Opium research yields synthetic painkillers

By Daniel Pagan

University of Calgary researchers are one step closer to producing synthetic morphine and codeine, after unlocking the genes that allow the opium poppy to produce these two drugs.

In the online edition of Nature Chemical Biology, U of C biochemist Peter Facchini explained the isolation of these genes allows for production of synthetic painkillers in a lab, bypassing the plant altogether. Codeine is one of the most widely used painkillers and can be extracted directly from the poppy and converted to morphine through an enzyme in the liver.

Facchini is excited about the discovery, after working on the opium poppy’s biochemistry for the past 18 years.

“It’s always inspiring to think that humans have been using [the] opium poppy for thousands of years and investigating the plant for hundreds of years,” said Facchini. “We are contributing pieces to the scientific puzzle that will remain part of the story long into the future.”

He pointed out the enzymes encoded by two genes have eluded scientists for 50 years, because others made the mistake of searching for a similar enzyme that converted codeine to morphine in human livers. However, the enzyme Facchini discovered belonged to a different family.

“The enzymes occur in the plant at relatively low abundance, so it would be difficult to detect them even if you knew what you were looking for,” said Facchini.

Researcher Jillian Hagel explained the process was a matter of elimination, as she and Facchini used a custom-made DNA microarray “which examine[d] the expression of 23,000 genes at once.”

They also used viral-induced gene silencing and observed the effects on metabolism. One single gene appeared “off” in the mutant poppy, compared with morphine-accumulating poppies. Upon close examination, it turned out to be the first of the two missing genes needed for morphine production.

“We started off with a mutant of opium poppy that appeared ‘blocked’ for morphine metabolism [that is, it couldn’t make morphine or codeine],” explained Hagel. “We compared the gene expression in this mutant to other morphine-accumulating varieties using a DNA microarray.”

Facchini warned the research is still in its early stages. He explained the next step is to use the new codeine gene to produce the medicine via yeast or bacteria.

“Basically, it’s a matter of putting all the genes from the plant that participate in morphine metabolism into yeast,” said Facchini. “That’s the science. After that the engineers work on optimizing production. We’re after three or four more key genes from the plant to complete the pathway.”

Hagel explained the team faced challenges, such as a lack of tools available to study poppies, so they had to develop their own.

“For example, I had to build the microarray used in this study, instead of just flipping through a catalogue to buy one,” said Hagel.

After the setbacks and obstacles, Hagel is excited about the big discovery and its implications for the drug trade.

“I feel . . . definitely excited to have been part of the process leading to this discovery,” said Hagel. “A key reason for my desire to work on [the] opium poppy was its importance not only in the field of plant biochemistry, but in social and political arenas.”

Canada is among the world’s top consumers of codeine, spending $100 million every year on the painkillers.

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