physiology

physiology is defined by dictionaries as ‘the science of the normal functions and phenomena of living things’. The physiology of animals emerged in Europe out of the Renaissance nterest in the experimental method, as exemplified by the work of William Harvey (doctor to Charles I). Harvey's book of 1628 on the Motion of the Heart, ‘Exercitationes Anatomicae de Motu Cordis’, brilliantly analyses structural and functional observations (quantitative as well as qualitative), which remorselessly led him, and similarly lead the present day reader, to the conclusion that the blood circulates, in man as well as in other animals. This volume remains central to our current understanding of the word ‘physiology’ because of its emphasis on experiment, data analysis, and hypothesis testing. Harvey's work also exemplifies the natural symbiois between physiology (‘function’) and anatomy (‘structure’), a science from which physiology was to emerge as a separate discipline in the second half of the nineteenth century. Harvey's book also connects physiology to medicine. Understanding of every disease follows from combining knowledge of the relevant normal physiology to the way in which it is perturbed in the particular disorder (‘pathophysiology’).

Historically, the subsequent meaning of ‘physiology’ is well illustrated by the way in which the word is used in the two following quotations. The first is from 1704 ( J. Harris, Lexicon Technica): ‘Physiology, is by some also accounted a Part of Physick’ (i.e. Medicine), ‘that teaches the Constitution of the Body so far as it is sound, or in its Natural State; and endeavours to find Reasons for its Functions and Operations, by the Help of Anatomy and Natural Philosophy’. The second (a definition of Charles Darwin's colleague T. H. Huxley), 150 years later, is virtually identical to current usage: ‘whereas that part of biological science which deals with form and structure is called Morphology; that which concerns itself with function is Physiology’.

It was the experimental work of Claude Bernard in France in the mid nineteenth century that led to the profound insight that homeostasis is central ot the success and survival of any organism. This implies that physiological systems must necessarily function in such a way as to regulate their internal environment, by means of what we now call ‘feedback’. A homeostatic mechanism requires, at a minimum, a set of sensors to measure the relevant variable (e.g. body temperature), feeding back ‘error signals’ to an integrator (the brain), which controls an effector mechanism to adjust that variable (sweating, shivering, etc.). Such a negative feedback control system will act to return the variable towards the non-perturbed state. Such ideas of control and order are central to understanding and defining the discipline of physiology, whether it be in microorganisms, plants or animals.

The significance of physiology as the key science underpinning health and disease (human and veterinary) accounts for the nomenclature adoped in 1900 by the Nobel Foundation. To recognize key developments in this field, the relevant Nobel Prize is still awarded in ‘Physiology or Medicine’, although many Nobel prize-winners in this category (working in such fields as immunology, molecular biology and bioengineering) would not readily have identified themselves as physiologists. But many would have done so. For example: in cardiovascular physiology, Krogh (for his studies of capillary function), Einthoven (who described the electrocardiogram) and Forssman (who developed cardiac catheterization); in neurophysiology, Sherrington (who conceived the idea of synapses), Adrian (responsible for our original understanding of coding of information by patterns of nerve impulses), and Hubel and Weisel (who worked out how the visual areas of the cerebral cortex analyse specific features of the image); in endocrinology, Banting (insulin) and Guillemin and Schally (identification of the hypothalamic peptides that control the pituitary gland).

The interface between physiology and chemistry led directly to the emergence, in the first half of the twentieth century, of the major new discipline of biochemistry. Hence, such Nobel laureates in ‘Physiology or Medicine’ as Warburg (respiratory enzymes), Krebs (metabolic integration), Brown and Goldstein (cholesterol) and Sutherland (cyclic AMP) would probably not have thought of their scientific research as being part of ‘physiology’.

Another science that grew out of physiology concerns nutrition; yet another is pharmacology, whose foundations arose from the experiemental studies of physiologists such as Loewi (the discoverer of the transmitter substance acetylcholine) and Dale (chemical transmission between nerve cells). Despite the natural and deepening methodological and cultural divergence, over time, of both biochemistry and pharmacology from physiology, they all share the goal of explaining the functions of the body. Moreover, now that the concepts of genetics and the power of molecular biology pervade the whole of biology, the communality of physiology, pharmacology and biochemistry has re-emerged. This is well illustrated by the recent discovery of Furchgott (another Nobel prize winner) and others, that nitric oxide, a tiny gaseous molecule, can convey information between cells simply by diffusing through their membranes.

Harder to define, yet critical to the discipline of physiology, is the term ‘general physiology’. This subject emerged originally from the convergence of nineteenth-century physical chemistry with experimental biology. It was founded on quantitative studies of plant and animal cells. Because of its reductionist goal, general physiology was an obvious forerunner of what is now described as cell and molecular physiology. However, more than this, it attempted to use the theoretical insights gained from the ‘hard sciences’ (physics and chemistry) to provide a rational basis for analyzing living matter, and was thus eager to embrace and test theory quantitatively. An outstanding example of the success of this approach is the experimental analysis of the resting potential and the action potential (nerve impulse) by Hodgkin and colleagues in the late 1940s. Indeed, successful analysis of ‘bioelectricity’ is one of the factors that led to the foundation by physiologists of yet another off-shoot — biophysics. Although there are still (notably in North America) a number of distinguished university departments of Biophysics, growth of this subject as an independent discipline has been hampered somewhat by its failure to meld its ‘physiological’ roots with its links to biological physics (especially X-ray crystallography). However, the work of Nobel laureates Neher and Sakmann provides a spectacular example of how electrophysiological analysis can give biophysical insight not available through other means. These scientists, through clever technical developments, were able to design experiments that allowed structural, and hence functional, changes in single protein molecules (membrane ion channels) to be followed in real time by recording the flow of ionic current through them. By tightly sealing a fine, fluid-filled capillary tube to an extremely small part of a cell membrane, and linking it to a sophisticated amplifier (‘patch clamping’), they were able to measure the current through individual channels, flicking quickly from closed to open states. This physiological insight has very recently been matched by structural studies by MacKinnon and colleagues on membrane channels at atomic resolution.

Physiology has a complex, deep relationship with the approach of reductive science. This is in part because ‘function’, particularly ‘interesting’ or unexpected function, emerges from interactions that can be found only in relatively complex systems; hence physiologists are unlikely (unless they are working on essentially trivial problems) to find that molecular structures in isolation give more than partial insight into the problem under attack. ‘Explanations’ of physiological questions seem more likely to arise from combining such reductionist approaches with, on the one hand, thermodynamics and, on the other, control systems theory. Life depends on ‘non-equilibrium’ properties — i.e. on complex interactions that require the constant expenditure of energy to maintain them. And networks of information and control (the nervous system, hormones etc.) are central to the development, function, and probably the evolution of complex biological systems.

Seen in this way, the information encoded in the genes provides a very challenging experimental opportunity for physiologists. To have read the sequence of DNA is only a small step on the route to understanding how and to what extent our genes build and control our bodies, and cause disease. Genes do just one thing: they translate their information into proteins. To understand how the products of genes work individually and together to create the magnificent complexity of a whole organism is part of the exciting challenge that faces the revitalized science of physiology in the twenty-first century. Indeed, the prospects for physiology are wider still: it will ultimately need to link such understanding ‘upwards’ to such disciplines as experimental psychology, ecology and human biology.

Richard Boyd

Bibliography

Hodgkin, A. L. (1977). The pursuit of nature. Cambridge University Press, Cambridge.
Boyd, C. A. R. and and Noble, D. (1993). The logic of life: the challenge of integrative physiology. Oxford University Press, Oxford.

See also Bernard, Claude; biochemistry; biotechnology; Harvey, William; molecular biology; pharmacology.