The Emergence of Cell-Free Biosensors

Over the last year and a half, the world has seen the critical importance of rapid diagnostics to address global issues. The emerging field of cell-free biosensors looks to take on that call.

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Eighteen months ago, we were thrilled to announce our publication titled ‘Plug-and-Play Metabolic Transducers Expand the Chemical Detection Space of Cell-Free Biosensors’ in Nature Communications[1]. When the editors of Nature Bioengineering requested that we write a ‘Behind the Paper’ accompanying blog piece, I was delighted as in addition to being proud of the research, I felt we had an entertaining story to tell. (It’s not every day that you go to the grocery store for your research.) Now, I’d like to reflect upon how that paper has helped contribute to an evolving field and my attitude towards research in general.

One of the main takeaways I have is the strength of good collaborations. The project began as a partnership between the cell-free technologies I was developing in our lab and the metabolic expertise of Jean-Loup Faulon’s group at the Micalis Institute. But this project proved to be just the beginning; since our publication, our groups have gone on to publish three additional papers[2][3][4] (two in Nature Communications) and three reviews[5][6][7] in the realm of cell-free diagnostics. We have uncovered new ways of formulating buffer compositions, pre-processing reactions, and even integrating complex ‘perceptron’ logic functions, furthering the limits of what cell-free systems can achieve.

I would be remiss if I focused only on the work of our groups, however. This emerging field has seen a variety of fascinating, high-quality papers published, particularly in the domain of water diagnostics[8][9][10][11]. Stemloop, a start-up spun out of the Lucks lab at Northwestern University, is even showing how cell-free diagnostics can progress beyond the academic benchtop and create actual products to address real-world problems. Additionally, the COVID-19 pandemic has emphasized the urgent need for rapid, point-of-care diagnostics, a challenge currently being tackled by CRISPR-based sensors at companies like Sherlock and Mammoth Biosciences. It has been humbling and inspiring to see what creative uses for the molecular machinery inside cells my colleagues have created.

For me personally, the development of proof-of-concept applications for our original paper helped affirm that sometimes crazy ideas can work. I have a bit of reputation as someone who dabbles in unconventional side projects, be they bioluminescent dinoflagellates or vinegar-mother bacterial cellulose. Frequently, they fizzle out as more pressing tasks fill my time and mental capacities for the day. However, as the late, great actor Robin Williams once said, “You’re only given a little spark of madness, and if you lose that, you're nothing.” So as I continue my work to make cell-free diagnostics functional for an increasing number of metabolic inducers in a variety of complex clinical samples, I think back to pipetting mayonnaise and how sometimes the crazy ideas can be the ones most worth pursuing.

Our paper: Voyvodic PL et al., Plug-and-Play Metabolic Transducers Expand the Chemical Detection Space of Cell-Free Biosensors. Nature Communications. 10, 1697 (2019).

References

1. Voyvodic PL, et al., Plug-and-Play Metabolic Transducers Expand the Chemical Detection Space of Cell-Free Biosensors. Nature Communications. 10, 1697 (2019).

2. Pandi A, et al., Metabolic perceptrons for neural computing in biological systems. Nature Communications. 10, 3880 (2019).

3. Borkowski O, et al., Large scale active-learning-guided exploration for in vitro protein production optimization. Nature Communications. 11, 1872 (2020).

4. Pandi A, et al., Optimizing Cell-Free Biosensors to Monitor Enzymatic Production. ACS Synthetic Biology. 8: 8, 1952–1957, (2019).

5. Voyvodic PL and Bonnet J, Cell-free biosensors for biomedical applications. Current Opinion in Biomedical Engineering. 13, 9-15, (2020).

6. Koch M*, Pandi A*, et al., Custom-made transcriptional biosensors for metabolic engineering. Current Opinion in Biotechnology. 59, 78-84, (2019).

7. Pandi A, et al., Synthetic Biology at the Hand of Cell-Free Systems. In: Singh V. (eds) Advances in Synthetic Biology. Springer, Singapore. (2020).

8. Silverman AD, et al., Cell-free gene expression: an expanded repertoire of applications. Nature Reviews Genetics. 21, 151-170 (2020).

9. McNerney MP, et al., Point-of-care biomarker quantification enabled by sample-specific calibration. Science Advances. 5: 9, eaax4473, (2019).

10. Silverman AD, et al., Design and Optimization of a Cell-Free Atrazine Biosensor. ACS Synthetic Biology. 9: 3, 671-677, (2020).

11. Jung JK*, Alam KK*, et al., Cell-free biosensors for rapid detection of water contaminants. Nature Biotechnology. (2020).

Peter Voyvodic

Postdoctoral Fellow, Centre de Biochimie Structurale

My research looks at how we can use the power of transcriptional regulation and cell-free protein synthesis to create a new class of low-cost, portable diagnostics, although my passions in synthetic biology are wide-ranging.

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