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 MELLON LECTURE 
 
 (UNDER THE AUSPICES OF THE SOCIETY FOR BIOLOGICAL RESEARCH) 
 UNIVERSITY OF PITTSBURGH 
 
 FIRST LECTURE 
 
 EXPERIMENTAL AND CHEMICAL STUDIES 
 OF THE BLOOD WITH AN APPEAL FOR 
 MORE EXTENDED CHEMICAL TRAIN- 
 ING FOR THE BIOLOGICAL AND 
 MEDICAL INVESTIGATOR 
 
 BY 
 
 JOHN J. ABEL 
 
 1915 
 
EXCHANGE 
 
 BIOLOGY 
 LIBRARY 
 
EXPERIMENTAL AND CHEMICAL STUDIES 
 OF THE BLOOD WITH AN APPEAL FOR 
 MORE EXTENDED CHEMICAL TRAIN- 
 ING FOR THE BIOLOGICAL AND 
 MEDICAL INVESTIGATOR 
 
 BY 
 
 PROFESSOR JOHN J. ABEL, M.D., M.A., Sc.D. 
 
 PROFESSOR OF PHARMACOLOGY IN THE JOHNS 
 HOPKINS UNIVERSITY 
 
 DELIVERED ON THE OCCASION OF THE OPENING OF THE 
 
 MELLON INSTITUTE FOR INDUSTRIAL RESEARCH ON 
 
 THE EVENING OF SATURDAY, FEBRUARY 27, 1915 
 
MELLON LECTURE 
 
 (UNDER THE AUSPICES OF THE SOCIETY FOR BIOLOGICAL RESEARCH) 
 UNIVERSITY OF PITTSBURGH 
 
 FIRST LECTURE 
 
 EXPERIMENTAL AND CHEMICAL STUDIES 
 OF THE BLOOD WITH AN APPEAL FOR 
 MORE EXTENDED CHEMICAL TRAIN- 
 ING FOR THE BIOLOGICAL AND 
 MEDICAL INVESTIGATOR 
 
 BY 
 
 JOHN J. ABEL 
 
 1915 
 
A3 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE 
 BLOOD: WITH AN APPEAL FOR MORE EXTENDED 
 CHEMICAL TRAINING FOR THE BIOLOGICAL AND 
 MEDICAL INVESTIGATOR 
 
 JOHN J. ABEL, . 
 
 Professor of Pharmacology in the Johns Hopkins University 
 
 Before beginning my address let me say that I feel it to be a 
 very great honor to have been asked to deliver the first Mellon 
 Lecture under the auspices of the Society for Biological Research 
 of this University. The establishment of a lectureship of this 
 character is a great encouragement to men of science. It affords 
 additional opportunity to bring to the attention of a wider pub- 
 lic the recent results of scientific investigation as well as to 
 emphasize again a truth which can not be too often repeated 
 "that science constitutes a sure and lasting part of the intellec- 
 tual treasure which mankind possesses." 1 
 
 I have ventured to take as the subject of my address some 
 recent experimental and chemical studies of the blood. In 
 order to give my subject a pfoper setting I must, first, refer 
 briefly -to the history of blood letting, and to make clear its 
 relation to pressing medical problems, I shall in the hour discuss 
 the interaction of the blood and the organs of internal secretion. 
 
 The overwhelming significance of the blood to all people in 
 all times is shown in folk sayings, in tradition and in literature. 
 The expressions, "the life of the flesh is in the blood," "tainted 
 blood," "blood wiU tell," "blood oath," "blood brother," all 
 suggest how nearly blood has been held to be synonymous with 
 life. It was an ancient Celtic custom to emphasize the inviola- 
 bility of a treaty by having it written with the blood of both 
 clans mixed in one vessel. 
 
 In the earlier systems of medicine, as those of Asiatic coun- 
 tries, of Egypt and of Greece, alterations in the composition 
 
 1 Ostwald. 
 
 384741 
 
4 e , i ^JOHN J. ABEL 
 
 of the blood were held to be of great significance. In Hippocratic 
 medicine the- right admixture of the four humors, the blood, 
 phlegm, yellow bile and black bile constituted health while 
 wrong proportions or distribution caused disease. This humoral 
 theory of disease, variously modified down to our own time, has 
 always fitted in well with the practice of blood letting, or making 
 running issues, and with other depletory measures. 
 
 Blood letting seems, however, to antedate all systems of medi- 
 cine and to have been one of the earliest therapeutic procedures 
 applied by primitive races. Leeches have been used for this 
 purpose since the earliest tunes in Asiatic countries, especially 
 in India, and let no one suppose that their use has been discon- 
 tinued in our day. Dr. Shipley, the master of Christ's College, 
 Cambridge, writing in the British Medical Journal 2 tells us that 
 the Allies and Germans are now fighting on some of the best 
 leech areas of Europe and goes on to state that the traffic in leeches 
 probably reached its height in the first half of the nineteenth 
 century, that for instance in the year 1832, 57^500,000 of these 
 annelids were imported into France, 60,000 to 80,000 leeches a 
 day frequently leaving Strassburg for Paris, having been shipped 
 overland from Hungary via Vienna. So great was the demand 
 that the artificial cultivation of leeches was taken up in various 
 countries and became a profitable industry. And now a new 
 use for leeches has arisen. Certain glands surrounding the oral 
 end of the digestive canal of this annelid secrete a remarkable 
 substance which keeps blood from coagulating and which has 
 been named hirudin. This substance is much used in our labora- 
 tories to keep the blood of man and animals in the fluid state. 
 Leeches have thus become an article of commerce quite aside 
 from their employment as depleting agents and the demand is 
 constantly growing. We are at present greatly hampered by 
 our inability to obtain them from Europe, as their importation 
 has practically ceased since the outbreak of the war. 
 
 2 No. 2813, November 28, 1914, p. 917, and No. 2814, Decembers, 1914, p. 962. 
 These papers contain much valuable information concerning the medicinal 
 leech as also the curious history of exotic leeches which in certain eastern coun- 
 tries constitute a serious menace to the life of men and animals. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 5 
 
 It is not my purpose to attempt to give a history of blood 
 letting, even in abstract; the history of the subject is practically 
 co-extensive with the history of medicine itself. I must therefore 
 content myself with a few selections from historical writing which 
 will demonstrate to you that the influence of this method of treat- 
 ing disease has been paramount since long before the time of 
 Hippocrates whose writings furnish one of the earliest prescrip- 
 tions for blood letting beginning with the direction to "Bleed 
 in the acute affections, if the disease appears strong, and the 
 patients be in the vigor of life, and if they have strength." 
 
 In the latter part of the twelfth century, when universities 
 as we now know them were coming into existence, there originated 
 in the School of Salernum the Regimen Sanitatis Salerni, or Code 
 of Health, a poem written in Latin hexameter verses and giving 
 the medical notions of the day, as derived from the Arabic 
 writers in regard to blood letting, diet and personal hygiene. 
 The high value placed on the Regimen may be seen from the 
 fact that it passed through some 240 different editions and was 
 translated into all the known languages. 3 In general praise of 
 blood letting the poem says: 4 
 
 Bleeding the body purges in disguise, 
 
 For it excites the nerves, improves the eyes 
 
 And mind, and gives the bowels exercise, 
 
 Brings sleep, clear thoughts, and sadness drives away, 
 
 And hearing, strength, and voice augments each day. 
 
 Other verses give directions as to what months are proper 
 and what improper for bleeding, tell what diseases are benefited 
 by blood letting and in what quantities blood should be drawn, 
 and the effect of age and other circumstances. 
 
 Acute disease, or only so in part, 
 Demands blood letting freely from the start, 
 In middle age, bleed largely without fear 
 But treat old age like tender childhood here. 
 
 3 Garrison: The history of blood letting, N. Y. Med. Journ., March 1 and 8, 
 1913. 
 
 4 Professor John Ordronaux's translation. 
 
6 JOHN J. ABEL 
 
 In the latter part of the middle ages blood letting was carried 
 to great excess. During this period astrology strongly influ- 
 enced medical thought, and physicians made diagnoses and bled 
 their patients according to the position of the planets, constella- 
 tions and single stars (horoscopic medicine). For their greater 
 convenience semi-popular calendars were even prepared with 
 illustrations such as the so-called venesection manikins of Johann 
 Nider von Gemlind (1470) and of Stoeffler (1518) with direc- 
 tions as to the vein to be opened for the cure of each malady. 
 Figures 1 and 2 are reproductions of old plates showing some of 
 these blood letting and wound-men. 5 
 
 In the sixteenth and seventeenth centuries we come upon 
 heated controversies between the upholders of the Hippo- 
 cratic and of the Arabian theories of blood letting. By the former 
 method it was thought that the vein to be opened should be as 
 near as possible to the diseased part in order that the "foul and 
 stagnant" blood might be directly removed from the inflamed 
 area ("Derivation"). On the other hand, the doctrine elabor- 
 ated by the Arabians taught that blood should be taken from a 
 vein remote from the inflamed part, for instance, in inflamma- 
 tion of the lungs and pleura, from the arm or even the foot of 
 the opposite side with the idea that this process ("Revulsion*') 
 prevented good blood from accumulating in the diseased part. 
 
 This latter doctrine was in the ascendancy in European coun- 
 tries in the sixteenth century, but the learned Pierre Brissot, 
 (1478-1522) basing his opinion on his own large clinical experi- 
 ence in Paris in 1514 when an acute affection of the lungs was 
 prevalent, revived the Hippocratic method of bleeding and 
 thus started the famous Brissot-venesection controversy in which 
 most of the great men of the century, including Vesalius, took 
 part. The importance attached to the controversy at the 
 tune is shown in the fact that the opponents of Brissot induced 
 the French Parliament to forbid the practice of his method, and 
 their attacks were so bitter as virtually to drive him from Paris 
 
 6 Figure 1 is taken f rom Heinrich Stern' s Theorie und Praxis derBlutentziehung, 
 Wurzburg, 1914. Figure 2 from Garrison: The history of blood letting, N. Y. 
 Med. Journ., March 1 and 8, 1913. 
 
FIG. 1. ADERLASS-MANNCHEN AUS STOEFFLER, CALENDARIUM ROMANUM 
 
 MAGNUM. OPPENHEIM 1518. FOL. 14. 
 
 The numbers indicate the points at which veins are to be opened for this or 
 that disease. 
 
 FIG. 2. SPECIMENS OF THE Lasstafelkunst (Horoscopic Medicine or Judicial 
 
 Astrology). 
 
 B: Blood-letting man (Aderlassmann), from the Calendar of Regiomontanus 
 (1475), showing the points of election for blood-letting under the signs of the 
 Zodiac. C: Wound-man (Wundenmanri) , from Gersdorff's Feldtbuch (1517), show- 
 ing the sites for ligation of the different arteries or for blood-letting. C is a 
 later evolutionary form of the old zodiacal diagrams, which combined an expo- 
 sition of planetary influences with schemata of the viscera (B). 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 7 
 
 and his professorship. Haeser 6 informs us that the quarrel 
 assumed such violence that when the University of Salamanca 
 took sides with Brissot, the Emperor Charles V who was called 
 on to render a "decision" in the matter was assured that the new 
 false doctrine was no less dangerous than the heresy of Luther. 
 While Brissot was anything but a "therapeutic nihilist" 
 as to bleeding and held firmly to the doctrine that the "foul 
 blood" of the inflamed area should be removed, some of his fol- 
 lowers rejected bleeding altogether in acute disease of the lungs 
 and pleura (the pleuritis of that day). Their moderation was 
 looked upon as little less than heretical and toward the end 
 of the sixteenth century we find Leonardo Botallo, a Piedmon- 
 tese, an eminent practitioner of his time, chief physician to Charles 
 IX, advising venesection to the limit regardless of the nature of 
 the disease, the age or condition of the patient. Blood lettings 
 of 3-4 pounds each repeated as often as four or five tirnes were 
 advised, says Haeser, and this historian adds that the explana- 
 tion of this "Vampyrismus" is probably to be found in the 
 circumstance that Botallo lived in northern Italy where diseases 
 of an inflammatory character were prevalent and more especially 
 that in his experience as an army surgeon he encountered only 
 patients of the most robust type. Botallo, in defending his 
 practice said, "the more foul water is drawn from a well, the 
 more good water can flow in to replace it." 7 An ardent follower 
 of Botallo was Riolan the younger who falls back upon Hippoc- 
 rates and Galen and lays down the rule that one must take away 
 as much blood as possible in every disease. As an adult is 
 judged to have about 30 pounds of blood 8 (!) the tapping of half 
 this amount, or 15 pounds, in the course of 14 days would be 
 about the right amount to take, says Riolan. Guy Patin (1602- 
 1672), himself an ardent bleeder and purger, informs us that 
 Bovard, body physician of Louis XIII, bled that monarch 47 
 times, gave him 312 clysters and prescribed emetics and purges, 
 215 times all in one year. 
 
 6 Geschichte der Medicin, vol. 2, p. 64. 
 
 7 Bauer: Geschichte der Aderlasse, Gekronte Preisschirft, Munich, 1870. 
 
 8 Bauer: loc. cit., p. 139. 
 
8 JOHN J. ABEL 
 
 A little later, that able and credulous Belgian mystic and 
 follower of Paracelsus, J. B. Van Helmont (1578-1644), an icono- 
 clast in general, called by his admirer, Haeser, "the fist of the 
 seventeenth century," went so far as to condemn venesection 
 entirely. To him is attributed the often quoted phrase "a bloody 
 Moloch presides in the chair of medicine." 
 
 Also as holding that in place of excessive blood letting should 
 be substituted therapeutic procedures ("Alterantia") and change 
 of diet, stands the genial and talented Franciscus de le Boe (Syl- 
 vius) (1614-1672), one of the leading medical authorities of the 
 seventeenth century and one of the earliest defenders of Har- 
 vey 's doctrine of the circulation, who taught at Ley den that 
 abnormal fermentations in the fluids of the body cause disease 
 a variant of the ancient humoral doctrine. In Chapter XX of 
 his "New Idea," (translated by Richard Gower, London, 1675) 
 entitled "On the Motion of Blood through the Lungs Affected," 
 he shows his good sense and his caution, when he says: 
 
 A Plethora of Blood is soon and safely Cur 'd, by a sufficient Empty- 
 ing of it by opening a Vein; whether it be together and at once, or by 
 repeted turns, according to the peculiar nature and strength of the 
 Sick. For there are many who cannot bear to have much taken away 
 together, but soon fall into a Swouning; by which seeing none can at 
 any time receive any good, I had rather th^t it should be prevented, 
 as often as may be, and every Cure be done securely rather than rashly, 
 seeing it often happens to those rash Blood Letters, that they educe 
 Life together with Blood." 
 
 An instance of lavish blood letting in a medical crisis may be 
 found in the experience of that adventurous spirit, Thomas 
 Dover, to whom we owe the much used "Dover's powder." 
 In 1708, Dover, then 48 years old, set out on a privateering 
 expedition and was given command of a ship, the Duke, while 
 his superior, Captain Woodes-Rogers, took command of the 
 other ship of the squadron, the Duchess. The three years' 
 voyage of these buccaneers is of interest historically because 
 "touching at the island of Juan Fernandez, they took on board 
 Alexander Selkirk who had lived alone on the island for four 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 9 
 
 years and four months, and whose story was to develop in the 
 skilful hands of Defoe into that of the immortal "Robinson 
 Crusoe." 9 In Dover's "Ancient Physician's Legacy to his 
 Country/' we find the following interesting passages: 
 
 When I took by Storm the two Cities of Guaiaquil, under the Line, 
 in the South Seas, it happened, that not long before, the Plague had 
 raged amongst them. For our better Security, therefore, and keep- 
 ing our People together, we lay in their Churches, and likewise brought 
 thither the Plunder of the Cities:, ... In a very few days after 
 we got on board, one of the Surgeons came to me, to acquaint me, that 
 several of my Men were taken after a violent Manner, with that Langour 
 of Spirits, that they were not able to move. I immediately went among 
 them, and, to my great Surprise, soon discerned what was the Matter. 
 In less than Forty-eight Hours we had in our several Ships, one Hun- 
 dred and eighty Men in this miserable condition. 
 
 I ORDER'D the Surgeons to bleed them in both Arms, and to go 
 round to them all, with Command to leave them bleeding till all were 
 blooded, and then come and tie them up in their Turns. Thus they 
 lay bleeding and fainting, so long, that I could not conceive they lost 
 less than an hundred Ounces each Man. 
 
 If we had lost so great a Number of our People, the poor Remains 
 must infallibly have perished. . . . We had on board Oil and 
 Spirit of Vitriol sufficient, which I caused to be mixed with Water to 
 the Acidity of a Lemon, and made them drink very freely of it; so that 
 notwithstanding we had one hundred and eighty odd down in this 
 most fatal Distemper, yet we lost no more than seven or eight; and 
 even these owed their Deaths to the strong Liquors which their Mess- 
 Mates procured for them. . . Now if we had had Recourse to Alexi- 
 pharmicks, such as Venice Treacle, Diascordium, Mithridate, and 
 such-like good-for-nothing Compositions, or the most celebrated 
 Gascoin's Powder, or Bezoar, I make no Question at all, considering 
 the heat of the Climate, but we had lost every Man. 
 
 Of non-medical literature the satire of Gil Bias, written early 
 in the eighteenth century but in reality giving a picture of 
 seventeenth century excesses in blood letting, is worth citing. 
 
 Dr. Sangrado is called in to prescribe for a gouty old canon, 
 and he at once sends for a surgeon and orders him to "take 6 
 
 9 Chronicles of Pharmacy, Wootton, ii, p. 130. 
 
10 JOHN J. ABEL 
 
 good porringers of blood in order to supply the need of perspira- 
 tion." The surgeon was ordered to return in three hours and 
 take as much more and to repeat the evacuation the next day. 
 The patient was "reduced to death's door in less than two days, 
 and the notary being summoned to make the will seized his 
 hat and cloak in a hurry when he learned from the messenger 
 Gil Bias, that Dr. Sangrado was the physician. "Zooks," 
 cried he, "let us make haste, for the doctor is so expeditious 
 that he seldom gives the patient time to send for notaries ; that 
 man has choused me out of a great many jobs." 
 
 But the misuse of bleeding continued in the centuries fol- 
 lowing and at no time was the practice more abused than in the 
 latter part of the eighteenth or even in the first five decades of 
 the past century. French and Italian authorities especially, 
 were great believers in blood letting. Broussais (1772-1832) 
 is said to have used 100,000 leeches in his hospital wards in 
 one year. This physician and his follower, Bouilland, actuated 
 by false theories of the cause of fevers, recommended the bleed- 
 ing of a patient' 10 to 12 and even 20 times in the course of 
 treatment. 
 
 But more and more the opponents of general and excessive 
 bleeding made headway in their respective countries. Many 
 are the names that might here be named, as Pinel, Andral, 
 Louis in France, Dietl, the pupil of Skoda, and Wollstein the 
 professor of veterinary medicine in Vienna, Mezler, Rademacher, 
 von Pfeufer and others in Germany, Marshall Hall 10 and later 
 Sir William Jenner, Sir William Gull, Bennet and others in 
 England, Strambio, Angeli, Meli in Italy, and Jackson in our 
 own country, and many others in all of these countries. 
 
 But what finally led to the entire abolition of bleeding after 
 the middle of the past century was not so much the opposition 
 of clinicians who failed by its use to abort pneumonia, ("the 
 queen of inflammations," as Dietl calls it), or some other acute 
 
 10 < <\yhile Marshall Hall favored venesection he was one of the earlier and 
 important members of the profession to throw doubt upon indiscriminate blood 
 letting." D'Arcy Power: Dr. Marshall Hall and the decay of blood letting, 
 The Practitioner, 1909, vol. 32, p. 320. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 11 
 
 disease, but the rise of new theories of disease, based on discoveries 
 of fundamental importance. The rise of the cell-theory and of 
 cellular pathology, the discovery of bacteria and their con- 
 nection with the inflammatory processes of the infectious diseases, 
 the appearance of hydrotherapy, the expectant medicine of the 
 school of Skoda and Oppolzer, new and quicker methods of ob- 
 taining the effects of drugs as by means of the hypodermic 
 syringe, the discovery of new hypnotics, of the analgesics and 
 anaesthetics, altered the views of medical theorists and practi- 
 tioners alike and inevitably led to the downfall of the theories 
 on which venesection has been based. 
 
 During a period of study of six and a half years, (1884-1891) 
 as a student of chemistry and medicine in several of the 
 larger medical centers in Germany, Austria and Switzerland, 
 I never once saw a patient bled in clinic or hospital. The pro- 
 cedure may have been employed now and then but so little 
 stress was laid upon it that it was not thought worth while to 
 demonstrate it to the young men who walked the wards. 11 
 
 Bleeding did not disappear, however, from the world. The 
 common man, especially in Germany and France, still held 
 firmly that benefits did follow the use of the wet cup, the lancet 
 and the leech. Tenaciously the old practices were upheld. If 
 physicians refused to bleed, there was always the barber sur- 
 geon, fully competent, as in teeth pulling, to give relief. I 
 remember that in my boyhood in Ohio the practice of blood let- 
 ting in the spring of the year was in vogue among the farm 
 laborers from southern Germany. After their return from a 
 visit to the barber surgeon in the town the scarified backs were 
 exhibited as a special favor, and irrefutable arguments advanced 
 
 11 See also F. de Havilland Hall: The Westminster Hospital Reports, Vol. 
 xvii, p. 1, 1911, who makes the following statement in a clinical lecture on blood 
 letting: "To such an extent had bleeding been discarded that during my student 
 days at St. Bartholomew's Hospital, I never heard of a patient being bled, so 
 that I was quite taken back, when, shortly after I was appointed house surgeon 
 at a country hospital, the senior surgeon came to me to be bled. Indeed in 1892 
 when I requested a member of the surgical staff at St. Bartholomew's to bleed a 
 patient for me, he told me that this was the first time he had ever been called upon 
 to perform phlebotomy." 
 
12 JOHN J. ABEL 
 
 in respect to the benefits of bleeding either to ward off disease or 
 to improve nutrition. Was it not true and known to all stock 
 breeders that the domestic animals could be fattened by judi- 
 cious bleeding at certain fixed intervals? 
 
 And it appears now that the common man was right after all. 
 An empirical method of treatment which has been practiced 
 by nearly all races since before the day of Hippocrates almost 
 certainly contains a basis of truth. This is now admitted, and 
 physicians are again saving lives by the judicious and timely 
 use of blood letting. Says the experienced Sir T. Lauder Brun- 
 ton: "Blood letting not only relieves symptoms but may save 
 the patient's life, as in engorged conditions of the right heart, 
 whether due to mitral incompetence or pulmonary affections." 12 
 In puerperal eclampsia, to mention but one more instance, we 
 also have a condition which is generally strikingly benefited by 
 blood letting. 13 
 
 Venesection, then, will probably never again be entirely ex- 
 cluded from medicine, as it was during the last quarter of the 
 past century, nor need we fear that the practice will be again 
 misused. 
 
 I. PLASMAPHAERESIS 
 
 But venesection, like all therapeutic procedures, has cer- 
 tain drawbacks which prescribe limits to its use and these draw- 
 backs are inherent in the very composition of the blood and in 
 the nature of the circulatory apparatus. As is known to all 
 the oxygen-carrying power of the blood resides in the red cor- 
 puscles, or erythrocytes, which constitute about 36 per cent of 
 the volume of the blood. These erythrocytes, like other cellular 
 constituents, can be built up only slowly in the body by the 
 
 12 On the use of leeches in relieving overdistension of the right heart, in cases 
 of pneumonia see D. B. Lees, Lancet, February 25, 1911. Also for cases in which 
 blood letting (either by venesection or by means of leeches), may be advan- 
 tageously employed, see F. de Havilland Hall; Westminster Hospital Reports, 
 vol. 17, p. 1, 1911. 
 
 13 See Zweifel: Zur Behandlung der Eklampsie, Centrabl, f. Gynakologie, 
 1895, No. 46. Alexander Strubell: Der Aderlass, eine monographische Studie, 
 Berlin, 1905. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 13 
 
 haemapoietic, or blood building, organs. It is apparent, there- 
 fore, that the bad effects of overbleeding, as formerly practiced, 
 might be due mainly to the loss of these cellular elements. Com- 
 mon experience has shown that the loss of too much blood is 
 either immediately fatal, or else is followed by a prolonged ill- 
 ness, recovery from which is often doubtful. 
 
 Reflecting on these drawbacks I conceived the idea that the 
 main objection of blood letting could be obviated by the speedy 
 return into the body of the red and the white corpuscles instead 
 of throwing them away as hitherto has been our custom. The 
 only thing that would be removed from the blood of a person 
 bled in this way would be its fluid part the plasma. If this 
 method were found to be practicable the value of bleeding would 
 be enhanced and its field of application extended. Such a 
 method, if successful, would appear to be advantageous for the 
 patients, not only in those instances in which venesection is 
 performed, admittedly with good results, but would also open 
 the way for the withdrawal of fluid when it is desired to decrease 
 the volume of blood in the vascular apparatus or to remove ex- 
 cess of deleterious substances, or where bleeding has hitherto 
 been contraindicated because of the danger of reducing the 
 oxygen-carrying capacity of the blood, as, for example, in aneur- 
 ism, or in cardiac decompensation with a low blood count. 
 
 In the work now going on in my laboratory, we are still in the 
 stage of experimentation and study, but our experiments on ani- 
 mals have proved the feasibility of the method. With the 
 skillful cooperation of my colleagues, Drs. Rowntree, Turner, 
 Marshall and Lamson, a considerable number of experiments 
 on animals have already been made. Our procedure, in a word, 
 is the following. Blood is withdrawn freely from an animal and 
 is prevented from clotting by addition of leech extract; Locke's 
 fluid in equal volume is then added to the blood, and the mixture 
 is sedimented in the centrifugal machine until the corpuscles 
 have settled out in the flasks. The supernatant plasma is then 
 drawn off and replaced by Locke's fluid, the corpuscles are 
 stirred up and the new mixture is returned to the animal. By 
 repeating this process it has been learned that blood letting can 
 
14 JOHN J. ABEL 
 
 be carried out repeatedly, without endangering the life of an 
 animal provided only that the cellular elements of the blood 
 are returned. We have named the procedure plasmaphaeresis. 
 
 It is apparent that when blood letting is practiced in the 
 usual way there is always the risk of greatly reducing the oxy- 
 gen-carrying capacity of the blood through loss of red corpuscles, 
 but in our experiments the fluid of the blood can be withdrawn 
 in large quantities without affecting this capacity, as far as we 
 can determine at the present moment. Just how large quan- 
 tities of plasma can be withdrawn without permanent injury 
 cannot at present be stated. In certain cases very large amounts 
 have been successfully removed in experiments extending over 
 several days. We have actually withdrawn from a dog by 
 repeated bleedings in a single day, a volume of blood more than 
 twice that contained in the body, with no apparent injury, 
 by our method of returning the corpuscles after each bleeding. 
 How far this exceeds the quantity of blood that may be safely 
 removed from a dog at one time without return of corpuscles 
 is seen when we recall that the loss at one time of 60 to 70 per 
 cent of the animal's blood is quickly fatal. 
 
 It may yet be possible to attach an electrically controlled 
 centrif ugalizing apparatus directly to the blood vessels of an 
 animal and tap off a desired quantity of the fluid part of the 
 blood while directing the stream of corpuscles back into the 
 body (or vice versa), the whole apparatus being analogous in 
 a way to the modern cream separator. 
 
 It has been our purpose in our recent experiments to find 
 the limits to which plasmaphaeresis may be carried and 
 to learn what pathological changes ensue when the procedure 
 is carried to a point beyond which life is endangered. With 
 the form of Locke's solution now employed by us, we have, in 
 the course of five days, carried the removal of plasma to a point 
 where the total volume of blood withdrawn from the body equals 
 at least five times that ordinarily contained in the body. In 
 this experiment the limit of the procedure was probably reached, 
 as the animal was very nearly lost during the last bleeding; 
 only the speedy return of the sedimented corpuscles saved the 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 15 
 
 dying animal. Unfortunately one cannot conclude from these 
 most successful experiments that similar or even markedly lower 
 quantities can always be removed without danger. We have 
 recently carried out a large number of experiments with a view 
 to determine the safe limits of plasmaphaeresis both as to quan- 
 tity per day and total quantity of blood withdrawn, but un- 
 fortunately these experiments are vitiated by an error which 
 has only recently been discovered. It has been found that 
 the imported hirudin which we are now using is strongly toxic. 
 This was not the case with the product which we ourselves 
 manufactured and which was used in our earlier experiments. 
 Further experiments will have to be done, therefore, to settle 
 this question. 
 
 Some interesting results have been obtained by studying 
 the chemical changes during plasmaphaeresis. Since the method 
 consists essentially in replacing the plasma of the blood by a 
 saline solution, it is natural to find a decrease in the soluble 
 proteins of the blood. While not as rapid as a purely mathemati- 
 cal calculation based on the amounts drawn off and returned 
 would indicate, if the vascular system were regarded as a vessel 
 of given capacity to be washed out, the decrease is considerable. 
 In three days the soluble proteins have been reduced ,to about 
 one-third their original value, after which there is a slight rise 
 as the process is continued. Evidently, as was expected, there 
 is a continual renewal of plasma proteins from the tissues. 
 
 In striking contrast to this, the non-pro teid nitrogen of the 
 plasma shows a slight rise on the first day in every case studied, 
 and a tendency to rise, with some fluctuations, as the process 
 is continued. This increase, which is chiefly due to urea, may 
 be due either to an increase in nitrogenous catabolism or to a 
 diminution of nitrogen excretion. 
 
 Studies have also been made of blood pressure and blood 
 counts. Plasmaphaeresis, like haemorrhage, causes seemingly 
 a paradoxical increase in the number of red cells per unit volume 
 of blood. This, which. appears to be a general phaenomenon 
 accompanying temporary asphyxia, is being investigated in all 
 its bearings by Dr. Lamson (Polycythaemia, P. D. Lamson; 
 
16 
 
 JOHN J. ABEL 
 
 Jour. Pharm. and Expt. Ther. vii, No. 1, July, 1915). The 
 blood pressure, which falls on bleeding, is restored to a satis- 
 factory value on returning the corpuscles and for a long period 
 the two changes may nearly compensate each other. A slight 
 downward tendency is noticed, however, as plasmaphaeresis 
 is continued and in the end a dangerously low point (about 50 
 mm.) will be reached on withdrawing amounts of blood consider- 
 ably smaller than those taken at the start. The previous 
 bleeding usually shows a fall to a point (from 60 to 80 mm.) 
 which should be regarded as a warning, even though 100 mm. 
 or more may be reached on reinjection. 
 
 The following tables give in condensed form some of the 
 data to which reference has been made in the foregoing pages. 
 
 The results obtained in continued plasmaphaeresis are shown 
 in table 3. The amount of blood taken was about one volume 
 on each day. The first two columns of analytical results, ob- 
 tained with samples taken at the beginning and end of the 
 
 TABLE i 
 
 Plasmaphaeresis on three dogs for several days. Nos. 8 and 11 three days each, 
 
 No. 10 two days 
 
 EXPERIMENT NO. 
 
 8 
 
 10 
 
 11 
 
 Weight before operation 
 (Estimated) blood volume 
 Total blood drawn 
 Ratio of volumes 
 
 9.6 kg. 
 730 cc. 
 2037 cc. 
 279 
 
 12.8 kg. 
 960 cc. 
 2046 cc. 
 2.13 
 
 8kg. 
 600 cc. 
 1835 cc. 
 3.06 
 
 Weights, July 8 
 Weights, July 10 
 
 10.5 kg. 
 10.7 kg. 
 
 11.8 kg. 
 12.5 kg. 
 
 8.5 kg. 
 8.0 kg. 
 
 Weights, July 15 
 
 11.2 kg. 
 
 12.8 kg. 
 
 8.2 kg. 
 
 Blood count (millions) July 8. . . . 
 Blood count (millions) July 9. . . . 
 Blood count (millions) July 13. .. 
 Blood count (millions) July 16. .. 
 Haemoglobin, July 8 
 Haemoglobin, July 9 
 
 4.5 
 4.6 
 4.2 
 5.2 
 52 per cent 
 52 per cent 
 
 5.3 
 5.9 
 5.5 
 6.2 
 74 per cent 
 65 per cent 
 
 6.5 
 5.1 
 
 5.8 
 
 78 per cent 
 
 Haemoglobin, July 13 
 Haemoglobin, July 16 
 Weights, July 22 
 Blood count, July 22 
 Haemoglobin, July 22 
 
 60 per cent 
 65 per cent 
 11.0kg. 
 4.1 
 72 per cent 
 
 80 per cent 
 79 per cent 
 1 13.35 kg. 
 5.4 
 80 per cent 
 
 79 per cent 
 80 per cent 
 8.5 kg. 
 5.3 
 75 per cent 
 
 
 
 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 17 
 
 TABLE 2 
 
 Chemical analysis 
 Plasmaphaeresis for one day, on three 
 
 DATE 
 
 DEC. 21 
 
 JAN 11 
 
 J\N 18 
 
 
 
 
 
 Weight of dog 
 
 15 1 kg 
 
 11 9 kg 
 
 7 1 ke 
 
 Blood volume estimated at 7.5 
 per cent 
 
 1132 cc. 
 
 892 cc. 
 
 532 cc 
 
 Total volume bled and per cent 
 of total blood 
 Number of bleedings 
 
 Results of Analyses 
 Percentages 
 
 Total protein of blood 
 Protein of plasma 
 
 1185cc. = 105% 
 3 
 
 Before After 
 Plasmaphaeresis 
 
 22.27 25.23 
 6 62 3 63 
 
 1150 cc. = 129% 
 3 
 
 Before After 
 Plasmaphaeresis 
 
 25.15 25.32 
 6 59 3 17 
 
 410cc.=77% 
 5 
 
 Before After 
 Plasmaphaeresis 
 
 17.34 17.19 
 6 28 3 68 
 
 Difference of above* 
 Blood counts, millions . . . 
 
 15.65 21.60 
 9 11.7 
 
 18.56 22.15 
 11 8 12.9 
 
 11.06 13.51 
 6.6 7.5 
 
 Total non-proteid N 
 Urea nitrogen 
 Non-urea nitrogen 
 
 0.037 0.039 
 0.016 0.019 
 021 020 
 
 0.029 0.036 
 0.011 0.017 
 018 021 
 
 0.045 0.055 
 0.016 0.023 
 029 032 
 
 Amino nitrogen 
 
 0.0041 
 
 
 0.0048 0.0048 
 
 *Blood taken for analysis not included unless made up by equal amount of 
 washed corpuscles from other dogs. 
 
 TABLE 3 
 Continued plasmaphaeresis on a dog for five successive days 
 
 Experiment No. 6, January 22 to 26, 1915, inclusive. A, before plasmaphaere- 
 sis; B, after plasmaphaeresis. 
 
 Weight of dog 8.5 kg. Estimated blood volume (7.5 per cent) = (640 cc.). 
 Total blood removed in five days 3335 cc. = 521 per cent. 
 
 Analytical results in percentage of total blood 
 
 DATE 
 
 A, JAN. 22 
 
 B, JAN. 22 
 
 B, JAN. 24 
 
 B, JAN. 26 
 
 FEB. 19 
 
 Total protein of blood 
 Plasma protein 
 Difference of above 
 
 19.28 
 6.38 
 12.90 
 
 19.31 
 3.44 
 
 15.87 
 
 16.81 
 2.23 
 14.58 
 
 15.83 
 2.92 
 12.91 
 
 11.78 
 5.75 
 6.03 
 
 Blood count millions 
 
 8 5 
 
 8.5 
 
 7.5 
 
 6.5 
 
 3.5 
 
 Total non-proteid nitrogen... 
 Urea nitrogen 
 Amino nitrogen 
 
 0.035 
 0.013 
 0047 
 
 0.040 
 0.019 
 0056 
 
 0.037 
 0.014 
 0.0033 
 
 0.042 
 0.021 
 0.0059 
 
 0.030 
 0.012 
 0.0038 
 
 
 
 
 
 
 
 day's work, compare closely with those in table 1. The third 
 column shows the results at the end of the third day's work, 
 
18 
 
 JOHN J. ABEL 
 
 when the plasma protein reached the lowest value, 2.23 per 
 cent. The fourth column gives the results at the end of five 
 days of plasmaphaeresis while the last column shows the results 
 24 days later. Here the plasma protein has gone up again nearly 
 to its original value. The corpuscles protein, and consequently 
 the total protein, also, are low owing to the anaemia. 
 
 Influence of plasmaphaeresis on blood pressure 
 
 Mean systolic pressures in millimeters of mercury 
 
 Experiment No. 6, January 22 to 26, 1915, inclusive 
 
 
 
 BLEEDING 
 
 RETURN OF CORPUSCLES 
 
 DAY OF EXPT. 
 
 VOLUME BLED 
 
 
 
 
 
 Before 
 
 After 
 
 Before 
 
 After 
 
 
 CC. 
 
 
 
 
 
 1st . . 
 
 250 
 
 208 
 
 165 
 
 
 202 
 
 
 250 
 
 115 
 
 65 
 
 95 
 
 135 
 
 
 170 
 
 140 
 
 65 
 
 85 
 
 115 
 
 2nd 
 
 200 
 
 
 
 
 
 
 125 
 
 pressures not observed on this day 
 
 
 170 
 
 
 
 
 
 3rd 
 
 195 
 
 130 
 
 
 
 110 
 
 
 210 
 
 130 
 
 60 
 
 
 110 
 
 
 200 
 
 110 
 
 55 
 
 70 
 
 110 
 
 
 185 
 
 135 
 
 50 
 
 
 105 
 
 4th 
 
 205 
 
 135 
 
 100 
 
 110 
 
 135 
 
 
 200 
 
 135 
 
 105 
 
 100 
 
 120 
 
 
 200 
 
 115 
 
 60 
 
 80 
 
 105 
 
 
 135 
 
 95 
 
 50 
 
 75 
 
 105 
 
 5th 
 
 180 
 
 
 105 
 
 100 
 
 110 
 
 
 190 
 
 120 
 
 52 
 
 65 
 
 105 
 
 
 175 
 
 100 
 
 50 
 
 47. 
 
 95 
 
 
 
 
 
 1 hr. later = 110 
 
 II. VIVIDIFFUSION 
 
 I should like now to describe a second method for the study 
 of the blood, and to state briefly some of the results that have 
 already been obtained by its use. But first let me remind you 
 that there are numerous constituents of the blood derived from 
 various organs which are of the most vital significance to the 
 
FIG. 3. PERSPECTIVE VIEW OF VIVIDIFFUSION APPARATUS; EARLIER FORM WITH 
 
 SIXTEEN TUBES 
 
 A, arterial cannula; B, venous cannula; C, side tube for introduction of 
 hirudin; D, inflow tube; E, outlet tube; F, G, supporting rod attached at H 
 and K to branched U-tubes; L, burette for h'rudin; M, N, tube for filling and 
 emptying liquid in outer jacket; 0, air outlet; P, dichotomous branching point 
 of inflow tube; Q and /?, quadruple branching points of same; S, S', wooden 
 supports; T, thermometer. At each of the points H and K the blood is collected 
 from four tubes into one, bending around to the back, and there redividing into 
 four return flow tubes. Arrows show the direction of flow. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 19 
 
 economy and which are present in the blood in only minute 
 quantity at any one time. Among these as yet unidentified 
 substances, which nevertheless are certainly known to pass 
 from one organ to others via the blood, are all of the so-called 
 hormones, the active principles of the organs of internal secretion. 
 Of these organs I shall presently speak more in detail. 
 
 Our present methods of blood analysis give us litle help when 
 we endeavor to isolate and identify one of these elusive yet vitally 
 important principles, not to mention other substances of the 
 greatest interest arising in the intermediary stages of metabolism. 
 
 Pondering over this problem it occurred to me that possibly 
 one might construct an apparatus which could be attached to 
 the blood vessels of a living animal and remove from the blood 
 flowing through it all traces of these substances as fast as they are 
 poured into it, without at the same time removing proteids or 
 the indispensible cellular elements (erythrocytes, leucocytes, 
 etc.), of the blood. Such an apparatus might conceivably be 
 employed also in an emergency in certain toxic states in which the 
 eliminating organs, more especially the kidneys, cannot act 
 rapidly enough to relieve the system. 
 
 An apparatus of this kind was constructed with the skillful 
 assistance of Dr. Turner and is shown in the accompanying 
 illustration. (Fig. 3.) Essentially, the method consists in connect- 
 ing an artery or a vein of the animal by a cannula to an apparatus 
 made of celloidin or other dialyzing membrane, in the form of 
 tubes, immersed in a saline solution or serum, and providing 
 for the return of the blood to the animal's body by another 
 cannula attached to a vein. The tubes and cannulae are filled 
 completely before attachment with a saline solution which ap- 
 proximates in composition to the salt content of the serum of 
 the animal. This is displaced into the body by the inflow of 
 blood, when the circulation in the apparatus is established. 
 The blood leaving the artery flows through a perfectly closed 
 system and returns to the body within a minute or two without 
 having been exposed to contact with the air or any chance of 
 microbial infection, while the diffusible substances which it 
 contains can pass out, more or less rapidly, through the walls of 
 
20 JOHN J. ABEL 
 
 the tubes. Coagulation of the blood is prevented by injection 
 of hirudin. We have named the process "vividiffusion" and 
 the apparatus itself constitutes an " artificial kidney," as it were, 
 but differs from the natural organ in that it makes no distinction 
 whatever between the various diffusible constituents of the 
 blood, permitting their escape from the celloidin tubes in a 
 manner which is presumably proportional to their coefficients 
 of diffusion. -As you are well aware, the natural kidney does 
 not ordinarily allow the sugar of the blood to escape into the 
 urine, its excretory function is elective and discriminatory. 
 The artificial kidney, as just stated, makes no such distinction. 
 Sugar is eliminated in proportion to its presence in the blood 
 equally with a waste product like urea. We have it in our 
 power, however, to give to this vividiffusion apparatus a certain 
 selective ability, at least in the sense that we can prevent any 
 given substances, as sugar, glycocoll, and the like, from escap- 
 ing from the blood, by the simple expedient of placing an equiva- 
 lent quantity on the outer side of the celloidin tubes. 
 
 With this apparatus we have already separated from the blood 
 a number of constituents which cannot be obtained with equal 
 ease by other methods. I shall not here enter into the details 
 of the chemical methods employed in differentiating the various 
 constituents of the dialysate, but will merely point out some of 
 the results that we have obtained. 14 It has been found: 
 
 (1) That the non-protein constituents of the blood can be 
 accumulated in any desired quantity by our method, the quantity 
 depending on the extent of the dialyzing surface of our apparatus 
 and the number of experiments made. 
 
 (2) That the rate of accumulation of various nitrogenous 
 substances in the dialysate and their relative proportions in it 
 do not differ very greatly from those in the blood. 
 
 (3) That alanine and valine can be obtained in crystalline 
 form; that histidine and creatinine can be shown by reactions 
 to be present. 
 
 14 See Jour, of Pharmacology and Experimental Therapeutics, vol. 5, pp. 275- 
 317, and 625-641. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 21 
 
 (4) Quite recently it has been found by Dr. Alice Rohde, 
 working in my laboratory, that the ammonia-yielding substances 
 of the blood can be divided into two classes by the vividiffusion 
 apparatus; the one, comprised of diffusible substances only 
 and giving off their ammonia rapidly and completely on the 
 addition of sodium carbonate; the other, non-diffusible and 
 therefore not escaping through our apparatus, and characterized 
 by the property of losing their ammonia only very slowly on the 
 addition of sodium carbonate. 
 
 (5) By means of our method of vividiffusion we have also 
 found that oxyacids circulate in the blood in noticeable propor r 
 tion. Lactic acid and 0-oxy butyric acid in particular have 
 been identified as constituents of the diffusate. 
 
 (6) From the residue from one of the processes employed (that 
 known as the " ester distillation") I obtained a crystalline sub- 
 stance having the composition, C 7 H]2N 2 O2. Dr. Turner and I 
 were finally enabled to identify this substance as a-isobutyl 
 hydantoin (1. isobutyl 2.4. diketo-tetrahydroimidazol) first pre- 
 pared by Pinner and Lifschiitz 15 and later by Fritz Lippich 16 
 from valeraldehydecyanhydrin and urea, also by E. Koenigs 
 and B. Mylo 17 from dZ-leucinamid and ethylchlorcarbonate. 
 I suspect that other hydantoins are present in the fraction from 
 which this particular hydantoin was isolated. As -isobutyl 
 hydantoin is the first of its class to be isolated from an animal 
 fluid or tissue, one must be certain that the substance has not 
 been formed as a by-product of the many chemical processes 
 that are involved in obtaining it; in other words, one is obliged 
 to prove conclusively that the substance in question really exists, 
 as such, in the blood of the dog. For the present we can not 
 offer this final proof. Dr. Turner, however, is now engaged in 
 searching for hydantoins in the blood of the pig by a method 
 that will remove the uncertainty that still attaches to the find 
 as it now stands. 
 
 15 Ber. d. d. chem. Ges., 20, p. 2356 (1887). 
 
 16 Ibid., 41, p. 2972 (1908). 
 
 17 Ibid., 41, p. 4439 (1908). 
 
22 JOHN J. ABEL 
 
 (7) Certain fractions of our dialy sates, those derived from the 
 so-called "phosphotungstic precipitate/' have not yet been ana- 
 lyzed in detail, owing to the pressure of other parts of the prob- 
 lem; it is apparent, however, that we are dealing with an indeter- 
 minate number of substances, and it is more than probable that 
 some hitherto unidentified constituents of the blood may here 
 be found. 
 
 Half a year after we made our first communication 18 in which 
 it was announced that we had separated from our dialysates sev- 
 eral grams of amino-acid esters, Abderhalden published a paper 19 
 in which he describes the separation of some of the amino acids 
 from large quantities of blood obtained from slaughter houses. 
 To secure the small amounts of amino acids needed for his 
 identification tests this investigator was obliged to use at one 
 time 50 or even 100 liters of beef blood. These large quantities 
 of blood were worked up partly by dialysis, partly by precipi- 
 tation methods which required the dilution of the blood by many 
 volumes of water. The method of vividiffusion can be used in 
 the most scantily equipped laboratory and has the great advan- 
 tage of separating the diffusible substances from the proteids 
 of the circulating blood of living animals. There can thus be no 
 question here of secondary changes, such as may conceivably 
 take place in shed and coagulated blood. 
 
 I come now to a newer application of the method of vivi- 
 diffusion, one to which I alluded a few moments ago, namely its 
 possible employment to abstract from the circulating blood 
 certain hormones or products of internal secretion in amounts 
 that will suffice for pharmacological study, if not for chemical 
 analysis. This application is still in its very beginning, many 
 difficulties yet remain to be surmounted, and I speak of it here 
 only because it leads me quite naturally to a field of study which 
 is of the greatest importance, a field which at present is ripe 
 
 18 On the removal of diffusible substances from the circulating blood by means 
 of dialysis, Trans. Assoc. Americ. Physicians., May, 1913. Also demonstration 
 of our apparatus before the pharmacological section, Int. Med. Congress at Lon- 
 don, August, 1913. 
 
 19 Zeitschr. f. physiol. Chemie., vol. 88, p. 478, Dec. 23, 1913. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 23 
 
 for the methods of the chemical explorer. I refer to the explora- 
 tion of the organs of internal secretion, especially to the study 
 by chemical methods of their specific products. In attempting 
 this, a vividiffusion apparatus of the proper sort is attached to 
 the veins of a particular organ, as the thyroid gland, and the 
 diffusate thus obtained is studied by pharmacological and 
 chemical methods. This diffusate must also be compared in 
 respect to its pharmacological properties, at least, with both 
 the arterial and the venous blood of the gland under investiga- 
 tion. But whatever may be the outcome of such studies I hope 
 to make it evident to you in what I am about to say that we are 
 here dealing with matters of the greatest importance to biology 
 and medicine. 
 
 III. THE BLOOD AND THE SPECIFIC SECRETORY PRODUCTS OF 
 THE ORGANS OF INTERNAL SECRETION 
 
 In this field we touch on the one hand upon knowledge which 
 is deeply rooted in the earliest practical experience of mankind, 
 and on the other on the results of epoch-making clinical observa- 
 tions and of experimentation in scientific laboratories up to the 
 present moment. Man has long made practical use of the fact 
 that the removal of the sex glands at a certain age will give us 
 the docile ox in place of the unruly bull, the easily fattened and 
 tender-fleshed capon for the muscular and stringy cock; and 
 human society in its various stages of development has also prac- 
 ticed this mutilation on its individuals for various reasons, 
 religious, economic or penal. The sale of eunuchs in Bagirmi 
 and other parts of North Central Africa still continues, we are 
 told, and it was only on the accession of Pope Leo XIII in 
 1878 that the practice of castrating boys in order to furnish the 
 Sistine Choir its famous adult soprano voices was discontinued. 
 
 From remote antiquity, therefore, man has known that the 
 gonads, or sex glands, exert a marked influence on the develop- 
 ment and structure of the body, but until recent times there has 
 existed no valid explanation, no correct theory of their relation- 
 ship to the rest of the body. It is true, there were not wanting 
 
24 JOHN J. ABEL 
 
 acute minds whose attempted explanation came close to the 
 truth, but experimental proof was lacking. We gather from 
 Aesop's fable that it will not do for the various members of the 
 body to fall out with one another, and the medicine of an older 
 time has long used the expression consensus par Hum as indicating 
 the interrelationship of the various organs. Even in quite 
 modern times this consensus of the various organs was supposed 
 to be entirely effected through the intermediation of the nerv- 
 ous system, a view tersely expressed by Cuvier when he said, 
 "Le systeme nerveux est, au fond, tout 1'animal, les autres 
 systemes ne sont la que pour le servir." 
 
 Side by side with this view of the preponderating rdle of the 
 nervous system we find the old humoral doctrine, having ob- 
 tained new support in Harvey's discovery of the circulation, 
 struggling to prove the importance of the blood stream for the 
 interrelationship of the organs. In 1775, Theophile de Bordeu 20 
 of Montpellier and later Paris, a fashionable practitioner with 
 considerable knowledge of anatomy, propounded the doctrine that 
 every organ lives its own life and is the source of specific chemical 
 substances (humeurs particulieres) which are yielded up to 
 the blood and which are necessary to the integrity of the body. 
 The idea that every organ has its own special life is repeated 
 again and again in Bordeu's writings: 
 
 It must be remembered that each organic part of the living organism 
 has its own manner of existence, of acting, of feeling and of moving : 
 each has its own particular savor, structure, external and internal 
 make up, odor, weight, manner of growth, of expanding and con- 
 tracting; each competes after its own manner and for its share in the 
 ensemble of all the functions, in the general life: each organ, in brief, 
 has its own life and its own functions quite distinct from all others. 21 
 
 From the organs the blood derives a multitude of humors and 
 "emanations" (nuees d'e*manations qui composent et animent le 
 sang). 
 
 20 See his Recherches anatomiques sur la position des glandes et sur leur 
 action, Paris, 1752; and his Analyse medicinale du sang, 1776. 
 
 21 P. 942, Analyse medicinale du sang, vol. 2, oeuvres completes de Bordeu 
 edited by Richerand, Paris, 1818. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 25 
 
 Comparable at bottom to fecundated white of egg, the blood (a fluid 
 tissue which fills the vessels of the body), is animated by the semen, 
 that is to sav, it contains a certain quantity of seminal emanations 
 which vivify it; it contains in the same way a portion of the bile, and 
 also a portion of the milky juices, especially in infancy and in women 
 at the time of pregnancy; it contains a colored part which is elaborated 
 in the entrails; it has serosity in abundance; it contains an extract of 
 each glandular organ which contributes its share to the emanations in 
 which all the solid parts (of the blood) swim; a certain quantity of air; 
 
 a portion of mucous substance. ... 22 
 * 
 
 Bordeu's theories in respect to the diseases that are conse- 
 quent to a superabundance or wrong admixture of these various 
 special principles or emanations, his various cachexias (cachexie 
 bileuse, albumineuse, etc.), cannot be considered here. 
 
 Three-quarters of a century after Bordeu, in 1849, we find a 
 German professor of physiology, in Gottingen, A. A. Berthold, 
 giving the first experimental proof of the correctness of this 
 theory. This experimenter, in a beautifully concise monograph 
 of only four pages, describes his experiments upon young cock- 
 erels. By removing the sex glands from their normal position 
 and transplanting them to another part of the body (to the 
 outer surfaces of the intestine in the peritoneal cavity), where 
 it was impossible for them to expel a secretion or to play any 
 external role as sex glands, he was able to prove that these glands 
 have two functions, (a) the well-known reproductive function, 
 and (b) an important function in maintaining, as he says, the 
 "consensus partium." Such cockerels did not show the changes 
 that were seen in the castrated bird; on the contrary, they devel- 
 oped into the usual type, remaining male birds in respect to their 
 vocal capacity, their desire for battle, the growth of comb and 
 wattles and the sexual instinct. Berthold draws the conclusion 
 from his experiments that the generative organs influence the 
 consensus partium by acting upon the blood and through this 
 upon the organism as a whole. 
 
 The observations of Berthold were forgotten and even dis- 
 credited (Rudolf Wagner) and they had no influence apparently 
 
 22 P. 1006, Ibid. 
 
26 JOHN J. ABEL 
 
 on the development of work in this field during the following- 
 half century. 
 
 I cannot leave this part of my subject without mentioning 
 the work of the great Frenchman, Claude Bernard, whose dis- 
 covery of glycogen in the liver and elsewhere must always rank 
 as one of the great discoveries of physiology. With perfect 
 justice Bernard declared that the conversion of glycogen into 
 sugar and the passage of the latter into the blood constitutes 
 the internal secretion of the liver while the bile constitutes its 
 external secretion. 
 
 One other investigator, the modern pioneer in this field, a 
 restless spirit, a man of enthusiasm, possessing an original 
 mind of a high order, one who is of especial interest to Americans, 
 cannot be passed by without mention. Charles Edward Brown- 
 Sequard was born at Port Louis, Mauritius, on the 8th of April, 
 1817. His father was an American, his mother a French woman, 
 but he himself, it is stated, always wished to be regarded as a 
 British subject. After a varied career in four countries (England, 
 France, Mauritius and the United States), having held the chair 
 of physiology in Harvard from 1864 to 1867, he finally, in 1878, 
 succeeded Claude Bernard as professor of experimental medicine 
 in the College de France, where he remained until his death in 
 1894. 
 
 As far back as 1869 Brown-Sequard took the position in his 
 lectures in Paris that all glandular organs, irrespective of whether 
 they possess external excretory ducts or not, give off to the 
 blood substances which are useful and necessary for the body as 
 a whole, an opinion, as we have seen, that had already been 
 stated by Theophile de Bordeu in 1775. He even made experi- 
 ments on himself with a testicular extract, and the meeting of 
 the Paris Socie*te* de Biologie, June 1, 1889, at which Brown- 
 Sequard, then 72 years old, made his report on these experiments, 
 Biedl calls "the true birthday of the doctrine of internal secre- 
 tion." 
 
 From this time an ever increasing army of experimental 
 laboratory workers have been engaged in this field. Their 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 27 
 
 names even cannot here be given, neither can I go into detail 
 with regard to the great and fundamental contributions that 
 have been made by medical clinicians, surgeons and anatomists, 
 as Basedow, Graves, Addison, Marie, Gull, Ord, Kocher, Rever- 
 din, Minkowski, Von Mering, Sandstrom and others, to name 
 only some of the leaders of the immediate past, not to speak 
 of the excellent contributions that have been made in recent 
 years by our own surgeons and internists. 
 
 And so there has gradually come into existence an enormous 
 store of facts, physiological, pathological, chemical and clinical, 
 in regard to a number of structures that are classed as endocrinous 
 glands or organs of internal secretion. 
 
 What is meant today by this term, products of internal secre- 
 tion, and what organs furnish principles that can be classed as 
 internal secretions? 
 
 For the present we shall follow custom and apply the term 
 to definite and specifically acting indispensable chemical products 
 of certain organs (organs that may or may not have an external 
 secretion), which are poured into the blood and modify the develop- 
 ment and growth of other organs, more especially during embryonic 
 and early life, and which also greatly affect the entire metabolism, 
 that of the nervous system included, during adult life. I regard 
 it as not unlikely that with the growth of knowledge of the 
 chemistry of the animal organism we shall drop the term entirely. 
 We have already seen that the liver, according to Claude Ber- 
 nard's view, has an internal secretion, yet this gland is not usually 
 classed with the endocrinous organs. In a sense, too, as has been 
 frequently pointed out, every cell of the body furnishes in the 
 carbon dioxide which it eliminates a hormone or product of inter- 
 nal secretion, since under normal conditions the carbon dioxide 
 of the blood is one of the chief regulators of the respiratory center, 
 influencing this center by virtue of its acidic properties. These 
 and other instances that could be given show that the term inter- 
 nal secretions could be greatly extended in its scope, but in the 
 present state of our knowledge it is convenient to limit it to the 
 products of a certain number of glands. 
 
28 JOHN J. ABEL 
 
 The generally accepted list of the organs of internal secretion 
 is as follows, though even at this moment a foreign investigator 23 
 is asking us to accept certain newly discovered small structures 
 located in the neck as belonging to our list: the thyroid, para- 
 thyroid, thymus, hypophysis cerebri, epiphysis cerebri, pan- 
 creas, mucosa of the duodenum, the two adrenal systems (the 
 chromaphil tissue and the interrenal bodies) and the gonads, or 
 sex glands. 
 
 Permit me to give you a few illustrations of the derangement 
 of health and bodily structure that follow upon the removal or 
 disease of these glands. Many of you have doubtless seen 
 these illustrations, but I am giving them here for the benefit 
 of those who have never been given proof of the great significance 
 of these glands in order that they may have a background of 
 fact for the better apprehension of certain chemical questions 
 which I wish presently to bring to your notice. 
 
 Figure 4 is an illustration taken from a well-known paper of 
 the Viennese surgeon, A. v. Eiselsberg, in which he describes 
 the effects of removing the thyroid gland from young goats. 
 The two animals here shown are of the same age and parentage. 
 On the twenty-first day after birth v. Eiselsberg removed the 
 thyroid gland from one of them. The incision healed by primary 
 intention. After three weeks the control animal began to out- 
 grow the one operated upon and when four months old the animals 
 presented the appearance here shown. The goat with thyroid 
 removed has shortened extremities, a shortened skull and an 
 altered pelvis due to a delayed ossification at the epiphyseal line. 
 The wool of this animal is longer and easily torn out by the 
 handful, the sex glands are atrophied, the hypophysis is enlarged, 
 the intelligence is lowered; in brief, a chronic pathological con- 
 dition is produced in this experiment which finds an analogy in 
 human beings and is known as cachexia thyreopriva. We can- 
 not enter into further details, but I may remark that the results 
 obtained in such removal experiments vary greatly with the 
 age and with the species of animal used. 
 
 23 Ueber erne neue Druse mit innerer Sekretion (Glandula insularis cervicalis) . 
 N. Pende; Arch. f. mikroscop. Anat., vol. 86, p. 193, 1914. 
 
FIG. 4. INFLUENCE OF THE THYROID GLAND 
 
 ON GROWTH. 
 
 The animals are four months old. The one 
 on the right had the thyroid removed on the 
 21st day after birth. Taken from v. Eiselsberg. 
 
 FIG. 5. GIRL THIRTEEN YEARS OLD. CASE 
 
 OF CONGENITAL MYXOEDAMA. From 
 
 v. Eiselsberg. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 29 
 
 In figure 5 we have the results of a similar experiment which 
 nature herself has performed for us. The child here shown is a 
 13-year-old idiotic myxoedematous dwarf whose general symp- 
 toms point to a congenital absence of the thyroid gland. Investi- 
 gators have proved this to be the true cause by anatomical studies 
 of the bodies of other congenital myxoedematous children of this 
 class. 
 
 [Further illustrations were then given by means of lantern slides 
 of endemic cretinism and goitre and it was shown by statistics and by 
 a map of Europe that these abnormalities have very great economic 
 significance, on account of their prevalence in certain parts of 
 central and western Europe and to a less degree in our own and other 
 countries. For instance in Switzerland one-sixth of the male popula- 
 tion is unfitted for military service by cretininism in some degree. 24 
 
 Pictures of persons suffering from other disorders as exophthalmic 
 goitre, acromegaly or giantism and parathyroid tetany were also 
 given with a brief statement of the glandular and general nutritive 
 changes involved. Animals such as the monkey, the dog, the rat 
 and others are likewise subject to diseases of this gland.] 
 
 After even these few illustrations of abnormalities that follow 
 on removal or disease of these glands, I think you will agree with 
 me that my colleague, Professor Barker, has not exaggerated 
 their importance when he says, 
 
 More and more we are forced to realize that the general form and 
 the external appearance of the human body depend to a large extent 
 upon the functioning, during the early developmental period (and later) , 
 of the endocrine glands. Our stature, the kinds of faces we have, the 
 length of our arms and legs, the shape of the pelvis, the color and con- 
 sistency of our integument, the quantity and regional location of our 
 subcutaneous fat, the amount and distribution of hair on our bodies, 
 
 24 Der Kretinismus, H. Vogt in Handbuch der Neurologic (Lewandowsky) , 
 vol. iv, Spezielle Neurologie iii, p. 139. Here also it is stated that the three 
 Italian provinces, Piedmont, Lombardy and Venice had 120,000 cases of goitre 
 and 13,000 cretins in 1883, the total population of these provinces at that time 
 being 9,400,000. In 1908, according to Biedl, Austria had on the average 64 cre- 
 tins to every 100,000 of the population. In 1873 France had 120,000 cretins in 
 Savoy, the Maritime Alps and the Pyrenees. It will be seen that the thyreo- 
 pathies constitute a heavy drain on the resources of European people. 
 
30 JOHN J. ABEL 
 
 the tonicity of our muscles, the sound of the voice and the size of the 
 larynx, the emotions to which our exterieur gives expression all are 
 to a certain extent conditioned by the productivity of our hormono- 
 poietic glands. We are simultaneously, in a -sense, the beneficiaries 
 and the victims of the chemical correlations of our endocrine organs. 25 
 
 I cannot here take up questions of therapeutics in this interest- 
 ing field. I can only say that aside from surgical intervention 
 and the brilliant results of thyroid treatment in cases once utterly 
 hopeless, we have little to offer that has been positively estab- 
 lished. Nor shall I attempt to discuss the interrelationship of 
 these glands. It has become increasingly evident that to touch 
 one of them is to touch all. Various writers have endeavored 
 to express this interrelationship in a series of charts or diagrams. 
 Of these diagrams D. Noel Paton has well said: 26 
 
 They may well be a grotesque parody of what will ultimately be 
 found to be the relationship of the activities of these organs. They 
 are probably as near the truth as those quaint ancient maps of the Inr 
 dies with their 'here be gold' scrawled across them which served as 
 the charts of our forefathers, and if, like them, they merely indicate 
 the direction which further investigation should take and suggest 
 lines of attack, they will have served their purpose. 
 
 Notable and well established, apparently, is the relationship 
 existing between the gonads, the thyroid and thymus glands, 
 the hypophysis and suprarenal glands. Very difficult is it also 
 to unravel the relationship of the interval secretions as a whole 
 to the nervous system, both central and peripheral. 
 
 In view of the fact that we so little understand the chemical 
 principles elaborated in these organs and discharged by them 
 into the blood whereby the remarkable changes described above, 
 are effected, it is evident that further progress now waits on 
 chemical discoveries. 
 
 The only fairly complete chemical work yet done on any of 
 these organs is that on the suprarenal glands. These organs 
 
 25 On abnormalities of the endocrine functions of the gonads of the male, 
 Am. Jour. Med. Sciences, vol. 149, p. 1, 1915. 
 
 26 Regulators of Metabolism, p. 183, Macmillan & Co., London, 1913. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 31 
 
 are two flattened, ductless, yellow-brown glands, each of which 
 is loosely attached to the anterior and inner part of the summit 
 of the corresponding kidney. The normal gland of a healthy 
 man weighs, according to Elliot, 27 between 4 and 5 grams, and 
 contains 4 or 5 mgm. of the characteristic principle concerning 
 which I shall speak in a moment. These organs are essential 
 to life; their destruction in man by tubercular and more rarely 
 by other processes leads to a chronic condition characterized 
 by gastro-intestinal symptoms, great muscular weakness and a 
 bronzing of the skin and mucous membranes, this whole symp- 
 tom complex being known as Addison's disease (1855). In man 
 and the higher animals generally this organ is a double structure 
 in which two parts which are quite separate and totally different 
 in lower forms, as in the elasmo-branch and teleostean fishes, 
 are united in such a manner that one constitutes the medulla 
 and the other the cortex of the gland, the latter completely 
 enclosing the former. 
 
 The cortical part of the gland is called by histologists the inter- 
 renal tissue. Biedl has shown that when this tissue is removed 
 from selachians (where, as just stated, it constitutes a separate 
 organ) the animal gradually weakens, no longer takes food and 
 dies in fourteen to eighteen days. Still other experiments demon- 
 strate that this cortical part of the gland exerts great influence 
 on bodily growth and sexual development. Numerous researches 
 of a chemical character have been carried out on this part of 
 the gland, especially in respect to its lipoid content. Last 
 year, Voegtlin and Macht 28 isolated from it and also from blood 
 serum a new crystalline substance which has a vaso-constricting 
 action on the blood vessels and a digitalis-like action on the 
 heart. This has been decided to be a lipoid closely related to 
 cholesterin. As we are entirely ignorant of the means by which 
 the adrenal cortex exerts its profound influence on the body, 
 
 27 Death and the adrenal gland, Quart. Jour, of Medicine, vol. 8, p. 47, 1914. 
 An interesting paper by E. R. Weidlein, a fellow of the Mellon Institute, on the 
 adrenal glands of the whale will be found in the Jour, of Industrial and Engi- 
 neering Chemistry, vol. 4, No. 9, Sept., 1912. 
 
 28 Isolation of a new vasoconstrictor substance from the blood and the adrenal 
 cortex, Jour. Amer. Med. Assoc., vol. 61, p. 2136, 1913. 
 
32 JOHN J. ABEL 
 
 the isolation of this substance is of especial interest. For the 
 present we cannot state whether it represents one or all of the 
 products of the internal secretion of the cortex, or whether in- 
 deed it has any connection at all with the function of the gland. 
 
 The medullary portion consists of cell groups which assume 
 a brown color when treated with chromic acid or dichromates, 
 in consequence of the reduction of these compounds to brownish 
 or reddish-brown basic chromates. For this reason it has been 
 designated the chromaphil tissue. Now such chromaphilic cell 
 groups are not confined to the medulla of the suprarenal gland 
 but are also found lying alongside the abdominal aorta, in the 
 carotid gland and in the sympathetic system. 
 
 It was known to earlier experimenters that aqueous extracts 
 of the entire capsules were highly toxic to animals when injected 
 directly into the circulation, but it remained for Oliver and 
 Schafer in 1894 to demonstrate that extracts of the medullary 
 part, in the most minute quantity, cause a marked rise in blood 
 pressure and greatly stimulate the heart. In 1897 I showed 
 that the substance responsible for these actions could be isolated 
 from the glands in the form of a benzoyl compound. 29 Salts of 
 a base obtained by saponifying this benzoyl derivative were 
 shown by me (1898) to possess the characteristic chemical and 
 physiological properties of the gland itself. To the principle 
 thus isolated I gave the name epinephrin. Very soon after 
 this v. Furth (1899-1900) isolated the principle under discussion 
 in the form of an amorphous indigo-colored iron compound, 
 and in 1901, Takamine and Aldrich succeeded, independently, 
 in precipitating the native substance with the help of ammonia, 
 and without first subjecting it to the more complicated processes 
 which had been used by myself some years before. 
 
 These results were soon followed by the brilliant researches 
 of a number of organic chemists, Dakin, Jowett, Pauly and Fried- 
 mann, which culminated in the synthetic production, first, of 
 the racemic form by Stolz in 1906, and later of the laevorotatory 
 form by Flacher in 1908, the form in which the substance exists 
 
 29 For literature see Abel and Macht: Jour, of Pharmacol. and Exp. Therapeu- 
 tics, vol. 3, p. 327, 1912. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 33 
 
 in the gland itself. The chemical history of this remarkable 
 blood-pressure-raising constituent which is found wherever 
 chromaphil tissue is encountered is therefore now a closed chap- 
 ter. We are no longer dependent upon the glands of the ox 
 or the sheep for its preparation for the many uses to which it is 
 put by the medical specialist, the surgeon and the general prac- 
 titioner, but shall always be able to produce it in our laboratories 
 as long as coal tar remains at our disposal. In chemical language 
 it is described as a di-hydroxymethyl-aminoethylol benzene, or 
 more concisely and simply, it is an aromatic amino alcohol. 
 It is as noteworthy for its instability in solution as it is remarkable 
 for its physiological properties. It is a true product of internal 
 secretion and can apparently be detected in the venous blood of 
 the adrenal glands. 30 I shall not further describe its chemical 
 properties, but would call your attention to the fact that in at 
 least one animal, a tropical toad, Bufo agua, this principle occurs 
 also as a constituent of an external secretion. 
 
 The toad I may say here has a very interesting history. 31 
 It has been regarded from the earliest times as a poisonous ani- 
 mal and various races, including our own, have long made medi- 
 cinal use of its skin. The Chinese to this day use as a cure for 
 dropsy a preparation derived from toad skin, called senso. 
 Among western nations it has always been a folk's remedy and 
 almost up to the time of the introduction of digitalis (1775) as 
 a medical agent our very best medical authorities used these 
 skins in cases of dropsy. Dr. Langworthy, Department of Agri- 
 culture, Washington, has given me the following recipe for mak- 
 ing a toad ointment which was in use among our early New 
 England colonists for the treatment of sprains and rheumatism. 
 Toad Ointment: Good sized live toads, 4 in number: put into 
 boiling water and cook very soft; then take them out and boil 
 the water down to | pint, and add fresh churned, unsalted but- 
 
 30 It has not been conclusively shown that the blood pressure-raising consti- 
 tuent of this blood is really epinephrin (adrenalin) and not an alteration product. 
 
 31 Abel and Macht: The poisons oi the tropical toad, Bufo agua, Jour. Amer. 
 Med. Assoc., vol. 56, p. 1531, 1911, and two crystalline pharmacological agents 
 obtained from the tropical toad, Bufo agua, Jour. Pharmacol. and Exp. Thera- 
 peutics, vol. 3, 1319, 1912. 
 
34 JOHN J. ABEL 
 
 ter 1 pound and simmer together; at the last add tincture of 
 arnica 2 ounces. 
 
 The particular toad, Bufo agua, to which I have referred, is 
 of further interest because the aborigines of the Upper Amazon 
 make an arrow poison from the creamy secretion that exudes 
 from its skin glands when it is irritated or overheated, a poison 
 so powerful that it kills in a few moments large game, such as 
 the stag or the jaguar. 
 
 Two years ago I was examining a specimen of this giant 
 among toads when I noticed that this creamy secretion made on 
 a scalpel a peculiar, greenish blue discoloration. I at once 
 remembered where I had seen this color years before on a scalpel 
 used in cutting into the medulla of a suprarenal gland. Work- 
 ing from this hint I was soon able to isolate the now familiar 
 substance, adrenalin or epinephrin, from this toad's glands. 
 Scientists have been not a little surprised to learn that this 
 substance is present in very large amounts in the skin of this 
 tropical toad. It is not found in the skin of the common Ameri- 
 can toad. 
 
 I also succeeded in isolating the principle to which the toad 
 skin owes its curative power for dropsy, a very different princi- 
 ple from epinephrin. It has been obtained in the form of beauti- 
 ful crystals and has the composition represented by the formula, 
 Ci 8 H 2 4O 4 , and has been named bufagin. 
 
 Just as in the case of bleeding, we have here another instance 
 of the every day observation of mankind justified by science. 
 That powdered toad skin could cure dropsy has been ridiculed 
 by the learned for a century, and now we possess in bufagin and 
 in the slightly different bufotalin, which has only recently been 
 obtained in crystalline form from the skin of the common Euro- 
 pean toad, the actual proof of the correctness of the old belief. 
 
 We are now studying the chemical constitution of bufagin in 
 my laboratory, and although this problem is one of great diffi- 
 culty, we hope nevertheless that our work will throw some 
 light on the fundamental chemical properties of cardiac stimu- 
 lants. We now also understand why the secretion of the skin 
 of Bufo agua may be used as an arrow poison, since it contains 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 35 
 
 these two powerful drugs, epinephrin and bufagin, which in 
 overdose act fatally on the heart and blood vessels. 
 
 We cannot leave the consideration of this subject without 
 noting the influence that the study of the pharmacological 
 properties of epinephrin has exerted on certain departments 
 of medical science. 
 
 Chromaphilic cells of the body, whether located in the medul- 
 lary portion of the suprarenal gland, or elsewhere, all yield epine- 
 phrin and modern studies have shown that these chromaphilic 
 cells are intimately related to the sympathetic nervous system 
 in their origin, and have differentiated themselves from it. We 
 are not surprised, therefore, to find that epinephrin, the secre- 
 tory product of these cells, has an elective affinity for the sym- 
 pathetic nervous system, the thoracico-abdominal part of the 
 antonomic system. The well known symptoms that follow 
 upon the administration of epinephrin; extreme vaso-constriction, 
 tachycardia, dilatation of the pupil, inhibition of peristaltic 
 movement in the alimentary canal, contraction of the pyloric 
 and ileo-coecal sphincters, increased motility. of the pregnant 
 uterus and glycosuria have all been shown to be due to the 
 fact that this hormone stimulates and sensitizes the sympathetic 
 myoneural and adenoneural junctions or terminations of the 
 sympathetic nervous system. Numerous experiments have 
 shown that the changes induced by epinephrin in the activity 
 of various organs which are innervated by the sympathetic 
 nervous system are in all respects like those that are brought 
 about by electrical stimulation of this system, and it is apparent 
 that such experiments have already assisted in elucidating many 
 obscure points in the functional activity of this part of the ner- 
 vous system. 
 
 Other interesting observations which deal with the action 
 of this principle upon the metabolism of the body or with the 
 pathological changes induced by toxic doses cannot be taken 
 up here. 
 
 The discovery of the chemical structure and pharmacological 
 properties of epinephrin has greatly encouraged investigators 
 
36 JOHN J. ABEL 
 
 to take up the isolation of other active principles. Thus Abelous 32 
 and his co-workers showed that the intravenous injection of 
 extracts from putrid meat caused a rise of an animal's blood 
 pressure. Barger and Walpole 33 then proved that this effect 
 was due to the presence of isoamylamine, phenylethylamine 
 and parahydroxyphenylethylamine. 
 
 These amines are produced by putrefactive bacteria from pro- 
 teids, and they exhibit pressor or blood pressure raising effects 
 that in general are very similar to those produced by epinephrin. 
 A close similarity in chemical structure of two of these amines, 
 phenylethylamine and parahydroxyphenylethylamine, to epine- 
 phrin is shown in the graphic chemical formulae which will pres- 
 ently be given. The last named base is of special interest to 
 us since Barger has discovered that it is also present in ergot 
 and is in some degree responsible for the characteristic activities 
 of this drug. It is also present to a small extent in Emmenthaler 
 cheese. More remarkable still is the discovery of Henze that 
 this amine is the effective principle of a highly active poison 
 produced by the . posterior, so-called, salivary glands of a cer- 
 tain cephalapod found in the Bay of Naples. It has long been 
 known that this mollusc renders its prey, as the crab, quickly 
 helpless by means of this poison and until Henze's discovery it 
 was believed to be a toxalbumin. 
 
 We find, therefore, that p-hydroxyethylamine is produced by 
 putrefactive bacteria, that it is present in ergot (the permanent 
 mycelium of the fungus, claviceps purpurea) and that it is the 
 product of the metabolism of a glandular tissue. In each case 
 it may be assumed that it is obtained by chemical reactions from 
 the protein molecule, its immediate precursor being the innocuous 
 tyrosine. 
 
 By merely splitting off a molecule of CO 2 from tyrosin, as was 
 demonstrated by Barger, we at once secure this amine, as shown 
 by the accompanying formulae. As a recent writer has remarked, 
 "Our poisons and our drugs are in many instances the close rela- 
 
 32 Compt. rend. Soc. de Biol. vol. 58, I, pp. 463 and 530, (1906); vol. 64, p. 
 907, 1908. 
 
 33 Jour, of Physiol., vol. 38, p. 343, 1909. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 37 
 
 tives of harmful compounds that represent the intermediary 
 steps in the daily routine of metabolism." 34 
 
 The fact that putrefactive micro-organisms .can produce 
 poisonous amines by decarboxylating the harmless amino acids 
 has become of the highest importance to medicine. It would 
 appear that we have at last got onto the right road for the chem- 
 ical investigation of alimentary toxaemia and its alleged conse- 
 quences, such as arteriosclerosis and chronic renal disease. 
 Phenylalanine, tyrosine, tryptophane and histidine, the harm- 
 less precursors of toxic amines, are always present in the intestine 
 and when they are acted upon by an excessive number of certain 
 micro-organisms, the resulting toxic bases will surely be formed 
 in excess. If they are then taken up into the blood in quantities 
 too large for transformation by the liver, or other defensive 
 organs, into less harmful derivatives they must inevitably mani- 
 fest their pharmacological and toxicological properties. Let 
 me give one further example of recent advances in this field. 
 It has been shown by Barger and Dale 35 that the highly poisonous 
 depressor base, /5-imino-azolylethylamine may be isolated from 
 the intestinal mucosa, and Berthelot and Bertrand 36 have demon- 
 strated that it is in all probability formed in the intestinal canal 
 from histidine by the decarboxylating action of a bacillus newly 
 discovered by them which they have named Bacillus aminophilus 
 intestinalis. .These investigators have shown that their bacillus 
 produces the base from histidine even in the presence of 0.3 
 per cent lactic acid, unless, indeed, an excess of glucose be pres- 
 ent, in which case only this is attacked, and they have also made 
 the interesting observation that rats, fed on a milk diet, are 
 not affected by either Proteus vulgaris or Bacillus aminophilus 
 
 34 Jour. Amer. Med. Assoc., editorial comment, vol. 62, Jan. 3, 1914. 
 
 35 Jour, of Physiol., vol. 40, p. 1910, vol. 41, p. 499, 1910-1911. Consult also 
 the work of Ackermann who first demonstrated that when pure histidine is sub- 
 mitted to the action of putrefactive bacteria a considerable yield of /3-imino- 
 azolylethylamine is produced. Ztschr. f. physiol. Chem., vol. 64, p. 504, 1910. 
 
 36 Compt. rend. de. 1'Acad. des Sciences, vol. 154, pp. 1643 and 1826. See also 
 Mellenby and Twort: On the presence of /3-imino-azolylethylamine in the in- 
 testinal wall, with a method of isolating a bacillus from the alimentary canal 
 which converts histidine into this substance, Jour, of Physiol., 45, p. 53. 
 
38 JOHN J. ABEL 
 
 intestinalis when these organisms are given separately, but that 
 when they are given simultaneously the rats succumb to a diar- 
 rhoea in from 4 to 8 days. 
 
 Investigations on the pharmcological behavior of /3-imino- 
 azolylethylamine have shown that it acts very powerfully on 
 plain muscle, stimulating the . isolated uterus, for example, to 
 contraction in the almost unbelievable dilution of 1 :250,000,000. 37 
 The muscular coats of the guinea pig's bronchioles are so sensi- 
 tive to its action that large pigs are killed in a few minutes by 
 the intravenous injection of a half a milligram. The death of 
 the animal is due to asphyxia produced by a spasm of the bron- 
 chioles. Recently investigators have been much occupied in 
 studying similar features in the symptoms of the poisoning by 
 large doses of the base and those observed in anaphylactic shock 
 (action on the circulation, body temperature, respiration, etc.), 
 and some do not hesitate to affirm that the poisons of anaphylac- 
 tic shock must be put into the same pharmacological class with 
 the proteinogenous bases that we have been considering. 
 
 We may now give the cherriical formulae that illustrate the 
 various relationships that have been discussed. 
 
 OH 
 
 1 . Epinephrin, adrenaline, suprarenin, pos- 
 
 sibly derived by decarboxylation from a 
 OH OH CH 2 NH CH 3 still unknown amino acid, dioxyphenyl- 
 
 a-methylamino-j8-oxypropionic acid, as 
 suggested by M. Guggenheim, Therap. 
 Monatsh., xxvii, p. 508, 1913 
 
 OH 
 
 CH . OH . CH . NH . CH 3 CH - OH - CH 2 NH . CH 3 
 
 Epinephrin 
 OOH 
 (Unknown amino-acid) 
 
 C 
 
 37 See Frohlich and Pick: Arch. f. exp. Pathol. u. Pharraakol., vol. 71, p. 23, 
 and Sugimoto: Ibid., vol. 74, p. 27. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE 'BLOOD 39 
 OH 
 
 2. | | p-Hydroxyphenylethylamine, derived from 
 
 \/ p-hydroxyphenyl-a-amino-propionic acid, or 
 
 CH 2 CH 2 NH 2 tyrosine, as follows : 
 
 OH OH 
 
 -t I I + co 2 
 
 H 2 - CH . NH 2 COOH CH 2 . CH 2 . NH 2 
 
 Tyrosine p -Hydroxyphenylethylamine 
 
 (Tyramine) 
 
 3. | | Phenylethylamine, derived by decarboxylation 
 
 from phenyl-a-amino-propionic acid or phenyl- 
 CH 2 CH 2 NH 2 alanine, as follows: 
 
 /\ 
 
 + C0 2 
 
 CH 2 - CH. NH 2 COOH CH 2 . CH 2 NH 2 
 Phenylalanine 
 
 CH 
 
 / \ 
 
 4. HN N jS-Imidoazolylethylamine, histamin, 
 
 obtained by decarboxylation of his- 
 C - CH 2 CH 2 NH 2 tidine, as follows : 
 
 CH CH 
 
 / \ / \ 
 
 HN N - > HN N + CO 2 
 
 I I I 
 
 HC=C . CH 2 CH NH 2 - COOH HC=C - CH 2 . CH . NH 2 
 
 IV. I come now to the concluding portion of my address. That 
 science in general is a basic fact in the development of com- 
 merce and industry seems to be fully appreciated in this city 
 as shown by the establishment of the Mellon Institute of Indus- 
 trial Research and School of Specific Industries, through the 
 munificence of two of your public spirited citizens, the Messrs. 
 Richard B. and Andrew W. Mellon. I believe that no act of 
 their lives will give them more enduring satisfaction than this 
 which marks out your city as one more great center of industry 
 
40 JOHN J. ABEL 
 
 which acknowledges the dependence of all advance in material 
 civilization upon the quiet labors of the investigator. This de- 
 pendence has been forcibly expressed by former ambassador 
 James Bryce in an address to the members of the National Acad- 
 emy of Sciences. 
 
 You men of science are really the rulers of the world. It is in your 
 hands that lies control of the forces of activity; it is you who are going 
 to make the history of the future because all commerce and all industry 
 is today far more than ever the child and product of science. . . . 
 It is in your hands that the future lies, far more than in those of military 
 men or politicians. 
 
 Let me also in this connection recall the inspiring words of 
 that great investigator and benefactor of mankind, Louis Pas- 
 teur, which point out the still wider influence of science: 
 
 "Laboratories and discoveries are correlative terms/' he wrote; 
 "if you suppress laboratories, physical science will be stricken with 
 barrenness and death, it will become mere powerless information 
 instead of a science of progress and futurity; give it back its laboratories 
 and life, fecundity and power will reappear. . . Ask that they be 
 multiplied and completed. They are the temples of the future, of 
 riches and of comfort. There humanity grows greater, better, stronger. 
 There she can read the works of Nature, works of progress and universal 
 harmony, while humanity's own works are too often those of barbarism, 
 of fanaticism and destruction." 
 
 And here I shall permit myself to speak more specifically of 
 the paramount importance of chemistry in biological and medical 
 research. The subjects to which I have been calling your atten- 
 tion tonight, viz., the still unknown chemical properties and 
 molecular structure, with the single exception of epinephrin, of 
 the mysterious, correlating substances stored and formed in the 
 many organs of internal secretion, and the equally unknown 
 character of numerous constituents of the circulating blood, 
 both offer a virgin field to the biologist with a chemist's training. 
 
 The practical importance of decisive chemical advances 
 along this line is hardly to be over-stated. At present we 
 meet only vast confusion and contradictory theories. A single 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 41 
 
 clean-cut discovery, the separation from another of these glands 
 of a definite chemical individual shown to possess one or more 
 of the specific actions of the gland would clear way the mists 
 at once, and we should see the same rapid progress that has 
 followed the isolation of epinephrin, which is only one, and 
 perhaps not the most important constituent of the suprarenal 
 gland. 
 
 What a flood of light was thrown on the whole question of 
 carbohydrate metabolism in the discovery by Claude Bernard 
 of glycogen in the liver! Innumerable fruitful researches have 
 come from this as a starting point, and their bearing on our 
 understanding of such diseases as diabetes mellitus has been of 
 the most fundamental nature. 
 
 Miescher's discovery of the existence of protamin nucleate 
 in the spermatozoan heads of the Rhine salmon is another case 
 of the far-reaching importance of a definite chemical fact for 
 both biology and medicine. For further discoveries in the 
 field of nucleinic acids, a later worker, Professor Kossel, received 
 the Nobel prize. To name only one practical outcome of these 
 discoveries, our theories of the origin of uric acid in gout and 
 of the purins in general have undergone entire transformation. 
 
 The actual finding of definite and specific chemical principles 
 in the organs of internal secretion has in each case an importance 
 in the way of explaining and correlating a large number of dis- 
 connected facts, only to be likened to the discovery of the etiologi- 
 cal cause of an infectious disease. The bacillus of tuberculosis 
 or of typhoid, or the protozoa of syphilis and sleeping sickness, 
 are illuminating examples in point. Here, too, simplicity at 
 once took the place of what had been confused and complex, 
 and a multitude of already recorded facts fell into their proper 
 place. 
 
 From my insistence on our ignorance of the specific secretory 
 products of the organs of internal secretion, and of numerous 
 constituents of . the blood, it is not to be inferred that important 
 chemical facts are lacking with regard to these tissues. On 
 the contrary, a vast number of facts, some of immediate, others of 
 potential significance, have been amassed by an army of workers 
 
42 JOHN J. ABEL 
 
 in the past 30 years; it is their relation to each other and to an 
 underlying cause that remains obscure. For example: it has been 
 recently shown by Cramer and Krause 38 that when fresh thyroids 
 are fed to cats or rats kept on a carbohydrate-rich diet, the 
 glycogenic function of the liver is inhibited, and in consequence 
 this organ is soon found to contain only traces of glycogen. 
 And these investigators suspect that the well known action of 
 thyroid secretion on the metabolism is effected through this 
 change in the carbohydrate metabolism. But this important 
 discovery cannot reach its full significance until we know the 
 chemical properties of the special hormone of the thyroid gland 
 which is carried in the blood to the liver and there prevents the 
 formation of glycogen even though the food may contain an 
 abundance of carbohydrate. 
 
 Thus, too, one of the facts known about the parathyroids, 
 as shown by MacCallum and Voegtlin, 39 is that their removal 
 from the body is followed by increased excretion of calcium salts. 
 This chemical discovery also cannot yet be brought into a causal 
 connection with a definite chemical constituent of the gland. 
 
 That I may not be accused of placing too much emphasis 
 upon only one mode of attack in biological and medical research, 
 let me say that I am fully aware of how many sided are all these 
 problems and that fundamental discoveries have been made 
 and will continue to be made without the aid of chemistry. 
 This is true especially in the field of morphology. But as soon 
 as we touch the complex processes that go on in a living thing, 
 be it plant or animal, we are at once forced to use the methods 
 of this science. No longer will the microscope, the kymograph, 
 the scalpel avail for the complete solution of the problem. For 
 the further analysis of these phenomena which are in flux and 
 flow, the investigator must associate himself with those who have 
 labored in fields where molecules and atoms rather than multi- 
 cellular tissues or even unicellular organisms are the units of study. 
 Today investigators in biology and medicine are reaching out with 
 eager hands into the more exact branches of science. The great 
 
 38 Proc. Roy. Soc. B., vol. 86, p. 550, 1913. 
 
 39 Jour. Exp. Med., vol. ii, p. 118, 1909. 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 43 
 
 progress in biology and in medicine that has been made during 
 the past century proves that advantages hardly to be imagined 
 must follow upon the further application of physics and chemistry 
 to these sciences. A striking example of the debt which medi- 
 cine owes to that newer branch of chemistry called physical 
 chemistry is seen in our better understanding in the last twenty 
 years of certain dynamic equilibria of the body, such as the 
 relationship between the hydrogen and the hydroxyl ions of the 
 blood and tissues, of surface tension, osmotic pressure and the 
 colloidal state. 
 
 I also recognize that all the various aspects of any one problem 
 in our field are intimately bound together, and that progress 
 along the chemical side, for instance, of a question may have 
 to wait on the clearing up of the morphological side. When I 
 have the honor of being consulted by a young man who has 
 not yet found himself intellectually but who is filled with the 
 desire to devote his life to some branch of medicine, be it clinical 
 medicine, pathology, hygiene, bacteriology, physiology or phar- 
 macology, my advice always is, "Study chemistry for at least 
 three years. Try with all your power to master enough of this 
 great science to start you in your career." Why not make 
 this attempt at a time of life when one still takes kindly to a 
 rigid discipline 40 such as this science exacts? To this prepara- 
 tion must be added the special medical training of another 
 four or more years. A long road to travel? But I find that many 
 young men have entered upon it with great enthusiasm. 
 
 I do not mean that this long tutelage is to be a cramming pro- 
 cess. I have in mind conditions where these students will 
 be constantly under the influence of teachers who are themselves 
 investigators and daily engaged in the search for new truths. 
 Under the stimulus of such examples our young man is saved 
 
 40 The professor of physics in McGill University, Dr. A. S. Eve, has recently 
 expressed himself as follows in a paper describing modern discoveries on the 
 constitution of the atom (Jour. Franklin Institute, 1915, p. 269): "It may be 
 noted that the discoveries set forth in this brief summary have been achieved 
 by savants in the western half of Europe, and it may be asked if the education 
 in the New World is at the present time sufficiently thorough, imaginative and 
 philosophical." 
 
44 JOHN J. ABEL 
 
 from the sterile life of the mere crammer, because he sees the 
 relation of what he learns to living questions. During this 
 period of study and growth he will himself make occasional at- 
 tempts at the solution of problems. Even with the best prepara- 
 tion, workers in our fields have always to return again and again 
 to the fundamental sciences for assistance. 
 
 But to what end is all this preparation for our young man? 
 Is it solely that he may solve problems whose solution is of 
 practical value to mankind? Is his mind to shape itself only to 
 the insistent demands of utility? Even then our method of 
 training will yield the largest profit. But it does vastly more 
 than that. Thus trained our young scholar will be able to see 
 beyond the immediately practical problem, even though it be 
 as great a thing as the discovery of the cause and cure of the 
 plague that decimates a people. Greater even than the greatest 
 discovery is it to keep open the way to future discoveries. This 
 can only be done when the investigator freely dares, moved as by 
 an inner propulsion, to attack problems not because they give 
 promise of immediate value to the human race, but because 
 they make an irresistible appeal by reason of an inner beauty. 
 Some of the greatest investigators indeed have been fascinated by 
 problems of immediate utility as well as by those that deal with 
 abstract conceptions only. Helmholtz invented the ophthalmos- 
 scope and thus made modern ophthalmology possible, and at 
 the same time did work of the highest order in theoretical physics 
 and wrote on the nature of the mathematical axioms and the 
 principles of psychology. Lord Kelvin took out patents on 
 great improvements in the compass and on oversea telegraphy 
 and also made contributions to our knowledge of the ultimate 
 constitution of the atom and the properties of the ether. From 
 this point of view the investigator is a man whose inner life 
 is free in the best sense of the word. In short, there should be 
 in research work a cultural character, an artistic quality, elements 
 that give to painting, music and poetry their high place in the life 
 of man. 
 
 Ladies and gentlemen, I have attempted in this hour to point 
 out some recent advances that have been made in the study of 
 
EXPERIMENTAL AND CHEMICAL STUDIES OF THE BLOOD 45 
 
 the blood and of the organs of internal secretion, and have cited 
 the beneficent effects of even these small advances a very few 
 bright stars in a darkened sky in order to emphasize the great 
 r61e that chemistry is destined to play in biology and medicine. 
 I have strongly urged that those who are to be medical teachers 
 and investigators should not content themselves with a mere 
 smattering, but endeavor to acquire a really sound training in 
 one of the fundamental sciences. 
 
 You, my colleages, working with open-minded and generous 
 trustees, must see to it that the men selected for important 
 posts shall be those that are capable of training and inspiring 
 the young men who in their turn will furnish the leadership of 
 the future. 
 
 In our country many agencies combine to foster the higher 
 learning. It is to the lasting honor of men of wealth that they 
 have appreciated the need for institutes of research and in a 
 number of notable instances have placed large sums at the 
 disposal of science. They have responded nobly to that appeal 
 of Pasteur which I have already cited in which he calls labora- 
 tories "the temples of the future, of riches and of comfort." 
 
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