Mutation Research and Human Welfare

Res Medica, Autumn 1969, Volume VI, Number 4

Page 1 of 6

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

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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is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL

Res Medica,

Autumn

1969, 6(4): 8-12

doi:

10.2218/resmedica.v6i4.861

MUTATION RESEARCH AND

HUMAN WELFARE

Professor Charlotte AuerBach, F.R.S.

T h e In stitu te o f A n im a l G e n e tics, E d in b u rg h .

From an address to the Society in November 1968

GENETICAL RADIATION DAMAGE

K n o w le d g e gained from m u tation research can be p u t to various uses fo r the ben efit of m ankind. O n e o f them is assessm ent of gen e tical hazards from io n izin g radiations. B e fo re th e w ar, this m ean t alm ost exclu sively X -rays used in diagnosis and therapy. I I. J. M u lle r, w ho in 19 2 7 discovered the m utagen ic action o f X -rays, alm ost at once entered upon a cam paign against th e reckless use o f radiation in m ed ical practice. E sp e cia lly in th e U S A , it was fash ion ab le fo r th e G .P . to h ave in his surgery a fluoroscope w ith , usually, an un­ kn ow n an d , o ften , a very h ig h o u tp u t o f radi­ ation and to use it in d iscrim in ately even w here less dangerous m ethods o f diagnosis were available. T h e re was also a practice o f tem ­ p orarily sterilizing m en b y rad iation; w hen these m en later on b ecam e fe rtile again they p ro duced child ren from sperm th at h ad been h eavily irradiated as sperm atogon ia. In w om en, sim ilarly high X -ray doses w ere used to pro­ d u ce fe rtility b y fo llicle rupture. U n til the w ar, the m edical profession took very little n otice o f M u lle r. T h is careless attitu d e ch an ged w hen fall-out and n u clear accidents b ecam e a m ajo r concern. N ow ad ays m an y n ation al and in tern ation al organisations, in all o f w h ich gen eticists play an im p o rtan t role, are engaged in m on itorin g the am o u n t of

radiation to w h ich w e are exposed, in assessing its ge n e tical con sequ en ces and in fixing “ per­ m issib le” levels o f radiation.

DOMINANT MUTATIONS

S o m uch has been said and w ritten ab out gen etical risks from radiation th at I can be b rief. M y m ain con cern is to p u t th em in to perspective. T h e y certain ly sh ou ld n o t be played dow n b u t they should also n o t be exag­ gerated. T h e re is, fo r exam ple, a w idespread b elie f th at ch ildren b orn to irrad iated m en or w om en are likely to be in som e w ay ab norm al. T h is is n o t b orne o u t b y observation nor is it exp ected on th eoretical grounds. T h e re are very few ab norm al you n g am on g the progeny o f h eavily irradiated m ice, and non e w ere found am on g the ch ildren o f Jap a n e se parents that had survived exposure to the atom b om bs. T h e o re tica lly , the type o f m u tatio n th at w ou ld b ecom e m an ifest already in a ch ild o f the irradiated person w ould be a d o m in an t m u t­ ation, and such m utations are know n to be very rare. It is true that som e Jap an ese w om en w h o had been pregn an t at the tim e o f the explosion s had ab n orm al ch ild ren , b u t these ab n orm alities w ere due to d irect radiation effects o n the foetus, not to effects on the germ c ells o f the parents. T h e y do n ot con­ stitu te a risk fo r fu tu re generations for, like

the effects of th alidom id e or G erm an measles on th e em bryo, they are n o t inherited . If, as has been claim ed , radiation o f th e em bryo in u tero increases th e risk o f in fan tile leukaem ia, this too would n o t b e a gen etical dam age.

CHROMOSOME BREAKAGE AND NON-DISJUNCTION

W h a t , th en , are the risks of radiation th a t causes so m u ch worry to th e gen eticist? C h ro m oso m e breaks are one of th em , although n o t th e m ost im p o rtan t one. T h e reason is th at chrom osom e breakage has serious conse­ quences only w hen it results in a type of translocation th at can b e in h erited and may result in the repeated birth s of children suffer­ ing from a “chro m o som e disease” like D o w n ’s syndrom e. H ow ever, sin ce a translocation re­ quires th e presence o f two broken ch ro m o ­ som es in th e sam e cell, it is n o t o ften produced by the low radiation doses from fall-ou t. M u ch greater is the risk th at even these low doses will produce chrom osom al disease through no n -d isju n ction , and this has been taken in to acco u n t in the m ost recen t assessm ents of radiation hazards.

RECESSIVE MUTATIONS

T h e m ost serious radiation dam age is due to recessive m u tation s, i.e. to m u tation s th at b eco m e apparent only in hom ozygous indiv­ iduals th at have inh erited the sam e m utated gene from b o th parents. R ecessive m u tations are n o t only the m o st freq u en t ones; they are also produced in d irect proportion to the m agnitud e of the dose, so th a t there is no low er threshold below w hich they do n o t occur. M oreover, the vast m ajority o f them are h arm ­ fu l or even leth al. T h is is n o t due to som e special m alice o f N ature. I t is sim ply a co n ­ sequ ence o f evolution w hich, in every organ­ ism , has selected an array of genes th a t act together harm oniously in d ev elop m ent and th at m ake the organism fit w ell in to its env ironm en tal n ich e. N ew m u tation s are m u ch m ore likely than n o t to disrupt this nicely adjusted interplay betw een th e genes w ith each o th er and w ith env ironm en t. A l­ though m ankind certain ly could b e improved gen etically, this can n o t be achieved b y radi­ ation . F o r the non-g eneticist, it is n o t easy to grasp th e danger o f recessive m u tation s for, by th eir very natu re, these w ill rem ain hid den for several and, o fte n , fo r m any generations un til affected individuals arise from th e com ing

to gether of two gam etes with the sam e m u t­ ated gene. M oreover, it will alm o st always be im possible to p in p o in t a particular case of, say, phenylketonu ria or recessive blindness as bein g due to a radiation-induced m u tatio n , for radiation does n o t create new harm ful genes, it only increases th e frequ en cy o f the already know n ones. Fin ally , n o t all recessive m u tation s have such drastic effects as b lin d ­ ness or idiocy. M a n y , probably the m ajority, arc h arm ful only because they low er som e co m p o n en t o f fitness, e.g. resistance to in fec­ tion or degree o f intelligen ce. T h is can be concluded w ith a high degree o f certain ty from experim ents on lower organism s, although it would b e difficult to prove it for m an. T h e re can b e little d o u b t th a t any increase in m u tation frequ ency will eventually lead to an im p airm en t o f hu m an h ealth and happiness. I t is our responsibility, especially th at of the gen eticists and politicians, to see th a t futu re generations will n o t have to pay too heavy a price for th e security, h ealth and co m fo rt of the present one.

IRRADIATED FOODSTUFFS

A lth ou gh i t is n o t easy to arrive at good qu an titativ e estim ates o f gen etical radiation dam age, there can b e no d o u b t th at such dam age exists in all organism s and at all doses. T h e situ atio n is qu ite d ifferent fo r an oth er possible type o f radiation dam age w hich has recently b eco m e a su b je c t o f discussion. T h is is the p ossibility th at foodstuffs m ay b eco m e m u tagenic when they have been sterilized by the very high X -ray doses required fo r this purpose. Already seven years ago, Indian cytologists found chrom osom e breaks in the cells of plants th at had b een grown in heavily irradiated fru it ju ice, sugar solu tion or potato m ash. M o re recently, th e jo u rnal “ N atu re” created q u ite a stir am ong the circles co n ­ cerned by publishing the results o f an experi­ m e n t in w hich a high frequ en cy o f m u tation s was found in D rosophila flies th at had been reared on X-rayed m ed ium . H ow ever, repet­ ition o f this experim en t in m any laboratories b o th h ere and abroad did n o t confirm these data : the results were eith er w holly negative or th e increase in m u tation frequ en cy was only m arginal. T h e re the m a tte r rests at the m o m en t. T h e w hole situ ation is typical for the un certainties th at b e se t attem p ts to gener­ alize findings obtain ed w ith chem ical m u ta­ gens; for it m u st be realized th a t, if heavily

irrad iated m ediu m sh ou ld pro d u ce m utation s, it w ould do so n o t through d irect tran sfer of rad iation energy b u t through the pro d u ction o f a ch em ical m utagen from o n e o f th e com ­ pon en ts o f food . W h e th e r such a chem ical is form ed w ill depend on the co m p osition of the fo od ; w h eth er it w ill pro d u ce m utations w ill dep end on th e d igestive and m etab olic processes o f th e organism tested; even in the sam e organism , d ifferen t cell types m ay re­ spond in d ifferen t ways to the sam e co m p o u n d . A ll these con siderations are o f im portan ce n o t o n ly fo r the special case o f irradiated n u trien ts b u t fo r the m uch m ore general question w h ether the exposure to m u tag enic in flu ences from chem icals used in in dustry, m e d ic in e , cosm etics, food ad d itio n s, etc., is n o t at least as dangerous as the exposure to io n izin g radiation from fall-out and X -rays. In d eed , this m ay w ell b e true, b u t the un­ certainties w h ich I h ave ju st m en tion ed m ake it exceed in gly d ifficu lt to arrive at conclusions.

GENETICAL DAMAGE FROM CHEMICALS

C a ffe in e is a case in q uestion . T h e situ ­ ation here is sim ilar to that o f irradiated m ediu m . It has been kn ow n fo r a lo n g tim e that caffein e produces m u tation s in m icro­ organism s, an d ch rom oso m e breaks and trans­ locations in plants. It has been calculated that — if h u m an germ cells show the sam e response — the am o u n t o f coffee con sum ed in th e U S A or o f tea con su m ed in this cou n try w ould give cause fo r serious con cern. E x p e ri­ m ents on an im als, h ow ever, seem ed to in valid ­ ate this con clusion . T h e results w ith D ro so ­ p hila w ere sim ilar to those ob tain ed w ith irrad iated m ed iu m : if there is an effe ct at all on D ro so p h ila germ cells, it is exceed in gly sm all. T h e question seem ed im p o rtan t enough to test it in experim en ts on m ice, w h ich are m uch m ore laborious and exp en sive than those on D ro so p h ila. M ic e w ere given as m uch coffee in their d rin k in g w ater as th ey could stand w ith o u t ill effects; in som e series, treat­ m en t was started alread y b efo re b irth by- givin g coffee to p regn an t fem ales and co n tin u ­ in g the treatm ent on th e progeny. Y e t n eith er m u tation s n o t tran slocation s w ere ob tain ed, and fo r a tim e this seem ed to settle the question . I t w as re-opened very recen tly by the finding th at caffein e causes chrom oso m e breaks in h u m an ce ll cu ltures. I t is true that these breaks do n o t seem to form translocations and therefore are n o t o f the kind th at is likely

to h ave gen etical con seq u en ces, b u t it is q u ite possib le th at this m ay be d iffe re n t in germ cells. O n the o th er h an d , it is also q u ite pos­ sib le th at no ch rom oso m e breaks at all are p ro duced in germ cells. A g a in , the final co n ­ clusion rem ains d o u b tfu l, alth ou gh the results w ith h um an cells c ertain ly w arn to cau tion .

It m ay seem overcautious to th in k th at the ch rom osom es in tw o types o f h u m an cell m ig h t respond d ifferen tly to th e sam e m u ta­ gen . B u t this is ju st w h at has b een fo u n d for Form aldehyde. W h e n Form aldehyde is m ixed w ith the Food o f D ro so p h ila, it p roduces high Frequencies of m u tatio n s in m ale larvae. F e m a le larvae and adults o f eith er sex are qu ite im m u n e to its m u tage n ic actio n , alth ou gh — as experim en ts w ith isotop ically lab elled Form aldehyde h ave show n — it p en et­ rates to th eir gon ads. E v e n in the testes oF m ale larvae, its action is restricted to one p articu lar type of germ cell, th e early sp e rm - a tocyte . I h ave rep eated ly been asked b y pig breeders w h eth er m u tation s m ay b e p roduced by the practice of Feeding b reed in g anim als w ith skim m ilk th at has been sterilized by Form aldehyde. N o w it so h ap p en s th at, m an y years ago and For an e n tirely u n related reason, I h ave show n that Form aldehyde-treated skim m ilk p o w d er is a good m utagen For D rosop h ila larvae. B u t h o w can one e xtrap o late From D ro so p h ila germ cells to p ig germ cells in the case of a m utagen th at d istingu ishes b etw een D ro so p h ila sperm atocytes an d D ro so p h ila sperm atogon ia?

It is this kind of con sid eration that m akes it so very d ifficu lt to assess gen etical hazards From ch em icals. Y e t the p ro b lem is so im ­ portan t th at at present m u ch m o n ey and effort is sp en t on arrivin g at som e con clusions, h ow ever ten tative. A m o n g th e su bstan ces For w h ich evid en ce o f gen etical effects is b eing so u gh t is L S D . So Far the results have been c o n tra d ic to ry : in som e exp erim en ts, it has produced ch rom oso m e breaks in m am m alian cells; in others, it has Failed to do so.

CANCER THERAPY

T h e re is on e grou p of substances of such high p en etration an d general m u tagen ic action that th eir efficacy in p ro d u cin g m u tation s also in hum an germ cells can h ard ly b e d ou bted . T h e se are alk ylatin g agents used in cancer th erapy, e.g. nitrogen m ustard . A lm o st c er­ tain ly the p ro b a b ility o f carrying a new m u tatio n is h ig h er am on g the p ro gen y of

10

persons treated w ith such a com p ou n d than am o n g the rest o f the p o p u latio n . Sin ce, h ow ever, the n u m b e r o f ch ild ren to w h ich this ap p lies form s a n e g lig ib ly sm all part of the w h o le p o p u latio n , this is n o t a serious g en etical hazard fo r the p o p u latio n as a w hole.

T h e use o f alk ylatin g agents in cancer th erap y b rings m e to the positive ap p lication s o f m u tatio n research to h u m an w elfare. E lim in a tio n o f can cer cells b y chrom oso m e b reakage is on e o f them . I t rests on the fa ct, m en tio n ed b efo re, that chrom oso m e breakage kills o n ly d ivid in g cells an d , therefore, acts sp ecifically on m align an t cells w ith th eir high d vision rate. A ll th e sam e, it is usu ally not possib le to exclu d e norm al d ivid in g cells, such as ep ith e lial cells, from the irrad iated area, and these too are likely to be killed by ch ro m o ­ som e breaks. O n e o f th e aim s o f can cer th erap y is, th erefore, to increase the d ifferen ­ tial response o f n orm al and m align an t cells to rad iation . M u ta tio n exp erim en ts have given valu ab le suggestions on this p ro b lem . S u b ­ stances h ave been fo u n d th at a ct as sensitizers fo r ch rom oso m e b reakage b y rad iation , w h ile oth ers a ct as protectors. I f m eans can be fo u n d to in trod u ce such substances selectively into m align an t or n orm al cells, on e m ig h t m ake the fo rm er m ore sen sitive or th e latter m ore resistant to k illin g b y X -rays. T h e m ost p o w erfu l and g e n erally e ffective ad ju van t to X -ray effects is oxygen . A given dose o f X-rays produces several tim es as m an y ch rom oso m e breaks in oxic as in an oxic cells. M o reo v er, o n ly a fraction o f the norm al oxygen pressure is required to yield fu ll se n sitivity to X -rays, so that the se n sitivity o f norm al cells is alread y at its m axim u m . So lid tum ou rs, h o w ­ ever, often have an an oxic core o f h ig h ly resistan t cells, and this m ay serve as a source o f ren ew ed m align an t grow th w hen the m ore perip heral and b ette r o xygen ated cells have been k illed . T h is has led to attem p ts to im prove the tream ent o f solid tum ours by rad iating p atien ts w h ile they b reath e oxygen or are in fu sed in tra-arterially w ith h ydrogen peroxide. N eu tro n s are e q u ally effective chrom oso m e breakers in an oxic as in o xic cells; this is in p art responsible fo r their efficiency in can cer treatm ent.

PEST CONTROL

C h ro m o so m e breakage is also m ade use of fo r a very d ifferen t purpose, the con trol of noxious insects. Y o u w ill rem em b er that

chrom oso m e breaks or certain types o f trans­ location kill zygotes in to w h ich th ey have been carried b y on e o f th e gam etes. W h e n m ales o f D ro so p h ila are exposed to very high X -ray doses, th ey rem ain ab le to m ate and tran sm it sperm , b u t m o st or all o f th e eggs fertilized b y th e sperm fail to hatch . T h e idea therefore arose th at the fe rtility o f w ild species m ig h t b e d rastically redu ced b y ca tch ­ ing or rearing m ales, exp o sin g them to high radiation doses and releasing them again in to in fected areas. T h is tech n iq u e has already had a spectacu lar success in th e case o f the screw w orm fly, w h ich lays its eggs in to the skin o f cattle and used to b e a great pest in the So u th ern States o f the U S A . N ow ad ays it has p ractically disappeared from these regions. O ccasion al invasions from M e x ico , w here no sim ilar p ro je ct has been carrie d out, are com b ated b y the release o f sterilized m ales from aeroplanes near the border. F o r oth er species, the tech n iq u e m ay h ave to b e m o d i­ fied in order to m eet th e special p h ysio lo gy or ecology o f the insects. T h u s in the b o ll w eevil, a cotton pest, th e dose o f X -rays th at kills m ales is o n ly a little h ig h er than that w h ich sterilizes th em , so th at X -rays can n o t b e used for sterilization ; ch em ical m utagen s m ay give b ette r results. F o r T se tse flies, a p ro je ct is n ow b ein g w orked ou t b y w h ich viable, h e rit­ ab le translocations — o f the kin d that in m an causes D o w n ’s syn drom e — w ill be in trodu ced into w ild p op u lation s. W h ile this w ou ld n o t lead to an im m e d ia te and drastic reduction in h atch a b ility, it should even tu a lly b eco m e a self-m ain tain in g d evice fo r p ro d u cin g heritab le sterility. In sect con trol via ch rom oso m e breakage in sperm atozoa is b ein g studied in m an y cou ntries and discussed at in tern ation al levels.

IMPROVING THE GENOTYPE

F in a lly , le t m e m en tion th e p ossib ility o f u tilizin g in duced gene m u tation s fo r th e b en e­ fit o f m an kin d. In w ork w ith m icro-organism s, this has already been don e successfu lly. F u n g i w ith a h ig h er yield o f an tib io tics or yeasts w ith im proved b akin g or b rew in g qu alities can be produced w ith the aid o f m utagen s. H o w ­ ever, in all these cases, the vast m ajo rity of m u tation s is n o t o f th e desired typ e an d m an y are leth al or at least h a rm fu l to the organism . W e h ave seen earlier w h y this m u st b e so. In m icro-organism s, o f w h ich h u g e n u m bers can b e raised easily and ch eap ly, this w astage is no

im p e d im e n t to the use o f m utagen s fo r im ­ p ro vem en t. E v e n in agricu ltu ral or orna­ m e n tal p lan ts, “ m u tatio n b reed in g” is b eing used q u ite exten sively, esp ecially in inbred strains w h ose gen etic p u rity on e does n o t w ish to destroy b y the in tro d u ctio n o f desirable genes through crossing. In these cases, too, the loss of, perhaps, a thousand un desirable m u tan ts fo r the sake o f on e desirable on e m ay b e w orth w hile. F o r agricu ltural anim als and, even m ore, fo r m an im p ro vem en t b y in duced

m u tatio n is ou t o f th e question unless treat­ m en ts can be fo u n d w h ich q u ite specifically produce certain types o f m u tation . T h e h op e fo r this to happen is exceed in gly sligh t, at least u n til the tim e w hen w e can im p la n t into em bryos genes th at h ave been extracted from selected donors or h ave even been tailor-m ade in the test-tube. A lth o u g h this is a d istin ct possib ility fo r the fu tu re, I do n o t th in k that it w ill m aterialize in m in e or even in your lifetim e.

DIAGNOSTIC PROBLEM

Pain fo r nine m on th s o f a sharp, grip p in g natu re lastin g a few seconds at a tim e and occurrin g several tim es per day. N o relation to m eals, etc.

ON E X A M I N A T I O N

A large m ass in th e righ t in gu in al fossa was noticed b y h e r G e n e ra l P ractitio n e r on the even in g o f adm ission. S o m e tenderness and gu ard in g was present. P a tie n t was afebrile.

P .V .: P elvis e m p ty b u t lo w er pole o f mass p alp ab le h igh u p on righ t side the m ass h avin g a so ft con sisten cy.

B .S .: Present.

P R E V I O U S H I S T O R Y

D u o d e n al U lc e r diagnosed several years earlier and treated m ed ically w ith success.

B ariu m m eal and fo llo w through tw o w eeks b efore adm ission sh ow ed no ab n orm ality.

I N V E S T I G A T I O N

E r e c t ab d o m in al X -ra y sh ow ed o p aqu e area in righ t iliac fossa w ith a fe w scattered fluid levels in the large bow el.

A . W h a t is the m ass in the right iliac fossa?

B . W h a t is the lik e ly cause o f th e sym ptom s and signs described?

( A n s w e r o n P a g e 22 ) O F F I C E - B E A R E R S F O R T H E 2 3 3 r d S E S S I O N S e n i o r P r e s i d e n t ... ...A. J . K. C O NN 1 s t J u n i o r P r e s i d e n t ... ...Miss M. F . O S B O R N 2 n d J u n i o r P r e s i d e n t ... ...J . W A L L W O R K 3 r d J u n i o r P r e s i d e n t ... ...C. F. J . G R I N O L E S e n i o r S e c r e t a r y ...R. J . C R A I G J u n i o r S e c r e t a r y ...T. F . B E N T O N C o n v e n o r of B u s i n e s s C o m m i t t e e ... ...I. S M I T H „ P u b l i c i t y ... ...M. P I C K I N „ H o u s e ... ...M is s M. Y. M O R R I S „ L i b r a r y ...R. d e S O L D E N H O F F M u s e u m ...Miss D. E. G I R D W O O D .. ,, D i n n e r C o m m i t t e e ... ...Miss M. Y. M O R R I S