Impact, orthodoxy and peer review.

J. H. Gaddum (then Professor of Therapeutics in Edinburgh), a pioneering clinical and basic pharmacologist, echoed Lord Kelvin in commenting that ‘a branch of science comes of age when it becomes quantitative’, and the history of clinical pharmacology has been fruitfully entwined with the development of statistical methods that underpin bioassay (in its broadest meaning) and clinical trials, to name but two examples among many of the synergies between clinical pharmacology and quantitative methods. However, striving for quantitative respectability is not always so successful – a personal favourite among (spoof) units that seek to quantitate the unmeasurable is the milliHelen, a unit of beauty cited by Colquhoun [1], ‘sufficient to launch a single ship’. Impact factor is a measure of the frequency with which the ‘average article’ in a journal has been cited in a particular year or period. The annual impact factor is a ratio between citations and recent citable items published. Thus, the impact factor of a journal is calculated by dividing the number of citations in a current year by the source items published in that journal during the previous 2 years [2]. BJCP's latest impact factor is now 3.063, down a tad since last year. We are naturally disappointed but not dismayed. Impact factor is not a spoof unit, but as Eugene Garfield notes ‘it must be used discretely’[2], and we do wonder about the three decimal places. Some of the most-cited articles of the last two centuries were published in specialist journals (including Annals of the West Riding Lunatic Asylum and Poultry Science), and some widely cited articles have not withstood the test of time – see [3] for example, for which the ISI web of knowledge identifies 230 citing articles. The senior author, Jacques Benveniste, was head of INSERM's immunology, allergy and inflammation unit. This paper described the actions of very high dilutions of anti-IgE and supported the concept of homeopathy, since only molecules of water, and no molecules of the original antibody, remained in these high dilutions. Benveniste and colleagues concluded that the configuration of molecules in water was biologically active; a journalist coined the term ‘water memory’ for this hypothesis [4]. After the article was published, a site visit was set up by Nature, including then editor John Maddox, a conjuror (James Randi) and a fraud expert (Walter Stewart). With the co-operation of Benveniste's own team, the group failed to replicate the original results. One can only guess why the paper was accepted in the first place*, but another brush with orthodoxy involving detection of seemingly extraordinarily (but by no means homeopathically) low concentrations in which, in contrast to the ‘water memory’ debacle, the authors were triumphantly vindicated, has some parallels. Radioimmunoassay (RIA) came into being as fall-out from an unrelated study. Dr I. Arthur Mirsky had hypothesized that maturity-onset diabetes might be caused by abnormally rapid degradation of insulin by hepatic insulinase. To test this hypothesis, Berson & Yalow studied the metabolism of 131I-labeled insulin following intravenous administration to non-diabetic and diabetic subjects. They observed that labelled insulin was cleared more slowly from patients who had received insulin, either for the treatment of diabetes or as ‘hypoglycaemic shock’ therapy for schizophrenia, than from healthy controls (see [5] for original references). They suspected that this was due to binding of labelled insulin to antibodies that had developed in response to administration of exogenous insulin. However classic immunological techniques were not adequate for the detection of antibodies that were likely to be in such low concentrations as to be nonprecipitating. They therefore introduced highly sensitive radioisotope methods to detect soluble antigen-antibody complexes. In the insulin-treated patients labelled insulin bound to and, during electrophoresis, migrated with gamma globulin. Using a variety of such systems they demonstrated the ubiquitous presence of insulin-binding antibodies in insulin-treated subjects [5]. Rosalyn Yalow subsequently wrote (in her Nobel Prize oration [5]): ‘This concept was not acceptable to the immunologists of the mid 1950s. The original paper describing these findings was rejected by Science and initially rejected by the Journal of Clinical Investigation. A compromise with the editors eventually resulted in acceptance of the paper, but only after we omitted “insulin antibody” from the title and documented our conclusion that the binding globulin was indeed an antibody by showing how it met the definition of antibody given in a standard textbook of bacteriology and immunity. Our use of radioisotopic techniques for studying the primary reaction of antigen with antibody and analyzing soluble complexes initiated a revolution in theoretical immunology, in that it is now generally appreciated that peptides as small as vasopressin and oxytocin are antigenic in some species and that the equilibrium constants for the antigen-antibody reaction can be as great as 1014 l mol–1, a value up to 1011 greater than the highest value predicted by Pauling's theory of 1940. ’ In her Nobel lecture Yalow listed an impressive array of peptides, drugs, non-peptide hormones and other biologically important substances to which RIA had been successfully applied. Scientific orthodoxy is favoured by the peer review system, much criticized, but still (we believe) invaluable (‘the worst system except for all the others' to paraphrase Churchill on democracy). Yalow's obituary in the Guardian newspaper (she died aged 89 years on 30 May 2011) stated that ‘this episode embittered Yalow for the rest of her life’[6], but we find this hard to believe. This feisty and immensely impressive scientist may have believed that the scientific establishment (Linus Pauling even? ) had rejected her work because it did not fit their preconceptions. But her response was the right one: she proved her point beyond all doubt, and in her Nobel lecture she not only included a facsimile of the initial rejection (the Guardian editorial says this was to the embarrassment of the medical world, but again we disagree – we all savour victories great or small and surely no one would grudge her this triumph over those pesky reviewers) but also cited another half dozen of her papers published in the Journal of Clinical Investigation over the next few years – hardly the journal of choice for an embittered reject! She closed her laboratory at Mount Sinai in New York in 1987 at the age of 66 years, because she felt research was becoming ‘grotesquely over-regulated and inhibited’, and embarked on a lecture campaign to encourage the entry of women into science [6]. So, we invite you to submit all your best clinical pharmacology papers to BJCP, especially those that add something important or unorthodox to what is already known about the subject – we may not get every decision right, but we do promise to take your work seriously and deal with submissions promptly and courteously, and we have no plans to inspect your laboratories. We should also like to take this opportunity to thank all our peer reviewers who give so generously of their precious time to making the imperfect peer review process as good as it can be: their names are recorded at http://onlinelibrary.wiley. com/doi/10.1111/j.1365-2125.2010. 03863.x/pdf