Organotherapy, British Physiology, and Discovery of the Internal Secretions Author(S): Merriley Borell Source: Journal of the History of Biology, Vol

Organotherapy, British Physiology, and Discovery of the Internal Secretions Author(s): Merriley Borell Source: Journal of the History of Biology, Vol. 9, No. 2 (Autumn, 1976), pp. 235-268 Published by: Springer Stable URL: http://www.jstor.org/stable/4330654 . Accessed: 21/06/2014 01:04

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This content downloaded from 185.2.32.134 on Sat, 21 Jun 2014 01:04:35 AM All use subject to JSTOR Terms and Conditions Organotherapy, British Physiology, and Discovery of the Internal Secretions

MERRILEY BORELL Department of History University of California, Berkeley

In April 1891, the Frenchphysiologist and neurologistC.-E. Brown- Sequard (1817-1894) and his assistant Arsene d'Arsonval(1851-1940) suggested to the Society of Biology at Paris that potent substances, which they called "internalsecretions," ought to exist in animaltissues, and that disease probably resulted from their lack. Brown-Sequardand d'Arsonvalproposed to their colleagues that one might discover these substancesby using extracts of specific tissues to treat certaindiseases. They argued that if a given condition could be successfully treated by the use of an extract, it was very likely that the condition was caused by inadequateproduction of an internalsecretion. In a brief note, they outlined a programof experimentaltherapy to searchfor these substances.I Organotherapy,as this form of therapy came to be called, had origi- nated two years earlier in Brown-Sequard'srejuvenation studies. At a similar meeting of the Society of Biology, Brown-S6quardhad argued that the testes probably produced a "dynamogenic"substance which mnightbe extracted from the testicles of animalsand injected into aging or debilitated individuals to restore their strength. Brown-Sequard based the argumentsfor pursuingthese experiments on commonly accepted assumptionsabout human sexuality. For example, it was widely held that loss of semen resulted in the loss of strength, and that the practice of masturbationled to debility. Brown-S6quardargued that retention of semen ought to lead to increasedstrength and vigor. Fur- ther, he suggested that the testes produced some substance which was nutritive to the nerves, and which might be extracted. In the light of these arguments, many physicians were willing to test his ideas, and "Brown-S6quard'sfluid" came to be employed in the treatment of a

1. C.-E. Brown-Sequard and A. d'Arsonval, "De l'injection des extraits liquides provenant des glandes et des tissues de l'organism comme m6thode thera- peutique," Comp. Rend. Soc. Biol., 9th s6r.,3 (April 18, 1891), 248-250. For a discussion of the events leading up to this communication, see my paper, "Brown- Sequard's Organotherapy and Its Appearance in America at the End of the Nine- teenth Century," Bull. Hist. Med., 50 (1976), in press.

Journal of the History of Biology, vol. 9, no. 2 (Fall 1976), pp. 235-268. Copyright ? 1976 by D. Reidel Publishing Company, Dordrecht, Holland.

This content downloaded from 185.2.32.134 on Sat, 21 Jun 2014 01:04:35 AM All use subject to JSTOR Terms and Conditions MERRILEY BORELL variety of nervous and debilitatingdiseases. This mode of therapy became popularnot only in France, but also in the United States and in Russia. By the spring of 1891, a number of investigatorshad realized that similarly potent medicaments might be extracted from other tissues, and physiciansin Pariswere askingBrown-Sequard and d'Arsonval to supply them with these preparations.? Although the rationale for the introduction of organotherapyinto medicine was developedlargely in France,much of the evidencefor the validity of its claims came from Britain.In the early 1890's, two important discoveries were made in Britain which added credence to the notion of internalsecretions developed by Brown-Sequardand d'Arson- val. These discoveries were the cure of myxoedema by subcutaneous injection of thyroid extract, reported in 1891 by George Redmayne Murray(1865-1939), and the observationof the vasopressoreffects of adrenal extract made in 1894 by George Oliver(1841-1915) and Ed- ward Schafer (1850-1935). As a result of these discoveries,investigations conceming internal secretions were graduallyremoved from the clinic to the laboratory:specific questions were asked by investigators and standardphysiological techniques were employed to answerthem. These discoveries effectively transformed the research program perceived by investigatorsby designatingan alternativeto the essentially therapeuticprogram developed by Brown-Sequard. It is the purpose of this paper to describe how Britishphysiologists came to recognize that internal secretionsexist in animaltissues and to examine how they learned to measurethe effects of these substances. The demonstration of a therapeutically-activethyroid extract and a physiologically-activeadrenal extract resultedin the explorationof new physiological problems, problems which, over the next decade, became the focus for the emergingfield of endocrinology. To understandthe context of these discoveries, it is necessary to review briefly the reception in England of Brown-Sdquard'sideas on internal secretions and to point out how the Britishmedical profession maintaineda skeptical attitude toward these ideas and the clinical evi-

2. 1 discuss these developments in detail in Chapters 1 and 2 of "Origins of the Hormone Concept: Internal Secretions and Physiological Research, 1889- 1905," Ph. D. diss., Yale University, 1976. 3. George R. Murray, "Note on the Treatment of Myxoedema by Hypoder- mic Injections of an Extract of the Thyroid Gland of a Sheep," Brit. Med. J., 2 (October 10, 1891), 796-797, and G. Oliver and F. A. Schafer, "On the Physiolog- ical Action of Extract of the SuprarenalCapsules,"Proceedings of the Physiolog- ical Society, March 10, 1894, J. Physiol., 16 (1894), i-iv.

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This content downloaded from 185.2.32.134 on Sat, 21 Jun 2014 01:04:35 AM All use subject to JSTOR Terms and Conditions Organotherapy,British Physiology, and the InternalSecretions dence advanced to support them. In retrospect, it is clear that a new kind of evidence was required to generate any widespreadinterest in Britain.

BRITISHPHYSICIANS AND THE TESTICULAREXTRACT

The precise impact of Brown-S6quard'sexperiments with testicular extract is difficult to characterizefrom the reports published in the leading British medical journals. Few reports were published between 1889 and 1891, and they tell us Littleof the responseof Britishphysi- cians, except by implication. Nonetheless, it is evident from later com- municationsthat some British physicians were interestedin the pheno- mena described by Brown-S6quard,and that some work on the therapeutic effects of testicularextract was undertaken. On June 22, 1889, three weeks after Brown-Sequard'sfirst communication on testicular extract, the British MedicalJournal publishedan account of the phenomenon of rejuvenation reported by Brown- S6quard. In an article entitled "The Pentacle of Rejuvenescence,"the journal described Brown-Sequard'sexperiments with testicular fluid.' Although its discussionof the experimentswas straightforward,preliminary comments in the report suggest that the popular reaction to the public announcement of Brown-Sequard's"discovery" had been quite unsettling to the medical profession.The second sentence of the report lamented: "The statements he [Brown-S6quard]made - which have unfortunately attracted a good deal of attention in the public press - recall the wild imaginingsof medievalphilosophers in searchof an elixir vitae"'.SThe choise of title is itself an indication of the disbelief with which Brown-Sequard'sresults were received. "Pentacle" refers to a symbol used in magic, the five-pointedstar. In the twenty-three line report, there was no request, such as Brown-S6quardhad made, directly urgingother experimentersto test the "spermaticfluid," only inclusion in the summaryof the opinions of the Parisianphysicians Fer6 and Dumontpallierthat they would require Brown-Sequard'sstatements to be "rigidly tested and fully confirmed by other self experimentersbefore they were likely to meet with general acceptance."6 The editors of the British Medical Journal merely commented that "in this opinion" they "fully" concurred.

4. "The Pentacle of Rejuvenescence," Brit. Med. J., 1 (June 22, 1889), 1416. 5. Ibid. 6. Ibid.

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Thus, although enthusiasm for the testicular extract developed in other countries duringthe next few months, and Brown-Sequardrepor- ted on the therapeutic successes of the fluid to his colleaguesin Paris, no comparableinterest appears to have been generated in Britain.In fact, only two foreign reports of treatmentsusing the testicularextract were cited by the British MedicalJournal in 1889. The first summarized the results of Variot in Parison the treatment of senile debility;7 the second relayed an unconfirmedreport from Indianapolis. A thirteen-line report concerning Variot's successful treatment of three debilitated men with testicular extract was published by the Bri- tish MedicalJournal on July 6.8 It stated that from these cases Brown- S6quardconcluded that "Variot'sobservation disposed of the objection that the results hie [Brown-Sequard]had observed in himself were due to 'suggestion.' "9 There was no indication that the editors of the British MedicalJoumal shared this view. Six weeks later in an articleof only eight lines, the journaldescribed a reportfrom Indianapoliswhich claimed that "Dr. Brown-Sequard'srejuvenating fluid" had invigorated a "decrepitold man."' 0 The articleindicated that no "medicalauthori- ty" had been given, implying that the observationhad yet to be confirmed. It is apparentthat the BritishMedical Journal maintained a skeptical attitude toward such reportsfrom abroad.The sensationalnature of Brown-Sdquard'srejuvenation claims, the possibility of these results being the outcome of suggestion, and the lack of reliable confirming data seemed, in 1889, to make this stance appropriate. Two letters published in the British Medical Journal during this period suggest, however, that insufficiency of data was not the only reason for the caution with which Brown-S6quard'sideas were received in Britain. At least two other factors were probably important: first, outrage among antivivisectionists,who objected to the use of extracts of animal organs,'' and, second, the outrage of some membersof the medical profession, who not only objected to the injection of the semi-

7. G. Variot, "Trois experiences sur I'action physiologique du suc testiculaire inject6 sous la peau, suivant la methode de M. Brown-Sequard," Comp. Rend. Soc. Biol., 9th ser., I (June 29, 1889), 451454. 8. "Dr. Brown-S6quard's Hypodermic Fluid," Brit. Med. J., 2 (July 6, 1889), 29. 9. Ibid. 10. "The New Elixir of Youth," Brit. Med. J., 2 (August 29, 1889), 446. 11. For the context of such attitudes, see Richard D. French, Antivivisec- tion and Medical Science in Victorian SocietY (Princeton, N.J.: Princeton Univer- sity Press, 1975).

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This content downloaded from 185.2.32.134 on Sat, 21 Jun 2014 01:04:35 AM All use subject to JSTOR Terms and Conditions Organotherapy,British Physiology, and the InternalSecretions nal fluid of animals into human beings, but who also abhorred the possibility that Brown-Sequard'srejuvenating treatment involved masturbation.12 One such member of the medical profession had by July 7, 1889, published six thousand copies of a circularwhich protested againstthe experimentsof Brown-Sequardon both grounds.The British MedicalJournal had respondedto the circularand criticized the naivete of the author regardingthe generaluse of castratedanimals in the meat industry.1 3It did not comment, however, on the moral objections raised by the unnamed author, who repeated those objections in his letter to the editor six weeks later:

You have not done me justice by your note on my circular relative to Dr. Brown-Sequard'sexperiments. Much as I disapprove of the animal torture in question, I should not have felt it my duty to print and post some 6,000 copies of my protest had that been all. I consider the idea of injecting the seminal fluid of dogs and rabbits into human beings a disgusting one, and when the treatment also involves the practice of masturbation, I think it is time for the medical profession in Englandto repudiateit. One may be a vivisec- tor without also encouraging a loathsome vice . . . Vivisection may be an open question, but self-abuseis not.'4

The summaryof the uncomfirmedreport from Indianapoliscited above was published two weeks after this letter appeared,but no additional articles on the subject of the testicular fluid were published in the BritishMedical Journal in either 1890 or 1891. The response recorded in The Lancet during those years is equally subdued. In 1889, that journal published only one article relating to

12. This criticism probably refers to the fact that Brown-S6quard observed that if debility were due to seminal loss, increased vigor might result from seminal retention. He had advocated sexual excitement without ejaculation to some of his patients. See Brown-S6quard, "Seconde note sur les effect produits chez I'homme par des injections sous-cutan6es d'un liquide retire des testicules frais de cobaye et de chien," Comp. Rend. Soc. Biol., 9th ser., I (June 15, 1889), 420. 13. "The Recent Experiments of Dr. Brown-S6quard," Brit. Mcd. J., 2 (July 27, 1889), 229.Thejournalclaimed thatits objections were quoted out of context by the author of this tract and, further, that the charges of barbarity were not justi- fied because it was common agricultural practice to castrate animals to improve the flavor of the meat. 14. "Dr. Brown-S6quard's Fxperiments: A Member of the Medical Profession Writes," Brit. Med. J., 2 (August 10, 1889), 347.

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experiments with the testicular extract.' 5 It was by Brown-Sequard, who had apparentlyvolunteered to write it. The editors of The Lancet respondedto him on July 10, 1889. As their letter indicates,they too had become concernedby the sensationalreports in the public press:

The Lancet Office. Strand.WC July 10, 1889

Dear Dr. Brown-Sequard,

We have not yet published any account of your experimentson the power of a liquid extracted from the spermaticglands of animals. We shall be glad to avail ourselvesof your kind offer to write a short paper on the subject for publicationin our columns.We think it desirablethat the article should appearunder your name as somewhat sensationaland no doubt inaccurateparagraphs have been late- ly appearingin the daily press. We are, dear Dr. Brown-S6quard,

Yours faithfully The Editors.1 6

Brown-Sequard'stwo-page article, "Note on the Effects Produced on Man by Subcutaneous Injections of a Liquid Obtained from the Testicles of Animals,"was sent from Brighton,where he was visitingin the summer of 1889. It concluded with his by then familiarexhorta- tion:

Whatevermay be thought of these speculations [regardingthe aging

15. Brown-S6quard, "Note on the Effects Produced on Man by Subcutaneous Injections of a Liquid Obtained from the Testicles of Animals," The Lancet, 2 (July 20, 1889), 105-107. This article is clearly written and provides an excellent summary of Brown-Sequard's ideas concerning the testicular fluid. It is based on his three notes to the Society of Biology: "Des effects produits chez l'homme par des injections sous-cutanees d'un liquide retire des testicules frais de cobaye et de chien," "Second note ...," and "Troisieme note sur les effets des injections sous-cutan6es de liquide testiculaire," Comp. Rend. Soc. Biol., 9th. ser., I (June 15, June 15, June 22, 1889) 415-419, 420-422, 430-431. 16. "Before Our Time," letter of the editors of Lancet to Brown-S6quard, The Lancet, 1(1965), 315.

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process] the results I have obtained by experiments on myself and those which have been observed by Dr. Variot on three old men show that this important subject should be further investigatedex- perimentally.' 7

Early in the next year, on January4, 1890, The Lancet's New York correspondent described the controversy raging in the United States over the efficacy of the testicular extract in "renewingthe vigour of youth in the aged."' 8 The opening sentences of the article suggestthe disbelief with which the correspondentwitnessed the vigorousresponse in America:

The announcement that this distinguishedphysiologist [Brown- S6quard]had discovered a method of renewing the vigourof youth in the aged was receivedin this country with an increduloussmile by the profession. But there is always a class of medical men who are ready at once to test the value of any new remedy, and during the past month [December 1889] the newspapershave been filled with experiments made in various parts of the country. It is surprisingat the first blush to note the different results obtained as reported.In the hands of one experimenterthe paralysedimmediately walk, the lame throw aside cane and crutches, the deaf hear, and the blind see. The same experimentsfailed altogetherin the practiceof another.' 9

No British reports on the testing of the testicular extract were published in The Lancet in either 1890 or 1891. Certainly,Brown-S6quard's scientific reputationin Britaincannot be judged on the basis of these few published responses to his studies on the physiological and therapeutic effects of testicular extract. Brown- S6quardhad traveled extensively between 1852 and 1872. He had lec- tured and held positions in Britain and America,as well as in Paris.His neurological and physiological work was well known to British physicians and physiologists. In fact, the eleventh edition of the Encyclopae- dia Britannica,published in 1910, refersto him as the "Britishphysiol- ogist and neurologist."2?

17. Brown-S6quard, "Note on the Effects," pp. 106-107. 18. "Dr. Brown-S6quard's "Elixir of Life" (New York, from our own Cor- respondent)," The Lancet, I (January 4, 1890), 57-58. 19. Ibid. 20. "Charles EIdward Brown-S6quard," in Encyclopaedia Britannica, 11th ed., IV, 674.

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Brown-Sequardwas a British subject by birth; Mauritiuswas under British rule when he was born there in 1817. He was trained in medicine at Paris,but he did not become a French citizen until 1878, when he took up the position of Professor of Medicine at the College de France after the death of his contemporaryand rival, Claude Bernard (1813-1878). Brown-Sequardwas one of the first physicians to the National Hospital for the Paralyzedand Epilepticin London.21 He was elected Fellow of the Royal Society and Royal Collegeof Physiciansin 1860. In 1861, he deliveredthe Croonianand Gulstonian Lecturesfor these societies. After 1863, Brown-Sequardtook up positions in the United States and then in Paris,lecturing occasionally to Britishaudien- ces. In 1881, he receivedan honoraryLL.D. from CambridgeUniversity and the Baly Medalof the Royal Collegeof Physicians.His work on the inheritanceof acquiredcharacteristics was well known to CharlesDar- win. His third wife, Elizabeth Emma Dakin, was an Englishwoman.22 Brown-Sequardwas, therefore,not without colleaguesand friendsin Britain.Moreover, it is evident from his correspondencewith d'Arson- val that the testicular extract was being sent to and tested by several Englishmen.23 Although there is no mention of such shipments prior to 1891, beginning in February 1891, there are severalreferences in the correspondence between Brown-Sequardand d'Arsonvalwhich indicate that testicular extract was being shipped to London by parcel post. In a letter of February1 3, d'Arsonvalcommented on the receipt of a letter from Dr. Fanton-Cameronof London, presumablya request for the testicular extract.24 Six days later, he wrote Brown-Sequardthat the most rapid and inexpensive way to send material to London was by parcel post.25 Then, in four consecutive letters 26 written between

21. Brown-S6quard served between 1860 and 1863. He greatly influenced J. Hughlings Jackson (1835-1911) during this visit. See J.M.D. Olmsted, Charles- Edouard Brown-Sequard: A Nineteenth Century Neurologist and Endocrinologist (Baltimore: The Johns Hopkins Press, 1946), p. 107. 22. Ibid. 23. See the correspondence between February 3 and May 3, 1891, in Leon Delhoume, De Claude Bernard a dArsonval (Paris: J.-B. Bailliere & Fils, 1939), pp. 357-402. Cited hereafter as Delhoume, Correspondence. 24. Ibid., p. 360. Letter of February 13, 1891. D'Arsonval wrote: "I have sent some liquid to Dr. Jacquard; I have likewise received a letter from London from Dr. Fanton-Cameron; I await your orders to dispatch (it)." I have been unable to locate any biographical information on Fanton-Cameron. 25. Ibid., p. 364. Letter of February 19, 1891. 26. Ibid., p. 365. Unfortunately, these letters were not published. Delhoume,

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February 17 and 22, Brown-Sequardgave d'Arsonvalinstructions for sending the testicular liquid to London, asking him to send some to Drs. Fanton-Cameronand BrudenellCarter,2 7 as well as to the surgeon Victor Horsley, then Assistant Professor of Pathology at University College, London.28 In the letter of February25, d'Arsonvalreported that he had sent two bottles to each of them.29 It is curious, then, that one day later Brown-Sequardwrote d'Arson- val, "I regret that you have sent some 'liquid' to Horsley: he will not know what to do with it and will be very surprised.7hat which I asked you (and I did it in two letters) was to forward him a sample of the no. of comptes rendus containing your work on filtration by the aid of carbondioxide."30 There is no furtherrecord of these exchangeswith Fanton-Cameron, Carter,or Horsley, only the suggestionby Brown-Sequardon March29 that it would be good if d'Arsonvalwere to show the laboratory to Horsley, who was at Parisfor the Congressof Surgery.Brown-Sequard directed d'Arsonvalto get in touch with Horsley in order to arrangethe visit.3 Horsley's response to this invitation or to the receipt of the extract has not been recorded.32 On April 10 and 14 and May 3, Brown-Sequardasked d'Arsonvalto send bottles of the testicular liquid to his old friend and wife's cousin,

editor of the correspondence between d'Arsonval and Brown-S6quard, notes in a footnote: "Brown-Sequard, in four consecutive letters from the 17 to 22 of February, gives some directions to d'Arsonval for the shipments of testicular fluid to England and requests him notably to address some to Doctors Fanton- Cameron, Brudenell Carter and to Professor Horsley, of London." 27. Robert Brudenell Carter (1828-1918) was an ophthalmicsurgeon.He served on the staff of both The Times and The Lancet. See d'Arcy Power, "Ro- bert Brudenell Carter," in Plarr's Lives of the Fellows of the Royal College of Surgeons of England (London: Royal College of Surgeons, 1930), I, 201-203; "RobertBrudenellCarter, F.R.C.S.," The Lancet, 2 (1918), 607; and "R. Brude- nell Carter, F.R.C.S.," Brit. Med. J., 2 (1918), 502-503. 28. See below. 29. Delhoume, Correspondence, p. 366. 30. Ibid., pp. 368-369. Letter of February 26, 1891. See also Brown-Se- quard, "De l'injection des extraits liquides," p. 248, for a summary of this proce- dure. 31. Delhoume, Correspondence, p. 385. Letter of March 29, 1891. 32. Stephen Paget does not mention this trip in his biography, Sir Victor Horsley: A Studv of his Life and Work (New York: Harcourt, Brace and Howe, 1920).

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Dr. W. D. Waterhouseof London.33 Waterhousewished to procureall the apparatusnecessary to make the liquid, and thus Brown-Sequard directed d'Arsonvalto ship the equipment to him. Waterhouse'sreport on the use of the extract did not appearin the BritishMedical Journal until January30, 1892,34 at which time organotherapywas becoming an acceptable mode of therapeuticsin Britain.To understandthis gro- wing respectability of organotherapyin 1892, one must turn to the progress of work on the thyroid gland, work in which the surgeon Victor Horsleyplayed a prominentrole.

THYROIDEXTRACT AND THE TREATMENTOF MYXOEDEMA

Horsley had been a member of the committee appointed by the London Clinical Society in 1883 to investigateexperimentally the rela- tionship between the conditions of myxoedema, cretinism,and cachexia strumipriva.In that year two Swiss surgeons,Jacques and Auguste Reverdin,extirpating the thyroid for the treatment of goiter, reported that the condition (later called cachexia strumipriva)which supervened after thyroidectomy was similar to the myxoedematous state first described by WilliamGull in 1873. In 1883, it appearedhighly probable that three conditions - myxoedema, cretinism, and cachexia strumipriva - were related to disturbed thyroid function, and the London Clinical Society undertook study of this question.3 Horsley began experimentalwork on thyroid extirpation in EdwardSchafer's physiology laboratoryat UniversityCollege in the autumn of 1884. Whenhe became Professor-Superintendentof the Brown Institution, a research facility for animal pathology affiliated with UniversityCollege, he continued his investigationsthere. He remainedwith the Brown Institution until 1890. In 1891, when d'Arsonvalshipped the vials of testicularextract to him, Horsleynot only held a position at UniversityCollege but was also on the surgicalstaff of both UniversityCollege Hospitaland the Natio- nal Hospital for the Paralyzedand Epileptic. He was no longer directly engaged in experimentalwork on the thyroid gland;that had occupied him principally during the years 1884-1886. He had since turned his attention to the prevention of rabies in Englandand had begun studies

33. Delhoume, Correspondence, pp. 394, 396-397, 402. 34. "Report of the Clinical Evening of the Harveian Society, January 7, 1891 (sic)," Brit. Med. J., I (January 30, 1892), 229. 35. Paget, Sir Victor Horsley, pp. 54-67.

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This content downloaded from 185.2.32.134 on Sat, 21 Jun 2014 01:04:35 AM All use subject to JSTOR Terms and Conditions Organotherapy,British Physiology, and the InternalSecretions on the localization of brain function.36 Nonetheless, in February 1890, following the report of successful grafting of thyroid glands into thyroidectomized animals, Horsley had advocated the graftingof thyroid tissue into myxoedematous patients as a treatment for the disease.3' This was an idea which his former student George Redmayne Murraytransformed and exploited by successfully treating a myxoedematous patient with subcutaneous injections of thyroid juice. Murrayhad been a student and house physician at UniversityCol- lege Hospital from 1886 until 1889. He had attended Horsley'scourse of practical pathology, as well as Horsley'soutpatient practice. Murray had set his mind "upon a career in experimentalmedicine" and "for this purpose he visited the most famous of the medicalclinics in Berlin and Paris."38 Horsley provided him with letters of introduction, and Murraytoured continental clinics between 1889 and 1890. It is possible that while in Paris he became acquainted with the therapeutic trials being made with testicularextract. After Murraysettled in Newcastle as pathologist to the Hospitalfor Sick Children,his friendshipwith Horsley grew.39 They corresponded regardingthe feasibility of injection experiments with thyroid juice. Horsleywrote him on December3, 1890:

The only experimentsI know of on injectionsof the gland have only produced slight results, similar so far as I could see to what might have been caused by injections from any other tissue. However, it cannot do any harm, and I think it would be worth trying, as it is possible from Schiff's results of imperfect transplantationthat an emulsion of the gland might possess some of its active properties.40

36. Edwvin Clarke, "Victor Alexander Haden Horsley," in Dictionary of Scientific Biography, ed. C. C. Gillispic, I (New York: Charles Scribner's Sons, 1972), 518-519, and Paget, Sir Victor Horsley. 37. Victor Horslcy, "Notc on a Possible Means of Arresting the Progress of Myxoedema, Cachexia Strumipriva, and Allied Diseases," Brit. Med. J., 2 (Febru- ary 8, 1890), 287. 38. J. C. Spence, "George Redmayne Murray," in Dictionary of National Biography, 1931-1940, ed. L. G. Wickham Legg (London: University Press, 1949), pp. 638-639. See also Paget, Sir Victor Horsley, pp. 65-66, n. 1. 39. Murray also held the post of lecturer in bacteriology at the Durham Uni- versity Collcge of Medicine. 40. Cited in Paget, Sir Victor Horsley, pp. 65-66. Horsley was referring to the work of Moritz Schiff (1823-1896), Professor of Physiology at Geneva. In 1884, Schiff published the results of his experiments on thyroid grafts. He sugges-

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On June 22, 1891, Horsley wrote again. He brought Murrayup to date on the current literature regardingthyroid disorders, citing the work of Vassaleand of the Spanishinvestigators Bettencourt and Serra- no. However, he did not mention the paper by Brown-Sequardand d'Arsonvalthat had been publishedthe previousApril: I am very glad to say that the reference only contains a suggestion, not the actual practiceof the use [of thyroidjuice to treat myxoedema]. In that, you have only been forestalledexperimentally. Thus, Vessale [sic] (Centralblattfur MedicinischeWissenschaften, 1891, p. 14) injected the expressed juice of the thyroid into dogs in which thyroidectomy had previously been performed, and he found that the cachectic symptoms did not occur or, if they did, were con- siderably modified. The clinical reference is as follows - Betten- court and Serrano (ProgrdsMedical, 1890, vol, xii. p. 170). These authors, who had adopted the suggestion of grafting the thyroid, suggest that the benefits obtained therefrom are due to absorption of materialfrom the gland, and the same idea had occurredto Schiff and others. Hoping this is not too late for your wants, and that you will publishat once - I am yours very sincerely.41 Murrayreported his observations on the treatment of myxoedema with thyroid juice within the month. His "Note on the Treatmentof Myxoedema by Hypodermic Injections of an Extract of the Thyroid Gland of a Sheep" was read in the Section of Therapeuticsat the annual meeting of the BritishMedical Association held in Bournemouth in July 1891.42 There was no referencein this paperto the generalized notion of internal secretions advancedby Brown-Sequardand d'Arson- val, only Murray'saccount, of the historicalroute by which the idea had occurred to investigators that the loss of thyroid function could be remediedby injections of juice of the thyroid.43

ted that ground thyroid gland might, like grafts of thyroid gland, be effective in eliminating the symptoms which followed experimental thyroidectomy; cf. A. Herzen and F'. Levier, ed., Moritz Schiff's gesammelte Beitrage zur Physiologie, IV (Lausanne: B. Benda, 1898), 391. 41. Paget, Sir Victor Horsley, p. 66. 42. Murray, "Note on the Treatment of Myxoedema". 43. Murray credited Horsley with the suggestion. The French investigator Jacques Abelous (1864-1940), however, claimed that this mentor Charles Bou- chard (1837-1915), Professor of General Pathology at the Faculty of Medicine in Paris, had recommended this treatment as early as 1887; see J.-E. Abelous,

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Murraystated: "The observationsof the symptoms which followed the removalof the thyroid gland in man made by ProfessorKocher, of Berne, and the results of the experimental removal of the gland in monkeys obtained by Mr. Victor Horsley have firmly establishedthe view that this disease myxoedema is due to the loss of function of the thyroid gland."44 He noted the experiments of the Austriansurgeon Anton von Eiselsberg(1860-1939), which showed that transplantation of the thyroid to another part of the body prevented the onset of the symptoms that usually followed removal of the thyroid from the neck, and he cited the article in which Horsleyhad suggestedthe graftingof a sheep's thyroid into a myxoedematouspatient. Such a graft had been successfully carriedout by Bettencourt and Serrano of Lisbon and reported by them in La semaine medicale on August 13, 1890. Accordingto Miurray,"these authorsconsidered that as the improvement commenced the day after the operation, it could not be due to the gland becoming vascularizedand so functional, but suggestedthat it was due to the absorption of the juice of the healthy thyroid gland by the tissues of the patient."45 Murrayconcluded, "it seems reasonable to suppose that the same amount of improvement might be obtained by simply injecting the juice or an extract of the thyroid gland beneath the skin of the patient."46 Further,he observed, "if we consider that myxoedema and cachexia strumiprivaare due to the absence from the body of some substance which is present in the normal thyroid gland, and which is necessary to maintain the body in health, it is at least rationaltreatment to supply that deficiency as far as possible by injecting the extract of a healthy gland."47 Murraygave no clear indication as to how such a substance might "maintainthe body in health." He only proposed a "rational treatment" that should be tried to treat such a deficiency. Murraycited Vassale'swork on the intravenousinjection of thyroid extract into thyroidectomized dogs, but did not indicate any knowledge of Eugene Gley's (1857-1930) correspondingstudy, publishedin the

"La physiologic des glandes a s6cr6tion internc: corps thyroide ct capsules surre- nales," Revue gen&raledes sciences pures et appliquees, 4 (1893), 275. 44. Murray, "Note on the Treatment of Myxoedema," p. 796. Murray was referring to Horslcy's conclusions in the Brown Lectures of 1885. Note that both Kocher and von Fiscisberg had been students of Theodor Billroth (1829-1894) of Vienna. 45. Murray, "Note on the Treatment of Myxoedema," p. 797. 46. Ibid. 47. Ibid.

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Comptes rendus of the Society of Biology for April 18, 1891.48 Mur- ray believed his work to be the first attempt to use this treatmenton a human subject and remarkedthat he had already suggestedthis treatment at the Northumberlandand DurhamMedical Society. Apparently, the use of thyroid extract as a medicament was "in the air" in the winter of 1890-91.4 Murray'streatment of a myxoedematous patient by the subcutaneous injection of thyroid juice in 1891 was the first generallyacknow- ledged success of the new organotherapy.Moreover, thyroid pathology was one of the first ongoing researchproblems to which the notion of intemal secretions was directly applicable. Acknowledginganalogies already pointed out by Brown-S6quardand d'Arsonval,British physicians soon began to test other organextracts.

"RATIONAL"ORGANOTHERAPY

Murray's note to the British Medical Association on the use of thyroid extract in the treatment of myxoedema was followed by a paper, "The Diuretic Action of Fresh Thyroid Juice," written by E. Harry Fenwick, Surgeon to the London Hospitaland St. Peter'sHospi- tal.50 Duringthe previousyear (1890), Fenwick had grafted a sheep's thyroid into a myxoedematous patient. He had split the gland priorto grafting and rubbed the secretion into the subcutaneous tissue. The next day the patient's temperaturerose, and urine output increased1 50 percent. Fenwick, not being certain that these effects were due to "the absorptionof the free secretion of the thyroid," attemptedhypodermic injection of the juice in his next patient. The diureticeffects following the injections were so striking that he suggestedthat "the state known as myxoedema depends upon a pervertedrenal function." He argued, "before submitting our patient and results to the Clinical Society we would wish that so simple an injection be tried in orderthat rebutting

48. E. Gley, "Note pr6liminaire sur les effets physiologiques du suc de di- verses glandes et en particulier du suc extrait de la glande thyroide," Comp. Rend. Soc. Biol., 9th ser., 3 (April 18, 1891), 250-25 1. Gley was Professeur agrege at the Faculty of Medicine in Paris. 49. This seems generally to have been the case for the use of organ extracts as therapeutic agents. On April 16, 1891, Brown-S6quard wrote d'Arsonval ur- ging him to present a communication to the Society of Biology on the following Saturday because "the thing is in the air - especially in Italy "; cf. Delhoume, Correspondence, p. 400. 50. E. Harry Fenwick, "The Diuretic Action of Fresh Thyroid Juice," Brit. Med. J., 2 (October 10, 1891), 798.

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This content downloaded from 185.2.32.134 on Sat, 21 Jun 2014 01:04:35 AM All use subject to JSTOR Terms and Conditions Organotherapy,British Physiology, and the InternalSecretions or confirmatory evidence might be brought forward at the same time."5 Additional data on the effects of thyroid injections were soon forthcoming. During 1892, Britishphysicians published numerous reports on the administrationof thyroid juice in the treatmentof myxoedema. Victor Horsley's two-part article, "Remarkson the Function of the Thyroid Gland: A Criticaland HistoricalReview," appearedon January30 and February 6.5 2 Clinical reports on the use of hypodermic injections in the treatment of myxoedema were publishedfirst by Beatty and Carter and later by Murray,Fenwick, and Barron. Among these papers appeared reports by Mackenzieand Fox which showed that thyroid could be given effectively by mouth, as well as by injection.53 These successes with the use of thyroid extract as a therapeutic agent led to the appearanceof an editorial in the BritishMedical Jour- nal of October29, 1892, announcingthat a rationaltherapy for myxoedema had been discovered.The article proclaimed:

He would have been a bold man who should have venturedto assert that the recent experimental investigation of the functions of the thyroid gland, and especially that of the effects of its removal, would so soon have been applied with the most striking success in the treatment of a disease than which none had shown itself more absolutely intractableto all previousforms of treatment.54

Not only had there been several reports of success by subcutaneous injections of the extract, but now the gland itself could be fed directly to myxoedematouspatients. The success of thyroid therapyin the treatmentof myxoedema soon led to the application of the same reasoningto a similarly intractable disease, diabetes. This approach appeared in a discussion foUowing a paper on the pathology of the pancreas, written by Vaughan Harley (1863-1923), later Assistant Professorof Pathology at University Col-

51. Ibid. Presumably, Fenwick thought the accumulation of fluid to be due to malfunctioning ot the kidneys. 52. Victor Horsley, "Remarks on the Function of the Thyroid Gland: A Crit- ical and Historical Review," Brit. Med. J., I (January 30, February 6, 1892), 215- 219 and 265-268. 53. See the British Medical Journal for the year 1892. The successful treatment of myxocdema by feeding of fresh thyroid was reported in October. 54. "The Treatment of Myxoedma," Brit. Med. J., 2 (October 29, 1892), 965.

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This content downloaded from 185.2.32.134 on Sat, 21 Jun 2014 01:04:35 AM All use subject to JSTOR Terms and Conditions MERRILEY BORELL lege.55 This paper was presented in 1892 at the same meeting of the British Medical Association at which Murraypresented an enlargedre- port on the treatment of myxoedema by hypodermic injection of thyroid juice.56 In the discussion after Harley'spaper, the use of pancreatic juice was advocated for cases of diabetes. Harleyremarked that extracts of the pancreas had been used in the treatment of diabetes, both in Englandand abroad, over the previous two years, but without success. His discussant, Dr. Ransom,had tried similarexperiments, also unsuccessfully.57 Such an analogy between the thyroid and the pancreas was drawnrepeatedly, however, in the next few months. In December 1892, in an article called "Physiology in 1892," the British Medical Journal called attention to the hitherto unrecognized role of the glands in general metabolism. The possible parallelbetween the thyroid and the pancreaspresented new and intriguingproblems to physiology:

Minkowskihas continued his important work on pancreaticdia- betes, and H6don has confirmed most of his results. They find that the glycosuria which follows extirpation of the pancreas can be stopped by transplantationof a portion of a living pancreasinto the abdominalwall. This, taken in conjunctionwith the beneficialresult that follows injection of the thyroid juice in myxoedema shows us that glands have actions in general metabolic processeswhich were before unknown but the modus operandi has yet to be discovered.58

55. Vaughan Harley, "The Pathogenesis of Pancreatic Diabetes Mellitus," Brit. Med. J., 2 (August 27, 1892), 452-454. Harley was the son of George Harley (1829-1896), who, under William Sharpey (1802-1896) at University College, began the first class of practical physiology in England. The elder Harley was also the first in England to repeat Brown-S6quard's experiments on adrenal extirpation; see Sir Edward Sharpey-Schafer, History of the Physiological Society during Its First Fifty Years, 1879-1926, supplement to the Journal of Physiology, De- cember 1927 (London: Cambridge University Press, 1927), p. 2. According to papers published in the Journal of Physiology, Vaughan Harley was Assistant Pro- fessor of Pathology in 1895. He later became Professor of Chemical Pathology; see Sharpey-Schafer, History of the Physiological Society, p. 108. 56. G. R. Murray, "Remarks on the Treatment of Myxoedema with Thy- roid Juice, with Notes of Four Cases," Brit. Med. J., 2 (August27, 1892),449- 450. 57. Harley, "The Pathogenesis of Pancreatic Diabetes Mellitus." 58. "Physiology in 1892," Brit. Med. J., 2 (December 31, 1892), 1442. For discussion of studies of pancreatic physiology, see below.

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Although such a parallel between thyroid and pancreatic physiology had been pointed out by Brown-Sequardand d'Arsonvalone and a half year earlier, the "hard"data supportingsuch a view of glandularfunc- tion were only now beginning to emerge. Organotherapybegan to have a noticeable appealin Britain. Two brief reports on Brown-Sequard'stesticular fluid appearedin the British MedicalJournal for 1892.59 In January,Waterhouse presented three cases of paralysistreated by testicularextract to the Harveian Society. In July, there appeareda brief letter by a Dr. Ambrose on the mode of preparationof Brown-Sequard'sfluid. Ambrose'snote did not directly advocate the use of testicular fluid, but its appearancein the British MedicalJournal probably marksa new receptivityto the testing of the extract in the treatmentof debilitatingand nervousdiseases. Early in the next year, on January7, 1893, the use of extract of the pancreas in the treatment of diabetes was advocated anew by Dr. R. Mansell-Jonesof Brighton. Drawing the analogy with the thyroid, he wrote:

As the juice of the thyroid glands appearsto be almost a specific in myxoedema, might I suggest that pancreatic juice, administered either immediately before or after meals, should be given a fair trail in diabetes, as this disease in most cases appeared to be due to diseaseor disorderedfunction of this gland?60

Dr. Hector W. Mackenzie, one of the first to note the successful feeding of thyroid gland in myxoedema, wrote that Mansell-Joneshad already been anticipated by Vaughan Harley in the previous year.61 And, in further responseto Mansell-Jones'ssuggestion, Neville Wood of the Victoria Hospitalfor Children62 and W. Hale Whiteof Guy's Hospi- tal6 3 each reportedtheir separateexperiences with the feeding of either

59. "Report of the Clinical Evening of the Harveian Society", and A. Ambro- se, letter to the editor in "Letters, Notes, and Answers to Correspondents," Brit. Med. J., 2 (July 16, 1892), 163. 60. R. Mansell-Jones, "Pancreatic Juices in Diabetes," under "Notes, Letters etc.," Brit. Med. J., I (January 7, 1893), 50. 61. Hector W.G. Mackenzie, "The Treatment of Diabetes Mellitus by Means of Pancreatic Juice," Brit. Med. J., I (January 14, 1893), 63-64. 62. Neville Wood, "The Treatment of Diabetes by Pancreatic Extracts," Brit. Med. J., I (January 14, 1893), 64. 63. W. Hale White, "On the Treatment of Diabetes Mellitus by Feeding on Raw Pancreas and the Subcutaneous Injection of Liquor Pancreaticus," Brit. Med. J., I (March 4, 1 893), 45 2-45 3.

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raw pancreasor pancreaticjuice in the treatment of diabetes. No one had yet cured diabetes with this mode of treatment, but the expecta- tion of success caused the experimentto be repeatedagain and again.

THE METHODOF BROWN-SEQUARDIN BRITAIN

In June 1893, the British MedicalJournal publisheda two-partarti- cle by Brown-Sequardentitled "On a New TherapeuticMethod Consis- ting in the Use of Organic Liquids Extracted from Glandsand Other Organs."64In this paper,Brown-Sequard reviewed the rationalefor thle introduction of this mode of therapy, presented his data on the inno- cuity of these injections, and outlined his procedurefor preparingthe liquid organic extracts. Then he proceededto reviewsystematically the data pertainingto the effects of kidney extract, liquid extract of the pancreas, hepatic extract, extracts of the sex glands, extracts of the vascularglands, and the serum of dog's blood. In his section on the "mode of action of the variousorganic liquids," he summarized:

Whena morbid state, as myxoedema, or a series of symptoms such as we see in cases of deficiency to the internal secretion of any gland, exists, it is very easy to understandhow the cure is obtained when glandularliquid extracts are used: we simply give to the blood the principle or principles missing in it . . . The great movement in therapeutics as regardsthe organic liquid extracts, has its origin in the experiments which I made on myself in 1889, experiments which were at first so completely misunderstood.65

One week after the concluding half of Brown-Sequard'spaper appeared,the BritishMedical Journal publisheda leadingeditorial entitled "Animal Extracts as TherapeuticAgents."66 The editors noted that "these experiments [of Brown-Sequard]have been publishedbefore in various Continental journals, and readers of our EPITOMEwill have noticed week by week abstracts of these, as well as those by other workerson the same lines." This comment confirmsthe generallack of such publicationsin Britain.They continued:

64. C.-E. Brown-S6quard, "On a New Therapeutic Method Consisting in the Use of Organic Liquids Extracted from Glands and Other Organs," Brit. Med. J., 2 (June 3 and 10, 1893), 1145-1147, 1212-1214. 65. Ibid., p. 1213. 66. "Animal Extracts as Therapeutic Agents," Brit. Med. J., I (June 17, 1893), 1279.

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It is now some years since Brown-Sequardannounced the wonderful effects which followed the subcutaneousinjection of testicular extracts as exemplified in his own person; and though manyjeered at him as the discoverer of perpetual youth, the notion has steadily gained ground that there is, after all, somethingin it. Since also, the success that has followed the injection of thyroid extract in myxoedema, we can hardly wonder that this belief has increased.67

Not only had belief in the efficacy of animal extracts as therapeutic agents increased,but the views of physiologists had been altered, too:

Physiologists have recently been making a number of observations which show that many organs do more than what was formerly regarded as their functions. The experiments . . . have led to the introduction of the expression "internal secretion." We think that this term is a rather unfortunately chosen one: but it, nonetheless, expresses that the organsin question have some action on the blood, and through it on the tissues generally,which influences their metabolic changes.68

Yet the editorial became increasinglyskeptical as, one by one, objections to the current fascination with organ extracts were raised. The modus operandi, as well as the chemical composition, of internalsecretions was yet undetermined.It was claimed that a temporarystimulant effect might well be expected from these extracts, which contained substances manufacturedby the organismitself. In myxoedema, "the curative result" had "justifiedthe method used." However,"fully gran- ting this," the editors still felt "compelled to doubt many of the other so-calledcures." They complained:

Manufacturingchemists are making extracts not only of the thyroid, but of nearly every organ in the body, even including the pituitary body, this last for the cure of acromegaly.We find medical men writing of these ideas and of the cures achieved in the most sanguine strain, and often upon no better evidence than quacks produce for their "cures."69 67. Ibid. 68. Ibid. The experiments cited were those of J. Rose Bradford on the kidney, Minkowski and von Mering on pancreatic diabetes, Langlois and Abelous on the adrenals, and Horsley and "others" on the thyroid. 69. Ibid.

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The editors explained that "these injections may be and often are extremely poisonous."70 They suggestedthat Massalongohad "hit the right nail on the head" in an article called "A New Phaseof Suggestive Therapeutics,"published in Riformamedica in February1893:

He found that in healthy animals testicularfluid had no effect; that in cases of disease the modifications are slight and transitory, and due to psychical tension and excitement; that in organicdisease the improvementis due to suggestionand the influence of the imagina- tion; and that such curative effects are best marked in cases of hysteria and neurasthenia,when there are expectations of relief, and that equally good results were here obtained by inert substances with equal facility.7"

Professor Brown-Sequardhad "unwittingly dropped" into "fallacies" that "the recent developmentsof Matteismshould have prepared[him] to guardagainst."72 Nonetheless, a wave of enthusiasmfor the use of animalextracts as therapeutic agents had already begun, and the British MedicalJournal could not really hope to turn the tide with its editorial. Only the introduction of a new kind of rigor for testing the effects of these extracts would effect a change. Massalongohad injected testicularfluid into healthy animals. Within the year, one means for measuringthe

70. Ibid. Brown-S6quard denied that the extracts were harmful when prepared properly; see Brown-Sequard and d'Arsonval, "Rejet dc l'emploi de tous les antiseptiques autre que la glycerine et l'acide carbonique pour la preparation des extraits organiques destin6s aux injections th6rapeutique sous-cutan6es," Comp. Rend. Soc. Biol., 9th ser., 3 (July 4, 1891), 5 35-5 36; and Brown-S6quardand d'Ar- sonval, "Innocuite6del'injection dans les sang d'extraits liquides du pancreas, du foie, du cerveau, et de quelques autres organes," Comp. Rend. Soc. Biol., 9th ser., 3 (October 24, 1891), 722-725. 71. These arguments are simular to those advanced by Putnam in the United States; see James J. Putnam, "Recent Observations on the Functions of the Thy- roid Gland; and the Relation of Its Enlargement to Graves's Disease; Also Re- marks on the Therapeutic Use of Sheeps' Thyroids and of Other Organic Ex- tracts' Boston Medical and Surgical Journal, 130 (February 8, 1894), 153-159. 72. Brown-S6quard refers to a brochure published in Paris in 1878 by a Dr. Mattei called "De la resorption de la liqueur seminale; de son action excitante sur l'homme et sur la femme;" see Brown-S6quard, "Nouveaux faits relatifs a l'injection sous-cutanee, chez I'homme, d'un liquide extrait de testicules de mammiferes," Achives de physiologie normale et pathologique, 5th ser., 2 (1890), 201-208. Presumably, it is to this work that the British Medical Journal was referring.

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DISCOVERY OF A SPECIFIC PHYSIOLOGICALRESPONSE TO ADRENALEXTRACT

Oliverand Schafer'sdiscovery of a specific physiologicalresponse to adrenalextract has been retold by Sir Henry Dale as one of those happy incidents of "accident and opportunism in medical research."7"Dale has argued that the discovery of the vasopressoreffects of adrenal extract was made "in circumstanceswhich, if not entirely accidental, had at least something of that character."76Although his account has served well to re-createthe sense of discoveryattendant upon the observation of a specific physiological response to the injection of adrenal extract into animals, it has also obscured the rational basis on which this investigation was originally undertaken.Oliver's decision to inves- tigate experimentallythe effects of organextracts on human beings was certainly motivated by good reasons: he expected to observea physiological responseto these fluids. In his account of the discovery, Dale did not explain that after 1889 physicians in France and abroad had become very interested in the therapeutic potential of extracts of animal tissues, and that Oliver's experiments with organextracts were by no means unique, especially in 1893. Physicians expected to find potent substances in extracts of animal tissues, and pharmacistsin Britainwere supplyingsuch extracts

73. Oliver practiced medicine in Harrogate between 1876 and 1908. His practicc was seasonal, and he spent the winter months in London. See Richard D. French, "George Oliver," in Dictionary of Scientific Biography, ed. C. C. Gillespie, X (New York: Charles Scribner's Sons, 1974), 204-206. I thank Dr. French for kindly allowing me to see the manuscript of this article prior to its publication. 74. Schafer succeeded John Burdon Sanderson as Professor of Physiology at University College in 1883. See Leonard Hill, "Sir Edward Albert Sharpey- Schafer, 1850-1935," Obituary Notices of Fellows of the Royal Society, I (1 932- 1935), 401-407; and Sir Charles Scott Sherrington, "Sir Idward Sharpey-Schafer and His Contributions to Neurology," Edinburgh Med. J., n.s., 42 (1935), 393- 406. 75. Sir Henry Dale, "Accident and Opportunism in Medical Research," Brit. Med. J., 2 (1948), 451455. 76. Ibid., p. 454.

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This content downloaded from 185.2.32.134 on Sat, 21 Jun 2014 01:04:35 AM All use subject to JSTOR Terms and Conditions MERRILEY BORELL to practitioners.In that very year the British MedicalJournal decried the excessive enthusiasm which had developed in Britain for organotherapy. It is significantthat the editors of the journaldid not question the theoretical assumptionsof Brown-Sequardand d'Arsonval.Rather, they were concerned about the effects of an uncriticaland unscientific applicationof those assumptionsto the practiceof medicine.Scientific medicine in Britain was threatened because organotherapywas becoming a fad. Eventually, adherents of "scientific" medicine were able to distin- guish themselves from the company of quacks and charlatansby speci- fying some of the physiologicalbases for these organotherapeuticcures. This specification came to be accomplishedas physiciansand physiologists leamed to measurethe effects of organ extracts by accepted physiological methods. Oliver and Schafer's discovery of the vasopressor effects of adrenalextract catalyzed this process. In the meeting of the clinician Oliver and the physiologist Schafer, one can observe a tension between two visions of what constitutes an adequate demonstrationof a new phenomenon.Oliver had observedan effect in a human subject. Schafer questioned that effect. It is this confrontation and complementationwhich constitutes the "accidental" circumstances which Dale related.7' Oliver and Schafer met in the autumn of 1893. Oliver, then a physician at Harrogate,went up to London to speak with Schafer, who was at that time Professor of Physiology at University College. He carried a vial of adrenalextract with him. Oliverhad been experimentingwith a variety of animalextracts. He had been giving these extracts by mouth to his son and measuringtheir effects on the circulationwith instrumentswhich he had designed. He believed that he had observed an effect with some of the extracts, and sought the advice of Schafer, who like himself had once been a student of WilliamSharpey (1802-1880) at UniversityCollege. Schafer described this encounter in 1908:

In the autumn of 1893 there called upon me in my laboratoryat UniversityCollege a gentlemanwho was personallyunknown to me, but with whom I had a common bond of interest - seeing that we

77. The tension between these two approaches constitutes a major theme in the history of endocrinology. The "crisis" of medical endocrinology which emer- ged in the 1920's effected a reevaluation of the relative merits of medical and physiological research for the progress of this field. Cf. Diana Long Hall, "Biolo- gy, Sex Hormones, and Sexism in the 1920's," Phil. Quart., 5 (1973-74), 84.

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had both been pupils of Sharpey,whose chair at that time I had the honour to occupy. I found that my visitor was Dr. George Oliver, already distinguishednot only as a specialistin his particularbranch of medical practice, but also for his clinical applicationof physiological methods. Dr. Oliver was desirous of discussing with me the results which he had been obtaining from the exhibition by the mouth of extracts of certain animal tissues, and the effects whiclh these had in his hands produced, upon the blood vessels of man, as investigated by two instruments which he had devised - one of them the haemodynamometer,intended to read variationsin blood pressure,and the other, the arteriometer,for measuringwith exact- ness the lumen of the radial or any other superficial artery. Dr. Oliver ascertained, or believed he had ascertained,by the use of these instruments, that glycerine extracts of some organs produce decrease in calibre of the arteriesand increase of pulse tension, of others the reverseeffect.7 8

Schafer recalled, in another summary written in 1908, that "amongst these [extracts] was extract of suprarenalcapsule, extract of thyroid gland, extract of brain, and so on."79 It is interesting that Oliver was using glycerine extracts, as Murrayhad done, and that, like many of his countrymen,he administeredextracts by mouth. One won- ders what other extracts had been tested by Oliver. One cannot help but suspect that these were far more numerousthan Schaferdeigned to mention in 1908, fifteen years after their first encounter. That Schafer was quite skeptical of Oliver's initial claims is clear from Dale's account of the discovery:

He [Oliver] went up to London to tell Professor Schafer what he thought he had observed, and found him engaged in an experiment in which the blood pressureof a dog was being recorded;found him, not unnaturally,incredulous about Oliver'sstory and very impatient

78. E. A. Schafer, "Oliver-Sharpey Lectures on the Present Condition of Our Knowledge Regarding the Functions of the Suprarenal Capsules," delivered before the Royal College of Physicians of London on April 7 and 9, 1908, Brit. Med. J., 2 (May 30, June 9, 1908), p. 1281. See also H. Barcroft and J. F. Talbot, "Oliver and Schafer's Discovery of the Cardiovascular Action of Suprarenal Ex- tract," Postgraduate Medical Journal, 44 (1968), 6-8. 79. Schafer's testimony before the second Royal Commission on Vivisection in British Parliamentary Papers, 57 (1908), 430; cited in French, "George Oli- ver," p. 205, and Sherrinton, "Sir Edward Albert Sharpey-Schafer," pp. 396-397.

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at the interruption.But Oliverwas in no hurry,and urgedonly that a dose of his suprarenalextract, which he producedfrom his pocket, should be injected into a vein when Schafer'sown experiment was finished. And so, just to convince Oliver that it was all nonsense, Schafer gave the injection, and then stood amazedto see the mercu- ry mounting in the arterial manometertill the recordingfloat was lifted almost out of the distal limb.80 Similarly,Schafer himself recalledin 1908: Although the conclusionswere interesting,it was easy to see that results which were obtained under mechanical conditions, which were somewhat complex and not easy of interpretation,could not be expected to decide an important physiologicalquestion of this nature, and that it was essential, in order to obtain exact knowledge of the actions, if any, of such extracts, to conduct the investigations with the employment of all means at the disposal of the modern physiologist. With the suggestionthat we should undertakesuch an investigationDr. Oliverpromptly agreed, and it was then and there arrangedto devote that winter to a thorough examination of the physiologicaleffects of such extracts. The result of this conjunction of effort, brought about by the fortunate chance forseen by old Montesquieu,speedily showed that, whilst many of the extracts which had been dealt with clinicallyby Oliver were inert or at any rate not specific in their action, the suprarenalcapsules, and to a lesser extent the pituitary body, yiel- ded to glycerine and to water and to saline solutions principles which have an extraordinaryeffect upon the tone of the heart and arteries,transcending that of any known drug.8' Schaferwas referringto Montesquieu'sremark of 1716 regardingthe then undetermined function of the adrenal glands: "Perhapschance may some day effect what all these careful labours[investigations sub- mitted for the prize of the Bordeaux Academy of Sciences] have been unable to perform."82 But it was certainly not chance which brought Oliver and Schafer together. At UniversityCollege, London, the clinic and the laboratorywere neververy widely separated.Oliver had sought verification for his clinical observationsin the physiologicallaboratory.

80. Dale, "Accident and Opportunism," p. 454. 81. Schafer, "Oliver-Sharpey Lectures," p. 1281. 82. Ibid. The question put to the applicants had been, "What is the use of the suprarenal glands?"

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On March 10, 1894, after a winter of collaboration, Oliver and Schafer presented their first report, "On the Physiological Action of Extract of the SuprarenalCapsules," to the PhysiologicalSociety. They had found that "the suprarenalcapsules yield to water (cold or hot), to alcohol or to glycerinea substancewhich exerts a most powerful action upon the blood vessels, upon the heart, and upon the skeletal muscles."83The extract caused an "extreme contraction of the arteries, so that the blood pressureis enormouslyraised," and an accelera- tion of the heartbeat after section of the vagi, as well as a modification of skeletal muscle contraction,when the extract was administeredintra- venously.8 4 Consideringthe widespreadinterest in organotherapyin 1894, it is no surprise to read at the conclusion of their paper: "We have also tested the effect of a clear watery extract obtained from Paris (in a sealed tube) and furnished to us by the kindnessof Dr. Hale White."85 Evidently, work in progressat Parishad not gone unnoticed in Britain, despite the silence of the major medical journals on this controversial topic. William Hale White (1857-1949) was physician to and Lectureron Materia Medica at Guy's Hospital.86 One year before this meeting of the Physiological Society, White's work on another organ extract had appearedin the British MedicalJournal. Assistedby F. G. Hopkinsand W. J. Harris,White had tried treatingdiabetic patients by feeding them raw pancreasor giving them subcutaneousinjections of a "liquor pancreaticus."8 '7 As White's furnishing of a French preparation of adrenal extract to Oliverand Schafer shows, some British physicianswere well aware of the continental work on organ extracts. It is unfortunate for the historian that Oliver and Schafer did not state which Parisianlabo- ratory had suppliedthis materialto White. Up until this point, that is, March 1894, British interest in thie effects of extracts of animal tissues had been more or less confined to clinicians, like Murrayand Oliver.Schafer, however, was a memberof a

83. Oliver and Schafer, "On the Physiological Action of Extract of the Su- prarenal Capsules," p. i. 84. Ibid., pp. ii-iii. 85. Ibid., p. iv. They reported, "The physiological effect of this solution, as to the mode of preparation of which we are wholly ignorant, proved to be precise- ly the same as that of our own extracts." 86. White's Materia Medica, Pharmacy, Pharmacology and Therapeutics was published in 1892. 87. White, "On the Treatment of Diabetes Mellitus."

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This content downloaded from 185.2.32.134 on Sat, 21 Jun 2014 01:04:35 AM All use subject to JSTOR Terms and Conditions MERRILEY BORELL tightly knit group of professionalphysiologists. By his influence, interest in the specific druglike effects of adrenal extract rapidly spread among his colleagues and students. Overthe next few years, physiological studies of the effects of a variety of organextracts began to appear with some frequencyin the Journalof Physiology. It is curious that there was no reference to the notion of internal secretion in Oliver and Schafer's first report, only the indication that adrenalextract contained a powerful drug.The significanceof this new observation for the general theory of internal secretions was rapidly noted. A year later, in 1895, Schafer delivereda majoraddress on the subject of internalsecretions.

RECOGNITIONOF THE PROBLEMOF INTERNALSECRETlONS

Schafer addressed the British Medical Association in London on August 2, 1895. It was the annual meeting of the association, and Schafer gave the "Addressin Phlysiology."He was then forty-fiveyears old, Jodrell Professorof Physiology at UniversityCollege, a Fellow of the Royal Society, and an active member of the PhysiologicalSociety. With his sanction, internal secretions became a problem of increasing importanceto Britishphysiologists. In his address, "On Internal Secretions,"88 Schafer defined a secreting organas "one which separatescertain materials from the blood and pours them out again, sometimes after effecting changeof some sort in them, usually upon external surfaces, or at least upon surfaceswhich are connected with the exterior."89 Those "secreted materialswhich are not poured out upon an external surface at all, but are returnedto the blood" are termed internalsecretions, "and they may be and are of no less importancethan the better known and more fully studied ordi- nary or external secretions."90 The secreting organ is called a gland; those secreting organs thought to possess only internal secretions are called "ductless glands." Schafer cautioned, "It is not, however, the ductless glands alone which possess the property of furnishinginternal secretions, for it is clear, according to our definition, that this will apply to any organof the body."91

88. Edward A. Schafer, "Address in Physiology on Internal Secretions," delivered at the annual meeting of the British Medical Association at London. August 2, 1895, The Lancet, 2 (August 10, 1895), 321-324. 89. Ibid., p. 321. 90. Ibid. 91. Ibid.

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Every part of the body does, in fact, take up materials from the blood. and does transform these into other materials.Having thus transformedthem they are ultimately returnedinto the circulating fluid, and in that sense every tissue and organof the body fumishes an intemal secretion.92

This is certainly the sense in which Brown-Sequardand d'Arsonval generalizedthe notion of internalsecretion in 1891. Schafer cited the liver, pancreas, and kidney as organs essential to life by virtue of their internalsecretions, that is, removalor "restriction of their internal secretions is inevitably followed by a fatal result."93 This effect did not occur after extirpation of other glands.The salivary or mammaryglands could be removed without "any markedsymptom intervening." Although "removal of the generative organs" led to "marked alterations in the development of other parts of the body," Schafer concluded, "the changesare without a doubt producedthrough the nervous system, and are not connected with the internal secretion of the glands."94 Here, by lack of direct comment, Schaferrejected Brown-S6quard's hypothesis regardingthe function of the sex glands. It is significantthat he did not comment on the numerous clinical studies which had been made with testicular and ovarianextracts. It is curious that he did not suggest the possibility of further study of sex glands physiology by means of experimentalgrafts. He simply dismissedthe idea that the sex glandsproduced internal secretions. In contrast, Schafer interpreted the data on the pancreasby reference to a hypothetical internalsecretion. Physiologistshad been led to conclude that the pancreassupplied an internal secretion to the body after Joseph von Mering (1849-1904) and Oscar Minkowski (1858-1931) reported, in 1889, that they had successfully extirpated the pancreas of dogs and produced experimental diabetes.95 Pancre- atectomy was followed by glycosuria,polyuria, and death. But it was possible to prevent the onset of these symptoms with grafts of pancreatic tissue, even when the secreting cells of these grafts had been

92. Ibid. 93. Ibid. 94. Ibid. 95. See J. von Mering and 0. Minkowski, "Diabetes mellitus nach Pankrcas- exstirpation," Archiv fur experimentelle Pathologic und Pharmakologie, 76 (1890), 371-387.

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destroyed by paraffininjection. Schaferargued from these observations that the islets of Langerhansprobably secreted an internalsecretion:

The only fact that appearscertain in connexion with tne manner in which the pancreasprevents excessive productionof sugarwithin the body is that this effect must be produced by the formation of some material,secreted intemally by the gland and probablyby the interstitial vascular islets, and that this internally secreted material profoundly modifies the carbohydratemetabolism of the tissues.96

The interpretationof the results of studies of the physiology of the thyroid gland was more controversial.Three theories had been advanced to account for the effects of thyroidectomy. First, some investigators held that "the effects of removal [of the thyroid] are entirely due to interference with the adjoining nervous structures in the neck."9 ' Schafer argued that this view was "absolutely negativedby the results of thyroid grafting." lt is worth noting that the theory of nerve-basedpathology correspondsto the one Schafer advancedto explain the results of castration. In that case, Schafer did not suggest grafting experiments, although in the case of the thyroid such grafts were sufficient to discount the neuralexplanation. Apparently, the data pertainingto the sex glands were being evaluatedby criteriasomewhat different from those appliedto studies of the other glands. The two theories that were offered as alternativesto the neural hypothesis were those of "autointoxication"and "internalsecretion." The autointoxication theory, which had been widely supported in France, held that the thyroid gland removed specific toxic substances from the blood, and that death upon removalof thiegland was due to the accumulationof the toxic substance(s).This view was supportedby experimental observation of the toxicity of the blood of thyroidectomized animals to normal animals or to those animalswhich had been thyroidectomized, but in which the symptoms of thyroid deprivation (cachexia strumipriva)had not yet developed.98 In contrast, the internal secretion theory explained "the phenomenon of extirpation as due to the absence of a secretion which is formed within the thyroid, and which is passedinto the blood, possibly throughthe medium of the

96. Schafer, "Address in Physiology on Internal Secretions," p. 322. 97. Ibid. Schafer credited this opinion to Munk, whom I have been unable to identify further. 98. See Abelous, "La physiologic des glandes a secretion interne."

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This content downloaded from 185.2.32.134 on Sat, 21 Jun 2014 01:04:35 AM All use subject to JSTOR Terms and Conditions Organotherapy,British Physiology, and the InternalSecretions lymphatics: a secretion which is necessary for certain of the metabolic processes witfin the body, and especially for those connected with the nutrition of the central nervoussystem and of the connective tissue."99 Schaferargued for the latter interpretationby pointing to the beneficial effects of thyroid juice following thyroidectomy and in the treatment of myxoedema. Moreover,he argued from the data of Oliverthat "the juice of the thyroid and extracts which are obtained from the gland have a distinct physiologicaleffect upon the vascularsystem."' 00 Thyroid extract had been observed to lower the blood pressure without immediately affecting the heart. Oliver had detected an increase in the caliber of the radialartery after administrationof thyroid juice. Schafer also cited the work of LorrainSmith,' 01 who had observed a rapid increasein carbonic acid production by thyroidectomized animals during cold stress. Schafer claimed that this response was due to the loss of vasomotor responses which normally prevent the rapid loss of heat from the body. The thyroid body was presumedto produce an internal secretion "which effects a useful purpose" in maintaining these responses.'02 Schafernoted:

Whether the gland also possesses the function of destroying toxic products of metabolism which would otherwise tend to accumulate in the blood is a point whiichrequires the production of more con- clusive evidence before it can be established.'0 3

Similarly, Schafer considered the pituitary body and showed that this gland "supplied an internal secretion which caused contraction of the heart's arteries."'04

99. Schafcr, "Address in Physiology on Internal Secretions," p. 322. 100. Ibid. Schafer was referring to data published in G. Oliver and E. A. Schafer, "On the Physiological Action of EIxtractsof Pituitary Body and Certain Other Glandular Organs. (Preliminary Communication)," J. Physiol., 18 (1895), 278. 101. Smith's earlier work concerned the study of the histological changes which followed thyroidectomy. The project Schafcr describes had been suggested by Hors- lcy. Smith was a John Lucas Walker Student in Pathology at Cambridge. See J. Lorrain Smith, "On Some t:ffects of Thyroidectomy in Animals," J. Physiol., 16 (1894), 378409. 102. Schafer, "Address in Physiology on Internal Secretions," p. 322. 103. Ibid. 104. A summary of thcsc comments was inserted by the editors; Schafer's complete comments on the pituitary were not published.

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Lastly, Schafer considered the "internalsecretion of the suprarenal bodies." He remarked:

Experimentsupon normal animalswith extracts of supra-renalhave been performed by a number of observers, but by all in a very incomplete manner. For the most part they have been satisfied to subcutaneouslyinject extracts made with water and other menstrua, and to observethe symptoms, if any, which result.' 05

The effects observedin this way were very variable,depending on the species of experimentalanimal used. Schafercontrasted these data with the new results that he and Oliver had achieved by focusing on "the physiological effects of intravenous injection of supra-renal extract."'0 6

They [these data] show conclusively that the medulla of the suprarenal capsule contains a dialysableorganic principle, soluble in water, and not destroyed by boiling for a short time, which producesa powerful physiologicalaction upon the muscularsystem in general, but especially upon the skeletal muscles, the muscularwalls of the bloodvessels, and the muscularwall of the heart. A certain amount of action is also manifested upon some of the nerve centres in the bulb, especially the cardio-inhibitorycentre, and to a small extent upon the respiratorycentre.' 0?7

Schafer described the specific physiological effects of this extract and comparedand contrastedits action with that of severalwell-known drugs - veratrin,curare, and atropine.'08 He concludedthat the effect of suprarenalextract was "an effect entirely different from the so- called autointoxication paralysiswhich is stated to resultafter removal of the suprarenalcapsules in animals and the materialwhich is extracted by water, therefore, from the supra-renalcapsules is certainly not the same material that is said to accumulate in the blood after the removalof those organs."'? 9

105. Schafer, "Address in Physiology on Internal Secretions," p. 322. 106. Ibid. 107. Ibid. 108. Over the next few years, internal secretions were often referred to as "drug-like" substances. 109. Schafer, "Address in Physiology on Internal Secretions," p. 322. Note

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Using standardvivisectional and pharmacologicaltechniques, Oliver and Schafer had shown that the effects of adrenalextract were unique. They had concluded that these effects were due "to the direct action of the extractive substance upon the muscular tissues of the smaller arteries."' 10 This substance was able to produce "very distinct physiological results" at a dosage of one-millionth part of a gram per kilogram of body weight. The conclusion necessarilyfollowed:

when we compare these resultsof suprarenalinjection with the con- verse effects obtained from the removalof the suprarenalsand from disease of suprarenals,we can come to no other conclusion than that we have before us a well-markedinstance of internal secretion., I

THE THEORY OF INTERNAL SECRETIONS: FOCUSING THE PROBLEMFOR RESEARCH

Schafer summarizedhis remarksto the British Medical Association with some general observations on the importance of continued re- searchon the subject of internalsecretions:

The generalresults to which we are led from a considerationof these facts, and others to which I have had no time so much as to allude, point strongly in favour of a theory of internal secretions, and it is obvious that such internal secretions may be of no less importance than the better recognisedfunctions of the external secretingglands. These internal secretions have to be definitely reckonedwith by the physician, while at the same time the therapeutist will be able to avail himself of the active principles which they contain, and in certain cases to use extracts of internallysecreting glands in place of the hitherto more commonly employed vegetable medicaments. That the subject has a vast future there can be no doubt, for, in spite of the advances which have been made in elucidating it during the last few years, a great number of points still remainobscure. Never- theless, the way which the physiologist had attempted to show may be followed by the practitioner,and the result of these physiological

that Schafer completely rejected the antitoxic theory of adrenal function, although he thought the theory might explain thyroid physiology. 1 10. Ibid. 111. Ibid.$ p. 324.

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experimentsmay now be utilised for the diagnosisand treatmentof disease.' 12

What did Schafer mean by "the way which the physiologist had attempted to show"? Whydid he raisethe notion of internalsecretions to the status of a theory in this address? In his discussion of the concept of secretion, both internal and external, and in his considera- tion of the role of the metabolic productsof animaltissues, there is no departure,major or minor, from the views advancedby Brown-Sequard and d'Arsonvalin 1891. Whathad changed? By 1895, "intemal secretions"seem to have acquireda new status in physiologicaltheory becauseof the direct applicabilityof the notion of internal secretion to the interpretationof recently accumulateddata on the physiology not only of the liver, pancreas,and kidney - all glands with ducts - but also of the thyroid gland, the pituitarybody, and the suprarenalbodies - all ductless glands. These data derived principally from the extirpation and transplantationexperiments performed by surgeonsfrom the 1880's on. Extracts of organs came to be advocated as a rational substitute for transplantedorgans. This line of reasoning was strongly reinforcedby the findingthat thyroidjuice was successful in alleviatingthe symptoms of thyroid deprivation,both in experimental animalsand in individualssuffering from thyroid disease. In 1889, Brown-Sequardhad advocated the use of testicularextract for the treatment of debilitating and nervous diseases because of the deductions he had made from generallyaccepted ideas of human sexuality. He had generalized this mode of replacementtherapy in 1891 because of the strong analogies he perceived between the glandular organs and because of his conviction that all living cells probably se- crete useful products. He saw this mode of therapy - injection of extracts of animaltissues - as being potentialiy useful in diseaseswhose etiology was unknown, but whose pathology was correlated with a particulartissue or organ. Brown-S6quardand d'Arsonval'sadvocacy of this form of therapy was based on clinicalgrounds, but it came to have a physiological basis as data on the thyroid, pancreas, and adrenal glandsaccumulated in the early 1890's. Schafer'sadvocacy of the theory of internalsecretions was basedon this new physiologicalevidence. These new data concernedthe specific effects of organ extracts on experimental animals in the laboratory, effects which were measurableby common physiologicalmethods and

112. Ibid.

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This content downloaded from 185.2.32.134 on Sat, 21 Jun 2014 01:04:35 AM All use subject to JSTOR Terms and Conditions Organotherapy,British Physiology, and the InternalSecretions capable of being contrasted with effects of drugs well known to the experimentalphysiologist. The question of the cure of a disease by an extract was thus circumventedand, for a time at least, put aside. The precise physiological effects of an extract could be recognized and studied by an appropriateprocedure in the laboratory. One no longer had to deal with the question of cure by suggestion.When the modus operandi of the internal secretion was understood,amelioration or per- haps even a cure could be effected. This was "the way which the physiologist [had] attempted to show." This was rational, scientific medicine.

EPILOGUE

By 1895 physicians and physiologists alike were searchingfor internal secretions in animal tissues, and therapeuticand physiological studies were undertakenside by side. Often the two kinds of data conflic- ted. For example, extirpation and graftingexperiments suggested that the islet cells of the pancreasprobably produced an internalsecretion. Nonetheless, extracts of the pancreaswere ineffective in the treatment of diabetes both in human beings and in experimentalanimals. Similar- ly, physical changes supervening after extirpation of the testes and ovaries suggestedthat the sex glands might elaborate these substances. Yet many physicians questioned the cures claimed to have been effected by a course of treatment involving extracts of these glands, and satisfactory biological assays for evaluatingthe plhysiologicaleffects of these extracts had not yet been determined. As a consequence, expec- tation and evidence were often in conflict. Over the next few years, Schafer and his students and colleaguesat University College attempted to specify the criteria for evaluatingthe potency of animal extracts by determining the precise physiological and pharmacologicaleffects of extracts of varioustissues. Their success was limited. They souglhtto measure changes in blood pressure and heart rate, yet many of the presumptiveinternal secretions were not detectable by these methods. For many years, clinical observationscon- tinued to motivate the repeated testing of these extracts. Nonetheless, Oliver and Schafer'sobservations focused scientific attention on internal secretions, demonstratingthat such substances did exist and that one could indeed measuretheir physiologicaleffects. By the turn of the century, the "theory of internal secretions," as Schafer called it, had come to represent a fruitful way of examining a hitherto unexplored problemin animalphysiology.

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In the next decade, the problem regardedas being associated with intemal secretions gradually changed from that of the mechanismof the regulationof metabolismin the body to that of the mechanismof cellular communicationby means of chemical messengers.This change in problemperception was accomplishedby the work of WilliamBayliss (1860-1920) and Ernest Starling (1866-1927), both colleagues of Schafer in the PhysiologicalSociety and affiliates of UniversityCollege. A new word, hormone, was then coined to denote this change.

Acknowledgments

This paper is based on Chapter 3, "From Therapeuticsto Physio- logy," of my doctoral dissertation,"Origins of the HormoneConcept: Internal Secretions and PhysiologicalResearch, 1889-1905." I wish to thank Dr. GeorgeRosen for his encouragementand counsel throughout this study. I am also indebted to ProfessorsJoseph S. Fruton, Diana Long Hall, and Nancy Maull for their detailed comments on earlier drafts of this manuscript.I also gratefully acknowledgesupport of the Josiah Macy, Jr. Foundation. Aspects of this paper were presentedat the History of Science Society's annual meeting in Atlanta, December 29, 1975.

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