Cancer Research : Its History and Prospects

Of all the invitations one has ever been privileged to receive, I wish you to know that the arrival of your own was a special honour, and a special delight to accept—giving me, among other things, the opportunity to re-visit the house of our ancient Society, and to recall at close hand many happy occasions within these walls some thirty years ago. It was the time of the great Sir Alfred Ewing as Vice-Chancellor, and, in the Medical School, of Sir John Fraser and Sir David Wilkie of glorious memory, whose portraits adorn your walls. We generated then, as doubtless you generate now, abiding affection for Edinburgh and its University, and not only affection but I confess it, sentiment, for our Royal Medical Society. Reading the leading article in the second number of Res Medica, I have been greatly struck by its closing sentences: “At a time when religions, cultures and individuals are menaced by nuclear weapons and foreign ideologies, living traditions assume an importance never envisaged by their inaugurators. Let us then foster unity and friendship and be worthy heirs of our heritage.” This is the ever-renewing and ever more significant function of the Royal Medical Society, and I esteem the great honour of inaugurating your two hundred and twenty-second Session. I mention these things to show how it is and why, that I received your invitation with such pleasure and gratitude. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISSN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, Autumn 1958, 1(3): 7-11 doi:10.2218/resmedica.v1i3.318

Of all the invitations one has ever been privileged to receive, I wish you to know th at the arrival of your own was a special honour, and a special delight to accept-giving m e, am ong other things, the opportunity to re-visit the house of our ancient Society, and to recall a t close hand m any happy occasions within these walls some thirty years ago.It was the tim e of the great Sir A lfred Ew ing as Vice-Chancellor, and, in the M edical School, of Sir John F raser and Sir D avid W ilkie of glorious m em ory, whose portraits adorn your walls.We generated then, as doubtless you generate now, abiding affection for E dinburgh and its University, and not only affection but I confess it, sentim ent, for our R oyal M edical Society.R eading the leading article in the second num ber of Res Medica, I have been greatly struck by its closing sentences: "A t a tim e when religions, cultures and individuals are m enaced by nuclear weapons and foreign ideologies, living traditions assum e an im portance never envisaged by their inaugurators.L et us then foster unity and friendship and be worthy heirs of our heritage."This is the ever-renewing and ever m ore significant function of the Royal M edical Society, and I esteem the great honour of inaugurating your two hundred and twenty-second Session.I m ention these things to show how it is and why, th at I received your invitation with such pleasure and gratitude.I have taken as my subject the history and the prospects of cancer research.I t could be regarded as a m orbid one, but I hope to show that this is not necessarily so; on the contrary, th at the history of the field is rom antic and inspiring, th a t its present state is active and exciting, and that its future-although by far the greater part rem ains to do-is full of hope and promise.
C ancer research can be regarded from two aspects-the purely m edical, as a great endeavour directed to the solution of a hum an problem ; and scientifically, from the unique character of the disease, as an integral part of m odern biology.It is unique since its basis lies in a perm anent accession in the growth of cells.Its history has largely been coterm inous with that of the m icroscope, perm itting the developm ent of the cell theory, which has been described as one of the greatest conceptions of the hum an m ind, and which, although it had m any precursors, was finally established as recently as the early p art of the nineteenth century.
It is often said th at the cancer cell has acquired the power of unlim ited growth.This is strictly not so, since m ost norm al cells are equally capable of unlim ited grow th in appropriate conditions.M ore and m ore certainly, cancer appears rather as due to the release or unm asking of that growth potential which cells all along possess, although exquisitely restrained.T he mechanics of cell division appear devised to effect an equal distribution.Yet soon in developm ent is superposed the mysterious feature of differentia tion, while the rate of growth declines.Even in the adult, however, cell division continues, either tem porarily as in the healing of wounds, or con tinuously as in the tissues of the bone m arrow , intestine and skin.T he m ain feature here is a matchless orderliness and precision.In the words of D r Isaac W atts in one of his hym ns, " Strange th at a harp of a thousand strings, should keep in tune so long."Sooner or later, however, a single cell may becom e transform ed to a cancer cell, with altered grow th properties which are now and henceforth no longer subservient to the needs of the body, but independent and frequently autonom ous.T he liability to this change appears inherent in all cells capable of growth.It is not surprising, therefore, that we should find evidence of it throughout the whole of the plant and anim al kingdom , not only in historic b ut also in pre-historic times.
So far we have spoken of the nature of cancer.W hat of its cause or causes?M odern cancer research largely dates from the tim e of R udolf Virchow, whose Die Cellular pathologie was published alm ost exactly one hundred years ago.R em em bered for his dictum omnis cellu la e cellula, he applied the cell theory to pathology, and inaugurated several decades of investigation of the m icroscopical structure of cancer in m an and anim als, carried out first in the great schools of Germ any and then the world over.A lthough historically necessary and im portant, this was not, however, sufficient.T ow ards the close of the century a need becam e ever clearer, namely, for the use of the experim ental m ethod.In this country, the new outlook led in 1902 to the establishm ent of the Im perial C ancer R esearch Fund, and in 1909 to th at of the R esearch Institute of the C ancer H ospital in London.The first director of the form er institution was E. F .Bashford, who with great genius and foresight, and with the support of a small but brilliant staff, was able within a brief ten years to lay the m ain foundations o f the whole subject, and to forecast its likely developm ent and requirem ents for many further years ahead.All this helped to prom pt, or was accom panied by, sim ilar developm ents in the U nited States, in E urope, and in Japan.
A lthough purely m edical m ethods alone were to prove insufficient, it should be noted that the first and vital clues arose from observations m ade in the; field of occupational and industrial m edicine.T ow ards the end of the eighteenth century, Sir Percivall Pott had described the special liability of chim ney sweeps to cancer of the scrotum , and had traced the cause to contam ination of the skin with soot.W ith the industrial revolution cam e m any m ore exam ples, m ainly due to occupational exposure to m ineral oil and tar.A notable case was the so-called " paraffin cancer" in the Scottish shalefield, described by the celebrated Joseph Bell, of whose association with the R oyal M edical Society we are justly proud.E xperim ental proof th at m ineral oil, coal tar and pitch do in fact induce skin cancer had, however, to be long deferred, indeed until 1915, when Y am agiw a first pro duced cancer artificially through chemical m eans, by applying coal tar to the skin of the rab b it ear.Coal tar being a complex m ixture of a great host of chem ical individuals, the search then began for the responsible agent o r carcinogen.In the early 'twenties, Bloch in Z urich adduced evidence th at the agent m ight be a com plex hydrocarbon, th at is, a com pound con taining hydrogen and carbon only-and virtual proof of this was later obtained by my own predecessor, Sir E rnest K ennaw ay, at the C ancer H ospital. T hrough his w ork and th at of his school, the picture gradually em erged of carcinogenic substances b u ilt through the conjugation of benzene rings.
E arly in these investigations, it was repeatedly noted that cancer-producing tars exhibited the property of fluorescence in ultraviolet light, th at is, to absorb invisible light of short wave-length, and to em it visible light of longer w ave-length.In 1927, W. V. M ayneord, again at the C ancer H ospital, took the m atter decisively forw ard when he indicated that the fluorescence spectra of such tars showed qualities which appeared to be characteristic.This spectrum of cancer-producing tar proved to be, in K ennaw ay's words, "the single thread tha t led all through this labyrinth," and it soon enabled him, and his colleagues, to track down the carcinogenic agent.Since it was already suspected to be a com plex hydrocarbon, the next step was to exam ine the spectra of those polycyclic hydrocarbons already know n in pure form , and constituted from the fusion of various num bers of benzene rings.Very shortly, H ieger was able to m ake the key discovery th at 1 :2-benzanthrace (com prising four such rings), also possessed the characteristic spectrum .By a curious accident, C lar in 1929 had just described the synthesis of the related hydrocarbon containing five fused rings, {1 :2:5 :6-dibenzanthrucene), and in the sam e year K ennaw ay and H ieger proved this substance to be carcinogenic in mice-the first pure chem ical individual to be recog nised as possessing this property.T he fluorescent spectrum was also used to great purpose in the isolation of the naturally-occurring carcinogenic agent from pitch.This proved to be another pentacyclic arom atic hydrocarbon, namely 3 : 4-benzpyrene, which C ook and Hew ett were soon (in 1933) to prove by synthesis.In the sam e year, Cook and H aslew ood produced methylcholanthrene from a bile-acid, so raising the whole question-still undecided-w hether traces of highly potent carcinogens can be form ed in vivo from perturbations of the norm al m etabolism of steroids.A chief result of all this work was eventually to provide an amazingly satisfying and com plete picture of the relationship existing, within this series, between chemical constitution and biological action.
In the intervening years, m any older chem ical classes had been uncovered, in no way related to the cyclic hydrocarbons, b u t equally endow ed with carcinogenic qualities-various arom atic am ines, especially those involved in the causation of cancer of the bladder; a host of azo dyestuffs with the special propensity to evoke tum ours of the liver; a series of aminostilbenes with very diversified carcinogenic properties; and m any others.T o these we m ust add a great range of purely physical agents, including ultraviolet radiation itself, X -rays, radium and thorium , and a host of radio-isotopes arising from the atom ic energy program m e, especially radiophosphorous, radioiodine and radiostrontium .Of late we have also recognised the carginogenicity of m any m acrom olecules and plastics, and the special function in carcinogenesis which may be played by the m etals, as also the role of m any biological agents, e.g.those viruses responsible for the induction and propagation of certain tum ours in anim als (although not so far in m an)topics any one of which could easily exhaust a whole lecture in itself.
In none of these cases have we precise know ledge of the m ode of action, or of the site a t which it is excited within the cell.Only in the past few years have there come certain hints, through the discovery of carcinogenicity in yet another chem ical class, nam ely the nitrogen m ustards-substances developed in the Second W ar for the purpose of chem ical w arfare, and nitrogen analogues of that sulphur m ustard or " m ustard gas" which had been used in the W ar of 1914-18.T he nitrogen m ustards have the advantage of relative chem ical sim plicity, with features which are suggestive, or even indicative, of possible modes of action.T he action upon dividing cells is highly direct, leading to cytological abnorm alities indistinguishable from many which can equally be produced by ionising radiation.On this account they are not unreasonably described as radiom im etic, and it is certainly rem arkable th at just as X -radiation is em ployed in the treatm ent of cancer, so also can some of the m ustards, in the palliation of certain form s a t least.Contrariw ise, just as X -rays can be cancer-producing, so also can the m u stard s.In m any cases th e tu m o u rs so p ro d u c e d b e a r signs-as a kind o f im p rin t-th a t th e actio n has involved th e nuclei a n d ch ro m o so m es.A ce rtain e x ten t o f chem ical reactivity is re q u ire d , suggesting a g a in th a t the b io lo g ical e n d -resu lt m ay d ep en d upon re actio n w ith so m e ce llu lar c o m p o n e n t so fa r undefined.T h e m ain featu res of the nitro g en m u stard s is th eir possession of tw o o r m ore h alo alk y l side-chains.W ithin th e series this indeed ap p e a rs to be a re q u ire m e n t fo r biological activ ity W e th e re fo re a p p ro a c h the view th a t carcinogenesis is a process of b io lo g ical m u ta tio n by loss, an d th a t th ere is no tru e acq u isitio n of a new g ro w th p ro p e rty on th e p a r t of th e can cer cell, b u t ra th e r th e u n m ask in g of th e g ro w th p o ten tial w hich its n o rm a l p re cu rso r h ad all alo n g possessed.in the future, th at cancer too will fall in this class, and becom e am enable to control through a re-im position, from w ithout, of that grow th regulation which the cancer cell itself has lost forever.A t any rate it can fairly be said we are at least approaching certain correlations, between the reactive properties of given carcinogens, the places a t which and the m ethods by which they com bine in the cell, and the perm anent alterations in growth behaviour, which com e about as the result.A lthough so m uch rem ains to do, the story is great and growing.W hen one day it comes finally to be told, it will be seen to have m eaning far beyond the sphere of m edicine alone, and to be in p art a m odel of w hat can be achieved by the hum an m ind through the interaction of biology, chem istry and physics.
I end as I began, with thanks to the Society and all its m em bers for this kindly privilege, I also wish to record special indebtedness to my colleague M r K. G. M orem an, and to the officers of the Society for indispensable assistance.M ay the Society enjoy strength and prosperity not only in the present new Session, but in all those which lie ahead, in a future which we are confident will continue that unfolding of the art, science, and achieve m ents of M edicine, tow ards which the Society itself, in its long history, has m ade no m ean contribution.
, a n d led to the p ro p o sa l th a t activ ity m ig h t in fa ct d ep en d upon ch em ical cross-linkage, as fo r ex am p le betw een th e co n tig u o u s lin ear m acro m o lecu les of the ch ro m o so m es th e m selves.A lth o u g h this hypothesis is now kn o w n to be u n d u ly sim ple, it proved trem en d o u sly fru itfu l in dev elo p m en t, lead in g for ex am p le to th e ap p lica tio n of m u ch k n o w led g e a lre ad y a v a ila b le in the field of cross-linking agents in tex tile technology, a n d hence to th e ra p id discovery o f o th e r series w ith s im ilar bio lo gical effects-epoxides, p o lyethylene im ines a n d dim esyl c o m p o u n d s-now classed u n d er th e g en e ral h ea d in g of b io lo g ical alk y latin g agents.T h e ex a ct n a tu re of the b io lo g ical re cep to r is still no t k now n.It is very p ro b a b ly genetical in fu n c tio n , as re actio n w ithin the nucleus a n d upon the ch ro m o so m es m ight infer.H o w ev er, su ch re actio n w ould certain ly in tro d u ce w id esp read rep ercu ssio n s in the cy to p lasm , a n d d irec t action by certain carcin o g en s u p o n the o rganelles of the cy to p lasm is by no m eans excluded.N o tw ith stan d in g , a p ro m in e n t c a n d id a te fo r the seat of action of th e ca rc in o genic a lk y latin g agents is w ith o u t d o u b t-a n d fo r m any reasons alth o u g h n o n e is as y e t decisive-th e d eo x y rib o n u c leic acid of the ch ro m o so m e stru c tu re, as th e chem ical basis o f cell genetics a n d heredity.A g re at im p etu s has b een given to these studies by the p ro p o sa ls fo r nucleic acid stru c tu re pu t fo rw a rd by C rick and W atso n -of the b o n d in g of p y rim id in e a n d pu rin e b ase p airs to yield essentially su p erp o sa b le stru ctu re s, a n d o f the co m p le m en tary d isp o sitio n of these as bridges in a d o u b le helix of p h o sp h ate-su g a r chains; a n d we alread y h av e som e precise chem ical in fo rm atio n as to the ac tio n u p o n such a stru c tu re b o th of ionising ra d ia tio n s an d of the ions y ield ed by a lk y latin g agents.B ut fu rth e r ad v a n ce m u st largely d ep en d upon o u r d ee p er k n ow ledge of ch ro m o so m e stru c tu re .W hile w aiting, we can gain m uch th ro u g h the use of w h a t is still th e m o st fa v o u ra b le m a te ria l-nam ely th e g ian t ch ro m o so m es of th e salivary glan d of th e fru it fly Drosophilain stu d ies of th e chem ical basis of biological m u ta tio n generally, of w hich carcin o g en esis m ay be a special case.A ctin g upon such m ateria l, the a lk y latin g ag ents freq u en tly p ro d u c e changes of the n a tu re o f d eletio n , and this, w ith o th e r co n sid eratio n s, has led to th e view th a t ca n cer ca u satio n could b e d u e to c o m b in a tio n of the ag en t w ith nucleic acid, so lead in g to defects in its synthesis o r stru c tu re .T h is process w ould in te rru p t the essential p re cision of th e nucleic acid , a n d p rev en t th e fo rm a tio n of certain protein m olecules (a n d especially p erh ap s g ro w th -reg u lato ry enzy m e-p ro tein s vital to th e c o n tro l of n o rm al cell d iv isio n ), fo r w hich we kn o w the integrity of th e nu cleic acid stru c tu re is necessary a n d responsible.In th e case of the carcin o g en ic h y d ro c a rb o n s a n d azo-dyestuffs, th ere is also evidence th a t the sam e deletio n of key p ro tein s can be b ro u g h t a b o u t by co m b in atio n of the carcin o g en w ith p rotein m olecules them selves, directly.
T h e g en eral co n cep tio n h as still to b e tested , a n d could clearly h av e th e w id est im p licatio n s.T h e re is an increasing n u m b e r of diseases recognised as d u e to enzym e deficiency, a n d som e o f them can b e co n tro lled by re sto r ing th e defect th ro u g h a k in d of su b stitu tiv e ch e m o th e rap y .It w ell m ay be.

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