CHAPTER I HISTORICAL INTRODUCTION
B Y G R E G O R Y P I N C U S AND K E N N E T H V . T H I M A N N
THE CONCEPT OF INTERNAL SECRETIONS OR SPECIAL TISSUE "FERMENTS" IN ANIMALS WAS ADVANCED AS EARLY AS 1 7 7 5 BY DE BORDEU OF MONTPELLIER AND EXTENDED BY LE GALLOIS IN 1801. THE EXPERIMENTAL DEMONSTRATION OF AN INTERNAL SECRETION WAS FIRST GIVEN BY BERTHOLD IN 1849, IN HIS CLASSICAL EXPERIMENT IN WHICH CASTRATION EFFECTS WERE PREVENTED BY THE TRANSPLANTA- TION OF TESTIS TISSUE IN THE FOWL. MANY OTHER DEMONSTRATIONS FOLLOWED.
YET THE UNDERSTANDING OF THE PRECISE NATURE OF A HORMONE, AND ALSO OF THE GENERAL PRINCIPLES INVOLVED, WAITED UNTIL THE BAYLISS AND STARLING WORK ON CONTROL OF PANCREATIC SECRETION BY THE INTESTINE, IN 1904. IT WAS ONLY THEN THAT THE CONCEPT OF A "CHEMICAL MESSENGER" WHICH COORDINATES THE ACTIVITY OF DIFFERENT PARTS OF THE BODY WAS CRYSTALLIZED. THE REASON FOR THE DELAY IN COMPREHENSION OF THE PRINCIPLE WAS CONCISELY PUT BY HOP- KINS: " U P TO NEAR THE END OF THE LAST CENTURY NEARLY EVERY EXPERT LOOKED TO THE INFLUENCE OF THE NERVOUS SYSTEM ALONE AS CONCERNED WITH THE CO-ORDI- NATION OF FUNCTIONS IN THE BODY; THE CONCEPTION OF CHEMICAL REGULATION AND CO-ORDINATION HAD ACHIEVED NO PLACE IN THE MINDS OF THE MAJORITY."
IN OTHER WORDS, CHEMICAL PHYSIOLOGY WAS A LATE COMER TO A FIELD IN WHICH ANATOMY, MORPHOLOGY, AND SURGERY HAD ESTABLISHED THEMSELVES. IT IS WORTH NOTING THAT, IN SUCH ACTIVITIES AS COLOR CHANGES IN THE SKIN OF FISH DUE TO MELANOPHORES, THE RELATIVE IMPORTANCE OF NERVOUS AND HORMONAL CONTROL IS A MATTER OF DISPUTE EVEN TODAY.
AS WITH THE CONCEPTS, SO WITH THE MATERIALS. EIGHTY-SIX YEARS AFTER BERTHOLD'S WORK LAQUEUR ISOLATED TESTOSTERONE FROM BULL TESTICLES TO BRING FORTH THE FINAL CHEMICAL PROOF FOR THE EXISTENCE OF THE TYPE OF SUBSTANCE INDICATED BY BERTHOLD'S EXPERIMENTS. FOR OTHER GLANDS THERE ARE SIMILAR, BUT NOT QUITE SO LONG, LATENT PERIODS BETWEEN THE FIRST EFFECTIVE EXPERI- MENTAL DEMONSTRATION OF INTERNAL SECRETORY FUNCTION AND THE ISOLATION OF A PURE ACTIVE HORMONE. IN TABLE I WE LIST THESE OCCASIONS FOR THOSE GLANDS FROM WHICH AUTHENTIC CHEMICAL ISOLATION HAS BEEN MADE. IN THE LAST INSTANCE LISTED, THE ISOLATION WAS MADE FROM QUITE OTHER SOURCES THAN WERE USED FOR THE ORIGINAL DEMONSTRATION.
DURING THESE "LATENT" PERIODS THERE HAS, OF COURSE, BEEN NO LACK OF 1
2 GREGORY PINCUS AND KENNETH V. THIMANN
T A B L E I
T H E L A T E N T P E R I O D B E T W E E N D I S C O V E R Y A N D H O R M O N E I S O L A T I O N
Endocrine gland
First experimental demonstration of endocrine activity
Isolation of a pure hormone
Latent period, years
Testis Berthold—1849 Laqueur—1935 86
Adrenal cortex. . Brown-Séquard—1856 Mason, Myers, and Ken-
dall—1936 80
Thyroid Schiff—1856 Kendall—1914 58
Ovary (estrogen) Knauer—1896 MacCorquodale, Thayer,
Doisy—1935 39
Pancreas Von Mehring and Minkow- Abel, Geiling, Rouiller, Bell,
ski—1890 Wintersteiner—1926 36
Posterior pitui- Oliver and Shafer—1895 K a m m , Aldrich, Grote,
tary Rowe, Bugbie—1928 33
Adrenal medulla Pellacini and Foa—1869 Takamine—1901 32 Corpus luteum Ancel and Bouin—1910 Butenandt, Allen, Winter- 24
of ovary steiner, Slotta, Ruschig,
Fels, Hartman, Wettstein, Hisaw, Fevold—1934 Tip of oat seed-
ling Boysen-Jensen—1910 K ö g l and Haagen Smit 1931 21
INVESTIGATIVE ACTIVITY. INDEED THEY HAVE FREQUENTLY BEEN MARKED BY ACTIVITY FAR MORE SIGNIFICANT THAN THE BOUNDING INVESTIGATIONS. ONE HAS ONLY TO RECALL THE EFFECTIVE DISCOVERY OF PANCREATIC INSULIN BY BANTING, BEST, AND THEIR CO-WORKERS, THE PENETRATING INVESTIGATIONS OF ESTRUS CYCLES BY MARSHALL, STOCKARD, AND PAPANICOLOU, LONG, EVANS, AND ALLEN, THE LABORIOUS ELUCIDATION OF TESTIS FUNCTION BY KOCH, MOORE AND OTHERS, AND THE QUANTITATIVE EXPLANATION OF PLANT TROPISMS BY CHOLODNY, DOLK, AND WENT, AS ISOLATED INSTANCES OF PROFOUND ADVANCEMENTS IN OUR KNOWLEDGE OF HORMONE PHYSIOLOGY AND BIOCHEMISTRY.
NOR ARE WE CERTAIN THAT THE ISOLATION^OF A PURE ACTIVE PRINCIPLE NECES- SARILY INFORMS US OF THE TRUE NATURE OF THE HORMONES AT WORK IN THE ORGANISM. WHETHER THE POSTERIOR PITUITARY HORMONE IS UNITARY OR DUAL IN NATURE IS STILL A MATTER OF UNCERTAINTY AND ABEL IN 1 9 2 3 MAY HAVE ISOLATED THE SINGLE EFFECTIVE SUBSTANCE. THE FUNCTIONING OF ACETYLCHOLINE AND ADRENALIN AS NEUROHORMONES IS NOTORIOUSLY CONTROVERSIAL. ALTHOUGH TESTOSTERONE HAS BEEN ISOLATED FROM BULL TESTIS, RUZICKA HAS FAILED TO OBTAIN IT FROM SWINE TESTIS AND EVEN NOW WORKERS ARE SEARCHING FOR OTHER TESTICULAR ANDROGENS. FURTHERMORE, WE ARE NOT CERTAIN OF THE TRUE STATE OF ANY OF THE STEROID HORMONES in vivo. EVIDENCE FOR A CORTICOSTEROID ASCORBATE HAS RECENTLY BEEN PRESENTED, AND THE PROBLEM OF PROTEIN-STEROID
I. HISTORICAL INTRODUCTION 3
CONJUGATES HAS SCARCELY BEEN TOUCHED. IN PLANTS, THE AUXIN-PROTEINS PRESENT A VERY SIMILAR CASE. AS A HISTORIC PARALLEL ONE MAY QUESTION THE AUTHENTICITY OF THYROXIN AS THE TRUE THYROID HORMONE IN VIEW OF THE ISOLA- TION OF ACTIVE THYROPROTEIN.
THE MODERN CONCEPT OF INTERNAL SECRETIONS IN ANIMALS ENUNCIATED BY BROWN-SÉQUARD IN 1889, AND CLARIFIED AND BAPTIZED BY BAYLISS AND STAR- LING, REQUIRED AND HAS RECEIVED VOLUMINOUS PROOF. IT WAS UNFORTUNATE THAT FOR A TIME ENDOCRINOLOGY WAS SOMEWHAT SUSPECT; A NONE TOO REPUTABLE STEP-CHILD OF PHYSIOLOGY. THIS WAS IN LARGE MEASURE DUE TO THE EXPLOITA- TION OF THE IDEA OF REJUVENATION BY HORMONES, AN IDEA THAT HAD ITS INCEP- TION ALSO WITH BROWN-SÉQUARD. THE USE OF TESTIS EXTRACTS, OF TESTIS TRANSPLANTS AND VARIOUS "REJUVENATION" OPERATIONS IN MEN WERE OBNOX- IOUSLY PUBLICIZED IN THE LATE 19TH AND EARLY 20TH CENTURY. BUT ALONG WITH THESE QUESTIONABLE OUTGROWTHS OF ENDOCRINOLOGY WERE ACTIVITIES REPRESENT- ING SOLID CONTRIBUTIONS TO OUR KNOWLEDGE OF THE SUBJECT. THE PAINSTAK- ING RESEARCHES THAT LED TO THE ESTABLISHMENT OF A GENUINE SCIENCE CANNOT, OF COURSE, BE DESCRIBED HERE; MANY OF THEM ARE OUTLINED IN THE SPECIAL CHAPTERS OF THIS BOOK.
TABLE I SHOULD NOT BE TAKEN AS A GUIDE TO THE HISTORY OF ADVANCES IN ANIMAL HORMONE DISCOVERY. AS A READING OF OUR CHAPTER TITLES INDICATES, IMPORTANT SECRETORY GLANDS AND THEIR PRODUCTS ARE OMITTED. MANY HORMONES, PARTICULARLY AMONG THE LOWER ANIMALS, ARE FAR FROM CHARAC- TERIZATION, LET ALONE ISOLATION. WHAT TABLE I DOES ILLUSTRATE IS THAT IN MOST CASES AT LEAST TWO GENERATIONS ARE REQUIRED TO ESTABLISH A HORMONE AS A BIOCHEMICAL ENTITY. DURING THIS TIME THE WORK FOLLOWS A BROADLY REPEATABLE PATTERN; CONFIRMATION AND EXTENSION OF THE FIRST OBSERVATIONS, STUDY OF THE REACTIONS OF OTHER TISSUES, THE GRADUAL EMERGENCE OF METHODS OF ASSAY, STANDARDIZATION OF THESE METHODS, AND THE CHEMICAL ISOLATION.
THEN BEGINS A NEW SERIES OF EXPERIMENTS WITN THE PURE MATERIAL OR A SYNTHETIC SUBSTITUTE.
THERE HAS, IN THE LAST DECADE, BEEN A NOTABLE QUICKENING OF GENERAL INTEREST IN HORMONES FOR TWO REASONS. THE FIRST IS THAT THE ORGANIC CHEMISTRY OF THE HORMONES, ESPECIALLY OF THE STEROIDS, HAS BEEN REMARK- ABLY ELUCIDATED. FOLLOWING THE ISOLATION OF ESTRONE IN 1 9 2 9 THE ORGANIC CHEMISTS HAVE NOT ONLY ISOLATED OVARIAN, ADRENAL, AND TESTIS STEROIDS BUT HAVE SYNTHESIZED A NUMBER OF THE PRINCIPAL ACTIVE SUBSTANCES. THE SECOND BASIS OF QUICKENING INTEREST HAS BEEN THE APPLICATION OF MODERN METHODS OF PROTEIN CHEMISTRY TO THE ELUCIDATION OF THE PROTEIN HORMONES.
THE PROBLEM OF POSTERIOR PITUITARY HORMONES HAS BEEN REATTACKED AND REAL PROGRESS IN THE PURIFICATION OF ANTERIOR PITUITARY HORMONES HAS BEEN MADE. THE IMPORTANCE OF THESE ADVANCES IN HORMONE CHEMISTRY LIES NOT MERELY IN THE CHEMICAL FACTS THEMSELVES. THE OPPORTUNITY IS OFFERED TO
4 GREGORY PINCUS AND KENNETH V. THIMANN
PHYSIOLOGISTS, BIOCHEMISTS, AND CLINICIANS TO INVESTIGATE IN THEIR FIELDS THE PROPERTIES AND USEFULNESS OF DEFINABLE, REPRODUCIBLE MATERIALS. FOR THIS REASON THERE IS NO NEED FOR THE TYPE OF CONTROVERSY ON THE EFFICACY OF VAR- IOUS EXTRACTS THAT CLOUDED THE EARLY YEARS OF ENDOCRINE RESEARCH. THE AVAILABILITY OF LARGE AMOUNTS OF PURE HORMONE HAS LED TO INTENSIVE STUDIES OF THEIR EFFECTS IN EVERY BRANCH OF THE ANIMAL KINGDOM.
BROWN-SÉQUARD WAS INSISTENT THAT EVERY TISSUE OF THE BODY PRODUCED HORMONES. SINCE HIS DAY EXPERIMENTERS WITH ANIMAL HORMONES HAVE LARGELY CONCENTRATED ON SPECIFIC GLANDS. THERE APPEARS, HOWEVER, TO BE A RETURN TOWARD HIS ORIGINAL INTERESTS. THE FACT THAT THE GUT PRODUCES HORMONES HAS LONG BEEN A CHALLENGE TO THE NOTION OF A SPECIFIC SECRETORY GLAND. BUT NOW IT IS BEING RECOGNIZED THAT THE FIELD IS MUCH WIDER. THE NEUROHUMORS ARE OBVIOUSLY SPECIAL TISSUE PRODUCTS. INSECT HORMONES DO NOT NECESSARILY COME FROM ORGANS OF SPECIFIC GLANDULAR FUNCTION. AND IN THE PLANTS WE FIND GROWTH HORMONES PRODUCED IN A VARIETY OF TISSUES, NONE OF WHICH IS MERELY A GLAND. IT IS TEMPTING TO LOOK FOR A CYCLE OF ACCOMPLISHMENT IN ANY SCIENCE.
THE FINAL STAGE IN THE STUDY OF A HORMONE AND ITS ACTIVITY, IF INDEED THE WORD "FINAL" CAN EVER BE APPLIED IN PHYSIOLOGY, IS THE ELUCIDATION OF THE MECHANISM OF ITS ACTION. BUT THIS INVOLVES VERY PROFOUND BIOCHEMI- CAL QUESTIONS; SOME OF THEM WE ARE NOT EVEN READY TO ASK, LET ALONE TO ANSWER. MANY OF THEM INVOLVE PROBLEMS OF GROWTH—CONTROL OF THE LIMITED SPECIFIC GROWTH OF A PARTICULAR TISSUE, LIKE THE VAGINAL EPITHELIUM OR THE CORPUS LUTEUM. SOME ARE INTERRELATED WITH GENERAL METABOLISM.
ALL MUST ENTAIL ENZYME SYSTEMS, PROBABLY SYSTEMS OF WHICH AS YET WE KNOW NOTHING. CAN A STEROID FUNCTION, FOR INSTANCE, AS A COENZYME?
HOW CAN THE UTILIZATION OF POTASSIUM, OR CALCIUM, BE INFLUENCED BY TRACES OF SUBSTANCES? THE FUTURE OF HORMONE RESEARCH WILL THUS BE IN LARGE PART BOUND UP WITH THE ADVANCES IN GENERAL BIOCHEMISTRY AND PHYSIOLOGY, ALTHOUGH HORMONES WILL DOUBTLESS PROVE TO BE INVALUABLE TOOLS FOR THE ATTACK OF THESE FUNDAMENTAL QUESTIONS. AS YET IT MUST BE SAID THAT THIS ASPECT OF THE WORK IS SCARCELY BEGUN. NEVERTHELESS, THE ACCUMULATION OF KNOWLEDGE NOW AVAILABLE MEANS THAT MUCH PROGRESS ALONG THESE LINES IS NOW POSSIBLE. PERHAPS, THEREFORE, THE PRESENT IS THE IDEAL TIME TO TAKE STOCK OF THE MATERIAL, AND TO PUT OUR KNOWLEDGE TOGETHER IN CAREFULLY CONSIDERED AND WELL DIGESTED FORM, READY FOR FURTHER ADVANCES.
