Scientists have created a living organism whose DNA is human-made
nytimes.com
nytimes.com
They really didn't.
In this case the claim that it's a fully synthetic genome is fairly suspect, basically it boils down to this:
A codon is 3 base pairs. Giving 64 possible codons.
Each codon codes for an amino acid except for 3 (I think?) stop codons.
This results in more unique codons than there are amino acids.
As a result some amino acids are represented by different codons.
In this paper all they did (not saying it's nothing, but it's definitely not what the headline says) was remove that redundancy. Effectively they ran sed over the genome of E. Coli (I think, I read it this morning which was hours ago), and replaced every occurrence of an alternative codon with a single "standard" one. Then they plonked it into an existing cell and it reproduced.
The biggest challenge was probably ensuring the correct construction over the 3 million odd base pairs in their root strain. Note that of 3 million base pairs, they only made 18000 changes, far from a synthetic genome.
It should not be surprising that given a correct assembly the bacteria reproduced - by design the experiment only replaced codons with a different equivalent codon.
There are also cases where using a "slower" codon help the protein fold well by giving it a bit of time before continuing translation. Changing the kinetics of translation can affect the outcome.
I am surprised. I was under the impression that while two codons may code for an equivalent protein, bacteria do play shenanigans with DNA, like re-reading the same genome multiple times with shifted read frame. I don't think codon equivalence is preserved when you shift the read frame by 1 or 2. Moreover, a DNA molecule with changed codons is slightly different chemically at that place - which means a protein that might have previously attached there for some reason now might not.
That shouldn't be a big concern. For one I think they only altered the base pairs inside the codons of the open reading frames. Most of the important protein binding during transcription and translation happens on regions outside the open reading frames which they left unaltered. Additionally the codons that code for the same amino acid share 2 out of the 3 bases, so they only had to alter a single base, which is usually not enough to change functionality a lot espacially when their main functional property is being translated.
Disclaimer: I only have access to abstract right now
Imagine you're writing a text editor and you get it working well enough to replace spaces with tabs throughout its own source code. Sure, you're not changing the semantic meaning of the code --- but still you're demonstrating that your tool actually works and that it's capable of controlled global edits that don't completely wreck what you're trying to modify. That'd be a pretty major milestone in your text editor project.
This global DNA search-and-replace is the same kind of milestone.
Running with it: They didn't do a sed in place, they split the file and did the sed in place in chunks.
Codons are never really equivalent because of differences in tRNA abundances. So replacing a codon with another that codes for same amino acid can disrupt the rate of translation, and downstream processes like protein folding.
The redundancy is probably there to so that the DNA->RNA copying is more robust against chance mutations in DNA that occurred during cell division.
> The bacteria are alive, though unusually shaped and reproducing slowly.
If I understand correctly, they completely removed two serine encodings and one stop codon encoding. Given how important tertiary DNA and RNA structure is, I think it's remarkable that they're alive at all.
Lab conditions are super friendly to E. coli - they're plated on agar that is tailored to them, kept at a temperature that is tailored to them, and the plates are sterilized so that they have no competitors.
So even if the initial cells were super unhealthy, as long as it wasn't directly fatal the bacteria would grow, and bacteria evolves quickly - fast enough that I'd be interested in seeing how much change was accumulated after 24 hours.
That said, they edits were deliberately just replacing like with like, so it would be expected that they survive.
Interesting follow on research: If you repeatedly ensured that they dropped the alternate serine codings, could you convince it to treat the alternate codings as being something other than serine: the careful engineering would have removed the selective pressure on those codings being serine.
To the extent that we only consider encoded proteins, sure. But DNA and RNA has secondary and tertiary structure that does things - it isn't just bits on a hard drive. Riboswitches and Catalytic RNA are good examples.
For example: (https://www.nature.com/scitable/topicpage/rna-functions-352)
> the elevated temperature inside the host's body melts the secondary structure of a segment in the 5' untranslated region of the mRNA produced by the bacterial prfA gene. As a result of this alteration in secondary structure, a ribosome-binding site is exposed, and translation of protein can take place
Riboswitch overview: (https://www.nature.com/scitable/topicpage/riboswitches-a-com...)
> as long as it wasn't directly fatal the bacteria would grow
The abstract states that 18,214 occurrences were edited. The fact that such drastic structural changes to DNA and RNA weren't immediately fatal is what surprises me. It's believable enough, but I would not have predicted it.
I wonder if they just got lucky with (or perhaps strategically chose) the specific codon substitutions to perform? Would a different set of synonym substitutions have been nonviable?
> I'd be interested in seeing how much change was accumulated after 24 hours.
Very much this. Also, a sibling comment mentions the E. coli long-term evolution experiment; I'd be very interested to find out what changed to compensate for this over hundreds or even thousands of generations.
Recoding scheme was strategically chosen. They cite 2016 paper (PMC5035903) which showed substituting AGA with CGA (synonymous codon for arginine) on E. coli was nonviable.
> Successful replacement codons tended to conserve local ribosomal binding site-like motifs and local mRNA secondary structure, sometimes at the expense of amino acid identity. Based on these observations, we empirically defined metrics for a multidimensional “safe replacement zone” (SRZ) within which alternative codons are more likely to be viable.
It'd be interesting to add these things to the famous E. coli long-term evolution experiment [1] and see how many of the removed codons reappear due to beneficial spontaneous mutations that revert Dr. Chin's changes.
[1] https://en.wikipedia.org/wiki/E._coli_long-term_evolution_ex...
Generally viruses and prions are not considered alive as they are not (theoretically) capable of self replication.
Viruses don't have any of the mechanisms required for self replication - they only reproduce if a different organism is coerced into duplicating the virus's genetic material. Specifically the virus genetic material gains precedence over the cell's own material once the cell dissolves the protein shell.
Prions are literally misfolded proteins - saying they're alive is not different from saying any arbitrary polymer is alive - plenty of polymerization processes essentially have the same construction behaviour: rely on the bond affinities to morph neighboring identical molecules into identical construction.
Other molecules alter the shape of proteins not like themselves, in otherwise similar ways. We don't call them alive, either. Prions are interesting in that their action produces more identical action, in an exponentially growing fashion, unlike other, otherwise similar, processes.
If you like, you could say the prion's shape, itself, reproduces, given a substrate of conformable prionic proteins. That makes it more like a meme.
However, arguing over this terminology is irrelevant.
I wonder whether anyone has measured temperature reduction in a runaway prion replication process.
Richard Dawkins has written an excellent essay on this matter (the human desire for absolute categories):
The tyranny of the discontinuous mind
https://www.newstatesman.com/blogs/the-staggers/2011/12/issu...
He's also written about this topic here: