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The role of synthetic biology as a basic research facilitator

PLOS Blogs Synthetic Biology

 

Last December, a very interesting journal article was published in Science about the reconstitution of functional plant RuBisCo in E. coli [1]. In this work, the authors expressed the plant RuBisCo complex by co-expressing several chaperones—a titanic task given the size and the complexity of the system. This breakthrough will allow the further research on the carbon-fixing enzyme, will facilitate protein engineering efforts, and pave the way for agricultural applications. This work brought to mind a previous RuBisCo study, where the cyanobacterial small subunit of the enzyme replaced the native one in tobacco plants, resulting in faster carbon fixation [2]. In both these synthetic biology works the enzyme of interest is the same, and the end-goal is similar (engineer carbon fixation), though the mentality is quite different. The RuBisCo reconstruction work is more exploratory, focusing on the understanding by synthesis rather than on potential applications.

 

The notion that synthetic biology is an applied discipline is quite widespread, as we (the researchers and the community) exclaim the potential of synbio to improve our daily lives, while the entrepreneurial aspect is well embedded in conferences, events, and student competitions. However, synthetic biology is not confined into translational research, and some of the most celebrated achievements of the field have no direct applications (e.g. the minimal bacterial genome [3] and the synthetic yeast project [4]).

 

The phrase “What I cannot create, I do not understand”, though written in a different context, has an important influence on the community’s mindset. The merge of engineering and biology has the promise to construct synthetic systems, genes, and even organisms to shed light on the big unknowns of life [5]. In the long synthetic biology definition given by EBRC, understanding by synthesis is mentioned. In the UK synthetic biology roadmap published in 2012, foundational science and engineering is one of the mentioned “Themes”. The iGEM competition includes a foundational advance track.

Biology is now able to build to understand.

In order to get a better insight on how synthetic biology is/can be incorporated into basic research, I contacted Dr Stephane Lemaire from CNRS, France, a passionate advocate of fundamental uses of SynBio. He mentioned that “Synbio is more than Biotech. It offers the possibility to understand by construction rather than deconstruction, and I think that biologists should integrate the synthetic approach in their basic research. Synthesis is a method of understanding by construction used by other disciplines including philosophy, chemistry, mathematics…  With the technical progress of the last 40 years, biology is now able to build to understand.”

 

Dr Lemaire pointed out two more sources. In the well-known ”La Biologie Synthétique” (1912), the French chemist Stéphane Leduc (1853-1939) wrote: “Like other sciences, biology has to be successively descriptive, analytic and synthetic. The unique use of observation and analysis, excluding the synthetic method, is one of the causes which retard the progress of biology“. Another one is a commentary by Yeh and Lim, where they discuss the link between chemical synthesis and advancements in the understanding of laws of chemistry [6]. The theories of how atoms interact to form molecules, the nature of the different types of bonds, the models that simulate and explain chemical reactions, all became possible with the ability to generate compounds on demand.

 

Will the same happen with biology? Dr Lemaire is adamant: “Synthesis will allow biology to become the central discipline of the 21st century as it will allow to explore new frontiers inaccessible until now. This shift of biology towards synthesis will be slow although dramatically faster than chemistry in the 19th century. This will drive the increase of fundamental understanding in biology which is required to allow biology and biotechnology to become the next industrial revolution”.

 

Though Dr Lemaire states that there are certain challenges: “These concepts have only been started to be taught in universities around the world, and biologists are not yet embracing these approaches. Many colleagues are still not aware and sometimes reluctant to change their practices. I use synbio for fundamental studies in my group, although limited funding and lack of institutional and political support are main limiting factors. However I have the feeling that the situation is slowly improving. For example, the importance of both applied and fundamental synthetic biology has dramatically raised in the current Horizon 2020 funding programme”.

 

This semantic map of most prominent terms used in synthetic biology reflects the diversity in research themes. Image from Raimbault, et al. [11]

One of the most appealing characteristics of synthetic biology is the liberty to “play” with the biological parts, think out of the box, and use that to solve the problem or answer the question of interest. The tools and the system do not matter. So whether you want to explore genetic circuits for applied or basic research questions [7], you are wondering what is a genome [8], want to understand evolution and abiogenesis [9], or want to determine the elements that determine gene expression [10], synthetic biology has something to offer. And don’t forget: the potential of CRISPR as a gene editing tool with such a variety of applications was discovered when a handful of people were wondering what is the raison d’être of those conserved repeating elements among so many organisms.

References

  1. Aigner, H.; Wilson, R. H.; Bracher, A.; Calisse, L.; Bhat, J. Y.; Hartl, F. U.; Hayer-Hartl, M. Plant RuBisCo assembly in E. coli with five chloroplast chaperones including BSD2. Science (80-. ). 2017, 358, 1272–1278, doi:10.1126/science.aap9221.
  2. Lin, M. T.; Occhialini, A.; Andralojc, P. J.; Parry, M. A. J.; Hanson, M. R. A faster Rubisco with potential to increase photosynthesis in crops. Nature 2014, 513, 547–550, doi:10.1038/nature13776.
  3. Hutchison, C. A.; Chuang, R.-Y.; Noskov, V. N.; Assad-Garcia, N.; Deerinck, T. J.; Ellisman, M. H.; Gill, J.; Kannan, K.; Karas, B. J.; Ma, L.; Pelletier, J. F.; Qi, Z.-Q.; Richter, R. A.; Strychalski, E. A.; Sun, L.; Suzuki, Y.; Tsvetanova, B.; Wise, K. S.; Smith, H. O.; Glass, J. I.; Merryman, C.; Gibson, D. G.; Venter, J. C. Design and synthesis of a minimal bacterial genome. Science (80-. ). 2016, 351, 6253–6253, doi:10.1126/science.aad6253.
  4. Richardson, S. M.; Mitchell, L. A.; Stracquadanio, G.; Yang, K.; Dymond, J. S.; DiCarlo, J. E.; Lee, D.; Huang, C. L. V.; Chandrasegaran, S.; Cai, Y.; Boeke, J. D.; Bader, J. S. Design of a synthetic yeast genome. Science (80-. ). 2017, 355, 1040–1044, doi:10.1126/science.aaf4557.
  5. Elowitz, M.; Lim, W. A. Build life to understand it. Nature 2010, 468, 889–890, doi:10.1038/468889a.
  6. Yeh, B. J.; Lim, W. A. Synthetic biology: lessons from the history of synthetic organic chemistry. Nat. Chem. Biol. 2007, 3, 521–525, doi:10.1038/nchembio0907-521.
  7. Bashor, C. J.; Collins, J. J. Understanding Biological Regulation Through Synthetic Biology. Annu. Rev. Biophys. 2018, 47, annurev-biophys-070816-033903, doi:10.1146/annurev-biophys-070816-033903.
  8. Goldman, A. D.; Landweber, L. F. What Is a Genome? PLOS Genet. 2016, 12, e1006181, doi:10.1371/journal.pgen.1006181.
  9. Attwater, J.; Holliger, P. A synthetic approach to abiogenesis. Nat. Methods 2014, 11, 495–498, doi:10.1038/nmeth.2893.
  10. Johns, N. I.; Gomes, A. L. C.; Yim, S. S.; Yang, A.; Blazejewski, T.; Smillie, C. S.; Smith, M. B.; Alm, E. J.; Kosuri, S.; Wang, H. H. Metagenomic mining of regulatory elements enables programmable species-selective gene expression. Nat. Methods 2018, doi:10.1038/nmeth.4633.
  11. Raimbault B.; Cointet J.P.; Joly P.B.  Mapping the Emergence of Synthetic Biology. Plos ONE 2016 11(9): e0161522 doi:10.1371/journal.pone.0161522

Featured image source: pixabay CC-0

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