Sunday, April 19, 2009

Mortality 1 and 2: the Divergence of Cells and the Convergence of Science

(In the picture, left: proliferating cells, right: senescent cells.
Hayflick and Moorhead, 1961)

In the late 1980s, four scientists reached similar conclusion towards an enigma in cell biology: the mortality of normal cells. Or, if you wish to frame the question from the other direction, why some cells, like malignant tumor cells, can reach immortality. The ways those three scientists approached the question, however, were quite dissimilar. One of them applied a procedure much like detail cataloging, another crossed cells holistically, another two took advantage of a viral probe to dissect the cellular machinery.

The conundrum sprang out of an influential discovery by Leonard Hayflick. Opposing to common belief, Hayflick serendipitously found human normal cells can not divide infinitely in cell cultures in 1961. The logical question followed was what mechanisms control the timing of the cessation of cell division. Parallel to typical theoretical debates in aging research, there was dichotomy in explanations about cellular senescence in terms of damage or genetic control.

More than two decades passed before the researchers advocating genetic control in cellular senescence constructed some experimental anchorages. They actually called this genetic control a “terminal differentiation”. They held, as how hematopoietic stem cells generate erythrocytes, the senescence of cells in culture was due to a process programmed by expression of differentiation factors.

Vincent Cristofalo apprehended the question of cellular senescence initially by cataloging the biochemical difference between dividing cells and senescent ones using meticulous molecular detection and measurement. As early as the mid-seventies, he listed dozens of biochemical changes as cells senesce. One feature Cristofalo characterized was the low activity in senescent cells of thymidine triphosphate (TTP) synthesis, a process which prepares DNA building blocks. In 1980s, Cristofalo realized the significance of this detail among many others. Since TTP synthesis only happened in late G1 phase in mitosis, Cristofalo proposed that the senescent cells are actually arrested in the late G1 phase. The cell cycle research was flourishing during 1980s and Cristofalo suddenly found himself in a large pool of literature about factors determining such arrest. Thus to obtain larger samples of ores might be advantageous, but to sharply discern real gold is definitely more important.

James Smith viewed cells as hodgepodges of various factors, in which some factors should be dominant and control others. Smith was inspired by revealing cell hybridization technique in genetic study and applied it to the fusion of senescent cells and proliferating ones. The resulting heterokaryons demonstrated senescent features and Smith proposed that the senescent factors were dominant and they should be inhibitors of cell divisions at large. This cell hybridization experiment started his pursuit of characterizing those inhibiting factors by more cell hybridizations, as well as extraction and microinjection. Much like how one can judge persons, one can characterize features of cells by evaluating how they interact with other cells as well.

Jerry Shay and Woodring Wright wielded audaciously a probing tool, Simian Virus 40 and its functional protein, large T antigen, to those senescent cells. They showed that large T antigen would make cells dividing longer before they reach yet another end with quite different characteristics to the former senescence. Thus the cells with large T antigen would bypass one boundary of mortality but not the latter hapless fate. Since it was already known that large T antigen binds many molecular targets, one or multiple of targets might be the factors in charge of the first mortality. While the large T antigen meddles with the mortality 1, the final declining fate of cells manifests another senescent phase, the mortality 2.

As the science of cellular senescence unfolded, mortality 1 were assigned many coordinating factors, including p53 and RB proteins, while mortality 2 were deemed to be most relevant to telomere and chromosomal stability. Since the subsequent development was regarded to be relevant to biomedical application, it gained much attention. For telomere and telomerase, much hype. The epistemological exercise was unnoticed as always, although it has much to tell about how the telomere story was constructed and can be evaluated. From the convergence of notions between the scientists who perhaps can be comically categorized as a phenomenologist, a cell crossbreeder, and two molecular interveners, the implication is twofold. On one hand, scientists captured traces radiating from one phenomenon in distinct ways, which might be hard to assign to certain paradigm, if not “research traditions” or “research programs”, but would be interesting to evaluate in terms of the epistemological level of outcomes each approach can generate. On the other hand, it shows how ridiculous it is to degrade a multi-cause, multi-step process into a linear change of one molecule, without contextualization in science or in history.

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