Constitutional hyperrecombinability and its consequences.

HANDLING human chromosomes is my metier. I realized that long ago; however, preparing an article for Perspectives led me to ask myself how this came to be. I, like others who took the premedicine curriculum in college in the 1940s, had learned about Boveri's discovery of the transmission of developmental determinants via chromosomes and of the stages of meiosis and mitosis, as well as more than a few things that were to be unlearned in due time, e.g., that cells rest between mitoses and that the human has 48 chromosomes! Early on, an unusual event convinced me that the nucleus was the place to direct my attention and, specifically, that handling chromosomes experimentally could be just plain exciting: In Galveston one day in the latter part of 1951, I was surprised to see the charismatic pioneer in cell culture, Charles Pomerat, ordinarily sedate and rather slow moving, smiling and jigging happily between the benches of his research laboratory. He was waving above his head a handful of freshly printed photographs and calling out to his associates: “Chromosomes! Human chromosomes!” Those little bearers of the determinants of human development about which he was so excited that day were not tightly entwined in the cells, hopelessly inaccessible to the eye of the microscopist as they had been until then, but rather nicely separated from each other. What had happened? The best explanation seems to be that a technical assistant erroneously had made the laboratory's stock of balanced salt solution hypotonic. When T. C. Hsu, Pomerat's new postdoctoral fellow, used what he thought was Tyrode's solution to rinse some cultures of human cells prior to fixing and staining them, the cells naturally had imbibed water. Those cells that by chance had been in mitosis had expanded their volume so much that their chromosomes had become sufficiently separated to permit their being counted and the observation of their individual morphology (relative lengths, centromeric constrictions). This pivotal discovery in a cell culture laboratory on the Gulf Coast of Texas in the early 1950s—that immersion of mitotic cells in a hypotonic medium will make the chromosomes suitable for microscopic analysis—was made by serendipity. Serendipity is a happy word that means (i) finding something of value that was not being sought (ii) by someone who has a mind suitably prepared to perceive its value (cf. Ingram 2004). Pomerat, long with an interest in the mammalian nucleus and its activities during the cell cycle, and T. C. Hsu, a newcomer to mammalian cell biology but with an interest in genetics, specifically Drosophila genetics, were prepared; they perceived the importance of their observations, and fortunately they reported them (Hsu and Pomerat 1953), thereby opening the modern era of human, including medical, cytogenetics. This story is interesting historically, but why do I introduce my article by relating it? Although I had left the Pomerat laboratory before the discovery of the hyposmotic treatment was made, it did happen in the place where I first realized my calling to cell research. Just that realization seems in some unconscious way to have provided me with continuing reassurance that handling chromosomes was what I should be doing. It has always seemed appropriate that I should be doing so and has been a continuing source of contentment.