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Gilbert Gorr - a great fan of the moss Physcomitrella patens

Dr. Gilbert Gorr has been fascinated by the moss Physcomitrella patens for many years – in fact it occupies a great deal of his waking moments. The enthusiasm with which the CSO of greenovation Biotech GmbH talks about the key object of his work is both intoxicating and contagious. After listening to Dr. Gorr expound on his favourite subject, one has a new respect for Physcomitrella patens and its capacities that are the result of intensive research by the greenovation team. The latest discovery: The moss produces a therapeutic antibody that is far more effective than its predecessors created in animal cell cultures.

Dr. Gilbert Gorr’s excitement about Physcomitrella patens is contagious (Photo: greenovation)
Gorr, who studied biology and chemistry, became acquainted with Physcomitrella whilst doing his doctorate in the laboratory of Ralf Reski who, back then, was working on his habilitation at the University of Hamburg. Gorr investigated whether the moss would be suitable as an expression system for human proteins. Nowadays, it is known that the moss Physcomitrella is a versatile protein producer: coagulation factors, growth factors, antibodies and other proteins can be produced with the moss. Following his PhD, Gorr wanted to prove himself in other fields and therefore accepted a position at the Institute of Pharmacology, Toxicology and Pharmacy within the University of Veterinary Medicine in Hanover. Despite his successful work in veterinary medicine, Gorr soon realised that he had close ties with the field of biology and with the moss Physcomitrella and he therefore wanted to go back to moss research.

A truly courageous step

When greenovation contacted him in 2000 to find out whether he was interested in establishing moss technology (today known as bryotechnology) in the company, he accepted on impulse. “It is great fun to work with the moss,” said Gorr explaining his move from Hanover to Freiburg, which back then was definitely a courageous one. Nobody knew whether the company would be able to successfully establish itself on the market. His former supervisor, Professor Reski, together with Professor Gunter Neuhaus, founded the company in 1999. Originally, Reski and Neuhaus had plans to focus on different fields of biotechnological interest, but soon realised that this was a strategy with pitfalls. As they did not want to lose ground, the company owners soon concentrated on the innovative Physcomitrella expression system and the production of high-quality proteins. That was when Gorr was offered his current position as the company’s chief scientific officer.
Gorr and his team’s investigations are based on the protonema (the haploid phase) of the moss, which only has a simple set of chromosomes. The buds of this thread-like chain of cells develop into moss plants. Thanks to the haploid genome it is easy to genetically modify Physcomitrella. It is easy to transfer foreign genes into the moss to produce specific proteins. The transgene also remains at the site where it has been inserted. The culture conditions can be varied and adapted to the products required. In contrast to animal cells, moss tissue does not require complex media. It is happy with light, a few salt compounds and carbon dioxide. In addition, it can be cultured under sterile conditions in closed bioreactors. The target proteins are released into the culture medium by way of specific signal sequences and can be harvested and purified. Moreover, moss expression systems are very safe because they are unable to transmit human pathogenic viruses.
Schematic of the generation and production of valuable transgenic proteins in Physcomitrella patens (Figure: greenovation)
In recent years, the greenovation laboratories have succeeded – in part also working in close cooperation with the Department of Plant Biotechnology at Freiburg University – in establishing a number of different production strains with different properties. An important step towards the production of pharmaceutically active proteins was to switch off the moss genes that add the typical plant sugar residues to glycoproteins. If the valuable recombinant proteins were to carry plant carbohydrate residues instead of sugar residues that are typical for humans, they would lead to immunogenic incompatibilities and become dangerous for those being treated. Astonishingly and luckily, the moss grows well despite such alterations.

The optimisation of moss genes practically imposed itself on the researchers

greenovation’s experience in the field of sugar biotechnology was also decisive in optimising a therapeutic antibody known as 311, the development of which was commissioned by a client. 311 is a completely humanised, monoclonal antibody that was originally produced in animal cell lines. The antibody is directed against the Lewis Y antigen that occurs frequently on tumours. This surface molecule is for example found on breast, intestinal, stomach, ovarian and lung cancer cells. When 311 recognises and binds to this structure, the tumour cells are destroyed. This leads to the recruitment of immunological cells and activation of cytotoxic effector cells which triggers the antibody-dependent cellular cytotoxicity – ADCC as the medics call immune reactions that lead to the destruction of the tumour. In the test tube, 311 also proved to have the ability to prevent the growth of cancer cells.

Despite the positive effects of 311 in the treatment of tumours, the researchers started to think about possibilities to effectively improve the antibody very early on after its original development. The antibody carries sugar structures on its surface, in particular fucose residues, which impede its effect. It is assumed that the sugar structures have a negative effect on ADCC. This led the researchers to think about the possibility of specifically altering the sugar residues and using moss as an expression system.

Considerable improvement of the lysis of cancer cells

Gorr and his team had already established a moss line that was able to produce proteins without the need to combine these proteins with fucose residues. “Nevertheless, it was very exciting to find out whether we would be able to improve the 311 antibody,” said the CSO. And the researchers did succeed – at least in the test tube. “If the fucose residues are missing then the antibody’s folding changes,” said Gorr explaining that although the structural difference is minimal the binding between the antibody and the cytotoxic immune cells alters drastically. Comprehensive analyses by the company’s Austrian partner, Vela Laboratories, showed that these alterations improve the lysability of the cancer cells.

The optimised antibody, known as 314, will soon enter clinical trials. greenovation will also in future produce the therapeutic, but this will be done in the city of Heilbronn where the company has its new headquarters. The planning of the production facility in Heilbronn is in full swing. In future, it will be possible to produce different therapeutic proteins under GMP (Good Manufacturing Practice) conditions. “We will use a method that is truly wonderful to work with. And that is the pleasure of working with Physcomitrella,” explains Gorr. 

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