Advances in Fungal Biotechnology for Industry, Agriculture, and Medicine

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Importantly, linking research findings to the respective genomes through public databases inevitably increases the impact of individual studies, the genomes and associated datasets. Most importantly, European researchers, funding agencies and policymakers should seriously consider the way fungal genomics data should be organized and the European role in this. Currently, infrastructure for fungal genomics is strongly dependent on US and UK initiatives and very few European funded initiatives contribute to a well-organized infrastructure to host and analyze fungal genomes, transcriptomes and proteomes.

Should access to the US infrastructures become limited for non-US scientists or US investment in databases significantly reduced, as recently seen for AspGD and the Broad Institute resources, this will create serious problems for European fungal research. Omics data is very cost effective but its utility is largely dependent on making the data accessible and usable by the wider research community. Without suitable investment in appropriate resources and structures much of the potential value of such data is lost and the investment in the original studies squandered.

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However, it must be acknowledged that the budding yeast is, for many aspects, too specialized and limited to play the same lighthouse role in the future. To put just a few examples, the genomic duplication that took place in the Saccharomycotina line [ 63 ] resulted in a notable degree of gene redundancy, which often complicates functional analyses. Moreover, even with the genome duplication notwithstanding, the budding yeast genome codes for half the number of genes of filamentous ascomycetes. Accurate annotation of filamentous fungal genomes had to overcome the difficulties imposed by the abundant introns, a problem that was not encountered by our budding yeast colleagues.

Budding yeast and its ancestors have lost RNA interference mediated transposon resistance and exhibit a high internal reverse transcriptase activity combined with an efficient homologous recombination system which is presumed to account for the unusually low number of introns [ 64 ]. The S. In terms of basic cell organization, laboratory strains of budding yeast have usually lost the natural ability to grow as filaments, which is restricted to pseudohyphal growth [ 65 ].

Remarkably, budding yeast uses microtubules MT solely for mitosis and nuclear positioning, whereas the organization of filamentous fungal hyphae largely relies on MT dependent transport, such that MT-dependent processes strongly affect growth, including invasiveness and pathogenicity, as well as secondary metabolite and enzyme production. From the organismal point of view, filamentous fungi undergo developmental processes, shaping the sexual and asexual reproductive structures that have no parallel in the budding yeast.

As development appears to be intimately connected to secondary metabolism [ 66 ] and, undoubtedly, to fungal pathogenicity - there is no infection without efficient propagation. For these and many other reasons we need to turn our gaze to organisms other than S. Indeed the mechanistic details may be slightly different in the different instances i.

This problem-focused approach might enable a more holistic understanding of the fungal kingdom. A frequently encountered problem common to all species is the need for better tools for gene inactivation. Studies with knockout alleles, albeit useful to take a quick glance at the function of a given gene, is restricted to those genes that are not essential or nearly so a score of knockout alleles debilitate growth to an extent that although not strictly leading to lethality preclude any further study.

Null mutations only provide clear mechanistic insights, when e. Here, conditional expression systems are limited by the fact that the turnover of the protein whose function is inactivated might be unbearably long. Thus, there is an urgent need of tools that permit the acute inactivation of gene expression.

One problem is that these mutations are available largely in those organisms that have been traditionally used for classical genetic studies, such as N. A second is that temperature-sensitive growth does not necessarily reflect the complete inactivation of an otherwise essential protein at the restrictive temperature, but in many cases, a stronger requirement for the function of the said protein at elevated stress-causing temperatures, under which a hypomorphic allele will not sustain growth.

Thus there is a very strong need for better genetic switches, such as those based on conditional degrons inspired in tools developed for the budding yeast [ 69 ]. For example, the identification of causative mutations by genomic mapping is largely facilitated by previously knowing the localization of the mutation in a genetic map [ 71 , 72 ]. Also transformation is mutagenic and it should be a rule of thumb to demonstrate that the phenotype of a recombinant allele segregates in a Mendelian fashion, as otherwise the phenotype might reflect a synthetic effect of more than one mutation i.

Finally, many important fungal characteristics will be polygenic and their understanding will require experimental systems permitting those mutant versions of many genes are combinable with relative ease by meiotic recombination. Fungi are efficient enzyme producers but their relative inability to make heterologous proteins limits their usefulness. A key issue is that our understanding of the different pathways of exocytosis is very limited, and actually we do not even know how many ways a cargo has to reach the extracellular milieu.

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A major standing bottleneck is the detailed understanding of these pathways and their regulatory circuitry to allow their tailored genetic manipulation. For example, the final steps of penicillin biosynthesis take place in the peroxisomes, such that these organelles have a profound influence on antibiotic titers [ 74 ]. Lastly, hyphal growth is strictly dependent on exocytosis, and thus essential fungal-specific aspects of intracellular traffic would be druggable for antifungal intervention.

A key issue is that with the notable exception of the unfolded protein response [ 75 ], intracellular traffic is mainly regulated at post-transcriptional levels by small GTPases, lipids and their respective effectors [ 76 ]. Several technological developments will be helpful to gain further insight. In vivo imaging: Studies with fungal cells growing on the microscopy stage using movies with high time resolution.

On the cell side these studies will require brighter fluorescent markers, ideally fully functional fluorescent fusion proteins expressed at physiological levels and, from the hardware side, equipment permitting 5-way multidimensional acquisition x, y, z, time, multiple channels of images.

Besides suitable microscopy hardware these studies will demand expert know-how on the techniques to image cells without perturbing the process that is being observed. Moreover, improving the time resolution of time-lapse sequences implies progressively larger files that demand specialized software, dedicated high-capacity digital storage resources and powerful computer workstations, a triple combination that will be only available in highly specialized central facilities. Lastly, the future of these microscopy studies undoubtedly passes through systems biology, and our capacity to perform automated image analysis, to statistically interpret large amounts of data and to match them to mathematical models.

Biochemistry combined with shotgun proteomics: Intracellular compartments are transient entities, and thus difficult to define unless their composition is very precisely determined. We need better subcellular fractionation procedures to obtain homogeneous populations of organelles and connecting carriers, possibly aided by appropriate genetic blocks. The composition of these organelle fractions needs to be elucidated by shotgun proteomics and by lipidomics a technology that is not generally available.

Improving the quality of peptide reference databases is essential to obtaining more reliable proteomics data. This objective should be a major target of genome information repositories. Electron microscopy: The subcellular organization of filamentous fungi will not be understood without exploiting the recent developments in this field. Whenever used by technically competent laboratories tomography studies have yielded significant insights see for example [ 78 ]. Further EM studies should undoubtedly involve the largely unexploited capabilities of immune-EM for example see [ 79 ] and correlative EM-light microscopy [ 80 ].

On the one hand, single-cell analytics will offer tremendous opportunities to study population heterogeneity at both the biological level stochastic variations, molecular noise, regulatory effects and environmental level inhomogeneity, fluctuations and gradients in natural habitats and bioreactors. Microfluidic single-cell cultivation devices equipped with time lapse imaging for high-throughput omics analyses are available for academic groups studying unicellular microorganisms [ 81 ] but not yet for filamentous fungal systems. There is thus a need for input from these research communities combined to make these technologies widely applicable for filamentous fungi [ 82 ].

Another technology frequently employed with unicellular microorganisms but that is underdeveloped for filamentous fungi is flow cytometry. This technique in combination with cell sorting is very powerful for high-throughput screenings, for example. Some preliminary approaches have already been published using large-particle flow cytometry [ 83 , 84 ]; however, further developments are clearly necessary. A third potentially important technological development has been the application and refinement of single-use bioreactors, such as wave-mixed bioreactors, for the medium-scale production of high-value products up to 2.

These offer many opportunities for filamentous fungi as cell factories in pharmaceutical and cosmetics industries. Not only is this platform technology safer decreased risk of microbial contamination and cross-contamination , greener reduced requirements for cleaning and sterilization , faster and more flexible easy process and product change , cheaper saving of time and costs and smaller reduced facility footprint [ 85 ], it offers better oxygen transfer rates, more homogeneous energy dissipation and comparable or better growth of filamentous fungi when compared to their cultivation classical stirred tank reactors [ 85 , 86 ].

Of special interest for small-scale controlled solid state fungal co- cultivations max. They provide a low shear environment, do not need the addition of antifoam agents and give similar or better results than in stirred reusable bioreactors as shown for A. There is a shortage of skilled researchers with multidisciplinary expertise in fungal molecular biology and biotechnology. The participants agreed that advanced research on fungal biology and biotechnology requires a multi-scale view—i.

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Moreover, transfer of in silico and experimental skills between the complimentary areas of medical mycology, plant pathology, and industrial microbiology are severely limited. Hence, training of multidisciplinary scientists with strong background in all fields will create an unparalleled environment for future developments such as antifungal drug discovery and new technological applications of filamentous fungi.

In addition, industrial partners of EUROFUNG identified that there is a lack of staff within the biotechnology industry with expertise in fungal systems—consequently bacterial and yeast systems tend to be the default, when fungal systems may be the rational choice. This underlines the need for better training, particularly at the postgraduate levels and improved mechanism to promote knowledge transfer if we are to realise the potential that fungal biology offers. These are trained bioinformaticians e. This would increase lab bioinformatics capacity and enable the exploitation of growing in silico resources.

Finally, there is a barrier for knowledge exchange between industry and academia. Companies have become repositories of key knowledge and innovative technologies needed for education and research but the dissemination of this knowledge is limited due to the lack of coordinated training between the two sectors. Likewise, much academic research does not reach relevant industrial research and business development activities. Hence, future multidisciplinary training programs should involve cross-sectoral elements to enable the new generation of fungal scientists and biotechnologists to understand the wider and economical potential of their work.

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Significantly improved scientific understanding and better translation of knowledge to underpin innovation is required to improve filamentous fungal based cell factories and to better control pathogenic fungi. Crucial for this are continuous efforts for high-quality annotation and curation of fungal genomes, with continuous financial support to make omics data and resources publicly available and comparable. Furthermore, a sophisticated synthetic biology tool box tailored to a range of filamentous fungal species needs to be developed to overcome our limited flexibility to genetically modify and optimize them.

Learning from work with well-chosen reference organisms, integrating systems-level functional studies of pathogen and industrial organism biology will facilitate the development of new products, biosynthetic systems and new anti-fungal drug discovery programmes. The fungal biotechnology revolution is happening—the more young academics become trained and interested in multidisciplinary fungal research the better! With their passion and enthusiasm the huge potential of filamentous fungal systems will be faster and better exploited, which will help society to address key challenges of the twenty-first century.

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Advances in Fungal Biotechnology for Industry, Agriculture, and Medicine

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    VM hosted the Eurofung meeting and conceived of the manuscript. VM and RMH compiled the various sections. All authors read and approved the final manuscript. Correspondence to Vera Meyer. Reprints and Permissions. Search all BMC articles Search. Commentary Open Access Published: 31 August Current challenges of research on filamentous fungi in relation to human welfare and a sustainable bio-economy: a white paper Vera Meyer 1 , Mikael R. Andersen 2 , Axel A. Brakhage 3 , 4 , Gerhard H. Braus 5 , Mark X. Caddick 6 , Timothy C. Cairns 1 , Ronald P. Mortensen 2 , Miguel A.

    Background The knowledge-based bio-economy is critical for European growth and development and has been prioritized by the EC as a key area that will underpin long term sustainable growth [ 1 ]. Key challenges to exploit and fight filamentous fungi The Think Tank identified several key barriers which limit optimum exploitation of filamentous fungi and hamper our ability to design new and sustainable antifungal strategies. The barriers fall into three categories: i Science: The limited range of molecular and synthetic biology tools and high-throughput technologies tailored to filamentous fungi delays research, product development and the identification of antifungal targets, limits flexibility in engineering the required combinations of genome modifications and appropriately regulated transgenes.

    To achieve this, the following key questions and challenges need to be answered: 1. How can synthetic biology contribute to the design of optimised fungal genomes? Citations Publications citing this paper. Scopulariopsis sp. Tracking the cellulolytic activity of Clostridium thermocellum biofilms Alexandru Dumitrache , Gideon M. A non-fluidic, fluorometric assay for the detection of fungi on cultural heritage materials Nick R.

    Fluorometric detection and estimation of fungal biomass on cultural heritage materials. Nick R. Konkol , Christopher J. McNamara , Ralph I. References Publications referenced by this paper. Lasure, Advances in fungal biotechnology for industry, agriculture and medicine. Magnuson , L. admin