59

CHANCE, DESIGN AND DISCOVERY*By J. HENRY DIBLE

Professor of Pathology, Postgraduate Medical School, London

Were I about to preach a sermon, which I amnot, I might take as my text some part of the ninthchapter of the first book of Samuel, and though Iknow that being all good Welsh Calvanists youwill immediately appreciate the allusion, yet incase there be one here who is not so informed, Iwould recall that it is told there how Saul, the sonof Kish, went out to seek his father's asses, whichwere lost, and found a kingdom-the kingdom ofthe Israelites. I should use such a text becausethis story was remembered by the colleagues ofthe German chemist Wohler when in I828 he setout to make ammonium cyanate by treatingpotassium cyanate with ammonium sulphate, ex-pecting by double decomposition to get potassiumsulphate and ammonium cyanate and to separatethem by crystallization. Under the conditions ofhis experiment, however, he found to his astonish-ment that a fairy godmother had given him urea,which has the same chemical composition asammonium cyanate but a different arrangement ofthe atoms. This discovery wholly upset the thenfirmly-fixed notion that animal products couldnot be made in the laboratory, but only by somemysterious ' vital force.' W6hler wrote toBerzelius: ' I must tell you that I can prepareurea without requiring a kidney or an animal, aman or a dog.' This event was the beginning ofsynthetic organic chemistry.Why have I commenced this address to you, the

young men of 1952, eager to enter upon yourgreat heritage of the wonders of modern discovery,and to discharge your therapeutic thunderbolts atthe suffering bodies of your patients, with thispiece of past history? I will tell you. It is not somuch that I am laudator temporis acti but thatthe present is the child of the past and the parentof the future, and if we are to look into the futurewe should learn something of the present and thepast. And so for a brief moment this afternoon Iwant, with you, to look at the story of present

*Opening address to Welsh National School ofMedicine, October 9, I952.

achievement, and to consider how this was wonand how we may use the knowledge we gain forwhat lies ahead of us.When you get old and tend to sit in your chair

dreaming,'Gone the fires of youth, the follies, furies,

curses, passionate tears,Gone like fires and floods and earthquakes ofthe planet's dawning years '

and you look up the valley which lies behind, yousooner or later become aware that you are seeingthings as it were through the other end of thetelescope; and that instead of the distance beingmade big for you you see a view in which thingsare dwarfed and shrunken to much smallerdimensions, and a lot of them seem hardly worthtalking about.

In this mood of philosophical equanimity let uslook back on medical progress and see what itall amounts to and how it has come about, and thisinvolves something of medical history. Now whenyou are young and eager and everything is to get,you are apt to be impatient of medical history. Sooften this seems a matter of musty old cracked-back, calf-bound volumes with yellow pages,written perhaps in quaint stilted English or-worse still-in ' dog Latin.' But do not be putoff by this idea; it is nothing of the sort but is afascinating study of exploration and slow advanceinto the unknown lands of knowledge that lie alongthe edge of our Continent of Things Certain. It isa study of trial and error, of false paths, of wholegenerations under the sway of wrong ideas leadingto wrong treatment and God knows what in theway of casualties-and the old tale yet goes on.A friend of mine said to me the other day, ' Inthe i8th century hundreds of people lost theirlives through blood being taken out of themneedlessly; today people are being killed throughblood being put into them needlessly,' and I-who only that morning had seen the body of ayoung man, dead as the result of an incompatibleblood transfusion, given after an operation of

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60 POSTGRADUATE MEDICAL JOURNAL February I953

convenience, could only agree with him sadly.But I was talking of medical history and I wouldask you not to disdain any of it and to rememberthat all is knowledge and that you are members ofa learned profession. In the urgency of accumulat-ing that vast mass of facts-right and wrong,relevant to your lives as well as irrelevant-whichis required of you, it will not be easy to cultivateand to maintain that interest in general learningwhich used to be associated with the word'Doctor.' But I counsel you to do it; it is worthstruggling for; if only that it will give you re-sources within yourselves which you can turn to atany time and under any circumstances, and whichwill abide with you as a continuing solace:'When all the world is old, lad, and all the trees

are brown,And all the sport is stale, lad, and all the wheelsrun down.'

A more immediate and maybe more practicaladvantage in knowing something of how presentinformation has been acquired, is that it is an easymethod of learning and remembering. I madethat discovery when I began to teach, and ithelped me, for I have a bad memory. If you takethe isolated statement that ' Vitamin B12 is thehaemopoietic factor requisite for the maturationof the cells of the erythroblastic series, from themegaloblastic to the normoblastic phase,' you havea mere jargonal assertion of fact that you may ormay not remember in times of trouble in theexamination hall or the viva voce, and you havenothing to tag it on to. But if you call to mindthe former procession of patients, such as theywere in my time, inevitably becoming yellow anddying of pernicious anaemia-a sequence whichhad continued uninfluenced by either mightytomes or a hundred forms of treatment, or byconvincing theories propounded with the weightof authority by the famous German professor,Ehrlich, and the well-known London physician,William Hunter-a macabre procession that hadgone on without interruption since ever thedisease began; and if you then turn another pageand come to the seemingly distant and uncon-nected academic observations of Whipple, madeabout I920, that dogs rendered anaemic by bleed-ing got their blood back most quickly if theywere fed on liver; if you then look back into oneof those musty books of the year of the Franco-Prussian War, and find that the EnglishmanFenwick discovered that the stomach was diseasedin pernicious anaemia, you begin to get a slanton the malady which escaped both Ehrlich andHunter. And if you then remember the experi-ments of Castle on men, and how he found thatmeat partially digested in the healthy humanstomach and then taken out and given to patients

with pernicious anaemia arrested the progressof the disease and restored the lost blood, you seethe whole jigsaw puzzle of isolated pieces fitsuddenly together, and you have a complete andsatisfying picture of pernicious anaemia: a diseaseof the stomach (Fenwick), which is unable tomanufacture a substance formed by the digestionof protein (Castle), which is stored in the liverand is required for the normal building of redblood cells (Whipple).

This story is a well-known one. So well knownthat I have hesitated to repeat its details before aninformed audience. But I have done so becauseit illustrates very well many of the facts which bearupon discovery and progress. Ehrlich and Hunterwere the victims of wrong hypotheses. Bound bythese, like Prometheus upon his rock, there theystayed. Fenwick's discovery was made, forgottenand rejected: its significance was not recognizedand the time was not, perhaps, quite ripe, nor thetechnique at hand for its development. Whipplewas not trying to discover a cure for perniciousanaemia, he was working on blood regeneration ingeneral and he made an incidental observation,which gave a clue to Minot and Murphy, whoutilized it in the treatment of this disease; andfinally the crucial experiments of Castle had towait until technical advances made the readyanalysis of intragastric digestion possible. Miscon-ception, failure to use an observation, chance,technical achievement-all are there in thisrelatively simple story.

tributed most to medical discovery, I should reply' chance.' But I should hasten to qualify this bysaying that the gifts which that Fairy Godmotherbrings only come to those who are industrious inusing them and whose minds are ready to receivethem. You cannot find diamonds by walking inthe pebbles of a South African river with youreyes shut, though you do it all your life. Thisassociation of chance with an ability to recognizethe gift, if and when it comes, has impressed allwho have been interested in the history of dis-covery and has, perhaps, been best put into wordsin the celebrated saying of Pasteur, that ' In thefield of observation chance favours only the pre-pared mind.' And I would go yet further andadd that the boundaries of any discovery are setby the limits of the technical resources of the time.Technical methods are the necessary handmaidensof the research worker, but in saying this I wouldstate immediately that elaborate technical methodsare most certainly not necessary to the discovery ofnew facts, any more than tney are necessary to theevolution of new ideas; indeed, they may by theirvery elaboration become a bar to progress. Byall means let us employ instruments of precision

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if we have them, but let us not throw up our handsin despair if they are out of our reach. 'Themachine,' said Chesterton's Father'Brown, ' cannotlie, Neither can it tell the whole truth.'But let us go back to chance, meaning the gift

it brings to those who can use it, and ask ourselveswhat it has contributed to the progress of dis-covery, and put it into the scales against theprocesses of logic and the discoveries which resultfrom planned investigation. To take the secondmatter first. I doubt if the logical sequence ofideas leading to great results can in the field ofmedicine claim any achievement as monumentalas the work of Pasteur. Every medical studentshould read Vallery-Radot's ' Life of Pasteur.'There is an English translation, but read it ifyou can in the original French and-even if yourFrench is not quite equal to the task-read it inthe original French! The son of a tanner, hegraduated as a chemist and early made the dis-covery that optically inert tartaric acid was amixture of dextro- and laevo-rotatory forms andthat the crystals of these two, which he separatedby hand, were optical isomers; thus he resolveda problem which had puzzled the most renownedchemists of the day, including Gay-Lussac andBerzelius. What is, perhaps, not so widely known,though it is there to be read in his writings, is thatin investigating the properties and preparation oftartrates he found that a certain organism couldutilize in its metabolism only the dextro-rotatoryform of tartaric acid and was incapable of usingthe laevo-rotatory and-extraordinary fact-theorganism he named was one to become worldsfamous 85 years later, penicillium glaucum.

Biology had entered his world and for the restof his life he was to work at it; being led fromfermentation to putrefaction, from putrefaction tothe action of micro-organisms in the body and thestudy of infective disease, and so on to the pro-tection of animals from microbial infection and,finally, to his crowning work upon the virusdisease, hydrophobia. The details of this longodyssey are for all to read and I have barely re-capitulated the chapter headings, but though theprocess was logical, and to us today may seem moreso than perhaps it was did we know the intimatesecrets'of laboratory life, yet it is stated by Duclauxand repeated by others that chance put her fingerin the pie at one critical period in this masterlyprogression. The whole basis of Pasteur's work onimmunization lay in the isolation of the causal or-ganism, the production of a strain of attenuatedvirulence for the animal, and the setting up ofactive immunity by means of sub-clinical in-fection with this attenuated strain. An undesignedevent showed him the way. He had been experi-menting on the cholera of fowls and the organism

which causes this. On going away for a shortholiday he found on his return that most of hiscultures were dead or inactive, and in attemptingto revivify them he inoculated them into freshfowls, but he found that these failed to contract thedisease and were none the worse for the inocula-tion, Later, he obtained some fresh virulent or-ganisms and found that whilst these killed ordinaryfowls in the ordinary way they did not kill the fowlshe had incoulated with his old cultures; to hissurprise these animals survived. They had beenimmunized by inoculationwith dead and attenuatedcultures, and the phenomenon of active immuniza-tion by such means, which was to occupy the restof his life so fruitfully, was laid bare. Nothing inthis detracts at all from Pasteur's glory, which isimperishable, for he had the mind to appreciatethe value of the unforeseen fact and the generalprinciple to which it pointed, together with theremorseless energy to follow the clue thus found,to the prevention of chicken cholera, of anthraxand to the crowning work of his life-the pre-vention of hydrophobia in those bitten by a maddog. He achieved this, be it noted, when he w.iswell over 60 years of age.

Paul Ehrlich, the German chemist and biologist,whose name I have mentioned to you already, mayalso be looked upon as one whose steady and un-remitting pursuit of an idea brought discovery andtriumph in the end-and there is much in this.Perhaps the idea is heightened in a way by thefact that his most famous discovery was named'6o6,' this being the 6o6th of a series of prepara-tions tried in the search for a drug potent againstthe spirochaete of syphilis and, at the same time,relatively harmless to the human body. If any-thing at all suggests a logical sequence this does.Ehrlich was impressed from the beginning by thespecific nature of some aniline dyes in stainingorganisms and conceived that if a micro-organismcould be stained specifically in the tissues itshould be possible to manufacture a substance ofantiseptic properties which, in a like manner,would link itself specifically to the organism andkill it whilst showing no affinity for the bodytissues. He laboured long with dyestuffs on theselines, and about 1904, in trypan-red, he had somesuccess and reached the conclusion that phenolderivatives and the introduction of a halogengroup into the benzene ring gave the most promis-ing results. But the goal still eluded him, andthen he switched to arsenical compounds whichwere not dyes and had, in a desultory manner,been used for years in the treatment of syphilisand the allied condition of trypanosomal diseases.I often wondered what profound chain ofreasoningcaused this step. Only a few weeks ago in search-ing for something else I found out. It appears

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that a man with the good Welsh name of Wolfer-stan Thomas had been experimenting at Runcornon the action of atoxyl in curing trypanosomal in-fections in animals and Ehrlich heard of this. Hewent to Runcorn, saw Thomas and on his returnto Germany he took up the investigation of atoxyl,which is a benzene ring compound containingarsenic and a pretty dangerous drug (it causes opticatrophy and blindness), and from this beginning heultimately evolved salvarsan, the first great mile-stone in the history of chemotherapy. But thetrail which Ehrlich blazed has been continued byothers who have found rewards as great or greaterthan did their master, for it followed directly uponhis work on the dyestuffs that his pupil Browning,an old teacher of mine in Glasgow, developed theflavine group of dyes as wound antiseptics; thesedid valuable service in the later years of the firstworld war. Nearly 20 more years passed and thenDomagk (I935), who had behind him the greatGerman chemical industry, showed the extra-ordinary action of the azo-dye sulphonamido-chrysoidin, or prontosil, on streptococcal infectionsin mice. But even so there was an element of theunsuspected in this. Domagk knew that this dyeprontosil-a red dye--was inactive in the test tube,and the Frenchman Trefouel was able to show thatthe efficacy of the pontosil was mainly due to itsbeing broken down in the animal body into para-amino-benzene sulphonamide which is a compara-tively simple compound and not a dyestuff at all,and one which had already been known to chemistsfor 27 years, but had lain perdu and had never beentried as a therapeutic agent. It might be said,fairly, that a false trail led to the discovery of itsaction. However this may be, the hunt was up.The organic chemists and the chemical manu-facturers rushed in and in the twinkling of an eyeproduced innumerable variations of the substanceof many different advantages and ranges of ac-tivity. To one of these (M. and B. 693) I certainlyowe my life. But although they did not know itthen the fairy, Chance, had already spiked theirguns for them in 1928 by dropping a spore ofpenicillium notatum on a culture plate of a Londonbacteriologist-of which more anon-and chemo-therapy, strictly speaking, became overshadowedby antibiotic therapy, after a considerable latentperiod and through the energy and vision ofFlorey.Now let us look a little at the more direct

activities of this Dame Chance. In one way oranother she has had a finger in every medicaldiscovery and the more you come to know aboutthis the more you find it holds. There are fewnames we revere more than Jenner's, and yet it wasa village girl who told Jenner that she was im-mune to smallpox because she had had cowpox,

and as he was 49 when he started inoculation withcowpox lymph, and had been in medical practiceas apprentice and doctor already for 36 years, itis evident that he pondered the matter long. Thelegend of immunity to the greater disease fromthe lesser was well established in the West Country,but in Jenner's mind-the friend and corres-pondent of that insatiable man John Hunter, whoexplicitly urged him to try the experiment-theseed fell upon the prepared soil.

In the year that I was born (i889) von Meeringand Minkowski in Strasburg disputed whether adog could live without the great digestive glandthe pancreas, and like good scientists they tried theexperiment. To their utter surprise-and thefact was first spotted by the laboratory attendant-the dogs which lived after the operation becamediabetic and remained so during their short sur-vival. Von Meering and Minkowski went on (themajor partner was Minkowski) to show that liga-tion of the pancreatic duct by itself, and the ex-clusion from the intestine of the pancreaticsecretion, had no such effect and thus, it may besaid, the science of endocrinology was born.

I do not want to weary you with the continuedrecitation of these ancient instances, but I cannotleave this theme without recalling the beginningsof another great branch of medical science-know-ledge of the vitamins. An appreciation of thenecessity for certain ill-understood accessory foodsis as old as the hills and it begins with scurvy, thatcurse of seamen, navies and maritime explorers,since ever men began to voyage upon the deepwaters. L. J. Harris in a most readable little bookupon the vitamins has written:'The scurvy flew through the schooner's crew

as they sailed on an Arctic sea,They were far from land and their food was

cannedSo they got no vitamin " C ".'

The long story of scurvy is a mixture of ac-curate observation, obscuration, misconception,acute insight, and pompous self-sufficiency andignorance, and the history of scurvy and its pre-vention in the Royal Navy and amongst Arcticexplorers alone would make up a lecture in itself.You should read it in Drummond's book 'TheEnglishman's Food.' Poor Drummond who lastsummer was so foully murdered in France. Butit is not of scurvy and vitamin C that I wish totalk, but of the events which led to the discoveryof the beri-beri vitamin : for this was really thebeginning of the modern phase of knowledge; andhere I must pay tribute to Dutch scientists for thepart they played.

In I886 the Dutch Government, which hasalways had a fine record of enlightened medicalwork in its East Indian dependencies, sent two

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scientists, Pikelharing and Winkler, to the EastIndies to investigate beri-beri, including also ayoung army doctor, Eijkman. They believed fora time that they had discovered an organism asthe cause of the disease and the two senior menreturned to Holland with it, leaving Eijkman be-hind to dot the i's and cross the t's. For two yearshe laboured at this and then chance took a hand.Eijkman was working with chickens and fundsbeing short he had to feed them upon what wasleft from the ward kitchens and, to his surprise,he found that they developed a disease which wasthe same as the beri-beri they were so concernedwith. The staple native diet was rice and Eijkmanand his assistant Grijns began to look into thematter and found that only polished rice gave hensberi-beri and that this disappeared when they weregiven unpolished rice, or could equally well becured by feeding them upon the stuff removed inpolishing. Thus was the substance vitamin Bdiscovered in I9oI, though some years were toelapse before it received this name.

It is to Pikelharing, Eijkman's chief, that thecredit must go of realizing that here was anentirely new principle in the causation of disease:that this could result from the lack of something inthe food in quantities so small that its calorificvalue was negligible. Up to this time dieteticshad been a matter of calories; professors decidedhow much food was required to provide thecalories necessary for subsistence in prisons andthe ungrateful convicts failed to thrive-and soon. True von Bunge at Basle in I890o had posedthe question: ' Does milk contain, in addition toprotein, fat and carbohydrate other organic sub-stances which are also indispensible to the main-tenance of life?' But like Pontius Pilate he didnot wait for an answer. Pikelharing took up thework Lunin and his chief von Bunge had leftat an inconclusive stage, and as a result he wasable to write in i905: ' It is impossible to keep ananimal alive by feeding it on protein, fat, carbo-hydrates, the necessary salts and water ... some-thing more must be present,' and 'There is anunknown substance in milk which even in smallquantities is of paramount importance to nutri-tion' and also ' Undoubtedly this substance notonly occurs in milk but in all sorts of foodstuffs.'Hopkins in this country obtained similar resultsin very beautiful quantitative experiments in 19I2,and showed that the explanation given by thecritics of the new views (which were now beginningto be discussed in a number of quarters); that theanimals became bored by the monotony of theirdiet and by merely failing to eat fell into a decline,was untrue. And so the vitamin story began andwent on, and the end of it is not yet. The goodfairy had other gifts to bestow in the same field,

and one of these was thrown to the NorwegiansHoist and Fr6lich in 1907, when they tried toproduce beri-beri in guinea-pigs by diet. Trueenough they produced a disease, but it turned outto be scurvy-and in this way they discovered anessential tool which previously had been lacking;an animal, other than man, upon which theefficacy of anti-scorbutic substances could be tried,and thus gave an immense impetus to the investiga-tion of vitamin C. I may add that Szent-Gy6rgifirst isolated pure vitamin C from the adrenalwhen studying the nature of reducing substancesin its cortex. He called this substance hexuronicacid and found it also in lemon and other vegetablejuices, but did not realize that he had obtainedcrystalline vitamin C until much later. He, too,was looking for an ass and found a kingdom.And where has all this brought us to? If I might

put it in as few words as possible I would say,'Progress from known data may be planned;for discovery we are indebted to chance.' Onemight liken the matter to the difference betweenthe biological processes of continuous variationand mutation. Once given the new idea, the newfact, the mutation in our routine of perceptions,then we can apply our minds to its perfection;we can polish it up and show its different facets, asis done by a host of busy little people once a dis-covery-such as that of the antibiotics--is made.But we do not as a rule have the wit to go out andlook for the new fact. It was the fairy Chancewho dropped the spores of penicillium notatum onFleming's culture plate in the dusty bacteriologicallaboratory at St. Mary's Hospital-and it was thesame fairy who arranged that the organisms grow-ing around should be of a species sensitive topenicillin; if they had been B. coli and notstaphylococci we might-still be without penicillin.The whole story and all the similar stories, ofwhich there are many, fill me with humility andalso with a sense of contempt for the powers ofthe human intellect we are so conceited about.The history of discovery is the most salutorycorrective to the view that you can purchase it bythe lavish outpouring of money and the creationof vast research institutes. It is true, and allthat I have told you goes to show it, that dis-covery only visits those who are working in thefields over which she hovers, and who have boththe prepared vision ready to recognize her giftswhen they are bestowed and the mind and in-dustry to put them to use; nor would I be sofoolish as to decry the value of intensive workupon any new fact. But the great gifts come fromon high; they can be neither bought nor com-manded. They are not the perquisite of prin-cipalities or powers but of ordinary men who haveused such gifts as God has given them.

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A moment ago I used the word humility. Iused it and I would commend it to you in a specialsense, meaning an absence of the conceit that goeswith ignorance. If you want to see an illustrationof this sort of conceit, portrayed by a master hand,go and look at the picture of 'Ignorance' byDalziel in the 'Pilgrim's Progress.' It is worthlooking at again, if only to see a fine woodcut by amaster of that craft and to send you back to agreat piece of literature.Too much confidence in our scientific attain-

ments, considerable though they may be, exposeus to dangers against which we must be eternallyvigilant. One is the uncritical acceptance ofauthority and authoritative pronouncements, andthis you have to be especially on your guard againstnow that medicine has come under the administra-tion of the State and the importance of the in-dividual withers. There will be a temptation toimpose methods of diagnosis and treatment fromabove, it makes for easy administration. But,believe me, the gentlemen in Whitehall do notalways know best, though they have the advantageof consultation with the best authorities extant.The history of medicine shows only too clearly,and sometimes with tragic emphasis, how theaccepted dogma of today is the error of tomorrow.The other danger which comes from confident

self-satisfaction is the dislike for new ideas. Howdisturbing they are! Do you remember the play'Milestones'? It has been said with much truththat the attitude of men to new and surprisingdiscoveries is that they say, firstly, ' It is untrue,'next' It is of no importance ' and finally, when thetruth is so absolute that it cannot be doubted,' We always knew it,' and this fault of distaste fornew ideas is not limited to the lower levels in thescientific hierarchy; the highest are fallible. TheRoyal Society refused to allow Jenner to presenthis findings and wrote ' He ought not to risk his;reputation by presenting to the learned bodyanything which appeared so much at variance withestablished knowledge, and withal so incredible.'Note that phrase ' established knowledge.' Timeand again established knowledge has proved to beestablished ignorance. Crystallized, petrified, and

built into the stony structure of static minds.Beware of authority. Do not be overshadowed orbrowbeaten by pompous elders. Cultivate sceptic-ism, scorn dogma. 'Prove all things: hold fastto that which is good.'How fallible is dogma! In that fascinating book

' The Sea Around Us,' you can read how in I938,off the coast of South Africa, some fishermencaught in their trawl a fish which the most learnedbiologists, zoologists, paleontologists, geologistsand archeologists had pronounced to have becomeextinct 60 million years ago, with the last of thedinosaurs and when the chalk hills of England werebeginning to be formed. Think of it! Sixtymillion years. A long time. Suppose Jones hadsaid in his zoology viva that Latimeria might befound swimming off the Cape! Short shift forJones in 1937-but honours for him in I939!Now to you who have listened to me so patiently

it may sound as if this is a story of cynicism tingedwith disillusionment-but it is not so. FatherMendel planting his peas, parson Stephen Halestying down his young mare and finding the bloodpressure *by inserting a tube into her femoralartery, Leeuwenhoek grinding his lenses andlooking at his 'little animals,' Shaw Dunn tryingto poison the kidney and poisoning the islets ofLangerhans, W6hler trying to make ammoniumcyanate and making urea; they were all urged onby an itch of curiosity and each in his own waybecame a begetter of modern medical science. Tothe seeker his reward. There is no crock of goldwhere the rainbow ends, but there is and alwayshas been much to be found. Much that maydelight and gratify and, if it is not a material, willalways be a spiritual reward. And so I wouldcounsel you in your progress through this life, andin the practice of the high art for which you areequipping yourselves, to remain seekers and tocultivate in the garden of your souls that plant ofcuriosity that will yield satisfying fruit. And atthe end of it all, when the light is failing and theshadows lengthening on the grass, even if the fairyhas not dropped a glittering prize in your path,you will find that you have been the better doctorsand will have acquired merit and peace.

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