The Origin of Individuals
- Jean-Jacques Kupiec
A central question in biology is how multicellular organisms develop from a single cell and how development is controlled. The standard view is that the process is deterministic, following directives governed by information located in the genome. Molecular biologist Jean-Jacques Kupiec contradicts this picture. In the fascinating The Origin of Individuals he argues that there is no plan, pre-pattern or program encoded in the genome. Instead, cell differentiation and development include a random element.
In the standard view, development is controlled by the binding of protein transcription factors to promoters that activate genes in the DNA. These genes in turn generate proteins, including other transcription factors and signalling molecules that activate yet more genes. A cascade of gene activation results, leading to the proliferation and differentiation of cells that ultimately generates the organism. Assuming that molecular interactions and gene activation are predictable, the development process should be deterministic.
Kupiec argues that this picture is wrong. Gene activation is inherently stochastic, he says, and, therefore, cell differentiation must also be stochastic. Transcription factors attach with certain probabilities to many binding sites in gene promoters, implying that chance plays a dominant role in gene activation and expression. Similarly, cell signalling pathways, and thereby cell interactions, are stochastic, as proteins may bind promiscuously to many partners with various odds. Many interactions and pathways are possible.
As a result of this underlying unpredictability, Kupiec claims, stochastic cellular actions such as cell growth, cell differentiation and cell death must be constrained somehow to ensure that the correct sequence of development occurs. Otherwise, a fertilized egg could grow into any organism.
The problem that ordered biological structures are rarer than the many possible random states led the physicist Erwin Schrödinger in his 1944 book What is Life? to contrast the science of life with physics: in statistical thermodynamics, macroscopic order is generated from disorder, whereas for life to develop, order must be generated from order. Schrödinger introduced the notion of a code script — analogous to a program — contained in the chromosomes, which acts as both plan and operative factor to prevent disorder by guiding the development process.
Kupiec disagrees with the idea of programs. Because of the stochastic nature of protein interaction and gene expression, he says, there can be no Aristotelian form or program to give order to life and ward off entropic chaos and death.
But without a code to follow, how can a particular organism develop from a single cell? Kupiec's radical solution is to apply Darwin's theory of evolution. Put simply, evolution requires two processes — variation and selection. An organism's offspring each varies slightly; natural selection picks out those that survive to generate more such organisms, again with their own subtle variations. In the development of an organism the stochastic nature of gene activation and protein interactions permits a vast array of possible developmental outcomes. Darwinian selection, Kupiec argues, constrains development so as to consistently form a particular organism. The local environment of the cell is the selecting agent, choosing which cells survive, differentiate, divide or die. He demonstrates his concept through computer simulations that generate simple patterns of two cell types. Each cell reacts with some probability to its local conditions to determine its next state.
In setting up local environment and metabolic interactions, cells must, however, use signalling protocols or programs that specify how the cells react — even if they involve probabilities. Yet Kupiec claims that because of stochastic protein interactions such programs cannot exist. But even if we allow simple reactive protocols to control any cell's reaction to its local environment, such strategies can produce only simple patterns. They cannot achieve the complex structures and functions generated in many multicellular organisms. Such reactive strategies can, at best, pass on information to determine the cell's next state.
Thus, in Kupiec's proposal, the local environment must host the constraining information necessary to form an organism. But it is not clear how this information could be stored and conveyed. In his view, the environment functions like a complex, external 'homunculus', magically controlling embryonic development at every step. Kupiec also fails to explain why differentiated cells remain stable if gene activation is stochastic, or why cellular control strategies and protocols exist at all.
Kupiec's version of a Darwinian-like cell-selection process needs to be robust and invariant. It must be more restrictive than typical Darwinian selection, which permits the formation of a diverse array of organisms and species to form. It must explain why a particular embryo forms, not just any embryo. It must account for the similarity of identical twins; the precision with which the left side mirrors the right in bilaterally symmetrical organisms; and why a mouse differs from a horse or a potato. A further issue is that even if there is local molecular randomness, it need not be passed on to the cell or to the developmental control architecture of the organism. Organisms consistently pass through the same stages during development, irrespective of minor variations in their local and maternal environments.
By treating the genome only as a generator of proteins, Kupiec adopts an implicitly reductionist view of development. But organisms of many species have virtually identical protein structures, yet their control architecture is vastly different, just as a house and a skyscraper can be made of the same parts. Every complex structure needs specific control information to develop, and the only reasonable source of that information is the genome, not some blind local evolutionary selection process. The genome and cell cooperate by means of an epigenetic interpretation system by which control information in the genome is interpreted and executed by the cell. Thus the genome encodes more than protein building-blocks — it contains a hidden control code. Such a feature could explain the vast non-coding regions in the genome; Kupiec prefers to think of these regions as mere space fillers determining gene-activation probabilities.
Kupiec's model also fails to account for global and temporal relationships. Local information is not powerful enough to generate global relationships in an organism — all the more so if it is probabilistic. Because the growth process of an embryo is ordered in time, directives from the genome must be linked to form control networks. The architecture of an organism is complex both spatially and temporally.
Kupiec is a very successful writer, deservedly so. I enthusiastically recommend this courageous book with its iconoclastic viewpoint. The Origin of Individuals is a pleasure to read, presenting complex ideas clearly and effectively. Whether one agrees with him or not, Kupiec's is an inspiring work, a thought-provoking rollercoaster ride through the history of ideas about the origins of ontogeny.
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Progress in Biophysics and Molecular Biology (2012)