The Courtyard Connection

Built around the sides of a quad in Jülich, the four institutes of the Center for Microbial Biotechnology move forward inspired by a fruitful linkage and legacy.

By Nicola Kuhrt

A 30 liter bioreactor in the microbial cultivation lab of the Institute of Biotechnology. An engineer is inspecting the bioreactor operation during the cultivation experiment.
© Research center Jülich

Karl-Erich Jaeger knows the 60-kilometer stretch of country between Jülich and Düsseldorf like the back of his hand. At least twice a week, the professor of molecular biology leaves Jülich and his workplace at the Research Center on a drive past fields of sugar beet, through the Garzweiler brown-coal mining area, and past Dyck Castle to the capital of North Rhine-Westphalia (NRW), Düsseldorf. As a professor at the University of Dusseldorf and head of the Institute of Molecular Enzyme Technology (IMET) his time is divided between research on...

There is a good reason why IMET is not on the university premises but on the campus of the Jülich Research Center: its breadth of expertise. Jülich is Germany's biggest nonuniversity research institution and one of the largest interdisciplinary research centers in Europe. IMET is only one of four biotechnological institutes on the campus. Within IMET, enzymologists, molecular biologists, chemists, and process engineers work hand in glove. Since the late 1970s they have jointly developed and exploited microorganisms for biotechnological products and processes. This is enough to regard Jülich as the germinator of white biotechnology in NRW. Chemical companies like Henkel and Evonik, as well as the Fraunhofer Institutes and integrated research units associated with the Technical University of Aachen are all long-standing cooperative partners of the Research Center.

Jülich's biotech quadruplets

Since 2007, when the Nobel Prize for physics went to the Center's Peter Grünberg, the Jülich Research Center has been back in the public eye. Though most of the staff of 4,400 are physicists, its work in the life sciences also enjoys international renown. The link between the four biotechnological institutes—IMET, the Institutes of Biotechnology I and II (IBT-1 and IBT-2), the Institute of Enzyme Technology, and the Institute of Bioorganic Chemistry (IBOC)—is their research on systems biotechnology and white biotechnology. They are grouped under the Center for Microbial Biotechnology (ZMB).

"We optimize the stages leading from the gene to the product," says Jaeger. "That's our stock in trade, and the conditions we have at the ZMB are ideal for the purpose." With its combination of research in chemistry, biology, and engineering, Jülich is a genuine one-stop biotechnology shop.

The basic constellation is as unusual as it is successful. The IBT-1 and IBT-2 are part of the Jülich Research Center and are funded by the Helmholtz Community. Jaeger's Institute of Enzyme Technology and IBOC both belong to the University of Düsseldorf. Back in the late 1970s the institutions realized that their research achievements could be significantly enhanced by pooling their resources at one location. Accordingly, on the Jülich campus there is nothing to indicate their different affiliations. The four buildings are all grouped around an inner courtyard, so at most there's only a patch of grass separating the experts working here. Rooms and large-scale equipment like the mass spectrometer or the pipette robot are shared, and movement between the labs and the different parts of the buildings is fluid.

The staff of IBT-1, headed by Michael Bott, study and manipulate the genetic make-up of microbial cells and the processes taking place in them, while Jaeger's concerns revolve around biocatalysts, the protein molecules that control all the processes in living cells. The IMET scientists track down new genes, use molecular-biological methods to derive new biocatalysts from them, and via "evolution in the test-tube" are even able to improve their properties.

Another crucial unit is the team of chemists led by Jörg Pietruszka at the IBOC working on the synthesis of complex natural and medicinally active substances. Finally, IBT-2 transforms the knowledge generated in the labs into commercial procedures for industry. Throughout, the combination of organic synthetic chemistry and enzymatic bio-catalysis is a big benefit, Jaeger notes.

Heritage of Excellence

Jaeger's chair in molecular biology is surrounded by quite an aura. His predecessor was chemist Maria-Regina Kula. In 2002 she and her associate Martina Pohl won the German Federal President's "Future Prize." The two scientists had succeeded in priming enzymes that can catalyze redox reactions for use in industrial production processes like the production of medicinal drugs. For this purpose enzymes normally require the help of smaller molecules called cofactors. But these cofactors get used up during the reaction and have to be constantly replaced, which made the use of redox enzymes prohibitively expensive. Kula and Pohl solved the problem. From yeast they isolated an enzyme—formaldehyde hydrogenase (FDH)—that continuously regenerates the cofactors. They also used systematic genetic manipulation to alter the hereditary information of FDH, greatly increasing its robustness. This was the clinching factor in making it economically viable.

Maria-Regina Kula founded the Institute of Enzyme Technology in 1978, subsequently joining forces with professors Christian Wandrey and Hermann Sahm to launch biotechnology in NRW. Wandrey's research focus was bioprocess development, with special emphasis on enzyme and fermentation technology, while Sahm concentrated on the extraction of amino acids, vitamins, and organic acids from microbes, using metabolic engineering to achieve systematic strain improvement. Many collaborative ventures still in existence today go back to these scientists, among them a 20-year collaboration with Degussa (now Evonik). The Degussa enzyme membrane reactor went into operation back in the 1980s, largely masterminded by Wandrey and Kula. The reactor is used to produce the L-methionine amino acid employed in infusion solutions.

Another feather in the cap of the Jülich scientists was the development of L-lysine, an amino acid used in animal fodder. "Two grams per kilo are enough to double the nutrition value of the fodder," says Wandrey. "It's good for the cows and profitable for the farmers. And fodder like that is also good for the environment." Today 800,000 tons of it are produced per year and used in 75 percent of the fodder produced worldwide. This, in turn, saves about 20 million hectares of arable land.

Generating new companies
2D gel of C. glutamicum proteins.
© Research center Jülich

The ZMB also has numerous spin-offs to its name, including X-Zyme, dedicated to the development of enzymes and enzymatic processes. Another successful offshoot is Jülich Fine Chemicals (JFC), a supplier of special enzymes (biocatalysts) for organic synthesis and of chiral components for pharmaceutical and chemical enterprises. JFC was bought by Redwood City, Calif.-based Codexis in 2005.

DASGIP, another spin-off started up in 1991 is now an international leader in the development and production of parallel bioreactor systems for the cultivation of bacterial, mammalian, and human cells. Celonic can also look back on 10 years experience in the cultivation of eukaryotic cells. The Research Center spin-off is located in Jülich and now employs a staff of ten.

Evocatal started up only two years ago and can already point to long-term cooperative ventures with companies like Henkel. Last year, the young team was nominated for the Evonik European Science-to-Business Award after developing a fluorescent protein that, unlike conventional varieties, requires no oxygen. This opens the way for novel applications in industrial biotechnology and biomedicine. But the core competency of Evocatal, located at the Life Science Center in Düsseldorf, is the development of high-performance biocatalysts. The team is working on new or improved enzymes for chemical syntheses and intends to market its own enzyme-based processes and products. Evocatal founder Thorsten Eggert and his staff are developing new screening procedures and plan to optimize enzyme properties using molecular-biological engineering with support from the German Ministry of Education and Research and the German Environmental Foundation. One of their programs is dedicated to the development of a novel bio-catalytic process for the production of colorants and synthetic flavors for the food sector. They are also working on oxidases from waste products like glycerol, a byproduct of biodiesel production, to derive components for the chemical industry.

"Our aim is to understand all the processes taking place in a cell. This would enable us to teach it how to produce a designated protein."

To date the Jülich biotechnology center has trained 200 doctoral students and 21 professors. Eggert is one such trainee, and a genuine "Jülich boy." After his doctorate in biotechnology, he established a research group called "Directed Evolution" at the Institute of Enzyme Technology in 2002. In 2007 he did his habilitation, the prerequisite for a professorship. "I knew we could make more out of this know-how," Eggert asserts. Alongside contract research, Evocatal systematically seeks and conducts research projects of its own, while the company also markets its own biocatalysts and fine chemicals. This strategy was quick to find support. Detlev Riesner, a cofounder of Qiagen, joined Evocatal as a partner in 2007. Today the start-up company has a staff of 12 and its premises have increased from an initial 180 m2 to the present 320 m2, with further expansion envisaged in the near future.

New structures make things easier
Evoglow in vivo fluorescence can do things that even the Nobel-Prize-winning protein GFP cannot: it glows under conditions of limited or no oxygen. This is relevant to many fields of research, such as hypoxia and the infection mechanisms of certain anaerobic pathogens.
Courtesy of Evocatal

The countless patents and spin-offs, awards, and well-known products developed is a formidable legacy that Jaeger and his colleague Bott have inherited from their predecessors Kula, Wandrey, and Sahm, all now retired. Jaeger and Bott are aware but undaunted by this even as times have changed. "Today it is increasingly difficult to make a name for yourself on your own," says Bott. "We form integrated research associations to pool resources and stay competitive on an international scale."

One such association is the cluster for industrial biotechnology (CLIB2021). Encouraged by the Federal Education and Research Ministry's competition BioIndustry 2021, academic institutions and companies (including the Universities of Münster, Bielefeld, Dortmund, Düsseldorf, and Fraunhofer Institute for Molecular Biology and Applied Ecology in Aachen; and industry leaders Bayer, Cognis, Lanxess, and Artes Biotechnology) decided to join forces. The aim of the competition was to find the best strategy for the development of white biotechnology. The NRW strategy—CLIB2021—won first prize, bagging €20 of the €60 million available in the framework of the federal government's high-tech strategy for the next five years.

The central objective of the research and development ventures planned is the use of renewable resources like sugar beet, rapeseed, maize, or wood as the basis for the production of basic chemicals, intermediate products, and ultimately plastics that are presently derived from petrochemicals. Molecular-biological methods are being employed to design new enzymes and equip microorganisms with new properties.

With its combination of research in chemistry, biology, and engineering, Jülich is a genuine one-stop biotechnology shop.

CLIB2021 has assembled many white-technology experts in NRW. One of them is Karl-Heinz Maurer, head of Henkel's enzyme technology research platform since 2001. "Of course physical proximity is not absolutely essential," says Maurer, when asked about the advantages of the NRW biotechnology network, "but it certainly makes things a lot easier." At Henkel Maurer is in charge of 14 labs, where he and his staff of 30 have been deriving enzymes from microorganisms since the early 1970s for use in detergents and cleaning agents. Within the CLIB2021 cluster Maurer intends to track down special peptides with adhesive properties for use in innovative glues. As biotechnological production is not part of the core business of the giant Düsseldorf-based chemical concern, Maurer has been working with other partners for a long time, including both the Center for Microbial Biotechnology in Jülich and Professor Jochen Büchs' Department of Bioprocess Technology at Aachen's Technical University. Together they intend to develop a process to screen post-cultivation production strains on microplates rather than in large-scale fermenters. Another project is the quest for production organisms and process conditions that can be cultivated from inorganic nitrogen sources, making the addition of nitrogen superfluous.

Where white meets green
SEM (artificially colored) from Corynebacterium glutamicum, one of the "workhorses" in industrial biotechnology. It is used for production of more than 2 million tons of amino acids per year and is currently the predominant organism for research in IBT1.
Courtesy of Michael Bott / Research Center Jülich

"Research links between the various actors in NRW are really very close," says Peter Welters, managing director of Phytowelt Green Technologies. This international enterprise grew out of a spin-off from the Max Planck Institute of Plant Breeding Research in Cologne and a start-up outfit from Nettetal. With core competencies in plant biotechnology and agricultural science, Phytowelt bridges the gap between industrial white biotechnology, strongly represented in NRW, and the green variety. The firm's most important product is phytomining, the detection of plant enzymes suitable for the environmentally benign production of chemicals. "This way we can replace traditional, petrochemical processes with the use of renewable resources and metabolites from plants," says Welters. This will greatly simplify the extraction of raw materials and substantially bump up yield. Alongside numerous projects in the industrial biotechnology sector, the Phytowelt scientists are presently involved in a project funded by the Office for Renewable Resources. Together with the University of Göttingen and the Max Planck Institute for Plant Breeding Research in Cologne, they are working on the production and study of new hybrid varieties of poplar with faster growth potential.

For Jaeger the commitment displayed by the many partners involved in CLIB2021 demonstrates just how unique the biotech scene in NRW really is. His main concern is to advance the "Expression" technology platform operating within the cluster. The aim of this project is to design new vectors and microorganisms as host strains with a view to achieving the over-expression, correct folding, and efficient secretion of hitherto inaccessible proteins. Various research groups at universities, research centers, and commercial enterprises will be collaborating on expression methodology, high-throughput screening and selection systems, ultrasensitive protein analytics, fermentation technology ranging from very small to large scales, and modern techniques in downstream processing.

Major projects are also under way at the Jülich Research Center. "Our aim is to understand all the processes taking place in a cell," says Jaeger. "Then we would know what signal to give for the cell to produce this or that protein." This requires both intricate global analysis methods and highly complex calculations. "It would be ideal if we could get a cell to function on the computer." Of course, these processes are too complicated for one person to handle. "But I'm not alone here," says Jaeger and points to the window. The offices of his colleague Michael Bott are just across the way, while those of chemist Jörg Pietruszka are in the very same building. The courtyard connections indeed work well.

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