CBMNet scientists identify key step in production of Body Odour

CBMNet-funded scientists from the Universities of York and Oxford, along with industrial partner Unilever, have unravelled a key part of the molecular process by which armpit bacteria produce the most pungent component of the noxious smell we recognise as BO. The findings could result in more effective deodorants with targeted active ingredients, the researchers suggest.

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CBMNet awarded ISCF Industrial Biotechnology Catalyst Early Stage Feasibility Projects

CBMNet awarded ISCF Industrial Biotechnology Catalyst Early Stage Feasibility Projects

We are pleased to confirm that UK Research and Innovation (UKRI), the Biotechnology and Biological Science Research Council (BBSRC)  has agreed to provide a grant of £233,222 to the CBMNet to support Industrial Biotechnology Catalyst: Early Stage Feasibility Projects, provided through Wave 1 of the Industrial Strategy Challenge Fund (ISCF). Read more

Converting Escherichia coli into an archaebacterium with a hybrid heterochiral membrane

Converting Escherichia coli into an archaebacterium with a hybrid heterochiral membrane

Antonella CaforioMelvin F. SiliakusMarten ExterkateSamta JainVarsha R. JumdeRuben L. H. AndringaServé W. M. KengenAdriaan J. MinnaardArnold J. M. Driessen and John van der Oost

Significance

Escherichia coli has been engineered toward an archaebacterium with an unprecedented high level of archaeal ether phospholipids. The obtained cells stably maintain a mixed heterochiral membrane. This finding challenges theories that assume that intrinsic instability of mixed membranes led to the “lipid divide” and the subsequent differentiation of bacteria and archaea. Furthermore, this study paves the way for future membrane engineering of industrial production organisms with improved robustness.

Abstract

One of the main differences between bacteria and archaea concerns their membrane composition. Whereas bacterial membranes are made up of glycerol-3-phosphate ester lipids, archaeal membranes are composed of glycerol-1-phosphate ether lipids. Here, we report the construction of a stable hybrid heterochiral membrane through lipid engineering of the bacterium Escherichia coli. By boosting isoprenoid biosynthesis and heterologous expression of archaeal ether lipid biosynthesis genes, we obtained a viable E. coli strain of which the membranes contain archaeal lipids with the expected stereochemistry. It has been found that the archaeal lipid biosynthesis enzymes are relatively promiscuous with respect to their glycerol phosphate backbone and that E. coli has the unexpected potential to generate glycerol-1-phosphate. The unprecedented level of 20–30% archaeal lipids in a bacterial cell has allowed for analyzing the effect on the mixed-membrane cell’s phenotype. Interestingly, growth rates are unchanged, whereas the robustness of cells with a hybrid heterochiral membrane appeared slightly increased. The implications of these findings for evolutionary scenarios are discussed.

CBMNet and IBCarb awarded BBSRC International Workshop Award

CBMNet and IBCarb awarded BBSRC International Workshop Award

BBSRC has identified industrial biotechnology and bioenergy as high-level priority areas in its Delivery Plan for 2016-2020. Supporting the BBSRC to achieve its strategic goals, this focussed workshop will identify the science and technological barriers that need to be addressed in order to harness the potential of plant ‘cell factories’ for producing biopharmaceuticals. A CBMNet-driven symposium (Manchester, September 2017) brought together key players from Canada, the EU and the UK, to discuss scientific and commercial opportunities and challenges in this space. The goal now is to regroup, with a more focussed set of individuals, to refine the landscape and to identify opportunities for collaborative R&D projects involving academia and industry in the UK and Canada. These aims are synergistic with those of CBMNet and IBCarb in the UK, and with the Canadian Glycomics Network, GlycoNet.


Organisms produce glycosylated proteins for multiple purposes (e.g. stabilizing protein structure; interacting with receptors; self-recognition; etc.). There is a significant body of work on mammalian and yeast cells – both to understand the mechanisms of glycosylation and to manipulate it to synthesize desired glycoforms (including biopharmaceutical applications). Although plants are increasingly being used as a platform for commercial manufacturing of proteins, our knowledge of the glycosylation systems of plants is incomplete. For example, the secretory pathway (the location where glycosylation takes place) and consequences of manipulation thereof are poorly investigated. However, the understanding of basic mechanisms is of utmost importance, because it has a significant impact on the expression level (yield) and quality of a glycoprotein product.

An introductory workshop driven by CBMNet was attended by 22 participants from the UK, Canada and the EU. Expertise spanned cell membrane biology, cell membrane transporters, yeast and bacterial glycosylation, glycobiology, protein secretion, structure/function of a set of nucleotide sugar transporters, glycomics, plant biotechnology, and in vitro remodelling of glycans on therapeutic proteins, enabled a focus on sharing knowledge and gaining a deeper understanding of the native plant glycosylation machinery and the manipulation thereof for the production of proteins with optimized functions. The workshop identified the differences and common features in different species (i.e. mammalian, yeast, bacterial), as a basis to better understand and control protein glycosylation in plants. Identifying potential bottlenecks in the transport of a proteins through the secretory pathway was also considered.

The goal now, through a slimmed-down working group, is to define potential ways forward that will overcome yield- and quality-restricting bottlenecks in plant glycoprotein production processes. This will require the development fundamental understanding, coupled with the generation and deployment of tools to manipulate pathways and processes.

Translation Stress Positively Regulates MscL-Dependent Excretion of Cytoplasmic Proteins

Translation Stress Positively Regulates MscL-Dependent Excretion of Cytoplasmic Proteins

ABSTRACT

The apparent mislocalization or excretion of cytoplasmic proteins is a commonly observed phenomenon in both bacteria and eukaryotes. However, reports on the mechanistic basis and the cellular function of this so-called “nonclassical protein secretion” are limited. Here we report that protein overexpression in recombinant cells and antibiotic-induced translation stress in wild-type Escherichia coli cells both lead to excretion of cytoplasmic protein (ECP). Condition-specific metabolomic and proteomic analyses, combined with genetic knockouts, indicate a role for both the large mechanosensitive channel (MscL) and the alternative ribosome rescue factor A (ArfA) in ECP. Collectively, the findings indicate that MscL-dependent protein excretion is positively regulated in response to both osmotic stress and arfA-mediated translational stress.

IMPORTANCE

Protein translocation is an essential feature of cellular organisms. Bacteria, like all single-cell organisms, interact with their environment by translocation of proteins across their cell membranes via dedicated secretion pathways. Proteins destined for secretion are directed toward the secretion pathways by the presence of specific signal peptides. This study demonstrates that under conditions of both osmotic stress and translation stress, E. coli cells undergo an excretion phenomenon whereby signal peptide-less proteins are translocated across both the inner and outer cell membranes into the extracellular environment. Confirming the presence of alternative translocation/excretion pathways and understanding their function and regulation are thus important for fundamental microbiology and biotechnology.

Read the full paper here.

€2.4M European ERA CoBioTech Project Success for CBMNet

€2.4M European ERA CoBioTech Project Success for CBMNet

 

We are proud to announce that a CBMNet led proposal to the First transnational Call for research projects within the framework of the ERA-NET Cofund on Biotechnologies (ERA CoBioTech) “Biotechnology for a Sustainable Bioeconomy”, has been successful.

Developed through CBMNet and led by CBMNet Management Board member Dr Alan Goddard, with CBMNet Co-Director Professor Gavin Thomas, as Co-investigator, ‘MEmbrane Modulation for BiopRocess enhANcEment’ (MEMBRANE), will deliver bespoke robust industrially-viable cell factory strains, engineered to overcome current bioprocess and production bottlenecks, accelerating the commercialisation of two significant industrial bioprocesses. Implementation of this project will significantly reduce production costs and environmental impact for two companies, increasing product sustainability.



“We are delighted with this EU funding, both as further recognition of CBMNet-led proposals bearing fruit, but also that the EU can recognise that there is much under-explored biology around the microbial cell membranes that could be exploited in industrial biotechnology and bioenergy” – Professor Gavin Thomas, CBMNet Co-Director, University of York


This 36-month project sees five leading research institutes (Aston University, University of York, Forschungszentrum Jülich, IATA-CSIC and Groningen) and two large industry partners (Lallemand and Pakmaya), across five countries, collaborate, and validate at pilot scale, engineered robust cell factories (yeast and Propionibacterium) that overcome existing toxicity challenges, improve efficiency and allow their effective commercialisation. The strategies developed within this project will be applicable across the sector to facilitate rational strain engineering with far-reaching benefits.

Our multinational multidisciplinary team are all CBMNet members and combines skills in lipidomics, proteomics, transcriptomics, biophysics, MD simulations, strain engineering, high throughput screening and commercial process and product development. The collaborative, integrated and iterative approach maximises impact; it would be impossible for any one partner to conduct this project alone and success is contingent upon the expertise of all partners.


“CBMNet was my first exposure to Industrial Biotechnology and I feel that I have had tremendous support from the network since its inception, both in terms of people I have met, networking events and conferences, and funding opportunities available.  The underpinning ideas for our successful ERA CoBioTech proposal emerged from a number of CBMNet-funded projects and fruitful conversations with both academics and industrial partners.  The consortium was built through CBMNet, utilising existing connections and also by leveraging the EU-wide reach of CBMNet to recruit relevant academic and industrial partners to work on a project of mutual interest.  CBMNet has been incredibly supportive throughout the process” –  Dr Alan Goddard, Aston University


The global economy has an unsustainable dependence on fossil raw material with demand for raw material inputs to industry growing steadily. Concerns about environmental sustainability are becoming more acute; thus, alternatives to traditional, fossil-fuel based chemical production are urgently required. Cell factories, which use microorganisms to produce materials from renewable biomass, are an attractive alternative, and an increasing number of platform chemicals are being produced at industrial scale using engineered microorganisms. These are expected to have a transformative impact in industrial biotechnology, but, first, we must meet the challenges of designing and optimizing high-yield cell factory strains that can produce commercially viable amounts of product. One reason for poor product output is that the production conditions are ultimately toxic to the producing cells. In addition to damage to intracellular components such as enzymes, the lipid cell membrane and associated proteins are vulnerable to biomolecules e.g. ethanol and propionate, as well as to physical parameters during production such as osmotic stress, pH, and temperature. An approach whereby membranes can be “tuned”, in terms of their lipid and protein content, to become more resistant to stresses brought about by toxicity would revolutionise the field. Additionally, expression of efficient membrane transporters to export ‘toxic’ products can mitigate intracellular damage. These approaches will ultimately enable production of higher concentrations of the desired molecules or cells making the bioprocesses more efficient, increasing product yield, reducing cost, and help to drive the move away from fossil-based raw materials. An adoption of such “green” processes and avoidance of depletion of non-renewable carbon sources will bring huge social and environmental benefits. Products and processes which  are currently economically unviable due to toxicity can be rendered profitable by even small increases in the resistance of strains and concomitant yield increases.

The project is divided into seven interconnected, iterative work packages (WPs) with a well-established build-test-analyse approach. Initial analysis of –omics data will identify key alterations in membrane protein and lipid content of both microbes subjected to stresses associated with bioproduction and those strains known to be somewhat resistant to such stresses (WP1). In vitro and in silico approaches will be used to rapidly delineate the roles of these alterations and rationally design more resistant membranes (WP2). Using synthetic biology and strain evolution approaches, we will alter the membrane composition of microbes to reflect the “optimal” membranes determined in WP2 (WP3). Optimal strains will be identified in a high throughput manner and subjected to large-scale testing to ensure that the changes made translate to the industrial setting (WP4). Following this, another iteration of the cycle will further optimise the strains. WP5 will evaluate the environmental and social sustainability of the innovative production processes and the final products. WP6 will develop and implement a strategy for the dissemination and exploitation of research results to different stakeholders. WP7 involves consortium management, project governance, communication activities and administrative oversight to ensure maximum impact of the project.

Project Partners:

Dr Alan Goddard, Aston University http://www.aston.ac.uk/lhs/staff/az-index/dr-alan-goddard/

Dr Gavin Thomas, University of York https://www.york.ac.uk/biology/research/biochemistry-biophysics/gavin-h-thomas/

Dr Amparo Querol, Consejo Superior de Investigaciones Científicas (CSIC) – Institute of  Agrochemistry and Food Technology https://www.iata.csic.es/en

Dr Stephan Noack, Forschungszentrum Jülich http://www.fz-juelich.de/ibg/ibg-1

Prof Siewert-Jan Marrink. The University of Groningen http://www.rug.nl/staff/s.j.marrink/

Dr Mustafa Turker, Pakmaya http://www.pakmaya.com.tr/tr

Dr Jose Heras, Lallemand http://www.lallemand.com/

CBMNet IN-FOCUS 2016-2017: Our Network’s Impact

CBMNet IN-FOCUS 2016-2017: Our Network’s Impact

**Download IN-FOCUS here.**

A welcome from Professor Jeff Green, CBMNet Director……

Welcome to the latest issue of IN-FOCUS. Since its launch in 2014 CBMNet has worked to build an international community of academics and industrial biotechnology practitioners to raise awareness of the importance of membrane function, and in particular the transport of substrates and products, in creating efficient bioprocesses. Our many events have brought together over 400 academics and industrialists to share knowledge and discuss a range of challenges where a better understanding of membrane function could provide innovative solutions. These meetings have cemented new relationships between academia and industry and the resulting collaborations, supported by our Proof-of-Concept and Business Interaction Voucher schemes, are now developing as longer-term partnerships and applications for further funding. At this point it is appropriate to thank our Network Manager Dr Jen Vanderhoven for her exceptional work in organising events, supporting developing collaborations and administering CBMNet finances.


“CBMNet has led the way in open, inclusive and interesting meetings that both inform of novel science and bring people together in useful teams. Their funding applications have been rigorously reviewed and their success in grant capture and stimulating new collaborations is excellent. Also their ability to encourage formation of new teams without even a hint of self-fulfilment in the leadership team – who seem to revel in the success of others as much as themselves – is exceptional. I think their outreach via websites, art installation and newsletters, including brokering partnerships via the network, is a great example of best-practice.” CBMNet Member, 2017


Working with the management board has been one of the many privileges of being a part of the CBMNet team. The high levels of knowledge, expertise and creativity embodied in the management board have contributed greatly to the success of CBMNet activities and ensured that our events attract leaders in the relevant fields. One of many highlights was the CBMNet Scientific Session entitled Membrane Transporters held during the 2016 Microbiology Society Annual Conference. This attracted world-leading experts in the full range of biological transport systems to share their knowledge and experience with industrial representatives and early career researchers (ECR). It has been a particular pleasure to have helped deliver several activities focused on ECRs. The CBMNet Vacation Scholarship Scheme has introduced undergraduate bioscientists to the world of IB and our bespoke nationwide IB careers event was full of energy and enthusiasm, as was our ECR Research symposium and our CBMNet Shortcourse in IBBE held at CPI and Fujifilm Diosynth Biotechologies on Teeside. The generosity of our industry partners in sharing their IB insights and opening their work places to offer fascinating insights into operating commercial IB plant was greatly appreciated by all attendees. In its present incarnation CBMNet has another 18 months to run so I would encourage you to keep an eye on our website for up-coming events and register early to avoid disappointment. As well as our event schedule we are actively helping members form consortia and co-ordinating grant applications.


“My experience with CBMNet has been one of the finest and most fruitful examples of   academic-industry exchange, networking and developing collaborative projects that I have experienced. This is all the more remarkable, because I have experienced  plenty of such events in other academic‑industry partnership involvement.” CBMNet Member, 2017

Let’s draw blue skies research out of our universities and into the economy

Let’s draw blue skies research out of our universities and into the economy

A great idea often starts with a lightbulb moment, a flash of inspiration that feels like it could be something big – but for many ideas that’s as far as it gets. For successful innovators, getting to the point where things really take off is a long and often winding road of hope, promise, disappointment and renewal.

Entrepreneurs who grow a good idea into a business are critical to our economic success, but entrepreneurs are not only born and raised in the business community. There are about 1,000 businesses in the UK that are run by university academics who have taken the plunge and are commercialising the research that they have invested years of their lives in.

These include companies such as 2D tech, which was spun out of Manchester University to find commercial applications for graphene, Run3D, an Oxford University spinout that uses biomechanical engineering to help sportspeople improve their performance, or Magnomatics from Sheffield University, which has developed a gearbox that doesn’t actually have any gears in it.

If we are to maintain our position as a world leader in innovation, the UK needs these research-led businesses to scale up, not sell up. As universities minister Jo Johnson recognised recently in a speech to the Higher Education Funding Council for England, our universities need to “find a new gear” and accelerate the adoption of the best practice on research commercialisation that already exists in some of our universities so that it becomes mainstream.

This view is backed up by statistics. Although patent applications in the UK have increased by around 150% over the last decade, most of that growth was in the first five years. While the number of businesses that are being spun out of our universities has been growing, the figures for those that are still operating after three years has been stagnant since 2009-10 and, on average, they have just four employees.

Poor commercialisation of UK research is a problem that Johnson has committed to solve through his new knowledge exchange framework. It will benchmark performance in university-business collaboration, with the aim of driving up standards and recognising that the strengths of different types of institution are not based solely on their work in research.

This should be welcomed, particularly by growing businesses that are faced with a wide choice of universities and which can struggle to identify the best partner. However, we need to make sure the framework takes a long-term view of investment and uses a measure of knowledge exchange that genuinely drives businesses to scale up and creates economic growth.

At the moment some university technology transfer offices are using funding models and measures of success that are just too short-term. We should not use a single measure, like the exploitation of intellectual property, simply because it is easier to quantify. Innovate UK will work with the government and Research England to make sure that the new framework looks to the long term, with a variety of measures that genuinely link through to growth and create the right incentives.

In particular, the framework must acknowledge that research that can transform our industries comes in many different forms, not just patents and IP. For instance, a great deal of work is already being done to develop artificial intelligence systems and algorithms that will analyse big datasets, but since you cannot patent an algorithm in the UK, using that as your indicator would be a flawed measure.

The framework will also need to drive knowledge from our universities into established businesses of all sizes to develop new products and services because this is just as important as support for new companies that are starting out.

That is where schemes like knowledge transfer partnerships can help. Run by Innovate UK, the research councils and devolved administrations, these transfer a graduate or more senior researcher into a business for between 12 and 36 months to deliver an innovation project identified by the business. This is a three-way partnership between the business, the university and the academic in which all benefit.

This week we received an additional £30 million from the national productivity investment fund to substantially expand the programme. When the framework is introduced, universities will be able to use schemes like these partnerships to demonstrate how they are commercialising research.

Knowledge transfer from our universities and the commercialisation of university research matters. So long as we get the measures and incentives right, the framework can bring benefits not just to the international reputation of our businesses and universities, but also to the wider economy.

Read the full article at https://www.theguardian.com/higher-education-network/2017/nov/10/lets-draw-blue-skies-research-out-of-our-universities-and-into-the-economy

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