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Biotechnology is regarded as one of the key technologies of the 21st century. It is a motor for the international competitiveness of Germany’s economy and makes an important contribution to the bioeconomy. Our author Katja Lüers visited the biotechnologist Prof. Wolfgang Wiechert at Forschungszentrum Jülich and talked with him about current developments and prospects of the so-called white biotechnology.

Even the ancient Romans loved wine, bread and cheese – for thousands of years, man has used microorganisms such as bacteria or yeasts to produce or refine food. What initially happened as a result of chance discoveries is today an entire branch of science whose fields of application extend far beyond food production: biotechnology. It is involved in antibiotics, animal feeds, skin creams or detergents: for example, enzymes in detergents accelerate chemical reactions and can remove proteins and stubborn dirt at low temperatures. The winner: the environment, because the washing powder contains fewer environmentally harmful substances.

Reaching into nature’s toolbox helps the industry to work in a more resource-conserving and environmentally friendly way – which is pivotal on the way to a bio-based economy and thus to the bioeconomy: renewable raw materials instead of crude oil. This industrial biotechnology is also known as “white biotechnology” and differs in content from “red biotechnology” (medical-pharmaceutical biotechnology) and “green biotechnology” (agricultural-plant biotechnology).

Large investments and long development times

The search for a suitable microorganism or enzyme for industrial production is reminiscent of the famous search for a needle in a haystack. Once the researchers have finally found what they are looking for, they first optimise the organism or the enzyme and the process in the test tube. This is followed by "up-scaling": the process must also work on an industrial scale as the desired substance, for example an amino acid, will not only be produced in grams, but in tons. Last but not least, the product has to be isolated from the nutrient broth and purified. Experts call this "downstream processing".

“All this happens much faster today than it did 20 years ago, but it is still too slow – especially in comparison to the chemical industry,” says Prof. Wolfgang Wiechert, head of Systems Biotechnology at IBG-1. If, for example, a biotechnologist has discovered a bacterium that produces an amino acid as a potential food supplement, he is unable to say whether a competitive production process will develop at all or how many years he will need for this. “These development times, which are difficult to calculate, and the associated economic uncertainties are the main reasons why investors are still avoiding biotechnology,” explains the Professor of Computational Systems Biotechnology at RWTH Aachen University. In order for biotechnology to remain on a growth course and expand its leading position on the international market, however, it must increase its competitiveness. This is the starting point for Wiechert’s position paper "Neue Schubkraft für die Biotechnologie" (Fresh Impetus for Biotechnology), which he wrote together with other scientists and presented at the 2018 annual conference of the DECHEMA Society for Chemical Engineering and Biotechnology. The authors are essentially focusing on how research and development will succeed in accelerating the overall development of biotechnological production processes and products: "We don’t talk about improving individual technologies, but about a radical change that will fundamentally change workflows, processes and business models," says Wiechert. The end result could be a development laboratory that resembles an automated production line. This is intended to shorten development times and, above all, make them easier to plan – the key to opening up new markets and developing business models.

Leuchtende Substanzen unterschiedlicher Farben in GlästernBiotechnical Laboratory at the Institute of Bio- and Geosciences, Biotechnology (IBG-1).
Copyright: Forschungszentrum Jülich / Sascha Kreklau

Revolution begins in the laboratories

Whether in the USA or in Europe – a lot is already happening in laboratories that are equipped for this purpose. “We are seeing a strong trend towards miniaturisation and automation worldwide,” says Wiechert. Laboratory robots have become established, and so have high-throughput technologies, i.e. methods with which certain information can be captured and analysed more simply, faster and to a greater extent: "All these automation technologies are already available and can be purchased," explains Wiechert.

The real driving force for change in biotechnology is miniaturisation. An example from Jülich: Wiechert and his team are cultivating microorganisms on a laboratory scale in specific containers, so-called bioreactors. The aim is to optimise the single-celled organisms in such a way that they can later be used in the industry on a large scale. What is crucial is that this cultivation must be carried out under conditions that are typical for the later industrial production bioreactor, i.e. a good oxygen and nutrient supply. This, however, has so far taken up a lot of space: "Only eight of such vessels fit onto a table," Wiechert explains.

Meanwhile, there is a space and time-saving alternative: the microtiter plates with their 50 or more bioreactors each fit onto a DIN A5 sheet (15 by 21 cm). They are filled and sampled automatically. "Nobody has to pipet any longer," says Wiechert. In addition, the interdisciplinary team is developing so-called microfluidic single-cell bioreactors: the researchers can carry out several hundred growth experiments simultaneously on a chip the size of a one cent coin. “In contrast to the microtiter plate, however, the chip is not yet ready for series production,” says the institute director.

Robotikanlage zum automatisierten Pipettieren"Automation technologies are already available and can be purchased:" Microtiter plates unit at Forschungszentrum Jülich.
Copyright: Forschungszentrum Jülich / Ralf-Uwe Limbach

Evaluation as the bottle neck

Experimenting in the smallest space, however, does not yet trigger a revolution. The interplay of miniaturisation, automation and digitisation is crucial: “If we scale experiments down microscopically, it is impossible for humans to keep setting them up by hand because of the large number of experiments. That is why we control processes electronically, automate and standardise them,” explains Wiechert. The mass of high-quality data, in turn, has to be evaluated quickly, making digitisation almost mandatory. “Automated data analysis is therefore the necessary next step – we have to catch up here,” says Wiechert. The bottleneck is thus no longer the experiment, but the evaluation.

Changed job profile

MikrotiterplattenMircrotiter plates at IBG-1.
Copyright: Forschungszentrum Jülich / Ralf-Uwe Limbach

As a result, the biotechnologist’s work shifts to the computer: the scientist becomes the final information expert and process decision maker. In future, he will design the experiment, write the “recipe” and feed the information into the computer that supervises the automation system in the laboratory. At the end of the experiment, the computer will supply the researcher with the evaluated data. The only people still allowed to enter the laboratory will be the technicians who maintain the robots.

What sounds like a laboratory of the future is already normal in some US biotechnology companies such as Amyris or Zymergen. German companies such as GeneArt and Boehringer Ingelheim are also increasingly focusing on the simplification of workflows in the culturing, expansion and monitoring of cells.

The challenge for the industry: “It will hardly be possible to gradually replace the classical laboratory workflows and methods still existing today with automated processes,” explains Wiechert. Instead, the automated approach will have to be established from scratch – the pieces of the puzzle are already available in individual working groups and institutes. “But it is only when the technologies interact that a change is possible,” Wiechert is convinced.

Jülich strengthens biotechnology as a growth engine

The biotechnologists at Forschungszentrum Jülich have set out on the path to further strengthen the growth engine of biotechnology: “Looking at Germany, we are a pioneer in the field of automation and digitisation and we are even at the leading edge internationally when it comes to automated process development,” says Wiechert. Two successful projects are located at IBG-1, for example: firstly, there is the Microbial Bioprocess Lab – short: MiBioLab – funded by the Helmholtz Association. "This is how we make our methods attractive to the industry, taster courses, so to speak, without a company having to invest immediately in an automated system. We now have global players such as Sandoz and Christian Hansen on board – we need such multipliers in order to advance the automated development of economic production processes for the manufacture of chemicals, pharmaceuticals, animal feed supplements or food additives," says the expert.

Secondly, the project DigInBio – Digitalisierung in der industriellen Biotechnologie (Digitisation in Industrial Biotechnology), funded by the Federal Ministry of Education and Research, was launched in early 2018. Digitisation methods are developed there that combine individual work steps into a continuous digitised process, i.e. moving away from isolated solutions toward a single workflow.

Not even Wiechert can fully predict how such a revolutionary change in biotechnology will affect the world of work in the long term. "It is clear, however, that if we do nothing and continue to invest in obsolete techniques and methods, other countries will take over the top position!"

Katja Lüers