Fifty years in human genetics—a career retrospective

In 1963, I decided to try my luck in the field of human genetics. In the last year of medical school at Johns Hopkins, Iwas persuaded by a fellow student to join a seminar course givenbyBartonChilds, aneminent geneticist. Iwas doing an elective in childpsychiatry, so I had the time.Our group of five studentswouldmeetweekly and each give a seminar on a human genetics topic. Now for a short flashback. Having done premedical liberal arts at Dartmouth, I was admitted to the 2-year medical school aftermy junior year.With the thought that I needed hospital experience, I went to the medical school dean for advice. Should I be an orderly that summer? He replied, “Haig, you have a good record in chemistry.Why don’t you speakwith a biochemist about doing research? ” He sent me to Lafayette Noda, an enzymologist, who offered me a summer position—my first research experience. The next two summers, I worked with another Dartmouth faculty on oxidative phosphorylation. As I always enjoyed solvingpuzzles, I found research interesting and challenging. Even more intriguing, in the first year of medical school, I learned thatDNA is the geneticmaterial, and its structurewas solved just fiveyears earlier.Our final exam in biochemistry was an oral, with each student assigned a different paper to discuss. Mine suggested that the canonical route of gene expression—DNA to RNA to protein—could be reversed. I argued that as RNA and DNA were similar in structure, there could be enzymes that synthesizeDNAfromRNA.However, because there are somany steps involved inprotein synthesis, I thought that going from protein to RNA would not occur in nature. It still surprises me that;30 years later, mywork concerned a human transposable element—a mobile DNA—that encodes a reverse transcriptase (RT) capable of copying RNA into DNA. Now, back toBartonChilds—an erudite, compassionate man. I had not studied genetics before his seminar course, neither in high school nor in college. When I related this to himhe responded,“Don’tworry, you’ll learnabout it! Look at theLancetover thepast fewmonths,andyou’ll see reports of cytogenetic abnormalities. Tell us about them. ” So I gave a cytogenetics seminar andwas enticed by Barton’s course. After an internship in pediatrics at the University of Minnesota in 1963, I decided to pursue human genetics. I had considered child psychiatry but was turned off by the lack of objective science therein; in contrast, genetics seemed to rely more on facts—“ice-cold dope,” in the words of another mentor. After the internship, I decided to complete only one more year of pediatric training instead of the two required to pass the boards; instead, I would begin training ingenetics. IwroteChildsaskingfor suggestionsonplaces to train. He suggested a few, including Hopkins, and with his recent receipt of a U.S. National Institutes of Health (NIH) traininggrant,hecouldsupport twofellows. Idecidedto join his programbecause I believed hewould be a greatmentor. Human geneticswas at a very primitive stage.We knew that every cell had 46 chromosomes, 22 pairs of autosomes, and 2 sex chromosomes. However, not one gene had been mapped to a specific autosome. From pedigree studies of the transmissionofX-linkeddiseases,weknewahandful of genes on the X chromosome. At that time, no one had yet manipulated DNA, and mutations at the nucleotide level were not yet visible. However, protein variants, both normal and disease causing, were being described. We knew nothingaboutDNAvariants, butwepresumedthatprotein variation reflected nucleotide variation in DNA. Childs had just shown with Ron Davidson, his postdoctoral fellow, and Harold Nitowsky, a cell culturist, that the Lyon hypothesis was correct: one of the two X chromosomes in cells of female mammals is inactive (1). He suggested that I use an X-linked enzyme in fruit flies to provide evidence for or against the Lyon hypothesis in invertebrates. Certain fly strains had variants of the X-linked enzyme 6-phosphogluconate dehydrogenase that could be separated by electrophoresis. Heterozygous flies had 3 bands instead of the single band of homozygotes, suggesting that these bands represented dimers composed of 2A(AA),2B (BB),andanAandaBsubunit (AB). In treating a mixture of A and B bands, one could reproduce the third band (AB), strongly suggesting that both X chromosomes were active in cells of the fly. This led to publication of my first paper that appeared in Science in 1965 (2).