Duda Jarek

Notice you can get all these protein by just copying DNA ... for minimal cells we are talking about hundreds of genes: https://www.nature.com/articles/s41586-023-06288-x - e.g. "493 genes, JCVI-syn3B". Synthesizing the central dogma + DNA, all these proteins will be created themselves ... e.g. enzymes for basic metabolism ... the hard part seem membrane structure, cytoskeleton, replication - which do you think will be technically impossible to recreate in a lab? It is said there are ~10x more bactoriophages than bacteria, coming from infected bacteria ... and this is only one of bacteria natural enemies, preventing exponential growth through e.g. Lotka–Volterra predator-prey cohabitation ... mirror bacteria will have nearly no natural enemies, with exponential growth limited nearly only by resources - taking it from other organisms, dominating succeeding ecological niches ... replacing especially higher organisms: with much slower evolution.

Mirror dogma as complete transcription/translation machinery - just chemistry, done everyday in labs, no problem to enclose it into a membrane ... so where are technical impossibilities for adding further functions like basic metabolism ... finally cell replication? The report is very detailed - if you have lots of concerns, maybe gather more skeptical biochemists and write some detailed critical answer to this report? (would gladly read) It needs sources of energy and materials, natural bacteria has adapted to mirror e.g. sugars so mirror bacteria should adapt to consume e.g. D-sugars ... but there are also lots of achiral molecules both chirality bacteria can directly consume - Table 1.1 of report: Citrate, fumarate, glycolate, glyoxylate, ɑ-ketoglutarate, pyruvate, succinate, Acetate, acetoacetate, butyrate, propionate, valerate, Medium-chain (C6–C10) fatty acids, Long-chain (≥C12) fatty acids, Butanol, ethanol, propanol, Dihydroxyacetone, ethylene glycol, galactitol, glycerol, mucate, Benzoate, m-coumarate, 2-furoate, 3-hydroxyphenylacetate, phenylacetate, phenylpropionate, phenylethylamine, γ-aminobutyrate, putrescine, γ-hydroxybutyric acid, methyl pyruvate, m-tartaric acid, Glycine, Agmatine, γ-aminobutyrate, dopamine, phenylethylamine, putrescine, spermidine, tyramine, Adenine, cytidine, thymine, uracil, Allantoin, urate. One basic question is immune response, and most of its mechanisms are chirality dependent, the report cites lots of research for various types of interactions between natural biology and enantiomers of natural biomolecules ... even if some of them would still work (the report distinguishes certain and unknown), many won't - this would be situation as in immunodeficiencies. Natural bacteria has lots of enemies starting with bacteriophages - mirror bacteria will not have. Also being different many new ecological niches will open for it - what through evolution could drastically change the ecosystem. Regarding Fermi paradox, sure there many dangers coming especially with new technologies - is there a hope our civilization will pass them for the next 10, 30, 100, 1000 years? Very serious question: how to make it more likely? If scientists will not have answers to such question, who to ask?

Like GMO? So you accept synthesizing mirror dogma is reachable (?) and further steps toward mirror bacteria (?), and now say consequences won't be that bad? (otherwise please define your uncrossable barrier on the way) So imagine such mirror bacteria got into the environment, if prepared by malicious player being able to feed on e.g. D-glucose, otherwise still consuming achiral molecules ... not having natural enemies like bacteriphages, being ignored by most immune systems, potentially toxic if consumed ... taking available ecological niches, evolving, spreading ... how do you think it would end? And we are still very early in synthetic life, which will lead to many further organisms relatively easy to create ... then practically impossible to stop spreading, evolving ... you don't see serious dangers to our civilization there? Can they be realistically overcomed? How? And what do you think about Fermi paradox: why, against statistics, we don't see advanced civilizations ... could synthetic life e.g. mirror be the reason?

From Craig Venture Institute, anyway 10-30 years could be also overstatement, and there could be e.g. malicious players paying to quickly get there ... for me it sounds very serious and dangerous, not some abstract SF story, but something really coming and nearly unavoidable (?) ... Can our civilization prevent such fate ? ("Fermi paradox explanation" in 10, 30, 100, 1000 years?) I am thinking about this question since 2007 and the most realistic way I see is another SF sounding technology - from articles observing response before impulse like https://www.scientificamerican.com/article/evidence-of-negative-time-found-in-quantum-physics-experiment/ ... as a physicists I believe in CPT theorem, which also says that causality should work in both time directions, e.g. in the action optimization or Feynman ensembles - in theory allowing for wormholes, but maybe also much more accessible ways to send just information back in time (e.g. using lasers https://arxiv.org/pdf/2409.15399 ) - if getting there, we could send back details about e.g. escaped mirror bacteria, hence physics should action optimize history of the Universe to one without such catastrophe.

I am just listening to discussion about this mirror bacteria report, somebody very serious just claimed that they are planning complete bottom-up synthesis of natural cell in a year(!), they are wondering if there should be moratorium already on mirror ribosome ... very serious, will respond later.

I have some experience in chemoinformatics (e.g. https://link.springer.com/article/10.1007/s11030-022-10589-0 predicting probability distributions of ADMET properties like cardiotoxicity) and yes - excluding various toxicities is extremely crucial and difficult part of drug design, from virtual screening to clinical trials. Some mechanisms should still work (e.g. achiral) and Chapter 5: Medical Countermeasures of the report discusses some approaches like achiral antibiotics, producing mirror antibiotics, or releasing mirror bacteriophages ... but many would not - as in immunodeficient persons we should compare with. From the other side, mirror bacteria would indeed have crippled mechanisms like adhesion, also feeding with natural components - but there are also many achiral sources (Table 1.1: Achiral organic molecules that can be utilized by wild-type or mutant E. coli K-12), and bacteria can adapt to feed on mirror sugars ... the question is if it can get into the bloodstream, e.g. through injuries, if so it could rather easily exponentially grow in population leading to e.g. sepsis for example from released mirror proteins in necrosis. And getting mirror bacteria, it would evolve, take new ecological niches having practically no natural enemies ... also malicious players could easily modify them to become more dangerous.

Sure one can synthesize proteins from single amino acids, but comparing with its production by bacteria, what would be the difference in cost and volume? A thousand? A million? My point is that there will be large financial incentives for such cost reductions and scaling up, and there is a quickly growing number of potential applications, e.g. from the report: > Are you also worried about naturally occurring mirror molecules? For naturally appearing around us, evolution should generally prepare us for. But for others it did not, what does not automatically mean toxicity, but that there is a probability of various toxicities due to looking random interactions (again thalidomide example) ... and the number of potential interactions grows with the square of number of chiral biomolecules, so multiply this probability by millions e.g. for necrosis of mirror bacteria in human bloodstream - for me it sounds worrying.

Sure a company could now produce mirror protein drug for maybe thousans of customers ... but what if millions would like to buy it? If we agree synthetic central dogma is doable, why they couldn't build on it adding further features? Where exactly is your boundary you believe they will not be able to cross?

Just watching a week old presented by Yutetsu Kuruma from Japan Agency for Marine-Earth Science and Technology: Design and construction of artificial cells based on cell-free system - mentions the most difficult is cell replication, where I completely agree ... but just recreating (mirror) central dogma looks doable (?) - and might be sufficient for safe mass production of mirror biomolecules (?) ... or will become the first step toward replicating mirror cells ... George Church Synthetic genomes & tRNAs in vitro & vivo (Nov 2024):

While as a physicists I can say FTL is forbidden by special relativity (but in theory allowed by general relativity) ... I honestly cannot imagine obstacles for recreating cell chemistry - generally easily made outside cell ... so recreating original cytosol composition of some minimal cell, why wouldn't it work? Which chemical processes? They would work individually, but couldn't synchronize like in a living cell? Anyway, looks like these are your words against their. Searching for "boot synthetic cell" I see lots of positive examples. Could you support your view with some references? ps. Lots of talks from Build-a-Cell seminar (tomorrow about mirror bacteria I plan to visit): https://www.youtube.com/playlist?list=PLb2LmjoxZO-gKWXZZadcko8tHHkPuEeJT E.g. 2020 John Glass from J. Craig Venter Institute (e.g. minimal genome: 483 kbp, 432 proteins, 39 RNAs):

Yes, they use this vague "boot" verb for kind of bringing life to a synthetic cell - but what exactly is it? Naively there is just chemistry - statistical reactions in cytosol as a dense soup of biomolecules ... recreating composition of this soup (for some minimal cell with just central dogma), what more is needed to make it alive?

There are programs searching for minimal cell (e.g. https://www.nature.com/articles/s41586-023-06288-x ) but for full synthesis it is not needed. Being able to synthesize mirror ribosome and DNA/RNA, they could get all required enzymes - then enclose it into a membrane ... and why wouldn't such minimal cell work? (to be further extended with more functions) From fig 2.4 of the report: This is bottom-up approach, but the report also discusses top-down: trying to stepwise convert natural cell into mirror one through various approaches, e.g. genetic code reprogramming like replacing tRNA with carrying mirror amino acids. Section 2.3 of report: "1. Production of mirror-image proteins in vivo by creating a crossover pathway made of natural-chirality components. 2. Production of mirror-image proteins in vivo by creating an entirely mirror-image central dogma. 3. Delivery or assembly of a full mirror-image DNA genome in vivo, and removal of the natural-chirality genome, to create a mirror bacterium."

> We have been just a few years away from synthetic life for a few decades now There is continuous progress (timeline from 2019 https://elifesciences.org/articles/45379 ), synthetic cells are created since 2010 ... where do you think will be the main difficulty for complete synthesis of natural minimal cell? I completely agree interactions between both chiralities are very complex, recommend in the report: "Table 1.1: Achiral organic molecules that can be utilized by wild-type or mutant E. coli K-12", "Table 1.2: Utilization of ʟ- and ᴅ-amino acids by E. coli", "Table 1.3: Utilization of the enantiomers of common monosaccharides by E. coli". And reminded thalidomide example - toxicity from basically random interactions, there would be a huge number of them e.g. from necrosis of mirror bacteria in human bloodstream - there is a large chance for various toxicities.

For me Chapter 2 is quite detailed, bottom-up, top-down and other approaches. If reaching first synthetic cell, what seems a matter of a decade, mirror one would just need to use enantiomers - and their synthesis is quickly developing, especially that there are financial motivations, like mass production of mirror proteins, DNA/RNA ... and there could be some malicious players, like nihilist terrorists, or AGI wanting to get rid of humans ... Chapter 4 is indeed extremely detailed, and difficult without immunology background, but basic scenario is such mirror bacteria getting into the bloodstream, and freely multiply being nearly invisible for immune system - reaching sepsis or different problems. Anyway, I agree this is still early (10-30 years away) - good time to discuss, understand, try to find protections if possible.

This is entire Chapter 4: Risks to Human Health of https://purl.stanford.edu/cv716pj4036, maybe take a look there. For example for macrophages looks like nearly nothing would work: