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slade19

Semi-synthetic lifeform

34 posts in this topic

Synthetic biologists have created the first functional creatures (modified E. coli) with an expanded genetic code (so ATGC and XY). They did not give them any of the machinery necessary to synthesize those new bases to keep a tight control on their lives (i.e, if one "escapes", it will quickly die).

Here is a quick article that develops some of the details.

It's a pretty quick development, the "new bases" back in 2014 seemed kind of gimmicky at the time and I didn't take a working organism to be achievable in the near future. CRISPR was also still in its infancy on the technical side despite high claims.

The big hurdle was this step, proving that a living organism can actually survive with it and replicate it. Engineering and introducing modified tRNA to include unnatural amino acids and recognize the new expanded code is in comparison a piece of cake since we are already able to do that.

The key interests of this new technology would be: developing a new form of Life with only synthetic bases, which would allow bioengineers to very tightily control those for production purposes for example, but that's on the long term (I hope, this time); but more immediately, we can now easily introduce a plethora of new amino acids that are not used in nature for protein synthesis (we are going from a 4^3=64 possibilites to a 6^3=216 unit code).

Feel free to ask any questions, or discuss the ethical and scientific implications of this new technology. I don't exactly know what to think of it yet.

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4 minutes ago, slade19 said:

Feel free to ask any questions, or discuss the ethical and scientific implications of this new technology. I don't exactly know what to think of it yet.

1. Can someone do this in their basement? Or, How long will it take before someone can do this in their basement?

2. Who is busy brainstorming the uses this could be put to? I sure would enjoy seeing a list. Not the type of list intended for the mainstream media. A list like some of the really creative brainstormers could come up with.

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1 minute ago, vertebrate said:

1. Can someone do this in their basement? Or, How long will it take before someone can do this in their basement?

Hard to say, the modifications using CRISPR/cas9 are not excessively difficult if you know what you are doing, and you would just need to replicate the modifications on the few enzymes they engineered (the real difficult part). If I tried to do it I would get stuck at the synthesis of the bases and the precise engineering of the enzymes they are using which is above what a hobbyist in his basement can do (if those are easily available comercially at any point, that's another story). I would need to take a deeper look at the methods but it's not unfeasible now that they did the heavy work.

1 minute ago, vertebrate said:

2. Who is busy brainstorming the uses this could be put to? I sure would enjoy seeing a list. Not the type of list intended for the mainstream media. A list like some of the really creative brainstormers could come up with.

I would say it's the wet dream of any synthetic biologist, biochemist, bioengineer and anyone involved with cellular biology (so that includes me actually), asking who is busy thinking about it is the wrong question, just like asking who is doing the work on CRISPR nowadays doesn't make sense since new uses are found by students everyday.

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25 minutes ago, slade19 said:

Synthetic biologists have created the first functional creatures (modified E. coli) with an expanded genetic code (so ATGC and XY). They did not give them any of the machinery necessary to synthesize those new bases to keep a tight control on their lives (i.e, if one "escapes", it will quickly die).

Here is a quick article that develops some of the details.

It's a pretty quick development, the "new bases" back in 2014 seemed kind of gimmicky at the time and I didn't take a working organism to be achievable in the near future. CRISPR was also still in its infancy on the technical side despite high claims.

The big hurdle was this step, proving that a living organism can actually survive with it and replicate it. Engineering and introducing modified tRNA to include unnatural amino acids and recognize the new expanded code is in comparison a piece of cake since we are already able to do that.

The key interests of this new technology would be: developing a new form of Life with only synthetic bases, which would allow bioengineers to very tightily control those for production purposes for example, but that's on the long term (I hope, this time); but more immediately, we can now easily introduce a plethora of new amino acids that are not used in nature for protein synthesis (we are going from a 4^3=64 possibilites to a 6^3=216 unit code).

Feel free to ask any questions, or discuss the ethical and scientific implications of this new technology. I don't exactly know what to think of it yet.

At quick glance, specific to e.coli, the 2014 development sounds more like a solution to combat e.coli by weakening it and then having it die out in the host body.  The second development is concerning since it sounds possible to create a strain that requires lifelong medication or can be weaponised.

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3. Eventually, could horizontal gene transfer from this technology occur accidentally in the wild, in some manner that worked?

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1 minute ago, Distance said:

At quick glance, specific to e.coli, the 2014 development sounds more like a solution to combat e.coli by weakening it and then having it die out in the host body.  

 I am not sure I see what you are talking about.

1 minute ago, Distance said:

The second development is concerning since it sounds possible to create a strain that requires lifelong medication or can be weaponised.

The first is already possible, and the second as well. It seems like a very inefficient roundabout way to create a weapon of unknown efficiency. We know the new E. coli can survive with these new letters, but it doesn't instantly make them militarily interesting.

 
 
...... added to this post 6 minutes later:
 
Just now, vertebrate said:

3. Eventually, could horizontal gene transfer from this technology occur accidentally in the wild, in some manner that worked?

Horizontal transfer, sure, but natural lifeforms wouldn't know what to do with it. Even the current one has no way to use the new bases for now. On the other hand, if we do introduce tRNA genes able to deal with these new letters, then yes, they can get passed down to another being.

Will it remain? Probably not, because the being who integrates this new information wouldn't be able to replicate it (it can't synthesize the bases, and the key modifications to make the organisms compatible was making enzymes able to even handle such foreign chemicals and integrate them in DNA.

It's not a serious concern.

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1 minute ago, slade19 said:

 I am not sure I see what you are talking about.

It's likely because I don't know what I'm talking about.  From the cursory glance and no knowledge, it appears to me that it might be possible to weaken the e.coli strain within an infected person's body.

1 minute ago, slade19 said:

The first is already possible, and the second as well. It seems like a very inefficient roundabout way to create a weapon of unknown efficiency. We know the new E. coli can survive with these new letters, but it doesn't instantly make them militarily interesting.

What if e.coli was enhanced to defy all meds, except for a specific variety that the nefarious creators produce? This way, the creating country can hold other countries hostage and reap financial gain while doing so.

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8 minutes ago, slade19 said:

It's not a serious concern.

OK, thanks, I didn't know.

4. What could this technology eventually be used for in more complex lifeforms? Say, a semi-synthetic horse.

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Just now, Distance said:

It's likely because I don't know what I'm talking about.  From the cursory glance and no knowledge, it appears to me that it might be possible to weaken the e.coli strain within an infected person's body.

No. They are separate entities, no connection.

Just now, Distance said:

What if e.coli was enhanced to defy all meds, except for a specific variety that the nefarious creators produce? This way, the creating country can hold other countries hostage and reap financial gain while doing so.

Well, again, that can be done with regular E.coli, the only advantage I can see is having perhaps less evolvable, more tightly controlled genetic material in whatever strain you are using (i.e, less of a risk for "spillovers" in other organisms, or it evolving in unpredictable ways) but that's a risk I don't see anyone taking. Besides, to make biologial weapons out of them, you would have to make them independent from the new bases' supply, basically losing your leverage over them, so pretty strategically dumb (no real control at all).

 
 
...... added to this post 5 minutes later:
 
4 minutes ago, vertebrate said:

OK, thanks, I didn't know.

4. What could this technology eventually be used for in more complex lifeforms? Say, a semi-synthetic horse.

We are not anywhere near that. The only feature it allows us to change, as far as anybody can tell for now, is adding a whole lot of new amino acids to the toolbox of proteins. It's great news for drug development (we can explore peptidic antibiotics no bacteria is prepared for) and overall chemical synthesis, but since it's so new, it will take a lot of work, and there are still major difficulties in understanding regular proteins' structure and function with their 22 amino acids. It's difficult to estimate at what pace this will advance, or if it will ever find a concrete practical use (very probably though).

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6 minutes ago, slade19 said:

No. They are separate entities, no connection.

Well, again, that can be done with regular E.coli, the only advantage I can see is having perhaps less evolvable, more tightly controlled genetic material in whatever strain you are using (i.e, less of a risk for "spillovers" in other organisms, or it evolving in unpredictable ways) but that's a risk I don't see anyone taking. Besides, to make biologial weapons out of them, you would have to make them independent from the new bases' supply, basically losing your leverage over them, so pretty strategically dumb (no real control at all).

Fair enough.

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22 minutes ago, slade19 said:

We are not anywhere near that. The only feature it allows us to change, as far as anybody can tell for now, is adding a whole lot of new amino acids to the toolbox of proteins. It's great news for drug development (we can explore peptidic antibiotics no bacteria is prepared for) and overall chemical synthesis, but since it's so new, it will take a lot of work, and there are still major difficulties in understanding regular proteins' structure and function with their 22 amino acids. It's difficult to estimate at what pace this will advance, or if it will ever find a concrete practical use (very probably though).

Thanks. I have a what-if, rather sci-fI brain. Off to work now. Glad you had patience with my questions, this development in biology is very interesting. I looked up the definition of life to see if (edit: semi-) synthetic life even meets the criteria, and it does. 

Edited by vertebrate

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2 hours ago, slade19 said:

No. They are separate entities, no connection.

Well, again, that can be done with regular E.coli, the only advantage I can see is having perhaps less evolvable, more tightly controlled genetic material in whatever strain you are using (i.e, less of a risk for "spillovers" in other organisms, or it evolving in unpredictable ways) but that's a risk I don't see anyone taking. Besides, to make biologial weapons out of them, you would have to make them independent from the new bases' supply, basically losing your leverage over them, so pretty strategically dumb (no real control at all).

The bolded is exactly what you want in a bio-weapon: something that kills then dies quickly itself.

A geneered E.coli that contained a neurotoxin-encoding plasmid along with a dependancy for synthetic nucleotides seems to have promise as a bio-weapon.
After infection, the host dies of neurotoxin poisoning, the E.coli dies soon after and your troops roll into conquered terrority without having to worry about NBC clothing, antidotes or rebuilding infrastructure.

How long does this strain live without the sythetic supplements?

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9 hours ago, slade19 said:

 but that's a risk I don't see anyone taking. Besides, to make biologial weapons out of them, you would have to make them independent from the new bases' supply, basically losing your leverage over them, so pretty strategically dumb (no real control at all).

Oh, I don't know about that. I would build a new race of humans based on novel amino acids, giving them the ability to synthesize these themselves. These humans would be immune to infection by all naturally occurring micro organism. They could release every kind of plague to kill off the competing natural humans and thus inherit the Earth.

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7 hours ago, Eclipsed said:

The bolded is exactly what you want in a bio-weapon: something that kills then dies quickly itself.

A geneered E.coli that contained a neurotoxin-encoding plasmid along with a dependancy for synthetic nucleotides seems to have promise as a bio-weapon.
After infection, the host dies of neurotoxin poisoning, the E.coli dies soon after and your troops roll into conquered terrority without having to worry about NBC clothing, antidotes or rebuilding infrastructure.

How long does this strain live without the sythetic supplements?

30 minutes, because it can't replicate; assuming it remains stuck and doesn't replicate but does survive a while, I would say a day, but not particularly operational. If it's going to be about neurotoxin, then you use them as factories to synthesize it then use the neurotoxin in another way, your version is extremely difficult to implement.

 
 
...... added to this post 6 minutes later:
 
1 hour ago, thod said:

Oh, I don't know about that. I would build a new race of humans based on novel amino acids, giving them the ability to synthesize these themselves. These humans would be immune to infection by all naturally occurring micro organism. They could release every kind of plague to kill off the competing natural humans and thus inherit the Earth.

It's a two way street, it would be very easy for the competition to synthesize in mass some inhibitor of your bases synthesis or of incorporation in DNA. It would be completely harmless to the regular population, but easily deadly to any of your mutants. We could also do inhibitors of protein synthesis specific to you and the few possibilities I just gave are non-exhaustive. You would basically be some kind of infection totally foreign to us and we would have endless attack vectors to eradicate you while not harming any other lifeform.

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3 hours ago, slade19 said:

30 minutes, because it can't replicate; assuming it remains stuck and doesn't replicate but does survive a while, I would say a day, but not particularly operational. If it's going to be about neurotoxin, then you use them as factories to synthesize it then use the neurotoxin in another way, your version is extremely difficult to implement.

If we're going to stick with E.coli, use it to poison a water supply.
Dumping it in a reservoir wouldn't work; too many water treatment steps, but a 24hr lifespan might be long enough to contaminate a good number of water faucets from a supply tank in a single building - bathrooms, cafeteria etc. Fancy filling a parliament building with corpses maybe?
Add in cholera toxin production and you could have a nice messy winner.
Or if you wanted to play a long-game, use a prion and give everyone mad cow in 10 years. A prion would probably survive standard cooking processes.

But 24 hrs isn't really a long enough lifespan. What we're looking for is a 3 to 4 day asymptomatic infective phase followed by a toxin-producing phase. Maybe find a way to allow our E.coli to stock-up internally on the synthetic nucleotide, and entice our organism to produce toxin in response to something in the diet, maybe caffeine.
What the hell, let's just use a eukaryote instead.
When are people going to start this line of work in S.cerevisiae or one of the Aspergillus species? Some of them are already quite nasty.

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2 minutes ago, Eclipsed said:

If we're going to stick with E.coli, use it to poison a water supply.
Dumping it in a reservoir wouldn't work; too many water treatment steps, but a 24hr lifespan might be long enough to contaminate a good number of water faucets from a supply tank in a single building - bathrooms, cafeteria etc. Fancy filling a parliament building with corpses maybe?
Add in cholera toxin production and you could have a nice messy winner.
Or if you wanted to play a long-game, use a prion and give everyone mad cow in 10 years. A prion would probably survive standard cooking processes.

But 24 hrs isn't really a long enough lifespan. What we're looking for is a 3 to 4 day asymptomatic infective phase followed by a toxin-producing phase. Maybe find a way to allow our E.coli to stock-up internally on the synthetic nucleotide, and entice our organism to produce toxin in response to something in the diet, maybe caffeine.
What the hell, let's just use a eukaryote instead.
When are people going to start this line of work in S.cerevisiae or one of the Aspergillus species? Some of them are already quite nasty.

While this is a rather interesting subject, I don't think this forum is ok with discussing the practicalities of bioterrorism (at least from the attacker's perspective).

Of course a eukaryote is the next step (although it would be substantially more difficult to make a functional one: you need to engineer specialized import of the nucleotides, and all the enzymes prokaryotes don't need).

But in the end it would solve nothing: either they are autonomous, or you are much better off producing the poison yourself and dumping it in the site. This way you can actually be sure the right dose is produced.

Bioterrorism is only interesting (and worth the effort) if the threat is crippling (i.e, highly contagious and debilitating) what you are describing is just poisoning the well. Of course you need to be able to occupy the places where it was used but you can do that by creating a vaccine/cure for you army.

Besides, it would take the engineering of only one enzyme to "immunize" the critical sites: a restriction enzyme that cuts any sequence containing a synthetic base or degrades the synthetic base.

The investment, both theoretical and practical, to make this a viable bioweapon is not light and the advantages not particularly interesting.

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How interesting!!!

 

It's cool, interesting and frightening at the same time. I cannot help but think that some of what science does is myopic in nature. While there is surely no intention to hastily end the human race, my mind is growing wild with ideas for a dystopian sci-fi novel with highly evolved synthetic base life-forms that have the potential to wipe out the human race. 

Edited by Lovecraftian

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23 minutes ago, Lovecraftian said:

highly evolved

Define highly evolved.

There is a reason four bases is all we are using and no other code ever evolved despite presence of other bases in nature (Life actively supresses those): evolutionarily, increasing the mutational space dilutes your solutions in a bigger sea of lethal deadends. It's not at all clear that this new life-form is stable on the long term (that is, without active oversight and maintenance).

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5 minutes ago, slade19 said:

Define highly evolved.

There is a reason four bases is all we are using and no other code ever evolved despite presence of other bases in nature (Life actively supresses those): evolutionarily, increasing the mutational space dilutes your solutions in a bigger sea of lethal deadends. It's not at all clear that this new life-form is stable on the long term (that is, without active oversight and maintenance).

More complicated would have been the more appropriate word: Multicellular organisms that evolved by natural selection and are capable of rational thought, manipulate their environment, and create civilization.  It might take a couple billion years, unless some mad scientists learn to accelerate their evolution. 

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Just now, Lovecraftian said:

More complicated would have been the more appropriate word: Multicellular organisms that evolved by natural selection and are capable of rational thought, manipulate their environment, and create civilization.  It might take a couple billion years, unless some mad scientists learn to accelerate their evolution. 

I am pretty confident in our tendency to kill what we fear to keep that in check. It could lead to the ultimate form of genocide pretty easily.

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do researchers use trial and error to find suitable synthetic bases? is there some underlying symmetry/structure that must be satisfied by candidate synthetic bases, hence can be potentially analyzed via, say, abstract algebra and the other mathematical tools?

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31 minutes ago, muddyglass said:

do researchers use trial and error to find suitable synthetic bases? is there some underlying symmetry/structure that must be satisfied by candidate synthetic bases, hence can be potentially analyzed via, say, abstract algebra and the other mathematical tools?

Great question!

Yes, there are, the overall geometry of DNA must be maintained (specific angles between bases and the phospho-ribose "spine", and the major and minor groove) while at the same time allowing it to move exactly like before: being bendable by proteins to make specific places repressed or accessible, being able to completely change the geometry (B form DNA is the most common, but there are proteins that bind very specifically and strongly to B', A, and Z form DNA), then you have to consider the conditions at which DNA "melts" i.e where the strands separate to be read, replicated, or form specific structures. Since DNA is also defined, in its geometry and stability, by the interactions between bases (interstrand sure, but most importantly intrastrand) you must find something that will interact just the right way with the rest to avoid altering the rigidity or chemical properties.

A, B, and Z form:

Spoiler

800px-Dnaconformations.png

It's overall a pretty impressive work they achieved.

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6 hours ago, slade19 said:

Great question!

Yes, there are, the overall geometry of DNA must be maintained (specific angles between bases and the phospho-ribose "spine", and the major and minor groove) while at the same time allowing it to move exactly like before: being bendable by proteins to make specific places repressed or accessible, being able to completely change the geometry (B form DNA is the most common, but there are proteins that bind very specifically and strongly to B', A, and Z form DNA), then you have to consider the conditions at which DNA "melts" i.e where the strands separate to be read, replicated, or form specific structures. Since DNA is also defined, in its geometry and stability, by the interactions between bases (interstrand sure, but most importantly intrastrand) you must find something that will interact just the right way with the rest to avoid altering the rigidity or chemical properties.

A, B, and Z form:

  Reveal hidden contents

800px-Dnaconformations.png

It's overall a pretty impressive work they achieved.

could you point me to some textbook that discusses this structure with greater technical details? it might be interesting to read up on in the future, thanks.

surely some folks must've done work translating the necessary underlying geometry into rules for how the sequences of letters representing the bases can be arranged, and how various subsequences of these letters can be arranged. dna seems like it could be studied as a combinatorics/algebra problem.

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