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Professor Mollie Holman was interviewed in 1998 for the Interviews with Australian scientists series. By viewing the interviews in this series, or reading the transcripts and extracts, your students can begin to appreciate Australia's contribution to the growth of scientific knowledge.
The following summary of Holman's career sets the context for the extract chosen for these teachers notes. The extract covers Holman's work on the smooth muscle of the vas deferens and her interest in neurotransmitters. Use the focus questions that accompany the extract to promote discussion among your students.
Mollie Holman was born in Launceston, Tasmania in 1930. She received a BSc (Hons) from the University of Melbourne in 1951. From 1953 to 1954 Holman was a demonstrator in pharmacology as well as working in a research laboratory where she developed equipment to measure membrane potentials in frog skin and muscles. She received an MSc from the University of Melbourne in 1955. Holman then went to the UK on a Melbourne University Travelling Scholarship to work on the physiology of smooth muscle at the University of Oxford. She received a DPhil from Oxford in 1957 for her research on the effects of changes in ionic environment on the electrical activity of smooth muscle.
Holman returned to Australia in 1955 to take up a lectureship in physiology at the University of Melbourne. Here she continued her work on changes in membrane potential by studying the transmission of a stimulus from an autonomic nerve to the smooth muscle of the vas deferens.
In 1963 Holman moved to the Department of Physiology at Monash University. Initially appointed as a senior lecturer, she became a reader in 1965 and professor in 1970. At Monash her work focused on the complex network of nerve cells that innervate the smooth muscle in the wall of the gut. She was particularly interested in the interaction of the autonomic nervous system and the smooth muscle of the gut. Holman retired in 1996, but remains actively engaged in teaching and research.
In 1970, Holman was awarded a DSc by Monash University and was elected a Fellow of the Australian Academy of Science. In 1998 she was appointed an Officer of the Order of Australia in recognition of her contributions to science and education, and in 1999 was awarded an honorary Doctor of Laws by Monash University. This was also the year of the inaugural award of the Mollie Holman Doctoral Medal, which was created in honour of her endeavours in postgraduate education. The medal is awarded annually for the best thesis for the degree of Doctor of Philosophy in each faculty of Monash University.
Vas deferens tissue was to go on to prove a major model.
That turned out to be one of the most densely innervated smooth muscles anywhere in the body. There were masses of nerves mingling with the smooth muscle cells. When you stimulate those nerves you get a little signal, a change in membrane potential once again. Unlike the action potential, these are very much smaller signals, which have to sum together to reach the threshold for generating an action potential. So we had a model very much like the skeletal neuromuscular junction – and it turned out to be a model for quite a number of other situations in the body as well.
So there was a summation sequence?
Yes. We looked at the signals we got in the smooth muscle when we stimulated the hypogastric nerve, and we saw the small movements of the membrane, in the same direction as action potential but very much smaller – you could grade them with the strength of stimulation. You had electrodes on the hypogastric nerve and you'd stimulate: at first nothing happened and then you increased the strength. Gradually you would come up to a point where you saw a very small change in membrane potential; with a stronger stimulus it would get bigger and bigger, and then you would get an action potential. So we now had a nice handle on what was going on in neuromuscular transmission in smooth muscle. That was good.
Eventually you got onto transmitters, didn't you?
Yes. Perhaps I should explain a bit about the nerves that go to smooth muscle and the other tissues in the body. The skeletal muscles are innervated by nerves whose cell bodies lie in the brain or the spinal cord and send out what we call an axon. That goes out to the skeletal muscle fibre, and at its terminal in the skeletal muscle it releases a substance called acetylcholine, which causes a change in membrane potential similar to but much larger than I described for the vas.
But in the autonomic nervous system – the heart, blood vessels, guts, the whole lot – although the nerve cells send out an axon which releases acetylcholine at its terminal in exactly the same way, that acetylcholine is released onto another nerve cell. It does not go directly to the muscle fibre: instead, there's a relay in the system, with the synapse. And the cells which are activated by acetylcholine coming out of the preganglionic fibre can release different transmitters. Some of them release acetylcholine when they go out to the periphery; some release noradrenalin; some probably release other substances as well.
So the vas deferens is innervated by sympathetic nerves, and we thought we were looking there at responses to stimulating nerves that worked through the release of noradrenalin. But quite early on in the piece the pharmacology, the way drugs acted on that neurotransmission process, made us wonder whether it really was noradrenalin that was causing the change in membrane potential.
Are you saying that if you blocked noradrenalin, you still got a response?
That's exactly right. One of the traditional drugs used to block the actions of noradrenalin and adrenalin on smooth muscle was phenoxybenzamine, which actually made those sub-threshold responses, the ones which were not big enough to be an action potential, bigger than in the control. So it was a bit of a puzzle, something new.
At that stage very little was known about neurotransmission and transmitters. I remember studying the standard number of transmitters – acetylcholine and nora but not a big field at all. But all of a sudden you were saying, 'There's got to be more.' You were rewriting the texts.
Yes. I felt for a long time that it could be a question of the noradrenalin acting on a different kind of receptor from any of the receptors that were known to latch on to it. I think most people nowadays believe that it is a different transmitter, and this was Geoff's baby: a little bit later on, he had the idea that the transmitter might be ATP, adenosine triphosphate.
Why did he come to that conclusion?
As a result of bits and pieces in the literature. There was a suggestion by Sidney Hilton, I think, that ATP might be a vasodilator. Possibly Graham Campbell had the idea – he was another collaborator of Geoff's and mine, a great reader of literature who had an excellent memory. It's very hard to attribute an idea like that to an individual, but Geoff certainly persuaded a lot of people that it was the explanation and I think most people nowadays would feel it was well and truly established.
You're not one who presents it.
Well no, just because you cannot readily mimic the exact changes in membrane properties that are caused by applying ATP to the bath with the changes that occur when ATP comes out of nerves. But it's an interesting story and I think most people would nowadays agree that ATP is a neurotransmitter.
Select activities that are most appropriate for your lesson plan or add your own. You can also encourage students to identify key issues in the preceding extract and devise their own questions or topics for discussion.
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