David Colquhoun

David Colquhoun (born 19 July 1936) is a British pharmacologist at University College London (UCL).

He has contributed to the general theory of receptor and synaptic mechanisms, and in particular the theory and practice of single ion channel function.

Colquhoun was born on 19 July 1936 in Birkenhead, UK.

He was educated at Birkenhead School and Liverpool Technical College.

After working unhappily as an apprentice pharmacist, he was motivated to go into research.

He obtained a BSc from the University of Leeds with a specialisation in pharmacology, and went on to complete a PhD at the University of Edinburgh where he studied the binding of immunoglobulins to lung tissue.

His supervisors were Walter Perry and W.E. Brocklehurst.

During his education, Colquhoun developed an interest in statistics and random processes, which would influence his research in years to come.

All the early work was based on mechanisms that were essentially generalisations of the simple scheme proposed by del Castillo & Katz in 1957, 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.

Subsequently, it was discovered that this extra "flipped" conformation was detectable too in the nicotinic acetylcholine receptor.

Upon completion of his PhD, Colquhoun conducted further research (largely unsuccessful) on immunological problems at UCL from 1964 to 1969.

During this time he published a book on statistics.

Following this, he completed stints at Yale University and at the University of Southampton.

In 1977 Colquhoun and Hawkes 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).

This work led to the first solution of the classical pharmacological problem of measuring separately the affinity and efficacy of an agonist.

In the context of ion channels, this problem is also known as the binding/gating problem.

He returned to the pharmacology department at UCL in 1979, where he has remained since.

In 1982 Colquhoun & Hawkes published a paper 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).

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.

He held the A.J. Clark chair of Pharmacology at UCL from 1985 to 2004, and was the Hon. Director of the Wellcome Laboratory for Molecular Pharmacology.

He was elected a Fellow of the Royal Society (FRS) in 1985 and an honorary fellow of UCL in 2004.

Colquhoun runs the website DC's Improbable Science, which is critical of pseudoscience, particularly alternative medicine, and managerialism.

The 1985 paper was later nominated as a "classic" by The Journal of Physiology.

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.

Although the Laplace transform of these distributions was known, it was thought that they were not invertible until Hawkes and Jalali found an exact solution in 1990.

The exact solution was a piecewise expression that got progressively more complicated as the length of the opening (or shutting) increased.

The solution became usable in practice after Hawkes and Jalali discovered an elegant asymptotic solution in 1992.

The application of the exact solution to joint and conditional distributions in 1996 opened the door to maximum likelihood fitting, which was implemented in a computer program, HJCFIT, which has been the basis of subsequent experimental work.

The distributions of apparent open and shut times are often referred to as HJC distributions (for Hawkes, Jalali, Colquhoun).

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.

In 2007, Malcolm Grant brought an end to the department, ending its eminent 102-year history (see Department of Pharmacology at University College London, 1905 – 2007).

Colquhoun researched the nature of the molecular interactions that cause single ion channels to open and shut, and what it is that controls the speed of synaptic events.

The invention and successful application of the patch clamp technique by Erwin Neher and Bert Sakmann allowed the individual openings and closings of single ion channels to be observed and recorded.

However, experimentally observed recordings are random in nature.

With the help of the statistician Alan G. Hawkes, Colquhoun developed a statistical method to interpret the data and test putative quantitative mechanisms for how ion channels function.

Lape et al. (2008) 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.