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Mosses in biotechnology
Eva L Decker1 and Ralf Reski1,2,3
Biotechnological exploitation of mosses has several aspects, active growth. They comprise mainly tissues one-cell
for example, the use of moss extracts or the whole plant for layer thick lacking stomata in the photosynthetically
diverse industrial applications as well as their employment as active leafy parts of the plants. Mosses develop stomata,
production platforms for valuable metabolites or dependent on the action of the bHLH transcription
pharmaceutical proteins, especially using the genetically and factors SCRM and SMF1, exclusively in the spore cap-
developmentally best-characterised model moss sule, the sporophytic generation of the plant [1]. The
Physcomitrella patens. Whole moss plants, in particular peat formation of a phenol-enriched cuticle in the moss Phys-
mosses (Sphagnum spec.), are useful for environmental comitrella patens only starts with the development of the
approaches, biomonitoring of environmental pollution and adult plant, the gametophore. It provides some protection
CO2-neutral ‘farming’ on rewetted bogs to combat climate against dehydration as well as stiffness to allow erect
change. In addition, the lifestyle of mosses suggests the growth and it displays commonalities shared among cutin,
evolution of genes necessary to cope with biotic and abiotic suberin, lignin and sporopollenin polymers of tracheo-
stress situations, which could be applied to crop plants, and phytes [2,3]. However, the poikilohydric lifestyle of
their structural features bear an inspiring potential for mosses (i.e. the water content of the cells is equivalent
biomimetics approaches. to that of their environment), required the establishment
of biochemical mechanisms to cope with abiotic stress, for
Addresses
1
example drought, which are valuable for future biotech
Plant Biotechnology, Faculty of Biology, University of Freiburg, applications in crop plants [4]. Moreover, lacking true
Schaenzlestr. 1, 79104 Freiburg, Germany
2
Signalling Research Centres BIOSS and CIBSS, Schaenzlestr. 18,
roots, mosses take up nutrients via their whole surface,
79104 Freiburg, Germany which makes them interesting targets for biomonitoring
3
Cluster of Excellence livMatS @ FIT – Freiburg Center for Interactive approaches of environmental pollution. Life in a wet
Materials and Bioinspired Technologies, University of Freiburg, environment in close contact to organisms involved in
Georges-Köhler-Allee 105, 79110 Freiburg, Germany
biodegradation could be the reason for the presence of
Corresponding author: Decker, Eva L several special metabolites with antimicrobial or antifun-
(eva.decker@biologie.uni-freiburg.de) gal effects in bryophytes, which have been used widely in
traditional medicine [4,5]. The antiseptic and water-
absorbing properties of Sphagnum mosses have been used,
Current Opinion in Biotechnology 2020, 61:21–27
for example for wound dressing [5]. More recently, how-
This review comes from a themed issue on Plant biotechnology ever, lab-grown P. patens and mixed samples of six moss
Edited by Ralf Reski, Gary Foster and Ed Rybicki species taken from the environment were successfully
used to create a bryoMFC (microbial fuel cell). The
importance of the microbial populations for electron
delivery was confirmed [6].
https://doi.org/10.1016/j.copbio.2019.09.021
0958-1669/ã 2019 The Author(s). Published by Elsevier Ltd. This is an The low degree of structural complexity and the predomi-
open access article under the CC BY-NC-ND license (http://creative- nant haploid gametophytic growth made mosses interest-
commons.org/licenses/by-nc-nd/4.0/).
ing objects for cell biology studies [7] and genetic-engi-
neering approaches, the latter furthered by the detection of
highly efficient gene targeting via homologous recombina-
Introduction tion in P. patens [8]. Homology-directed repair is a means of
Mosses are an inconspicuous group of plants, which are DNA repair frequent in mosses compared to other plants
perceived by people in extremely different fashions: and all other higher eukaryotes, but it is enhanced in the G2
While being an indispensable element of Japanese gar- phase of the cell cycle in vertebrates [9]. The G2 phase,
dens, they are combatted in Western-European lawns, however, is the dominant cell-cycle phase within Physcomi-
but due to their small size, are neglected by most. Mosses, trella protonema (the simple juvenile moss tissue which
however, which belong to the evolutionary oldest land- develops from a germinated spore and has filamentous or
plant group, the bryophytes, developed lifestyles and sometimes thalloid morphology) [10]. Recently, members
strategies making them attractive for biotechnological of the RecQ helicase family were found to antagonistically
exploitation. While vascular plants resist desiccation by influence gene targeting in P. patens [11].
having protective layers of structural biopolymers (cutin,
suberin and lignin) and in parallel allow gas exchange via These features, together with an easy cultivation under
stomata, mosses are dependent on wet environments for axenic conditions in various types of devices, including
www.sciencedirect.com Current Opinion in Biotechnology 2020, 61:21–27
22 Plant biotechnology
photobioreactors, also promoted the genetic characterisa- Figure 1
tion by transcriptomics [12,13,14,15] and genome
sequencing of initially P. patens [16,17], but also the (a) (b)
liverwort Marchantia polymorpha [18] and peat moss
(Sphagnum) species [19]. Sequencing of Physcomitrella
was executed by the U.S. Department of Energy Joint
Genome Institute (JGI) as one of seven Plant flagship
genomes because of its genetic amenability, the simple
morphology, which allows cell biology and developmen-
tal studies and its evolutionary position at the base of land
plant evolution (https://jgi.doe.gov/why-sequence-
physcomitrella-patens/). This extremely good genetic
characterisation also largely facilitated biotechnological
engineering approaches, for example the successful use of
Physcomitrella as a bioreactor for metabolite and especially
biopharmaceutical production [20]. In the following, we
will summarise the recent strategies for moss biotechno-
logical approaches. (c)
Metabolites from mosses
The traditional medicinal use of mosses may be based on
a multitude of genes, which can be connected to special-
ised metabolism [5,12]. Consequently, earlier approaches
aimed at identifying interesting moss metabolites and
deducing the encoding genes to increase the nutritional
value of crop plants via genetic engineering [21,22]. Of
special importance are the high contents of polyunsatu-
rated and very long-chain fatty acids in several moss
species [23].
A very recent use of a biotechnologically produced aque-
(d)
ous cell extract from the moss P. patens led to the
development of the first moss-based active cosmetic
ingredient MossCellTecTM No. 1 by Mibelle Biochem-
istry. The extract, generated from a wave-bag photobior-
eactor protonema culture (Figure 1), demonstrated a
protective effect on a 3D human reconstituted skin model
under climatic stress conditions [24]. It improved the
expression of nuclear envelope and transport genes in
epidermal keratinocyte cells derived from an older donor,
thus leading to the cosmetics concept of cell nuclear
health [25].
Current Opinion in Biotechnology
In addition, Physcomitrella demonstrated its feasibility for
Cultivation of Physcomitrella patens for biotechnological processes.
metabolic engineering, that is, as a production host for
(a) The filamentous juvenile tissue, protonema, allows standardised
commercially valuable metabolites, among those diter- cultivation conditions (scalebar 50 mm). (b) Stirred tank
penoids as taxadiene and sesquiterpenoids like the fra- photobioreactor for small-scale production. (c) GMP-production
grance patchoulol or the anti-malaria drug artemisinin facility. (d) 100 L wave-bag photobioreactor for industrial applications.
[20,26,27]. From the fragrance-producing mosses [27], Photographs credit to Nelly Horst (a), Melanie Heck (b), (c + d) taken
from Ref. [38] with permission.
the product Fragrant Moss was developed as natural air
freshener, and launched by Mosspiration Biotech in Jan-
uary 2019 (https://www.mosspirationbiotech.com/
fragrant-moss/). A Physcomitrella line lacking endogenous
diterpenoids due to targeted knockout of the single relevant diterpene biomaterials [29]. As metabolite for-
existing bifunctional diterpene synthase gene [28] was mation often employs multigenic biosynthesis pathways,
used to produce three different diterpenes from flowering the establishment of an efficient protocol for in planta
plants, suggesting moss as production host for industrially self-assembly of several linear DNA building blocks via
Current Opinion in Biotechnology 2020, 61:21–27 www.sciencedirect.comMosses in biotechnology Decker and Reski 23
homologous recombination [30] may further promote the the human complement system, an important part of the
industrial use of Physcomitrella as an engineering platform. so-called innate immunity [39,40,45,46]. Factor H is
the main regulator of the alternative pathway of comple-
Moss-based biopharmaceuticals ment activation and mutations affecting FH could lead to
As high-value pharmaceutical products, recombinant severe kidney and eye diseases, among those the atypical
pharmaceutical proteins display an increasing sector haemolytic uremic syndrome (aHUS) and C3 glomeru-
within the pharmaceutical market [31]. In contrast, there lopathies (C3G) as well as age-related macular degenera-
is still only one plant-made pharmaceutical which has tion (AMD), the main cause for loss of central vision in the
received market release. Elelyso, a b-glucocerebrosidase elder population. In pre-clinical studies moss-FH
developed by Protalix and marketed by Pfizer as an reduced disease indicators in a FH-deficient mouse
enzyme-replacement therapy for Morbus Gaucher is pro- model bearing C3G symptoms, thereby suggesting itself
duced in carrot cell cultures and was released by the FDA as the first physiologic therapeutic for patients suffering
in 2012. More recently, ZMapp from Nicotiana benthami- from complement-related disorders [39]. MFHR1 is a
ana-based production was administered to patients synthetic protein comprising domains of FH and the
infected with the Ebola virus during the Ebola epidemic related protein FH-related 1 thus being able to target
in West Africa in 2014 [32]. The first plant-derived dysfunctions on all levels of complement activation [40].
vaccine, haemagglultinin virus-like particles against influ- Current treatment of FH-related complement disorders
enza, which was developed by Medicago Inc., reached are by plasmapheresis or the monoclonal antibody Ecu-
phase 3 clinical trials [33]. lizumab, currently the most expensive biopharmaceutical
protein product, which, however, is only partially effec-
In addition to these plant-based systems P. patens has tive for esp. C3G patients [47]. Thus, the moss-FH
proven itself as a host to be reckoned with for plant-derived related products may become well tolerated, cost-effi-
biopharmaceutical production. The excellent genetic ame- cient complement therapeutics [39,40].
nability helped to prevent the attachment of plant-specific
O-linked glycans to proteins of interest [34] as well as to Moss for biomimetics
humanise the Physcomitrella protein N-glycosylation pat- Recently, mosses from the Funariaceae family (P. patens and
tern via precise gene targeting [35,36]. The host-cell pro- related species) have been employed in inspiring architec-
teome in the medium, to which products are secreted, is tural design or the development of new biomaterials from
identified, and standardised photobioreactor cultivation moss research. In an interdisciplinary collaboration of archi-
processes with a scale up to 500 L are developed [37,38] tects and biologists the genomic relationships of different
(Figure 1). These factors triggered the synthesis of several mosses will be computed to derive algorithms for evolution-
recombinant glycoproteins in this system [38,39,40]. ary processes that could be applied for exploratory (architec-
The first product, Greenovation’s moss-aGal, successfully tural) design approaches [48]. A second collaborative initia-
passed clinical phase I at the end of 2017 [41]. This enzyme tive aimed at analysing structural and functional features of
is being considered as an enzyme replacement therapy FtsZ networks, which display polymeric structures within
(ERT) for patients suffering from deficient or defective chloroplasts which form the plastoskeleton in Physcomitrella
a-galactosidase A resulting in the lysosomal storage disease [49,50]. 3D confocal laser scanning microscopy was used for
Morbus Fabry. A single dose of moss-aGal was tolerated by the acquisition of the networks built by different fluores-
the patients without any severe side effects and decreased cence-labelled FtsZ isoforms. From these a computational
the levels of the substrate globotriaosylceramide (Gb3) framework was developed to classify the different protein
even after 28 days [42]. network structures. With the help of machine learning,
features could be extracted that allowed a classification to
The parental line used to produce the glycoprotein moss- distinguish between two FtsZ isoforms [49,51]. By linking
aGal [43] was a line in which posttranslational Asparagine network structure and dynamics with functionality, the
(Asn, N)-linked protein glycosylation had been engi- design of protein-engineered biomaterials for regenerative
neered to be free of plant-specific sugar residues. This medicine is a vision for future applications [52].
was accomplished by targeted knockout of a b1,2-xylo-
syltransferase (XT) and an a1,3-fucosyltransferase (FT) Biomonitoring and Sphagnum farming
gene [44] to avoid any adverse side effects during For several years, various moss species have been used for
patients’ treatments. biomonitoring approaches to measure air quality. Mosses
are particularly suitable as they take up elements and
While alternative products are available on the market to nutrients via their surface directly from atmospheric
fight Fabry disease, the glyco-engineered Dxt/ft line was deposition thus reflecting the chemical composition of
also the basis for the production of two completely new their environment [53]. Among four frequently used moss
pharmaceuticals, moss-derived human factor H (moss- genera the genus Sphagnum was suggested for superior
FH) and the synthetic FH-related multitarget protein uptake of heavy metal ions [53]. Biomonitoring is per-
MFHR1. Both proteins may have regulatory functions in formed with the so-called moss-bag technique, the
www.sciencedirect.com Current Opinion in Biotechnology 2020, 61:21–2724 Plant biotechnology
exposition of moss material in inert mesh bags at different Figure 2
sites of interest [54]. To provide standardised and com-
parable raw material for the measurements, however, (a) (c)
transplants from the environment are not suitable and
in the case of Sphagnum, peat mosses, were unacceptable
due to their environmental protection, for example by the
European Council Habitats Directive (92/43/EEC). A
breakthrough towards standardisation and high biomass
increase was the development of an axenic in vitro-culti-
vation process in 5 L and 12 L-tank photobioreactors [55] (b)
(Figure 2). Biomass increased around 30-fold within
4 weeks of bioreactor cultivation of the clonal gameto- (d)
phore material. Process parameters included were
mechanical stress, inoculum density, medium compounds
and pH [55]. This material was used to monitor atmo-
spheric metal pollutants in lab experiments [56] and for
the first time, the uptake of polystyrene nanoparticles was
demonstrated, offering the possibility for monitoring
microplastics in fresh water environments with the
biotechnologically produced peat moss [57]. In a compar-
(e)
ative field trial, covering different environmental areas of
Italy and Spain, bioreactor-produced S. palustre was
superior to native Pseudoscleropodium purum in terms of
metal uptake and accumulation [58]. These studies were
performed with the ‘mossphere’, a passive contaminant-
sampling device superior to former techniques and
invented by the EU-funded MOSSclone consortium
(www.mossclone.eu) [59]. This device contains devita-
lised moss within the space of a hollow inner and outer
sphere from perforated nylon and plastic material, assur-
ing free air passage and homogenous distribution of the
moss. The further improvement of vegetative Sphagnum
proliferation for biotechnological use or physiologic and
Current Opinion in Biotechnology
cellular interventions might be facilitated by a recently
developed method of Sphagnum protonema growth [60].
Use of peat moss, Sphagnum, for environmental applications. (a)
Young Sphagnum palustre clone with protonema and early
In addition to monitoring environmental pollution, peat gametophores (i.e. the adult tissue; scalebar 1 mm). (b)
mosses contribute to a large extent to global climate. Photobioreactor with the Sphagnum clone. 25 40 cm patch of in
Peatlands, comprising fossil peat mosses, display a tre- vitro grown material at the setup (c) and after 14 months of growth (d)
mendously important carbon storage. Covering only 0.5% in Germany (Rastede). (e) Large-scale Sphagnum farming site (in
of the overall land surface, their drainage by harvest of Rastede) with excavator for harvest in the background. Photographs
credit to Melanie Heck (b), Anja Prager (c), Greta Gaudig (d + e).
peat for the horticultural industry or for their use as, for
example farmland or grassland, contributes with 32% to
the global cropland greenhouse gas (GHG) emissions
[61,62]. ‘Sphagnum farming’ – the production of Sphag- Federal Ministry of Nutrition and Agriculture in 2017
num biomass on rewetted peatlands – will help to halt (https://www.moorwissen.de/en/paludikultur/projekte/
GHG emissions from drained peatlands, thus meeting torfmooskultivierung/mooszucht.php).
urgent political objectives to reduce CO2 emissions.
Additionally, Sphagnum farming is meant to provide a Conclusions
sustainable source for peat moss-biomass as an effective These small plants, mosses, have made their way from
replacement of peat, which still displays the best-quality use in traditional medicine to a manifold of uses today:
potting soil growth medium by far [61]. While Sphagnum is They please consumer affections with a genetically engi-
propagating slowly under natural conditions, the axenic neered fragrant moss and the first bioactive ingredient
large-scale production in photobioreactors will speed up from a moss for the cosmetic industry on the market.
the production of starting material drastically (Figure 2). They also provide opportunities for treating severe
Setting up large-scale production processes is one of the human diseases and the first moss-made drug candidate
aims of the MOOSzucht initiative funded by the German successfully passed clinical trial phase I. Peat-moss
Current Opinion in Biotechnology 2020, 61:21–27 www.sciencedirect.comMosses in biotechnology Decker and Reski 25
farming will help to halt greenhouse gas emissions, 11. Wiedemann G, van Gessel N, Köchl F, Hunn L, Schulze K,
Maloukh L, Nogué F, Decker EL, Hartung F, Reski R: RecQ
thus tackling tremendous ecological problems. Mosses helicases function in development, DNA repair, and gene
deserve our attention. targeting in Physcomitrella patens. Plant Cell 2018, 30:717-736.
This paper resolves the different roles of two moss RecQ helicases for
DNA repair and gene targeting and identifies a molecular enhancer of
gene targeting with possible biotechnological applications.
Conflict of interest statement
12. Rensing SA, Ick J, Fawcett JA, Lang D, Zimmer A, Van de Peer Y,
The authors are inventors of patents and patent applica- Reski R: An ancient genome duplication contributed to the
tions related to topics described here. RR is an inventor of abundance of metabolic genes in the moss Physcomitrella
patens. BMC Evol Biol 2007, 7:130.
the moss bioreactor and a founder of Greenovation Bio-
tech. He currently serves as advisory board member of 13. Hiss M, Laule O, Meskauskiene RM, Arif MA, Decker EL, Erxleben A,
Frank W, Hanke ST, Lang D, Martin A et al.: Large-scale gene
this company. expression profiling data for the model moss Physcomitrella
patens aid understanding of developmental progression,
culture and stress conditions. Plant J 2014, 79:530-539.
Acknowledgements 14. Ortiz-Ramı́rez C, Hernandez-Coronado M, Thamm A, Catarino B,
We acknowledge current funding by the German Research Foundation Wang M, Dolan L, Feijó JA, Becker JD: A transcriptome atlas of
(DFG) under Germany’s Excellence Strategy (CIBSS – EXC-2189 and Physcomitrella patens provides insights into the evolution and
livMatS – EXC-2193/1 – 2100247729), the German Federal Ministry of development of land plants. Mol Plant 2016, 9:205-220.
Food and Agriculture (BMEL22007216), and by the Marie Curie Actions of In this study, a transcriptome atlas of Physcomitrella was generated with
the European Union’s Horizon 2020 (Grant agreement no. expression data of most moss tissues. The integration of these data in the
765115 MossTech). We are indebted to Anne Katrin Prowse for proof- eFP browser at the portal BAR, the Bio-Analytic Resource for Plant
reading of the manuscript. Biology, provides an indispensable handy tool for all scientists interested
in functional genomics of Physcomitrella.
15. Perroud P-F, Haas FB, Hiss M, Ullrich KK, Alboresi A,
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