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Putting the Systems back into Systems Biology

This page is the third of a series containing the article Putting the Systems back into Systems Biology by Athel Cornish-Bowden, published in Perspectives in Biology and Medicine (2006) 49, 475–489. A PDF file is also available.

The birth of systems biology2

If someone were to analyze current notions and fashionable catchwords, he would find systems high on the list.

Ludwig von Bertalanffy (1969)

Bertalanffy, L. von (1969) General system theory, New York: George Braziller

2The quotation marks are to stress that much of the work that currently goes under the name of systems biology hardly merits this name.

3Bertalanffy’s capital letters.

After a very slow start, the ideas of Kacser and Burns (1973) are gradually coming to be accepted as the appropriate basis for analyzing the kinetic behavior of multienzyme systems. What, however, does this acceptance of one kind of systemic view of biology have in common with the sudden vogue for systems biology on the one hand, or with the older ideas of systems theory advocated by Ludwig von Bertalanffy and Robert Rosen on the other? At the moment it would seem that there is remarkably little connection with either. Bertalanffy in particular laid great stress on the need to see systems as wholes, and he was critical of what he saw of the ever-increasing specialization of modern science, necessitated by the enormous amount of data, yet the very popularity of systems biology is itself a product of the amount of data generated by genome sequencing—enormous beyond anything that Bertalanffy encountered. His major concern was to emphasize the essential Unity of Science3, which he thought was granted not by a utopian reduction of all sciences to physics and chemistry, but by the structural uniformities of the different levels of reality (Bertalanffy, 1969). He was very skeptical of reductionist ideas, and these played little part in his thinking. In practice it has proved very difficult for others to build on any details of his work.

When I started thinking about this essay in 2003 I was already thinking that systems biology was a vogue term, but the vogue that existed then was as nothing compared to what it has become. More than half of the 600 or so publications one can find by searching for this combination of words at the end of 2005 date from 2005, and much more than half of the remainder from 2004. This sudden apparent enthusiasm for systemic ideas after many years in the wilderness must, however, offer little comfort to those who have thought in terms of systems for a long time, because systems biology in current practice is not easy to distinguish from old-style reductionist biochemistry applied on an ever-larger scale. The main novelty is the recognition that many aspects of cell biology have to be understood in terms of interactions between two or more proteins, or two or more other entities: this is certainly an advance on the way of thinking that characterized much of classical biochemistry, but it is still far from an appreciation of systems as systems.

Cornish-Bowden, A. and M. L. Cárdenas (2001b) Information transfer in metabolic pathways: effects of irreversible steps in computer models, Eur. J. Biochem. 268, 6616–6624

A simple example of the importance of system-level thinking is provided by feedback inhibition of a biosynthetic pathway by its end-product, a type of metabolic regulation described in any textbook of biochemistry. For example, aspartokinase (which in some organisms is a mixture of two or more isoenzymes with different regulatory properties) catalyzes the first step in the interconversion of the aminoacids aspartate and lysine, and it is inhibited by lysine. As drawn in most textbooks, the pathway ends there, at lysine, but that representation leaves much unclear, because it fails to indicate why the cell needs to make lysine in the first place, or what purpose is served by having the first enzyme in the pathway inhibited by lysine. The point that is left unstated, and that some will consider too obvious to need stating, is that lysine is needed for protein synthesis; more generally, the end-product in almost any biosynthetic pathway is not the end of anything, but just the link between two processes. People who claim that that is obvious may then go on to claim that it is also obvious that feedback inhibition of aspartokinase is needed to ensure that lysine is synthesized at the rate needed for protein synthesis, neither faster nor slower. This second point is not only not obvious; it is not even true, because if regulation of rates were the only thing needed it could be perfectly well satisfied by the ordinary product inhibition backwards through the pathway that arises from the everyday properties of virtually all enzymes. As long as rates are the only concern no feedback loop is needed, but it becomes absolutely necessary when one recognizes that metabolite concentrations need to be taken into account as well: without feedback inhibition (and other classical regulatory mechanisms) flux control would be achieved at the expense of huge uncontrolled variations in the concentrations of intermediates (Cornish-Bowden and Cárdenas, 2001b); these would normally be very harmful, even lethal, to the organism, and explain why suppressing regulatory mechanisms is not normally a useful way of achieving biotechnological aims. All of this can be summarized by saying that the regulation of most biosynthetic metabolic pathways can be understood in terms of ideas of supply and demand, with the benefit that in general economic laws work much better in metabolism than they do in economics (Hofmeyr and Cornish-Bowden, 2000).

General systems theory

Savageau, M. A. (1990) Biochemical systems theory: alternative views of metabolic control. In Control of metabolic processes (ed. A. Cornish-Bowden and M. L. Cárdenas), 6987. New York: Plenum

Woese, C. R. (2004) A new biology for a new century, Microb. Molec. Biol. Rev. 68, 173–186

What about the influence of Bertalanffy’s view of systems on Kacser and Burns and their more recent followers? As long as one connes oneself to general remarks there may seem to be some influence, but when one examines the major modern systemic approaches in detail they prove to be entirely mechanistic. Carl Woese (2004) makes a useful distinction between what he calls empirical reductionism and fundamentalist reductionism, the former being purely methodological, a way of analyzing systems into their component parts in order to understand them better. As we have seen, reductionist ideas played little part in Bertalanffy’s thinking, but Kacser and Burns, as well as Heinrich and Rapoport and Savageau, are empirical reductionists in Woese’s sense, as they explain the properties of systems essentially as the sums of the properties of their components. Savageau (1990), however, makes the valuable point that any respectable reductionist is also a reconstructionist: it is not enough to show how a system can be reduced to its components; one should also show that the components can be put together again to make a functional whole. He adds, however, that the problem is that the reconstructionist phase of this program is seldom carried out.

By contrast, fundamentalist reductionism is essentially metaphysical, a belief about the nature of living organisms, that they can be completely understood in terms of the properties of their components. Anything else may be, and has been, derided as a return to vitalism, but Rosen in particular has argued very strongly that there is a third way of interpreting life that is neither vitalism nor exclusively mechanism, but is complexity. Before discussing Rosen’s view, however, a detour is necessary to outline Erwin Schrödinger’s question about the nature of life, and his efforts to answer it.