GM microbes created that can’t escape the lab (2015) | Hacker News Reader

GM microbes created that can’t escape the lab (2015)

nature.com

Life... uh... finds a way.

They literally use the same method: Make the bacteria dependent on a supplied nutrient.

So they use "selection" to engineer such bacteria and hope that random mutations and gene-swapping won't find a way out of this?

Gene-swapping is at least mentioned in the fourth paragraph of the article. I would like some more detail on this part, too. They also have more references to virus resistance for what sound like the same reasons:

> Fourth paragraph:

> The microbes also do not swap their engineered DNA with natural counterparts because they no longer speak life’s shared biochemical language. “Establishing safety and security from the get-go will really enable broad and open use of engineered organisms,” says Farren Isaacs, a synthetic biologist at Yale University in New Haven, Connecticut, who led the other study.

sorta, but the amino acid doesn't exist in nature. so unless something starts making something that nature has never on an atomic level made before, these GM organisms have no where to get it from. In The book JP2 it was noted that the herbivorous dinosaurs ate loads of soy, which has naturally occuring lysine, and the carnivorous dinos ate the herbivores.

Or, what, like they, uh, "adapt" in some way, like a process of "evolution" or something?

Yeah, you know, how we humans can adapt and evolve in a few generations to use nitrogen instead of oxygen or replace our mitochondria with microscopic oompa loompas. /s

Without knowing how critical the added genes are to the organism's metabolism or how they are integrated into its lifecycle, there is no way to tell if it is even possible for the organism to evolve an alternative in any practical time frame. Evolution does wonders over long time scales but even it is beholden to basic physics.

> Yeah, you know, how we humans can adapt and evolve in a few generations to use nitrogen instead of oxygen or replace our mitochondria with microscopic oompa loompas.

I think that a major difference here is that the length of a generation for bacteria is way shorter than for humans, so that it is feasible for them to evolve in unforeseen ways in an observeable amount of time.

Unforeseen, sure, but evolution is practically incapable of wholesale changes to an organism at a fundamental level. For example, if we engineered a microbe to use AUCG instead of ATCG for DNA, which would require massive changes to its cellular machinery, even a generation a minute for a million years would not be enough to switch back to regular base pairs because the microbe would be incapable of basic horizontal gene transfer with other microbes or giant evolutionary leaps that require precise simultaneous changes to all of its reproductive machinery. Obviously this is not 100% guaranteed but if we can engineer an organism that fundamentally depends on a metabolic process that is prohibitively difficult to evolve naturally, we can maintain an extreme level of control.

> Unforeseen, sure, but evolution is practically incapable of wholesale changes to an organism at a fundamental level.

Oh, I see. I incorrectly read the emphasis of your post as being the unlikelihood of change occurring "in a few generations", rather than on the fundamental nature of the changes.

Not really, evolution has a very low probability of making large scale changes. However it can operate in any direction giving many many options for getting from A to B.

Many single celled organisms can for example swap small segments of code between them. https://en.wikipedia.org/wiki/Horizontal_gene_transfer Thus the minimum change required for some information exchange is only transcription not survival and thus fairly simple. Sure, the original organism died, but as long as some information carries on that's what evolution is about.

A larger barrier is the value of such transcription being limited until it works. But again if there happens to be a simple way to do it then it might show up.

The E. coli long-term evolution experiment [0] has observed 65000 generations in 28 years. That's the length of about 0.88-1.27 human generations.

But humans no longer rely on only sexual reproduction, mutation, and horizontal gene transfer to evolve. We have this CRISPR/Cas9 mechanism now, which is putting us closer to doing something like flipping a known SNP--perhaps changing rs6152(G) to rs6152(A), to prevent baldness. Or we can splice the Bt gene into ourselves, so we won't ever be eaten by corn borer larvae.

In five human generations (110-160 years), humans will probably be able to replace/augment their mitochondria with captive subcellular oompa loompa biomachines. But even in 5000 human generations, we would not replace aerobic O2 metabolism with anaerobic N2 metabolism, simply because N2 is not as reactive as O2, thus is not as useful biologically in any environment where oxygen is available. It's more likely that we would add a supplementary anaerobic metabolism such that nitrogen asphyxiation results in a hibernation or torpor state, rather than death.

Complexity pays off sometimes.

[0] https://en.wikipedia.org/wiki/E._coli_long-term_evolution_ex...

Using CRISPR/Cas9 to modify an organism isn't evolution by natural selection, it's genetic engineering, which is my whole point. Natural selection has the benefit of time but we have the benefit of intelligence and culture, which can be far more powerful because our modifications aren't bound by the fitness of all of the intermediary states. This allows us to make increasingly complex changes to biomolecular machinery that are all but impossible to [d]evolve within our current ecosystem because of the billions of years of biological debt, to borrow a term from software engineering.

The question isn't whether we can augment ourselves through advanced technology, it's whether or not we can design a microbe that is so different from existing life that we can control its reproduction indefinitely (in the face of evolution) without crippling the organism's usefulness to our civilization.

How are engineers supposed to cope with evolution's god-like prowess?

I give it about 50-50 odds someone was actually inspired by the fiction, directly.

I would read an entire novella on the Lysine Contingency

Seriously. This was the plot of Jurassic Park (the book) where the Velociraptors required lysine dietary supplements. http://jurassicpark.wikia.com/wiki/Lysine_contingency

This effort was made possible by the earlier work by Isaacs and Church groups on reclaiming the UAG stop codon by removing all instances of it genome wide [1]. Today the Church group published a followup on progress on removing six more codons [2]. If they can finish this, they should be able to make an organism dependent on not one but 4 different synthetic amino acids. Yes, life might evolve away from needing one, but with proper design all four would make an organism that would be exceedingly unlikely to escape.

[1]. http://science.sciencemag.org/content/342/6156/357

[2]. http://science.sciencemag.org/content/353/6301/819

EDIT COI: I am a former member of the Church lab.

More exciting will be the first mutation that undermines this constraint.

They could hide it in a deep potential well, where such mutation will be virtually impossible to happen before the lifetime of the universe.

We have proven time and time again that humans have a terrible ability to predict the "virtually impossible."

It's not hard to do a lousy job, doesn't mean it's the only possibility.

Full PDF (not open access): http://www.nature.com/nature/journal/v518/n7537/pdf/nature14...

Auxotrophy[1] been exploited for years to select for engineered organisms. Reverse mutation to prototrophic strain is often an issue. This work by Mandell, et al., is novel because it relies on the organism being auxotrophic for a non-standard amino acid, L-4,49-biphenylalanine. It's cool the system is stable.

1. https://en.wikipedia.org/wiki/Auxotrophy

I feel the key sentence is “Our strains, to the extent that we can test them, won’t escape,

Is GM a common abbreviation to be used in a headline?

Thanks! Only after reading your comment the headline started making sense grammatically. I was wondering why would they write such a malformed sentence, with "General Motors" in my head the whole time.

I feel like "GMO" would have made all the difference

I notice a lot of people are concerned that these GM microbes will evolve and escape.

Could anyone comment on the probability of that compared to the probability of an equally severe microbe surfacing in the wild?

Curious overlap between biocontainment and encryption. You're trying to "encrypt" away from the life form some "key" it needs and that you control. Your key needs to be sufficiently complex that evolution can't brute force it; your "lock" thoughtfully integrated so something similar enough to it can't be substituted.

Except that in cryptography there is always the accepted reality that given time, any lock is subject to being broken. Apparently no one informed this brain trust of that little fact, and how it might relate to their organisms.

That's a great analogy. Although I think it's rather more like DRM - you want a "program" to only "run" if some "key" is present, and your adversary wants to make the smallest possible change to the program to run it without the key.

It was something of a lightbulb moment for me when it finally clicked why "perfect" DRM is impossible: no matter how convoluted and obfuscated your locking mechanism is, somewhere in there it all boils down to a final if-then - "did the authentication pass?". And this can always be patched to return "yes" instead of "no", trivially bypassing the whole thing. And you can't get around it even with drastic measures like encrypting the source and providing the key on demand - the key can always be saved. The code can always be made to run, and DRM can always be short circuited.

Carrying the analogy back to biology: so they've made their organisms reliant on a new amino acid. Who's to say it won't learn to synthesize its needed building block? After all, it's all the same atoms. The key can always be saved...

Still, it seems they did attempt to provoke this, and failed. DRM doesn't have to be theoretically perfect to be effective. It's impressive stuff, engineering organisms with an incompatible genetic code - maybe not be a panacea, but it definitely helps.

A simple fix for many of the objections in this thread: can't means low probability.

And they took out all the genes that would prevent an easy fall-back to working without this amino acid ? As well as the code/DNA required to steal genes from other bacteria ?

Why can't the bacteria evolve enzymes to produce these amino acids? After all, they evolved enzymes to produce every other amino acid...

Anyone instantly thinking of Neal Stephenson's Zodiac?

How are they generating the amino acid?

[edit] I also noticed that this article is over a year old.

I guess we can look forward to Jurassic Pork.

Sounds familiar somehow

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