Tribute to Thomas H. Shepard: Scholar, mentor, friend

Authors

  • Alan G. Fantel

    Corresponding author
    1. Department of Pediatrics, Division of Genetics, and Developmental Medicine, University of Washington, Seattle, Washington
    • Department of Pediatrics 356320, University of Washington, Seattle, WA 98195-6320
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It is a privilege to write this brief tribute to Tom Shepard, who during his long and productive career served as teacher, mentor, colleague, and friend to so many of us in teratology and pediatrics. Thomas Hill Shepard, wise and humane, is one of the premier figures of modern teratology.

Tom was born in Milwaukee, Wisconsin, in 1923. His father was a renowned sedimentologist who taught at Scripps Institute of Oceanography. Tom received his undergraduate degree from Amherst College in 1945 and his M.D. from the University of Rochester in 1948. Between his second and third years of medical school, he was a Student Research Fellow in bacteriology and pathology. Because so many medical graduates were enlisted in the war effort, Tom served as a de facto house officer while in medical school. He was Chief Resident in Pediatrics at Rochester from 1951 to 1952. As Chief Resident, Tom had admitting privileges for a free bed at Strong Memorial Hospital. Based on his study of endocrinology, he admitted a six-year-old boy with bone growth appropriate for a 12-year-old, large penis, and small testes. Treating him with cortisone, he was able to normalize the boy's growth over time. Tom's presentation of his findings caught the attention of Lawson Wilkins at Johns Hopkins, who offered him a fellowship in 1955. In 1946 Tom married Alice Kelly, and they had three daughters, Betsy, Donna, and Annie. Sadly, Alice died in 2004 after a long illness. Tom married Gretchen McCoy in 2006, and they have many grandchildren between them.

Tom joined the Department of Pediatrics at the University of Washington in 1956 and directed the Division of Endocrinology at what was then called Children's Orthopedic Hospital in Seattle. From 1961 through 1962 he was a Research Associate in Embryology and Visiting Assistant Professor of Pediatrics at the University of Florida, where he studied embryology and teratology with the late Jim Wilson. He subsequently spent time as a Visiting Investigator at the Carnegie Institution of Washington, studying human embryology with James Ebert. In 1962, he worked with Henning Anderson at the University of Copenhagen examining the relationship between athyreotic cretinism and the ability to taste PTC. This was followed by a sabbatical year with Pierre Ferrier in Geneva.

At the University of Washington, Tom headed the Division of Teratology and Human Embryology from 1964 through 1993. In 1990 he studied electron microscopy at the University of Washington with Karen Holbrooke, who later became president of The Ohio State University. Tom used his newly developed skills to examine the effects of glucose concentrations on villous morphology in the interior of the neural tube and in describing early mitochondrial development. The latter had been an area of interest of his for many years, during which he collaborated with the late Bruce Mackler at the University of Washington. In these studies they examined the effects of a variety of conditions including altered oxygenation, carbon monoxide, and iron deficiency on mitochondrial development and energetics. They were especially interested in anomalies they detected in mitochondrial energetics in tissue from achrondroplastics, a subject that intrigued and frustrated Tom and Bruce for many years.

Less well known to members of the Teratology Society, Tom's medical practice combined pediatrics, endocrinology, dysmorphology, and teratology. He had a devoted following among children and their families, and he treated many of his patients from infancy through young adulthood. He was particularly interested in the basis and management of achondroplasia and was an early proponent of counseling and dietary intervention in pregnancies complicated by phenylketonuria.

Tom performed early studies of the teratogenicity of vitamin A in monkeys and riboflavin deficiencies in rodents. He also studied the effects of various cytochalasins on neurulation. Few recall that Tom was one of the first investigators to employ whole embryo culture as a research tool in teratology. This resulted from his reading of papers by Denis New. In the late 1960's, Tom, Maurice Robkin, a nuclear engineer at the University of Washington and Takashi Tanimura, Tom's fellow from Kinki University in Japan, developed a type of surrogate rat mother they named the PLASMOM. This device enabled them to culture and observe gestational day 11 rat embryos for up to 24 hours, although most experiments were of shorter duration. It included of a bundle of semipermeable tubing bathed in warmed, oxygenated water serving as the lung and maternal blood, respectively. A peristaltic pump circulating freshly drawn human serum served as the heart and embryonic blood, respectively, and a squared-off glass cuvette served as the uterus. Embryos were attached to nylon rafts by Reichert's membrane, a difficult and time-consuming procedure. The heart could be transilluminated with a red laser, the light projecting onto a photomultiplier tube. Because the medium flow was relatively nonpulsatile, they could graph acute changes of heart rate in response to various exposures as well as observe development in real time.

Tom spent his entire academic career in the Department of Pediatrics at the University of Washington and its associated hospital now known simply as Seattle Children's. In 1964 he started the Central Laboratory for Human Embryology, now known as the Birth Defects Research Laboratory. This laboratory has been continuously funded by the National Institutes of Health since its inception, making it the oldest extant grant in the NICHD portfolio. Direct costs for the first grant year were $10,774 plus an additional 20% for indirect costs. Numerous fellows, students, and residents circulated through the laboratory and were trained by Tom (Table 1). Many of the presidents of teratology societies in the United States and abroad as well as other important figures in teratology and pediatrics worked and studied with Tom.

Table 1. List of Students and Fellows of Tom Shepard
Prasanta K. Dattta
Sorel Waxman
Pierre Ferrier
Charles P. Mahoney
Ronald J. Lemire
Ralph R. Hollingsworth
Thomas Nelson
Takashi Tanimura
Alan G. Fantel
Godfrey P. Oakley
Gerald J. Bargman
Theodore H. Regimbal
Larklyn H. Fisher
Trent D. Stephens
Philip E. Mirkes
Kohei Shiota
Margot Van Allen
Marlissa Campbell
John Rogers
Carol J. Quaife
Jack M. Fitzsimmons
Masahiko Fujinaga
Raj Kapur
Hyung W. Park

An initial goal of the laboratory was collection and distribution of fresh human embryonic and fetal specimens to local investigators, but the study of normal and abnormal development was always a major goal. At first, most specimens were derived from spontaneous abortions. The number of therapeutic or elective abortions increased rapidly as voters in the state of Washington approved abortion on demand in the early 1970's. As Tom's reputation spread, specimens were sent to him for study from across the United States. During the 1960's and 1970's, a significant percentage of induced abortions were delivered by hysterotomy or hysterectomy. Tom developed close working relationships with obstetricians and gynecologists in the Seattle area who were only too willing to help his developmental studies in exchange for postmortem study of conceptuses they received or delivered. Consequently he was able to collect and analyze extraordinarily fresh and well-preserved specimens.

With the ability to collect extraordinarily fresh specimens, Tom developed an extensive collection of serially sectioned human embryos representing most of the first trimester of development. These blocked and sectioned specimens remain valuable today for at least two reasons. First, embryos in earlier collections were generally fixed in formalin, which penetrates relatively slowly, leaving unfixed and necrotic deeper tissues. Embryos used for histology in Tom's laboratory were generally fixed in alcoholic solution (Lillie's fixative), which penetrates rapidly, ensuring the presence of mitotic figures in deeper tissues. Second, unlike those of the 1960's and 1970's, intact embryos or fetuses rarely result from the surgical or medical termination procedures commonly employed today. These specimens tend to be severely fragmented and anatomic relationships are largely lost. The earliest embryos in Tom's collections resulted from painstaking dissection of ectopically implanted and surgically removed gestational sacs. Other laboratory collections include precisely dated macaque conceptuses obtained in collaboration with the Washington Regional Primate Research Center at the University of Washington and a large sample of embryos and fetuses with various anomalies.

Tom's collection grew rapidly during the period when, under the guidance of Tom Shepard and Dave Smith, the University of Washington was a world leader in teratology and dysmorphology. Dave, along with his students and fellows, spent many hours in Tom's laboratory studying normal and abnormal fetuses and testing their numerous hypotheses. Many fellows were trained and numerous publications resulted, including ones that served as standards for prenatal growth and development.

In the late 1960's Ron Lemire, Dave Smith, and Tom, among others, founded an informal Teratology Club that met monthly after work at the homes of faculty members and fellows. The club was fertile ground for developing and demolishing new ideas and hypotheses in dysmorphology and teratology. Presentations often previewed manuscripts in preparation or upcoming presentations, and fueled by liberal amounts of beer and wine, discussions could be intense as well as prickly. Wearing of ties was strictly prohibited, a code enforced by Ron Lemire, known on occasion to have employed a pair of scissors on the neckwear of violators.

Tom's involvement in teratology dates to the early years of modern teratology in the United States. He is a charter member of the Teratology Society and served as its president in 1969. Originally the society's president was responsible for selecting the date and site for its annual meeting. Characteristically and whimsically, Tom chose a spot of unparalleled beauty, the Crystal Mountain Ski Resort in Washington state. The meeting date was selected after Tom conducted extensive analysis of decades of climatologic data to minimize the likelihood of precipitation. All this effort was handsomely rewarded, as those of us fortunate enough to have been there are unlikely to forget the salmon bake at sunset atop Crystal Mountain with its stunning views of the Cascade Mountains and Mount Rainier to the southeast.

As noted, Tom spent time studying with Jim Wilson at Gainesville, exposing him to one of what might be considered the ‘first generation’ of modern American teratologists. Later he worked closely with Josef Warkany, another member of this generation, as Joe spent many of Cincinnati's annual ragweed seasons in Tom's relatively allergen-free Seattle laboratory. Joe's nearly annual presence was an intellectual stimulus to everyone in the laboratory, reinforcing relationships between dysmorphologists and teratologists. Tom's collection of Warkany etchings testifies to their friendship and collaboration.

Around his 50th birthday, and I suspect feeling restless, Tom developed the idea of organizing and writing his Catalog of Teratogenic Agents. To fit this new task with his clinical and laboratory responsibilities, Tom devoted the hours of 5:00 to 8:00 AM to research and writing, which in pre-computer days required extensive hours in the library. The first editions of the Catalog necessitated the installation of an enormous IBM card punch device in the laboratory along with a trained card puncher. It also required vast stacks of IBM cards that (those of us of a certain age remember) could not be folded, spindled, or mutilated to work properly. The job of card punching was complicated by the inability to correct errors on the cards. Fortunately, Tom's secretary at the time, Barbara Brownfield, became adept at the punching process, and the catalog eventually went to press. Barbara's input was critical as Tom, never known for mechanical prowess, never acquired much in the way of typing skills. In reality, there is little evidence he even truly mastered the laboratory telephone with its four buttons.

The first edition of the Catalog, published in 1973, was physically small and compact, consisting of only 211 pages and including information on a total of 649 exposures (all in capital letters). By comparison, the latest, 12th edition, coauthored with Ron Lemire, is significantly larger, comprising 545 pages and including summary reports on 3261 agents. As readers undoubtedly know, the catalog now represents a basic tool in teratogen information and counseling and is a major part of Tom's legacy. Needless to say, he is currently working on a 13th edition, sadly, though, without Ron's help.

In addition to the many research, training, clinical, and academic responsibilities he fulfilled, Tom has served in advisory and consulting positions on a wide variety of national and international panels including ones associated with the National Research Council, NIEHS, National Center for Toxicological Research, EPA, WHO Working Group, Toxicology Information Program of the NAS, and March of Dimes, among others.

By the time Tom retired in 1993, his curriculum vitae listed nearly 250 journal and book publications, many resulting from the study of specimens he and his fellows collected. Tom was exceedingly generous with first authorships, and many careers were built on research carried out in his laboratory. Tom's accomplishments are well known through his many presentations, publications, and associations, but he is especially distinguished by his eclectic approach to research. While trained as a pediatrician, endocrinologist, and embryologist, he worked with investigators in a broad range of disciplines. These included biochemistry, dysmorphology, epidemiology, psychology, anatomy, embryology, cell biology, obstetrics, and gynecology as well as nuclear engineering. His associates came from all over the world, including the United States, Denmark, England, Australia, France, Japan, and Korea. Tom's eclecticism and inquisitiveness have served the society and the field of teratology exceedingly well.

Tom's service to the society continues as does his service to the cause of dissemination of teratogen information. The latter is marked by his long-standing membership in the Organization of Teratogen Information Services (OTIS). In 2002 Tom was honored by the establishment of the Shepard Lecture presented at the annual Teratology Society meeting. This lecture focuses on the acquisition and dissemination of teratogen information. Tom's dedication is highlighted by his personal financing of the Seattle teratogen information service, ‘Care Northwest’ for many years.

No reflection on Tom's life would be complete without reference to his profound love of sailing (Fig. 1). Beginning in the 1960's, Wednesday evenings were dedicated to racing his small sailboat on Lake Washington, irrespective of the weather. Laboratory personnel frequently crewed but did so at their own peril because Tom was a serious sailor and very, very serious about winning. Walls of trophies in his house testify to that seriousness. Crew members generally had little idea of race rules, how to sail, or even what was expected of them. Uncharacteristically, Tom provided only the barest minimum of training. One incident from the 1970's illustrates the perils of crewing for Tom. As usual, he was at the helm, heading downwind when he called on his hapless fellow, Tom Nelson, to go forward and set the spinnaker. Running forward as ordered, crewman Nelson disappeared down the open hatch. Captain Shepard, ever laconic on the water, shouted only, “Damn it, not there.” Fortunately, Tom Nelson's injuries were not physical.

Figure 1.

Tom sailing in The San Juan Islands.

Finally, Tom is also an accomplished artist (Figs. 2–5), working primarily in watercolor and to a lesser extent in etching, which he studied with Joe Warkany. Much of Tom's art is marine and set in his beloved San Juan Islands. These wild and beautiful islands are set between the mainland coast of Washington State and British Columbia to the east and Vancouver Island to the west. Tom has had a second home on one of the islands, Shaw Island, since the 1950's. There, he and Alice introduced many of us to the islands and boating in the pristine waters of the Pacific Northwest. One incident that occurred many years ago stands out. Tom had acquired an 11-foot sailing dingy that he kept in a wooded cove north of the current-swept Wasp Passage in the San Juan Islands. On a warm summer day, three teratologists, Tom, the late Jim Miller, and I, went for a sail in his tiny boat. Well off shore, the boat developed a significant leak. Water temperatures in this area run around 10°C year round, limiting immersion survival times to around 20 minutes, and I do not recall the presence of life jackets on board. Lacking a bailer (bucket), two of us frantically bailed with our handkerchiefs while Tom intently but calmly attempted to steer and row against the current with tiller and oar. We did eventually arrive safely on shore, but Tom has only recently acknowledged that he was at least as unnerved by the situation as were his passengers.

Figure 2.

Early Morning, Jones Island.

Figure 3.

Sketch, Kauai.

Figure 4.

Orcas Knob.

Figure 5.

Shaw Island.

Tom's contributions to the field of teratology are well known to readers of this journal. Equally important have been his commitments to patients, students, fellows, friends, and associates. In so many instances, these commitments have been critical to lives and to successful careers. His influence in academics, science, and medicine have been thoroughly tempered by modesty. Tom's dedication makes him thoroughly worthy of this celebration.

Acknowledgements

The author would like to thank the following individuals: Janine Polifka and Ian Glass for their help organizing the festschrift, Donna Richards, Tom Shepard's daughter, for generously providing information, photographs, and artwork, and Jane Fantel for proofing, suggestions, and remembrances.

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