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Bacteria with synthetic DNA is carefully controlled to be unable to survive outside the lab -- we hope

Deoxyribonucleic acid (DNA) -- helical polymers of nucleic acids attached to a phosphate backbone -- is the blueprint of all life on Earth.  From humans to even some lowly parasitic viruses (essentially bundles of DNA looking for a host), DNA is used daily to encode ribonucleic acid (RNA), which in turn are used to make the proteins that regulate life as we know it.
 
I. It's Life Jim, But Not as We Know It
 
In 1953, Rosalind Franklin and Raymond Gosling photographed double-helical DNA, offering a final conclusive proof of life's genetic code. James Watson and Francis Crick, a pair of famous biologists, popularized the finding.
 
Life as we know it is produce by combinations of two kinds of base-pairs:
  • Adenine -- Thymine (A-T)
  • Cytosine -- Guanine (C-G)
DNA bases
[Image Source: Wikimedia Commons]

These bases are recycled in RNA except for thymine, which is replaced with the nearly identical uracil (U) -- this eliminates thymine's methyl group.  Modern biochemists have recognized the importance of other nucleosides, such as Xanthine and Hypoxanthine, however these do not typically occur in the genetic code.
 
Indeed, the genetic code -- a redundant, binary chemical code -- is naturally resistant to modifications.  In pioneering work 1989 Professor Steven Benner -- today a senior fellow at the Foundation for Applied Molecular Evolution -- examined potential chemically altered nucleic acids.  But that early effort to produce synthetic DNA was stymied by  instability.  Most modified bases did not form strong pairs.  Hence they would ead to lesions in the DNA and difficulty replicating the DNA molecule, which in either case typically leads to cell death.
 
But genetic engineers with The Scripps Research Institute and New England Biolabs have at last cracked that barrier, identifying several usable synthetic base pairs.  The team has successfully "played God" and done what nature has been unable (or unwilling?) to, adding a new base pair to the genome of Escherichia coli (E. coli) bacteria -- d5SICS–dNaM.  The so-called "unnatural base pair" (UBP) is one of several the researchers toyed with.
 
Floyd E. Romesberg
Professor Floyd E. Romesberg, The Scripps Institute

The d5SICS-dNaM base pair shows relatively strong stability despite lacking hydrogen bonding.  It includes a methylated ester side-chain on the dNaM interacting with a thiocarbamate side-chain d5SICS.  The researchers chose the letter "X" to represent dNaM and "Y" to represent d5SICS, so the pair is referred to as an X-Y pair.
 
The special DNA was housed in artificial plasmids inserted into the cell, so as not to upset the delicate epigenetics of the primary genome.
 
In a study published in the prestigious peer-reviewed journal Nature, the researchers showed that the genetically modified organisms (GMO) replicated and preserved the synthetic code when fed a special diet of the new triple-phosphorylated versions of the bases (X and Y).
 
XY UBP DNA
An unnatural base pair is seen here aside a natural base pair (dC-dG). [Image Source: Nature]

Professor Eric Kool, a biological chemist at Stanford University in California, says that for now the chances of these cellular "X-Men" mutants from escaping into the wild are mitigated by their dependence on the special died.  He comments:
 
These organisms cannot survive outside the laboratory.  Personally, I think it’s a less dangerous way to modify DNA.
 
A key advanced by the team behind the work -- led by Professor Floyd Romesberg -- was the creation of DNA polymerases compatible with the UBPs in a previous paper published in 2012 in the journal Chemistry - A European Journal.
 
II. Synthetic Superimmunity, Alien Lifeforms
 
Okay, so it's nifty that geneticists have developed this new and novel expansion of the genetic code, but what's the point?
 
The idea is that eventually organisms may be able to be genetically engineered to produce unique protein enzymes based on exotic amino acids.  Most proteins in living organism are based on a set of 20 commonly occurring amino acids.
 
tRNA matches
tRNA can transcribe certain actions (start/stop encoding) and 20 commonly occurring amino acids.
[Image Source: 3D Molecular Designs]
 
Professor Peter G. Schultz, who heads another lab at the Scripps Institute, has started work to produce dozens of exotic amino acids, which could lead to better antibodies.  An example of his work can be found in this 2012 JACS paper, one of his latest studies on the topic.
 
To finish the work, the labs will have to tie their work together to complete set of finished transcription, translation, and duplication biopathways, including the compounds involved such as enzymes to produce exotic amino acid loaded tRNAs (delivery vessels for translation), which correspond to the UBPs.
 
Professor Romesberg also published a 2002 paper (also in JACS) on developing biosynthetic pathways to transform everyday chemicals into exotic bases.  If she can complete that work things will head in a truly exciting, yet concerning direction, with a new organism capable of living and reproducing without synthetic support using a more advanced genetic code.
 
Typically, 4 base pairs (plus the directionality) encode for an tRNA landing site, yielding a maximum of 64 possibilities (some of which are redundant, hence DNA's "double redundancies"), 20 of which are typically used (corresponding to tRNAs for the 20 common amino acids.  By contrast adding two more bases to the mix would yield 172 possible unique combinations, or up to an additional 152 exotic amino acids.
 
artificial DNA
An expanded genetic code could encode more advanced proteins. [Image Source: Synthorx]

One potential long term application would be to create synthetic, unnatural-sequence gene therapies, which could target cancers and other diseases with devastating accuracy, while leaving the host's body intact.  In that regard mankind could eventually supplement its own modest immune system with a more exotic genome variation, a goal that Professor Schultz's work is clearly targeting.
 
The work could also provide hints at the kinds of exotic biochemistries mankind might one day find if it encounters alien lifeforms during its journeys through our solar system and to other solar systems.

Professor Romesberg has dubbed the new in situ synthetic DNA technology "expanded DNA" or "eDNA".  He and his colleagues have founded a spinoff company, Synthorx LLC, to monetize the invention.

Source: Nature [journal paper]



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Patton Oswald
By Vertigo2000 on 5/14/2014 9:11:03 AM , Rating: 3
We're Science. We're all about 'coulda' not 'shoulda'. We've made cancer airborne and contagious... you're welcome.




RE: Patton Oswald
By Da W on 5/14/2014 10:00:02 AM , Rating: 1
You're right! Lets go back to religous dance around the fire with our shamans.


RE: Patton Oswald
By Reclaimer77 on 5/14/2014 10:12:57 AM , Rating: 1
He's not suggesting that at all.

But let's be clear, we're now talking about altering human DNA at the most fundamental levels. Completely virgin territory, and the ramifications of such a thing haven't even begun being explored.

I don't think you should be shunned for having an ethical concern about such matters. Nay, it's absolutely crucial that we DO have that discussion.

Personally, I'm neutral. I know when I'm out of my element, and there's just no way I'm knowledgeable enough about this field to even have an informed opinion yet.


RE: Patton Oswald
By maxxcool on 5/14/2014 11:44:40 AM , Rating: 2
Idiots, That is a Cave Johnson quote ...


RE: Patton Oswald
By drycrust3 on 5/14/2014 12:51:49 PM , Rating: 5
No it isn't. Look at Super bugs, they are essentially bugs that should have died, but didn't, they somehow escaped being killed by antibiotics, somehow developed a resistance, first to one antibiotic, then another, then another, and now they hang around hospitals waiting for people with weakened resistance to come along and be a host.
If that can happen to natural bacteria, then there is no reason the reverse can't happen to manmade bacteria: they shouldn't escape, but some will, they have special dietary needs that should kill them, but a few won't be killed when they do escape, there shouldn't be any other bacteria for them to breed with, but there will be, and when they do their modified DNA will then be "in the wild".
Every day there are paths in life that one avoids. This is a path that should be avoided unless it is really carefully thought about. By that I mean we should wait for 20 years until we're a bit more grown up about this stuff, we're still just kids at this stuff compared to God.


RE: Patton Oswald
By maxxcool on 5/14/2014 1:54:05 PM , Rating: 2
Still a portal 2 joke... must not have google in your country..


RE: Patton Oswald
By inighthawki on 5/15/2014 1:31:03 AM , Rating: 2
Uhm, no it's not?


RE: Patton Oswald
By wasteoid on 5/16/2014 1:10:41 AM , Rating: 2
I don't see that line in these Cave Johnson quotes:

http://theportalwiki.com/wiki/Cave_Johnson_voice_l...

It does sound like something Cave Johnson would say.


RE: Patton Oswald
By daboom06 on 5/14/2014 2:00:49 PM , Rating: 1
we're all entitled to our own opinions, but some are just wrong. that we don't understand something should never mean it is bad. call me a libertarian, but all the inventions that wreaked havoc on humanity were put into practice by politicians and businessmen.

science just is. it does not do.


RE: Patton Oswald
By Nightbird321 on 5/14/2014 2:03:03 PM , Rating: 1
In the war against pathogens, you can choose to take the pacifist approach if you'd like. (Please don't involve your children though thank you)


RE: Patton Oswald
By geddarkstorm on 5/15/2014 7:27:47 PM , Rating: 3
Don't worry. Seriously, don't.

Firstly, the bacteria here have an essential gene knocked out and replaced with a plasmid (a transient circularized piece of DNA kept separate from the actual genome chromosome) that contains these special bases; thus they require these special bases to live. But they can't synthesize them, not even remotely.

Secondly, the bacteria adapt and get around this severe problem of unnatural bases required for an essential gene by using DNA repair mechanism to -remove- the unnatural bases and -replace- them with normal ones. The unnatural bases do not persist without supplementation, even if the bacteria lives. They ditch those bases absolutely as soon as they can manage it; it's basically poison.

Thirdly, this is nothing like the development of antibiotic resistance. That was selection in a population where naturally, before antibiotics were even a thing we knew of (remember, antibiotics have been made by other organisms long before we discovered that fact, so they are -not new-), mutations existed at a low rate that conferred resistance. "Super bugs" didn't magically appear; they were -always there- to begin with.

Lastly, just like "super bugs", having these unnatural bases would make any bacteria carrying them weaker and at a disadvantage in the world compared to normal bacteria. This is why "super bugs" exist at a very low rate in the absense of antibiotics: they are basically messed up compared to normal bacteria in normal situations, don't live well, and are easily out competed by their non "super" breathern. It's only in the context of antibiotics that suddenly they get a chance to proliferate. It's an unmasking due to removal of the normal population.

In this situation, there is a reason why all of life uses only 4 bases (with uracil as a pitch hitter for thymine in RNA). That's the minimum set possible to have to allow all making all the plethora of proteins required for life, and with room for error correction. If you add another pair of bases, you -vastly increase the energy cost- and burden on the organism. They would have to synthesize the new bases along with all the others (which is expensive); maintain the new bases along with all the others (which is expensive), make new DNA polymerization, repair, and recognition enzymes (which is expensive). In the end, this means such bacteria will be at such an extreme energy and competition disadvantage compared to their normal cousins, they'll be wiped out by life.

Again, there's a -reason- there are only four bases. It's the minimal set and the most energy efficient way. Life is all about maximizing energy efficiency, because in the end, it's always those that are most efficient at exploiting some niche that survive, and the rest do not. Like these unnatural bases constrained guys -- they suck at living, and everyone knows it, even them.


RE: Patton Oswald
By Hakuryu on 5/14/2014 12:28:27 PM , Rating: 2
You might want to actually read the article. Perhaps you can point out where 'altering human DNA' is mentioned?

While 'altering human DNA' is an interesting concept, it has nothing to do with this work, or the article.


RE: Patton Oswald
By Skywalker123 on 5/14/2014 12:56:09 PM , Rating: 4
"I know when I'm out of my element, and there's just no way I'm knowledgeable enough about this field to even have an informed opinion yet"

Wow! I guess there's a first time for everything!


RE: Patton Oswald
By NellyFromMA on 5/14/2014 12:36:01 PM , Rating: 4
Wasn't it discovered early last year that DNA was actually twice as dense genome-wise as we thought. That science was only looking at half of the picture with regard to DNA.

I think even if we understand it 100% we shouldn't be creating new organisms or any life forms, but to do so knowing so little...

I love science, obviously. But I personally have moral issues with this area of science.

Don't degrade people for thinking for themselves. Embracers of science aren't inherently immoral, and those who believe in religious values are not luddites.

What's immoral is putting others down for not believing in what you believe, whether based in science or religion. What makes someone a luddite is not challenging themselves to see things through another perspective.

In short: Be open-minded, even if opinionated, or GTFO.


RE: Patton Oswald
By Da W on 5/15/2014 11:28:35 AM , Rating: 2
How do you know what i think?
I just posted a 5 word sentance in reply to a 10 words one.


RE: Patton Oswald
By tayb on 5/15/2014 4:59:19 PM , Rating: 2
Why shouldn't we be creating new organisms? What is your moral opposition to this? Please don't tell me it is religious.


RE: Patton Oswald
By geddarkstorm on 5/15/2014 7:46:18 PM , Rating: 4
Because there's always a chance we'll create something that'll mess us up, or our ecosystems. Did you really have to make such a shallow sounding post that didn't even think of that on its own but instead pulled the "oh no religion" card?

There's a reason we scientists are obligated -- ethically and morally and often even legally depending on the institution -- to thoroughly bleach or autoclave or otherwise sterilize anything that comes into contact with bacteria that we so much as transform with a plasmid even at the Biosafety level 1 (such as for cloning a piece of DNA or protein production). That's something we do on a near daily basis where I work. And why? Because every time we do a transformation, and select for only bacteria carrying a clone we wanted, we've created an antibiotic resistant "super bug". Yep, that's what we do for a living; so you can imagine why we don't want those running about, especially since bacteria fully believe in "sharing is caring" and give away their plasmids to all their friends and most distantly related cousins.

Modifying organisms is a dangerous game, not for fools or the shortsighted to undertake.

But don't worry, we already know the possible ramifications and take a ton of precautions. But it is always a danger, and only a fool wantonly goes around modifying organisms (at a molecular level) without thought about that. These researchers that the articles is about put a lot of thought into those matters, and we don't have to worry at all about these particular modifications.


RE: Patton Oswald
By NellyFromMA on 5/21/2014 11:55:39 AM , Rating: 2
Well said!


RE: Patton Oswald
By NellyFromMA on 5/21/2014 11:54:45 AM , Rating: 2
I'm not overly religious, as I've been to church all of one time as a kid and don't feel an inexplicable need to define the unknown with a deity, but I think attacks on religious beleifs are disgusting, so hopefully that's not your angle.

I think that its foolish to believe we as humans are so all-knowing that we can venture into any and every facet of science and tweak it to our satisfaction without ramification.

I think that if we had said perfect-working-knowledge PRIOR to manipulating science such as this then that would certainly make it less worthy of extreme caution.

However, while most may not believe in God per-se, its just as if not more foolish to think Man is All-Knowing.

I think there are more than a few contagious diseases out there that were created by man-kind as it is, most probably on accident.

That's where I'm coming from, but if I was coming from a religious perspective, who is anyone to judge that. No one knows the truth so its odd how someone could be put down for believing in something as personal as the spirit.


RE: Patton Oswald
By japlha on 5/14/2014 11:32:46 AM , Rating: 2
Maybe but some people are highly resistant to certain types of cancer. So those are the ones that may be able to survive. Or nothing will happen and we've simply learned something new about how things work. In the worst case, well, that's the end of the human species. Nice knowing you. Chances are our species will eventually go extinct so don't worry about it.

So we can face our extinction by living in caves, fearing new discoveries that may help or harm and let natural selection take over or we can continue to learn how stuff works and do our best to be careful not to blow ourselves up.

But I think this is just an example of the same type of fear and ignorance people had with nuclear explosions vaporizing our atmosphere or the LHC causing black holes that would destroy the earth.


RE: Patton Oswald
By NellyFromMA on 5/14/2014 12:42:38 PM , Rating: 1
quote:
But I think this is just an example of the same type of fear and ignorance people had with nuclear explosions vaporizing our atmosphere or the LHC causing black holes that would destroy the earth.


Nuclear explosions are catastrophic to the environment last time I checked.

quote:
Maybe but some people are highly resistant to certain types of cancer. So those are the ones that may be able to survive. Or nothing will happen and we've simply learned something new about how things work. In the worst case, well, that's the end of the human species. Nice knowing you. Chances are our species will eventually go extinct so don't worry about it.


Hey, I'll certainly commend you for thinking for yourself. However, just because we all die some day doesn't mean we have to compromise the quality of our existence every day.


RE: Patton Oswald
By japlha on 5/15/2014 11:20:54 AM , Rating: 2
quote:
Hey, I'll certainly commend you for thinking for yourself. However, just because we all die some day doesn't mean we have to compromise the quality of our existence every day.


Isn't that what I said?

quote:
So we can face our extinction by living in caves, fearing new discoveries that may help or harm and let natural selection take over or we can continue to learn how stuff works and do our best to be careful not to blow ourselves up.


quote:
Nuclear explosions are catastrophic to the environment last time I checked.

Who said they're not? I'm talking about the extreme fear-mongering doomsday predictions people spout about when dealing with new discoveries or technologies. Last I checked we're not detonating nuclear bombs everyday and we recognize the impact nuclear technology has on us and our world. However, we can also use nuclear technology to generate electricity. So, it's a risk to reward ratio situation. There's some good and there's some bad.


RE: Patton Oswald
By chripuck on 5/15/2014 12:46:00 PM , Rating: 2
You must not know your history. There was a very real fear that if a nuclear bomb was exploded the entirety of Earth's atmosphere would ignite in a nuclear chain reaction.

While nuclear bombs are very, very bad, thankfully they don't cause chain reactions in the atmosphere.


RE: Patton Oswald
By Brockway on 5/16/2014 5:48:33 PM , Rating: 2
The lysine contingency is intended to prevent the spread of the animals in case they ever get off the island. Dr. Wu inserted a gene that makes a single faulty enzyme in protein metabolism. The animals can't manufacture the amino acid lysine. Unless they're continually supplied with lysine by us, they'll slip into a coma and die. - Ray Arnold


Jurassic park anyone?
By iheartzoloft on 5/14/2014 1:04:51 PM , Rating: 2
Paraphrased:
We've altered their genetic code so they cannot procreate... we all know how that turned out. :)




RE: Jurassic park anyone?
By drycrust3 on 5/14/2014 1:11:59 PM , Rating: 2
Yep. Nature will find a way.


RE: Jurassic park anyone?
By geddarkstorm on 5/15/2014 6:51:27 PM , Rating: 2
Yes, by reverting back to normal DNA and losing all special characteristics :).


lol...
By maxxcool on 5/14/2014 11:45:57 AM , Rating: 2
“When life gives you lemons, don’t make lemonade. Make life take the lemons back! Get mad! I don’t want your damn lemons, what the hell am I supposed to do with these? Demand to see life’s manager! Make life rue the day it thought it could give Cave Johnson lemons! Do you know who I am? I’m the man who’s gonna burn your house down! With the lemons! I’m gonna get my engineers to invent a combustible lemon that burns your house down!”




Did not create life
By KITH on 5/14/2014 3:39:33 PM , Rating: 2
I would point out that they did not create life. They merely altered an existing living thing.

I guess before this accomplishment they were only altering DNA with the assistance of viruses?




Way forward
By Munna*** on 5/15/2014 3:18:35 AM , Rating: 2
I think this can provide a lot of work to code writers in future. As an Indian, I'm always fascinated to find the next job. I think in future Indians can get more jobs in code writing for the next DNA strand. People would just get them inserted for improvement of their life, longevity and what not. Best code writers will get the best pay too.




Guys.. come on guys, guys.
By geddarkstorm on 5/15/2014 6:48:29 PM , Rating: 2
I feel there are some important clarifications that need to go on here.

1. The bacteria cannot synthesize those unnatural bases themselves; that would require complex enzymatic pathway machinery that does not exist. Hence, they cannot survive without a supplemented media that provides the bases to them.

2. DNA repair mechanisms remove the unnatural bases and replace them with normal DNA bases. In the absence of supplementation, the bacteria lose the unnatural bases and revert completely to normal DNA.

3. To utilize the unnatural bases requires man altered polymerases that don't naturally occur; otherwise, again, the bacteria default to normal DNA.

4. It makes modifying bacteria -safer- to work with, for everyone.

5. It disrupts epigenetics and thus cannot be used in actual chromosomes (i.e. us).

These buggers will either die if they escape, or the lucky few will return to normal DNA and lose all special characteristics. There's no mystery or problem imposed by these unnatural bases. But they could be useful to us to very carefully -control- production of unnatural products and remove the risk of compound producing bacteria escaping into the environment as happens currently where we can only use normal DNA for everything.

It could give biologists a lot of flexibility, power, and safety when using these unnatural bases for carrying out experiments. This technology also potentially allows us to turn bacteria (or plasmid carrying yeast eventually) into pure bioreactors without the worry of interfacing with and disrupting the natural bacterial systems.

On top of that? It's bloody cool! But it isn't earth shattering.

Will this work in humans? NO.

Will this ever work in humans? NO. Not without extreme genetic modification in a whole frick ton of other genes (remember, gotta change the polymerases to even recognize these unnatural bases). And that's something we aren't even beginning to do yet (human generation time makes us utterly useless for such work anyways -- take way too long).




5th element
By WLee40 on 5/16/2014 11:51:02 AM , Rating: 2
Hey, didn't that 5th element chick have something like 100 base pair combinations??!! Maybe we should make a super human like that??!! ;)




By Bad-Karma on 5/14/2014 8:36:37 AM , Rating: 1
"You were so preoccupied with whether or not you could you didn't stop to think if you should."

-Dr. Ian Malcolm




sensationalize much?
By surt on 5/15/2014 12:06:50 AM , Rating: 1
A more reputable source on Watson & Crick vs others.

http://en.wikipedia.org/wiki/Molecular_Structure_o...




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