How to cite this article: Kelly TE. 2009. An undifferentiated pediatrician. Am J Med Genet Part A 149A:298–300.
An undifferentiated pediatrician†
Article first published online: 11 FEB 2009
Copyright © 2009 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Volume 149A, Issue 3, pages 298–300, March 2009
How to Cite
Kelly, T. E. (2009), An undifferentiated pediatrician. Am. J. Med. Genet., 149A: 298–300. doi: 10.1002/ajmg.a.32676
- Issue published online: 24 FEB 2009
- Article first published online: 11 FEB 2009
- Manuscript Accepted: 17 NOV 2008
- Manuscript Received: 28 OCT 2008
I grew up with my mother and brother in the home of my maternal grandparents in the small town of Conway, SC. The 1950s were a great time to be in high school and college; I spent many idyllic summers as a lifeguard at Myrtle Beach. Davidson College was a financial challenge for my mother and academic challenge for me. Davidson had, however, prepared me well for medical school. After my first year, I married the girl of dreams, Carolyn Turner. She taught first grade and I had odd jobs to finance my medical education. When I graduated in 1963, the draft was in place and all able-bodied physicians could either serve in the military or the National Health Service. I chose the U.S. Navy which had provided me with funds during medical school.
My internship was straight medicine in Memphis, and I had visions of training later in adult cardiology. Upon completion of my internship, I went on active duty with the Navy. I was the only general duty medical officer in the Navy in South Korea, in Chinhae, a port facility and training center. A pediatric residency at the U.S. Naval Hospital in Bethesda followed. There, my mentor, Andrew Margileth, a self-trained pediatric dermatologist, advised me if I saw physical findings that I did not understand, take a picture of it. This proved quite valuable advice for later work in clinical genetics. From 1968 to 1971, I served as the Director of Pediatrics at the U.S. Naval Hospital in Naples, Italy.
In 1969, my wife and I took a trip to The Hague to attend The International Birth Defects Conference. This had a major impact on my career. There, I met David Smith, and his fellow, Jon Aase. We discussed a possible fellowship beginning in 1971 in Seattle. I also had the opportunity to spend some time with Victor McKusick. It was at this conference that he proposed an international effort to map the human genome. Exchanges of letters over the next two years concluded with my decision to go to Baltimore and join McKusick's merry group of fellows.
Meetings with McKusick were brief and to the point. At my first meeting, three points were covered. First, I was “an undifferentiated pediatrician” and his job was to make a medical geneticist of me. Second, in order to do that, he felt that I should enroll on the Homewood Campus of Johns Hopkins University as a Ph.D. candidate. Finally, I should undertake a gene-mapping project.
The defect in hexosaminidase A had recently been described as the basis for Tay-Sachs disease. Michael Kaback devised a serum-screening test for carrier detection that was offered to synagogues in the Washington-Philadelphia corridor. But Mike had left Baltimore and I inherited this job with the idea that I could use the studied population for linkage analysis. However, it was hard to find large three generation, Jewish families needed for in-phase analysis. I was informed of a non-Jewish couple in Berks County, PA who had had two children with Tay-Sachs disease. I spent many evenings in this couple's kitchen where after Rolling Rock beer and potato salad, I drew blood samples on the expanding pedigree. Finally, we held a community-wide screening at the local fire department and many of my co-fellows spent a delightful day in Shoemakersville. In the end we had tested more than 300 members of the family, confirmed positive screening tests with leukocyte assays and submitted samples to Wilma Bias' immuno-genetics laboratory. Gary Chase undertook the linkage analysis and obtained no positive scores. The next year, the Hex A locus was mapped to chromosome 15 and none of the markers used in our analysis were on chromosome 15. I was not particularly excited about doing further autosomal linkage analysis. However, there were several things that came of this project that helped shaped my future research. The pedigree analysis had clearly established a common founder for the carriers of Tay-Sachs disease in Berks County. He had entered the port of Philadelphia in the mid-1700s. The population frequency of carriers in Berks County was very close to that of the Askenazic Jewish population in the U.S. We used that to argue that founder effect, not a selective heterozygous advantage, accounted for the frequency of Tay-Sachs disease in Askenazic Jews [Kelly et al., 1975a]. We also identified three healthy adults who appeared to be completely deficient in Hex A [Kelly et al., 1976]. Further assays and our pedigree showed that these individuals had inherited a Tay-Sachs mutation and a second mutation. The second mutation eliminated activity against the umbelliferyl substrate but not against the natural substrate [O'Brien et al., 1977]. Finally, this project brought me in daily collaboration with Hal Taylor and George Thomas [ Taylor et al. 1973]. This was the heyday of the biochemistry of lysosomal storages diseases (LSD). I was fortunate to spend a summer in the lab of Liz Neufeld at the NIH, despite the 60-mile commute. I was most impressed with the efficiency of her work. As a staff member of the Kennedy Institute, I had a small lab where I completed my work on lysosomal storage diseases for my PhD thesis [Kelly et al., 1975b; Kelly, 1976].
I was also quite fortunate to be in Baltimore during some of the peak activity of The Moore Clinic. There were a number of fellows from the U.K. with whom I became life long friends: Peter Harper, Sarah Bundy, David Siggers, Dorothy Elliott, Michael Pope, John Burns. Other fellows included Judy Hall, Charles Scott, Stefan Levine, Ron Jorgenson, Yves Lacassie, Aida Hernandez, Dan Miller, Jack Licktenstein, John Rodgers, Carlos Salinas and Claude Stoll. The MOD Birth Defects Conferences were held in Baltimore during my time there. McKusick took great pride in these conferences and fellows prepared many cases for presentations. Another fun aspect of being a McKusick fellow was working on MIM. We met monthly at the McKusick home, each fellow having been assigned a journal. To find a new entry for the catalogue entitled the fellow to a second beer. The data were collected on index cards.
In 1974 Bob Blizzard left Hopkins and moved to the University of Virginia (UVA). He took along a number of fellows completing their training at Hopkins. After year-long discussions, I moved to Charlottesville in the summer of 1975. In some respects this was like leaving Mecca for the desert. However, within 18 months we had expanded a modest cytogenetics lab, hired a genetic counselor and began offering prenatal diagnosis. We set up a biochemical genetics lab to assist the state metabolic program, and I was able to set up my LSD lab. We even convinced the Dean of the Medical School and the powers in the basic sciences to carve out room in the first year curriculum for a course in Medical Genetics.
For a medical investigator, a career highlight must be to see a patient with an unknown condition and go to the laboratory to find the answer. Shortly after arriving at UVA, I was referred a patient from Richmond with obvious features of a LSD, but not one that I recognized. The severity was somewhere between I-cell disease and Hurler syndrome. The current series of lysosomal enzymes was all normal, but electrophoresis of hexosaminidase showed a slightly altered pattern akin to that seen in ML II and ML III. Cultured fibroblasts contained large amounts of storage material. Investigators at the NIH recognized a major role played by sialic acid in the immune response elicited by influenza. They had published simple assays for free- and bound-sialic acid as well as neuraminidase. With their assays we showed that the cultured cells, urine sediment and frozen tonsillar tissue had greatly elevated levels of bound-sialic acid. Fibroblasts, serum and lymphocytes showed no neuraminidase activity. Levels in the heterozygous parents were half-normal. As we were completing these assays, the mother told us that she was pregnant. We were able to monitor her pregnancy and predict the birth of an unaffected son [Kelly and Graetz, 1977; Kelly et al., 1978].
UVA serves as the tertiary center for the western half of Virginia, an area that stretches for 300 miles north to south and 150 miles east to west; the vast southwest part of the state was medically underserved. With initial funding from the March of Dimes and later the Genetic Diseases Act, we were able to hire additional counselors and set up monthly clinics in six locations throughout our catchment area. Meinhard Robinow was part of the Division from 1975 to 1980 and these satellite clinics offered him an exciting opportunity to search for new syndromes. It also provided a productive setting for students, residents, fellows and counselors to engage in clinical research [Janku et al., 1980; Barnabei et al., 1981; Reynolds et al., 1982; Schmitt et al., 1982; Shires et al., 1982; Maury et al., 1983; Schnatterly et al., 1984; Bialer and Kelly, 1989; McClellan et al., 1993; Allinson and Kelly, 1995; Niewiadomski and Kelly, 1996; Shashi et al., 1996; Ferguson et al., 2000; Ohle et al., 2002; Brown et al., 2008].
Bill Wilson joined the Division in 1980 and immediately upgraded our biochemical labs and expanded our role with the State Health Department. Bill has been the mainstay in the Division and is currently the Division head.
Carolyn and I consider the sabbatical year (1986–1987) spent in Cardiff, Wales as one of the most enjoyable years of our marriage. I spent every day in the lab learning molecular techniques with the assistance of the excellent staff assembled by Peter Harper at the new Welsh National Institute of Medical Genetics. There was no problem with chromosomal assignment as I worked on mapping genes for Emery-Dreifuss MD, Bulbo-spinal Neuronopathy (Kennedy syndrome) and X-linked Charcot-Marie-Tooth disease [Kelly et al., 1987]. Carolyn and I spent our weekends exploring Wales and the south of England.
A truly enjoyable time during my career was spent on the American Board of Medical Genetics (ABMG). On my first trip to Philadelphia for exam writing, Board members were given an exam to see if we understood the concept of “smart exam takers”. For those of us who thought that we knew how to write exam questions, it was a revelation. We started at the beginning, learning how to create a clear “stem” and then put together a series of five reasonable answers. I had the job of insuring that both the general exam and the specialty exams were well coordinated. My two terms as president of the Board were during the time that the ABMG joined the American Board of Medical Specialties. Previous Board members had done a marvelous job of creating an opportunity for Medical Genetics to enter the main stream of medicine in the U.S. But, it was not without a price. The American Board of Radiology had certified Ph.D.s involved in radiation therapy creating a precedent for the ABMG to continue certification of our Ph.D. population geneticists and laboratory specialists. However, we could no longer offer certification to M.S. genetic counselors. This resulted in some hard feelings among our members, but in the long run, it seems that establishment of the American Board of Genetic Counseling has proven to be quite successful. Sharon Robinson has served as the executive director of the Board from its beginning; for me and other Board members, she was a god-send.
In 1994, I suffered a heart attack; although mild, it was quite a wake-up call. Up until that time, my wife and I had enjoyed “the good life.” We decided it was time to start “giving back.” I negotiated a gradual retirement plan that would provide me with blocks of time adequate to undertake medical mission activities. With the help of missionary friends, Carolyn and I arranged to spend four months at the Chigora Presbyterian Hospital in rural Kenya. On the day we arrived, the Kenyan MD who handled the Pediatric Service showed me the 60-bed ward, the outpatient clinic and the nursery. Incubators consisted of apple crates with a bare light bulb. I asked where I should meet him for rounds the following morning. He laughed and said that he was leaving that afternoon for a three-month vacation. Talk about a baptism under fire! It was hard but exhilarating work. Carolyn taught English composition and music and we were taken whole-heartedly into the community. I was able to make two return trips to provide vacation time for the Kenyan staff. Thereafter, we have made at least one international mission trip each year.
My professional career in Medical Genetics began with unbanded karyotypes and extended through the modern age of molecular genetics. There always seemed to be exciting advances with new information and technology to learn. The reward was ever improving capabilities to meet the needs of our patients. In the early 1970s we were delineating the enzyme detects in LSD. Today, we have genotype–phenotype correlations and for a number of these disorders, enzyme replacement therapy is available.
My family has always been the central and defining influence in my life. My wife, Carolyn, and I take great pride in our children. Our eldest daughter, Caroline has truly found her calling as a Presbyterian minister in Atlanta. Last year, she was happily married to James Mooney. Our son, Elliott, teaches science in Amherst, MA and he and his wife, Sue, have two lovely daughters. Our youngest daughter, Mary Sidney, is an investigator with the Southern Center for Human Rights in Atlanta. She and her husband, Harold Harbert, hope to start a family soon. I have been extremely fortunate to have spent the last 48 years married to Carolyn. From having typed the first draft of my PhD thesis to caring for me during my terminal illness, she has been a constant source of love and support.
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