In the laboratory, these are vessels with a nutrient solution that hold between 5 and 20 liters. The Eleva company, which I founded in 1999, has even larger reactors with a capacity of up to 500 liters. The right lighting is a challenge, especially for the larger ones: ideally, we have to ensure that all our plants get light. At the same time, the specimens floating on the outside of the reactor should not burn up. And of course we have to ensure that the gas exchange between the plants and their environment works. The small reactors are shaken, air is blown through the large ones. Controlling such a system is a science in itself. Especially since different species also have different requirements in terms of temperature, pH value and nutrients. Bringing a specific moss from nature to the laboratory may look easy, but it takes a lot of work.
What do you do with the material you extract from these plants?
We use it for genetic studies, for example. A few years ago, in an international team, we sequenced the entire genome of the little bladder cap moss. We found around 35,000 genes that encode the building instructions for proteins. A plant that does not even have flowers, wood or roots has 10,000 more genes than humans! Of course, that scratches a bit on our self-image as the crown of creation. And one involuntarily asks oneself: What does the moss need all this genetic information for?
How to find out?
In the laboratory, we switch off individual genes using so-called gene targeting and then see what these knockout mosses can and cannot do afterwards. We have now performed this reverse genetics on more than 100 genes to see which metabolic pathways they are responsible for and have found, for example, that mosses do not produce lignin, which causes the cells in flowering plants to lignify. However, they do have some enzymes that are important for the biosynthesis of this molecule. Mosses use these tools to produce the cuticle. This is a waxy layer on the cell surface that plants use to protect themselves from excessive water loss.
Moss Bioreactor | For a long time, mosses were difficult to grow in the laboratory, but this can now be done quite well in larger bioreactors. Here is an example from the Reski lab.
And have you discovered any other protective mechanisms?
Clearly. In general, mosses need a good part of their genes for various protective mechanisms. They produce far more bioactive substances than flowering plants do. This includes, for example, various weapons against enemies. Or polyunsaturated fatty acids, which serve as protection against freezing and make the membranes soft and flexible. Such substances are important for the mosses to cope with the challenges of their environment.
If mosses are small chemical factories by nature, can they also produce substances that are useful to us humans?
In fact, we are working on extracting human proteins from mosses that can later be used as medicines. To do this, we have to modify the genome of the plants in such a way that they not only produce the protein themselves, but also grow sugar structures in certain places that are as similar as possible to those in humans. The Eleva company deals intensively with such challenges. And indeed, with an enzyme called alpha-galactosidase A, she has already very successfully brought the first human protein from moss production through clinical phase I.
What could this enzyme be used for?
Used to treat Fabry disease, a rare metabolic disorder. Those affected cannot produce the enzyme at all or not in sufficient quantities. This disrupts the detoxification pathways in the body. This can be treated with enzyme replacement therapy, in which the patient is regularly injected with the missing enzyme. There are already corresponding drugs on the market. But they are made in animal cells. And our data suggests that mosses may be better at it.
What are the advantages of producing medicines in mosses?
Many medicines are now produced in genetically modified bacteria. However, this is not possible for everyone. The so-called CHO cell line, which was obtained from the ovaries of the Chinese dwarf hamster, is therefore used for the production of antibodies, glycoproteins and many other human proteins. However, mosses can produce the desired substances in a higher quality and purity than animal cells. And the proteins obtained are also easier to clean. A genetic trick can be used to get the mosses to release the product from the cells into the medium in the bioreactor.
Are you also working on other drug candidates from moss production?
Yes, we are working intensively on the so-called factor H. This is a very complex protein from the blood plasma that influences the regulation of the innate immune system. It’s difficult to make in animal cells, but mosses can. And that might be a big opportunity. A lack of factor H leads to excessive inflammation and a risk of tissue damage. This protein could also be of interest for the treatment of many other diseases. For example, when it comes to age-related macular degeneration, which can lead to blindness. Or with severe viral infections. For example, we have hope that Factor H could help against Long Covid. Of course that electrified us. That’s why we want to start phase I clinical trials as soon as possible.
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Mosses cover deadwood | Mosses grow almost everywhere, including other plants. They make an important contribution to the health of the ecosystem, for example by storing water.
Do you and your team want to develop a drug from moss production to market maturity?
As a university, we can’t afford something like that, it’s a company matter and always a question of money. We estimate that getting the alpha-galactosidase through clinical phases II and III and then to the market would cost around €350 million. An investor would have to be found.
Human proteins can only produce mosses through genetic engineering. Can you also use substances that they produce naturally?
In any case. For example, we work together with the Swiss company Mibelle Biochemistry. They already sell a natural anti-aging ingredient made from moss that is used in many skin creams. And I am sure that there are many more interesting substances to discover. We have only researched a small part of the diversity of mosses and their biochemical components.
A good portion of the world’s biological diversity is in danger of disappearing before it is even discovered. Does this danger also exist with mosses?
I hardly know of any reports of major species extinctions in mosses. This can of course be due to the fact that their occurrence is not examined enough. But it probably also has something to do with their enormous resilience. These plants have seen dinosaurs come and go. And if we’re not careful, chances are they’ll see us humans walking too.