Mirror, mirror: Which is the most dangerous bacterium of them all?

Such a question is, of course, impossible to answer. What is the social context? What are the vectors for transmission and are they likely to occur? Anyone schooled in risk management will understand the fluctuations of uncertainty.

This leads us to future states and the possibility of creating artificial biological lifeforms. Should we be worried? A group of researchers, from 38 countries, think so and they have called the world’s attention to potential risks to humans and global ecosystems from the development of mirror bacteria’. In other words, synthetic organisms that, at the molecular level, are ‘mirror’ versions of those found in nature.

For this week’s article, we go through the looking glass to consider the technology and the concerns raised by the researchers.

Mirror bacteria

Scientists have begun early work toward creating synthetic mirror bacteria. This involves creating macromolecules like DNA and proteins that are mirror images of those in nature. With synthetic biology, this includes expanding biotechnology to design and build an engineered living biological system.

The concept has arisen as something technically possible in the near future only over the past few years, although the theory was first proposed by Louis Pasteur [1].

What does ‘mirror’ mean?

As set out by the researchers, all known life is homochiral (any object is classed as chiral it cannot be superposed by its mirror image). DNA and RNA are made from “right-handed” nucleotides, and proteins are made from “left-handed” amino acids.

As to why this is the case, the existence of this phenomenon in nature is unclear. It is reasoned homochiral occurs because it is the most appropriate form for information storage [2].

In terms of microbial life, the research path is towards creating a functioning cell. This is in the form of a natural-chirality bacterium entirely from synthetic DNA, synthetic proteins, and synthetic lipids. After this, experiments could be run to create a mirror bacterium, one bioengineered to produce mirror proteins and nucleic acids [3].

As to why scientists would want to create mirror bacteria, the primary area is with improved bioproduction facilities, whereby synthetic bacteria could be harnessed to churn out novel chemicals (or current chemicals with improved yields) and in a more efficient way, since they would be more resistant to contamination.

Where are we now?

This type of research doesn’t mean we’ll have mirror bacteria created with any immediacy for the capability is at least a decade away (currently, scientists can create mirror image biomolecules) [4].

As to the purpose of current research, the experiments with biomolecules show that reversed chirality makes biomolecules resistant to normal forms of biological degradation. This presents opportunities to create longer lasting nonimmunogenic therapies.

As to creating a synthetic mirror bacterium, the researchers present this as arising from a ‘bottom up’ approach, based on:

1. Synthesis of a mirror genome in vitro.        

2. Creation of mirror ribosomes and a high-efficiency in vitro mirror protein synthesis system from mirror components.        

3. Encapsulation of the mirror genome and mirror protein synthesis system into a membrane and “booting” of the mirror bacterium.        

However, based on current progress, the trajectory is clear. Once a mirror bacterium is created, it would become much easier for others to duplicate that feat. Hence, the rate of development will become progressively easier (as with many other technologies, according to sociotechnical systems theory).

Risks

The researchers who are expressing concerns with mirror bacteria projects, which includes the scientists from University of Michigan, have outlined worries in a new paper in the journal Science (“Confronting risks of mirror life”).

The core argument is, if created, these organisms may pose significant dangers to human, animal, plant and environmental health. This is especially so should a robust mirror organism be developed.

Immune system

Specifically, this is because the immune defenses in humans, animals and plants rely on recognizing specific molecular shapes found in invading bacteria. However, if these shapes were reflected — as they would be in mirror bacteria — recognition would be impaired and many basic immune defenses could fail.

This is likely because the mirror proteins developed thus far can resist cleavage into peptides and do not reliably trigger important adaptive immune responses such as the production of antibodies [5].

Consequently, the potential for infection, including from organisms that do not currently pose a significant threat to those with fully-functional immune systems, could be significant.

Avoiding natural predators

A second set of concerns surrounds what happens if mirror bacteria enter the environment and are able to evade natural predators (such as bacteriophages or amoebas). This arises because viruses parasitize their host’s cellular translation system and nucleoside triphosphate pool in order to produce proteins and new viral genomes. Mirror ribosomes could not produce natural-chirality proteins and hence bacteriophages would be unable to take command of the bacterial cell.

The interactions between viruses and simple protozoa with bacteria help to limit bacterial populations and this helps to keep the microbial ecosystem in balance.

Altering ecosystems

Transport via animals and humans could enable the spread of mirror bacteria between diverse ecosystems, moving certain types of organisms to environments where they are not typically present thereby altering global ecosystems [6]. Microorganisms can diffuse considerable distances throughout human populations (as the recent case of COVID-19 demonstrated).

Evolution

Synthetic mirror bacteria in the natural environment would be expected to mutate at the same rate, when subject to the same conditions, as other species of bacteria. This introduces a further unknown and concerning bio-variable. It would also be unknown how competing populations of natural and synthetic bacteria would interact and what the outcome of natural selection would be – synthetic mirror bacteria could outgrow other organisms within a niche.

Bioterrorism

Another possibility exists if a pathogenic mirror bacterium were to be created with the intent of causing deliberate harm to human populations (either developed within a country or from a rogue state).

Ethical debate

The researchers are not calling for a cessation of the research; however, from the perspectives of ethics and policy making, they are asking for a broad conversation among scientists, governments, and other stakeholders so there is a clear mitigation strategy to address the potential risks from mirror bacteria.

The researchers are calling for a cessation in research directly involving genomes and proteomes, which are key to creating an artificial cell until robust risk-mitigation strategies are in place in conjunction with the necessary ethical conversations.

A proposed risk-mitigation involves intentionally constraining mirror bacteria by engineering dependence on molecules not present in nature (synthetic auxotrophy). This would mean if such organisms escaped from a laboratory they would be unable to grow in the natural environment. Such approaches have already been used on strains of Escherichia coli used in batch culture [7].

It is also feasible that new ‘antimirror compounds’ could be developed to target mirror bacteria (achiral and racemic antibiotics); although a more pressing concern would relate to most existing antibiotics being nonfunctional (since most antibiotics work by inhibiting chiral enzymes or targeting other specific chiral biomolecules within bacteria).

Media attention

The Science report has attracted a large volume of media attention (unusual for a microbiology related subject).

“The threat we’re talking about is unprecedented,” Professor Vaughn Cooper, an evolutionary biologist at the University of Pittsburgh was quoted by The Guardian as saying. “Mirror bacteria would likely evade many human, animal and plant immune system responses and in each case would cause lethal infections that would spread without check.” [8]

Of course, there is a lot of uncertainty in understanding the precise risks and with estimating how severe or likely each risk factor would be. Yet the opening of the conversation is both necessary and timely.

Further reading

The Science article is supported by a 300-page technical report “Technical Report on Mirror Bacteria: Feasibility and Risks”, hosted by Stanford University) [9].

Tim Sandle is a pharmaceutical microbiologist. Please visit Pharmaceutical Microbiology Resources.

References

1. Siegel, J.S. (1992) Left-handed comments, Science. 258 (5086): 1290, doi:10.1126/science.1455216

2. Carroll, James D. (2009) A new definition of life. Chirality. 21 (3): 354–358

3. F. Rohden, J. D. Hoheisel, H.-J. Wieden, Through the looking glass: Milestones on the road towards mirroring life. Trends Biochem. Sci. 46, 931–943 (2021)

4. K. Harrison, A. S. Mackay, L. Kambanis, J. W. C. Maxwell, R. J. Payne, Synthesis and applications of mirror-image proteins. Nat. Rev. Chem. 7, 383–404 (2023)

5. M. Uppalapati, D. J. Lee, K. Mandal, H. Li, L. P. Miranda, J. Lowitz, J. Kenney, J. J. Adams, D. Ault-Riché, S. B. H. Kent, S. S. Sidhu, A potent d-protein antagonist of VEGF-A is nonimmunogenic, metabolically stable, and longer-circulating in vivo. ACS Chem. Biol. 11, 1058–1065 (2016).

6. J. Bohannon, Mirror-Image Cells Could Transform Science — or Kill Us All, WIRED, 29 November 2010; https://www.wired.com/2010/11/ff-mirrorlife

7. J. R. Bober, C. L. Beisel, N. U. Nair, Synthetic biology approaches to engineer probiotics and members of the human microbiota for biomedical applications. Annu. Rev. Biomed. Eng. 20, 277–300 (2018)

8. Sample, I. ‘Unprecedented risk’ to life on Earth: Scientists call for halt on ‘mirror life’ microbe research, The Guardian, 12th December 2024: ‘Unprecedented risk’ to life on Earth: Scientists call for halt on ‘mirror life’ microbe research | Science | The Guardian

9. K. P. Adamala et al., “Technical report on mirror bacteria: Feasibility and risks” (Stanford Digital Repository, 2024); https://doi.org/10.25740/cv716pj4036