Professor D Colquhoun, FRS held the established (A.J. Clark) chair of Pharmacology at UCL, and was the Hon. Director of the Wellcome Laboratory for Molecular Pharmacology. In October 2004, he became a Research Fellow. Like many previous holders of the chair (in particular, A.J. Clark, J.H. Gaddum, H.O. Schild and J.W. Black) his interests are in quantitative analysis of receptor mechanisms.
He graduated from Leeds with a BSc and then went to Edinburgh
to work for a PhD. After doing research at University College
from 1964-69 on immunological problems and completing a book
on statistics, he went to Yale University to work on nerve
conduction. After returning from the USA he eventually returned
to the Pharmacology Department at UCL in 1979, and has worked on single ion channel mechanisms since then. [interview][bio]
"What are you going to do, then?" I [Watson] asked.
"To smoke," he [Holmes] answered. "It is quite a three-pipe problem, and I beg that you won't speak to me for fifty minutes." The Red-Headed League. Adventures of Sherlock Holmes, Arthur Conan-Doyle [watch video, ITV]
Transmission of an impulse from one nerve cell to another, or
to a muscle cell, occurs by the release of a chemical substance,
such as acetylcholine or glutamate, which combines with specific
protein molecules- receptors- in the membrane of the downstream
cell. These receptors form molecular pores which span the cell
membrane, and the combination of the transmitter with them causes
the pore to open, which allows the passage of sodium and other
ions. The current caused by movement of these ions across the membrane
then initiates an electrical impulse. We are studying the receptors for glutamate, acetylcholine and
glycine by a combination of biophysical and molecular biological
approaches. We record the currents through individual receptor-channels
which are in their natural environment, the membranes of nerve
cells from the brain or ganglia. We also record from channels that
have been made from cloned DNA and artificially inserted into a
convenient cell membrane. The latter method has the advantage that
(with luck) you know which molecule you are dealing with, and also
that altered receptors can be made by mutating the amino acid sequence
of the receptor proteins. These methods allow us to address a variety
of questions. A major question that concerns us is the exact molecular
nature of the receptors that occur in living cells in various parts
of the nervous system.
At a more basic level we are interested
in the nature of the molecular interactions that cause the channels
to open and shut, and what it is that controls the speed of synaptic
events. Once one knows the rates of individual steps in the ion channel reaction
mechanism, the binding-gating problem is solved,
the way is cleared for rational interpretation of the effects of mutations in the
receptor protein, and the response to any arbitrary time course of synaptic
concentration of transmitter can be calculated. We have taken this approach
to analysis of natural disease-causing mutations in
human muscle nicotinic acetylcholine receptors, and in human glycine receptors (the latter being in collaboration with Sivilotti's lab).
Analysis and theory
We have also been closely involved in developing new methods
for the analysis of single channel recordings which, because
originate from single molecules, are random in nature. And,
in collaboration with Professor A.G. Hawkes (who does all the
stuff), we have developed much of the underlying stochastic
theory which is necessary for the interpretation of these recordings.
This theory allows us to interpret single channel recordings
in which short events are undetected, and most recently has
extended to deal with non-stationary channels, such as those
observed after a brief pulse of agonist is applied. This theory has proved essential for the interpretation of
our experimental observations. For example, we have been interested
in questions such as
'what does an individual activation of an ion channel look like,
and how is it related to synaptic currents?',
'how can we understand the effect of mutating an amino acid in
the receptor?', and 'how can we tell whether a particular amino acid forms part of
the binding site?'. One outcome of the theory has been the development of an optimum method (the HJCFIT program) for estimation of rate constants in a mechanism, with exact correction for missed events).
We run a graduate school course each June or July, in which the necessary mathematical background for the understanding of these methods is taught. Photographs for the 2003 and 2004 schools here.
We have developed, in the course of our work, a number of programs
for single channel analysis, for curve fitting and for theoretical
calculations. They have a lot of features that are not available
in any commercial program, and they are free (for academic users).
. . . in Iraq, the British have been “led into a trap from which it will be hard to escape with dignity and honour. They have been tricked into it by a steady witholding of information. . . . We are today not far from a disaster”, Lawrence of Arabia, on occupation of Iraq in 1920 [read more].
“Amid all the natural and political disasters it faces, the White House is certainly tireless in its effort to legalize torture” New York Times. [read more].
" . . . the people can always be brought to the bidding of the leaders. That is easy. All you have to do is tell them they are being attacked, and denounce the pacifists for lack of patriotism, and exposing the country to greater danger." Herman Goering (at the Nuremberg trials).
"All that is necessary for the triumph of evil is that good men do nothing." Attributed to Edmund Burke (1729-1797)
"They that can give up essential liberty to obtain a little temporary
safety deserve neither liberty nor safety." Benjamin Franklin, Historical Review of Pennsylvania, 1759
"I wish to propose for the reader's favourable consideration a doctrine which may, I fear, appear wildly paradoxical and subversive. The doctrine in question is this: that it is undesirable to believe a proposition when there is no ground whatever for supposing it true. I must, of course, admit that if such an opinion became common it would completely transform our social life and our political system: since both are at present faultless, this must weigh against it. I am also aware (what is more serious) that it would tend to diminish the incomes of clairvoyants, bookmakers, bishops and others who live on the irrational hopes of those who have done nothing to deserve good fortune here or hereafter. In spite of these grave arguments, I maintain that a case can be made out for my paradox, and I shall try to set it forth."
Bertrand Russell, 1935. On the Value of Scepticism
Reporter: "What do you think of Western Civilisation?" Gandhi: "It would be a good idea".
Gandhi: "Almost everything you do will be insignificant, but it is important that you do it."
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