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Harvey, pasteur, and the truth
Harvey, Pasteur, and the Truth MARK JOY, M.D.
T
ruth. We constantly seek it, in science, in art, in life. The correct diagnosis is the goal of every physician with every patient, with all actions directed towards that ideal. Musicians struggle for the perfect notes, the most passionate interpretations; a chef strives for the finest taste. A large portion of human activity is focused upon truth, in attaining and adhering to it. Truth is understood by all, but is it capable of being defined to the satisfaction of all? When it emerges, it often must endure many harsh blasts before it can finally stand erect. Although truth, like beauty, may be ineffable, many have tried imparting their personal vision to it. Keats saw them as one:
scientific truths, confirmed by time and repeated observation, could rarely have evolved on ineluctable paths. New facts arrive in minute fragments, usually seen as ripples, not felt as waves; experiments, when duplicated, produce results that may confirm, contradict, or confuse the original findings; and after a professional life devoted to the elucidation of a long-held theory, those whose reputations rest upon it do not suffer lightly its refutation. Time becomes the last arbiter, as the new dogma awaits time’s judgment. Two of the most revered persons in medical history are William Harvey and Louis Pasteur. Both were scientists devoted above all else to scientific truth, and the work of each was marked by an extraordinary thoroughness and patience. Their accomplishments stand as towering achievements, and time has not diminished their importance, but they did not escape, mixed with acclaim, neglect and strident reproach.
Beauty is truth, truth beauty-that is all Ye know on earth, and all ye need to know. Milton found it in pursuits of the intellect: Beholding the bright countenance of truth in the quiet and still air of delightful studies.
WILLIAM HARVEY
Coleridge contrasted science and poetry: The proper and immediate object of science is the acquirement, or communication, of truth; the proper and immediate object of poetry is the communication of immediate pleasure.
William Harvey was born in Folkstone, England in 1578. He studied at Caius College, Cambridge from 1593 to 1600 and may well have been influenced by the tradition of the Padua medical school brought there by John Caius. From 1600 to 1602, he was at Padua and was fortunate to be taught by Fabricius, whose study of valves in the veins was an obvious prelude to Harvey’s work on the circulation, although the master never guessed their function. Few details are known of his days as a student in the great Italian medical mecca, but life for the young scholars who traveled there from many parts of Europe was doubtlessly of a raucous and sometimes dangerous nature. Most carried daggers for protection, and it was written of Harvey that he, “was, as all the rest of the brothers, very cholerique; and in his young days wore a dagger. . ., but this Doctor would be too apt to draw out his dagger upon every slight occasion.” Ater receiving his Doctor of Medicine on April 25, 1602, he returned to England and settled in London. Harvey seems to have
H. L. Mencken found truth behind falsehood: Nine times out of ten, in the arts as in life, there is actually no truth to be discovered; there is only error to be exposed. Many verities of nature appear from our modern vantage as unassailable, and the idea of their ever having been strongly challenged may strain our faith in human progress and perspicacity. Yet few theories, based upon even the most well-reasoned and thorough studies, have escaped attack. The flat Earth, the geocentric Earth, alchemy, phrenology, spontaneous generation, and countless other fopperies have all known their committed and often intelligent advocates, and eventually met their inevitable deaths. But the universal acceptance of most
From the Department of Medicine, Woodhull Medical and Mental Health Center, Brooklyn, New York. Requests for reprints should be addressed to Dr. Mark Joy, Department of Medicine, Woodhull Medical and Mental Health Center, 760 Broadway, Brooklyn, New York 11206. Manuscript accepted April 10, 7985.
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as it seemed, variously and confusedly together. My
begun his medical practice in 1603 and may have done some anatomic “research” at that time, although no record exists of such work. In 1604, he married and was elected as a Licentiatus in the College of Physicians in London. He obtained his fellowship with the college in 1607, and by 1609 he was busily engaged in private practice, with duties at St. Bartholomew’s Hospital, in studies of anatomy and physiology, and in activities of the College of Physicians. In August 1615, Harvey was appointed Lumleian Lecturer and gave the first of these on April 16 to 18, 1616. Harvey’s great discovery overthrew a doctrine dating from Galen’s theories in the 2nd century A.D. and, before him, the anatomic and physiologic writings of Aristotle. In our own time, the route of the circulation appears simple and direct, and we thushave difficulty empathizing with the feelings of confusion, frustration, and awe felt by all who questioned the established teachings of the ancient and medieval medical masters. Harvey was instructed in the Galenical scheme of two distinct systems for the passage of blood, the venous (natural) and the arterial (vital), with movement in an ebb-and-flow manner. Blood of the venous system, containing the “natural spirit,” originated in the liver whence it passed to the veins and to the right ventricle. The pulmonary artery was thought to convey a small amount of blood to the lungs for their nourishment, while a much larger portion of the venous blood was presumed to pass through tiny openings in the ventricular septum, which closed after death, into the left ventricle, where it mixed with the “pneuma” inspired through the lungs and entering the ventricle via the pulmonary vein, resulting in the formation of the “vital spirit” of the arterial system. The work of Servetus, Columbo, and others in the 16th century established the importance of the pulmonary circulation and the immixture of air and blood in the lungs, but the circuitous path of blood through the arteries, veins, capillaries, and portal channel had yet to be unravelled when Harvey began his questioning. The enormity of the task he faced may be appreciated from the account Harvey gave in De moth cofdis ef sanguinis when discussing his motives:
mind was therefore greatly unsettled, nor did I know I should myself conclude, nor what believe from others; I was not surprised that Andreas Laurentius should have said that the motion of the heart was as perplexing as the flux and reflux of Euripus had appeared to Aristotle. It has long been assumed that Harvey’s notes from the Lumleian Lecture of 16 16 indicate that he was in possession of the correct theory of the circulation at this early date, but because of his caution and diligence, he did not rush to publish his ideas. In his study of the recently deciphered notes, from Harvey’s nearly unintelligible jottings, Keynes found that statements were added by Harvey in retrospect several years after the notes had originally been made. In one section, there is the suggestion that he may have arrived at the solution to the puzzle around 1619, but it seems most likely that the unified concept evolved in steps between 1616 and 1628. Only when all doubts were removed was Harvey able to present his findings, and it was necessary for him to anticipate the inevitable criticisms that would follow, not only because he was propounding views that would be considered heretical, but because as a Fellow he was forbidden by the College of Physicians from advancing ideas contradictory to those of Galen under the threat of fine and the accompanying harm to his reputation. Ekercitatio anatomica de motu cordis et sanguinis in animalibus was published in 1628. No records exist of any initial protest, and Keynes attributes this to a combination of disbelief and a failure to comprehend the true significance of what Harvey was proposing. The first known attack came in 1630 in fxercifationes et animal versiones in librum G. hhrveii de motu cords et circuh tione sanguinis, by James Primrose, a colleague of Harvey’s at the college. The next year, Jacob Schwabe, a Danish student 21 years of age, wrote to his teacher in Copenhagen in July 1631 after reading De motu cordis, This doctrine so greatly impressed my mind that, for a full week, I was quite heart-sick owing to these profound thoughts. Hardly being able to calm myself by my own efforts I revealed the whole matter to an industrious student of medicine of the name of Conringius, who is a friend of mine. Having been shown Harvey’s dissertation he explained the circulation of the blood so admirably and plainly, that he himself almost seemed to be of the same heretical opinion. He soon perceived, however, that, being very desirous of a new thing, the mind inclines to be much titillated and allured, and now he said, ‘Certainly this explanation in itself is elegent, and, at first glance, highly probable. If Harvey had only been able to prove it by means of autopsies and anatomical demonstration, he would have solved the whole problem’. After that I took myself to the famous men, Heurnius and Falconburgius. They were willing to accept the opinion of Conringius with all their hearts, as the saying is, if they
When I first gave my mind to vivsections, as a means of discovering the motions and uses of the heart, and sought to discover these from actual inspection, and not from the writings of others, I found the task so truly arduous, so full of difficulties, that I was almost tempted to think, with Fracastorius, that the motion of the heart was only to be comprehended by God. For I could neither rightly perceive at first when the systole and when the diastole took place, nor when and where dilatation and contraction occurred, by reason of the rapidity of the motion, which in many animals is accomplished in the twinkling of an eye, coming and going like a flash of lightening; so that the systole presented itself to me now from this point, now from that: the diastole the same; and then everything was reversed, the motions occurring,
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had not to add that in changing old theories and approving of new ones we must rather be timid and hesitating
than audacious and temerarious. For the student to fault Harvey for lack of experimental proof truly epitomizes the absurd, although allowance may be made for his youth. His other critics had no such excuse. Many of Harvey’s contemporaries and associates simply chose to ignore what they wished not to believe. Dr. Thomas Winston (1575 to 1655) lectured in anatomy at Gresham College from 1613 to 1643 and from 1652 to 1655. In his lectures published in 1659, his editor proclaimed, “You may find his name next to Dr. Harvey’s in the Dispensatory of the College of Physicians.” Winston made no mention of Harvey while advancing Galen’s errors and citing the works of Columbo and Riolan. Alexander Real (1566 to 1641), a surgeon and lecturer in anatomy, was elected a Fellow of the College of Physicians in 1624. He too made no reference to Harvey or his theories, when publishing his A&ma// of the Anatomy, or Dissection of the body of A&n in 1634. Even the great Thomas Sydenham (1624 to 1689), the “English Hippocrates, ” never wrote of Harvey’s discovery. Ren6 Descartes embraced much of what Harvey described, but could not accept the concept of the heart as an involuntary muscle, believing that in some manner it was propelled by the will. He also thought the primary cardiac motion was active expansion rather than contraction and that the blood was “heated” in the heart, supplying motive power to the blood through “innate heat.” Although De n-tofu cordis encountered both censure and neglect, it was also enthusiastically received by many who discerned the clarity and force of Harvey’s reasoning. He wrote in 1547 in De generatione anin?a/ium, ‘I perceive the wonderful circulation of the blood, first found out by me, is consented to almost by all: that no man hath hitherto made any objection to it greatly worth a confrontation.” In 1648 came one denial that could not be ignored. Jean Riolan was Regius Professor of Medicine in Paris, Dean of the Faculty of Medicine, and physician to Marie de Medici. In 1648, he published fncheiridian anatomicurn et pathologicurn, in which he repudiated Harvey’s theory of the circulation. In contrast to his usual practice, Harvey felt compelled to respond, and in his two letters of reply, his keen intellect is ever evident, along with his restraint and absence of personal animosity. Throughout, Harvey declares his respect for the honorable nature and high scholarship of his adversary, even when his criticisms of Harvey’s theories are specious. Harvey was sufficiently confident of his knowledge, derived from tireless questioning and experiment, that he needed to depend only on the evidence as it stood. In one letter, he demonstrated the passage of blood from arteries to veins and then to the heart:
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Open an animal’s chest and ligate the vena cava near the heart so that nothing can go into that viscus by that route. Forthwith let the neck arteries be opened up without damage to the veins on either side. If as a result you see the arteries, with not the veins, I think it will for the blood to be drawn through the ventricles of
their free egress, empty, but be obvious that the only route off the veins into arteries is the heart. For otherwise we
should see the veins, like the arteries, emptied of blood in an extremely short space of time (as Galen noted) through the outflow from the arteries.
In another passage, Harvey explained that the empty arteries found in a corpse resulted from the fact that when the lungs subside on closure of their passages they are no longer respiring.
So the blood
cannot pass freely through them. The heart however continues for a space of time to force blood out. In consequence the left auricle of the heart and the left ventricle,
are relatively
contracted,
and equally the arte-
ries appear empty and devoid of content, being unfilled by their due succession of blood. In the second letter to Riolan, Harvey recounted the reception his discovery had received after 20 years, and neither side of the controversy had yet been silenced, although as Harvey had earlier noted, no one had effectively disproved his findings: It is now many years ago, learned Riolan, since with the assistance of the press I published a part of my work. Since that birthday of the circuit of the blood there has of a truth been scarcely a day, or even the smallest interval of time passing, in which I have not heard both good and ill report of the circulation which I discovered. Some tear the as yet tender infant to bits with their wranglings, as
undeserving of birth; others by contrast consider that the offspring ought to be nurtured, and cherish it and protect it by their writings. The former oppose it with strong dislike, the latter defend it vociferously. These think that by means of experiments, observations, and my own visual experience I have established the circuit of the blood against the whole strength and force of argu-
ments; the others that it is scarcely as yet sufficiently elucidated,
and not yet freed from objections.
There are,
moreover, those who cry out that I have striven after the empty glory of vivisections scurrilous language.
. . . Nor do they abstaln from
To William Harvey we are indebted less for his explication of the heart’s motion and the circulation than for the example and standard he set for modern medical investigation. Harvey’s genius derived from no divine inspiration nor extravagant quirk, but from an ordered, curious, patient mind, unable to rest with the disparity it perceived between venerated tradition and observed detail. Through the force of his vision and his desire for truth, he was carried over an exhaustive journey to the solution of an arcane puzzle. That he was in possession of an unyielding verity did not prevent his being disregarded and contradict-
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of spontaneous generation or even to deny its existence altogether, I have undertaken a series of researches with the object of elucidating this vexed question.” He wished to demonstrate that “. . . animals and plants could be generated in a medium absolutely free from atmospheric air, and in which, therefore, no germ of organic bodies could have been brought by air.” Pasteur set himself to disproving several of Pouchet’s suppositions, beginning with a study of the microscopic constituents of air: “If germs exist in atmosphere could they not be arrested on their way?” In a long series of experiments, he demonstrated that air aspirated through a cotton or asbestos fiber plug would cause a black deposit to form on the filter. If the deposit was then placed in a pure liquid, the solution would soon become putrid, whereas if a putrescible liquid was placed out of reach of the dusts, it would indefinitely remain pure. To Pouchet and his fellow advocates of spontaneous generation or heterogenia, the idea that air was the medium for an infinite number of “spores and loose eggs” was preposterous; to them, life arose not from nothing but rather represented “. . . the production of a new organized being, lacking parents, and of which the primordial elements are drawn from ambient organic matter.” It was during the pursuit of this question that Pasteur devised his ingenious flasks with the long, thin, curved necks that permitted air to enter, while any particles present would be deposited on the sides of the neck and would not reach the liquid contained therein. A liquid made sterile by ebullition in the flasks remained free of putrescence even though exposed to the air; if the vessel was tilted so that the liquid came into contact with the dust on the neck, the solution invariably became putrid. Pouchet would not accept the idea of air containing a high concentration of invisible life: “How could germs contained in the air be numerous enough to develop in every organic infusion? Such a crowd of them would produce a thick mist as dense as iron.” To this difficult question Pasteur posed an answer-that the density of “germs” might vary according to atmosphere and locale: “Yet it is ever possible to take up in certain places a notable though limited volume of ordinary air, having been submitted to no physical or chemical change, and still absolutely incapable of producing any alteration in an eminently putrescible liquor.” He devised a set of experiments to prove the variable composition of air in different environments as to their concentration of microbes. He had developed a method of preparing within a specially designed flask a corruptible liquid such as yeast water, made sterile by ebullition, which was sealed from the air during the boiling process by closing the thin, vertical neck of the flask with an enameller’s Ian-p. The flask could then be opened at the chosen time and place to allow air to enter, closed again, and placed in a temperature of 25 to 30°C to allow the growth of any microorgan-
ed by learned authorities, but within that truth was contained a seed of a medical enlightenment. The majority of Harvey’s contemporaries seem to have eventually accepted his great discovery, as his statements show, and never again would the teachings of the ancient masters be blindly accepted by receptive minds nor serve as an unassailable barrier to medical progress. A new age had arrived. LOUIS PASTEUR In Louis Pasteur’s long life of experiment and discovery, he seems to have rarely escaped controversy, which forced his naturally inquisitive and piercing intellect to probe ever more deeply, constantly questioning his own findings while anticipating the judgments of others. Like Harvey, Pasteur acquired a confidence born of patience and meticulousness, and he too eventually found his labors rewarded with universal acceptance. Pasteur was born in tile, France in 1822. He graduated from the Royal College of Franche Comte with a “bachelier des lettres” in 1840 and shortly after took a position as preparation master at the Royal College of Besangon. He began his studies at the Ecole Normale in Paris in 1843. His early researches as a student focused on tartaric and paratartaric (racemic) acids, crystals, polarized light, the extraction of phosphorus from bone, the saturation capacity of arsenious acid, and molecular dimorphism. After his discovery of rotatory polarization and the mirror images of crystals, Pasteur was appointed Professor of Physics at the Dijon Ly&e and shortly thereafter to a position on the faculty at Strasbourg. In 1852, he succeeded in transforming tartaric to racemic acid, for which he was honored with the red ribbon of the Legion of Honor in 1857. In that year, he returned to the Ecole Normale as a professor, and in 1860, the Academic des Sciences awarded him the Prize for Experimental Physiology for his work on alcoholic fermentation, lactic fermentation, and the fermentation of tartaric acid. In a letter to his father dated February 7, 1860, Pasteur told of the announcement he had made the day before to the Acatimie des Sciences that he had embarked on the study of spontaneous generation. Many colleagues implored him to abandon such a futile question, one of whom was his revered elder friend Professor Biot, the oldest member of the AcadClmie, who advised, “You will never find your way out.” Another warned, “I would advise no one to dwell too long on such a subject.” In the midl9th century, spontaneous generation was fiercely debated and defended by many eminent scientists. M. Pouchet, director of the Natural History Museum of Rouen, sent to the Academic onDecember 20, 1858 his Note on Vegetable and Animal Proto-organisms Spontaneously Generatedin Artificial Air andin Owgen Gas; he declared, “At this time when, seconded by the progress of science, several naturalists are endeavoring to reduce the domain
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isms that might be present. In one series of tests in early 1860, Pasteur broke the points of the flasks in various locales, capturing the air, and resealed the containers. From the cellars of the Paris Observatory, with its calm air of unchanging temperature, only one flask became putrid, whereas 11 others exposed to the winds of the surrounding lawns all displayed alteration. In his characteristic manner, Pasteur experimented with as many variations in local climate and enclosures as his imagination and energies permitted, culminating in a journey to the rarified air of the Alps. On September 2 1, 1860, he traveled from his inn in the town of Chamonix with a guide and a mule laden with 33 glass vials. After reaching a sufficient altitude, he attempted to entrap the air and seal it within the flasks, but found that the wind and the brightness of the sun shining on the snow prevented his closing the vials with his eolipyle spirit lamp. He was forced to return to the inn that night with 13 open flasks, and nearly all became altered in the air of his dusty room. The next day, with adjustments having been made to the lamp, he ventured back to the mountain. Of 20 flasks opened and resealed that day, only one became putrid. Pasteur wrote to the Academic on March 5, 1860, “If all the results are compared that I have obtained until now it seems to me that it can be affirmed that the dusts suspended in atmospheric air are the exclusive origin, the necessary condition of life in infusions.” As Pasteur roamed on mountaintops, in cellars and public squares, Pouchet was also to be found exploring diverse places. He wrote that everywhere he found “air equally favorable to organic genesis, whether surcharged with detritus in the midst of our populous cities, or taken on the summit of a mountain, or on the sea, where it offers extreme purity. With a cubic decimetre of air, taken where you like, I affirm that you can ever produce legions of microzoa.” Most of those who concerned themselves with the issue sided with Pouchet. A scientific journalist wrote in La Presse in 1860, “that the experiments you quote, M. Pasteur, will turn against you . . . The world into which you wish to take us is really too fantastic. . . . ” Pasteur never became daunted by lack of support from the majority. While Pasteur became involved in other areas of study such as putrefaction of blood and urine and fermentation of wine, Pouchet and two fellow heterogenists, Joly and Musset, continued their investigations into spontaneous generation. In 1863, they set out with glass flasks, provisions, and guides on an expedition to duplicate Pasteur’s experiments in the mountainous atmosphere. They stopped at 2,083 meters above sea level and opened a series of flasks, and they then proceeded to 3,000 meters, 1,000 meters higher than Pasteur had traveled, where more flasks were opened. To their delight, the contents of all became putrid, and Pouchet wrote, “Therefore the air of Maladetta, and of high mountains in general, is not incapable of producing alteration in an
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eminently putrescible liquor: therefore heterogenia or the production of a new being devoid of parents, but formed at the expense of ambient organic matter, is for us a reality.” In November 1863, Joly and Musset requested that the Academic des Sciences appoint a commission to repeat the experiments of Pasteur and Pouchet, although by that time many scientists had become convinced by Pasteur’s elegant studies. One wrote, “I am blamed in certain quarters for having no opinion on the question of spontaneous generation. As long as my opinion was not formed, I had nothing to say. It is now formed, and I give it: M. Pasteur’s experiments are decisive. If spontaneous generation is real, what is required to obtain animalculae? Air and putrescible liquor. Pasteur puts air and putrescible liquor together and nothing happens. Therefore spontaneous generation is not. To doubt further is to misunderstand the question.” Pasteur also had the support of the Academie, which in the previous year had accepted his paper, Organized Corpuscles Existing in Atmosphere, as decisive. It would have been easy for Pasteur to rest upon the laurels he had received, but of far greater importance to him was that the matter should be put to rest; he thus implored the Academic to appoint the commission demanded by his adversaries. Despite his normally patient character, Pasteur was anxious to dispense with the question and pressed for the discussions to begin in early March 1864. The heterogenists requested a delay, fearing the cold would adversely affect the growth of organisms. Pasteur responded, “I am much surprised at the delay sought by Messrs. Pouchet, Joly, and Musset; it would have been easy with a stove to raise the temperature to the degree required by the gentlemen. For my part I hasten to assure the Acadbmie that I am at its disposal, and that in Summer, or in any season, I am ready to repeat my experiments.” In June 1864, the adversaries announced to the Academic that they were ready to meet Pasteur. The Natural History Commission set the terms of the contest, determining rather than having a long series repeated, that one simple experiment be used to prove the point of essential difference. The heterogenists found this unacceptable and refused to be so judged, at which point the controversy temporarily and for several years halted. The argument resumed in 187 1 on two fronts. Pouchet was preparing a book entitled The Universe: the lnfinitey Great and the infinitely Small, part of which was devoted to the world of microscopic organisms. No mention was made of Pasteur or putrefaction, and although he conceded that “. . . a few microzoa did fly about here and there . . ., the existence of germs was to him “a ridiculous fiction.” Pasteur also found opposition from a German chemist, Liebig, who contended that fermentation depended upon the presence of decomposing animals or plants, while Pasteur had shown in an elaborate series of
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experiments that merely the presence of yeast was suff icient for the process to occur. As with Pouchet and his group before, Liebig declined a challenge offered by Pasteur. More critics appeared, including two members of the Academic des Sciences; M. Fremy questioned the origin of fermentation, while M. Trecul spoke in support of spontaneous generation and its three leading exponents, Pouchet, Joly, and Musset. On December 26, 167 1, Pasteur addressed Trecul at the Academic: I can assure our learned colleague that he might have found in the treatises I have published decisive answers to most of the questions he has raised. I am really surprised to see him tackle the question of so-called spontaneous generation, without having more at his disposal than doubtful facts and incomplete observations. My astonishment was not less than at our last sitting, when M. Fremy entered upon the same debate with nothing to produce but superannuated opinions and not one new, positive fact. In his studies of fermentation, putrefaction, and the actions of microorganisms, Pasteur was inevitably drawn by his humanistic ideals to seek the role of organisms in disease. Although he is often depicted as a paradigm of the rational, calculating scientist, he was also in possession of an active, searching imagination, a quality as important for the scientist as for the artist. Robert Boyle had stated in the 17th century, “He that thoroughly understands the nature of Ferments, and Fermentation, shall probably be much better able then [sic] he that ignores them, to give a fair account of divers Phenomena of several diseases (as well Fevers as others) which will perhaps be never thoroughly understood, without an insight into the doctrine of Fermentation.” Pasteur was frequently reminded of these words as the origin of contagious diseases began to occupy his ever-questioning mind: “What would be most desirable would be to push those studies far enough to prepare the road for a serious research into the origin of various disease.” He was to eventually enjoy the fulfillment of his fantasies. One of Pasteur’s great personal regrets was that he never acquired a medical degree, for he felt constrained by the distance between the scientists and physicians of his day. In 1655, Drs. Trousseau and Pidoux wrote in their Trait6 de Thkrapeutique, When a chemist has seen the chemical conditions of respiration, of digestion, or the action of some drug, he thinks he has given the theory of those functions and phenomena. It is ever the same delusion which chemists will never get over. . . but let us beware of trying to profit by the precious researches which they would probably never undertake if they were not stimulated by the ambition of explaining what is outside their range. Between a physiological fact and a pathological fact there is the same difference as between a mineral and a vegetable.
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In spite of the animosity, both subtle and overt, between the two groups, the medical community honored Pasteur’s contributions by electing him to a position in the Free Associates of the Academy of Medicine in 1873, where he was pleased to find himself in the same company as Claude Bernard. Bernard had for many years felt bitter at the way in which he had been treated with supercilious diffidence by many physicians; at the time of his early lectures on experimental physiology, it was the opinion of many medical persons that “physiology can be of no practical use in medicine; it is but a science de luxe which could well be dispensed with.” Bernard once commented to Pasteur, “Have you noticed that, when a doctor enters a room, he always looks as if he was going to say ‘I have just been saving a fellow’?” Bernard was also convinced that despite many advances in physiology made by himself and others through the experimental method, medicine yet had very far to travel: “No doubt we shall not live to see the blossoming out of scientific medicine, but such is the fate of humanity; those that sow on the field of science are not destined to reap the fruit of their labors.” In 1877, Pasteur became involved in the study of anthrax, also known as splenic fever and charbon. It was a devastating illness, responsible for the deaths of thousands of domestic animals and humans. As early as 1838, small rods were noted in the blood of its victims, but these were dismissed by various observers as harmless curiosities. Some investigators tried inoculating the blood of an animal dying of anthrax into healthy animals and found that although the animals died, no organisms could be found in their blood. Through the work of Koch and others, it was discovered that the Bacillus anthracis could reproduce by forming spores, and in its early growth phases in fresh lesions, the organisms had slightly rounded ends, referred to at that time as “vibrio” forms. When the bacterium was inoculated into healthy animals, disease inevitably ensued. However, Paul Bert announced in January 1877 that after destroying the bacteria in a drop of blood and then injecting the blood into an animal, it was possible to “reproduce the disease and death without any trace of the bacterium . . . Bacteria are therefore neither the cause nor the necessary effect of splenic fever, which must be due to a virus.” Pasteur devised a series of experiments in which he grew the anthrax bacillus in a flask containing culture medium; he then seeded a second medium with a tiny drop from the first, producing an abundant proliferation of bacteria, and then seeded a third medium with a drop from the second. He continued this through 40 inoculations, each culture being derived from the preceding one. From any flask in the series, a small amount could be injected into an animal, with disease inevitably resulting. Pasteur reasoned that only a live agent, reproducing in every flask, could in each case serve as the disease agent, rather than
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an inanimate substance, passed through a long series of extremely large dilutions, causing disease from the first flask to the 40th. Pasteur also demonstrated that from a single spore a vast number of multiplying rods were produced. One question remained: how was it possible to produce anthrax in an animal and yet not find the organism? In an intricate series of experiments, Pasteur found that the timing was important when obtaining blood samples from an animal that had died of the disease. If taken early while still containing viable organisms, the blood samples of an animal subsequently injected would also contain the filamentous rods; if the samples were taken later, disease and death still occurred, but without organisms being found in the blood. Pasteur also showed that blood samples taken several days after an animal had died of anthrax contained the “vibrio” form rather than the bacillus, and blood treated with heat or compressed oxygen to kill the bacillus and “vibrio” could still transmit the disease via the spore. As expected, Pasteur met both approbation and scorn for his findings. Professor Colin of the Alfort School would not accept the existence of another virulent form besides the bacterium, and maintained that anthrax could exist without an organism. Pasteur had claimed that birds, and especially hens, did not contract anthrax, whereas Colin boasted that he could easily induce the disease in these animals. Despite repeated challenges by Pasteur, he was unable to produce the corpse of a hen dying of the disease. Pasteur then asserted that he would accomplish what Colin could not. Pasteur thought the higher body temperature of hens might confer immunity, and he sought to prove this by an ingenious experiment involving three animals. One was inoculated with anthrax bacilli and submerged with one third of its body in a bath to lower its body temperature. A second hen was placed in the bath without inoculation, and a third was inoculated with twice the inoculum of the first but was not placed in water. The first hen soon died, with anthrax bacilli found throughout its blood and organs; the other two remained healthy. Clearly, it was necessary to inoculate a hen and lower its temperature to that of cattle, rabbits, and other mammals in order for the bacillus to survive. M. Lereboullet wrote in the Weekly Gazetie of Medicine and Surgery in 1878 of Pasteur’s latest experiment, “those facts throw a new light in the theory of the genesis and development of the bacillus anthracis . . . it seems very probable that M. Pasteur, who never brings any premature or conjectural assertion to the academic tribune, will deduce from them conclusions of the greatest interest concerning the etiology of virulent diseases.” Many viewed the reports with uneasy caution. Some were outspokenly critical. Leon Le Fort, a surgeon and member of the Academic de Medicine, denied the clinical relevance of germs: “That theory, in its applications to clinical
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surgery, is absolutely unacceptable.” “I believe in the interiority of the principal of purulent infection in certain patients; that is why I oppose the extension to surgery of the germ theory which proclaims the constant exteriorly of that principal.” Pasteur’s struggle for the acceptance of anthrax as an infectious disease did not end easily, and the debate acquired another dimension with his work on a vaccine. In this instance as in others, he argued passionately when convinced of his findings, not motivated by self-aggrandizing impulses, rather that scientific advancement should not be impeded in its service to humanity. Many of the sharpest critiques of his work came from the medical profession, whose members, devoted to a discipline based in science but in practice more of an art, have always viewed skeptically the opinions of those not included in their noble calling. Another notable example involved the cause of typhoid fever, a disease responsible for widespread illness, often fatal, and thought by Pasteur and others to be spread by an infectious agent. To the medical community, it originated within the body, representing a normal part gone awry. Even when acknowledging the existence of microscopic organisms in some diseases, they often failed or refused to appreciate their significance. M. Peter proclaimed at the Academic de Medicine, “These are but natural history curiosities, interesting no doubt, but of very little profit to medicine, and not worth either the time given to them or the noise made about them. After so many laborious researches nothing will be changed in medicine, there will only be a few more microbes.” It was the same M. Peter who, in foreseeing the age of antibiotics more than 50 years later, attacked “microbicidal drugs which may become homicidal.” Pasteur’s works encompassed a vast array of subjects, his mind forever seeking solutions; as long as his health permitted, his energies were engaged. Rabies, diphtheria, yellow fever, and infections of domestic animals were among the other riddles that he confronted. Towards the end of his life, the controversies subsided, and in his last years Pasteur received praise and acclaim enjoyed by few scientists. His work with the rabies vaccine in particular was viewed by the public as miraculous; his reputation became international, and patients came to him from many countries for treatment of an illness that had been invariably fatal until his discovery. Throughout his career of researches, Pasteur steadfastly set as his prime goal scientific truth, because he knew that from this flowed rewards priceless to mankind, most importantly relief of disease and suffering. He also took great pride in the honor bestowed not upon himself but to France, that its greatness would be recognized by all. Pasteur never lost his selflessness nor his painstaking inquisitiveness, and to review his words and deeds reveals him, in the sentiment of some, as the person most nearly attaining perfection in the realm of science.
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mise, servile imitation, and complaisance, without becoming original for there is in every creature a foundation of life which, if not choked back by stones and other dead rubbish, will create a fresh atmosphere, and bring to life fresh beautv.”
TRUTH
None have pursued truth more passionately than Harvey and Pasteur, although both were forced to confront authoritetive and forceful opposition. Yet many of their peers and subsequent posterity recognized what both knew could be explained in no other way. We hail them today for their genius, while we daily utilize end build upon the knowledge they extracted and bequeathed. John f&sefield might have been speaking of these two giants in his Shakespeare
and Spiritual
Note: This essay represents an historical perspective, not a work of original research. Thus, the references are only secondary sources. The intent is not to uncover any unknown facts, but rather to illuminate the struggles of two great medical scientists as they fought strong resistance to bring into the light what they, and subsequently the world, knew was real and true.
Life,
There is another way truth: by the minute examination of facts. That is the way of the scientist: a hard and noble and thankless way.
REFERENCES
Margaret Fuller’s definition of genius and truth may also aDDlv: Truth is the nursing mother of genius. No man can be absolutely true to himself, eschewing cant, compro.
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Keynes
GL: The life of William Harvey. 1966. Vallery-Radot R: The life of Pasteur. Doubleday, Page, 1926.
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ruth. We constantly seek it, in science, in art, in life. The correct diagnosis is the goal of every physician with every patient, with all actions directed towards that ideal. Musicians struggle for the perfect notes, the most passionate interpretations; a chef strives for the finest taste. A large portion of human activity is focused upon truth, in attaining and adhering to it. Truth is understood by all, but is it capable of being defined to the satisfaction of all? When it emerges, it often must endure many harsh blasts before it can finally stand erect. Although truth, like beauty, may be ineffable, many have tried imparting their personal vision to it. Keats saw them as one:
scientific truths, confirmed by time and repeated observation, could rarely have evolved on ineluctable paths. New facts arrive in minute fragments, usually seen as ripples, not felt as waves; experiments, when duplicated, produce results that may confirm, contradict, or confuse the original findings; and after a professional life devoted to the elucidation of a long-held theory, those whose reputations rest upon it do not suffer lightly its refutation. Time becomes the last arbiter, as the new dogma awaits time’s judgment. Two of the most revered persons in medical history are William Harvey and Louis Pasteur. Both were scientists devoted above all else to scientific truth, and the work of each was marked by an extraordinary thoroughness and patience. Their accomplishments stand as towering achievements, and time has not diminished their importance, but they did not escape, mixed with acclaim, neglect and strident reproach.
Beauty is truth, truth beauty-that is all Ye know on earth, and all ye need to know. Milton found it in pursuits of the intellect: Beholding the bright countenance of truth in the quiet and still air of delightful studies.
WILLIAM HARVEY
Coleridge contrasted science and poetry: The proper and immediate object of science is the acquirement, or communication, of truth; the proper and immediate object of poetry is the communication of immediate pleasure.
William Harvey was born in Folkstone, England in 1578. He studied at Caius College, Cambridge from 1593 to 1600 and may well have been influenced by the tradition of the Padua medical school brought there by John Caius. From 1600 to 1602, he was at Padua and was fortunate to be taught by Fabricius, whose study of valves in the veins was an obvious prelude to Harvey’s work on the circulation, although the master never guessed their function. Few details are known of his days as a student in the great Italian medical mecca, but life for the young scholars who traveled there from many parts of Europe was doubtlessly of a raucous and sometimes dangerous nature. Most carried daggers for protection, and it was written of Harvey that he, “was, as all the rest of the brothers, very cholerique; and in his young days wore a dagger. . ., but this Doctor would be too apt to draw out his dagger upon every slight occasion.” Ater receiving his Doctor of Medicine on April 25, 1602, he returned to England and settled in London. Harvey seems to have
H. L. Mencken found truth behind falsehood: Nine times out of ten, in the arts as in life, there is actually no truth to be discovered; there is only error to be exposed. Many verities of nature appear from our modern vantage as unassailable, and the idea of their ever having been strongly challenged may strain our faith in human progress and perspicacity. Yet few theories, based upon even the most well-reasoned and thorough studies, have escaped attack. The flat Earth, the geocentric Earth, alchemy, phrenology, spontaneous generation, and countless other fopperies have all known their committed and often intelligent advocates, and eventually met their inevitable deaths. But the universal acceptance of most
From the Department of Medicine, Woodhull Medical and Mental Health Center, Brooklyn, New York. Requests for reprints should be addressed to Dr. Mark Joy, Department of Medicine, Woodhull Medical and Mental Health Center, 760 Broadway, Brooklyn, New York 11206. Manuscript accepted April 10, 7985.
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as it seemed, variously and confusedly together. My
begun his medical practice in 1603 and may have done some anatomic “research” at that time, although no record exists of such work. In 1604, he married and was elected as a Licentiatus in the College of Physicians in London. He obtained his fellowship with the college in 1607, and by 1609 he was busily engaged in private practice, with duties at St. Bartholomew’s Hospital, in studies of anatomy and physiology, and in activities of the College of Physicians. In August 1615, Harvey was appointed Lumleian Lecturer and gave the first of these on April 16 to 18, 1616. Harvey’s great discovery overthrew a doctrine dating from Galen’s theories in the 2nd century A.D. and, before him, the anatomic and physiologic writings of Aristotle. In our own time, the route of the circulation appears simple and direct, and we thushave difficulty empathizing with the feelings of confusion, frustration, and awe felt by all who questioned the established teachings of the ancient and medieval medical masters. Harvey was instructed in the Galenical scheme of two distinct systems for the passage of blood, the venous (natural) and the arterial (vital), with movement in an ebb-and-flow manner. Blood of the venous system, containing the “natural spirit,” originated in the liver whence it passed to the veins and to the right ventricle. The pulmonary artery was thought to convey a small amount of blood to the lungs for their nourishment, while a much larger portion of the venous blood was presumed to pass through tiny openings in the ventricular septum, which closed after death, into the left ventricle, where it mixed with the “pneuma” inspired through the lungs and entering the ventricle via the pulmonary vein, resulting in the formation of the “vital spirit” of the arterial system. The work of Servetus, Columbo, and others in the 16th century established the importance of the pulmonary circulation and the immixture of air and blood in the lungs, but the circuitous path of blood through the arteries, veins, capillaries, and portal channel had yet to be unravelled when Harvey began his questioning. The enormity of the task he faced may be appreciated from the account Harvey gave in De moth cofdis ef sanguinis when discussing his motives:
mind was therefore greatly unsettled, nor did I know I should myself conclude, nor what believe from others; I was not surprised that Andreas Laurentius should have said that the motion of the heart was as perplexing as the flux and reflux of Euripus had appeared to Aristotle. It has long been assumed that Harvey’s notes from the Lumleian Lecture of 16 16 indicate that he was in possession of the correct theory of the circulation at this early date, but because of his caution and diligence, he did not rush to publish his ideas. In his study of the recently deciphered notes, from Harvey’s nearly unintelligible jottings, Keynes found that statements were added by Harvey in retrospect several years after the notes had originally been made. In one section, there is the suggestion that he may have arrived at the solution to the puzzle around 1619, but it seems most likely that the unified concept evolved in steps between 1616 and 1628. Only when all doubts were removed was Harvey able to present his findings, and it was necessary for him to anticipate the inevitable criticisms that would follow, not only because he was propounding views that would be considered heretical, but because as a Fellow he was forbidden by the College of Physicians from advancing ideas contradictory to those of Galen under the threat of fine and the accompanying harm to his reputation. Ekercitatio anatomica de motu cordis et sanguinis in animalibus was published in 1628. No records exist of any initial protest, and Keynes attributes this to a combination of disbelief and a failure to comprehend the true significance of what Harvey was proposing. The first known attack came in 1630 in fxercifationes et animal versiones in librum G. hhrveii de motu cords et circuh tione sanguinis, by James Primrose, a colleague of Harvey’s at the college. The next year, Jacob Schwabe, a Danish student 21 years of age, wrote to his teacher in Copenhagen in July 1631 after reading De motu cordis, This doctrine so greatly impressed my mind that, for a full week, I was quite heart-sick owing to these profound thoughts. Hardly being able to calm myself by my own efforts I revealed the whole matter to an industrious student of medicine of the name of Conringius, who is a friend of mine. Having been shown Harvey’s dissertation he explained the circulation of the blood so admirably and plainly, that he himself almost seemed to be of the same heretical opinion. He soon perceived, however, that, being very desirous of a new thing, the mind inclines to be much titillated and allured, and now he said, ‘Certainly this explanation in itself is elegent, and, at first glance, highly probable. If Harvey had only been able to prove it by means of autopsies and anatomical demonstration, he would have solved the whole problem’. After that I took myself to the famous men, Heurnius and Falconburgius. They were willing to accept the opinion of Conringius with all their hearts, as the saying is, if they
When I first gave my mind to vivsections, as a means of discovering the motions and uses of the heart, and sought to discover these from actual inspection, and not from the writings of others, I found the task so truly arduous, so full of difficulties, that I was almost tempted to think, with Fracastorius, that the motion of the heart was only to be comprehended by God. For I could neither rightly perceive at first when the systole and when the diastole took place, nor when and where dilatation and contraction occurred, by reason of the rapidity of the motion, which in many animals is accomplished in the twinkling of an eye, coming and going like a flash of lightening; so that the systole presented itself to me now from this point, now from that: the diastole the same; and then everything was reversed, the motions occurring,
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had not to add that in changing old theories and approving of new ones we must rather be timid and hesitating
than audacious and temerarious. For the student to fault Harvey for lack of experimental proof truly epitomizes the absurd, although allowance may be made for his youth. His other critics had no such excuse. Many of Harvey’s contemporaries and associates simply chose to ignore what they wished not to believe. Dr. Thomas Winston (1575 to 1655) lectured in anatomy at Gresham College from 1613 to 1643 and from 1652 to 1655. In his lectures published in 1659, his editor proclaimed, “You may find his name next to Dr. Harvey’s in the Dispensatory of the College of Physicians.” Winston made no mention of Harvey while advancing Galen’s errors and citing the works of Columbo and Riolan. Alexander Real (1566 to 1641), a surgeon and lecturer in anatomy, was elected a Fellow of the College of Physicians in 1624. He too made no reference to Harvey or his theories, when publishing his A&ma// of the Anatomy, or Dissection of the body of A&n in 1634. Even the great Thomas Sydenham (1624 to 1689), the “English Hippocrates, ” never wrote of Harvey’s discovery. Ren6 Descartes embraced much of what Harvey described, but could not accept the concept of the heart as an involuntary muscle, believing that in some manner it was propelled by the will. He also thought the primary cardiac motion was active expansion rather than contraction and that the blood was “heated” in the heart, supplying motive power to the blood through “innate heat.” Although De n-tofu cordis encountered both censure and neglect, it was also enthusiastically received by many who discerned the clarity and force of Harvey’s reasoning. He wrote in 1547 in De generatione anin?a/ium, ‘I perceive the wonderful circulation of the blood, first found out by me, is consented to almost by all: that no man hath hitherto made any objection to it greatly worth a confrontation.” In 1648 came one denial that could not be ignored. Jean Riolan was Regius Professor of Medicine in Paris, Dean of the Faculty of Medicine, and physician to Marie de Medici. In 1648, he published fncheiridian anatomicurn et pathologicurn, in which he repudiated Harvey’s theory of the circulation. In contrast to his usual practice, Harvey felt compelled to respond, and in his two letters of reply, his keen intellect is ever evident, along with his restraint and absence of personal animosity. Throughout, Harvey declares his respect for the honorable nature and high scholarship of his adversary, even when his criticisms of Harvey’s theories are specious. Harvey was sufficiently confident of his knowledge, derived from tireless questioning and experiment, that he needed to depend only on the evidence as it stood. In one letter, he demonstrated the passage of blood from arteries to veins and then to the heart:
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Open an animal’s chest and ligate the vena cava near the heart so that nothing can go into that viscus by that route. Forthwith let the neck arteries be opened up without damage to the veins on either side. If as a result you see the arteries, with not the veins, I think it will for the blood to be drawn through the ventricles of
their free egress, empty, but be obvious that the only route off the veins into arteries is the heart. For otherwise we
should see the veins, like the arteries, emptied of blood in an extremely short space of time (as Galen noted) through the outflow from the arteries.
In another passage, Harvey explained that the empty arteries found in a corpse resulted from the fact that when the lungs subside on closure of their passages they are no longer respiring.
So the blood
cannot pass freely through them. The heart however continues for a space of time to force blood out. In consequence the left auricle of the heart and the left ventricle,
are relatively
contracted,
and equally the arte-
ries appear empty and devoid of content, being unfilled by their due succession of blood. In the second letter to Riolan, Harvey recounted the reception his discovery had received after 20 years, and neither side of the controversy had yet been silenced, although as Harvey had earlier noted, no one had effectively disproved his findings: It is now many years ago, learned Riolan, since with the assistance of the press I published a part of my work. Since that birthday of the circuit of the blood there has of a truth been scarcely a day, or even the smallest interval of time passing, in which I have not heard both good and ill report of the circulation which I discovered. Some tear the as yet tender infant to bits with their wranglings, as
undeserving of birth; others by contrast consider that the offspring ought to be nurtured, and cherish it and protect it by their writings. The former oppose it with strong dislike, the latter defend it vociferously. These think that by means of experiments, observations, and my own visual experience I have established the circuit of the blood against the whole strength and force of argu-
ments; the others that it is scarcely as yet sufficiently elucidated,
and not yet freed from objections.
There are,
moreover, those who cry out that I have striven after the empty glory of vivisections scurrilous language.
. . . Nor do they abstaln from
To William Harvey we are indebted less for his explication of the heart’s motion and the circulation than for the example and standard he set for modern medical investigation. Harvey’s genius derived from no divine inspiration nor extravagant quirk, but from an ordered, curious, patient mind, unable to rest with the disparity it perceived between venerated tradition and observed detail. Through the force of his vision and his desire for truth, he was carried over an exhaustive journey to the solution of an arcane puzzle. That he was in possession of an unyielding verity did not prevent his being disregarded and contradict-
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of spontaneous generation or even to deny its existence altogether, I have undertaken a series of researches with the object of elucidating this vexed question.” He wished to demonstrate that “. . . animals and plants could be generated in a medium absolutely free from atmospheric air, and in which, therefore, no germ of organic bodies could have been brought by air.” Pasteur set himself to disproving several of Pouchet’s suppositions, beginning with a study of the microscopic constituents of air: “If germs exist in atmosphere could they not be arrested on their way?” In a long series of experiments, he demonstrated that air aspirated through a cotton or asbestos fiber plug would cause a black deposit to form on the filter. If the deposit was then placed in a pure liquid, the solution would soon become putrid, whereas if a putrescible liquid was placed out of reach of the dusts, it would indefinitely remain pure. To Pouchet and his fellow advocates of spontaneous generation or heterogenia, the idea that air was the medium for an infinite number of “spores and loose eggs” was preposterous; to them, life arose not from nothing but rather represented “. . . the production of a new organized being, lacking parents, and of which the primordial elements are drawn from ambient organic matter.” It was during the pursuit of this question that Pasteur devised his ingenious flasks with the long, thin, curved necks that permitted air to enter, while any particles present would be deposited on the sides of the neck and would not reach the liquid contained therein. A liquid made sterile by ebullition in the flasks remained free of putrescence even though exposed to the air; if the vessel was tilted so that the liquid came into contact with the dust on the neck, the solution invariably became putrid. Pouchet would not accept the idea of air containing a high concentration of invisible life: “How could germs contained in the air be numerous enough to develop in every organic infusion? Such a crowd of them would produce a thick mist as dense as iron.” To this difficult question Pasteur posed an answer-that the density of “germs” might vary according to atmosphere and locale: “Yet it is ever possible to take up in certain places a notable though limited volume of ordinary air, having been submitted to no physical or chemical change, and still absolutely incapable of producing any alteration in an eminently putrescible liquor.” He devised a set of experiments to prove the variable composition of air in different environments as to their concentration of microbes. He had developed a method of preparing within a specially designed flask a corruptible liquid such as yeast water, made sterile by ebullition, which was sealed from the air during the boiling process by closing the thin, vertical neck of the flask with an enameller’s Ian-p. The flask could then be opened at the chosen time and place to allow air to enter, closed again, and placed in a temperature of 25 to 30°C to allow the growth of any microorgan-
ed by learned authorities, but within that truth was contained a seed of a medical enlightenment. The majority of Harvey’s contemporaries seem to have eventually accepted his great discovery, as his statements show, and never again would the teachings of the ancient masters be blindly accepted by receptive minds nor serve as an unassailable barrier to medical progress. A new age had arrived. LOUIS PASTEUR In Louis Pasteur’s long life of experiment and discovery, he seems to have rarely escaped controversy, which forced his naturally inquisitive and piercing intellect to probe ever more deeply, constantly questioning his own findings while anticipating the judgments of others. Like Harvey, Pasteur acquired a confidence born of patience and meticulousness, and he too eventually found his labors rewarded with universal acceptance. Pasteur was born in tile, France in 1822. He graduated from the Royal College of Franche Comte with a “bachelier des lettres” in 1840 and shortly after took a position as preparation master at the Royal College of Besangon. He began his studies at the Ecole Normale in Paris in 1843. His early researches as a student focused on tartaric and paratartaric (racemic) acids, crystals, polarized light, the extraction of phosphorus from bone, the saturation capacity of arsenious acid, and molecular dimorphism. After his discovery of rotatory polarization and the mirror images of crystals, Pasteur was appointed Professor of Physics at the Dijon Ly&e and shortly thereafter to a position on the faculty at Strasbourg. In 1852, he succeeded in transforming tartaric to racemic acid, for which he was honored with the red ribbon of the Legion of Honor in 1857. In that year, he returned to the Ecole Normale as a professor, and in 1860, the Academic des Sciences awarded him the Prize for Experimental Physiology for his work on alcoholic fermentation, lactic fermentation, and the fermentation of tartaric acid. In a letter to his father dated February 7, 1860, Pasteur told of the announcement he had made the day before to the Acatimie des Sciences that he had embarked on the study of spontaneous generation. Many colleagues implored him to abandon such a futile question, one of whom was his revered elder friend Professor Biot, the oldest member of the AcadClmie, who advised, “You will never find your way out.” Another warned, “I would advise no one to dwell too long on such a subject.” In the midl9th century, spontaneous generation was fiercely debated and defended by many eminent scientists. M. Pouchet, director of the Natural History Museum of Rouen, sent to the Academic onDecember 20, 1858 his Note on Vegetable and Animal Proto-organisms Spontaneously Generatedin Artificial Air andin Owgen Gas; he declared, “At this time when, seconded by the progress of science, several naturalists are endeavoring to reduce the domain
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isms that might be present. In one series of tests in early 1860, Pasteur broke the points of the flasks in various locales, capturing the air, and resealed the containers. From the cellars of the Paris Observatory, with its calm air of unchanging temperature, only one flask became putrid, whereas 11 others exposed to the winds of the surrounding lawns all displayed alteration. In his characteristic manner, Pasteur experimented with as many variations in local climate and enclosures as his imagination and energies permitted, culminating in a journey to the rarified air of the Alps. On September 2 1, 1860, he traveled from his inn in the town of Chamonix with a guide and a mule laden with 33 glass vials. After reaching a sufficient altitude, he attempted to entrap the air and seal it within the flasks, but found that the wind and the brightness of the sun shining on the snow prevented his closing the vials with his eolipyle spirit lamp. He was forced to return to the inn that night with 13 open flasks, and nearly all became altered in the air of his dusty room. The next day, with adjustments having been made to the lamp, he ventured back to the mountain. Of 20 flasks opened and resealed that day, only one became putrid. Pasteur wrote to the Academic on March 5, 1860, “If all the results are compared that I have obtained until now it seems to me that it can be affirmed that the dusts suspended in atmospheric air are the exclusive origin, the necessary condition of life in infusions.” As Pasteur roamed on mountaintops, in cellars and public squares, Pouchet was also to be found exploring diverse places. He wrote that everywhere he found “air equally favorable to organic genesis, whether surcharged with detritus in the midst of our populous cities, or taken on the summit of a mountain, or on the sea, where it offers extreme purity. With a cubic decimetre of air, taken where you like, I affirm that you can ever produce legions of microzoa.” Most of those who concerned themselves with the issue sided with Pouchet. A scientific journalist wrote in La Presse in 1860, “that the experiments you quote, M. Pasteur, will turn against you . . . The world into which you wish to take us is really too fantastic. . . . ” Pasteur never became daunted by lack of support from the majority. While Pasteur became involved in other areas of study such as putrefaction of blood and urine and fermentation of wine, Pouchet and two fellow heterogenists, Joly and Musset, continued their investigations into spontaneous generation. In 1863, they set out with glass flasks, provisions, and guides on an expedition to duplicate Pasteur’s experiments in the mountainous atmosphere. They stopped at 2,083 meters above sea level and opened a series of flasks, and they then proceeded to 3,000 meters, 1,000 meters higher than Pasteur had traveled, where more flasks were opened. To their delight, the contents of all became putrid, and Pouchet wrote, “Therefore the air of Maladetta, and of high mountains in general, is not incapable of producing alteration in an
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eminently putrescible liquor: therefore heterogenia or the production of a new being devoid of parents, but formed at the expense of ambient organic matter, is for us a reality.” In November 1863, Joly and Musset requested that the Academic des Sciences appoint a commission to repeat the experiments of Pasteur and Pouchet, although by that time many scientists had become convinced by Pasteur’s elegant studies. One wrote, “I am blamed in certain quarters for having no opinion on the question of spontaneous generation. As long as my opinion was not formed, I had nothing to say. It is now formed, and I give it: M. Pasteur’s experiments are decisive. If spontaneous generation is real, what is required to obtain animalculae? Air and putrescible liquor. Pasteur puts air and putrescible liquor together and nothing happens. Therefore spontaneous generation is not. To doubt further is to misunderstand the question.” Pasteur also had the support of the Academie, which in the previous year had accepted his paper, Organized Corpuscles Existing in Atmosphere, as decisive. It would have been easy for Pasteur to rest upon the laurels he had received, but of far greater importance to him was that the matter should be put to rest; he thus implored the Academic to appoint the commission demanded by his adversaries. Despite his normally patient character, Pasteur was anxious to dispense with the question and pressed for the discussions to begin in early March 1864. The heterogenists requested a delay, fearing the cold would adversely affect the growth of organisms. Pasteur responded, “I am much surprised at the delay sought by Messrs. Pouchet, Joly, and Musset; it would have been easy with a stove to raise the temperature to the degree required by the gentlemen. For my part I hasten to assure the Acadbmie that I am at its disposal, and that in Summer, or in any season, I am ready to repeat my experiments.” In June 1864, the adversaries announced to the Academic that they were ready to meet Pasteur. The Natural History Commission set the terms of the contest, determining rather than having a long series repeated, that one simple experiment be used to prove the point of essential difference. The heterogenists found this unacceptable and refused to be so judged, at which point the controversy temporarily and for several years halted. The argument resumed in 187 1 on two fronts. Pouchet was preparing a book entitled The Universe: the lnfinitey Great and the infinitely Small, part of which was devoted to the world of microscopic organisms. No mention was made of Pasteur or putrefaction, and although he conceded that “. . . a few microzoa did fly about here and there . . ., the existence of germs was to him “a ridiculous fiction.” Pasteur also found opposition from a German chemist, Liebig, who contended that fermentation depended upon the presence of decomposing animals or plants, while Pasteur had shown in an elaborate series of
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experiments that merely the presence of yeast was suff icient for the process to occur. As with Pouchet and his group before, Liebig declined a challenge offered by Pasteur. More critics appeared, including two members of the Academic des Sciences; M. Fremy questioned the origin of fermentation, while M. Trecul spoke in support of spontaneous generation and its three leading exponents, Pouchet, Joly, and Musset. On December 26, 167 1, Pasteur addressed Trecul at the Academic: I can assure our learned colleague that he might have found in the treatises I have published decisive answers to most of the questions he has raised. I am really surprised to see him tackle the question of so-called spontaneous generation, without having more at his disposal than doubtful facts and incomplete observations. My astonishment was not less than at our last sitting, when M. Fremy entered upon the same debate with nothing to produce but superannuated opinions and not one new, positive fact. In his studies of fermentation, putrefaction, and the actions of microorganisms, Pasteur was inevitably drawn by his humanistic ideals to seek the role of organisms in disease. Although he is often depicted as a paradigm of the rational, calculating scientist, he was also in possession of an active, searching imagination, a quality as important for the scientist as for the artist. Robert Boyle had stated in the 17th century, “He that thoroughly understands the nature of Ferments, and Fermentation, shall probably be much better able then [sic] he that ignores them, to give a fair account of divers Phenomena of several diseases (as well Fevers as others) which will perhaps be never thoroughly understood, without an insight into the doctrine of Fermentation.” Pasteur was frequently reminded of these words as the origin of contagious diseases began to occupy his ever-questioning mind: “What would be most desirable would be to push those studies far enough to prepare the road for a serious research into the origin of various disease.” He was to eventually enjoy the fulfillment of his fantasies. One of Pasteur’s great personal regrets was that he never acquired a medical degree, for he felt constrained by the distance between the scientists and physicians of his day. In 1655, Drs. Trousseau and Pidoux wrote in their Trait6 de Thkrapeutique, When a chemist has seen the chemical conditions of respiration, of digestion, or the action of some drug, he thinks he has given the theory of those functions and phenomena. It is ever the same delusion which chemists will never get over. . . but let us beware of trying to profit by the precious researches which they would probably never undertake if they were not stimulated by the ambition of explaining what is outside their range. Between a physiological fact and a pathological fact there is the same difference as between a mineral and a vegetable.
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In spite of the animosity, both subtle and overt, between the two groups, the medical community honored Pasteur’s contributions by electing him to a position in the Free Associates of the Academy of Medicine in 1873, where he was pleased to find himself in the same company as Claude Bernard. Bernard had for many years felt bitter at the way in which he had been treated with supercilious diffidence by many physicians; at the time of his early lectures on experimental physiology, it was the opinion of many medical persons that “physiology can be of no practical use in medicine; it is but a science de luxe which could well be dispensed with.” Bernard once commented to Pasteur, “Have you noticed that, when a doctor enters a room, he always looks as if he was going to say ‘I have just been saving a fellow’?” Bernard was also convinced that despite many advances in physiology made by himself and others through the experimental method, medicine yet had very far to travel: “No doubt we shall not live to see the blossoming out of scientific medicine, but such is the fate of humanity; those that sow on the field of science are not destined to reap the fruit of their labors.” In 1877, Pasteur became involved in the study of anthrax, also known as splenic fever and charbon. It was a devastating illness, responsible for the deaths of thousands of domestic animals and humans. As early as 1838, small rods were noted in the blood of its victims, but these were dismissed by various observers as harmless curiosities. Some investigators tried inoculating the blood of an animal dying of anthrax into healthy animals and found that although the animals died, no organisms could be found in their blood. Through the work of Koch and others, it was discovered that the Bacillus anthracis could reproduce by forming spores, and in its early growth phases in fresh lesions, the organisms had slightly rounded ends, referred to at that time as “vibrio” forms. When the bacterium was inoculated into healthy animals, disease inevitably ensued. However, Paul Bert announced in January 1877 that after destroying the bacteria in a drop of blood and then injecting the blood into an animal, it was possible to “reproduce the disease and death without any trace of the bacterium . . . Bacteria are therefore neither the cause nor the necessary effect of splenic fever, which must be due to a virus.” Pasteur devised a series of experiments in which he grew the anthrax bacillus in a flask containing culture medium; he then seeded a second medium with a tiny drop from the first, producing an abundant proliferation of bacteria, and then seeded a third medium with a drop from the second. He continued this through 40 inoculations, each culture being derived from the preceding one. From any flask in the series, a small amount could be injected into an animal, with disease inevitably resulting. Pasteur reasoned that only a live agent, reproducing in every flask, could in each case serve as the disease agent, rather than
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an inanimate substance, passed through a long series of extremely large dilutions, causing disease from the first flask to the 40th. Pasteur also demonstrated that from a single spore a vast number of multiplying rods were produced. One question remained: how was it possible to produce anthrax in an animal and yet not find the organism? In an intricate series of experiments, Pasteur found that the timing was important when obtaining blood samples from an animal that had died of the disease. If taken early while still containing viable organisms, the blood samples of an animal subsequently injected would also contain the filamentous rods; if the samples were taken later, disease and death still occurred, but without organisms being found in the blood. Pasteur also showed that blood samples taken several days after an animal had died of anthrax contained the “vibrio” form rather than the bacillus, and blood treated with heat or compressed oxygen to kill the bacillus and “vibrio” could still transmit the disease via the spore. As expected, Pasteur met both approbation and scorn for his findings. Professor Colin of the Alfort School would not accept the existence of another virulent form besides the bacterium, and maintained that anthrax could exist without an organism. Pasteur had claimed that birds, and especially hens, did not contract anthrax, whereas Colin boasted that he could easily induce the disease in these animals. Despite repeated challenges by Pasteur, he was unable to produce the corpse of a hen dying of the disease. Pasteur then asserted that he would accomplish what Colin could not. Pasteur thought the higher body temperature of hens might confer immunity, and he sought to prove this by an ingenious experiment involving three animals. One was inoculated with anthrax bacilli and submerged with one third of its body in a bath to lower its body temperature. A second hen was placed in the bath without inoculation, and a third was inoculated with twice the inoculum of the first but was not placed in water. The first hen soon died, with anthrax bacilli found throughout its blood and organs; the other two remained healthy. Clearly, it was necessary to inoculate a hen and lower its temperature to that of cattle, rabbits, and other mammals in order for the bacillus to survive. M. Lereboullet wrote in the Weekly Gazetie of Medicine and Surgery in 1878 of Pasteur’s latest experiment, “those facts throw a new light in the theory of the genesis and development of the bacillus anthracis . . . it seems very probable that M. Pasteur, who never brings any premature or conjectural assertion to the academic tribune, will deduce from them conclusions of the greatest interest concerning the etiology of virulent diseases.” Many viewed the reports with uneasy caution. Some were outspokenly critical. Leon Le Fort, a surgeon and member of the Academic de Medicine, denied the clinical relevance of germs: “That theory, in its applications to clinical
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surgery, is absolutely unacceptable.” “I believe in the interiority of the principal of purulent infection in certain patients; that is why I oppose the extension to surgery of the germ theory which proclaims the constant exteriorly of that principal.” Pasteur’s struggle for the acceptance of anthrax as an infectious disease did not end easily, and the debate acquired another dimension with his work on a vaccine. In this instance as in others, he argued passionately when convinced of his findings, not motivated by self-aggrandizing impulses, rather that scientific advancement should not be impeded in its service to humanity. Many of the sharpest critiques of his work came from the medical profession, whose members, devoted to a discipline based in science but in practice more of an art, have always viewed skeptically the opinions of those not included in their noble calling. Another notable example involved the cause of typhoid fever, a disease responsible for widespread illness, often fatal, and thought by Pasteur and others to be spread by an infectious agent. To the medical community, it originated within the body, representing a normal part gone awry. Even when acknowledging the existence of microscopic organisms in some diseases, they often failed or refused to appreciate their significance. M. Peter proclaimed at the Academic de Medicine, “These are but natural history curiosities, interesting no doubt, but of very little profit to medicine, and not worth either the time given to them or the noise made about them. After so many laborious researches nothing will be changed in medicine, there will only be a few more microbes.” It was the same M. Peter who, in foreseeing the age of antibiotics more than 50 years later, attacked “microbicidal drugs which may become homicidal.” Pasteur’s works encompassed a vast array of subjects, his mind forever seeking solutions; as long as his health permitted, his energies were engaged. Rabies, diphtheria, yellow fever, and infections of domestic animals were among the other riddles that he confronted. Towards the end of his life, the controversies subsided, and in his last years Pasteur received praise and acclaim enjoyed by few scientists. His work with the rabies vaccine in particular was viewed by the public as miraculous; his reputation became international, and patients came to him from many countries for treatment of an illness that had been invariably fatal until his discovery. Throughout his career of researches, Pasteur steadfastly set as his prime goal scientific truth, because he knew that from this flowed rewards priceless to mankind, most importantly relief of disease and suffering. He also took great pride in the honor bestowed not upon himself but to France, that its greatness would be recognized by all. Pasteur never lost his selflessness nor his painstaking inquisitiveness, and to review his words and deeds reveals him, in the sentiment of some, as the person most nearly attaining perfection in the realm of science.
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mise, servile imitation, and complaisance, without becoming original for there is in every creature a foundation of life which, if not choked back by stones and other dead rubbish, will create a fresh atmosphere, and bring to life fresh beautv.”
TRUTH
None have pursued truth more passionately than Harvey and Pasteur, although both were forced to confront authoritetive and forceful opposition. Yet many of their peers and subsequent posterity recognized what both knew could be explained in no other way. We hail them today for their genius, while we daily utilize end build upon the knowledge they extracted and bequeathed. John f&sefield might have been speaking of these two giants in his Shakespeare
and Spiritual
Note: This essay represents an historical perspective, not a work of original research. Thus, the references are only secondary sources. The intent is not to uncover any unknown facts, but rather to illuminate the struggles of two great medical scientists as they fought strong resistance to bring into the light what they, and subsequently the world, knew was real and true.
Life,
There is another way truth: by the minute examination of facts. That is the way of the scientist: a hard and noble and thankless way.
REFERENCES
Margaret Fuller’s definition of genius and truth may also aDDlv: Truth is the nursing mother of genius. No man can be absolutely true to himself, eschewing cant, compro.
924
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Keynes
GL: The life of William Harvey. 1966. Vallery-Radot R: The life of Pasteur. Doubleday, Page, 1926.
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