
New organisms have been formed using the first ever 6-letter genetic code - walterbell
http://www.sciencealert.com/new-organisms-have-been-formed-using-the-first-ever-6-letter-genetic-code
======
_throwaway1843
Star Trek depicted one of the scarier applications of such a technology:
There, The Jem'Hadaar are a genetically engineered race of warriors controlled
by the Dominion, who exert power over them by being the sole provider of a
substance (Ketracel-White) that they need in order to survive:

[https://en.wikipedia.org/wiki/Dominion_(Star_Trek)](https://en.wikipedia.org/wiki/Dominion_\(Star_Trek\))
[http://memory-alpha.wikia.com/wiki/Ketracel-white](http://memory-
alpha.wikia.com/wiki/Ketracel-white)

If my reading of the paper is correct, the unnatural XY base pair doesn't have
any function per se, but without it the organism fails to replicate its DNA
and quickly dies. Hence you can argue that after introducing it, the XY base
pair has a vital function, as without it the organism can't survive anymore.
And since the organism has no way to synthesize X & Y itself, it needs to be
supplied from the outside for its whole lifetime. This, in turn, provides a
neat way to build "self-terminating" organisms that depend on a steady
supplement of the given substance. One could of course argue that vitamins are
exactly the same, but contrary to those the artificial base pairs would not be
found in the wild, so supply could be controlled more easily.

~~~
_yosefk
It's good as long self-termination is a nice-to-have feature. If you REALLY
want them to self-terminate but you found out that they mutated and can now
synthesize X & Y, you're in trouble.

Genetically modified organisms are a bit scary, but genetically modified
organisms that replicate autonomously are more than a bit scary. As
programmers - a profession that managed to spread Shellshock, the dumbest
imaginable backdoor, so widely as to make much of human population vulnerable,
we should understand this better than others. We have no idea what happens in
our own code, code that we copy from place to place ourselves, written in
languages we designed and running on machines we designed, and there's nothing
like mutation and self-replication with this stuff, for the most part. I kinda
doubt that biologists modifying "code" which is actually pretty large
molecules existing and interacting in a 3D space with a lot of forces pulling
and pushing things, and without the benefit of comments or design documents,
can make something that can be trusted to autonomously replicate and gradually
mutate.

~~~
stcredzero
_We have no idea what happens in our own code, code that we copy from place to
place ourselves, written in languages we designed and running on machines we
designed, and there 's nothing like mutation and self-replication with this
stuff, for the most part._

Documented: Computer viruses mutating in the wild by two different viruses
accidentally copying themselves into overlapping regions of memory.

~~~
PhasmaFelis
Interesting. When has that happened? It seems awfully unlikely to create
"viable offspring" that way, but I suppose most biological mutations are
neutral or negative as well...

------
madebysquares
> "The other reason we don't need to be freaking out, says Romesberg, is that
> these molecules have not been designed to work at all in complex organisms,
> and seeing as they're like nothing found in nature, there's little chance
> that this could get wildly out of hand."

This is how the plot of every horror/disaster movie starts.

~~~
mitchty
> This is how the plot of every horror/disaster movie starts.

Because its a trope. Can you explain how it gets wildly out of hand beyond
speculation?

~~~
zhengyi13
At the risk of oversimplifying, because "even the very wise cannot see all
ends."

Unknown unknowns. You can know your specific problem domain inside and out,
and still have other things show up that rapidly invalidate your assumptions
about the set of possible outcomes.

------
88e282102ae2e5b
Definitely interesting work, and some very clever solutions to difficult
problems, but to be clear, they only had a single unnatural base pair, and it
was only in a plasmid.

Addressing the other comments about this leading to some crazy scifi scenario,
imagine telling someone you used machine learning to identify spam emails and
they started freaking out about how you're going to start Skynet. If you
understand how things really work you can see it's not just implausible, it's
that things fundamentally don't work that way.

~~~
Joeri
Then again, nobody knows how skynet will get started. If it does happen, you
can be sure it'll be done by someone who is sure that things just don't work
that way, right up to the moment they are crushed by a giant metal boot.

~~~
jcoffland
Let's hope that Skynet is not able to feed off of spam. There's so much of
it's food already. We'd never be able to stop it.

~~~
B1FF_PSUVM
I expect that 'Skynet' will be descended from spambots.

------
ambrop7
Can the organism replicate the XY pairs during DNA replication (and pass it on
to divided cells)? I haven't seen that mentioned, only that it "holds onto it
for its entire lifespan" which is not clear to me.

There's also nothing about the interaction of these pairs with existing
mechanisms, like transcription (DNA-->RNA) and translation (RNA-->protein).
Could the new new pair increase the space of aminoacids from which proteins
can be formed?

~~~
oever
The XY pairs are not replicated. To replicate them would require the presence
of a slew of specialized proteins that can deal with XY pairs.

The achievement is that the E. Coli lifetime is not affected. The XY's are
probably inserted in a part of the DNA that is not transcribed.

~~~
88e282102ae2e5b
The paper specifically states that these unnatural base pairs were chosen
because they can be handled by natural polymerases. Also, the only way to
maintain a plasmid over time is to replicate it. In fact, the whole logic of
the strategy is to have Cas9 target mutations to the plasmid so that loss of
the XY base pair during replication would lead to loss of the plasmid, and
thus loss of the antibiotic resistance gene that it also carried.

------
MiddleEndian
Very interesting. I like how about half the article was about reassurance that
this won't lead to out of control monsters.

Along with the recent article about pig embryos, I wonder if the not-too-
distant future will lead to bizarre custom pets, like something out of the
Spore video game.

~~~
andai
When I was very young I spoke with a man who informed me in no uncertain terms
that the digital age was old news and the next big thing would be bio-
entertainment.

~~~
DiabloD3
I'm not sure if that refers to highly customized psychoactive drugs... or
prostitution.

~~~
andai
He elaborated a little: my understanding (at the time) was basically "Pokémon
in real life".

~~~
MiddleEndian
I was thinking Pokemon myself, but the whole fighting aspect would probably be
illegal like dog fighting or cock fighting.

------
vivekd
So will this actually mean anything? Can adding extra letters to an organisms
genetic code actually have the capacity to change it's attributes in any
meaningful way. Every biological characteristic on the planet seems to have
been achieved through using the same 4 molecules, will the addition of more
molecules create new characteristics or be useful in any way?

~~~
maxander
Not really; essentially all DNA "really does" is code for RNA, which in turn
codes for amino acid sequences that fold into proteins. As long as the RNA and
amino acid libraries are the same, it's just representing the same stuff with
a different set of symbols.

In practice, it's probably going to be used as tools for manipulating
organisms for experimental purposes, since scientists can do things to the
synthetic bases that can't be done to real ones (or that effect natural and
synthetic bases differently.)

~~~
dnautics
The biggest application will be introducing unnatural amino.acids into
proteins.

~~~
vivekd
This is what I'm wondering about, can RNA meaningfully make proteins using an
instruction manual that contains molecules that it doesn't recognize? The
scientists created an organism with new DNA molecules but there is nothing in
the paper about whether RNA is actually recognizing and transcribing these new
molecules and how the result of that looks.

My guess is that it would be considered an error by the RNA and corrected but
your parent suggest that the RNA is just treating it like it would one of the
other four molecules with is also a possibility.

~~~
dnautics
correcting does happen at the tRNA stage and it's not as trivial as one might
think[0], but the technology to incorporate unnatural amino acids using
reengineered stop codons has been around for a while and presumably it will
work with X and Y. Note that Romesburg (author of the DNA paper) was a postdoc
in the Schultz lab, where he was originally working on this DNA stuff -- I was
across the street > 10 years ago when they first got the DNA stuff to work in
vitro. He got his own lab across the street and continued on the DNA stuff
(but also other things).

e coli:
[http://www.nature.com/nmeth/journal/v3/n4/full/nmeth864.html](http://www.nature.com/nmeth/journal/v3/n4/full/nmeth864.html)

yeast:
[http://link.springer.com/protocol/10.1007%2F978-1-61779-331-...](http://link.springer.com/protocol/10.1007%2F978-1-61779-331-8_12)

mammalian cells (very very very very very hard):
[http://www.nature.com/nmeth/journal/v4/n3/full/nmeth1016.htm...](http://www.nature.com/nmeth/journal/v4/n3/full/nmeth1016.html)

[0] the trick is to steal a tRNA from an archaeon; scuttlebutt is that the
postdoc on the paper stole the idea from the lab across the hall, which was
actually working on that archaeon.

------
singularity2001
"create organisms with wholly unnatural attributes and traits not found
elsewhere in nature" I'd argue that this shouldn't add anything categorically
new, just like switching from 32 to 64 bit programs doesn't change the world.

~~~
rmah
This is less like 32bit to 64bit and more like moving from binary to trinary
logic.

~~~
lorenzhs
Well binary and ternary number systems can express the same numbers, they just
do it in a different way. I don't think there's a good computer analogy here.

------
gort
There are a number of questions that are probably answered behind the
paywalled article...

* In order to reproduce (and maintain the new bases in its DNA), does the organism need a source of these nucleotides in its growth medium? (i.e. in its food?) The alternative would be to produce them itself, but that would require scarily advanced genetic engineering, I think.

* If one of these bases is in a gene, what happens during mRNA transcription? Total failure?

Point 1 at least should more-or-less ensure this can't escape the lab.

~~~
philipov
I don't see a paywall.

------
NeutronBoy
> But Romesberg says there's no need for concern just yet, because for one,
> the synthetic base pair is useless. It can't be read and processed into
> something of value by the bacteria - it's just a proof-of-concept that we
> can get a life form to take on 'alien' bases and keep them.

While it might not be useful to the organism, could the synthetic base pairs
lead to a way to store data? Imagine a bacteria that can be used as a living,
self-healing datastore.

~~~
jakeogh
[http://www.extremetech.com/extreme/134672-harvard-cracks-
dna...](http://www.extremetech.com/extreme/134672-harvard-cracks-dna-storage-
crams-700-terabytes-of-data-into-a-single-gram)

~~~
NeutronBoy
Yeah that's the sort of thing I'm thinking of! From my total layperson
perspective, the OP article seems to be a step in the right direction for
this.

------
tunnuz
This question that I asked on StackExchange a while ago seems relevant here
[http://biology.stackexchange.com/questions/2874/why-are-
ther...](http://biology.stackexchange.com/questions/2874/why-are-there-
exactly-four-nucleobases-in-dna)

------
jayajay
> Initially, the engineered bacteria were weak and sickly, and would die soon
> after they received their new base pair, because they couldn’t hold onto it
> as they divided.

> Finally, the team used the revolutionary gene-editing tool, CRISPR-Cas9 to
> engineer E. coli that don’t register the X and Y molecules as a foreign
> invader.

> "This will blow open what we can do with proteins."

> [The base pairs] can't be read and processed into something of value by the
> bacteria - it's just a proof-of-concept that we can get a life form to take
> on 'alien' bases and keep them.

> ...have not been designed to work at all in complex organisms, and seeing as
> they're like nothing found in nature, there's little chance that this could
> get wildly out of hand.

To quote Jeff Goldblum, "life, uh... finds a way".

------
Ericson2314
It would be really cool, once the new base pairs code for something, to see
whether this increases evolutionary fitness.

I'm not at all sure whether or not denser information and thus bigger-step
mutations are evolutionary advantageous.

------
peter303
There may be a simpler two codon system embedded inside the three codon system
currently by Earth life. That is when multiple codons specify the same amino
acid, they almost always share the first two nuclides. So it could be that
Earth life experimented with 2 and 3 and maybe even higher codon systems
before settling on the one nearly all life uses. There may have been tradeoffs
in protein complexity, reliability, energy requirements, etc with system that
survived. Maybe just some accidental luck too.

------
elcct
So 5 letter codes are all taken now?

~~~
philipov
How do you propose to make pairs out of an odd number? Each nucleotide binds
to only one other nucleotide.

~~~
dnautics
romesburg made 5 letter pairs, by allowing let's say a third one called "P"
for no good reason, to do the following matches:

A:T T:A C:G G:C P:P

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grandalf
The four letter genetic code is simply one mechanism that works, and leverages
many properties of chemistry and physical chemistry.

[https://www.ncbi.nlm.nih.gov/pubmed/19046126](https://www.ncbi.nlm.nih.gov/pubmed/19046126)

[http://pubs.acs.org/doi/abs/10.1021/acs.jpcb.5b01983](http://pubs.acs.org/doi/abs/10.1021/acs.jpcb.5b01983)

------
hodwik
This opens a lot of possibilities for genetic manipulation, especially in
connection with CRISPR. I imagine the X and Y bases are being kept secret for
proprietary reason

------
msl09
We are only 2 pairs away from encoding 8 bits DNAs

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sebleon
This seems like technology for technology's sake, with zero consideration for
ethics.

~~~
sperglord
On what are you basing that? I'm sure they've also read Jurassic Park.

------
te_chris
Getting closer and closer the world of MaddAddam.

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hellbanner
Confusing to me that "X and Y" are the name of these new letters when X and Y
are commonly referred to as sex chromosomes

~~~
88e282102ae2e5b
Well, the actual names of the base pairs they used are dNaM, d5SICS and dTPT3.
It doesn't seem to me there are any good choices.

------
steffenfrost
What could possibly go wrong?

