BioTransistors

Synthetic biology aims to develop protocols, reusable biomolecular components, and engineering tools for the rational design of synthetic biological systems that fulfil certain biotechnological, bioprocessing or biomedical purposes. It builds on genetic engineering and combines traditional molecular biology approaches with systems-level information and engineering perspectives. Progress in this fledgling and rapidly developing discipline has followed two complementary lines of research: first, molecular machines have been constructed and characterised that mimic electronic devices (such as switches, simple oscillators and sensors); second, pathways are reengineered --- increasingly with considerable success --- to produce biotechnologically important compounds at reliable rates. But most components generated thus far are limited to simple logic elements; equally, the bulk of engineered biological systems are ``dumb" in the sense that they fulfil their function in a predetermined and non-adaptive or environmentally aware manner.

In the proposed project we will try to generate a novel class of biomolecular device which mimic the characteristics of transistors in electronics. Transistors have revolutionised the field of electronics and fuelled the progress in computing and consumer technologies . They are used widely in digital and analog electronics and at the most basic level they are devices that amplify and switch signals and power. They do so in more efficient way than previous technologies which has allowed the integration of vast numbers of transistors in single devices which underlies modern computer and processor technologies.
In the biological domain transistors have remained elusive but are highly desirable; in recent surveys they were regarded as important milestones towards synthetic biology becoming a reliable tool in biotechnology and bioprocessing. The proposed project will deliver biological equivalents of transistors, characterize their design features and performance under realistic biological settings, and investigate their use in exemplar applications. We will furthermore determine the extent to which naturally evolved systems harbour transistor-like features already. Finally, we will develop novel statistical and computational approaches that can be used in the design of biosynthetic systems.

In this project we will construct biological transistors which mimic the behaviour of their electronic counterparts. We will use a Bayesian statistical framework for the design of these systems; as part of the research we will also further develop this approach and adapt it to situations where a priori mathematical model representations are absent. This framework is particularly useful as it allows us to deal with the stochastic dynamics that frequently characterise cellular dynamics (and which are absent from typical engineering problems). Candidate design for BioTransistors proposed by our framework will be evaluated and implemented (i) using commodity electronic components, and (ii) in vivo in E. coli. We will then asses their characteristics at the population and single cell level and verify their behaviour as transistors; we will also assess their characteristics and seek to determine any shared properties among the successful (and validated) designs. This will allow us to distill the essential characteristics which allow biological circuits to function as transistor-equivalents, and to comprehensively survey the distribution of transistor-like structures in prokaryotic and eukaryotic microbial organisms. Finally, we will investigate how BioTransistors can be employed in real-world biotechnological applications.

Transistors have revolutionised electronics and enabled computer technology. Recent perspectives in Nature (463, 288-290 (2010)) and the IEEE's Spectrum (48, 38-43 (2011)) have stressed the pressing needs for more reliable biosynthetic components. In each case the lack of a transistor equivalent was stressed and the present proposal aims to address this need. Being the first to deliver such a component will have profound scientific impact, and if they are - as is widely believed - found useful also have economic impact. Biological transistors may (realistically) be less widely applicable than their electronic counterparts, but the proposed research will enable us to assess their potential in real-world applications. Example applications could include, for example, the amplification of environmental signals (including in environmental monitoring applications; use in robust and reliable logic gates and switches; the rational redirection of metabolic fluxes in response to environmental stimuli or changes; and, further down the line, providing engineered bio-systems with rudimentary computing abilities. How much of this is achievable remains to be seen, but being the first to develop such a components (or at least being amongst the first to be able to generate and characterize them) will enable us to explore their uses.

The main beneficiaries of a successful BioTransistor design will in the short to medium term be the biotechnological sector and we are engaged in discussions with Imperial Innovation and will be ready to patent promising designs as they become available. Transistor-like elements have enormous potential across all biotechnological application areas. As amplifiers they could be used in bio-sensing and bioremediation. As switches they could be used in robust logic gates in order to guide cellular information processing; in a metabolic engineering context transistor-based switches could be used to control the metabolic state of microbes in a manner that overrides their naturally evolved mechanisms.

In addition we will address the distinct lack of individuals trained and conversant in both computational and laboratory techniques. The need for such individuals in academia and industry is likely to increase. But a suitable trained individual will be able to lead innovative new research programmes and it is one of our essential aims to aid the named RA to become a recognized researcher at the wet/dry interface of systems and synthetic biology. We believe that he has great potential to become a future research leaders and the proposed research project will form an important milestone in his career progression.

Finally we seek to engage with the interested public through preparing a popular account of our work (and the interplay between synthetic biology and the biology of naturally evolved systems more generally) in a popular science journal.