Chemical bonding

David Weatherall looks at the link between lab and clinic in medical advances

Francis Crick once observed that the term molecular biology is unfortunate because it has two meanings. In the broad sense, it encompasses an explanation for any biological phenomenon in terms of atoms and molecules. But, as it is usually used, it lays particular emphasis on proteins and nucleic acids, and studies of gene structure, replication, and expression.

Crick claimed that he was forced to call himself a molecular biologist because it was more convenient to do so when visiting clergymen asked what he did, rather than try to explain that he was a mixture of an X-ray crystallographer, biophysicist, biochemist and geneticist.

This limited definition of molecular biology, and its more recent offspring molecular medicine, has not been received with universal joy, however. In the Nuffield Department of Medicine in Oxford, where Hans Krebs spent his latter years, it was never mentioned; those who broke this rule provoked a violent reaction in that otherwise benign old gentleman who, when he was able to speak again, pointed out to them at length and in no uncertain terms that biochemists such as himself had been studying a much more interesting and diverse set of molecules for many years before DNA was put on the map.

Soraya de Chadarevian and Harmke Kamminga, the editors of a multi-author book on the molecularising of biology and medicine, based on a conference held in Cambridge in 1994, take an even broader view. They use the term molecularisation to refer to any medical activities centred on molecules. In particular, they are interested in the interactions between different groups in the creation and development of these practices. Taking a social historian's approach that, they warn us, includes network and interest theory, and social interactionism, they focus on technical advances and alliances that have forged links between the laboratory, clinic and industry, and place them in their wider societal contexts. While at first this way of viewing the evolution of molecular medicine might seem to be of interest to only a limited audience of social historians of science and medicine, and, considering the cost of the book, wealthy ones at that, in the event this collection offers fascinating insights into the way in which scientific medicine evolved during the early part of this century.

The editors have chosen an extremely wide-ranging collection of examples of the way in which different areas of medical research and practice have slowly moved from being focused on experimental animals or human beings and their organs to the characterisation of disease at the levels of cells and molecules. There is, for instance, a fine account by Olga Amsterdamska of the birth of clinical biochemistry and of how chemistry was taken into the clinic at Rockefeller University by Donald Dexter Van Slyke, which, among other things, emphasises the enormous gap between the classification of disease based on biochemical phenomenology and a genuine understanding of the underlying pathological processes. Although present-day clinicians have a much deeper knowledge of the relationship between disease processes at the cellular level and how they are reflected in biochemical disturbances, they still have a tendency to treat the laboratory findings rather than the patients who have generated them.

The story of the collaboration between Max Perutz and Herman Lehmann is a good example of how a chance partnership between the basic and clinical sciences can be of so much value to both parties; Lehmann's collection of abnormal haemoglobins and the effects they had on patients appear to have been as valuable to Perutz as his knowledge of the structure and function of the molecule was to Lehmann. The outcome was, on the one hand, major insights into how haemoglobin works as an oxygen carrier while, on the other, a much clearer understanding of why inherited abnormalities of this wonderfully adaptive molecule produce such a diversity of illnesses.

De Chadarevian, in recounting this particular tale, concludes that work of this type, though helping to explain disease processes at the molecular level, has been of little value to patients. This is unfortunate timing; the results of a clinical trial, the first to show any form of treatment to be of help to those with sickle-cell anaemia, and which was based at least to some extent on an understanding of the molecular interactions of sickle-cell haemoglobin, was published while this book was in preparation. The answer to why it took 50 years from the discovery of sickle-cell haemoglobin to the development of any form of treatment of proven value, particularly in view of the massive amount of money that has been thrown at the problem, would have been very relevant to the objectives of this book.

The chapter by Lara Marks, with the eye-catching title "Cage of ovulating females", describes how, perhaps not surprisingly, laboratory animals proved to be inadequate models on which to try to develop human oral contraceptives. Considering the recent outbursts in the United States about research on pregnant women with Aids in the developing world, it is interesting to reflect on how little fuss was made about the clinical trials of the oral contraceptive pill carried out between 1950 and 1959 in some of the poorer populations of the middle Americas; the changing professional and public perceptions of what is acceptable in medical research will be another rich area of investigation for social historians in the future.

The central message of these essays, and one that must be of little comfort to those in government who hold the purse strings for funding research, is the extraordinarily diverse and serendipitous roots that underlie advances in medical science and, in particular, whether its fruits ever reach the clinic. Scientists, though they may initiate many novel and potentially productive lines of investigation, are at the mercy of chance, fashion, personal and inter-institutional intrigues, war, commercial interests and a continually changing social climate. Those who are struggling with the uncertainties of how and when to start using the tools of molecular medicine for wide-range population screening for common diseases should read Diane Paul and Paul Edelson's excellent account of the prolonged battles over the development of screening for phenylketonuria; nothing has changed, evidence, if such were needed, of why historians of medicine have so much to offer medicine, if only it has the wit to listen.

Apart from very occasional lapses into the kind of jargon and arcane prose that make the social sciences such heavy going for the rest of us, this compilation of the many different influences that led to the application of the basic biological sciences to clinical practice earlier this century offers an excellent overview of a particularly fascinating period in the changing face of clinical practice, and one that should be of great interest not only to professional historians but to anybody who wishes to try to understand how medicine has reached its present complex mixture of genuine scientific understanding and hopeful empiricism.

Sir David Weatherall is regius professor of medicine, University of Oxford.