p53: guardian of multicellularity? A short essay on multicellular evolution and p53

p53 is a well known tumour suppressor gene. What we know about p53 and other similar genes, for that matter, no matter how independent the information may be, is always put in the context of disease. This is so common that it is almost impossible to think of genes like p53 out of the context we study them in. If I tell you that p53 responds to DNA damage and stops cellular growth, you may ask: “How does it affect cancer in the overall picture? Or how may we use what we know about p53 to help us treat cancer? ” – p53 is always related back to cancer, understandably so, since it was discovered and is important in this context. In this article I’ll attempt to go a step further relating what we know of p53 in normal and cancer cells to a more general topic of evolution of life forms. Specifically, I’ll address one question: What role did p53 play in evolution of multicellular organisms? I will simply take p53 and the context in which we know this gene, cancer, and set it in a different context – evolution. Before I address the question, I’ll first talk about multicellular evolution itself. I will briefly go over the transition of unicellularity to multicellularity, and then focus on problems possibly encountered during this transition from primitive multicellular organisms to larger, more complex ones. Only after I’ve set this stage, will I ease p53 into the discussion, proposing that the role p53 played was important for the evolution of larger multicellular organisms from primitive, smaller multicellular organisms.

In his famous book “ The selfish gene ”, Richard Dawkins described living organisms as “survival machines for genes” (5). We are essentially great neat packages that self-replicators called genes use to ensure their immortality. When we die, the only remaining traces of us are in copies of our genes that have been passed onto our children. In the world of natural selection, this means that the most fit DNA packages or organisms, i.e. ones that are capable of carrying their DNA luggage to adulthood and successfully mating to pass on their DNA, will tend to survive better – hence “survival of the fittest”.

In the evolution of unicellular to multicellular life, Dawkin’s view begs some interesting questions about this transition. One question is why did this transition occur? Was complexity better suited for survival than simplicity? In other words, were genes more likely to survive onto the next generation when packaged into say a bird or mouse than when packaged into a single-celled organism like E. coli? One way to look at the problem comes from relating the organism to its environment. E. coli has evolved and adapted to its niche in the environment, as have humans to theirs. Neither would survive in each other’s niche (if you think otherwise consider the possibility of bumping around with a bunch of other people in a giant flask of LB broth– no, I didn’t think so). Therefore, a satisfying answer may be that some environments demand organized complexity and that’s why we live where we are and other environments like water or LB have bacteria in them rather than us.

A second question is, how did this occur and what problems were encountered along the way? The story of multicellular evolution, grossly brief, may have been something like this. Presumably after life evolved in a pond somewhere into simple unicellular organisms, chance mutations permitted some of them to group together in a primitively organized and beneficial way. Each new beneficial trait was selected for and inherited. The increase in size (due to numbers) was found to be beneficial because that took them off the menu of smaller predators and added a lot more to theirs. Eventually intercellular communication mechanisms evolved that allowed the coupling of the behavior of one cell to that of another. Processes such as death (apoptosis), specialization (motility) and differentiation (formation of spores) began to take place, all contributing to the survival of the whole – or shall we say to the genes they carried?

This process took place until two problems began to impose limitations on progress: 1) organization to support a harmonious whole and 2) the presence of renegade cells that arose due to the base rate of genomic instability.

The first is a bit of an engineering and architectural problem. How can one fertilized cell develop into an organism of elaborate form and structure? A small fertilized egg can give rise, depending on the developmental program, to a crab or to a whale. You may ask why form and structure are required in the first place. Consider the following: the logical progression of a growing mass of cells is simply to become a larger mass of cells. If there were no physical and biological limitations associated with larger sizes, there would be no reason why cellular masses would not grow to the size of elephants! Cells do divide and grow to make up elephants, but only when they are organized in a way to support the whole. For example, beyond a certain size of cells, there would be limitations on oxygen diffusing to the inner cells. Therefore, evolution beyond a certain size would be absolutely dependent on the development of an oxygen transport system to all parts of the organism, the end product of which are the respiratory and vascular systems that have evolved. Another example is the structural support that multicellular organisms need whether as an exoskeleton in crabs or endoskeleton in us.

The second problem is that of “the renegade cell”. The James Dean of cells, the one cell that wants to do things differently, employing the free will principle with a zeal for adventure. Why was this a problem? There are two factors to consider. The first had to do with the fundamentals of evolution and the second with size. Every dividing cell has a basal rate of mutations – a truism that is a fundamental property of all living organisms. Mutations that give rise to genetic diversity and an environment, which drove the selection of genetic variants, are the two ingredients that made the evolution of life possible. This problem was negligible in unicellular organisms but became increasingly problematic when cells began to clump together to form increasingly larger sizes.

The argument that size is the other factor is as follows. If there is a basal rate of mutations in every dividing cell, there is a certain probability that each cell may develop a “renegade promoting mutation”. The more cells there are, the greater the probability that some cell somewhere will go bad. The “renegade problem” then, is really a product of one of the fundamental tenets of evolution – that of mutation and evolution of size (as a function of cell number). It provided the basis of genetic diversity and at the same time a major hurdle that must have been overcome for complex multicellular organisms to evolve.

Where does p53 fit in all of this? With respect to the architectural/structural problem, p53 seems to plays no role. There is no evidence for p53 having an important function in the development and maintenance of any essential processes. p53 deficient mice develop and grow with no evident defects in basic cellular processes (2).

How about the “renegade problem”? Does p53 represent a class of genes evolved to primarily address this renegade problem? I think so.

p53 has probably been the most studied gene for over a decade. The data amassed over this period have given us a decent understanding, although incomplete and still under intensive investigation as any quick Pubmed search will show, of p53 itself (structure and properties), the processes it is required for and its importance in preventing disease. Very briefly, we know it’s a DNA binding protein that can repress or upregulate a large number of genes in response to stresses that cause DNA damage, causing cellular growth arrest in some systems or death in others. Current understanding is that its primary role is to prevent formation of tumours by employing its gene regulating properties (1).

What evidence is there that p53 is important in dealing with the renegade problem? Firstly, p53 is the most widely mutated gene in human cancer, and mice in which p53 has been eliminated, develop tumours at an average age of four months. I think it important to note that this tendency to develop tumours reflects an inherent basal rate of mutations that eventually give rise to tumours, since these mice are laboratory bred and not exposed to cancer promoting agents. Secondly, besides developing tumours, there is substantial evidence that a small but significant number of mice succumb during development (2). Since the frequency of this developmental phenotype is so low and together with our knowledge of p53 and tumourigenesis, the following view of p53 can be argued: p53 is a watchdog that contains and eliminates any mutant cell arising during the life course of an organism from the moment of fertilization onwards. The role of p53 is the same during embryogenesis as in adults. Its absence in embryos causes loss of embryos and (presumably because cells that have gone bad were not eliminated and therefore led to developmental problems leading to resorption of the fetus). The embryos that make it to adulthood accumulate many mutations that eventually give rise to the 100% tumour incidence observed in these mice.

The third reason is the role of p53 in spermatogenesis. Evidence argues that p53 acts using the same mechanism as in the first two reasons – to eliminate damaged cells, in this case sperm cells. Mice deficient in p53 have less progeny than normal pairs (3).

Besides providing evidence of how important p53 is, it underlines the importance of preventing or containing renegade cells in mammals and quite possibly in worms, flies and all other higher organisms – in all of which p53 has been found to exist. It seems that tumour formation, greatly making an organism unfit for survival, is an early by-product in mice and humans lives, and by logical extension, all mammals. The question I am putting forward is: if p53 did not exist, is it reasonable to suggest the evolution of mammals could have been significantly compromised because of the “renegade problem”? I think the answer is yes.

The seemingly singular role of p53 (halting or eliminating abnormal cells) and its requirement in restricting cancer to a post-reproductive age, argues that at some point during multicellular evolution, renegade cells were a problem – enough to provide selective pressure to evolve genes designated to ease this. If size was indeed an important factor, then it must have become important with the evolution of the worm, C. elegans, since p53 is not found in any lower organism (4). p53 seems to have evolved to shift the timing of cancer development from a young age, when reproductive vitality is at its peak, to old when it is all but gone (Viagra may have changed this now, – at least in men).

From a selfish gene’s point of view, p53 was hired as a bodyguard by a bunch of other self-replicating genes bent on making themselves better survival machines.


1. Vousden KH et al. Nat Rev Cancer. 8, 594-604. (2002)

2. Hall PA, et al. Curr Biol. 3, R144-7 (1997)

3. Yin Y. et al. A. Dev Biol. 204 (1), 165-71 (1998)

4. Derry WB et al.. Science. 294 (5542),591-5 (2001)

5. Dawkins, R. (1989). The selfish gene. Oxford: Oxford university press.

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