SMITH, PHILIP EDWARD

(b. DeSmet, South Dakota, 1 January 1884; d. Florence, Massachusetts, 8 December 1970),anatomy, endocrinology.

Prior to Smith many investigators had attempted to study the effects of the removal of the physis (pituitary gland). Since this gland lies at the base of the brain, most workers used an intracranial approach, which involved some possibility of damage to the brain. For many years there was an intensive controversy as to which of the symptoms of hypophyseal removal (hypophysectomy) were due to brain damage and which to actual removal of the gland. Smith developed a surgical approach through the neck to the base of the skull, where he drilled a small hole that exposed the hypophysis directly without any contact being made with the brain. The results of removal of the gland by this route resulted in a number of symptoms, which were completely reversible by daily implants of the anterior lobe of the hypophysis from donor animals into the operated animal. He further placed lesions in the base of the brain close to the hypophyseal region and demonstrated that these were the cause of the remarkable adiposity that many previous investigators had attributed to hypophyseal insufficiency. He showed that uncomplicated hypophysectomy in mammals resulted in cessation of growth; loss of weight; atrophy of the reproductive system, the thyroid gland, and the cortex of the adrenal gland; and a number of other symptoms.

Philip E. Smith was the youngest of the three children of John E. Smith, a congregationalist minister, and his wife, Lydia Elmina Stratton. Not long after Philip’s birth, the family moved to Niobrara. Nebraska, where his father was both a government agent and a schoolteacher at a Ponca Indian mission.

The Smith family remained in Niobrara until Philip was about six years old, at which time they acquired an eighty†acre farm in Moorpark, California (Ventura County).

Smith attended the local elementary school and spent much of his time helping with the farm work. There was no high school near the farm and all three children had to leave home to attend the Pomona Preparatory School. They subsequently went to Pomona College. Philip and his older brother did plumbing work for the college and helped to run the college heating plant. When he graduated with a B.S. degree in 1908, Philip was president of his class.

After his graduation from Pomona, he worked for a year as an entomologist engaged in the control of certain insect infestations on citrus fruit trees in southern California. During this year his sister Hope died of appendicitis.

Probably influenced by one of his instructors at Pomona, William Atwood Hilton, who had obtained his degree in histology at Cornell. Smith applied for admission to the Cornell Graduate School. He requested a first major in advanced systematic entomology and a first minor in advanced economic entomology. He entered Cornell in the fall of 1909. Shortly afterward. Smith asked to change his minor subject (for his M. S. degree) to histology under Kingsbury in the anatomy department, but it seems that the M.S. (1910) was in entomology. In October 1910 Smith applied for candidacy for a Ph.D. with a major in histology and embryology, a minor in vertebrate zoology, and a minor in systematic entomology. Sometime later he requested a change of his minor in vertebrate zoology to a minor in human anatomy. It appears that this request was granted; Smith obtained his Ph.D. in anatomy under Kingsbury in 1912.

In his doctoral thesis, “Some Features in the Development of the Central Nervous System of Desmognathus fusca” Smith discussed in depth the development of the hypophysis cerebri (pituitary gland), but he also devoted an almost equal amount of attention to the pineal body. It is clear from his thesis that even before he left Cornell. Smith faced the scientific crossroads of his career. He was intensely interested in the embryology, morphology, and function of the pituitary gland, but he also appeared to have an equally intense interest in the pineal body. It is also clear which road he decided to follow. All of his many subsequent published paper were directly or indirectly concerned with the pituitary gland. It is probable that Smith selected this path because he had already foreseen possible approaches to experimental ablation of the hypophysis in the amphibian embryo.

In the summer of 1912 Smith accepted a position as an instructor in the Department of Anatomy at the University of California (Berkeley). Here he shared an office with Irene A. Patchett, an assistant in anatomy. It is significant that she shortly obtained her master’s degree with a thesis on the development of the hypophysis of the frog.

Irene Patchett and Philip Smith were married in December 1913.

During this time, Smith was preparing to start his experimental operations aimed at the ablation of the pituitary anlage in the amphibian embryo. Research funds were scarce, and Smith and his wife spent much of their time on field trips collecting frogs, tadpoles, and frog eggs. He set up facilities in the laboratory to raise amphibian and at the same time he devoted many hours to the meticulous task of hand†grinding sewing needles into the microscalpels which he needed for his work. He launched his first classic experiments on the pituitary gland. He surgically removed the anlage of the pars distalis of the hypophysis at a very early stage in the developing frog embryo (early tail bud stage). Although this work progressed rapidly and successfully, it was not published until 1916.

During the same period, B. M. Allen, an investigator at the University of Kansas, was conducting almost identical research. He and Smith chanced to meet socially and thus discovered their common interest and discussed their experiments fully and frankly. It is said that there was an understanding between them in regard to the initial publication of this very important work. Allen’s work was published in the same journal as Smith’s and in the same year, but several issues later. Throughout his life Smith retained the highest admiration for Allen as a scientist.

Meanwhile an event occurred which significantly influenced Smith’s subsequent scientific career. In 1915 Herbert M. Evans came from Johns Hopkins to Berkeley as professor of anatomy (he was only a few years older than Smith). He brought with him from Hopkins another brilliant young anatomist, George W. Corner. During the first few years of this new departmental regime Smith and Evans were the best of friends. But with the passage of time Smith developed rather negative feelings toward Evans. Smith and Corner remained lifelong friends.

This change in Smith’s attitude may have been due to Evans’ rather close observation of Smith’s work. In his memorial biography of Evans (Anatomical Record, 1971), Corner stated: “Daily observations of Philip Smith’s pioneering study of the effects of ablation of the hypophysis of frog larvae (begun at Berkeley before Evans took over the department of anatomy) turned Evans’ attention to the hypophyseal hormones.” It seemed that Smith felt that this “daily observation” of his work overstepped the bounds of scientific propriety. Smith remained at Berkeley until 1926, and it appears that he continued to feel that Evans might be taking advantage of his work.

Smith continued his work on hypophysectomy in amphibia, which ultimately led to his classic monograph “The Pigmentary, Growth and Endocrine Disturbances Induced in the Anuran Tadpole by the Early Ablation of the Pars Buccalis of the Hypophysis” (1920).

In 1919 Smith took a six†month sabbatical leave from the University of California. He moved his family to Boston, where he worked with W. B. Cannon. Smith was greatly stimulated to repeat in mammals what be had done in amphibia and he had been considering approaches to this problem. Probably the greatest obstacle blocking the progress of endocrinology was the confusion and controversy about the function of the hypophysis.

Many investigators in Europe had already published reports on hypophysectomy in various mammals. The results were as varied as the investigators. In 1912, in the United States, Harvey Cushing “hypophysectomized” dogs and came to the conclusion that survival for more than a few days was impossible without the hypophysis.

Most of the investigators in this field had used an intracranial approach to the pituitary gland. This procedure led to considerable difference of opinion as to whether the results obtained in various experiments were the consequence of ablation of the pituitary gland or the result of damage done to the brain along the course of the surgical approach employed.

After his return to Berkeley from Cannon’s laboratory. Smith continued his work on amphibia, but he now started to concentrate on an approach to the mammalian hypophysis. It is interesting that his first efforts (in the rat) utilized the intracranial approach. But the method Smith used was novel. He designed and constructed a microsyringe which was capable of accurately injecting quantities of less than .002 milliliters. He used this instrument to inject .010 to .013 milliliters of a chromic acid solution into the anterior lobe of the hypophysis. In 1923, in a little†known paper (“The Production of the Adiposogenital Syndrome in the Rat, With Preliminary Notes Upon the Effects of a Replacement Therapy”), Smith described one single rat in which he had obtained adequate histological evidence of the complete destruction of the anterior lobe and at the same time he could find no evidence of any damage to neural components of the hypophysis or of brain damage. In this single rat, Smith was able to demonstrate that there was ovarian and uterine atrophy with no adiposity. He also showed that the genital atrophy was reversible by replacement therapy with a material derive from anterior pituitary extracts. It may seem strange that Smith should have published a paper which included his findings on a single rat. However, it is typical of the man that his extreme intellectual honesty and his intelligence never permitted any of his intuitive feelings or theories to interfere with the objective realities of an experiment. When one single experimental animal did not fit in with his previous ideas on hypophyseal function, he thought that this was worthy of public comment. Smith Smith later published extensive accounts of this chromic acid injection technique and its results.

Nevertheless, he realized that this intracranical approach was unsatisfactory. He proceeded to develop a parapharyngeal approach to the hypophysis in the rat. This involved a surgical route through the neck to reach the sphenoid bone at the base of the skull; by drilling through the sphenoid at the proper site he exposed the gland. By means of suction applied through a glass cannula he attained a complete hypophysectomy without touching the brain. The very vital hypothalamic region in the floor of the brain is separated from the pituitary body by the very tough double reflection of dura mater (the diaphragma sella) which is pierced by the pituitary stalk. This adequately protected the floor of the brain from any possible damage during the course of the operation, and made it possible to clearly distinguish the effects of hypophysectomy from the symptoms which followed damage to the hypothalamic region. Furthermore he was able to reverse the symptoms which followed this hypophysectomy by daily implants of anterior pituitary tissue into his operated animals.

In 1921 Smith had been promoted to associate professor of anatomy at the University of California. In 1926 he refused an offer of a full professorship in physiology. He felt that he was primarily an anatomist. In the same year he was offered an associate professorship in anatomy at Stanford and he accepted. Both he and his family were quite happy in this new location and he quickly set up his laboratory to continue his work on hypophy†sectomy in rats. Smith probably did not realize that as a result of his work on amphibia, he was already internationally known in scientific circles. Although at this date he had published little on his mammalian work, the news of his great breakthrough in this field had spread.

He had barely become settled at Stanford when he was offered a position as a full professor of anatomy at the College of Physicians and Surgeons at Columbia. He accepted this position as of July 1927 but proceeded with a planned leave. He visited various laboratories in Europe, spending three months in one laboratory in Vienna. Smith returned to New York in December 1927 to assume his new position.

Smith’s years at Columbia were his most productive. His classic paper “Hypophysectomy and a Replacement Therapy in the Rat” (1(1930) was published there. This work gave a complete account of his great breakthrough in hypophyseal physiology.

Smith continued his studies of the mammalian hypophysis and finally extended this work to the monkey (rhesus). This later work made possible the study of the role of the hypophysis in a primate whose reproductive cycle was very similar to that of the human species.

During this period many young postdoctoral students from the United States and Europe came to spend a year or more in his laboratory. Also a number of graduate students obtained their Ph.D. degrees under Smith’s direction.

Smith was also instrumental in bringing two of his former co†workers from the West Coast to Columbia; Earl Theron Engle, an anatomist from Stanford, and Goodwin Lebaron Foster, a biochemist from the University of California. Both these men remained at Columbia for the balance of their careers.

In the late fall and winter of 1939–1940 Smith and his wife spent three months at the School of Tropical Medicine in Puerto Rico. The U.S. Public Health Service maintained a large colony of rhesus monkeys on a small island off the coast of Puerto Rico. Smith thus had access to a supply of moneys that was far superior to his own colony at columbia and this gave great stimulus to his work on the rhesus monkey. which he continued at Columbia until his retirement.

Smith’s work was interrupted for some months in 1951 when he was run over by a small cultivator tractor while working on a hillside on his property in Westwood. New Jersey. He returned to active work in his laboratory. Smith became professor emeritus of anatomy in 1952; but he continued at Columbia with an appointment as a lecturer in anatomy until 1954, at which time he decided to retire. He and his wife settled in Sunderland, Massachusetts, near their daughter Fredrika, a pediatrician in Northampton.

Smith was obviously restless without a laboratory, and in 1956 he returned to Stanford as a research associate. His wife received an appointment as his research assistant. Their work at Stanford was supported by the National Science Foundation. The Smiths intended to spend a year at Stanford, but remained in active work there for seven years. Shortly before his final retirement in 1963, the endocrinologists A. S. Parkes and E. C. Amoroso journeyed from London to Stanford to present to Smith the Sir Henry Dale Medal of the Society of Endocrinology of Great Britain.

After the Smiths left Stanford they returned to Florence, Massachusetts. They also had a cabin in Maine, where they spent the summer months. All his life, from the five†year†old boy riding his pony with the Ponca Indians to the eightly†live†year†old man fly†fishing for salmon in Maine, he loved the outdoors. He remained active until a few weeks before his death.

BIBLIOGRAPHY

I. Original Works. Smith’s writings include “A Study of Some Specific Characters of the Genus Pseudococcus,”in Journal of Entomology and Zoology, 5 (1913), 69–84; “Some Features in the Development of the Central Nervous System of Desmognathus fus†ar. in Journal of Morphology. 25 (1914). 511–557: “The Development of the Hypophysis of Amia calva” in Anatomical Record. 8 (1914). 490–508; “Experimenttal Ablation of the Hypophysis in the Frog Embryo,” in Science, 44 (1916). 280–282; “On the Effects of the Ablation of the Epithelial Hypophysis on the Other Endocrine Glands.” in Proceedings of the Society for Experimental Biology and Medicine, 16 (1919), 81; “Studies on the Conditions of Activity in the Endocrine Glands,” in American Journal of Physiology, 60 (1922), 476–494, written with W. B. Cannon: “The Pigmentary, Growth and Endocrine Disturbances Induced in the Anuran Tadpole by the Early Ablation of the Pars Buccalis of the Hypophysis.” in American Anatomical Memoirs, 11 (1920), 1–151; “The Production of the Adiposogenital Syndrome in the Rat With Preliminary Notes on the Effects of a Replacement Therapy,” in Proceedings of the Society for Experimental Biology and Medicine, 21 (1923), 204–206, written with A. T. Walker and J. B. Graeser; “The Function of the Lobes of the Hypophysis as Indicated by Replacement Therapy With Different Portions of the Ox Gland,” in Endocrinology, 7 (1923), 579–591: “The First Occurrence of Secretory Products and of a Specified Structural Differentiation in the Thyroid and Anterior Pituitary During the Development of the Pig Foetus,” in Anatomical Record, 33 (1926), 289–298; “Hastening Development of the Female Genital System by Daily Homoplastic Pituitary Transplants,” in Proceedings of the Society for Experimental Biology and Medicine, 24 (1926), 131–132; “The Genital System Responses to Daily Pituitary Transplants,” ibid., 24 (1927), 337–338; “Induction of Precocious Sexual Maturity in the Mouse by Daily Pituitary Homeo and Heterotransplants,” ibid., 24 (1927), 561–562. written with E. T. Engle; “The Induction of Precocious Sexual Maturity by Pituitary Homotransplants,” in American Journal of Physiology, 80 (1927), 114–125: “Hypophysectomy and Replacement Therapy”, in Journal of the American Medical Association, 87 (1926), 2151–2153, written with G. L. Foster; “A Comparison in Normal, Thyroidectomized and Hypophysectomized Rats of the Effects Upon Metabolism and Growth Resulting From Daily Injections of Small Amounts of Thyroid Extract”, in American Journal of Pathology, 3 (1927), 669–687, written with C. L. Greenwood and G. L. Foster; “Experimental Evidence Regarding the Role of the Anterior Pituitary in the Development and Regulation of the Genital System”, in American Journal of Anatomy, 40 (1927), 159–217, written with E. T. Engle; “The Disabilities Caused by Hypophysectomy and Their Repair.” in Journal of the American Medical Association, 88 (1927), 158–161; “The First Appearance in the Anterior Pituitary of the Developing Pig Foetus of Detectible Amounts of the Hormones Stimulating Ovarian Maturity and General Body Growth.,” in Anatomical Record, 43 (1929), 277–297, written with C. Dortzbach; “Hypophysectomy and a Replacement Therapy in the Rat,” in American Journal of Anatomy, 45 (1930), 205–273; “Disorders Induced by Injury to the Pituitary and the Hypo-thalamus,” in Journal of Nervous and Mental Diseases, 74 (1931), 56–61; “The Effect of Hypophysectomy on Ovulation and Corpus Luteum Formation in the Rabbit,” in Journal of the American Medical Association, 97 (1931), 1861–1863; “The Non-essentiality of the Posterior Hypophysis in Parturition,” in American Journal of Physiology, 99 (1932), 345–348; “Prevention of Uterine Bleeding in the Macacus Monkey by Corpus Luteum Extract (Progestin),” in Proceedings of the Society for Experimental Biology and Medicine, 29 (1932), 12–25, written with E. T. Engle; “Effect of Injecting Pregnancy Urine Extracts in Hypophysectomized Rats. I . The Male,” in Proceedings of the Society for Experimental Biology and Medicine, 30 (1933), 1246–1250, written with S. L. Leonard; “Effect of Injecting Pregnancy Urine Extracts in Hypophysectomized Rats. II. The Female,” ibid., 30 (1933), 1248, written with S. L. Leonard; “Increased Skeletal Effects in Anterior Pituitary Growth Hormone Injections by Administration of Thyroid in Hypophysectomized, Thyroparathyroidectomized Rats,” ibid., 30 (1933), 1252–1254; “The Effect of Castration Upon the Sex Stimulating Potency and the Structure of the Anterior Pituitary in Rabbits.” in Anatomical Record, 57 (1933), 177–195, written with A. E. Severinghaus and S. L. Leonard; “Responses of the Reproductive System of Hypophysectomized and Normal Rats to Injections of Pregnancy Urine Extracts, I. The Male,” ibid., 58 (1934), 145–173, written with S. L. Leonard; “Responses of the Reproductive System of Hypophysectomized and Normal Rats to Injections of Pregnancy Urine Extracts, II. The Female,” ibid,. 58 (1934), 175–203, written with S. L. Leonard; “Differential Ovarian Responses After Injections of Follicle Stimulating and Pregnancy Urine in Very Young Female Rats,” in Proceedings of the Society for Experimental Biology and Medicine, 31 (1934), 744–746, written with E. T. Engle and H. H. Tyndal; “The Role of Estrin and Progestin in Experimental Menstruation,” in American Journal of Obstetrics and Gynecology, 29 (1935), 787–798; “Effect of Hypophysectomy on Blood Sugar of Rhesus Monkeys,” in Proceedings of the Society for Experimental Biology and Medicine, 34 (1936), 247–749, written with L. Dotti, H. H. Tyndal, and E. T. Engle; “The Reproductive System and Its Responses to Ovarian Hormones in Hypophysectomized Rhesus Monkeys,” ibid., 34 (1936), 245–247; “Response of Normal and Hypophysectomized Rhesus Monkeys to Insulin,” in Proceedings of the Society for Experimental Biology and Medicine, 34 (1936), 250–251, written with H. H. Tyndal, L. Dotti, and E. T. Engle; “Is the Blood Calcium Level of Mammals Influenced by Estrogenic Hormones?,” in Endocrinology, 22 (1938), 315–321, written with L. Levin; “The Endometrium of the Monkey and Estrone-Progesterone Balance,” in American Journal of Anatomy, 63 (1938), 349–365. written with E. T. Engle; “Responses of Normal and Hypophysectomized Immature Ratsto Menopause Urine Injections.” in American Journal of Physiology, 124 (1938), 174–184, written with L. Levin and H. H. Tyndal; “Certain Actions of Testosterone on the Endometrium of the Monkey and on Uterine Bleeding,” in Endocrinology, 25 (1939). 1–6, written with E. T. Engle; “Effect of Equine Gonadotropin on Testes of Hypophysectomized Monkeys,” in Endocrinology, 31 (1942), 1–12; “Continuation of Pregnancy in Rhesus Monkeys (Macaca mulatta) Following Hypophysectomy,” in Endocrinology, 55 (1954), 655–664; “The Endocrine Glands in Hypophysectomized Pregnant Rhesus Monkeys (Macaca mulatta) With SpecialReference to the Adrenal Glands,” in Endocrinology, 56 (1955), 271–284; “Postponed Homotransplants of the Hypophysis Into Region of the Median Eminence in Hypophysectomized Male Rats,” in Endocrinology,68 (1961), 130–143; “Postponed Pituitary Homotransplants Into the Region of the Hypophysial Portal Circulation in Hypophysectomized Female Rats,” in Endocrinology, 73 (1963), 793–806. written with Irene P. Smith; and Baileys Text book of Histology, 7th–13th eds. (1932–1958), coauthor.

II. Secondary Lliterature. On Smith and his work, see Frederic.J. Agate, Jr., “Philip Edward Smith,” in Anatomical Record,4 , no. I (1971). 135–138; Nicholas P. Christy, “Philip Edward Smith,” in Endocrinology, 90 , no. 6 (1972), 1415–1416; and Aura E. Severinghaus, “Philip Edward Smith,” in American Journal of Anatomy, 135 , no. 2 (1972), 161–163.

Frederic J. Agate, Jr.