David Colquhoun

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David Colquhoun
David Colquhoun.jpg
Born (1936-07-19) 19 July 1936 (age 77)[1]
Birkenhead, Merseyside, England
Fields Pharmacology
Biophysics
Stochastic processes
Markov processes[2]
Institutions Yale University
University of Southampton
University College London
University of Leeds
University of Edinburgh
Alma mater University of Leeds (undergraduate)
University of Edinburgh (postgraduate)
Thesis The characterisation and adsorption of sensitising antibodies (1965)
Known for Single Ion channels
Criticism of pseudo-science[3]
Notable awards Fellow of the Royal Society (1985)
Website
www.dcscience.net

David Colquhoun, FRS (b. 1936) is a British pharmacologist at University College London (UCL).[4] 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,[3] which is critical of pseudoscience, particularly alternative medicine, and managerialism.[2]

Early life and education[edit]

Colquhoun was born on 19 July 1936 in Birkenhead,[1] 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.[5] 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[6] 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.[7] Following this, he completed stints at Yale University and at the University of Southampton.[5] He returned to the pharmacology department at UCL in 1979, where he has remained since.

Scientific career[edit]

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.[8] 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.[9]

Work with single ion channels[edit]

Course mug design for the Department of Pharmacology at UCL

In 1977 Colquhoun & Hawkes[10] 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).[11][12] This work led to the first solution of the classical pharmacological problem of measuring separately the affinity and efficacy of an agonist.[13] 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.[14]

The 1985 paper was later nominated as a "classic"[15] by The Journal of Physiology.[16] In 1982 Colquhoun & Hawkes published a paper[17] 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).[18]

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.[19]

Missed short events[edit]

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.[20] 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.[20] The application of the exact solution to joint and conditional distributions in 1996[21] 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).[9]

Intermediate shut states[edit]

All the early work was based on mechanisms that were essentially generalisations of the simple scheme proposed by del Castillo & Katz in 1957,[22] 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.[23] Subsequently it was discovered that this extra "flipped" conformation was detectable too in the nicotinic acetylcholine receptor. Lape et al. (2008)[24] 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),[25] who generalised it to the case where the subunits can flip independently.

Criticism of scientific fraud, alternative medicine and managerialism[edit]

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[26][27][28][29][30][31][32][33][34][35][36][37][38] and The Guardian.[39] 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,[26] stating that they are "anti-science" and that "universities that run them should be ashamed of themselves."[40] His interest in inference extends to methods that are used to assess and manage science, and critical assessment of research "metrics".[41] 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.[42][43]

DC's Improbable Science website[edit]

Colquhoun created his personal website, DC's Improbable Science,[3] 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. His blog discusses also wider problems in science, medicine and Higher Education. It was listed among the 100 best blogs in 2009.[44] 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.[45]

Controversy over website hosting[edit]

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.[46] 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 13 June 2007, he and Colquhoun released a joint statement that Colquhoun's website would be reinstated with slight modifications.[47] By that time, the web pages had been moved to a proper blog and never did return to the UCL server.

Alternative medicine and the government[edit]

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.[48]

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:[49]

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.

References[edit]

  1. ^ a b "COLQUHOUN, Prof. David" (Who's Who 2013, A & C Black, an imprint of Bloomsbury Publishing plc, 2013; online edn, Oxford University Press). (subscription required)
  2. ^ a b List of publications from Google Scholar
  3. ^ a b c "David Colquhoun's Improbable Science: Truth, falsehood and evidence, investigations of dubious and dishonest science". Archived from the original on 2013-03-05. 
  4. ^ UCL Pharmacology: Prof. David Colquhoun. University College London. 
  5. ^ a b An Uncommon Scientist with a lot of Common Sense. University College London. 
  6. ^ Colquhoun, David (1965). The characterisation and adsorption of sensitising antibodies (PhD thesis). University of Edinburgh. (subscription required)
  7. ^ Colquhoun, David (1971). Lectures on biostatistics: an introduction to statistics with applications in biology and medicine. Oxford: Clarendon Press. ISBN 0-19-854119-8. 
  8. ^ Scholars: David Colquhoun. University College London. 
  9. ^ 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. doi:10.1113/jphysiol.2002.034165.  edit
  10. ^ 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. doi:10.1098/rspb.1977.0137.  edit
  11. ^ 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. doi:10.1038/294464a0. PMID 6273743.  edit
  12. ^ 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. PMC 1192660. PMID 2419552.  edit
  13. ^ 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.  edit
  14. ^ 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.
  15. ^ 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
  16. ^ Colquhoun, D. (2007). "What have we learned from single ion channels?". The Journal of Physiology 581 (2): 425–421. doi:10.1113/jphysiol.2007.131656.  edit
  17. ^ 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. doi:10.1098/rstb.1982.0156. PMID 6131450.  edit
  18. ^ UCL’s workshop Analysis and interpretation of single ion channel records and macroscopic currents using matrix methods.
  19. ^ 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.  edit
  20. ^ a b 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. doi:10.1098/rsta.1990.0129.  edit
  21. ^ 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. doi:10.1098/rsta.1996.0115.  edit
  22. ^ 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. doi:10.1098/rspb.1957.0018.  edit
  23. ^ 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. PMID 15574743.  edit
  24. ^ Lape, R.; Colquhoun, D.; Sivilotti, L. G. (2008). "On the nature of partial agonism in the nicotinic receptor superfamily". Nature. doi:10.1038/nature07139.  edit
  25. ^ 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. doi:10.1038/nature07923. PMC 2712348. PMID 19339970.  edit
  26. ^ a b Colquhoun, D. (2007). "Science degrees without the science". Nature 446 (7134): 373–374. doi:10.1038/446373a. PMID 17377563.  edit
  27. ^ Colquhoun, D. (2009). "The arrogance of trying to sum up abilities in a number". Nature 458 (7235): 145. doi:10.1038/458145c. PMID 19279607.  edit
  28. ^ Lape, R.; Colquhoun, D.; Sivilotti, L. G. (2008). "On the nature of partial agonism in the nicotinic receptor superfamily". Nature. doi:10.1038/nature07139.  edit
  29. ^ Colquhoun, D. (2003). "Challenging the tyranny of impact factors". Nature 423 (6939): 479. doi:10.1038/423479a. PMID 12774093.  edit
  30. ^ Chen, C. C.; Akopian, A. N.; Sivilottit, L.; Colquhoun, D.; Burnstock, G.; Wood, J. N. (1995). "A P2X purinoceptor expressed by a subset of sensory neurons". Nature 377 (6548): 428–431. doi:10.1038/377428a0. PMID 7566119.  edit
  31. ^ Colquhoun, D.; Farrant, M. (1993). "The binding issue". Nature 366 (6455): 510–511. doi:10.1038/366510b0. PMID 7504782.  edit
  32. ^ Edwards, F. A.; Gibb, A. J.; Colquhoun, D. (1992). "ATP receptor-mediated synaptic currents in the central nervous system". Nature 359 (6391): 144–147. doi:10.1038/359144a0. PMID 1381811.  edit
  33. ^ Colquhoun, D. (1987). "A new type of ion-channel block". Nature 329 (6136): 204–205. doi:10.1038/329204a0. PMID 2442618.  edit
  34. ^ Colquhoun, D. (1986). "Molecular pharmacology: Structure and function of acetyl-choline-receptor ion channels". Nature 321 (6068): 382–383. doi:10.1038/321382a0. PMID 2423877.  edit
  35. ^ Gardner, P.; Ogden, D. C.; Colquhoun, D. (1984). "Conductances of single ion channels opened by nicotinic agonists are indistinguishable". Nature 309 (5964): 160–162. doi:10.1038/309160a0. PMID 6325934.  edit
  36. ^ Colquhoun, D.; Neher, E.; Reuter, H.; Stevens, C. F. (1981). "Inward current channels activated by intracellular Ca in cultured cardiac cells". Nature 294 (5843): 752–754. doi:10.1038/294752a0. PMID 6275271.  edit
  37. ^ Ogden, D. C.; Siegelbaum, S. A.; Colquhoun, D. (1981). "Block of acetylcholine-activated ion channels by an uncharged local anaesthetic". Nature 289 (5798): 596–598. doi:10.1038/289596a0. PMID 6258085.  edit
  38. ^ Colquhoun, D.; Dionne, V. E.; Steinbach, J. H.; Stevens, C. F. (1975). "Conductance of channels opened by acetylcholine-like drugs in muscle end-plate". Nature 253 (5488): 204–206. doi:10.1038/253204a0. PMID 1078602.  edit
  39. ^ Colquhoun, David (2007-08-15). "The age of endarkenment". The Guardian. 
  40. ^ Clark, Laura (2007-07-26). "Row over surge in 'scandalously un-academic' university courses". Daily Mail. 
  41. ^ Colquhoun, David (2007). "How to get good science.". Physiology News 69: 12–14. 
  42. ^ Information Tribunal appeal judgement
  43. ^ Colquhoun's response to judgement
  44. ^ Appleyard, Bryan (22 February 2009). "A guide to the 100 best blogs: part II". The Sunday Times. Times Newspapers. Retrieved 5 February 2013. 
  45. ^ UK Science Blog. Good Thinking Society.
  46. ^ "Freedom of speech and litigious herbalists". 
  47. ^ Joint Statement by Professor Colquhoun and UCL. University College London. 
  48. ^ "Why the Complementary and Natural Healthcare Council (CNHC) can’t succeed (in which DC gets fired)". 
  49. ^ Colquhoun, David (2012). "Regulation of Alternative Medicine- why it doesn’t work". Scottish Universities Medical Journal. 

External links[edit]