Herbal and other natural medicine can often not be tested and approved as drugs because it cannot be produced in sufficient quantity or purity. Researchers have now developed a yeast strain that produces much more of a compound – known from traditional Chinese herbal medicine – that has previously been shown to be very effective against cancer. The new method will enable clinical trials and mass production so that the medicine can be approved and used for treatment.
People with a life-threatening illness and their loved ones often turn to alternative treatments when they have tried all approved treatments without success. However, determining what works and what is quackery in herbal and other natural medicine is a real challenge. New research may confirm whether beta-elemene, derived from the Chinese medicinal plant Curcuma wenyujin, will be useful in treating cancer, as previous research has shown.
“We are the first to make beta-elemene in sufficient quantities that will both enable it to be used in major clinical trials and to produce the compound for pharmaceutical use,” explains an author, Anastasia Krivoruchko, project leader in the Systems and Synthetic Biology Group at Chalmers University of Technology in Gothenburg, Sweden and affiliated with the Novo Nordisk Foundation Center for Biosustainability at the Technical University of Denmark.
Sunflowers and lettuce
The Chinese medicinal herb Curcuma wenyujin produces incredibly small quantities of beta-elemene naturally – so little that producing enough to treat people with cancer has been too expensive and difficult. Biotechnology researchers have been trying unsuccessfully for years to induce microorganisms to produce beta-elemene. Previously, various microorganisms have successfully produced germacrene A, and this can easily be converted chemically to the active ingredient beta-elemene. Unfortunately, the quantity produced has still been much too small for pharmaceutical use. Research collaboration between researchers in Denmark, Sweden and China has now solved this problem.
“We have developed and refined a yeast strain that can produce about 20 times more germacrene A than other types of yeast previously produced. And because germacrene A can easily be converted chemically at room temperature to beta-elemene, we seem to have developed a production method that can be used, especially because the process can certainly be optimized further.”
The solution was somewhat unexpected. The researchers tried to transfer the enzyme production system of Curcuma wenyujin to yeast, but without success. Instead they examined other plants and ultimately found a much more efficient enzyme system in both sunflowers and lettuce, and they had much greater success in splicing them into and making them function in yeast cells.
Enzymes on an assembly line
Sunflower and lettuce enzymes therefore took researchers part of the way, but more was needed to achieve an acceptable yield, requiring other means.
Some of the precursors produced in the initial stages of creating germacrene A are also used in producing other compounds. We therefore tried to ensure that as many of the precursors as possible ended up producing germacrene A. We did this by fusing together the enzymes used in the synthesis and testing various fusion configurations and linkers.
The precursors thus moved past the enzymes in a similar way as to an assembly line, increasing the probability of maximizing the desired substance obtained for a given quantity of raw materials, thereby further optimizing the production.
Treasure trove of plants
Many plants that have previously been used for pharmaceutical purposes contain beta-elemene, and it has attracted great attention in recent years because it has slowed the growth of many types of cancer cells in laboratory experiments. In China, beta-elemene has been tested in human clinical trials, and the researchers reported that it is effective in treating cancer. Unfortunately, the trials produced low-quality evidence because very little beta-elemene has been available, thereby minimizing the number of trial participants.
“Our new results may help once and for all to demonstrate whether beta-elemene is effective against cancer cells. If it is, and the method can be further optimized, a pharmaceutical company could use the method in production.”
For now, the research collaboration is continuing to optimize the production of germacrene A and to try and get yeast cells to produce other potentially useful products from the beta-elemene family such as terpenoids. These comprise the world’s largest group of natural products synthesized by plants in a veritable treasure trove of more than 40,000 compounds.
“Metabolic engineering of Saccharomyces cerevisiae for production of germacrene A, a precursor of beta-elemene” has been published in the Journal of Industrial Microbiological Biotechnology. The Novo Nordisk Foundation Center for Biosustainability employs many of the key participants in the project.