Failure to scale- What happened to the SynBio poster-child?

 

When I was first introduced to the field of synthetic biology in 2013, there was one example, one success-story that seemed to be mentioned in every article, every video and every conversation about the wonders of synthetic biology. The malaria-drug Artemisinin.

Artemisinin is traditionally derived from the Sweet Wormwood plant; a process which involves growing said plant, extracting and refining its active substances in order to turn it into a pill. Through Synthetic Biology, a team of scientist at Berkeley were able to take this process from the plant and instead put it into bacteria. It was hailed as a massive success in synthetic biology. Even though the yeast could only produce a precursor of the finished drug, microorganisms grow massively faster than plants, and thus the production could be sped up and scaled up. This, researchers said, would make the drug both faster and cheaper to produce,  reaching more malaria sufferers in need. After this small scale proof-of-concept, the up-scaling for mass production of Artemisinin received millions in funding from the Bill and Melinda Gates foundation. This also brought the achievement praise and publicity in most every synbio magazine, blog, and review article. It quickly became the posterchild and flagship of synthetic biology.

 

But then what?

Unfortunately, this synbio venture ran into the same problem as many other microbial-production projects; moving from small- to large scale production. It’s easy to think that the big problem is to make yeast  produce something new at all, like drugs or biofuel: getting the complex metabolic pathways right, balancing the effect of multiple enzymes working in tandem. It is certainly challenging, but it is not the only challenge. Once the actual production is figured out, it is often just as hard to take this process and adjust it to make it cost effective on the larger scale. It’s not enough to simply produce the substance, you have to be able to do so effectively on the big scale.

 

Regardless, since the breakthrough in artemisinin production in yeast in 2009, the company Sanofi have been developing the large scale production of the drug. But it has yet to hit any market. Sanofi was able to produce large quantities of the artemisinin precursor-drug. However,they struggled to produce it at a cost where it would be able to sell cheaper, or even at the same prize, as the plant-derived artemisinin. Microbial-artemisinin was not competitive in the drug market, and so it failed to deliver on its promise to make the drug more accessible to patients. In 2014, Sanofi sold the microbial-production-plant.

Why did artemisinin fail to scale cheaply? There are multiple potential reasons. The type of fermenters used in small-scale require high oxygen feed, which cannot be achieved in larger fermenters. In larger microbial tanks, as opposed to small tanks, expression of the desired protein must sometimes be switched on by addition of a trigger. This trigger compound can in itself be expensive and thus add to production-costs.

In fact, artemisinin is not the only microbial-production synbio mile-stone to have suffered this fate. Biofuels are very much in the same boat; being hailed as a miracle as soon as proof-of-concept occurred, only to run into the scale-up problem and fail to reach their market.

 

A hyped science?

It may not be very inspiring to see the poster-child of synbio stumble and fall. This threatens to give the public and scientists alike the impression that perhaps synthetic biology is merely a hyped-up science, unable to make any significant translations to the real world.

This needs to serve as a lesson to synbio, not to assume victory until the finish-line is actually behind them. Although the science community and media should acknowledge great discoveries, but one also need to realize that proof-of-concept is not proof-of-concept at any and every scale. It might prove that the concept works on a small scale in a lab, but it says nothing about whether it will work in a factory scale reactor. Furthermore, it might serve as a lesson to synbio companies to calm down, and think before setting up huge production plants, before they are confident that they are able to actually be competitive in the market. Do the proper research fully, first. THEN take to the market. Otherwise, stories like artemisinin and biofuels may become disheartening warning tales, sending the signal that synbio can’t actually deliver, and only lives on vague and false promises. A hyped science.

 

Note

In 2018, the Gates foundation made a new push for the drug, advertising funding opportunities for research looking to effetivice the synbio production of artemisinin in order to indeed make it cheaper, as the original intent was. But so far, there are no new results

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