Thursday, 6 April 2017

Technological Challenges for Synthetic Biology

Technological and scientific challenges facing synthetic biology are manifold. Natural selection has had millions of years to build complex, working systems, and although we can make intentional changes, their effect on biological output is generally unexpected and riddled with unintentional effects. Natural systems have likely considered every single feasible aspect to solve a given problem, and indeed some companies are using similar approaches, using large numbers of mutants and screening them for a “better” desired activity. This can however hardly be called engineering biology and, to return to the aerospace analogy, if airplanes were built like this we would likely be confined to the ground.

[…] relative to its ambitions, synthetic biology is where aerospace engineering was in the 1800s – pre-flight. 
(Timothy S. Gardner, 2013)

In general Biology contains few simplifying rules and principles, while exceptions to rules seem more common. We have a very limited understanding of even many relatively simple cell systems. There are several suggestions for dealing with this complexity. One is to strip down cells or create minimal cells from the ground up. The idea being that in natural cells there are many systems and genes that are not necessarily needed in controlled lab or industrial environments. The reality is that minimal cells are normally much less efficient and have slower growth than other cells. Why this is isn’t entirely clear, but it seems that it will be necessary to understand and tackle the complexity of biological systems rather than attempt to strip it down to its basic components. At the same time, building a minimal cell from scratch may reveal understanding of cells.
Biological systems have always been hard to understand as they behave with a certain stochasticity and a flexibility that does not compare with traditional engineering. Natural systems have to be able to account for varying environments and varying conditions. As a result it is hard to design systems such as a simple on/off switch, as oftentimes there is some very small level of “on” transcription. This “leakiness” of transcription is vital for cells to survive and adapt to changes in their environment but is undesirable in designed systems. Similar challenges are faced at every point when attempting to design biological systems. Cells do not behave in a standardised way, and even if a system works in one cell there is no guarantee that it will also work in another cell of even the same genus or even species or in different conditions.
Indeed the main and one of the more achievable problems to solve is the standardisation of biological characterisation. As it stands many labs have their own standards and record different background information on their own biological parts. Using these parts in different contexts may or may not work, it requires large amounts of time to track down these parts in the first place. This uncertainty and lack of full characterisation of biological parts is one of the things synthetic biology hopes to erase.

Biobricks - an attempt at standardisation of biological parts. [Image Source: MIT]

Indeed it has been said that the future of synthetic biology rests on solving the problems of measurements and design. The relative importance of design methods in synthetic biology applications can be determined by certain information based measures. Although modelling and exact mathematical design has in the past been limited by data gathering and inaccurate assay protocols. This could potentially be solved by new calibrated flow cytometry, which could provide a sufficient foundation for a further investigation into precise mathematical modelling and design.
One thing that is also needed for example are legal standards, in order to share and use genetic parts from several sources, in order to solve problems and realise applications. Current legal standards such as Material Transfer Agreements (MTAs), can take several weeks to resolve and often do not resolve rights to application of standard parts. Indeed with chemical synthesis of genes becoming cheaper, synthesis of large DNA fragments being commercially available and viable for many labs, is a reality. Therefore new legal standards which can for example protect biological parts as well as facilitate the exchange of ideas and specific parts. Another example would be setting standards for ‘barcoding’ or ‘watermarking’ DNA, in order to improve detection and authentication of designed or engineered biological systems. 

The challenges facing Synthetic biology are comparable to the challenges facing many emerging fields in academic sciences. In terms of technological challenges, revolutionising a field of science as synthetic biology is claiming to do is never easy. Biology is known to not be a discipline in which simplifying rules are common. Exceptions and strange unintuitive natural processes are prevalent, and as such standardisation of both biological parts and for characterisation of biological systems is hard and faces numerous issues.

However, I am confident that in time these challenges will be addressed and resolved. 

Sources and Further Reading

Gardner TS. Synthetic biology: From hype to impact. Trends Biotechnol. 2013;31(3):123-125.

Milestones in synthetic (micro)biology. Nat Rev Micro. 2014;12(5):309-309.

Gibson DG, Glass JI, Lartigue C, et al. Creation of a bacterial cell controlled by a chemically synthesized genome. Science. 2010;329(5987):52-56.

Annaluru N, Muller H, Mitchell LA, et al. Total synthesis of a functional designer eukaryotic chromosome. Science. 2014;344(6179):55-58.

Endy D. Foundations for engineering biology. Nature. 2005;438(7067):449-453.

Kitney R, Freemont P. Synthetic biology – the state of play. FEBS Lett. 2012;586(15):2029-2036.

Kwok R. Five hard truths for synthetic biology. Nature. 2010;463:288-290.

Carlson R. Biology is technology: The promise, peril, and new business of engineering life. Cambridge, MA: Harvard University Press; 2010. 10.1080/00033790.2010.510941.

Esvelt KM, Wang HH. Genome‐scale engineering for systems and synthetic biology. Molecular Systems Biology. 2013;9(1). doi: 10.1038/msb.2012.66.

Beal J. Bridging the gap: A roadmap to breaking the biological design barrier. Frontiers in Bioengineering and Biotechnology. 2015;2.

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