David Colquhoun
Encyclopedia
David Colquhoun, FRS (b. 1936) is a British
pharmacologist at University College London
(UCL). 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
.
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. Following this, he completed stints at Yale University
and at the University of Southampton
. He returned to the pharmacology department at UCL in 1979, where he has remained since.
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. 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.
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. 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.
The 1985 paper was later nominated as a “classic” by the The Journal of Physiology
. 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).
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.
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
. Lape et al. (2008) found that partial agonist
s 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), who generalised it to be the case where the subunits can flip independently.
of pseudoscience
and scientific fraud
for many years. He has written extensively on the topic, including articles in Nature
and The Guardian
. 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
, stating that they are "anti-science
" and that "universities that run them should be ashamed of themselves." His interest in inference extends to methods that are used to assess and manage science, and critical assessment of research "metrics
". 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.
, 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.
had resulted in a complaint to Malcolm Grant
, provost
of UCL. 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.
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
pharmacologist at University College London
University College London
University College London is a public research university located in London, United Kingdom and the oldest and largest constituent college of the federal University of London...
(UCL). He has contributed to the general theory of receptor and synaptic mechanisms of single ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
function. He previously held the A.J. Clark
A.J. Clark
Alfred Joseph Clark MC FRS was a British pharmacologist, Professor of Pharmacology, University College, London. He was elected to the Royal Society in 1931. He was the author of the classic textbook Applied Pharmacology....
chair of Pharmacology
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
at UCL, and was the Hon. Director of the Wellcome
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
Laboratory for Molecular Pharmacology. He was made a fellow of the Royal Society
Royal Society
The Royal Society of London for Improving Natural Knowledge, known simply as the Royal Society, is a learned society for science, and is possibly the oldest such society in existence. Founded in November 1660, it was granted a Royal Charter by King Charles II as the "Royal Society of London"...
in 1985 and an honorary fellow of UCL in 2004. Colquhoun runs the website DC's Improbable Science, which is critical of pseudoscience
Pseudoscience
Pseudoscience is a claim, belief, or practice which is presented as scientific, but which does not adhere to a valid scientific method, lacks supporting evidence or plausibility, cannot be reliably tested, or otherwise lacks scientific status...
, particularly alternative medicine
Alternative medicine
Alternative medicine is any healing practice, "that does not fall within the realm of conventional medicine." It is based on historical or cultural traditions, rather than on scientific evidence....
and managerialism
Managerialism
Managerialism is the belief that organisations have more similarities than differences, and thus the performance of all organisations can be optimised by the application of generic management skills and theory. To a practitioner of managerialism, there is little difference in the skills required...
.
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. He obtained a B.Sc. from the University of LeedsUniversity of Leeds
The University of Leeds is a British Redbrick university located in the city of Leeds, West Yorkshire, England...
with a specialization in pharmacology, and went on to complete a Ph.D.
Ph.D.
A Ph.D. is a Doctor of Philosophy, an academic degree.Ph.D. may also refer to:* Ph.D. , a 1980s British group*Piled Higher and Deeper, a web comic strip*PhD: Phantasy Degree, a Korean comic series* PhD Docbook renderer, an XML renderer...
at the University of Edinburgh
University of Edinburgh
The University of Edinburgh, founded in 1583, is a public research university located in Edinburgh, the capital of Scotland, and a UNESCO World Heritage Site. The university is deeply embedded in the fabric of the city, with many of the buildings in the historic Old Town belonging to the university...
where he studied the binding of immunoglobulins to lung tissue. During his education, Colquhoun developed an interest in statistics
Statistics
Statistics is the study of the collection, organization, analysis, and interpretation of data. It deals with all aspects of this, including the planning of data collection in terms of the design of surveys and experiments....
and random processes
Stochastic process
In probability theory, a stochastic process , or sometimes random process, is the counterpart to a deterministic process...
, 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. Following this, he completed stints at Yale University
Yale University
Yale University is a private, Ivy League university located in New Haven, Connecticut, United States. Founded in 1701 in the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States...
and at the University of Southampton
University of Southampton
The University of Southampton is a British public university located in the city of Southampton, England, a member of the Russell Group. The origins of the university can be dated back to the founding of the Hartley Institution in 1862 by Henry Robertson Hartley. In 1902, the Institution developed...
. 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 synapticSynaptic
Synaptic may refer to:*Synapse, part of the nervous system*Synapsis, the pairing of two homologous chromosomes*Synaptic , a Linux graphical package management program for APT See also...
events. The invention and successful application of the patch clamp
Patch clamp
The patch clamp technique is a laboratory technique in electrophysiology that allows the study of single or multiple ion channels in cells. The technique can be applied to a wide variety of cells, but is especially useful in the study of excitable cells such as neurons, cardiomyocytes, muscle...
technique by Erwin Neher
Erwin Neher
Erwin Neher is a German biophysicist.Erwin Neher studied physics at the Technical University of Munich from 1963 to 1966. In 1966, He was awarded a Fulbright Scholarship to study in the US...
and Bert Sakmann
Bert Sakmann
-External links:*...
allowed the individual openings and closings of single ion channels to be readily 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
Quantitative property
A quantitative property is one that exists in a range of magnitudes, and can therefore be measured with a number. Measurements of any particular quantitative property are expressed as a specific quantity, referred to as a unit, multiplied by a number. Examples of physical quantities are distance,...
mechanisms for how ion channels function.
Work with single ion channels
In 1977 Colquhoun & Hawkes predicted that ion channelIon channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
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
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
. 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.
The 1985 paper was later nominated as a “classic” by the The Journal of Physiology
The Journal of Physiology
The Journal of Physiology is a biweekly peer-reviewed scientific journal established in 1878, published by Wiley-Blackwell on behalf of The Physiological Society....
. 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).
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.
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. 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).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, in which the receptor existed in only two conformations, open and shut. It was only when the glycine receptorGlycine receptor
The glycine receptor, or GlyR, is the receptor for the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current...
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
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
. Lape et al. (2008) found that partial agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s 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), 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 criticScientific skepticism
Scientific skepticism is the practice of questioning the veracity of claims lacking empirical evidence or reproducibility, as part of a methodological norm pursuing "the extension of certified knowledge". For example, Robert K...
of pseudoscience
Pseudoscience
Pseudoscience is a claim, belief, or practice which is presented as scientific, but which does not adhere to a valid scientific method, lacks supporting evidence or plausibility, cannot be reliably tested, or otherwise lacks scientific status...
and scientific fraud
Scientific misconduct
Scientific misconduct is the violation of the standard codes of scholarly conduct and ethical behavior in professional scientific research. A Lancet review on Handling of Scientific Misconduct in Scandinavian countries provides the following sample definitions: *Danish definition: "Intention or...
for many years. He has written extensively on the topic, including articles in Nature
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...
and The Guardian
The Guardian
The Guardian, formerly known as The Manchester Guardian , is a British national daily newspaper in the Berliner format...
. He is particularly critical of alternative medicine
Alternative medicine
Alternative medicine is any healing practice, "that does not fall within the realm of conventional medicine." It is based on historical or cultural traditions, rather than on scientific evidence....
, and of the decision of a number of UK universities to offer science degrees incorporating courses in complementary and alternative medicine such as homeopathy
Homeopathy
Homeopathy is a form of alternative medicine in which practitioners claim to treat patients using highly diluted preparations that are believed to cause healthy people to exhibit symptoms that are similar to those exhibited by the patient...
and acupuncture
Acupuncture
Acupuncture is a type of alternative medicine that treats patients by insertion and manipulation of solid, generally thin needles in the body....
, stating that they are "anti-science
Antiscience
Antiscience is a position that rejects science and the scientific method. People holding antiscientific views are generally skeptical that science is an objective method, as it purports to be, or that it generates universal knowledge. They also contend that scientific reductionism in particular is...
" and that "universities that run them should be ashamed of themselves." His interest in inference extends to methods that are used to assess and manage science, and critical assessment of research "metrics
Metric (mathematics)
In mathematics, a metric or distance function is a function which defines a distance between elements of a set. A set with a metric is called a metric space. A metric induces a topology on a set but not all topologies can be generated by a metric...
". 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.
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 homeopathyHomeopathy
Homeopathy is a form of alternative medicine in which practitioners claim to treat patients using highly diluted preparations that are believed to cause healthy people to exhibit symptoms that are similar to those exhibited by the patient...
, Traditional Chinese medicine
Traditional Chinese medicine
Traditional Chinese Medicine refers to a broad range of medicine practices sharing common theoretical concepts which have been developed in China and are based on a tradition of more than 2,000 years, including various forms of herbal medicine, acupuncture, massage , exercise , and dietary therapy...
, 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 herbalistHerbalist
An herbalist is:#A person whose life is dedicated to the economic or medicinal uses of plants.#One skilled in the harvesting and collection of medicinal plants ....
had resulted in a complaint to Malcolm Grant
Malcolm Grant
Malcolm John Grant, CBE is the Provost and President of University College London. He took up the post – the principal academic and administrative officer and head of UCL – on 1 August 2003. Since then, UCL has developed as one of the world's leading universities and he has tackled critical...
, provost
Provost (education)
A provost is the senior academic administrator at many institutions of higher education in the United States, Canada and Australia, the equivalent of a pro-vice-chancellor at some institutions in the United Kingdom and Ireland....
of UCL. 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
Academic freedom
Academic freedom is the belief that the freedom of inquiry by students and faculty members is essential to the mission of the academy, and that scholars should have freedom to teach or communicate ideas or facts without being targeted for repression, job loss, or imprisonment.Academic freedom is a...
. 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.
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.External links
- David Colquhoun @ UCL Pharmacology
- Publications
- DC's Improbable Science website
- Account of the DC's Improbable Science incident - Columnist Ben GoldacreBen GoldacreBen Michael Goldacre born 1974 is a British science writer, doctor and psychiatrist. He is the author of The Guardian newspaper's weekly Bad Science column and a book of the same title, published by Fourth Estate in September 2008....