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Ralf Reski: from moss to humans

Prof. Dr. Ralf Reski conducts basic research at the University of Freiburg. But this is not all the well-known plant biotechnologist does. He also wants his ideas to become concrete products. This is why he established Greenovation Biotech GmbH, a company which produces novel drugs in mosses. The company’s first moss-produced drug candidate – Moss-aGal – a recombinant form of human α-galactosidase, is now being tested in a phase I clinical trial.

Prof. Dr. Ralf Reski is a plant biotechnologist at the University of Freiburg. He is the founder of Greenovation, a company that uses mosses to produce novel drugs for the treatment of rare diseases. © Sigrid Gombert

Prof. Dr. Ralf Reski came up with the idea of producing more complex proteins using moss cells during his university studies when his supervisor asked him to develop a DFG project proposal for a biotechnology research training centre. The research programme was approved and at the end of the six-year funding phase, the researchers had produced the first moss-produced human protein.

Bryotechnology – mosses are scientifically classified as bryophytes – remained one of Reski's favourite research areas, even after he was appointed Chair for Plant Biotechnology at the University of Freiburg. In 1999, Reski and cell biologist Prof. Dr. Gunther Neuhaus jointly established Greenovation Biotech GmbH. According to Reski, the two researchers decided to set up their own company because they were doing research that was relevant for practical application. Reski comments: “My department conducts excellent basic biotechnological research in plants, but taking research findings to practical application is something that cannot be done at a university. We needed to set up a company for this particular purpose. We were also hoping that our ideas would eventually have clinical application potential, from moss to humans, so to speak.”

Moss cells produce pharmaceuticals

Back then, the young biotech company started off with a broad range of ideas. But the founders soon realised that they had to focus on a single aspect if they wanted to succeed. Nowadays, Greenovation develops novel therapeutics for treating rare diseases. The drugs are produced in moss cells that are grown in large biorectors. This platform is called BryoTechnology, a technology that was developed for the purpose of producing human glycoproteins on the large scale.

Glossary

  • Biotechnology is the study of all processes involving life cells or enzymes for the transformation and production of certain substances.
  • A gene is a hereditary unit which has effects on the traits and thus on the phenotype of an organism. Part on the DNA which contains genetic information for the synthesis of a protein or functional RNA (e.g. tRNA).
  • Recombination is the process in which DNA is recombined. As a natural process, recombination takes place in sexual reproduction during meiosis. In vitro recombination involves the joining of DNA molecules of different origin using recombinant DNA technologies.
  • A cell line is a permanently established cell culture that will proliferate indefinitely under defined conditions.
  • Glycosylation is the addition of carbohydrate to an organic molecule, mostly proteins.
  • Heterogeneity means dissimilarity, diversity.
The moss plants used for basic research are produced on the small scale. © Plant Biotechnology, University of Freiburg

In autumn 2015, the company was given the go-ahead for a phase I clinical trial with the first moss-produced drug candidate. It is successes like these that, in Reski's opinion, bear out the decision to set up a company. “This is a quality label for me as scientist,” Reski says. “The clinical study was approved by the Federal Institute for Drugs and Medical Devices BfArM because the production system was considered safe and the data were excellent. Receiving this go-ahead was fantastic. I am first and foremost a professor, and my job is carrying out research. But as a co-owner of Greenovation, I still have a small share in the company and am also a member of the company’s scientific advisory board. I also believe that there should be a clear distinction between the university department and the company. This is very important for me.”

Novel drug candidates for rare diseases

The moss Physcomitrella patens can produce human proteins. © Plant Biotechnology, University of Freiburg

Reski does no longer come to Greenovation every day. However, his department and the company are working together on a number of cooperative projects. The company’s most successful product so far is Moss-aGal, a recombinant form of the human α-galactosidase enzyme, which is currently being tested in a clinical trial. The protein has been developed as an enzyme replacement therapy for patients with Fabry disease, a genetic lysosomal storage disorder. “The enzyme already exists on the market, but is produced with animal cells, which has the disadvantage that the glycosylation pattern of the proteins can be very heterogeneous,” says Reski. “We are hoping that Moss-aGal will have a much better effect.”

Reski’s department and Greenovation have successfully developed another drug candidate called Moss-FH. It is a recombinant protein that is very similar to the factor H of the human complement system and intended as a therapeutic agent for atypical haemolytic uraemic syndrome (aHUS), a rare life-threatening disease that restricts the blood flow of organs, and permanently damages them.

Factor H was originally developed in Reski’s department. “Factor H is a very complicated protein,” said the biotechnologist. “And we were asked whether we could also produce similarly complex molecules in mosses. We tried it, and it actually worked. The same thing had previously been attempted with other systems, but without success,” said Reski, going on to add, “at present there are only two options for treating aHUS. One involves lifelong twice-weekly blood transfusions, and the other an antibody, which is the most expensive drug on the market and associated with severe adverse effects.” The results on factor H have already been published, and Moss-FH is currently undergoing preclinical testing by Greenovation and the Freiburg University Children’s Hospital.

Company and university department – skills that complement one another

Here too, Professor Reski is careful to clearly distinguish the university and the company from one another. “All contracts are negotiated between the university administration and the company. The fact that we are different players is a wonderful situation for me. Everyone involved brings their own unique skills to the project. We have developed the substance, but producing it in a 20-l bioreactor does not generate the quantities required. Greenovation has a completely different production system, one that no university has. The development process that leads up to the product is a lot of fun, partly because I am still learning a lot.”

Greenovation produces human proteins in large moss bioreactors for use as biopharmaceuticals. © Greenovation

Reski sees no problem in reconciling research, teaching and company interests. “I am a professor, but both the university and the authorities are very positive about industrial collaborations of this kind. The University of Freiburg is particularly supportive of start-up companies, and as far as industrial cooperations in general are concerned, it is one of the leading universities worldwide. This is also hugely advantageous for basic research. Here in Freiburg, I have acquired more than 24 million euros in third-party funding; 51 percent of this money has come from industrial cooperations. As university professors, we are financed by the taxpayer, so I think that we should be looking at how we can improve people’s lives. And if we succeed in doing so, this is very satisfying for me personally.”

When in doubt, science has priority

As far as the education of students is concerned, we are also in a position to be able to tell them about other opportunities besides an academic career. Reski comments: “This makes training broader. For example, students learn about financial issues, which is of benefit for our teaching activities as well. And this also helps make our department more attractive.” Reski also believes that although many innovations are made in Germany, the ideas are then taken abroad, partly due to the reluctance of big companies to take risks. “Most recombinant human proteins on the market are produced with established systems such as CHO cell lines. Why would you want to establish a completely different production system based on moss cells?” he asks provocatively. “This can only be done with own resources.”

And Reski does not believe that patents and publications are mutually exclusive: "We are focused on being involved in top-notch research, in both the BIOSS excellence cluster and FRIAS and USIAS, the Institutes for Advanced Studies in Freiburg and Strasbourg. It goes without saying that we want to publish our research. However, if we think that the results would be suitable for a patent, then we file a patent before disclosing our data in scientific publications. The same applies to student dissertations. These are also published with a delay. There is no disadvantage at all in doing it this way. On the contrary, it is a fantastic experience for students to see that their efforts have led to two scientific achievements.” He adds: “However, if problems occur, then I personally believe that science should always come first.”

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