June, 2016:

https://www.geneticliteracyproject.org/2016/06/17/synbio-tobacco-plant-produces-vital-malaria-drug-met-skepticism-scientists/

Artemisinin is by far the world’s most important weapon against the main parasite that causes malaria—a disease which still claims around 500,000 lives, mostly young children, annually around the world.

There’s just one problem with artemisinin: making it in large enough quantities to meet the demand is very difficult because the plant it is isolated from is difficult to cultivate. This led scientists from the Max Plank Institute to modify the much more malleable tobacco plants to produce the lifesaving drug—an achievement they announced on June 14, 2016. Somewhat surprisingly though the responses to the announcement by scientists have been skeptical—from a scientific and political perspective.

The World Health Organization recommends the drug be administered to all those infected with Plasmodium falciparum (the most common malarial parasite) with both uncomplicated and severe malaria. The WHO also says keeping artemisinin efficacious in endemic areas is imperative as no other malaria drugs are in the pipeline for the foreseeable future. Ralph Bock, the tobacco project’s leader at the Max Planck Institute of Molecular Plant Physiology called the drug the “most powerful weapon” we have against malaria.

In nature, artemisinin is found in an herb called the sweet wormwood (Artemisia annua). For two millennia, the Chinese ground the leaves of the fern-like plant into a tea for its purported healing properties such as reducing fevers. In the 1970’s, it was discovered that the plant may have anti-malarial properties by Tu Youyou who would go on to win a Nobel Prize for the discovery in 2015. However, it wouldn’t reach wide scale use in the western world until the early 2000’s after the WHO recommended it be a staple of malaria treatment around the world.

Yet, producing the drug is no small task: it cannot be made synthetically in a lab and has to be extracted from the sweet wormwood crop directly. Unfortunately, the crop is very volatile with dramatic yield shifts from year-to-year and it only grows well in a just a few places. This makes it difficult to get large, affordable quantities of the drug to the places that need it the most.

Bock and his team, in a paper published in the journal eLife, described how they were able to transplant the genetic sequences necessary to co-opt tobacco into producing an artemisinin precursor in large quantities in its leaves. This was particularly difficult as the metabolic pathway for the compound involves many genes that need to be active at various times. Making things more complicated was the fact that some of the genes involved in the metabolic pathway play unknown, yet salient, roles.

Despite the apparent need for new ways to produce this drug, scientists who commented to GLP sister site Genetic Expert News Service (GENeS) were mostly underwhelmed by the study.

Tsafrir Mor a professor at Arizona State University referred to the technique Bock’s team developed to modify the tobacco plant as “not revolutionary” and doubts that these plants would be of much use because of the general anti-synthetic biology sentiment in Europe. He said, “European conservative, borderline reactionary approach toward transgenic plants, makes it unlikely that the technology will be implemented in Europe.” Although, in places like the US, South America, and China he does think the plants could catch on and be of some value both medically and economically.

Pamela Weathers, a biology and biotech professor at Worcester Polytechnic University told GENeS that she did not believe the technology would ever be of much value to the fight against malaria:

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.

Weathers stated that her own work on the medicinal properties of A. annua finds that consuming the leaves of the sweet woodworm whole is the best way to receive all its benefits—as well as the most economical. She also pointed out that Bock’s tobacco only makes a precursor and not artemisinin itself—meaning an additional step will be required to produce the active compound.

De-Yu Xie a professor at North Carolina State University described the work of Bock’s team as a ‘proof of concept’ and that it is not particularly close to being of any value to fighting malaria. He also noted that other synthetic biology solutions to artemisinin production are already more well-established:

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…

Xie went on to say that even these synthetic biology approaches have had trouble competing with the more cost effective traditional field grown artemisinin. For this reason he sees the future of artemisinin production as not synthetic biology—either in microbes or tobacco—but in genetically modified sweet woodworm.

Nicholas Staropoli is the associate director of GLP and director of the Epigenetics Literacy Project. He has an M.A. in biology from DePaul University and a B.S. in biomedical sciences from Marist College. Follow him on twitter @NickfrmBoston.