The Novo Nordisk Foundation Center for Biosustainability/ Christian Als
A vehicle for a sustainable future Metabolic engineering holds a lot of promise as a means of sustainably producing foods, chemicals, proteins and other important products. The DD-DeCaF project is developing computational tools that will help biotechnology companies understand the impact of changes in biological networks and develop better, more effficient cell factories, as Dr Nikolaus Sonnenschein explains. A large amount of biological data is available nowadays which could help inform the design of cells and microbial communities, including proteomics and transcriptomics data for example. However, this data is not currently being utilised to its full potential, believes Nikolaus Sonnenschein, Associate Professor in the Department of Biotechnology and Biomedicine at the Technical University of Denmark. “There is data out there but we’re not really taking advantage of it, in the sense that we lack the required analytical approaches and bioinformatics pipelines,” he explains. This is an issue at core of DD-DeCaF, an EC-backed project co-ordinated by Professor Markus Herrgård which brings together scientific and industrial partners to develop new cell design tools. “We are trying to speed up the design of cell factories and microbial communities for biotechnology applications,” outlines Professor Sonnenschein. www.euresearcher.com
Cell factories This is an increasingly important area of the commercial sector, with cell factories used for the sustainable production of chemicals, proteins, and many other valuable substances. While biochemists and cell engineers hold deep expertise in their own field, they may not necessarily be experts in mathematical modelling, so Professor Sonnenschein says accessibility is an important consideration. “The DD-DeCaF software platform called Caffeine is for people that work in the lab. They might have generated some data, but they need some insights into what they should do next in terms of engineering targets, or achieving a production goal,” he says. The main interface on the platform is a representation of a cell’s metabolic pathways, which is familiar to bioengineers and cell biologists. “It’s a network depiction of metabolism, which is essentially the chemical reactions that can happen inside those cells,” continues Professor Sonnenschein.
This platform enables engineers to assess the impact of a specific change within a cell, such as removing or adding a gene. It is also possible to integrate further data and so gain a deeper picture of biological networks. “In order to do that you need to log in to the platform, then you get access to data in the public domain, and can also upload your own data,” says Professor Sonnenschein. Users of the platform can select a specific dataset of interest, for example on how a microbial community uses sugar, then both look at reactions that have occurred and also forecast future developments. “You can actually gain more insights beyond the measurements than you’ve done, essentially extrapolating beyond the existing data,” outlines Professor Sonnenschein. “Using our knowledge of the organisms, and some sophisticated mathematical approaches and models, we can draw further insights beyond the existing data points alone.”
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There is also a kind of design pipeline in the platform which will help engineers identify how to produce a particular chemical. If the aim is to produce a specific chemical compound, then the pipeline can be used to identify how that compound can be produced and what is required. “If it’s not a chemical that the cell can natively produce, then what other genes from other organisms would you have to borrow in order to make a full production pathway possible?” explains Professor Sonnenschein. It may also be necessary to remove genes in order to produce a certain compound. “How might a microbe react to the removal of certain parts of its metabolic system, for example the deletion of certain genes?” continues Professor Sonnenschein. “Some of the sugar that microbes eat could be redirected to production. That can be achieved by manipulating cells and removing genes, and therefore removing reactions.” The platform enables engineers to work through these different scenarios and understand their likely effects. A very large number of genes can potentially be removed from a cell or added to it, so Professor Sonnenschein says the platform can play an important role here in helping cell engineers. “The methods that we have implemented are very useful, because they come up with
designs that are not necessarily intuitive. That’s also interesting from a commercial perspective,” he says. Many of the more intuitive cell designs have been patented, so it’s difficult for a new company to enter the market without paying expensive licensing fees; the DD-DeCaF platform opens up new possibilities in this respect. “It could allow companies to find more efficient approaches to produce existing chemicals. They could
Bioinformatics Services for Data-Driven Design of Cell Factories and Communities
Project Objectives
The DD-DeCaF project aims to make a broad spectrum of omics data useful to the biotechnology industry by integrating data analysis with design within the same platform. This platform can be used in a wide range of application areas, ranging from industrial biotechnology to agriculture and human health.
Project Funding
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 686070.
The DD-DeCaF software platform could allow companies to find more efficient approaches to produce existing chemicals. They could potentially identify alternative designs and pathways that have not yet been patented by their competitors. potentially identify alternative designs and pathways that have not yet been patented by their competitors,” explains Professor Sonnenschein.
Production efficiency A particular production pathway might be more efficient than another, resulting in a higher yield, which is an important issue for biotechnology companies. Where a cell factory is being used to produce bulk
companies to identify projects that would not succeed commercially, because they would not be able to get the yield necessary to compete with a purely chemical industrybased process,” continues Professor Sonnenschein. “The models that we have on this platform allow you to make these kinds of calculations.” The biotechnology industry evolves rapidly, and the way in which software tools and innovative new technologies will
https://youtu.be/RXAfxYxnpoc The DD-DeCaF software platform available at https://caffeine.dd-decaf.eu/
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DD-DeCaF
chemicals, they may be in competition with the conventional chemical industry for example, so efficiency would be a priority. “They would be very keen to reach the theoretical maximum yield,” says Professor Sonnenschein. The DD-DeCaF platform is an important asset in this respect, enabling biotechnology companies to identify efficient pathways and also avoid unproductive investments. “It helps
EU Research
Scientific Partners
• Technical University of Denmark • European Molecular Biology Laboratory • Chalmers University of Technology • École polytechnique fédérale de Lausanne • Centre of Biological Engineering, University of Minho
Industrial Partners
• SilicoLife • Genialis d.o.o. • biobyte solutions GmbH • Biosyntia ApS • DSM Full partner details at: http://dd-decaf.eu
Contact Details
The Novo Nordisk Foundation Center for Biosustainability/ Christian Als
be used is by nature difficult to foresee. The project’s platform is intended to be used not just by experts in computational biology, but by the staff of companies involved in cell engineering, widening the user base considerably. “Cutting-edge tools, programming and data analysis, are all accessible to a minority of people that know how to use them, but they have not really been used very much in the rest of industry. That’s what we are trying to address with this web-based interface,” outlines Professor Sonnenschein. This brings new challenges however, as the software tools themselves are not completely infallible, so Professor Sonnenschein believes it’s important that users are aware of their limitations and how to use them effectively. “The methods that we use for predicting the cellular state are not perfect, but they’re definitely useful,” he says. A lot of effort has gone into demonstrating this to the biotechnology sector, through frequent interactions with industrial partners. The wider aim here is to develop a platform that is useful for scientists and will help them solve some of the problems that they face. “We did tests with end-users within the consortium, as well as others from outside the project. It was definitely an iterative process towards ending up with something that is intuitive and easy to use,” continues Professor Sonnenschein. This research has generated a
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lot of interest, and Professor Sonnenschein is keen to build on the foundations that are already in place. “I’m working towards establishing an industrial consortium based here at the university. The idea would basically be for companies to financially support the continuous maintenance and development of this platform,” he outlines. The vast majority of biotechnology companies are of course very careful with commercially-sensitive data, yet installing and running this type of software is quite a complex and labour-intensive task. One possibility could be establishing a non-commercial business model, where companies can get support for deploying the DD-DeCaF tool on companies’ premises in exchange for financial support. “It could run through a kind of contributory system,” says Professor Sonnenschein. A number of trial set-ups have been established, where companies have installed the software and tested it on their own data, models and maps, and the feedback so far has been extremely positive, which could encourage further development. “The hope would be that if this stays as a non-commercial activity then other parties will also contribute in future, including companies. They may decide that this is an essential piece of IT infrastructure, and they are willing to support it,” says Professor Sonnenschein.
Nikolaus Sonnenschein Department of Biotechnology and Biomedicine SB-Computer-Aided-Biotechnology Technical University of Denmark Søltofts Plads Building 223, room 224 2800 Kgs. Lyngby T: +45 2 1798922 E: niso@dtu.dk W: http://dd-decaf.eu https://youtu.be/RXAfxYxnpoc
Nikolaus Sonnenschein
Nikolaus Sonnenschein, now an Associate Professor at the Department of Biotechnology and Biomedicine at the Technical University of Denmark (DTU), has coordinated the technical development of the Caffeine platform at The Novo Nordisk Foundation Center for Biosustainability at DTU in his role of Scientific Deputy of the DD-DeCaF project.
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