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David Colquhoun

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David Colquhoun FRS MAE (born 19 July 1936) is a British pharmacologist at University College London (UCL).[5] He has contributed to the general theory of receptor and synaptic mechanisms, and in particular the theory and practice of single ion channel function. 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[6] and an honorary fellow of UCL in 2004. Colquhoun runs the website DC's Improbable Science,[3] which is critical of pseudoscience, particularly alternative medicine, and managerialism.[1]

David Colquhoun
FRS MAE
David Colquhoun in 2013
Born (1936-07-19) 19 July 1936 (age 88)[2]
Birkenhead, Cheshire, England
Alma mater
Known for
AwardsHumboldt Prize (1990)
Scientific career
Fields
Institutions
ThesisThe characterisation and adsorption of sensitising antibodies (1965)
Doctoral advisorW.L.M. Perry
W.E. Brocklehurst[citation needed]
Website

Early life and education

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Colquhoun was born on 19 July 1936 in Birkenhead, UK.[2] He was educated at Birkenhead School and Liverpool Technical College. After working unhappily as an apprentice pharmacist, he was motivated to go into research.[7] 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[8] 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.

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.[9] Following this, he completed stints at Yale University and at the University of Southampton.[7] He returned to the pharmacology department at UCL in 1979, where he has remained since. 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).

Scientific career

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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.[10] In a lifelong collaboration With the statistician Alan G. Hawkes (1938 -2023),[11] Colquhoun developed a statistical method to interpret the data and test putative quantitative mechanisms for how ion channels function.[12]

He and Lucia Sivilotti run a website,[13] which gives information about UCL's work on single ion channels and on statistical inference.[14]

Work with single ion channels

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Course mug design for the Department of Pharmacology at UCL

In 1977 Colquhoun and Hawkes[15] 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).[16][17] This work led to the first solution of the classical pharmacological problem of measuring separately the affinity and efficacy of an agonist.[18] 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.[19]

The 1985 paper was later nominated as a "classic"[20] by The Journal of Physiology.[21] In 1982 Colquhoun & Hawkes published a paper[22] 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).[23]

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.[24]

Missed short events

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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 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.[25] 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.[26] The application of the exact solution to joint and conditional distributions in 1996[27] opened the door to maximum likelihood fitting, which was implemented in a computer program, HJCFIT,[28] 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).[12]

Intermediate shut states

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All the early work was based on mechanisms that were essentially generalisations of the simple scheme proposed by del Castillo & Katz in 1957,[29] 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.[30] Subsequently, it was discovered that this extra "flipped" conformation was detectable too in the nicotinic acetylcholine receptor. Lape et al. (2008)[31] 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),[32] who generalised it to the case where the subunits can flip independently.

Statistical inference

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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,[33] 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,[34] and which have investigated in more depth the alternatives to using p values.[35][4] The hazards of reliance on p-values was emphasised in[35] 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 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,[35][4] or, more simply, with a web calculator.[36]

Criticism of scientific fraud, alternative medicine and managerialism

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Colquhoun has been an outspoken critic of pseudoscience and scientific fraud for many years. He has written extensively on the topic, including articles and letters in Nature[37][38][39] and The Guardian.[40] 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 homoeopathy and acupuncture,[37] stating that they are "anti-science" and that "universities that run them should be ashamed of themselves".[41]

His interest in statistical inference extends to methods that are used to assess and manage science, and critical assessment of research "metrics".[42] 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 homoeopathy.[43][44]

DC's Improbable Science website

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Colquhoun created his personal website, DC's Improbable Science,[3] devoted to criticism of pseudoscience, in 2001. It has a particular focus on alternative medicine (AM), including such practices as homoeopathy, 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. His blog discusses also wider problems in science, medicine and higher education. It was listed among the 100 best blogs in 2009.[45] It was blog of the week in the New Statesman (30 May 2010). And in 2012 it was co-winner of the first UK Science Blog Prize, awarded by the Good Thinking Society.[46] The most-read post on his blog is not related to alternative medicine however, instead dealing with the death of Stefan Grimm: "Publish and perish at Imperial College London: the death of Stefan Grimm",[47] which has been viewed more than 200,000 times.

Controversy over website hosting

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In May 2007, Colquhoun announced on his website that recent comments he had made questioning the validity of claims made by Ann Walker, a lecturer in Nutrition at the University of Reading and a herbalist, had resulted in a complaint to Malcolm Grant, provost of UCL.[48] In response to legal threats from Alan Lakin, husband of Walker, 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 13 June 2007, he and Colquhoun released a joint statement that Colquhoun's website would be reinstated with some modifications effected on advice of counsel.[49] By that time, the web pages had been moved to a proper blog and never did return to the UCL server.

Controversy over election of Prince Andrew to the Royal Society

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See also: Prince Andrew, Duke of York § Reaction to election to the Royal Society

In 2013, Prince Andrew, Duke of York, was elected as a "Royal Fellow" by the Royal Society. Some fellows of the society thought this was a bad idea because the press had been critical of some aspects of his behaviour. Colquhoun wrote two blog posts on the topic,[50][51] which resulted in media attention.[52][53][54] As a result, the voting form was changed by the Royal Society, though Prince Andrew remained a Royal Fellow until 2022 when he resigned in the wake of his involvement in the Epstein scandal.

Alternative medicine and the government

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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.[55]

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:[56]

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

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Colquhoun was elected a Fellow of the Royal Society (FRS) in 1985[6][2] and awarded the Humboldt Prize in 1990.

Personal life

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

Outside academia, Colquhoun has enjoyed (in chronological order) boxing, flying light aircraft, sailing (21 ft, and later 31 ft sloops), long-distance running (10 km, half-marathon and marathon), and mountain walking.[57] 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).[58]

References

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  1. ^ a b David Colquhoun publications indexed by Google Scholar
  2. ^ a b c Anon (2015). "Colquhoun, Prof. David". Who's Who (online Oxford University Press ed.). A & C Black. doi:10.1093/ww/9780199540884.013.U11583. (Subscription or UK public library membership required.)
  3. ^ a b c "David Colquhoun's Improbable Science: Truth, falsehood and evidence, investigations of dubious and dishonest science". Archived from the original on 2 March 2013.
  4. ^ a b c d Colquhoun, David (2019). "The False Positive Risk: A Proposal Concerning What to Do About p-Values". The American Statistician. 73 (Sup 1): 192–201. arXiv:1802.04888. doi:10.1080/00031305.2018.1529622. S2CID 85530643.
  5. ^ "UCL Pharmacology: Prof. David Colquhoun". University College London. 14 February 2019.
  6. ^ a b "Professor David Colquhoun FRS". London: Royal Society. Archived from the original on 17 November 2015.
  7. ^ a b "An Uncommon Scientist with a lot of Common Sense" (PDF). University College London.
  8. ^ Colquhoun, David (1964). The characterization and adsorption of sensitizing antibodies (PhD thesis).
  9. ^ Colquhoun, David (1971). Lectures on biostatistics: an introduction to statistics with applications in biology and medicine. Oxford: Clarendon Press. ISBN 978-0-19-854119-6.
  10. ^ "Scholars: David Colquhoun" (PDF). University College London.
  11. ^ "Alan G. Hawkes". Swansea University. Retrieved 7 June 2024.
  12. ^ a b Colquhoun, D.; Hatton, C. J.; Hawkes, A. G. (2003). "The quality of maximum likelihood estimates of ion channel rate constants". The Journal of Physiology. 547 (3): 699–728. doi:10.1113/jphysiol.2002.034165. PMC 2342730. PMID 12562901.
  13. ^ OneMol.org.uk
  14. ^ Statistical inference
  15. ^ Colquhoun, D.; Hawkes, A. G. (1977). "Relaxation and Fluctuations of Membrane Currents that Flow through Drug-Operated Channels". Proceedings of the Royal Society B: Biological Sciences. 199 (1135): 231–262. Bibcode:1977RSPSB.199..231C. doi:10.1098/rspb.1977.0137. PMID 22856. S2CID 6060354.
  16. ^ Colquhoun, D.; Sakmann, B. (1981). "Fluctuations in the microsecond time range of the current through single acetylcholine receptor ion channels". Nature. 294 (5840): 464–466. Bibcode:1981Natur.294..464C. doi:10.1038/294464a0. PMID 6273743. S2CID 4353962.
  17. ^ Colquhoun, D.; Sakmann, B. (1985). "Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle end-plate". The Journal of Physiology. 369: 501–557. doi:10.1113/jphysiol.1985.sp015912. PMC 1192660. PMID 2419552.
  18. ^ Colquhoun, D. (1998). "Binding, gating, affinity and efficacy: The interpretation of structure-activity relationships for agonists and of the effects of mutating receptors". British Journal of Pharmacology. 125 (5): 923–947. doi:10.1038/sj.bjp.0702164. PMC 1565672. PMID 9846630.
  19. ^ 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.
  20. ^ 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
  21. ^ Colquhoun, D. (2007). "What have we learned from single ion channels?". The Journal of Physiology. 581 (2): 425–427. doi:10.1113/jphysiol.2007.131656. PMC 2075201. PMID 17363381.
  22. ^ Colquhoun, D.; Hawkes, A. G. (1982). "On the Stochastic Properties of Bursts of Single Ion Channel Openings and of Clusters of Bursts". Philosophical Transactions of the Royal Society B: Biological Sciences. 300 (1098): 1–59. Bibcode:1982RSPTB.300....1C. doi:10.1098/rstb.1982.0156. PMID 6131450.
  23. ^ UCL's workshop Analysis and interpretation of single ion channel records and macroscopic currents using matrix methods.
  24. ^ Wyllie, D. J. A.; Behe, P.; Colquhoun, D. (1998). "Single-channel activations and concentration jumps: Comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors". The Journal of Physiology. 510 (Pt 1): 1–18. doi:10.1111/j.1469-7793.1998.001bz.x. PMC 2231013. PMID 9625862.
  25. ^ Hawkes, A. G.; Jalali, A.; Colquhoun, D. (1990). "The Distributions of the Apparent Open Times and Shut Times in a Single Channel Record when Brief Events Cannot Be Detected". Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences. 332 (1627): 511–538. Bibcode:1990RSPTA.332..511H. doi:10.1098/rsta.1990.0129. S2CID 122883551.
  26. ^ Colquhoun, D.; Jalali, A.; Hawkes, A.G. (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 of London B. 337 (1282): 383–404. Bibcode:1992RSPTB.337..383H. doi:10.1098/rstb.1992.0116. PMID 1279733.
  27. ^ Colquhoun, D.; Hawkes, A. G.; Srodzinski, K. (1996). "Joint Distributions of Apparent Open and Shut Times of Single-Ion Channels and Maximum Likelihood Fitting of Mechanisms". Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences. 354 (1718): 2555–2590. Bibcode:1996RSPTA.354.2555C. doi:10.1098/rsta.1996.0115. S2CID 118010415.
  28. ^ Sivilotti, Lucia (10 March 2011). "Programs description". OneMol.org.uk.
  29. ^ Castillo, J. D.; Katz, B. (1957). "Interaction at End-Plate Receptors between Different Choline Derivatives". Proceedings of the Royal Society B: Biological Sciences. 146 (924): 369–381. Bibcode:1957RSPSB.146..369C. doi:10.1098/rspb.1957.0018. PMID 13431862. S2CID 6302752.
  30. ^ Burzomato, V.; Beato, M.; Groot-Kormelink, P. J.; Colquhoun, D.; Sivilotti, L. G. (2004). "Single-Channel Behavior of Heteromeric 1 Glycine Receptors: An Attempt to Detect a Conformational Change before the Channel Opens". Journal of Neuroscience. 24 (48): 10924–10940. doi:10.1523/JNEUROSCI.3424-04.2004. PMC 6730200. PMID 15574743.
  31. ^ Lape, R.; Colquhoun, D.; Sivilotti, L. G. (2008). "On the nature of partial agonism in the nicotinic receptor superfamily". Nature. 454 (7205): 722–727. Bibcode:2008Natur.454..722L. doi:10.1038/nature07139. PMC 2629928. PMID 18633353.
  32. ^ Mukhtasimova, N.; Lee, W. Y.; Wang, H. L.; Sine, S. M. (2009). "Detection and trapping of intermediate states priming nicotinic receptor channel opening". Nature. 459 (7245): 451–454. Bibcode:2009Natur.459..451M. doi:10.1038/nature07923. PMC 2712348. PMID 19339970.
  33. ^ Colquhoun, David (2015). "An investigation of the false discovery rate and the misinterpretation of p-values". Royal Society Open Science. 1 (3): 140216. arXiv:1407.5296. Bibcode:2014RSOS....140216C. doi:10.1098/rsos.140216. PMC 4448847. PMID 26064558.
  34. ^ Colquhoun, David. "The problem with p-values". Aeon Magazine. Retrieved 11 December 2016.
  35. ^ a b c Colquhoun, David (2017). "The reproducibility of research and the misinterpretation of p-values". Royal Society Open Science. 4 (12): 171085. doi:10.1098/rsos.171085. PMC 5750014. PMID 29308247.
  36. ^ Longstaff, Colin; Colquhoun, David. "Calculator for false positive risk (FPR)". UCL.
  37. ^ a b Colquhoun, D. (2007). "Science degrees without the science". Nature. 446 (7134): 373–374. Bibcode:2007Natur.446..373C. doi:10.1038/446373a. PMID 17377563. S2CID 29071826.
  38. ^ Colquhoun, D. (2009). "The arrogance of trying to sum up abilities in a number". Nature. 458 (7235): 145. Bibcode:2009Natur.458..145C. doi:10.1038/458145c. PMID 19279607.
  39. ^ Colquhoun, D. (2003). "Challenging the tyranny of impact factors". Nature. 423 (6939): 479. Bibcode:2003Natur.423..479C. doi:10.1038/423479a. PMID 12774093.
  40. ^ Colquhoun, David (15 August 2007). "The age of endarkenment". The Guardian.
  41. ^ "Rise in applications for 'soft' subjects panned as traditional courses lose out". 27 July 2007.
  42. ^ Colquhoun, David (2007). "How to get good science". Physiology News. 69: 12–14.
  43. ^ Information Tribunal appeal judgement
  44. ^ Colquhoun's response to judgement
  45. ^ Appleyard, Bryan (22 February 2009). "A guide to the 100 best blogs: part II". The Sunday Times. Archived from the original on 28 May 2015. Retrieved 5 February 2013.
  46. ^ UK Science Blog. Good Thinking Society.
  47. ^ Colquhoun, David (1 December 2014). "Publish and perish at Imperial College London: the death of Stefan Grimm". DCscience.net. Retrieved 25 September 2015.
  48. ^ "Freedom of speech and litigious herbalists".
  49. ^ "Joint Statement by Professor Colquhoun and UCL". University College London. 12 June 2007.
  50. ^ Colquhoun, David (3 May 2013). "Reaction to election to the Royal Society". DCscience.net. Retrieved 26 May 2024.
  51. ^ Colquhoun, David (25 May 2013). "The election of Prince Andrew to the Royal Society. What Fellows think". DCscience.net. Retrieved 26 May 2024.
  52. ^ Devlin, Hannah. "Royal Society upset as Andrew joins Wren, Boyle and Babbage". Sunday Times. Retrieved 26 May 2024.
  53. ^ Wilsdon, James (5 May 2013). "Prince Andrew's election to the Royal Society sparks anger among fellows". The Guardian. Retrieved 26 May 2024.
  54. ^ Morris, Kate (6 May 2013). "Election of Prince Andrew angers scientists at Royal Society". The Independent. Retrieved 26 May 2024.
  55. ^ "Why the Complementary and Natural Healthcare Council (CNHC) can't succeed (in which DC gets fired)". 11 August 2010.
  56. ^ Colquhoun, David (2012). "Regulation of Alternative Medicine- why it doesn't work" (PDF). Scottish Universities Medical Journal.
  57. ^ "DC's sports". David Colquhoun. Retrieved 3 December 2019.
  58. ^ "Walk across the Alps, 2001". David Colquhoun. Retrieved 2 June 2019.
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