Malaria Drug Gathers Some Moss

The current monsoon season in India and Southeast Asia has brought along some of the worst flooding the region has ever seen. Moreover, hurricane season in the North Atlantic is producing some of the strongest storms on record. All of this devastation will leave affected areas primed for sharp increases in mosquito-borne diseases – the most devastating among them being malaria.

Compared to smallpox or typhoid, malaria is proving one of the most challenging human diseases to eradicate – and so remains a real and constant danger to nearly half the world’s population. Complicating matters is the fact that the malaria parasite is rapidly becoming resistant to most of the currently used drug treatments.  20 years ago, two million people died each year on average from malaria, according to the World Health Organization (WHO). Despite numerous advances in treatment, 212 million cases were reported in 2015 alone and an estimated 429,000 people died from the disease.

Yet, one drug, artemisinin, is still proving effective when used in combination with other, previously used antimalarial compounds such as mefloquine and chlorproguanil. However, a major problem remains: the supply of artemisinin is not stable or sufficient, and as a result, treatment remains expensive. Although now, an international team of researchers led by scientists at the University of Denmark has recently demonstrated that artemisinin can be rapidly produced by genetically engineered moss at an industrial scale. Findings from the new study were just published in Frontiers in Bioengineering and Biotechnology through an article entitled “Stable Production of the Antimalarial Drug Artemisinin in the Moss Physcomitrella patens.”

Artemisinin is typically derived from the plant Artemisia annua, a summer annual with a short growing season and known to gardeners as sweet wormwood. Due to its complex structure, the drug is difficult and not economically feasible to chemically synthesize. Other researchers have attempted to bioengineer artemisinin using Nicotiana tobacum (cultivated tobacco plants) or yeast, but these approaches either required much more engineering than the current analysis or yielded a semi-pure product.

In the current study, the investigators introduced five genes responsible for biosynthesizing the precursor of artemisinin, dihydroartemisinic acid, into the moss Physcomitrella patens using multiple DNA fragments. The final conversion of this acid into artemisinin occurs by photooxidation in the moss cell.

“The five genes involved in artemisinin biosynthesis were engineered into the moss Physcomitrella patens via direct in vivo assembly of multiple DNA fragments,” the authors wrote. “In vivo biosynthesis of artemisinin was obtained without further modifications. A high initial production of 0.21 mg/g dry weight artemisinin was observed after only three days of cultivation. Our study shows that P. patens can be a sustainable and efficient production platform of artemisinin that without further modifications allow for industrial-scale production.”

Since moss is a non-vascular plant, it has a simple structure that offers an ideal setting for genetically engineering drugs. The genetically engineered moss was grown in both liquid and solid media under 24h LED-light.

“This moss produces like a factory,” noted senior study investigator Henrik Toft Simonsen, Ph.D., formerly an associate professor at the University of Denmark and currently ceo at Mosspiration Biotech. “It produces artemisinin efficiently without the precursor engineering or subsequent chemical synthesis that yeast and tobacco require. This is what we hope for in science: a simple, elegant solution.”

This research expands the frontiers of synthetic biotechnology by offering a genetically robust plant-based platform, which can be scaled up for industrial production of other complex, high-value, plant-based compounds. Because P. patens uses light as an energy source, it is, in the long run, more cost effective than approaches such as yeast, which must be fed with some form of sugar.

“A stable supply of artemisinin will lower the price of artemisinin-based treatments, hence become more affordable to the lower income communities most affected by malaria; an important step toward containment of this deadly disease threatening millions every year,” the authors commented.

Producing artemisinin from moss in simple liquid bioreactors means that industrial-scale production is easily possible in a cost-effective manner. The next steps would be to further optimize the process, particularly reducing any unnecessary products and ensuring the metabolic process is as efficient as possible. Also, while it may seem extraordinary to develop a drug in three to 12 days, by comparison, microorganisms can be cultivated in a matter of hours, said Simonsen. Plants simply take longer to cultivate than microorganisms. Even so, this approach has built-in savings: moss does not have to be re-engineered every time—stock cells can be reused.

“It will be a great day if scientists can eradicate malaria worldwide,” concluded Dr. Simonsen. “This is a disease that affects 200 to 300 million people every year. It’s especially deadly for kids.”