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New synthetic biology technologies are revolutionising microbial design

Text: Anssi Rantasalo, Dominik Mojzita and Jussi Jäntti | 14.12.2017

The rapid development of DNA sequencing technologies is providing a huge amount of information about biology and living things. With an increasing pace we are uncovering the code that has evolved during evolution and that describes the building blocks of life. Uncovering this code has been enabled not only by highly efficient methods for DNA sequencing, but at the simultaneous reduction in price and the time that is required to read millions of base pairs of DNA sequence.

In parallel with our ability to read the DNA code rapid development of computational methods, novel algorithms, data bases and increased computing power are now making it possible to extract meaningful data from the exponentially growing pool of sequence data. Now we can start to answer questions such as what are the essential chemical reactions that are required to maintain life and how individual cells and multicellular organisms react and communicate (Figure 1).

While the ability to read DNA sequence is highly exciting the possibility to now take this information and combine it in completely new ways offers unprecedented possibilities to learn how biological systems function, and importantly, generate new combinations of biological molecules and systems. This is to large extent based on our ability to computationally design the DNA code and synthetize it with a moderate cost. It is now possible to design and synthetize even complete microbial genomes. This has been already accomplished for a one million base pair long bacterial genome (www.jcvi.org). At the moment the synthesis of an over 10 times larger genome of the biotechnologically broadly used baker's yeast is close to completion (http://syntheticyeast.org​). Collectively, the technological approaches that design and write the code for biology are called synthetic​ biology. It can now be used for example for biotechnology to help us solve many of the great challenges in bio and circular economy for sustainable use of raw materials on earth.

Figure 1. New emerging technologies enable sampling from databases genes from the global biota that has evolved through evolution, generate new combinations and new biological activities and products for biotechnological production.

​​VTT's SES toolkit harnesses yeasts and moulds for industrial use

Our ability to design and write the code for biological systems can be harnessed for the full effect only if we have genetic tools at hand that enable efficient reading and translation of the DNA code into systems that perform the designed biological tasks such as production of fuel molecules or pharmaceutical compounds in large scale. While the nature contains a vast number of microbes the presently used industrial biotechnology-based processes use only a few of them. This is partly due to the fact that in most organisms there have not been tools available that enable control of gene expression in a predictable and robust manner. In case broadly applicable genetic tools would exist an increasing amount of productions systems and end products could be generated.

Fungal species are used in biotechnology because of their diverse metabolic activities and ability to withstand industrial conditions. VTT has recently developed a novel synthetic biology toolkit which allows expression of genes in a wide spectrum of fungal species. The synthetic expression system, called SES, is based on well characterized modular DNA parts which exhibit a specific, yet universal functionality in different fungal species. The parts of this system can be combined, like Lego blocks, to synthetic genetic devices within the cell to perform designed tasks, such as synthesis of fuels, industrial chemical(s) or proteins (Figure 2).

Figure 2. SES system consists of modular genetic parts which can be assembled to functional genetic devices with predictable behaviour. The SES system has several advantages making it an attractive solution for multiple biotechnical applications.

Predictive technology assists in the optimisation of production systems

The SES system has been assembled from modules which are necessary for gene expression. The great advantage of the SES system is that it is very easy to assemble synthetic gene regulators which have a predictable strength, varying from minimal to levels above the strongest ones found in nature. The system is also independent of growth conditions. It allows for example easy and fast optimization of enzymatic production pathways because the construction of a large collection of different gene regulator variations is straightforward. In many cases suboptimal enzyme levels cause bottlenecks or excessively consume important nutrients. Therefore, optimization of production pathway now possible with SES can significantly impact bioprocess economics. SES is also an attractive technology for other applications, such as for protein production for industrial enzymes for a broad range of applications.

The robust functionality of the SES modules in different organisms enabled us to develop a universal expression tool which is functional in different fungal species (Figure 3). This opens completely new possibilities for the industry because the lack of gene expression tools is a common problem which limits the use of numerous highly promising organism for biotechnology. Many fungal species are robust and tolerant for industrial conditions, and they are able to produce high amounts of commercially interesting compounds, such as organic acids. Previously, the establishment of a new production host has been very difficult and time consuming, but because of the SES technology and latest developments in DNA editing techniques such as CRISPR/Cas9, it has never been easier and faster than now. However, even existing production hosts can benefit greatly from SES technology because the system expands the selection of tools and brings the latest technology with new features available for them for improved control and productivity.

Figure 3. The SES system provides universal tools for gene expression decreasing the need for organism specific technologies. The functionality of the SES system has already been demonstrated in wide spectrum of fungal species.

Clean products cost-effectively, using SES technology

The traditionally used gene expression tools are based on the use of native DNA sequences. The weakness of this strategy is that these elements are prone to native regulation which may lead to unexpected behaviour during scale up and manufacturing process. In addition, some systems have specific requirements for cultivation conditions. For example, the use of native parts may exclude the use of the cheapest available nutrient solution and require the supplementation of a valuable inducer compound.

The SES system is composed of parts which originate from genetically and evolutionary distant organism and do not have counterparts in the host. The idea is that the engineered system functions as an independent entity without cross-talk with native regulation. This decreases the chance for unexpected behaviour and makes the system independent of growth conditions. This can allow for example the use of the most economical nutrient solution for the production and it can eliminate the need for inducers. The SES technology offers also other great benefits, such as possibility to produce pure proteins at high levels. In some applications, the protein purification costs may comprise up to 90% of the manufacturing costs. Thus, by decreasing the need for down-stream purification, companies can potentially achieve substantial savings. We have used the SES system with the filamentous fungus T. reesei, which is one of the most commonly used industrial enzyme production hosts, for the production of almost pure, high value proteins. The advantage comes from the fact that with SES system the production can be done in industrially relevant conditions which are not compatible with existing gene expression tools. For example, the commonly used T. reesei's strong CBH1 gene regulator element is activated in the presence of cellulose containing material. However, in addition to protein of interest, also a spectrum of other naturally produced proteins is secreted under these conditions thus decreasing the purity of the end product. We have solved this problem by expressing the protein of interest in T. reesei using the SES system and running the cultivation in a medium in which the expression and secretion of unwanted proteins can be avoided. With this strategy we have been able to produc​​e significantly purer proteins whose levels are comparable or exceeding the levels achieved with the currently widely used CBH1 regulator element.

New biotechnology applications and startup companies?

In spite of the great opportunities that the SES system can already offer, our recent work has taken the SES technology a step forward. We have been expanding the toolkit with additional parts to enable the establishment of novel genetic devices and circuits which can perform complex tasks. For example, these kinds of systems can be used to regulate complex metabolic pathways in future applications. In addition, the systems coupled with biosensors could be engineered to ensure the vitality and productivity of the host during the manufacturing process.

The latest development in the field of synthetic biology has radically changed the way how biological system can be engineered for the industrial use. The novel tools and technologies, such as SES and the genome editing tool CRISPR-Cas9, combined with automation and high throughput screening can significantly speed up strain development work and improve our knowledge about biological systems. Faster design-test-build-learn cycle time means reduced cost for the development work. This Design-Test-Build-Learn approach has started to resemble classical engineering instead of the trial and error approach which has been typical in biotechnology. The very positive sign is that the new opportunities have already given rise to several new biotechnical applications and start-up companies. However, the enthusiasm is not limited to bioindustry and chemical companies, but the interest is also increasing in industry that has not traditionally used biotechnology solutions.

 

 

Anssi Rantasalo, Research Scientist, PhD student works in Industrial Biotechnology and Food solutions Research Area. In his research, he focuses on development of novel tools for efficient genetic engineering of industrially relevant microbes.

 

Dominik Mojzita, PhD, Principal scientist, works in Industrial Biotechnology and Food solutions Research Area. He works on identification and characterization of novel genes and metabolic pathways and development of synthetic biology tools for genetic control circuits in industrial microbes and beyond.

 

Jussi Jäntti, PhD, Research team leader, works in Industrial Biotechnology and Food solutions Research Area. He is interested in development of synthetic biology tools and robotic pipelines for their effective use in engineering of industrial microbes.

 

 

 

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