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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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