Mitchell's formulation of the chemiosmotic theory of oxidative phosphorylation in 1961 lacked any experimental support for its three central postulates. The path by which Mitchell reached this theory is explored. A major factor was the role of Mitchell's philosophical system conceived in his student days at Cambridge. This system appears to have become a tacit influence on his work in the sense that Polanyi understood all knowledge to be generated by an interaction between tacit and explicit knowing. Early in his (...) life Mitchell had evolved a simple philosophy based on fluctoids, fluctids and statids which was developed in a thesis submitted for the Ph.D. at the University of Cambridge, England. This aspect of his work was rejected by the examiners and became a tacit element in his intellectual development. It is argued from his various publications that this philosophy can be traced as an underlying theme behind much of Mitchell's theoretical writing in the 50's leading, through his notion of vectorial metabolism, to the formulation and amplification of the chemiosmotic theory in the sixties. This philosophy formed the basis for Mitchell of his understanding of biological systems and gave him his unique approach to cell biology. (shrink)

The origins of oxidative phosphorylation, initially known as aerobic phosphorylation, grew out of three research areas of muscle metabolism, creatine phosphorylation, aerobic metabolism of lactic acid in muscle, and studies on the nature and role of adenosine triphosphate . Much of this work centred round the laboratory of Otto Meyerhof, and most of those contributing to the study of aerobic phosphorylation were influenced by that laboratory: particularly Lipmann and also Ochoa. The work of Engelhardt on ATP levels in blood also (...) appears to have been influenced by the studies of Meyerhof’s laboratory. However, with the work of Kalckar, influenced by Lipmann, biochemists began to realise the potential importance of the process. This was confirmed and extended by Belitzer and Ochoa and the theoretical contribution of Lipmann. Thus it is not easy to identify a single point that marked the initiation of studies in this field.The early work was based on the use of tissue homogenates and cells but ultimately this approach limited research possibilities. The development of techniques based on mitochondria opened up new possibilities and brought this first phase of the study of oxidative phorphorylation to a close. (shrink)

In the same year, 1961, Peter D. Mitchell and Robert R.J.P. Williams both put forward hypotheses for the mechanism of oxidative phosphorylation in mitochondria and photophosphorylation in chloroplasts. Mitchell's proposal was ultimately adopted and became known as the chemiosmotic theory. Both hypotheses were based on protons and differed markedly from the then prevailing chemical theory originally proposed by E.C. Slater in 1953, which by 1961 was failing to account for a number of experimental observations. Immediately following the publication of Williams's (...) hypothesis and before his own was published, Mitchell initiated a correspondence. Examination of the letters shows the development of a dispute based on the validity of the proposals, who should have priority and particularly whether Mitchell had drawn on Williams's work without acknowledgement. We have concluded that Mitchell's proposals were original although it is evident that prior to the correspondence Williams had considered and rejected a proposition similar to Mitchell's theory. However, a major cause of the dispute was the difference in disciplinary backgrounds of Mitchell, a microbial biochemist and Williams, a chemist. (shrink)

In the same year, 1961, Peter D. Mitchell and Robert R.J.P. Williams both put forward hypotheses for the mechanism of oxidative phosphorylation in mitochondria and photophosphorylation in chloroplasts. Mitchell's proposal was ultimately adopted and became known as the chemiosmotic theory. Both hypotheses were based on protons and differed markedly from the then prevailing chemical theory originally proposed by E.C. Slater in 1953, which by 1961 was failing to account for a number of experimental observations. Immediately following the publication of Williams (...) 's hypothesis and before his own was published, Mitchell initiated a correspondence. Examination of the letters shows the development of a dispute based on the validity of the proposals, who should have priority and particularly whether Mitchell had drawn on Williams 's work without acknowledgement. We have concluded that Mitchell's proposals were original although it is evident that prior to the correspondence Williams had considered and rejected a proposition similar to Mitchell's theory. However, a major cause of the dispute was the difference in disciplinary backgrounds of Mitchell, a microbial biochemist and Williams, a chemist. (shrink)

Attempts to solve the puzzling problem of oxidative phosphorylation led to four very different hypotheses each of which suggested a different view of the ATP synthase, the phosphorylating enzyme. During the 1960s and 1970s evidence began to accumulate which rendered Peter Mitchell’s chemiosmotic hypothesis, the novel part of which was the proton translocating ATP synthase (ATPase), a plausible explanation. The conformational hypothesis of Paul Boyer implied an enzyme where ATP synthesis was driven by the energy of conformational changes in the (...) respiratory proteins. This was finally abandoned as an explanation of the overall process. Nevertheless the conformational understanding of the enzyme became an acceptable proposal during the early 1970s and eventually led Boyer to a view of the enzyme that incorporated both hypotheses. The correspondence between Mitchell and Boyer, both Nobel laureates, exposes their different approaches to both this enzyme and to the hypotheses of oxidative phosphorylation and illuminates a key step in the development of bioenergetics. In particular Boyer was suspicious of proton gradients, because he could not envisage a chemical mechanism for the synthesis of ATP, while Mitchell distrusted conformational arguments because he believed the proton must act vectorially at the active site of the enzyme. This resulted in two different views of the mechanisms operating in this enzyme. Ultimately while Boyer was able to marry the two approaches, Mitchell retained his insistence on the role of the proton at the active site and was thus unable to give significance to Boyer’s conformational ideas. The underlying issues in this debate are discussed particularly with reference to the differing styles of Boyer and Mitchell and the influence of molecular biology, especially the development of protein technology. (shrink)