A chemical extracted from a small flowering plant has helped in the fight against cancer for decades. Now, after a 60-year hunt, scientists have finally uncovered how it creates this medically important molecule.
This small flowering plant houses an inscrutable chemical processing plant.
The Madagascar periwinkle, or rosy periwinkle, is a pleasing little plant that adorns many a garden.
But there is more to this angiosperm than meets the eye — in fact, it’s a life-saver.
For decades, scientists have eagerly extracted a chemical called vinblastine from its leaves.
In Canada, in the 1950s, scientists discovered that vinblastine is an incredibly useful cancer drug.
It stops cells from entering mitosis, thereby interrupting cell division, and it has been used against bladder, testicular, lung, ovary, and breast cancer.
The World Health Organization (WHO) list it as an essential medicine, classing it as one of “the most efficacious, safe, and cost-effective medicines for priority conditions.”
The trouble with vinblastine
One significant issue has marred vinblastine’s usefulness: it is very difficult and inefficient to extract. Despite advances in technology that have helped to streamline the procedure, it remains slow and expensive. Currently, around 500 kilograms of dried leaves are required to produce just 1 gram of vinblastine.
Because of the incredible amount of legwork necessary to produce the drug, scientists have been on a 60-year-long mission to understand how the plant makes this chemical.
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If they can understand the natural process, hopefully, they can mimic it in the laboratory and design ways to produce vinblastine more efficiently and, importantly, at a lower cost.
For the past 15 years, researchers at Prof. Sarah O’Connor’s laboratory at the John Innes Centre in Norfolk, United Kingdom, have been trying to unravel the genetics of the Madagascar periwinkle.
Finally, Dr. Lorenzo Caputi and his team — in conjunction with scientists at the Courdavault group based in Tours, France — have described the last piece of the puzzle.
Using state-of-the-art genome sequencing techniques, they have pinned down the missing genes in the pathway to vinblastine production.
“Vinblastine is one of the of the most structurally complex medicinally active natural products in plants, which is why so many people in the last 60 years have been trying to get where we have got to in this study. I cannot believe we are finally here.”
Prof. Sarah O’Connor
The 31 steps to vinblastine
As the study authors point out, their findings are built upon years of work carried out in a number of laboratoriess across the world. It truly has been a joint effort.
Their recent paper, entitled ‘Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle,’ is published in the journal Science. In the article, the researchers also identify the enzymes involved in the final steps of synthesizing vinblastine: catharanthine and tabersonine.
Using modern technology, traditional chemistry, and literature penned in the 1960s and ’70s, they pieced together the chemical steps involved in converting the precursor molecule to vinblastine — a staggering 31 steps in total. The rosy periwinkle is an impressive plant indeed.
The enzymes that they identified can be coupled using synthetic biology techniques that are already in use, creating a much-needed shortcut to producing vinblastine.
There is good reason to be excited about these results. Prof. O’Connor says, “With this information, we can now try to increase the amount of vinblastine produced either in the plant or by placing synthetic genes into hosts such as yeast or plants.”
They predict that within the next 12–18 months, their laboratory, or a competitor’s, should be able to create small quantities of vinblastine or its precursors vindoline and catharanthine.