Tobacco engineered for more efficient production of antimalarial drug

By genetically engineering tobacco, scientists have developed a method of more efficiently producing artemisinin, the world’s most important malaria drug.  Artemisinin occurs naturally in the plant Artemisia annua, which is difficult to cultivate. The researchers designed a method to transfer the entire metabolic pathway of artemisinic acid, from which artemisinin can be derived, from A. annua into tobacco, allowing for easier cultivation.

 

Dr. Tsafrir Mor, Professor, The Biodesign Institute and the School of Life Sciences, Arizona State University (webpage):

Expertise: Molecular biology, biochemistry, using plants to produce useful and therapeutic polypeptides, proteins and enzymes

“Artemisinin, an anti-malarial compound, was isolated by the 2015 Nobel laureate Tu Youyou from extracts of the traditional Chinese medicinal plant Artemisia annua. The molecule cannot be synthesized in the lab and has to be extracted from the plants. Those plants are not easy to grow and the relatively small and highly variable amounts of the active ingredient make them an unreliable and expensive source of the drug. Now, through the efforts of the Bock lab, the direct precursor of artemisinin can be produced in large amounts in the very common crop, tobacco.

“The major feat reported here is ‘lifting’ the whole metabolic pathway required for the biosynthesis of artemisinin from A. annua and transplanting it in a host plant (tobacco) that didn’t possess it before, allowing the production of the artemisinin precursor in plants that are easy to grow and process for downstream applications. The reported COSTREL technique does not represent a new method to transform plants. It is a combination of methods to engineer both the plastid and the nuclear genomes of the tobacco plant, which have been with us for three decades. In fact, even combining transformation methods is not revolutionary and examples of it can be found elsewhere.

“European conservative, borderline reactionary approach toward transgenic plants, makes it unlikely that the technology will be implemented in Europe. In contrast, tobacco had been a staple crop in the old South, which rose and fell with the changing tides of market demands for tobacco products. It is conceivable that engineered tobacco as a source for value-added products like artemisinin could literally transform tobacco from being an agent of disease into a medicinal plant while boosting the economy of rural areas that depend on tobacco cultivation. This will certainly come after the required careful and exhaustive approval process by the USDA and FDA. I don’t foresee too many obstacles in bringing the technology into practice in the US and in other countries such as Brazil and China that embraced the modern tools of plant breeding”

 

Dr. Pamela Weathers, Professor, Biology & Biotechnology, Worcester Polytechnic University (webpage):

Expertise: Artemisinin biosynthesis in Artemisia annua, edible artemisinin development for malaria treatment

“This new synthetic biology approach is a nice piece of technology, but it’s not terribly applicable to artemisinin production. Malaria hits the poorest people in the world. Any technology that adds cost to these patients without great benefit is not advantageous. There are other more practical platforms for artemisinin production, foremost including the plant, Artemisia annua, which naturally makes artemisinin at amounts much greater than the reported tobacco variety.

“The artemisinin plant also produces many other natural compounds that enhance the therapeutic activity of artemisinin if, as we and other showed in animals and in human malaria clinical trials, a patient eats the dried leaves of the plant (as compressed leaf tablets or in capsules). There is certainly no more affordable way to deliver a drug. Also, it is highly effective. We estimated from our and other field trials that the dried leaf therapy could treat several 100,000 patients from just a hectare of A. annua plants.

“By using tobacco instead of A. annua to produce artemisinin, the current global group of small stakeholder growers would be adversely affected, possibly put out of business. What then does that achieve? Also, they are making a precursor to artemisinin and thus the process still has to extract artemisinic acid and convert it semi-synthetically to artemisinin, which must be purified for therapeutic use.”

 

Dr. De-Yu Xie, Associate Professor, Department of Plant and Microbial Biology, North Carolina State University

Expertise: Plant secondary metabolism centering on biosynthesis and metabolic engineering of terpenes and flavonoids

“Over the past three decades, one of global antimalarial research efforts has been focused on improvement of artemisinin yield. Approximately 25% of medicines are directly produced from plants, including artemisinin. Many plant-derived medicines are biosynthesized from complicated pathways. Synthetic production of many medicinal chemicals is impossible to reach an industrial scale. From a long term perspective, plants will play a main role as effective bioreactors to produce medicines.

“In this report, authors developed a COSTREL plant transformation.  Although plastid transformation is not a new approach anymore, the technology developed by the authors shows a novel strategy to introduce a complex genetic pathway into plants to produce a target metabolite.

“Numerous research efforts have developed different metabolic engineering technologies to improve artemisinin production. This research provides significant proof-of-concept to show that the artemisinin pathway can be partially introduced into tobacco plants to obtain low levels of precursors of artemisinin. However, major efforts would be necessary to reach an industry scale with a cost-effective output.

“In comparison, synthetic biology of artemisinic acid and its precursors in microbes developed by Dr. Keasling’s laboratory at Berkeley has reached an industrial scale to supplement artemisinin. This is likely the most successful examples of synthetic biology for pharmaceuticals, but has had difficulty competing with the cost-effective A. annua growth in the field.

“A lot of efforts including ours are focusing on metabolic engineering of A. annua and many promising results have been obtained from different laboratories. The advantage of this approach is that a few ecotypes can produce more than 2% artemisinin and other ecotypes can produce more than 2% artemisinic acid. These high yields form the basis of current artemisinin production.

“Much research has shown that these productions can been improved by genetic modification of the pathway gene expression activities. In addition, there are more than 10 artemisinin extraction companies, who have developed good business models to work with experienced A. annua farmers. More importantly, A. annua can grow in marginal lands not competing with crop fields. In the long term, growing of engineered A. annua is likely one of the most effective approaches to reducing malaria-caused death.”

 

Declared interests (see GENeS register of interests policy):

No interests declared.

Reference:

‘A new synthetic biology approach allows transfer of an entire metabolic pathway from a medicinal plant to a biomass crop’ by Fuentes et al., published on Tuesday, June 14th, 2016 in eLife.

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