A commonly used cancer drug called vinblastine is sourced from certain flowers, but unfortunately it takes literally tons of plant matter to make each gram of the drug. To find an alternative source, scientists have now engineered yeast to produce the precursors of vinblastine, which could help make this vital drug more available and affordable.
Madagascar periwinkle (C. roseus) is a flowering plant that’s been used in traditional medicine for thousands of years, and as a source of chemotherapy drugs vinblastine and vincristine since the 1950s. Vinblastine interferes with cell division and is used to treat lymphoma, breast, bladder and lung cancers, among others, while vincristine can be used to treat leukemia thanks to its ability to inhibit the production of white blood cells.
Both are listed on the World Health Organization’s List of Essential Medicines, but frustratingly they can be subject to shortages. That’s because of the huge amounts of the plant required to produce usable quantities of the drug – it takes 500 kg (0.5 tons) of dried leaves to make one gram of vinblastine, and as much as 2,000 kg (2.2 tons) for vincristine.
Making synthetic versions in the lab might seem like the obvious solution, but the complexity of these molecules means that’s eluded scientists so far. For the new study, researchers at Berkeley Labs and the Technical University of Denmark (DTU) have turned to microbes for help, engineering common baker’s yeast to produce the drug’s precursors.
The team made a total of 56 genetic edits to the yeast genome, including adding 34 plant genes, while deleting, suppressing and overexpressing other genes native to the microbe. It takes the yeast 30 steps to produce two molecules, catharanthine and vindoline, which are the precursors of vinblastine. The 31st and final step of the process is for scientists to then combine these molecules to make the drug.
While the team hasn’t specified how much of the drug the yeast is able to produce, this proof-of-concept study should indicate that, with further work, microbial factories could be scaled up to make vinblastine and related therapeutic molecules that are tricky to extract from natural sources.
“The yeast platform we developed will allow environmentally friendly and affordable production of vinblastine and the more than 3,000 other molecules that are in this family of natural products,” said Jay Keasling, co-leader of the project. “In addition to vinblastine, this platform will enable production of anti-addiction and anti-malarial therapies as well as treatments for many other diseases.”
The research was published in the journal Nature.
