Researchers have incorporated the biosynthetic pathway that produces the anticancer drug vinblastine into the genetic material of baker’s yeast, showing that many drugs can potentially be produced more cost-effectively while avoiding global supply bottlenecks.
The chemotherapy drug vinblastine is usually biosynthesized from the leaves of the Madagascar periwinkle (Catharanthus roseus), which grows in Madagascar and other places.
Two active ingredients in the leaves, vindoline and catharanthine, can be combined to create vinblastine, which inhibits cancer cells from dividing.
Hospitals globally faced vinblastine supply problems exacerbated by the COVID-19 pandemic from summer 2019 until 2021, and obtaining vinblastine and the necessary ingredients became more difficult.
Further, between 500 and 2,000 kg of dried plant material is required to make one gram of vinblastine.
Researchers from the Technical University of Denmark and elsewhere have now developed a method to potentially ensure that future supply problems will not reduce access to vinblastine and many other drugs.
They used synthetic biology to show that baker’s yeast can be engineered to make vinblastine and other useful drugs locally in large fermentation tanks rather than harvesting the ingredients from distant corners of the world.
“People have used plants for millennia to combat many diseases from cancer to malaria, and plants inspire many modern medicines, including ones on the WHO Model List of Essential Medicines. The problem, however, is that various things can go wrong, which can influence access to the medicines – including natural disasters, pandemics, or geopolitical situations. Being able to produce these medicines in different ways is therefore much more attractive, and we have now enabled this,” explains a researcher behind the discovery, Jie Zhang, Senior Researcher, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby.
The discovery has been published in Nature.
56 genetic edits
The researchers extracted the entire biosynthetic pathway that produces vindoline and catharanthine in the Madagascar periwinkle.
The biosynthesis includes 31 steps in converting the native metabolites geranyl pyrophosphate and tryptophan into vinblastine.
These 31 steps are an unusually long biosynthetic pathway to transfer from one organism to another, and the researchers first divided the Madagascar periwinkle pathway into three different yeast strains before combining the three steps into the same yeast.
The first yeast produces strictosidine, a common precursor for making several thousand monoterpene indole alkaloids (MIAs). The second yeast produces tabersonine and catharanthine from strictosidine, and the third produces vindoline from tabersonine. The final yeast, which required 56 genetic edits to function as intended, could thus make both vindoline and catharanthine, which can be chemically assembled into vinblastine in a single step.
“This involved changing the expression of many genes so the yeast could produce the various components and optimising the process for fermentation in small bioreactors,” says Jie Zhang.
Producing medicine to combat substance abuse and depression
Jie Zhang says that developing a yeast that can produce vindoline and catharanthine will enable vinblastine to be produced in large quantities without having to harvest tonnes of plants.
However, the researchers have greater ambitions than just producing one anticancer drug. They have shown that the technology can induce baker’s yeast to make many MIAs that may be useful drugs.
The researchers are already developing other types of yeast for producing MIAs that can treat people with mental disorders such as substance abuse and depression.
“We want to identify where the market is greatest and where replacing the current methods of producing medicines with yeasts is most useful. Our study is therefore a proof of concept that this can be done,” explains Jie Zhang.
Demonstrating the commercial potential
Although the researchers have already developed various types of yeast that can produce the relevant MIAs, they still have much work ahead to achieve industrial success.
They must identify the bottlenecks in the process and resolve them to speed up production. In addition, they must also develop better methods for extracting the pure MIAs from the mixture in which the yeasts exist.
The methods used today to extract plant metabolites are designed to work on dry plant materials such as leaves, seeds and bark and from fermentation broth.
“We need to do more than show that our yeasts can make useful drugs. We must also be able to do this more rapidly and preferably also more inexpensively that the methods used in industry today. But we can see clearly that the technology needs to demonstrate its commercial potential,” concludes Jie Zhang.