The importance of being random

Albert Michelson, who as a young experimentalist proved the jaw-dropping proposition that the speed of light is a constant regardless of the movement of the light source, declared in 1894, “It seems probable that most of the grand underlying principles have been firmly established and that further advances are to be sought chiefly in the rigorous application of these principles to all phenomena” [1xCrease, RP and Mann, CC. : 10See all References[1]. It is disheartening, but not surprising, that Lewis Wolpert, one of the founders of modern developmental biology, should make an almost identical statement about his own field a hundred years later [2xThe good fairy godmother of science. Wolpert, L. Curr Biol. 1996; 6: 2Abstract | Full Text | Full Text PDF | PubMedSee all References[2].Cell biology is now at a stage analogous to physics at the end of the last century. We can describe cellular behavior reasonably well, and we have the tools needed to “…fill in the details of how the thousands of genes …work” [2xThe good fairy godmother of science. Wolpert, L. Curr Biol. 1996; 6: 2Abstract | Full Text | Full Text PDF | PubMedSee all References[2]. But when we have done that, it will mark the beginning of a new phase, not the end of the field. The next grand principles that will revolutionize our thinking about cellular and developmental biology will not lie simply in the identification or characterization of any particular gene or gene product, any more than the future of physics in Michelson's day lay in refinement of the measurement of the speed of light. Paradigm shifts come about when we think about familiar data in unfamiliar ways.Although we cannot specifically predict where the next major shifts in our own field will arise, in biology we are fortunate to have many areas where observation has thus far outstripped theory. By analogy with physics at the turn of the century, we can expect that some new insights into the nature of life will evolve as we study phenomena less and examine cause and effect more. One area deserving consideration is the importance of random events in generating cell behavior.All biological processes, at the cellular as well as the organismal and evolutionary levels, rely on the energy-dependent reinforcement and perpetuation of random accidents to maintain and transmit information. We appreciate the overwhelming importance of random events in evolution, but randomness rules biology at the microscopic level as well. To give one example, the first event in frog development is a random collision between sperm and egg. The arbitrary choice of sperm entry point then determines the direction of the first cortical rotation and, in direct consequence, the primary body axis of the tadpole. If the direction of the cortical rotation is experimentally altered, a normal tadpole still develops but with its body axis defined by the artificial rotation [3xCortical rotation of the Xenopus egg: consequences for the anteroposterior pattern of embryonic dorsal development. Gerhart, J, Danilchik, M, Doniach, T, Roberts, S, Rowning, B, and Stewart, R. Development. 1989; 107 Suppl: 37–51PubMedSee all References[3]. No level of detail in understanding the chemistry of the egg could enable us to calculate exactly how it will develop without this absolutely critical random input. How can frog eggs accept random initial axial determinants but all generate tadpoles that look more or less alike?This property of living systems — the capacity for plucking order and reproducibility out of random chaos — is not unique to the egg. In many developing tissues, if a particular cell is destroyed, one of its neighbors will assume its fate. The differing fates of individual cells within an ‘equivalence group’ of cells with the same set of potential fates may be determined by signals arising either from outside the group (induction) or from other cells within the group (lateral specification or lateral inhibition) [4xLateral specification of cell fate during vertebrate development. Raible, DW and Eisen, JS. Curr Opin Genet Devel. 1995; 5: 444–449Crossref | PubMed | Scopus (5)See all References[4]. In vertebrates, invertebrates, and even cooperative colonies of free-living amoebae, lateral specification often occurs when one cell in the equivalence group, apparently at random, gains a slight lead on its fellows in the race towards a chosen fate. The winning cell then sends signals to the other members of the equivalence group to prevent them from assuming the same fate, or to direct them to assume an alternative fate. In most cases, it cannot be predicted and does not seem to matter which cell in an equivalence group wins the race. Each embryo becomes a functional adult, regardless of the precise origin and history of any given cell.We can predict that the explanations for these amazing feats must lie in the spectacularly wasteful expense of energy by living cells. Living systems are always in a state very far from chemical equilibrium, but not all non-equilibrium states are equally likely, and very few of them are conducive to the perpetuation of life. How particular non-equilibrium states are assiduously pursued by every cell, and how every cell maintains its profound metastability and remains poised to follow an effectively infinite variety of behaviors, remain fundamental mysteries. Cells do not disobey the laws of thermodynamics, but rather hydrolyze enormous quantities of ATP in a highly directed way in order to defy them. Thus, we can expect that one particularly important principle in cell biology will be defined when my question for Wolpert's “good fairy godmother of science” has been answered: how exactly does the cell trade off energy consumption against the normal effects of entropy, so that it can exploit random events in such a way as to yield consistent, predictable behavior? Once we know this, we may begin to answer arguably the most fundamental question in biology: what exactly is the difference between living and non-living chemical systems?