BioEssays Vol. 3, No. 1 3

The Limits of Molecular Biology

It is a truism that biology as a whole has been strikingly transformed by the subdiscipline known as ‘molecular bio- logy’. Inaugurated by the Watson-Crick model and substan- tially completed by the technological revolution of recombinant DNA research, molecular biology has left few if any areas of biology untouched. Indeed, the principal function of this journal is to report on these changes and examine the integrating effects of molecular biology on pre- viously separate branches of biological science.

Yet, while recognizing the enormous contributions that molecular biology has made, it is necessary to remember that this discipline has certain significant limitations as an ana- lytical approach. It might seem paradoxical to posit the existence of any such limits since the properties of cells and organisms are ultimately a function of their macromolecules and since the subject matter of molecular biology is the whole range of structure/function relationships of macro- molecules in cells. The reason for doing so is that molecular biology as a theory is incomplete: for many fundamental problems in biology, the present molecular canon provides no theoretical predictions and therefore cannot serve as a source of testable hypotheses in these areas.

The conceptual boundaries are of two.sorts. In the first place, we often do not know and cannot predict the relevant molecules that are involved in particular cellular phenomena. Secondly, as discussed by Brian Goodwin in this issue,l we have no general rules for deducing the properties and behaviours of individual cells or groups of cells from their macromolecular composition, however complete our molecu- lar inventory is; only new theories on the dynamic organiz- ation of cells can provide these.

Two examples will illustrate the first problem, our ignorance of the molecules involved in particular phenomena. In several embryonic systems there is now good evidence that determin- ative gradients exist which are responsible for the first fate- setting events. It is not at all clear what these gradients consist of, how they are generated or how they act, nor do present molecular concepts provide much clue. The problem is usually either ignored by molecular biologists or dealt with in only the most abstract terms; some combination of new charac- terization of the gradients and of new theory is almost certainly needed for the solution. A second instance of molecular ignorance concerns pattern formation, and specifi- cally the mechanism(s) that act to restore or duplicate pattern elements during regeneration of appendages in a wide variety of organisms. Gradients may be involved here too but it is at least equally likely that the whole system involves primarily certain key cell surface molecules, perhaps glycoproteins, as positional markers. Immunological methods are beginning to provide some support for the notion of localized cell surface markers but the precise nature and mode of action of these molecules remain mysterious matters.

The second problem, that of reconstructing the properties of a system from the properties of its components, is the long-standing one of the adequacy of reductionist approaches. The simple fact is that the properties of complex systems often derive from unexpected or unknown interactions of their components, these interactions often setting the stage for secondary interactions and so forth. The consequence is that many of the properties of such systems are neither directly

reducible to nor reconstructible from the properties of their individual components.2 A prime example in biology of such a phenomenon is that of morphogenesis, as discussed by Goodwin. The eventual answer may well lie in a better understanding of cytoskeletal dynamics but analysis solely of the components of the cytoskeleton (actin microfilaments, microtubules, etc.) can never provide the complete explana- tion; a mix of new studies on the aggregate behaviour of cytoskeletons in neighbouring cells plus new theory to assim- ilate the findings is probably essential to provide the needed breakthroughs.

The related problem of pattern formation, mentioned above, is also in this category. On the one hand, much of the cellular phenomenology of pattern formation is summed up within the polar coordinate model.3 On the other hand, the principal molecular approaches to the problem at present lie in analyses of the genes and gene products of several of the homoeotic genes in Drosophila, whose activities in some sense control pattern. It is impossible to see how these molecular findings, however complete, can yield the full explanation of the pattern regeneration phenomena described by the polar coordinate model.

The above-cited examples are all from developmental biology but other areas present comparably deep challenges to molecular biology. The functioning of higher nervous systems is, of course, the outstanding example. Theories of aging provide another.* Finally, evolution presents several major conceptual problems, of which understanding the origins of life is the most fundamental. If living forms, for instance, began with either clay minerals or tar-like sub- stances not present in contemporary organi~ms,~ the nature of the transition stages to present forms constitutes a major challenge to present molecular concepts about the origins and transmission of biological information.

To identify conceptual or technical limits of a scientific enterprise should not be construed as an exercise in pessimism. Molecular biology will certainly make large contributions to the solutions of the above-listed problems but it cannot be expected to do so unaided by new theoretical departures and more data on the biological phenomena of interest. To become aware of limits is, of course, the first step in trans- cending them.

ADAM S. WILKINS Staff Editor, BioEssays

Cambridge University Press Cambridge CB2 2RU

United Kingdom

R E FER ENC ES 1 GOODWIN, B. C. (1985). What are the causes of morphogenesis? BioEssays 3, 32-36. 2 THORPE, W. H. (1974). Reductionism in biology. In Studies in The Philosophy of Biology (ed. F. J. Ayala & T. Dobzhansky), pp.

3 BRYANT, S. V., FRENCH, V. & BRYANT, P. J. (1981). Distal regeneration and symmetry. Science 212, 993-1002. 4 RATTAN, S. I. S. (1985). Beyond the present crisis in gerontology. BioEssays 2, 226228. 5 PIRIE, N. W. (1985). Parochial, visionary, and factual thinking on the origins of life. BioEssuys 2, 18CL-181.

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