Understanding the limits of synthetic biology through the origins of SARS-CoV-2

OVER THE LAST few months, numerous theories relating to the origin of the novel coronavirus SARS-CoV-2 have invaded the internet. Sometimes, these theories can give rise to more interesting discussions than what is originally intended by the authors. For example, the theory that the new coronavirus has been purposely made as a biological weapon would mean that SARS-CoV-2 is a synthetic organism, which simultaneously implies that scientists can create synthetic viruses. How much truth is there in that implication? How far can current technologies go in terms of artificial microorganisms’ design? To answer these questions, we first need to understand the current state of synthetic biology as a field and acknowledge its limitations.

A synthetic approach

Synthetic biology greatly relies on predictive models and computer simulated structures. Computer programmes use the information collected by years of research in molecular biology, which is stored in huge libraries of microorganisms, molecules and domains, to explore their potential when modified or combined in silico – that is, on a computer. The idea of these programmes is to form combinations that, presumably, do not exist in nature in order to analyse potential structures for multiple uses. However, despite in silico models providing valuable information and saving time and money on in vitro experimentation, they are far from perfect.

Professor JA Davies, from the University of Edinburgh, published a paper in the open access journal Life that analysed the current flaws of the ‘engineering approach’ in synthetic biology. While he recognises that this approach, based on the design-build-test dogma, is interesting and that relying on standard pre-existing parts simplifies the overall design of synthetic structures, it lacks biological understanding.¹

In biology, every component from a microorganism has a metabolic cost, ie, the more components you add to a cell, the less energy the cell can direct to each part. Therefore, the fewer parts used for a function, the better. In genetic engineering this is a crucial consideration, since adding new genes normally supposes that pre-existing genes are deleted in order for the organism to be viable. In addition, the interactions between two different pre-existing parts might affect its original function. Hence, as Professor Davies argues, using a novel part, designed for a specific function, might prove easier than trying to reproduce the same function with two pre-existing ones. Ultimately, evolution is based on constant changes of previous structures – induced by a huge number of factors – and not on the combination of unchanging structures. So, while synthetic biology can cover a lot of unexplored possibilities, it is still far from being an almighty tool or competing with natural evolution.

Returning to coronaviruses

This brings us to the next question: how capable are current scientific approaches in terms of virus engineering? Researchers can recreate an existing virus from scratch, and this is what many research teams have been attempting since the coronavirus started to spread in order to understand the virus better.² However, creating a new one is another story. It is possible to create new viruses from original ones; though, there are some restrictions. As aforementioned, synthetic biology relies on the use of pre-existing parts, which means we would need to use different parts of existing viruses and assemble them in order to produce a new virus. Dr Robert F Garry, a microbiologist specialising in virology, commented in Business Insider that there is no consensus on what exactly makes a virus pathogenic.³ Therefore, while making a new virus from scratch is not technically impossible, it would require a level of knowledge that is implausible to imagine in any scientific institution at present. Nevertheless, our current knowledge of molecular science allows us to identify potentially man-made structures or microorganisms.⁴ This is possible because they are based on pre-existent parts; an engineered virus would have identifiable segments of DNA that belong to other viruses whose sequences are stored in libraries. This means that we should be able to identify if a new virus was artificially designed or is a product of natural evolution.

What do we know about SARS-CoV-2?

To study the case of the novel coronavirus, we need to have access to its genetic sequence. This has been a major advancement in epidemiology, as for previous pandemics researchers had to wait from months to years in order to study the microorganism responsible for the outbreak, whereas the structure of SARS-CoV-2 was available within weeks. By analysing its genetic structure, scientists have realised that the backbone of the virus is, indeed, a new one.⁵ However, this does not mean that the virus was not artificially made; we just know that the backbone was not copied from another virus.

What about prompting an existent virus to mutate? It could be that biotechnologists induced mutations to a known virus in order to produce a novel one, like what we see in nature. However, when scientists evaluated the structure of SARS-CoV-2 and compared it to other viral structures, the closest relative they found was SARS-CoV RaTG13, which showed a 96 percent similarity to the novel coronavirus.⁶ Although 96 percent may seem a lot, considering the size of SARS-CoV-2, which is close to 30,000 nucleotides long, this four percent difference is quite significant – around 1,200 nucleotides.⁷

Nevertheless, there may still be some resistance to debunking certain theories. One might argue that, while using known parts of similar viruses, targeted mutations could have been applied to give the virus the ability to attach to human cells – which is essentially what makes this virus able to infect humans. One of the most curious facts about the coronavirus is that the receptor binding domain – the part that makes SARS-CoV-2 able to attach to human cells – was simulated in silico once the sequence of the virus was made available. This sequence showed poor efficiency on the simulations, meaning that nature has found a mechanism that we had not been able to predict.3 If we put together all the facts and reflect on the fact that 75 percent of the new emerging diseases are from zoonotic origin, it appears the theories around SARS-CoV-2 being a man-made virus are quite unrealistic, to say the least.⁸

Something I have found interesting since the search of the origin of the SARS-CoV-2 started, is that we have confirmed that synthetic biology still has a long way to go. We still need to understand a lot about nature to get a bigger picture of how things work and to grasp all the possibilities that molecular biology has to offer. Studying the evolution of viruses not only benefits the epidemiologists, but also the synthetic biologists, who gain insights into how molecular interactions work. This newfound knowledge can be used to improve current models and propose frameworks for the creation of new molecules. Therefore, one can conclude that studying evolution and natural processes is key for synthetic biology to expand and become an even more powerful tool.

References

1. Davies J. Real-World Synthetic Biology: Is It Founded on an Engineering Approach, and Should It Be?. Life. 2019;9(1):6.
2. Biologists rush to re-create the China coronavirus from its DNA code [Internet]. MIT Technology Review. 2020 [cited 26 August 2020]. Available from: https://www.technologyreview.com…
3. How we know the COVID-19 coronavirus wasn’t made in a lab [Internet]. Business Insider. 2020 [cited 26 August 2020]. Available from: https://www.businessinsider.com…
4. Developing biosecurity tool to detect genetically engineered organisms in the wild [Internet]. ScienceDaily. 2020 [cited 26 August 2020]. Available from: https://www.sciencedaily.com/releases/2019/05/190521162437.htm
5. Internet]. 2020 [cited 26 August 2020]. Available from: https://news.tulane.edu/pr…
6. Issa E, Merhi G, Panossian B, Salloum T, Tokajian S. SARS-CoV-2 and ORF3a: Nonsynonymous Mutations, Functional Domains, and Viral Pathogenesis. mSystems. 2020;5(3).
7. SARS-CoV-2 Resources [Internet]. Ncbi. nlm.nih.gov. 2020 [cited 26 August 2020]. Available from: https://www.ncbi.nlm. nih.gov/sars-cov-2/
8. Branch C. NC DPH: Zoonotic Diseases [Internet]. Epi.dph.ncdhhs.gov. 2020 [cited 26 August 2020]. Available from: https://epi.dph.ncdhhs.gov/cd/diseases/zoonotic.html