Our bodies harbor a huge array of microorganisms both internally and externally. While bacteria are the biggest players, we also host single-celled organisms known as archaea, as well as fungi, viruses and other microbes – including viruses that attack bacteria. Together these are dubbed the human microbiota. The body’s microbiome includes all the genes our microbiota contains, however colloquially the two terms are used interchangeably. Rapid advances in DNA sequencing and bioinformatics technologies in the past two decades have substantially improved our understanding of the microbial world inside our bodies.
“We’ve come to the fascinating conclusion that life is multi-organismic – we are metaorganisms,” says Thomas Bosch, a developmental biologist and head of “Kiel Life Science” (KLS) research at the Christian-Albrechts-Universität Kiel (CAU). Biologists have only started to uncover the important role of microbial communities in human physiology. Microbes help to break down the array of sugars. Other key roles of our microbes include programing our immune systems, providing nutrients for our cells and preventing colonization by harmful bacteria and viruses.
In recent years, the gut microbiome has been linked to a plethora of diseases and conditions, from diabetes to autism and anxiety to obesity. Targeting or modifying the microbiome has emerged as a hot topic in biomedical research. Bosch is convinced the microbiome provides a powerful way to approach complex diseases. He also says it is worth being cautious: many studies show correlations rather than cause and effect. “The field has to move from describing the structure of microbiomes to generating mechanistic insights on how these ecosystems work,” Bosch underlines. He is convinced that basic researchers must now design experiments such that they find out how the microbiota and their host interact and communicate with each other.
Bringing causality to microbiome research is at the heart of the DFG-funded Collaborative Research Center CRC 1182 “Origin and function of Metaorganisms” at CAU. Bosch is its spokesperson. A key issue for the researchers is how the composition of an organism’s microbiome forms during its unique development. To reduce complexity in their analyses, Bosch and his team use the freshwater polyp Hydra as an experimental model. The transparent animal has a tube-like body that is akin to the vertebrate intestine. And it is colonized by a simple microbiome. “The interesting thing is that we can create germ-free animals,” Bosch says. “Combined with sophisticated genetic techniques, this allows us to assemble or also to deconstruct the metaorganism.”
This way of microbiome engineering has, for example, generated novel insight into how bacteria and the 3,000 neurons in the simple nervous system of Hydra communicate with each other. The intact natural Hydra microbiome can play an important role in the spontaneous contractile activity of the polyp’s body column. “The microbes also play a role in dysmotility of the human intestine, a disorder seen in inflammatory bowel disease or Parkinson’s disease. “Thus, Hydra is a very informative model system that allows us to develop novel concepts which we can discuss with our medical colleagues here in Kiel.”
Microbiome research relevant to clinical application is also part of the new Cluster of Excellence “Precision Medicine in Chronic Inflammation”, a Kiel and Lübeck University cluster with partner institutions in Plön and Borstel.
Living Biotherapeutics as new modality
Influencing the function of the gut microbiome is regarded as a new frontier in pharma research and development. That is why a growing number of companies working in the microbiome field are now developing live biotherapeutics — single or multi-strain bacterial cultures that can recolonize intestines with ‘beneficial’ bacteria to restore the balance of the microbiome.
However, outside of their natural habitat, most gut bacteria are sensitive creatures. Being strict anaerobes they die on contact with oxygen. This is only one aspect that makes dealing with microbes as drugs so challenging. It requires specialized know-how which is scarce in the field of biopharma. Nordmark Arzneimittel GmbH & Co. KG is a biopharma company that can deliver this expertise.
The company headquartered in Uetersen, close to Hamburg, has successfully joined the small club of manufacturers that can produce live biotherapeutics targeting the human gut microbiome. The drugmaker employs nearly 600 people and has a large biotech division specialized in the manufacturing of therapeutic proteins. Apart from supplying its own biologics pipeline, Nordmark also acts as a contract development and manufacturing organization (CDMO). “We are a fully integrated pharmaceutical company, providing service and expertise along the entire value chain,” says Jan Heyland, who is responsible for research and development at Nordmark’s Biotech division. “This includes process development, GMP-compliant production and formulation,” he explains.
How to manufacture a microbe cocktail
Nordmark can build on decades of expertise in microbial fermentation and cell culture processes. But bringing microbiome-based therapeutics to the clinic means navigating several tough production challenges. Unlike traditional pharmaceuticals and biomolecules, microbial-based therapeutics consist of a mix of living organisms, meaning biotechnologists must figure out how to keep their microbes alive while also considering things like product stability and shelf life. “It is a steep learning curve for all parties involved: big pharma, authorities and of course for us as biopharmaceutical contract manufacturers,” Heyland underlines.
It’s not only the gut bacteria species which must be cultivated under strict anaerobic conditions. “They also form spores, which can increase cross-contamination risks,” Heyland says. This requires special equipment and handling to keep the microbes under anaerobic conditions as well as stringent hygienic control. In addition, the biotechnologists cannot rely on standard protocols or established production platforms when cultivating their bacteria. The development of a pill including a mix of microbial species is another challenge, since the live biotherapeutics must be encapsulated and handled under oxygen-free conditions and need to be characterized in detail. Thereby, sophisticated analytic tools are needed to differentiate between closely related strains, to spot living and dead cells and to ensure a homogenic drug product.
“We are breaking new ground in many aspects,” Heyland resumes. His team has successfully achieved the first milestones in microbiome engineering. Recently, Nordmark supplied an Active Biological Ingredient (API) in the form of a capsule to a partner with a view to conducting a clinical study. Although he cannot provide detailed information on the condition addressed in the study, Heyland is convinced that the therapeutic expectations within the scientific community seem to justify the efforts. “At this stage it appears that big pharmaceutical companies prefer to outsource such complex projects to specialists,” he says.
Autor: Philipp Graf für LSN
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