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Athel Cornish-Bowden

Publications and source records attributed to Athel Cornish-Bowden.

11 recordsLinked to original sources
PubMed2006

Putting the systems back into systems biology.

In recent years the term "systems biology" has become widespread in the biological literature, but most of the papers in which these words appear have surprisingly little to do with older notions of biological systems: they often seem to imply little more than reductionist biology applied on a large scale, with a little attention to interactions between some of the components, but with minimal attention to the kinetic properties of enzymes, which supplied much of the reductionist foundation of biochemistry. A systemic approach to biology ought to put the emphasis on the entire system; insofar as it is concerned with components at all, it is to explain their roles in meeting the needs of the system as a whole. Genuinely systemic thinking allows us to understand how biochemical systems are regulated, and why clumsy attempts to manipulate them for biotechnological purposes may fail. At a more abstract level, it is necessary for understanding the nature of life, because as long as an organism is treated as no more than a collection of components, one cannot ask the right questions, and certainly cannot answer them.

Biotechnology↗
PubMed2005

Organizational invariance and metabolic closure: analysis in terms of (M,R) systems.

This article analyses the work of Robert Rosen on an interpretation of metabolic networks that he called (M,R) systems. His main contribution was an attempt to prove that metabolic closure (or metabolic circularity) could be explained in purely formal terms, but his work remains very obscure and we try to clarify his line of thought. In particular, we clarify the algebraic formulation of (M,R) systems in terms of mappings and sets of mappings, which is grounded in the metaphor of metabolism as a mathematical mapping. We define Rosen's central result as the mathematical expression in which metabolism appears as a mapping f that is the solution to a fixed-point functional equation. Crucially, our analysis reveals the nature of the mapping, and shows that to have a solution the set of admissible functions representing a metabolism must be drastically smaller than Rosen's own analysis suggested that it needed to be. For the first time, we provide a mathematical example of an (M,R) system with organizational invariance, and we analyse a minimal (three-step) autocatalytic set in the context of (M,R) systems. In addition, by extending Rosen's construction, we show how one might generate self-referential objects f with the remarkable property f(f)=f, where f acts in turn as function, argument and result. We conclude that Rosen's insight, although not yet in an easily workable form, represents a valuable tool for understanding metabolic networks.

Animals↗
PubMed2004

Understanding the parts in terms of the whole.

Metabolism is usually treated as a set of chemical reactions catalysed by separate enzymes. However, various complications, such as transport of molecules across membranes, physical association of different enzymes, giving the possibility of metabolite channelling, need to be taken into account. More generally, a proper understanding of the nature of life will require metabolism to be treated as a complete system, and not just as a collection of components. Certain properties of metabolic systems, such as feedback inhibition of the first committed step of a pathway, make sense only if one takes a broader view of a pathway than is usual in textbooks, so that one can appreciate ideas such as regulation of biosynthesis according to demand. More generally still, consideration of metabolism as a whole puts the emphasis on certain systemic aspects that are crucial but which can pass unnoticed if attention is always focussed on details. For example, a living organism, unlike any machine known or conceivable at present, makes and maintains itself and all of its components. Any serious investigation of how this can be possible implies an infinite regress in which each set of enzymes needed for the metabolic activity of the organism implies the existence of another set of enzymes to maintain them, which, in turn, implies another set, and so on indefinitely. Avoiding this implication of infinite regress represents a major challenge for future investigation.

Animals↗
PubMed2003

Metabolic analysis in drug design.

Biotechnology is often presented as if progress in the past two decades represented a major success, but the reality is quite different. For example, ten major classes of antibiotics were discovered between 1935 and 1963, but after 1963 there has been just one, the oxazolidones. To illustrate the possibilities of doing better by taking account of the real behaviour of metabolic systems, we can examine how one might modify the activity of an enzyme in the cell (for example by genetic manipulation, or by the action of an inhibitor, etc.) to satisfy a technological aim. For example, if the objective is to eliminate a pest, one might suppose that the effect of an inhibitor could be to depress an essential flux to a level insufficient for life, or to raise the concentration of an intermediate to a toxic level. The former may seem the more obvious, but the latter is easier to achieve in practice, and there are some excellent examples of industrial products that work in that way, such as the herbicide 'Roundup' and antimalarials of the quinine class. A study of glycolysis in the parasite Trypanosoma brucei (which causes African sleeping sickness) indicates that for this approach to work the selected target enzyme must have a substrate with a concentration that is not limited by stoichiometric constraints. That is not necessarily easy to find in a complicated system, and typically needs the metabolic network to be analysed in the computer.

Animals↗
PubMed2002

The role of stoichiometric analysis in studies of metabolism: an example.

Stoichiometric analysis uses matrix algebra to deduce the constraints implicit in metabolic networks. When applied to simple networks, it can often give the impression of being an unnecessarily complicated way of arriving at information that is obvious from inspection, for example, that the sum of the concentrations of the adenine nucleotides is constant. Applied to a more complicated example, that of glycolysis in Trypanosoma brucei, it yields information that is far from obvious and may have importance for developing therapeutic ways of eliminating this parasite. Even in simplified form, the network contains nine reactions or transport steps involving 11 metabolites. This immediately shows that there must be at least two stoichiometric constraints, and indeed two can be recognized by inspection: conservation of adenine nucleotides and conservation of the two forms of NAD. There is, however, a third, which involves eight different phosphorylated intermediates in non-obvious combinations and is very difficult to recognize by inspection. It is also difficult to recognize by inspection that no fourth stoichiometric constraint exists. Gaussian elimination provides a systematic way of analysing a network in such a way that all the stoichiometric relationships that it contains emerge automatically.

Animals↗
PubMed2002

Enthalpy-entropy compensation: a phantom phenomenon.

Enthalpy-entropy compensation is the name given to the correlation sometimes observed between the estimates of the enthalpy and entropy of a reaction obtained from temperature-dependence data. Although the mainly artefactual nature of this correlation has been known for many years, the subject enjoys periodical revivals, in part because of the frequent excellence of the correlation. As with other cases of impossibly good correlation between two biological variables, the explanation is that what purports to be two variables are very largely the same variable looked at in two different ways.

Animals↗
PubMed2002

Modulation of metabolite concentrations with no net effect on fluxes.

The concentration of a metabolite in a metabolic system can be varied without affecting any other concentrations or any fluxes by varying the concentrations of two inhibitors, one a competitive inhibitor of the enzyme that produces the metabolite, the other a competitive inhibitor of the enzyme that consumes it. The two concentrations need to be varied in opposite directions in such a way that the they add up to 100% when each is expressed as a percentage of the concentration that gives the desired flux in the absence of the other. The general approach can be extended to systems in which the inhibited enzymes do not catalyse consecutive reactions.

Enzyme Inhibitors↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗