Its not all about the mean....

Biology as we understand today is a result of the study of averages. We attempt to study the life and fate of the individuals by studying the properties of the population. The assumption has always been that the properties of the mean is a good representation of the individual. The outliers were ignored as a minor population whose fate may not change things much. However, it is increasingly clear that the study of the outliers could largely determine more phenomena. For example, imagine treating a population of bacteria with a particular antibiotic... while most would succumb, it is the few outliers who are resistant to the drug who will determine the next outbreak. Imagine the case of chemotherapy... while resecting a tumor and chemotherapy will take care of the bulk of the tumor, the few resistant cells are sufficient to repopulate a tumor. This has increasingly shifted the focus towards measuring the properties of individual cells and not the mean or the median of the population. The conventional outlook was of course largely adopted due to technological limitations and not just as a matter of choice. The sensitivity of our imaging systems and the size of our cells make population measurements the only option left. Of late however, technology has evolved to permit the study of individual cells but the availability and the accessibility have been other limitations still preventing their widespread usage.

I have however remained a skeptic about these fancy single cell imaging systems till I came across a recent paper in the reputed journal "Cell" by Loewer et al, detailing the novel dynamics of an important tumor suppressor protein- p53, in individual cells. p53 is one of the most widely studied tumor suppressor (proteins which suppress tumor growth) which is lost in more than 50% of the cancers and is inactivated in most of the others. Since its discovery in 1979, p53 has emerged at the center stage of cancer biology as a possible therapeutic target whose restoration and reactivation in cancer cells could hold the key to successful therapy. Thus, a comprehensive understanding of this protein and its cellular functions is essential. What is presently understood is that the p53 protein, having a short half life, gets activated in cells upon conditions of cellular stress. Upon activation, p53 activates a set of downstream targets which subsequently determine cell fate. The activation of p53 was known to be mediated through post-translational modifications which alter its stability and activity.

Through imaging p53 dynamics in live cells, this paper shows that the p53 protein exhibits pulsatile dynamics in both stressed and unstressed cells spanning over a few hours. The difference under the two conditions only being in the synchorinicity and the frequency of the pulses. This however could not have been detected earlier since the occurrence of sporadic increases in the p53 protein would not have been detected by the earlier population averages.

In a very elegant way, this study causes a paradigm shift in our current understanding of p53 biology. They show that instead of being absent under stress-free conditions and active upon conditions of DNA damage, the p53 protein is actually pulsing in the cells showing a cyclical increase and decrease. The activation seen upon stress by conventional studies is only a result of the increased frequency and duration of these pulses arising out of post translational modifications of the p53 protein.


Thus, this paper by Galit Lahav from the Harvard Medical school, has managed to convince the skeptic in me that the mean, no matter how informative can still be misleading in biology. And it is thus wiser to focus on the single cell dynamics of the various proteins and signal transduction cascades towards garnering a more comprehensive understanding.

And if SJ Gould came to the conclusion that the "median isn't the message", it seems true that the mean too, is not always the message !!

Here's to a new wave in biology focusing on the individuals and not just the population...