uses for the benefit of mankind. One of them is assessment of DOMINANT MUTATIONS genetical hazards from ionizing radiations. Before the war, this meant almost exclusively So much has been said and written about X-rays used in diagnosis and therapy. II. J. genetical risks from radiation that I can be Muller, who in 1927 discovered the mutagenic brief. My main concern is to put them into action of X-rays, almost at once entered upon perspective. They certainly should not be a campaign against the reckless use of radiation played down but they should also not be exag­ in medical practice. Especially in the USA, it gerated. There is, for example, a widespread was fashionable for the G.P. to have in his belief that children born to irradiated men or surgery a fluoroscope with, usually, an un­ women are likely to be in some way abnormal. known and, often, a very high output of radi­ This is not borne out by observation nor is it ation and to use it indiscriminately even where expected on theoretical grounds. There are less dangerous methods of diagnosis were very few abnormal young among the progeny available. There was also a practice of tem­ of heavily irradiated mice, and none were porarily sterilizing men by radiation; when found among the children of Japanese parents these men later on became fertile again they that had survived exposure to the atom bombs. produced children from sperm that had been Theoretically, the type of mutation that would heavily irradiated as spermatogonia. In women, become manifest already in a child of the similarly high X-ray doses were used to pro­ irradiated person would be a dominant mut­ duce fertility by follicle rupture. Until the ation, and such mutations are known to be war, the medical profession took very little very rare. It is true that some Japanese women notice of Muller. This careless attitude who had been pregnant at the time of the changed when fall-out and nuclear accidents explosions had abnormal children, but these became a major concern. Nowadays many abnormalities were due to direct radiation national and international organisations, in all effects on the foetus, not to effects on the of which geneticists play an important role, germ cells of the parents. They do not con­ are engaged in monitoring the amount of stitute a risk for future generations for, like the effects of thalidomide or German measles together of two gametes with the same mut­ on the embryo, they are not inherited. If, as ated gene. Moreover, it will almost always has been claimed, radiation of the embryo in be impossible to pinpoint a particular case of, utero increases the risk of infantile leukaemia, say, phenylketonuria or recessive blindness as this too would not be a genetical damage. being due to a radiation-induced mutation, for radiation does not create new harmful CHROMOSOME BREAKAGE AND NON-DISJUNCTION genes, it only increases the frequency of the already known ones. Finally, not all recessive mutations have such drastic effects as blind­ What, then, are the risks of radiation that ness or idiocy. Many, probably the majority, causes so much worry to the geneticist? arc harmful only because they lower some Chromosome breaks are one of them, although component of fitness, e.g. resistance to infec­ not the most important one. The reason is tion or degree of intelligence. This can be that chromosome breakage has serious conse­ concluded with a high degree of certainty quences only when it results in a type of from experiments on lower organisms, although translocation that can be inherited and may it would be difficult to prove it for man. result in the repeated births of children suffer­ There can be little doubt that any increase in ing from a “chromosome disease” like Down’s mutation frequency will eventually lead to an syndrome. However, since a translocation re­ impairment of human health and happiness. quires the presence of two broken chromo­ It is our responsibility, especially that of the somes in the same cell, it is not often produced geneticists and politicians, to see that future by the low radiation doses from fall-out. Much generations will not have to pay too heavy a greater is the risk that even these low doses price for the security, health and comfort of will produce chromosomal disease through the present one. non-disjunction, and this has been taken into account in the most recent assessments of radiation hazards. IRRADIATED FOODSTUFFS

RECESSIVE MUTATIONS Although it is not easy to arrive at good quantitative estimates of genetical radiation The most serious radiation damage is due damage, there can be no doubt that such to recessive mutations, i.e. to mutations that damage exists in all organisms and at all doses. become apparent only in homozygous indiv­ The situation is quite different for another iduals that have inherited the same mutated possible type of radiation damage which has gene from both parents. Recessive mutations recently become a subject of discussion. This are not only the most frequent ones; they are is the possibility that foodstuffs may become also produced in direct proportion to the mutagenic when they have been sterilized by magnitude of the dose, so that there is no the very high X-ray doses required for this lower threshold below which they do not occur. purpose. Already seven years ago, Indian Moreover, the vast majority of them are harm­ cytologists found chromosome breaks in the ful or even lethal. This is not due to some cells of plants that had been grown in heavily special malice of Nature. It is simply a con­ irradiated fruit juice, sugar solution or potato sequence of evolution which, in every organ­ mash. More recently, the journal “Nature” ism, has selected an array of genes that act created quite a stir among the circles con­ together harmoniously in development and cerned by publishing the results of an experi­ that make the organism fit well into its ment in which a high frequency of mutations environmental niche. New mutations are was found in Drosophila flies that had been much more likely than not to disrupt this reared on X-rayed medium. However, repet­ nicely adjusted interplay between the genes ition of this experiment in many laboratories with each other and with environment. Al­ both here and abroad did not confirm these though mankind certainly could be improved data : the results were either wholly negative genetically, this cannot be achieved by radi­ or the increase in mutation frequency was only ation. For the non-geneticist, it is not easy marginal. There the matter rests at the to grasp the danger of recessive mutations for, moment. The whole situation is typical for by their very nature, these will remain hidden the uncertainties that beset attempts to gener­ for several and, often, for many generations alize findings obtained with chemical muta­ until affected individuals arise from the coming gens; for it must be realized that, if heavily 9 irradiated medium should produce mutations, to have genetical consequences, but it is quite it would do so not through direct transfer of possible that this may be different in germ radiation energy but through the production cells. On the other hand, it is also quite pos­ of a chemical mutagen from one of the com­ sible that no chromosome breaks at all are ponents of food. Whether such a chemical produced in germ cells. Again, the final con­ is formed will depend on the composition of clusion remains doubtful, although the results the food; whether it will produce mutations with human cells certainly warn to caution. will depend on the digestive and metabolic It may seem overcautious to think that the processes of the organism tested; even in the chromosomes in two types of human cell same organism, different cell types may re­ might respond differently to the same muta­ spond in different ways to the same compound. gen. But this is just what has been found for All these considerations are of importance Formaldehyde. When Formaldehyde is mixed not only for the special case of irradiated with the Food of Drosophila, it produces high nutrients but for the much more general Frequencies of mutations in male larvae. question whether the exposure to mutagenic Female larvae and adults of either sex are influences from chemicals used in industry, quite immune to its mutagenic action, medicine, cosmetics, food additions, etc., is although — as experiments with isotopically not at least as dangerous as the exposure to labelled Formaldehyde have shown — it penet­ ionizing radiation from fall-out and X-rays. rates to their gonads. Even in the testes oF Indeed, this may well be true, but the un­ male larvae, its action is restricted to one certainties which I have just mentioned make particular type of germ cell, the early sperm- it exceedingly difficult to arrive at conclusions. atocyte. I have repeatedly been asked by pig breeders whether mutations may be produced by the practice of Feeding breeding animals GENETICAL DAMAGE FROM CHEMICALS with skim milk that has been sterilized by Formaldehyde. Now it so happens that, many Caffeine is a case in question. The situ­ years ago and For an entirely unrelated reason, ation here is similar to that of irradiated I have shown that Formaldehyde-treated skim medium. It has been known for a long time m ilk pow der is a good m utagen For D rosophila that caffeine produces mutations in micro­ larvae. But how can one extrapolate From organisms, and chromosome breaks and trans­ Drosophila germ cells to pig germ cells in the locations in plants. It has been calculated case of a mutagen that distinguishes between that — if human germ cells show the same Drosophila spermatocytes and Drosophila response — the amount of coffee consumed spermatogonia? in the USA or of tea consumed in this country It is this kind of consideration that makes would give cause for serious concern. Experi­ it so very difficult to assess genetical hazards ments on animals, however, seemed to invalid­ From chemicals. Yet the problem is so im­ ate this conclusion. The results with Droso­ portant that at present much money and phila were similar to those obtained with effort is spent on arriving at some conclusions, irradiated medium : if there is an effect at all however tentative. Among the substances For on Drosophila germ cells, it is exceedingly which evidence of genetical effects is being small. The question seemed important enough sought is LSD. So Far the results have been to test it in experiments on mice, which are contradictory: in some experiments, it has much more laborious and expensive than those produced chromosome breaks in mammalian on Drosophila. Mice were given as much cells; in others, it has Failed to do so. coffee in their drinking water as they could stand without ill effects; in some series, treat­ ment was started already before birth by- CANCER THERAPY giving coffee to pregnant females and continu­ ing the treatment on the progeny. Yet neither There is one group of substances of such mutations not translocations were obtained, high penetration and general mutagenic action and for a time this seemed to settle the that their efficacy in producing mutations also question. It was re-opened very recently by in human germ cells can hardly be doubted. the finding that caffeine causes chromosome These are alkylating agents used in cancer breaks in human cell cultures. It is true that therapy, e.g. nitrogen mustard. Almost cer­ these breaks do not seem to form translocations tainly the probability of carrying a new and therefore are not of the kind that is likely mutation is higher among the progeny of 10 persons treated with such a compound than chromosome breaks or certain types of trans­ among the rest of the population. Since, location kill zygotes into which they have however, the number of children to which been carried by one of the gametes. When this applies forms a negligibly small part of males of Drosophila are exposed to very high the whole population, this is not a serious X-ray doses, they remain able to mate and genetical hazard for the population as a whole. transmit sperm, but most or all of the eggs The use of alkylating agents in cancer fertilized by the sperm fail to hatch. The idea therapy brings me to the positive applications therefore arose that the fertility of wild of mutation research to human welfare. species might be drastically reduced by catch­ Elimination of cancer cells by chromosome ing or rearing males, exposing them to high breakage is one of them. It rests on the fact, radiation doses and releasing them again into mentioned before, that chromosome breakage infected areas. This technique has already kills only dividing cells and, therefore, acts had a spectacular success in the case of the specifically on malignant cells with their high screw worm fly, which lays its eggs into the dvision rate. All the same, it is usually not skin of cattle and used to be a great pest in possible to exclude normal dividing cells, such the Southern States of the USA. Nowadays as epithelial cells, from the irradiated area, and it has practically disappeared from these these too are likely to be killed by chromo­ regions. Occasional invasions from Mexico, some breaks. One of the aims of cancer where no similar project has been carried out, therapy is, therefore, to increase the differen­ are combated by the release of sterilized males tial response of normal and malignant cells to from aeroplanes near the border. For other radiation. Mutation experiments have given species, the technique may have to be modi­ valuable suggestions on this problem. Sub­ fied in order to meet the special physiology or stances have been found that act as sensitizers ecology of the insects. Thus in the boll weevil, for chromosome breakage by radiation, while a cotton pest, the dose of X-rays that kills others act as protectors. If means can be males is only a little higher than that which found to introduce such substances selectively sterilizes them, so that X-rays cannot be used into malignant or normal cells, one might for sterilization; chemical mutagens may give make the former more sensitive or the latter better results. For Tsetse flies, a project is more resistant to killing by X-rays. The most now being worked out by which viable, herit­ powerful and generally effective adjuvant to able translocations — of the kind that in man X-ray effects is oxygen. A given dose of X-rays causes Down’s syndrome — will be introduced produces several times as many chromosome into wild populations. While this would not breaks in oxic as in anoxic cells. Moreover, lead to an immediate and drastic reduction in only a fraction of the normal oxygen pressure hatchability, it should eventually become a is required to yield full sensitivity to X-rays, self-maintaining device for producing heritable so that the sensitivity of normal cells is sterility. Insect control via chromosome already at its maximum. Solid tumours, how­ breakage in spermatozoa is being studied in ever, often have an anoxic core of highly many countries and discussed at international resistant cells, and this may serve as a source levels. of renewed malignant growth when the more peripheral and better oxygenated cells have been killed. This has led to attempts to IMPROVING THE GENOTYPE improve the treament of solid tumours by radiating patients while they breathe oxygen Finally, let me mention the possibility of or are infused intra-arterially with hydrogen utilizing induced gene mutations for the bene­ peroxide. Neutrons are equally effective fit of mankind. In work with micro-organisms, chromosome breakers in anoxic as in oxic cells; this has already been done successfully. Fungi this is in part responsible for their efficiency in with a higher yield of antibiotics or yeasts with cancer treatment. improved baking or brewing qualities can be produced with the aid of mutagens. How­ ever, in all these cases, the vast majority of PEST CONTROL mutations is not of the desired type and many are lethal or at least harmful to the organism. Chromosome breakage is also made use of We have seen earlier why this must be so. In for a very different purpose, the control of micro-organisms, of which huge numbers can noxious insects. You will remember that be raised easily and cheaply, this wastage is no impediment to the use of mutagens for im­ mutation is out of the question unless treat­ provement. Even in agricultural or orna­ ments can be found which quite specifically mental plants, “mutation breeding” is being produce certain types of mutation. The hope used quite extensively, especially in inbred for this to happen is exceedingly slight, at least strains whose genetic purity one does not wish until the time when we can implant into to destroy by the introduction of desirable embryos genes that have been extracted from genes through crossing. In these cases, too, selected donors or have even been tailor-made the loss of, perhaps, a thousand undesirable in the test-tube. Although this is a distinct mutants for the sake of one desirable one may possibility for the future, I do not think that be worth while. For agricultural animals and, it will materialize in mine or even in your even more, for man improvement by induced lifetim e.

DIAGNOSTIC PROBLEM

SET BY JOHN WALLWORK

SUBJECT B.S.: Present. Female, age 51. PREVIOUS HISTORY HISTORY Duodenal Ulcer diagnosed several years Pain for nine months of a sharp, gripping earlier and treated medically with success. nature lasting a few seconds at a time and Barium meal and follow through two weeks occurring several times per day. No relation before admission showed no abnormality. to meals, etc. INVESTIGATION ON EXAMINATION Erect abdominal X-ray showed opaque area A large mass in the right inguinal fossa was in right iliac fossa with a few scattered fluid noticed by her General Practitioner on the levels in the large bowel. evening of admission. Some tenderness and guarding was present. Patient was afebrile. A. W hat is the mass in the right iliac fossa? P.V.: Pelvis empty but lower pole of mass palpable high up on right side the mass having B. W hat is the likely cause of the symptoms a soft consistency. and signs described?

(A nsw er on Page 22)

OFFICE-BEARERS FOR THE 233rd SESSION

Senior President ...... A. J. K. CONN 1st Junior President ...... Miss M. F. OSBORN 2nd Junior President ...... J. WALLWORK 3rd Junior President ...... C. F. J. GRINOLE Senior Secretary ...... R. J. CRAIG Junior Secretary ...... T. F. BENTON Convenor of Business Committee ...... I. SMITH „ Publicity ...... M. PICKIN „ House ...... Miss M. Y. MORRIS „ Library ...... R. de SOLDENHOFF Museum ...... Miss D. E. GIRDWOOD .. ,, Dinner Committee ...... Miss M. Y. MORRIS