Technical University of Denmark: Tomorrow’s climate-friendly chemical plants

Global climate change has created a great need for technologies that limit carbon emissions into the atmosphere. The focus has primarily been on the battle to develop alternative forms of energy that can reduce the use of coal, oil, and gas. But another battleground is the organic-chemical industry, where petrochemical processes—based on the conversion of fossil oil and gas—have been completely dominant for nearly 100 years.

Now the Danish company Cysbio is facing a breakthrough in which sugar replaces oil as the principal basic substance, and where coli bacteria function as small efficient biological chemical plants when they convert the sugar and form amino acids and other biochemicals.

Spin-out from DTU Biosustain
The biotech company Cysbio saw the light of day in 2019 as a spin-out from DTU Biosustain, which is a research centre founded by the Novo Nordisk Foundation for the purpose of developing sustainable biotechnologies.

Alex Toftgaard Nielsen was employed as a professor at DTU Biosustain when the centre was established in 2011, and he has gathered a group of researchers who have worked determinedly with bacteria and fermentation techniques that are more climate and eco-friendly than conventional methods.

“Cysbio was established after more than seven years of research at DTU Biosustain, where two postdoc researchers in my group—Christian Bille Jendresen and Hemanshu Mundhada—have developed the two main technologies that we use in Cysbio,” explains Alex Toftgaard Nielsen.

“We hope that our first products will be launched on the market at the end of 2022 or beginning of 2023.”
Henrik Meyer, CEO, Cysbio
Together with Henrik Meyer—who has extensive managerial experience from the biotech companies Novozymes and Evolva, among other companies—the three researchers make up the management team in Cysbio.

Amino acids
At DTU Biosustain, the researchers focused on a specific type of amino acids used in a number of areas, including in food products, cosmetics, and pharmaceuticals. Conventional production of these products is often energy intensive and based on fossil oil, and it also involves toxic chemicals in some cases. The researchers wanted to change this by using fermentation processes in which microorganisms convert sugar in their propagation process. The choice of microorganism fell on E. coli bacteria.

“E. coli is a real workhorse. And it has been a model organism for many years, so it’s well described. In addition, there are detailed computer models that can calculate what happens to the coli bacterium when you change it, and we have utilized this,” says Alex Toftgaard Nielsen.

The researchers therefore started genetically engineering E. coli so that the bacterium began producing amino acids.

“We’ve designed the bacteria so that they grow slower and slower, the more time that passes, and they end up instead using the most energy and carbon from the sugar than on producing chemicals,” says Alex Toftgaard Nielsen.

Useful mutations
Getting the bacteria to produce the coveted biochemicals was not completely unproblematic. The tests quickly showed that high concentrations of amino acids were toxic to E. coli, resulting in the bacteria dying before they had produced sufficient quantities.

“We’ve spent a lot of energy on making the bacteria tolerant to the product,” explains the professor.

This has been achieved by gradually increasing the concentration of the substance against which the bacteria are to become resistant.

“You actually utilize that the bacteria start mutating. The mutations that make the bacteria most resistant make the cells grow faster, and they will then dominate,” says Alex Toftgaard Nielsen.

By subsequently genome sequencing the bacteria, the researchers were able to analyse the resistant mutations. In some cases, they were used directly in the further development process. In other cases, the researchers used the analysis results to design bacteria that contained the most successful mutations.

The result of the researchers’ work meant that they were now able to produce amino acids that could compete on price with their oil-based counterparts, and which reduce carbon emissions into the atmosphere considerably relative to conventional petrochemical production. The foundation for establishing a commercial business had been laid.

First commercial products are in the pipeline
Henrik Meyer—CEO of Cysbio—says that two amino acids are on their way to commercial production. One of these amino acids will be used for food production. However, Henrik Meyer also sees great commercial opportunities in the feed industry. The other amino acid product will be widely used in pharmaceuticals and cosmetics, but there is also a potential market in food supplements.

“We hope that our first products will be launched on the market at the end of 2022 or beginning of 2023,” says Henrik Meyer.

In the longer term, Cysbio expects to develop other biochemicals, including some types that can be used in paints and pharmaceuticals, as well as in the polymer industry, where they can form part of the production of plastic substitutes and be used in adhesives.

Upscaling
An essential point in any experimental production is upscaling from laboratory test setup to factory. In the case of Cysbio, this is from 1-litre bioreactors to 200,000-litre fermentation tanks necessary to produce the amino acids in quantities that are commercially interesting.

Here, Cysbio has entered into a partnership with the Chinese chemical company Zhejiang NHU, which has invested an amount running into millions in Cysbio. Zhejiang NHU will build the huge fermentation tanks and be responsible for the production of the first two commercial amino acid products.

In the longer term, however, the plan is for Cysbio to build production facilities in Europe, where it will be much simpler to obtain approvals for sales of the products in the EU.

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