A vast majority of the amazing feats accomplished by biological organisms hinge on the controllable expression of genes with precise temporal resolution. At the center of this control scheme is the promoter, a sequence of DNA upstream of a gene that recruits RNA polymerase and other proteins such as activators and repressors (collectively known as cis-regulatory elements) to specific sites in its sequence in order to modulate transcription. While most current biotechnology applications use naturally occurring promoters to drive gene expression, an attractive alternative is to design synthetic promoters that are optimized for a certain task. Although this objective presents many challenges, the UK based synthetic biology start-up, Synpromics, is making considerable strides toward cracking the code of synthetic promoter design, and has the results and high profile collaborations to prove it.
Synpromics is designing synthetic promoters
Synpromics was founded in 2010 by Dr. Michael Roberts, whose interest in synthetic promoter design began while working as a post-doc in the field of gene therapy. Roberts’ subsequent experience as a Marie Curie research fellow at the National Hellenic Research Foundation in Greece working in the field of bioinformatics formed the foundation of the company’s technology. Synpromics uses functional genomics approaches to analyze gene expression profiles to create combinatorial libraries of synthetic promoters for a wide array of host organisms. These synthetic promoters have numerous advantages of natural promoters as Roberts, now the Chief Scientific Officer of Synpromics, explained: “The vast majority of possible promoters are unknown in nature, in part because some may be deleterious to the host organism but mostly because the number of potential promoters is extremely large (usually >> 10^30). Natural promoters are constrained by the need to optimise the fitness of the host organism to its environment, expressing genes at levels commensurate to these constraints. In constructing its synthetic promoters, the constraints on Synpromics are much less restrictive: we need only optimise the expression and specificity of our promoters to match our target application.”
However, researchers and biotech companies have tried to make synthetic promoters before and either fall short of beating the capabilities of the promoters that nature has supplied or only produce marginal improvements on these. So what makes the Synpromics synthetic promoters so much better than those of the competitors? When I asked him about this, Roberts simply replied “Rationalization.” As he went on to explain, the typical methods used to create synthetic promoters rely solely on random assembly of sequence variants, which are then assayed for the desired function. However, because of the highly random nature of the process only a very small percentage of these sequences end up having any function whatsoever. Synpromics is able to produce synthetic promoter libraries that far exceed the functionality and capability of those produced using standard methods by taking an engineering approach to the problem, something Roberts stressed is key to Synpromics’ vision and methodology. Because bioinformatics approaches yield insight into what elements of a promoter are necessary and we know that these elements are essentially modular, Synpromics uses this genomics approach to aid in the generation of promoter libraries by randomly combining these elements of predefined function. From there, elements are screened for function and custom stochastic and machine learning algorithms are used to deconstruct the relationships between the promoter elements and the sequences are then modified and improved for another iteration. This method is detailed enough to generate promoters with very specific abilities, yet flexible enough to allow it to be used to construct promoters for a variety of species.
Synthetic Promoter structure from Roberts 2011, “The use of functional genomics in synthetic promoter design.”
With such powerful abilities in hand, Synpromics is looking to employ its synthetic promoters in a wide range of applications and companies are taking notice. The most recent collaboration Synpromics has is in the field of gene therapy. “The resurgence of gene therapy over the last few years has meant that we have received a lot of interest in applying our technology to that area. Also, now that we have signed a deal with uniQure (the world’s leading gene therapy company) to make liver-directed AAV promoters, the gene therapy community is starting to take notice of our technology” says Roberts. In plant sciences, Synpromics is partnering with Dow AgroSciences (subsidiary of the chemical industry giant Dow) in order to use synthetic promoters in crops, and recently Synpromics has demonstrated the effectiveness of their designs in plants, creating a promoter that can give higher expression than the ubiquitin-1 promoter, which is commonly used for high expression in plants. Additionally, for pharmaceutical production, Synpromics is in the process of creating CHO (Chinese hamster ovary) cell promoters, with initial results showing that their synthetic promoters can give higher expression than any synthetic promoters currently available.
In all of these collaborations, the specialized abilities of Synpromics are allowing a sort of division of labor that is often seen in engineering disciplines. For example, for the development of the iPhone Apple creates its own operating systems but leaves the production of the microprocessors used in their phones to Samsung. Similarly, with companies like Synpromics the synthetic biology industry could potentially move in the same direction; for example, one company working on metabolic pathway design and another working on chassis engineering. In regard to the specialization of Synpromics and successful partnerships their expertise has engendered, Roberts stated “Our business model is to…design promoters that are custom-built to [our collaborators’] needs” and that “In every application we have applied our technology to thus far we have been able to generate panels of promoters, each with a unique sequence and each mediating different levels of protein expression; from very high to relatively low levels. We can therefore give a set of very powerful tools to companies that are engineering biological pathways for product manufacture.”
In regard to the future of Synpromics, Roberts hopes to “Continue to build our relationships …and anticipate that the data that comes out of all these partnerships will help to increase the value of our company and boost our efforts to imbed our technology across the entire biotech sector. We would thus hope to see Synpromics promoters routinely used to produce a variety of products; from fine chemicals or biopharmaceuticals produced from industrial biotech processes to a new generation of gene therapies to treat a wide array of disease.” Given their initial success, sophisticated engineering approaches to a fundamental problem in synthetic biology, string of impressive results and high profile collaborations, the future looks bright for Synpromics.
Excited to learn more about Synpromics and want to hear from Michael Roberts in person? Check out the SynBioBeta London Conference by clicking here!0