Novel in situ base editing of gut bacteria - inconsistencies, gaps, and anticipated dangers on treated humans, animals, and the entire ecosystem

New preprint published

On July 19, I became aware of a recent article published in Nature. When I read about the experiments that were being done, I thought they may be worse than anything I had previously known. I was shocked.

I emailed some of my friends about the dangerous lab manipulation of microbiota that must be stopped. My first plan was to just write a Substack post. When I began writing, I unearthed more and more things I regard as very serious. Last week, I submitted my work to OSF preprints where it was approved today.

Nature Magazine had announced the work in question as follows:

“Gut microbes in mice edited at will

“The bacteria found in mouse guts can be altered at will thanks to a gene-editing tool. Researchers used a bacteria-infecting virus to deliver a ‘base editor’ that targets specific nucleotide bases in the DNA of Escherichia coli in the guts of the living mice. With the base editor, scientists changed A to G in the E. coli gene that produces β-lactamases — enzymes that drive bacterial resistance to several types of antibiotic. After eight hours, 93% of the genes had been edited. The same team also adapted the base editor so it could modify an E. coli gene that produces a protein that is thought to play a part in several neurodegenerative and autoimmune diseases.”

However, when you read the underlying Nature article itself, the experiments by Broedel and collaborators look scary. They are aware that gene editing can have unintended side effects. Now, they are not aiming to “just” improve those major issues. Rather, they purport to edit “bad genes” of microbiota inside the gut of animals – and humans, ostensibly for clinical purposes.

Yet, when I considered their novelties and the improvements they reported to mitigate previous dangerous and unwanted consequences of gene editors, I was not at all convinced it works as claimed! It seemed the article hides several inconsistencies that emerged from the experiments. And I could easily envision real potentials of additional scary consequences that the authors did not consider, both to the treated humans/animals but also the entire biosphere!

Below are parts from the “Conclusion and Open Questions” section of my new preprint (emphasis added).

“The research by Br¨odel and collaborators sounds exciting. The notion that genes of targeted organisms can be “edited at will,” even inside the gut of a living organism, is incorrect. The experiments were not done in a manner to demonstrate the lack of unwanted effects or those to off-target species. The authors are aware of the potential of some of the adverse consequences their engineered system could have. To counteract these, specific synthetic genes and constructs were manufactured. These, they argue, guarantee that their conditional editor will only edit the targeted population and that the editor will only be transiently expressed.

“However, the experiments to validate this are done in a limited context, in part based on wrong assumptions. ... 

“Just because the editor was designed to be inducible and transient does not mean it will be when it encounters many conditions in real life that were not envisioned. Indeed, some of the experiments done in the lab raised questions to the authors themselves, who try to explain them away with incorrect arguments that reveal they are unaware of some of the findings and results about bacterial evolution and the dissemination of transgenes obtained elsewhere.

“Terms such as editing and delivery particles conceal the true nature of the experiments. Gene editing is a misnomer...

“The incomplete or flawed assumptions that dictate the lab experiments by Br¨odel et al. cannot predict how the engineered system will behave or evolve in real life. There is no reason to believe that synthetic virus vectors could not transfect non-target species nor that the maintenance and dissemination of the payload is “prevented” by the design of the complex cosmid payload. Several findings in the paper suggest the opposite. The depiction of the engineered bacteriophage as a simple vector whose sole job is to deliver synthetic payload hides the gruesome reality that both the bacteria as well as these viruses are biological entities that are normally engaged in delicate and complex host-pathogen interrelationships. The claim that the synthetic virus (the delivery vehicle) can only transfect the targeted population cannot be guaranteed in the open environment. In fact, the study only analyzes its sensitivity by measuring the presence and maintenance of its synthetic payload and its effect. But even this led to some strange effects that need further explanation...

“Likewise, the dangers of abuse of gene editors that work in a hidden manner in vivo have not been acknowledged. Br¨odel and colleagues are all current or former employees, or paid advisors, of Eligo Bioscience5, a company that promotes the “first-in-class proprietary platform to edit the microbiome gene repertoire in vivo.” The system is planned to be delivered either orally or topically. However, there is no guarantee that such treatment, acting as an under-appreciated gene therapy system, could not also adulterate the genetic material of the treated human or animal. Furthermore, the false claims that the engineered editor does not disseminate nor maintain synthetic genetic material is extremely dangerous. This false premise could easily be exploited by bad actors to build novel types of biological weapons and hide this endeavor behind the flawed narratives of their proven safety and efficacy. If the destructive effects are realized, these would be easy to deny as they would be deemed implausible...

“The main shortcomings of the study are summarized in the figure below. Considering the devastating potential of an unintended lab escape, unpredicted dissemination of these agents, toxins, and delivery system, or their deliberate misuse as a biological weapon, such types of experiments must urgently be halted."

(Source: https://osf.io/preprints/osf/m3bf8?view_only=) Some of the main interrelated issues with the gene editing experiments developed by Br¨odel et al. their analysis, gaps, and potential adverse consequences

I spent less than two weeks on this. So, my preprint is certainly not exhaustive. Each time I think about it, I come up with new concerns. If the entire thing also seems dangerous to you, please read and share my preprint. Perhaps some of you have some ideas of how to reach policy and decision-makers.