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Increasing incidences of oesophageal adenocarcinoma?


The gastrin story
James Black Scientist
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We knew, by a... way back in the 70s, we knew that if you took cimetidine and gave... treated patients with duodenal or peptic ulcers, that in four to six weeks we could stop acid immediately; we'd stop the acid; the ulcers would heal. And then we knew that within the next year about a third of them would relapse. And it was assumed that this was... whatever gave you an ulcer in the first place brought it back again. However, then we learned three things. One was the discovery, in the States, about how to measure gastrin levels in blood with radioimmunoassay; second, we have the discovery that the cells that gastrin acts on in the stomach, that synthesize histamine and store it are called enterochromaffin-like cells [ECL cells]. This was done by Rolf Håkanson in Lund. And so we have... now we were able to measure gastrin in blood. We could identify these ECL cells which secrete histamine when stimulated by gastrin. The ECL cells are lying just next to the histamine, the acid secreting cells, in... in the lining of the stomach. And then we found that when you give the histamine antagonist inhibit acid... that was the third bit that was brought into play... had been shown by Woodward in the States that acid in the antrum of the stomach would inhibit the secretion of gastrin. So you put it all together and we get what you might call the central dogma of acid secretion. That is: you eat, the chemistry of the food acts on cells in the antrum of the stomach to tell the cells that make gastrin, the G-cells, to secrete gastrin into the blood which circulates, comes to the ECL cell receptors, which have got the gastrin receptors, to stimulate the release of histamine, out comes the acid. The acid then interacts with the food which started this process, and it neutralises it there. So initially you... acid is coming out, but this acidity... the pH doesn't fall, but as digestion proceeds and the contents move away, the buffering capacity gets less and so the pH begins to fall, and it's low pH which acts on the G-cells – it actually acts on somatostatin secreting cells, the D-cells – to say... tell the G-cells to stop secreting. So this is the classic negative feedback loop that you get throughout physiology. The point is food stimulates: gastrin stimulates acid; acid ultimately stops the gastrin. So if you stop the acid there's nothing to switch the gastrin off, and so that was the big discovery we made in the early 80s: that when you inhibit acid secretion, the gastrin levels in response to food go shooting up.

That's the first thing. The next thing Håkanson showed was that gastrin is a growth factor to the ECL cells, so when you get higher levels of gastrin these ECL cells get bigger, they divide, get more of them, so you get ECL cell hyperplasia in the stomach. And then when you stop, that which made the gastrin go up, stop your histamine antagonist, then gastrin levels fall, but you're left with these ECL cells which are all up-regulated, and so you get rebound hypersecretion. And so the idea was developing that it was rebound hypersecretion which might be contributing to the relapse.

Then in the 80s the so-called proton pump inhibitors were introduced. Now, when they were studied first of all, it was an accidental observation, made in Sweden, that these compounds would inhibit the acid secretion at the level of the acid secreting mechanism, the proton pump as it's called, so they're called proton pump inhibitors. Now, when they did the toxicology they found that after two years of exposure to this drug rats who were the animals being used for the toxicology studies, developed cancers of the stomach – cancers of these ECL cells. So this held up the introduction of these drugs into medicine for a good number of years, but eventually the regulatory authorities, particularly the Food and Drug Administration in the States, were persuaded that this was a rat phenomenon, and that it was entirely benign to give it in man. And so now, one... as you know, one of the world's biggest drug sellers have been the use of proton pump inhibitors, and it's been a big seller, not because of ulcers – duodenal – because we had pretty well taken care of them by another discovery, and that was the relationship between helicobacter infection and ulcers. And so if we took patients with ulcers and treated it with antibiotics to remove the helicobacter then these ulcers would heal. So the incidence, the problem of duodenal and peptic ulcer was getting less. But another disease had appeared which I don't remember being taught as a medical student during the war. This is reflux disease; this is reflux of acid into the lower end of the oesophagus. Now... the big use of these drugs has been treating patients with reflux disease which, for many patients, is severe pain not long after eating food. Gradually, of course, the drugs are being used now for any type of indigestion and so they're almost given out. In fact, you can buy them across the counter now, as you know.

The late Scottish pharmacologist Sir James W Black (1924-2010) revolutionised medical treatment of hypertension and angina with his invention of propranolol, the first ever beta blocker. This and his synthesis of cimetidine, used for the treatment of peptic ulcers, earned him the Nobel Prize in Physiology or Medicine in 1988.

Listeners: William Duncan

After graduating with a BSc Bill Duncan went on to gain a PhD from Edinburgh University in 1956. He joined the Pharmaceuticals Division of ICI where he contributed to the development of a number of drugs. In 1958, he started a collaboration with Jim Black working on beta blockers and left ICI with him in 1963 to join the Research Institute of Smith Kline & French as Head of Biochemistry. He collaborated closely with Black on the H2 antagonist programme and this work continued when, in 1968, Duncan was appointed the Director of the Research Institute. In 1979, he moved back to ICI as Deputy Chairman (Technical), a post he occupied until 1986 when he became Chairman and CEO of Coopers Animal Health. He ‘retired’ in 1989 but his retirement was short-lived and he held a number of directorships in venture capital backed companies. One of his part-time activities was membership of the Bioscience Advisory Board of Johnson and Johnson who asked him to become Chairman of the Pharmaceutical Research Institute of Johnson and Johnson in New Jersey. For personal reasons he returned to the UK in 1999, but was retained by Johnson and Johnson until 2006 in a number of senior position in R&D working from the UK. From 1999 to 2007 he was a non-executive director of the James Black Foundation. He is now fully retired.

Tags: USA, Lund, FDA, WWII, Rolf Håkanson, ER Woodward

Duration: 7 minutes, 18 seconds

Date story recorded: August 2006

Date story went live: 02 June 2008