Did experimental biology die? Lessons from 30 years of p53 research.

The recent decade has greatly challenged biological research because there has been exponential growth in the amount of information that has been accumulated and published. Now, more than ever before, piles of biological data are waiting to be sieved through robust scientific reasoning and experimentation to produce the final product of basic science: conclusions. Given this situation, biological research is becoming increasingly dependent on computers. New branches of biology have sprung up in recent years in an effort to comprehensively understand the cell and the organism as a system. As biology becomes more and more computerized, classic molecular biology is sometimes considered old-fashioned and even obsolete. As molecular biologists we often wonder about the significance and relevance of our research. Are we in an era in which experimental biology should be abandoned and computational biology should be adopted exclusively? Have we reached the limit of what can be learned from experimental biology and should now continue to a mathematical representation of cells and organisms? Did experimental biology die? An elegant solution to this challenge was offered by Yuri Lazebnik as he points out a basic flaw in the experimental biologist approach: The absence of a common language among biologists creates confusion and may lead to a paradox in which the more facts we know the less we understand the process we study. According to Lazebnik, similar to a radio circuit, a living cell is comprised of certain components. If these components could be properly categorized and formally described, it would be easier for us to understand living cells and even fix their malfunctions much like an engineer who can repair a radio. At the end of the day the living cell, albeit complex, obeys a set of physical rules like any other system we know. Embracing a universal language in which all the components in a given system are eventually tagged and categorized will lead to a much more thorough understanding of the cellular system as a whole, and will eventually enable us to produce precise predictions as to the behavior of the system (1). Let us put this approach to a test. In the late 1970s several reports revealed the existence of a new protein in transformed cells (2, 3). It soon became clear that this protein was overexpressed in cancer cells at large (4, 5). The overwhelming concentrations of this protein in cancer cells, followed by the observation that it enhanced transformation in mouse cells, prompted the notion that this protein was associated with a transformed phenotype (6–8). This newly discovered protein was given the unpresumptuous name p53. At this point, at least according to the formal description approach, after establishing the involvement of p53 in tumorigenesis the scientific community would carry on defining other essential components in the cellular puzzle. Should new evidence surface that related p53 with anticancerous traits it would clash with the formal description of p53 and therefore might be more conveniently attributed to other yet undefined cellular components. In the lack of formal description, this evidence would no doubt confuse the researchers but because they were not shackled to any rigid definitions they would more easily question the very essence of p53 function. As it happens, this was exactly the case some 20 years ago. Although p53 seemed to be associated with malignancy, clear proof of its oncogenic activity was debatable because some laboratories obtained inconsistent data (9). Moreover, some tumors seemed to lack p53 altogether (10–12). These controversial observations resulted in confusion that led scientists to question the relevance of p53 to cellular transformation. The debate peaked in a very dramatic statement published in an editorial in the journal Nature in 1983: ‘‘If one transformed cell type can survive without p53, how essential is it for anything?’’ (13). From this bafflement the resolution arose that wild-type p53 was actually a tumor suppressor, whereas a mutant form of p53 that was often present in cancer cells seemed to facilitate transformation. Given that the mutant form is abundant in cancer cells, it was the first to be discovered and thus was misconceived as wild-type p53. Eventually this theory was confirmed by several studies showing the tumor suppressive activity of wild-type p53 (14–16). (For a detailed overview of the p53 history see ref. 17). Another point that should be taken into account is that a protein might be involved in a variety of cellular processes. Tagging it to a certain function might limit our thought to this function only, and may result in a biased interpretation of newly discovered evidence that alludes to different functions of the protein. Once again, p53 can serve as an example. Years of research illuminated our understanding of the involvement of p53 in cancer. Unfortunately, it cast a shadow over other p53 activities that had been wrongfully neglected for years. Several discoveries gave rise to the notion that the initial role of p53 was surveillance of cell division integrity. In higher organisms, harboring somatic cells that can redivide, this surveillance received extra meaning, as p53 activity serves to prevent these cells from deviating into malignancy. This insight allows us to zoom out and grasp the function of p53, not merely as a tumor suppressor, but in a broader sense as a protein maintaining normal cell division and perhaps participating in other processes such as development and differentiation (18). Surprisingly, mice lacking p53 were born without any apparent abnormalities (19). The fact that these mice did not exhibit any developmental defects disheartened many Note: S. Madar and I. Goldstein contributed equally to this work. Requests for reprints: Varda Rotter, Weizmann Institute of Science, P.O. Box 26, Rehovot 76100, Israel. Phone: 972-8-9344070; Fax: 972-8-9465265; E-mail: [email protected]. I2009 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-09-0940