Poppy's morphine-making gene discovered

26 June 2015

Interview with

Professor Ian Graham, York University

Opiates, like morphine, are some of the most powerful and effective painkilling Red_poppydrugs available. They're made using cultivated opium poppies, which have naturally evolved to produce these chemicals, probably as a way to fend off attacks from insects. But despite decades of study, scientists hadn't been able to unpick the biochemical production line, controlled by cellular catalysts called enzymes, that leads to the production of these morphine-like chemicals. One key part of the process remained obscure. Now, by studying poppy plants carrying genetic changes that prevented them from making morphine, York University's Ian Graham and his colleagues have found the missing piece of the puzzle, as he explained to Chris Smith...

Ian - We've been studying opium poppies for a number of years in a partnership with the pharmaceutical company GlaxoSmithKline. In fact, not a lot of people realise it but they grow poppies for the production of morphine and codeine. And a lot of people have had those drugs where they've been suffering from severe pain.

Chris - I mean indeed, they're some of the most powerful and the most effective drugs that we have in our medicine chest. What was the question that you were asking here?

Ian - The challenge for us has been that all of those enzymatic steps for synthesis of morphine and codeine have been described over the last 20 years except for this one important gateway step. When I say 'gateway step', I mean if you could think of a production line and components coming down the production line then, that could go into making a Volkswagen Polo or a Volkswagen Scirocco. So, this gateway step, diverts the molecules go in one route or the other. And so, it's extremely important because once we could understand that then, in the plant, we could influence the flux down one pathway into morphine or down other pathway into another molecule in fact called noscapine which is an anticancer compound.

Chris - Why has this step proved rather difficult to get to grips with in the past?

Ian - The answer to that came with the discovery in fact because it turns out when we discovered this gene which we call STORR, it's a fusion of two other genes and that fusion event brought together two enzymes. What that allows to happen is that instead of two separate enzymes floating around a cell, you have the two enzymes together and there's more rapid channelling of the two reactions together.

Chris - How did you discover that that's what had happened?

Ian - We looked through a large population of plants. This is poppy plants that are unable to make more morphine. So, they just were not making any morphine. The interesting thing was that they were accumulating another compound that we know goes into this gateway reaction that I talked about.

Chris - So, it's rather like, if you had a worker on the conveyor belt and they went on strike, there'd be loads of the things that they would normally do as part of the production line which would build up behind where they were standing, and you were spotting, A. there was a build-up of these things and B. you could therefore workout what the worker was doing who was missing.

Ian - Yes, exactly. So basically with it, when we saw there was an accumulation of this compound then we thought there's a real opportunity here to now discover what this gene actually is. And then we used various other tricks to identify what the gene was.

Chris - Now you've got the gene, what is that telling you? What do you think you can do with it?

Ian - So, the gene is interesting in a number of ways because we're interested in developing poppy plants by using DNA markers. So, we can breed plants that are making this compound called noscapine which is an anticancer compound rather than morphine. We can also look for plants that are making more morphine or more codeine. So, it's a very valuable tool for plant molecular breeding.

Chris - Looking at it from a different perspective, in recent years and months, we've seen people speculate and now say they're on the verge of genetically modifying things like yeast so that they could make yeast growing in effectively the same gear as you'd use to make home brew in your living room and have it churning out morphine. Now you've made this discovery, does that mean that people have got the missing part of the puzzle to make their home brew kit for morphine work?

Ian - Yes. Well effectively, this discovery is the missing tool in the tool kit. It's inevitable now that in the not too distant future, the proof of concept objective will be making morphine in yeast from simple molecules such as sugars.

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