David Colquhoun

David Colquhoun
David Colquhoun
Born 19 July 1936 (1936-07-19) (age 75)
Birkenhead, Merseyside, England
Fields Pharmacology
Institutions Yale University,
University of Southampton,
University College London
Alma mater University of Leeds,
University of Edinburgh
Known for Single ion channels, stochastic theory and experimental tests. Criticism of pseudo-science.

David Colquhoun, FRS (b. 1936) is a British pharmacologist at University College London (UCL).[1] He has contributed to the general theory of receptor and synaptic mechanisms of single ion channel function. He previously held the A.J. Clark chair of Pharmacology at UCL, and was the Hon. Director of the Wellcome Laboratory for Molecular Pharmacology. He was made a fellow of the Royal Society 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.

Contents

Early life and education

Colquhoun was born July 19, 1936 in Birkenhead, UK. After working unhappily as an apprentice pharmacist, he was motivated to go into research.[2] He obtained a B.Sc. from the University of Leeds with a specialization in pharmacology, and went on to complete a Ph.D. at the University of Edinburgh where he studied the binding of immunoglobulins to lung tissue. During his education, Colquhoun developed an interest in statistics and random processes, which would influence his research in years to come.

Upon completion of his Ph.D., Colquhoun conducted further research on immunological problems at UCL from 1964-1969. During this time he published a book on statistics.[3] Following this, he completed stints at Yale University and at the University of Southampton.[2] He returned to the pharmacology department at UCL in 1979, where he has remained since.

Scientific career

Colquhoun now researches 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 readily observed and recorded. However, experimentally observed recordings are random in nature.[4] 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.[5]

Work with single ion channels

In 1977 Colquhoun & Hawkes[6] 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).[7][8] This work led to the first solution of the classical pharmacological problem of measuring separately the affinity and efficacy of an agonist.[9] 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.[10]

The 1985 paper was later nominated as a “classic”[11] by the The Journal of Physiology.[12] In 1982 Colquhoun & Hawkes published a paper[13] 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).[14]

Course mug design

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.[15]

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). In order 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 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.[16] 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.[17] The application of the exact solution to joint and conditional distributions in 1996[18] 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).[19]

Intermediate shut states

All the early work was based on mechanisms that were essentially generalisations of the simple scheme proposed by del Castillo & Katz in 1957,[20] 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.[21] Subsequently it was discovered that this extra “flipped” conformation was detectable too in the nicotinic acetylcholine receptor. Lape et al. (2008)[22] 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),[23] who generalised it to be the case where the subunits can flip independently.

Criticism of scientific fraud, alternative medicine and managerialism

Colquhoun has been an outspoken critic of pseudoscience and scientific fraud for many years. He has written extensively on the topic, including articles in Nature[24] and The Guardian.[25] He is particularly critical of alternative medicine, and of the decision of a number of UK universities to offer science degrees incorporating courses in complementary and alternative medicine such as homeopathy and acupuncture,[24] stating that they are "anti-science" and that "universities that run them should be ashamed of themselves."[26] His interest in inference extends to methods that are used to assess and manage science, and critical assessment of research "metrics".[27] In December 2009, Colquhoun won a Freedom of Information judgement, after a three-year campaign, requiring the University of Central Lancashire to release details of their BSc course in homeopathy.[28][29]

DC's Improbable Science website

Colquhoun created his personal website, DC's Improbable Science, devoted to criticism of scientific fraud and quackery, in 2001. It has a particular focus on alternative medicine (AM), including such practices as homeopathy, Traditional Chinese medicine, herbal medicine, and others, calling them "pure gobbledygook". In addition to his outspoken disapproval of AM in academia, Colquhoun frequently speaks out on his website against misrepresentation of AM as science in the media, and against governmental support of AM.

Controversy over website hosting

In May 2007, Colquhoun announced on his website that recent comments he had made questioning the validity of claims made by a British herbalist had resulted in a complaint to Malcolm Grant, provost of UCL.[30] In response to legal threats from Alan Lakin, husband of the herbalist, Grant required Colquhoun to remove his website from the UCL server. This resulted in an outcry from the scientific community, citing a violation of Colquhoun's academic freedom. Grant ultimately reconsidered his decision and on June 13, 2007, he and Colquhoun released a joint statement that Colquhoun's website would be reinstated with slight modifications.[31]

Complementary and Natural Healthcare Council

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.[32]

References

  1. ^ UCL Pharmacology: Prof. David Colquhoun. University College London. http://www.ucl.ac.uk/npp/dc.html 
  2. ^ a b An Uncommon Scientist with a lot of Common Sense. University College London. http://www.ucl.ac.uk/Pharmacology/dc-bits/dc-mol-int.pdf 
  3. ^ Colquhoun, David (1971). Lectures in Biostatistics: An Introduction to Statistics with Applications to Biology and Medicine. Oxford University Press. 
  4. ^ Scholars: David Colquhoun. University College London. http://www.ucl.ac.uk/Pharmacology/dc-bits/scholars2.pdf 
  5. ^ Colquhoun, D.; C. Hatton, A.G. Hawkes (2003). "The quality of maximum likelihood estimation of ion channel rate constants". Journal of Physiology (London) 547 (Pt 3): 699–728. doi:10.1113/jphysiol.2002.034165. PMC 2342730. PMID 12562901. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2342730. 
  6. ^ Colquhoun D & Hawkes AG (1977). Relaxation and fluctuations of membrane currents that flow through drug- operated channels. Proc. R. Soc. Lond. B November 14, 1977 199:231-262.
  7. ^ Colquhoun D & Sakmann B (1981). Fluctuations in the microsecond time range of the current through single acetylcholine receptor ion channels. Nature 294:464-466.
  8. ^ Colquhoun D & Sakmann B (1985). Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle end-plate. J Physiol (Lond) 369:501-557.
  9. ^ Colquhoun D. (1998) Binding, gating, affinity and efficacy. The interpretation of structure- activity relationships for agonists and of the effects of mutating receptors. Br J Pharmacol 125:923-948.
  10. ^ Colquhoun D (1987). Affinity, efficacy and receptor classification: is the classical theory still useful? In Perspectives on hormone receptor classification, eds. Black JW, Jenkinson DH, & Gerskowitch VP, pp. 103-114. Alan R. Liss Inc., New York.
  11. ^ Classical Perspectives, "Classical Perspectives are commentaries on 'classic' articles in The Journal that have stimulated new lines of research and continue to be highly cited. The articles are commissioned from acknowledged experts in the area covered by the article and should indicate how the article has contributed to current developments in the field." The Journal of Physiology
  12. ^ Colquhoun D (2007). What have we learned from single ion channels? The Journal of Physiology, 581:425-427. June 1, 2007
  13. ^ Colquhoun D & Hawkes AG (1982). On the stochastic properties of bursts of single ion channel openings and of clusters of bursts. Philosophical Transactions of the Royal Society London B 300:1-59.
  14. ^ UCL’s workshop Analysis and interpretation of single ion channel records and macroscopic currents using matrix methods.
  15. ^ Wyllie DJA, Béhé P, & Colquhoun D (1998). Single-channel activations and concentration jumps: comparison of recombinant NR1/NR2A and NR1/NR2D NMDA receptors. J Physiol (Lond) 510:1-18
  16. ^ Hawkes AG, Jalali A, & Colquhoun D (1990). The distributions of the apparent open times and shut times in a single channel record when brief events can not be detected. Philosophical Transactions of the Royal Society London A 332:511-538.
  17. ^ Hawkes AG, Jalali A, & Colquhoun D (1992). Asymptotic distributions of apparent open times and shut times in a single channel record allowing for the omission of brief events. Philosophical Transactions of the Royal Society London B 337:383-404.
  18. ^ Colquhoun D, Hawkes AG, & Srodzinski K (1996). Joint distributions of apparent open times and shut times of single ion channels and the maximum likelihood fitting of mechanisms. Philosophical Transactions of the Royal Society London A 354:2555-2590.
  19. ^ Colquhoun D, Hatton CJ, Hawkes AG (2003). The quality of maximum likelihood estimates of ion channel rate constants. The Journal of Physiology, 547:699-728. March 15, 2003. doi: 10.1113/jphysiol.2002.034165
  20. ^ del Castillo J & Katz B (1957). Interaction at end-plate receptors between different choline derivatives. Proc R Soc Lond B 146:369-381
  21. ^ Burzomato V, Beato M, Groot-Kormelink PJ, Colquhoun D, & Sivilotti LG (2004). Single-Channel Behavior of Heteromeric {alpha}1{beta} Glycine Receptors: An Attempt to Detect a Conformational Change before the Channel Opens. J Neurosci 24:10924-10940.
  22. ^ Lape R, Colquhoun D, & Sivilotti LG (2008). On the nature of partial agonism in the nicotinic receptor superfamily. Nature 454:722-727.
  23. ^ Mukhtasimova N, Lee WY, Wang HL, & Sine SM (2009). Detection and trapping of intermediate states priming nicotinic receptor channel opening. Nature 459:451-454
  24. ^ a b Colquhoun, D. (2007). "Science degrees without the science". Nature 446 (7134): 373–374. doi:10.1038/446373a. PMID 17377563. 
  25. ^ Colquhoun, David (2007-08-15). "An age of endarkenment". The Guardian. http://www.guardian.co.uk/science/2007/aug/15/endarkenment. 
  26. ^ Clark, Laura (2007-07-26). "Row over surge in 'scandalously un-academic' university courses". Daily Mail. http://www.dailymail.co.uk/pages/live/articles/news/news.html?in_article_id=471045&in_page_id=1770. 
  27. ^ Colquhoun, David (2007). "How to get good science.". Physiology News 69: 12–14. 
  28. ^ Information Tribunal appeal judgement
  29. ^ Colquhoun's response to judgement
  30. ^ "Freedom of speech and litigious herbalists". http://www.dcscience.net/improbable.html#freedom1 
  31. ^ Joint Statement by Professor Colquhoun and UCL. University College London. http://www.ucl.ac.uk/news/news-articles/0706/07061303 
  32. ^ "Why the Complementary and Natural Healthcare Council (CNHC) can’t succeed (in which DC gets fired)". http://www.dcscience.net/?p=3311. 

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