"Moss bioreactors do not smell" - Interview with Professor Ralf Reski
Molecular farming is the growing and harvesting of genetically engineered crops of transgenic plants in order to produce biopharmaceuticals. One of the pioneers employing and developing this method in Germany is Professor Dr. Ralf Reski, Director of the Department of Plant Biotechnology at the University of Freiburg and co-founder of the company greenovation BioTech GmbH. The company uses the moss “Physcomitrella patens” in order to produce antibodies and other commercially interesting proteins. Further information on greenovation is also provided on this website (see articles listed in the right hand column). Karin Bundschuh of the Freiburg BioRegion talked with the scientist on the history, risks and opportunities of molecular farming.
When did the idea of using plants as protein bioreactors come about?
The idea is already twenty years old. In plants, the first pharmaceutically relevant proteins were produced in the late 1980’s and early 1990’s. At that time, only small amounts were produced and were too small to be exploited commercially. However, publications of our American colleagues in 1989 showed that it was possible to produce complete antibodies in plants. This really caused a stir throughout the whole world.
What are the advantages of plants over transgenic animal or bacterial cell cultures?
Prof. Dr. Ralf Reski: "Plants can be easily cultivated, the proteins can be purified and there is no risk of contamination with human pathogens"
Bacteria are prokaryotes and are only able to produce relatively simple proteins. Such proteins do not have complicated sugar residues. When simple proteins have to be produced, bacterial cultures are the best choice. Bacterial cultures are extraordinarily efficient and cheap. Insulin is one of the best-known examples and, despite its human origin, can be produced efficiently in bacteria. However, we also need more complex proteins such as antibodies, which need to be assembled and modified in a complex way. Such proteins can only be produced in eukaryotic cells. Ovarian cells of the Chinese hamster (CHO cells) have been the most thoroughly investigated and are the most frequently used for such applications. Molecular farming tries to use plants as an alternative production system to CHO cells. Animal cell cultures are very costly; they require constant 37 degrees Celsius in steel fermentors as well as complex media. They are very susceptible to contamination with human pathogens and to undesired genetic alterations. In contrast, plants have many advantages. Plants can be easily cultivated, the proteins can be purified and there is no risk of contamination with human pathogens. In addition, the quality control of plants is much cheaper. And a further advantage is that moss bioreactors do not smell, unlike bacterial, fungal or animal systems. Expressed in more scientific terms, plant systems enrich their waste gas with healthy oxygen.
Are there risks associated with molecular farming?
It is impossible to envisage the growing of tobacco plants on fields, for example, for the purpose of producing human growth factors. The consumers have reservations and the production of pharmaceuticals is controlled by GMP (Good Manufacturing Practice) standards. This means we need to guarantee a well-controlled cultivation and production process. This is of course not possible in the field. One possibility would be the cultivation of plants in greenhouses. A second alternative would involve the growth of plants or plant cell cultures in bioreactors. With this we can prevent the release of genes into the environment and can guarantee GMP conditions. Then there is also the difficulty with the sugar residues. In principle, plants have the same glycosylation pattern as animals. However, plants have two additional sugar residues that lead to allergic reactions in humans if the proteins are administered intravenously. However, with Physcomitrella patens we succeeded in knocking out the genes that are responsible for attaching these two plant-specific sugar residues and introducing a gene that attaches a human-specific sugar residue. Having done that, the new proteins show a human glycosylation pattern. With the combination of a bioreactor and the specific moss strains, humanised proteins can be produced. This means that this particular problem could be solved.
You mentioned problems in growing complete plants in the field. Do you believe that the future of molecular farming lies in the cultivation of algae, mosses and plant cell cultures that are grown in the bioreactor? Or do also classical field crops such as maize, tobacco or hop have a chance?
The last three could possibly be used if they are grown under controlled conditions in the greenhouse. They could be very important for the production of therapeutic proteins which have to be controlled by GMP conditions. If the proteins are exclusively used for diagnostic purposes or as food supplements, then they can also be grown in the field. However, I personally and as a matter of principle, do not think much of molecular farming in plants that are also used as animal fodder or food. This is always associated with the principal problem that the two types of processing need to be separated at all costs. Or to put it another way: the production of tacos that can accidentally contain a human growth factor must be prevented at all times. Such production systems will not be accepted by the consumers and adversely affect the image of the whole sector.
Some of your colleagues believe that molecular cloning is only worth the effort if particularly valuable substances are concerned, such as for example secondary plant substances with pharmaceutical effect. Otherwise their development would be much too time-consuming and costly. What is your opinion?
Taxol, produced by the yew tree as an important weapon in cancer therapy, shows that secondary plant substances are already being marketed and already generate high revenues. One must not forget that many drugs that are used today and that are partially chemically synthesised have their origin in plants. Plants have a much more complex metabolism than animals. One must also not forget the success of the CHO cells. This system is based on more than 20 years of intensive development and optimisation work. Now that system is coming to the end of its product cycle. This means, it is mature, it works and produces, but nevertheless the market is demanding alternatives.
Some people think that the safety risk caused by human pathogens is much too high. Others see considerable advantages in the altered patent situation arising through the use of plants as production system rather than animals. The use of plants means that generic drugs can be commercialised a lot sooner. Whether this is worth it, remains a completely economic calculation. I believe it will be really worth it. Right now, we are just starting to commercialise such products. However, I am sure that we will make important breakthroughs in the production of proteins in plants and will have introduced several plants to market in ten to 15 years time. In addition, we are also talking about medicine tailored to the individual. We are not talking about bulk production of proteins. It is more important to produce a protein that is made to measure for certain patients as quickly and as efficiently as possible - whether it be antibody or enzyme. In this case, plants have a decisive advantage over animal cell cultures.
You just mentioned a timeframe of five to fifteen years? How important will molecular farming be in ten to fifteen years’ time?
I am very optimistic. I think that by that time the technology will be as established as CHO cells today. We will see that a number of companies will have understood this trend and become market leaders. Today, many companies rely on the well-established technology of CHO cells. However, these companies can only make cosmetic changes and are unable to increase their competitive position through this production system. I am sure that innovative spirit will be rewarded. I can even imagine entire halls equipped with moss reactors with which it will be possible to produce complex biopharmaceuticals efficiently and safely.
Prof. Dr. Ralf Reski
Department of Plant Biotechnology
University of Freiburg
Phone: +49 (0)761/203-6969
Fax: +49 (0)761/203-6967