David Colquhoun

David Colquhoun FRS MAE
David Colquhoun in 2013
Born	(1936-07-19) 19 July 1936 (age 87)[2] Birkenhead, Cheshire, England
Alma mater	University of Leeds (BSc) University of Edinburgh (PhD)
Known for	Single Ion channels Criticism of pseudo-science[3] Statistics[4]
Awards	Humboldt Prize (1990)
Scientific career
Fields	Pharmacology Biophysics Stochastic processes Markov processes[1]
Institutions	Yale University University of Southampton University College London
Thesis	The characterisation and adsorption of sensitising antibodies (1965)
Doctoral advisor	W.L.M. Perry W.E. Brocklehurst[citation needed]
Website	dcscience.net

David Colquhoun

In 1977 Colquhoun and Hawkes^[12] predicted that ion channel openings would be expected to occur in brief bursts rather than as single openings, and this prediction was verified in experiments with Bert Sakmann, in Göttingen and London (1981).^[13][14] This work led to the first solution of the classical pharmacological problem of measuring separately the affinity and efficacy of an agonist.^[15] In the context of ion channels, this problem is also known as the binding/gating problem. This problem remains unsolved for G protein-coupled receptors, because it was shown in 1987 that the classical methods for determining affinity and efficacy were based on a misapprehension.^[16]

The 1985 paper was later nominated as a "classic"^[17] by The Journal of Physiology.^[18] In 1982 Colquhoun & Hawkes published a paper^[19] on the theory of bursts (and clusters of bursts) which gave a general expression for the distribution of the burst length (shown here on the design for a mug for those who attend a course designed to teach the mathematics needed for the equation).^[20]

It was clear that the burst length was what controlled the decay rate of synaptic currents, though the formal relationship was not derived until 1998.^[21]

Missed short events

Although the general theory of single channel behaviour was completed in 1982, it could not be used in practice for fitting mechanisms to data, because the recording apparatus is incapable of detecting events shorter than, at best, about 20 microseconds. The effect of missing short shuttings is to make openings appear to be longer than they really are (and likewise for shuttings). To use the method of maximum likelihood it was essential to derive the distribution of the length of what is actually seen, apparent open times and apparent shut times. Although the

All the early work was based on mechanisms that were essentially generalisations of the simple scheme proposed by del Castillo & Katz in 1957,[26] in which the receptor existed in only two conformations, open and shut. It was only when the glycine receptor was investigated that it was realised that it was possible to detect an intermediate shut state (dubbed the "flipped" conformation), between the resting conformation and the open state.^[27] Subsequently, it was discovered that this extra "flipped" conformation was detectable too in the nicotinic acetylcholine receptor. Lape et al. (2008)^[28] found that partial agonists were partial, not, as had been supposed since 1957, because of a deficiency in the open reaction itself, but because of a deficiency at an earlier stage, a reluctance to move from the resting conformation to the intermediate shut state that precedes opening. The actual shut-open conformation change turned out to be much the same for partial agonists as it was for full agonists. In the original formulation the flipping reaction was supposed to be a concerted transition. The essentials of this new mechanism were confirmed by Mukhtasimova et al. (2009),^[29] who generalised it to the case where the subunits can flip independently.

Statistical inference

After retiring from single ion channel work, Colquhoun maintained an interest in statistical inference. His 2014 paper, An investigation of the false discovery rate and the misinterpretation of p-values,^[30] contributed to the p-value debate, and to the discussion of reproducibility in science. This paper has been followed by others which have explored the basis of inductive inference,^[31] and which have investigated in more depth the alternatives to using p values.^[32][4] The hazards of reliance on p-values was emphasised in^[32] by pointing out that even observation of p = 0.001 was not necessarily strong evidence against the null hypothesis. Despite the fact that the likelihood ratio in favour of the alternative hypothesis over the null is close to 100, if the hypothesis was implausible, with a prior probability of a real effect being 0.1, even the observation of p = 0.001 would have a false positive risk of 8 percent. It would not even reach the 5 percent level. It was recommended that the terms "significant" and "non-significant" should not be used. P values and confidence intervals should still be specified, but they should be accompanied by and indication of the false positive risk. It was suggested that the best way to do this is to calculate the prior probability that would it would be necessary to believe in order to achieve a false positive risk of, say, 5%. Or, perhaps more simply, the p value could be supplemented by the minimum false positive risk, FPR₅₀, -that calculated for a prior probability of 0.5.^[4] Although this would be safe only for plausible hypotheses, it would be a great improvement on giving on p values and confidence intervals. The calculations can be done with R scripts that are provided,^[32][4] or, more simply, with a web calculator.^[33]

Criticism of scientific fraud, alternative medicine and managerialism

Colquhoun has been an outspoken

Colquhoun was a member of the Conduct and Competence Committee of the Complementary and Natural Healthcare Council (CNHC), a regulatory body for alternative medicine in the UK. Colquhoun has stated he was surprised at being accepted for the position. However, he was dismissed in August 2010.[47]

Colquhoun continues to write on the danger of the alternative medicine industry using government regulation for its own ends. In a 2012 article from the Scottish Universities Medical Journal, he wrote:^[48]

There are various levels of regulation. The "highest" level is the statutory regulation of osteopathy and chiropractic. The General Chiropractic Council (GCC) has exactly the same legal status as the General Medical Council (GMC). This ludicrous state of affairs arose because nobody in John Major's government had enough scientific knowledge to realise that chiropractic, and some parts of osteopathy, are pure quackery. The problem is that organisations like the GCC function more to promote their discipline rather than regulate them.

Awards and honours

Colquhoun was elected a

Personal life

In 1976, he married Margaret Ann Boultwood. They have a son and two granddaughters.

Outside academia, Colquhoun has enjoyed (in chronological order) boxing, sailing (21 ft, and later 31 ft sloops), flying light aircraft, long-distance running (10 km, half-marathon and marathon), and mountain walking.^[49] In 1988 he did the London marathon in 3 hours 57 minutes. For his 65th birthday, in 2001, he walked across the Alps (Oberstdorf, Germany, to Merano, Italy).^[50]

References