Hotchkiss and MacLeod: An Historical Perspective

This is an affectionate tribute to Dr Robert S. Hotchkiss and Dr John MacLeod, master teachers and giants in the field of male infertility. They were my remarkable mentors, whose work has probably touched and influenced every male-infertility investigator and every infertile male patient of the present generation. I would like to tell you about them and their close and warm relationship to one another. Dr Robert Hotchkiss (Figure 1), a true pioneer in the field of male infertility and an inspiring teacher, was Director of the Department of Urology at New York University (NYU) Medical Center and at Bellevue Hospital when I started my urology training there in July 1951. Impressed by his enthusiasm, I decided to learn as much as I could about this young specialty of aiding couples to have children. My guide, the only one available at the time, was Dr Hotchkiss' textbook Fertility in Men, which had been published in 1944 (Hotchkiss, 1944). . Robert Hotchkiss, MD. Dr John MacLeod (Figure 2) was an authority on the human sperm cell and an avid explorer of the reproductive physiology of males at the New York Hospital—Cornell Medical Center. . John MacLeod, PhD. John MacLeod was born in Edinburgh, Scotland, in 1905 and was the oldest of 4 children. His father, Alexander, was a printer. John left school in 1917 at the age of 12 years to bring more money into the household. He began work, initially cleaning and delivering fish and then delivering hats part-time as a messenger. Seeking better employment, he searched newspaper ads and saw an advertisement for a “lab boy” in the physiology department at the University of Edinburgh. He told his current employers he was going to apply for this full-time job. The hatters were prominent people in Edinburgh, and they helped him get an interview and secure the job (Swan, 1981). The University of Edinburgh had an outstanding department of physiology, and young John MacLeod was one of 6 boys assigned to keep the laboratory clean and set up laboratory experiments for the large first-year class of students (approximately 400 individuals) at the medical school. He was soon promoted to laboratory assistant, and his additional duties included teaching students how to smoke a kymograph drum and how to dissect a frog muscle-nerve preparation. When John was 16 years old, he was appointed to a position in which he assisted members of the faculty in their research. At that time, he first came into contact with Dr Edward Ponder, a physiologist whose specialty was the kinetics of red blood cell hemolysis. Dr Ponder later played a very important role in MacLeod's life. At 17 years of age, MacLeod was made chief laboratory assistant to the chairman of the department, 70-year-old Sir Edward Sharpey-Schafer, and he prepared and participated in all of Sir Sharpey-Schaefer's research experiments and lectures. John was impressed by what seemed to him as the wonderful life of a scientist, and with this profession as his goal, he knew that he must acquire a formal education. He was permitted to attend evening lectures at a prep school for the University of Edinburgh, as well as all of the lectures given by members of the department. However, he realized that it was going to take more time and more money than he had, to qualify for a college degree. During 1925 and 1926, there was a great influx of medical students from the United States, most of whom were Jewish. These students came to Edinburgh to study because they had been unable to gain admission into American medical schools because of their religious background. MacLeod recalled that he was most impressed with these American boys. John became friends with them, and during the next few years, he became thoroughly Americanized and began to think about coming to America, although he never lost his fine Scotch burr nor his taste for his favorite fine Scotch whiskey (The Glenlivet Single Malt). His chance to come to America came in 1927 at the age of 22 years, when Dr Edward Ponder was appointed professor of biology at NYU. Dr Ponder invited John MacLeod to come with him to NYU and arranged for travel expenses, for a salaried job as his research assistant, and for a scholarship to NYU, which would enable MacLeod to get his bachelor's degree. John's first job at NYU was to study photographs of hemolyzing red blood cells, measuring their diameters with a micrometer. Gradually, he came to participate in Ponder's research, and his name and Ponder's appeared on a series of papers on the kinetics of hemolysis. Subsequently, with Ponder's encouragement, MacLeod became interested in the dynamics of white blood cells, which had a great deal more metabolic activity than red blood cells. He received a bachelor's degree from NYU in 1934 at the age of 29 years (Figure 3). . John MacLeod, 29 years of age, on the day he graduated from New York University. He had majored in English and biology, and when he graduated with honors in English, he received an offer to stay on as an assistant in the English department but decided to remain in science. At about that time, Dr Ponder was appointed director of the Laboratories at Cold Spring Harbor Research Center, located in a rustic setting on the north shore of Long Island, and invited MacLeod to join him. MacLeod was offered his own laboratory at Cold Spring Harbor, to pursue his interest in the metabolism of the white blood cell. He was pleased to go to Cold Spring Harbor Laboratory with Ponder, because of the presence there of a young secretary named Catherine Brown, referred to as “Kit.” John had first met her in 1929 on a brief trip to Cold Spring Harbor with Ponder. He and Kit were married after John's graduation from NYU in 1934. Their daughter, Joan, was born the next year at Cold Spring Harbor. He earned a master's degree at NYU, which required traveling into the city 2 days per week, but he found it impossible to qualify for a PhD while at Cold Spring Harbor. During the summer of 1937, while participating in a symposium at Cold Spring Harbor, he received an offer from Dr Joseph C. Hinsey, the head of the department of physiology of Cornell Medical College, to come to Cornell, work in Hinsey's department, and earn his PhD. At that same meeting, he met Dr Cornelius Rhodes, who was head of Rockefeller Hospital and was studying blood diseases. Rhodes was interested in the work John was doing on the metabolism of the white blood cell and offered him a position at Rockefeller Hospital with an annual salary of $2400 and the additional opportunity of taking as much time from work as necessary to earn his PhD degree at Cornell Medical College. John MacLeod left Cold Spring Harbor for Rockefeller Hospital and Cornell Medical College in 1938. Robert Sherman Hotchkiss' ancestors arrived in America on the Mayflower in 1620. He was born on July 7, 1903, in Jamestown, New York. He had a relatively privileged childhood and was the younger son of Dr and Mrs Walter Hotchkiss. His father was an eye, ear, and nose specialist. Robert Hotchkiss received his BS degree in 1925 and his MD degree in 1928 (both from the University of Michigan) and was elected to membership in Alpha Omega Alpha during his junior year of medical school. Upon graduation, he was appointed as an intern at the Royal Victoria Hospital in Montreal. The following year, he joined the house staff at Bellevue Hospital, and after completing an internship of 18 months on the medical and surgical services, he was appointed as resident in urology on the Bellevue Hospital Cornell Division. He completed a chief residency in urology in l932 at the age of 29 years and was appointed to the attending staff at New York Hospital as an assistant urologist in the outpatient department. Dr Howard Jeck, who later became director of the department of urology at the Bellevue Hospital Cornell Division, was then the chief of the urology outpatient department at New York Hospital. All of this was taking place at a time when the importance of the role of the male in infertility was first being acknowledged. In 1929, Macomber and Sanders published their article “The Spermatozoa Count” (Macomber and Sanders, 1929). The authors described a technique that, in all its essentials, closely resembles methods in use today, and involved use of blood-counting pipettes, diluting fluid, and use of the hemocytometer. They concluded that, whereas pregnancy could occur with sperm counts of less than 60 million sperm/mL, higher counts were more favorable to fertility. An interesting sidelight of the Macomber and Sanders article was their description of the restoration of fertility in a man with bilateral varicoceles who underwent surgery. Hotchkiss developed an interest in male infertility. At the same time, Dr William Carey, a gynecologist at Cornell, had been studying sperm migration in postcoital tests. They collaborated in their research. Hotchkiss' first published paper, concerning staining procedures for the evaluation of sperm morphology, and with Carey as senior author, appeared in 1934 (Cary and Hotchkiss, 1934). Margaret Sanger, a pioneer advocate of family planning in America, whose credo was “every child a wanted child,” was a wealthy lady and was interested in funding a project concerned with the investigation of childless couples. In 1938, she made a novel proposal to Dr Jeck to establish a Male Sterility Clinic in the Outpatient Department at New York Hospital. Dr Jeck endorsed her proposal and assigned Dr Hotchkiss, the “low man on the totem pole,” to direct the newly funded Male Sterility Clinic. Henricus Stander, director of the department of obstetrics and gynecology, gave support to the venture. Paul Reznikoff provided laboratory space in the department of medicine, and Ephraim Schorr was an advisor who supervised endocrinologic diagnosis and treatment. Hotchkiss, with the research grant received from Margaret Sanger, went to Dr Joseph Hinsey, head of the physiology department at Cornell Medical College, with the request that Hinsey recommend someone from the physiology department to work under the grant to study the biologic behavior of human spermatozoa. Hinsey, who had lured John MacLeod to Cornell, promptly recommended MacLeod, who accepted the assignment with enthusiasm. He applied the experience he had already gained in studying the metabolism of blood cells to study the unique metabolism of the human sperm cell. MacLeod did not fully realize, when he started, that he was going to encounter one of the most unusual cells of all. The unique metabolism of human spermatozoa would provide him with a lifetime of research. There began a close collaboration between Hotchkiss, the clinician, and MacLeod, the researcher, which continued for 2 decades. Their close, warm friendship lasted the rest of their lives. In the course of his research, which was funded by Margaret Sanger through Dr Hotchkiss, MacLeod discovered that, unlike sperm of nonhuman species, human sperm have an anaerobic metabolism. The role of oxygen in human sperm metabolism is an extremely minor one. Unlike the behavior of other mammalian cells, high oxygen tensions are toxic to human sperm. MacLeod discovered that, in the presence of oxygen, human sperm produce hydrogen peroxide, which destroys their own motility. The MacLeods' son, Ian, was born in 1940, a year before John MacLeod received his PhD in physiology from Cornell. His thesis, “The Metabolism of Human Spermatozoa,” was summarized in the American Journal of Physiology (MacLeod, 1941). Meanwhile, at Cornell, the money to support MacLeod's work came from Cornelius Vanderbilt (Sonny) Whitney, who sat on the Boards of Governors and Trustees at New York Hospital and Cornell Medical College. It was customary during the dinner hour at the combined monthly Board meetings for Dr Hinsey to select one of his faculty to present an informal discussion for these laymen on the work with which he was involved. When John MacLeod was selected in early 1942, he captivated his wealthy lay audience by telling them about his sperm studies on infertile men. MacLeod recalled that his financial support had its beginning with a phone call from Sonny Whitney's race-horse farm manager in Kentucky. He passed on the request that MacLeod come to Kentucky to examine Sonny Whitney's stallion, Boojum, who had been very productive in terms of his racing performance but was completely unsuccessful as a stud. At that same congenial dinner, another trustee, John Hay (Jock) Whitney, told MacLeod that he was also interested in his work because he, too, owned an apparently sterile horse, Twenty Grand, who had won the Kentucky Derby and the Triple Crown. John MacLeod went down to Kentucky and saw Boojum at Sonny Whitney's stable and then saw Twenty Grand at Jock Whitney's stable next door. As MacLeod described it, there he was, never having seen a thorough-bred in his life, invited to Kentucky to try to determine what was wrong with these 2 splendid race horses. It so happened that, as a result of his metabolism research, MacLeod was interested in the B-complex vitamins. In fact, he had suggested giving B-complex vitamins to infertile men, which had some beneficial results. So he put B-complex vitamin supplements into Boojum's feed, and Boojum impregnated 4 mares during the subsequent breeding season. Unfortunately, Twenty Grand had another problem, with a genetic sperm-tail defect that could not be corrected. MacLeod recalled that, although his trip to Kentucky was hardly worthwhile for Twenty Grand, it was certainly valuable to himself and to Cornell: Sonny Whitney liberally supported MacLeod's human research for the next 14 years. It is a remarkable coincidence that Robert Sherman Hotchkiss, Cornelius Vanderbilt Whitney, and John Hay Whitney could all trace their ancestry back to Governor William Crawford, who arrived at Plymouth Rock on the Mayflower in 1620. Charles Charny published the first article on testicular biopsy in 1940, in which he acknowledged that Hotchkiss had been the first to use this technique in humans to differentiate cases of azoospermia due to obstruction of the ductal system from cases in which lack of sperm was due to absent or incomplete spermatogenesis (Charny, 1940). The use of testicular biopsy was gradually extended to include cases of oligospermia, and information was gathered about types of disturbances in sperm maturation in oligospermic men. Testicular biopsy also became an important research tool studying testicular effects of hormonal toxic and in 1942, at years of age, Dr Hotchkiss was a in the United and saw in the as senior medical the which and (Figure The was at in The when the there in Hotchkiss from the with the of in His Fertility in was published in 1944 while he was in the and it went through 4 (Hotchkiss, 1944). . at the to life, Hotchkiss Dr Howard Jeck as the director of urology in the Cornell at Bellevue Hospital. He in that when he was appointed professor and chairman of the department of urology at NYU of Dr In only 4 years after his PhD from Cornell, MacLeod was the first of the by The of America for his research on the metabolism of human spermatozoa. At that same Dr Hotchkiss was for his Fertility in Men, which had been published by as a to Fertility in by the gynecologist Dr 1944). There was close collaboration between Hotchkiss, the clinician, who of involved in infertile and MacLeod, the researcher, who the these for studies were on from a large of whose were The from were to The of as an of the of spermatogenesis in the was also These combined the that a involved of sperm cell and the and of and was a tool in laboratory research. These studies also gave about the of for men. MacLeod was that the then for the of human sperm in terms of fertility were He decided to the of for (MacLeod, He soon realized that his were and required the of a He was in the full-time of the next years with MacLeod, his they published a series of papers on of as to of which have received for their and My own early research on before subsequent and on the of human in to fertility to my that the of 6 of my with bilateral of the to because of the of the This could be with a for before the diagnosis by the In the same I also described 2 methods for to sperm motility. the of this paper, I collaborated with Dr Hotchkiss in and biopsy studies in testicular with bilateral of the and and Hotchkiss, In I with Dr Hotchkiss on a study of from in infertile that there are between the first and of the human with to sperm sperm and sperm and that, with the these be and Hotchkiss, This information is to the of the infertile his is MacLeod research, which was funded by Cornelius Vanderbilt Whitney, on that the and behavior of as and and and This to the for better methods to study the of sperm cells, and he the staining technique to the study of sperm His interest in the toxic effects of on the to research on the which were initially found to be and later found to be toxic to the of and humans (MacLeod, of 60 to participate in studies and testicular MacLeod of spermatogenesis and found that the effects were completely This the of in the of that this would to be an for men, but were when it was found that became they an this study to to a that completely male fertility with of MacLeod's to the field of human was his of human sperm cells into 6 in the had as as 60 types of human spermatozoa. the to and their with (MacLeod, He cells of the from the in the as sperm and that this was a of This to his description of the (MacLeod, and its in who had as well as in with (MacLeod, MacLeod most the of his work, and in he had the opportunity to with Dr the head of at Cornell Medical Center. Dr for the of and the became sterile as a result of the of the Dr MacLeod the opportunity to research on a a of human from the of He that, when human spermatogenesis was after of the he could spermatogenesis completely with of after the patient had been with in the of human This work by MacLeod has been in of infertility in the MacLeod's to and his interest in the of him to a between infertility due to and its a of sperm and sperm with a high of and in the the He to the role of and the of this in the of the infertile In I a meeting, arranged by Dr MacLeod, with a of from NYU Brown, Hotchkiss, and who were interested in male infertility. At a in the at Cornell Medical College, Dr MacLeod a study with in which he would the studies on before and after was for that MacLeod's research At the age of years, from the department at the Cornell University College of in but he at the Medical Center, setting up a laboratory for male infertility in the department of obstetrics and He continued his studies as professor of cell biology and and he in in collaboration with a Dr Dr MacLeod published his which was a the he had between and with he had between and and In an of the years, and concluded that there had been in sperm counts and that the on and of made years by MacLeod were John MacLeod in New York Hospital of on at the age of years. His life and work as an to young who be that is and lack of are there is Dr Hotchkiss with as director of the department of urology at NYU Medical Center and Bellevue Hospital from his in that in a to the faculty and friends and current and and staff at his dinner, he very I to have so in to the experience of the years, is not given to all. The between the attending and the house a unique that has in human it are of and that a which not with the of There is an to the of an in the which qualify him to the senior resident and then to a position of in his years. The experience of the of a these young with novel which the in its as or These who to and provide a for his he was to more time at with family and In he of at the age of years. In this I would like to on the of my the from The American of in It was an to be selected by the to in the of my mentors, Dr Robert S. Hotchkiss and Dr John MacLeod, who received this in and My information concerning Dr MacLeod's early years from a published interview I found in the New York Hospital that Dr had with him (Swan, 1981). At the time of the Dr was the Joseph C. Hinsey of at the Cornell University College of I most to Dr MacLeod's son, Ian, and to Dr Hotchkiss' son, for being giving of their time and in with family and and I have my meetings with of

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.