Mirror Bacteria: An AMR threat of unprecedented magnitude

Dear All (wonkish but stick with it … I’m going to try very hard to de-wonk it),

In an absolutely terrifying paper and technical report in today’s issue of Science, we are introduced in detail to the concept of “mirror” bacteria in which all chiral elements of the bacterium are replaced by their enantiomeric counterparts. And if that’s completely unintelligible to you, please stick with me and read just a bit further — you really will want to understand this. To get us started, here are the links and ideas you need:

• The 4-page article itself: Adamala KP et al., “Confronting risks of mirror life.” Science 2024, DOI: 10.1126/science.ads9158.
  • The 299-page technical report that accompanies the article: K. P. Adamala et al., “Technical report on mirror bacteria: Feasibility and risks” (Stanford Digital Repository, 2024); https://doi.org/10.25740/cv716pj4036.
  • A version of the article’s text that is deeply cross-referenced into the full technical report. 
• The Mirror Biology Dialogues Fund (MBDF) that has been created “to advance a global discussion to chart the path forward for mirror biology research.”
• General articles
  • An informative introductory-level article entitled “Mirror Life” from Wikipedia that both covers the scientific idea and also provides a nice summary of mirror image stories from popular fiction.
  • (12 Dec 2024 addendum): An outstanding long-read at a medium technical level: McCarty N and Moorhouse F: “The Dangers of Mirror Life”, https://www.asimov.press/p/mirror-life.
  • 18 Jan 2025 addendum: “Opinion: Reflecting on the Risks of ‘Mirror Life’” dated 16 Jan 2025 is a good short summary of the concepts.
• Some words that matter in following the story:
  • Chiral / Chirality: An object is chiral (or has chirality) if it can be distinguished from its mirror image. Your left and right hands are chiral.
    • Enantiomer: Each object of a mirror-image chiral pair is called an enantiomer. Your left and right hands are enantiomers.
    • Racemic mixture (or racemate): A 50-50 mixture of the enantiomers of a chiral pair. The clapping left and right hands of the audience are a racemic mixture.
  • Achiral: An object is achiral (NOT chiral) if it cannot be distinguished from its mirror image. A solid white sphere is achiral.

OK, so what’s going on here? What is a mirror bacterium? The core concept begins with understanding that most molecules have a natural property that can be called “handedness” or chirality. Your left and right hands are great example of this. Further, think about a pair of gloves … the left glove won’t work very well (if at all) on your right hand. 

Extending this a bit, it turns out that all living things on our lovely planet have agreed to use a consistent set of choices when molecules are sufficiently complex to be chiral. All proteins and all DNA/RNA strands use the same set of choices for their underlying amino acids and nucleotides. The opposite chirality would have worked, but it’s not what was chosen. (12 Dec 2024 addendum: The origins of our planetary agreement on homochirality are unknown, but if you are curious you can see Ozturk et al. (DOI: 10.1126/sciadv.adg8274) for a “prebiotically plausible way of achieving system-level homochirality from completely racemic starting materials, in a shallow-lake environment on early Earth where sedimentary magnetite deposits are expected to be common.” So there!)

A reasonable parallel would the concept of left-hand vs. right-hand traffic. Most of the world drives on the right … but the mirror image of driving on the left works just fine with a little practice (as I learned while living in the UK some years ago).

And that (drum roll) brings us at last to the idea of a mirror bacterium (or organism). If you could replace every chiral molecule in an E. coli with its enantiomer, you’d have a mirror E. coli. If put in a growth medium that contained achiral simple sugars as its carbon source, it would grow and divide normally.

So what’s the fuss? Why is this report creating such news? Although the idea of mirror life is known (at least to sci-fi fans), the potential to actually make a mirror organism has gone from speculative fiction to the possibility of near-term reality based (in particular, but not exclusively) on work exploring ways to make non-mirror organisms from basic chemical building blocks (see this ACS 2021 article for a very deep dive). The ability to actually do this is still at least a decade away, but it is coming … and once we can make a normal (non-mirror) bacterium from scratch, then making a mirror version would also be possible.

And with this, we come to the point of the paper and technical report in Science: All life on earth is in balance (even apex predators have each other as predators) but mirror bacteria would interact with existing life in profoundly different ways from non-mirror bacteria. The mirror bacteria would have many advantages that would mean that the mirror bacteria could easily come to dominate the global ecosystem:

1. The natural innate immune defenses that all living things possess are designed to work against pathogens of the agreed (standard) chirality. A mirror bacterium might go unscathed.
2. Similarly, adaptive immunity (e.g., the antibodies you make when you get vaccinated) will usually have a chiral nature and might well not work vs. a mirror bacterium.
   • We might be able to develop vaccines for the mirror bacterium, but that would be a new vaccine.
3. Natural predators of bacteria (bacteriophage and the protists that prey on bacteria) would be ineffective vs. mirror bacteria.
4. Many antibiotics are chiral and would be ineffective vs. mirror bacteria.
   • A handful of achiral (or racemic) antibiotics would still work: sulfas, quinolones, metronidazole, nitrofurantoin, and trimethoprim. 
   • But we’d lose the penicillins, the cephalosporins, the aminoglycosides, the tetracyclines, vancomycin, linezolid, and others.
   • We could directly synthesize the mirror version of some compounds (e.g., linezolid) as it is readily made by direct synthesis.
   • But anything that starts with a natural product (a large molecule made by bacteria or yeast; vancomycin would be an example) would be very hard to convert to a mirror form.

Or as the authors note, “We cannot rule out a scenario in which a mirror bacterium acts as an invasive species across many ecosystems, causing pervasive lethal infections in a substantial fraction of plant and animal species, including humans.”

Ugh! I encourage you to read the paper and the technical report for more details, but hopefully this paints the picture with clarity: Pandora’s Box for real!

What’s to be done? The authors get us started with these arguments. Note in particular the call for public conversation — the accompanying Mirror Biology Dialogue Fund (MBDF) website gives an initial view on how those conversations would be organized:

• “Unless compelling evidence emerges that mirror life would not pose extraordinary dangers, we believe that mirror bacteria and other mirror organisms, even those with engineered biocontainment measures, should not be created.
• “We therefore recommend that research with the goal of creating mirror bacteria not be permitted, and that funders make clear that they will not support such work.
• …
• “We believe that there is a productive path ahead in which a range of stakeholders collaboratively consider the risks from mirror life and develop appropriate governance without unnecessarily impeding scientific research.
• “Drawing inspiration from the Tianjin Biosecurity Guidelines and other relevant frameworks, we invite the global research community, policy-makers, research funders, industry, civil society, and the public to join this discussion.
• “To facilitate greater understanding of the risks associated with mirror life and further progress on governance, we plan to convene discussions on these topics in 2025.”

Nice ideas … but can we really stop this speeding train? At the very least, the science is still some years from reality and (provided we don’t delay) there’s time for the AMR development community to develop adequate responses: The current crisis of antimicrobial resistance (AMR) that has developed from the natural emergence of superbugs already threatens health worldwide and this report shows that mirror bacteria would sharply accelerate this crisis.

While hoping to keep this Pandora’s Box closed as long as possible, we should prepare for the day that mirror bacteria become a reality — and perhaps this would help us address the AMR crisis that is already afoot.

Critically, we have lamented in prior newsletters the lengthening R&D timelines for new antibacterial agents (e.g., the 30 June 2020 newsletter discussing Dheman et al., FDA’s analysis of 40 years of antibacterial development). The current typical time lags of a decade or more from start to approval would be much too slow to be an effective response: we really should start now to develop dramatically accelerated pathways for discovery, development, and manufacturing of innovative antimicrobials.

Yow! Terrifying, no? Put on your thinking caps. We’ll be talking about this again.

Meditatively yours, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.