Scientists Develop New Genetic Bases

       
Chris Miller

Main Article:

          Pollack, Andrew. "Scientists Add Letters to DNA’s Alphabet, Raising Hope and Fear." The New York Times. The New York Times, 07 May 2014. Web. 23 May 2014.

Additional Sources:

Greenfieldboyce, Nell. "Chemists Expand Nature's Genetic Alphabet." NPR. NPR, 7 May 2014. Web. 23 May 2014.

Landau, Elizabeth. "New Life Engineered with Artificial DNA." CNN. Cable News Network, 9 May 2014. Web. 20 May 2014.

Malyshev, Denis A., Kirandeep Dhami, Henry T. Quatch, Thomas Lavergne, Phillip Ordoukhanian, Ali Torkanami, and Floyd E. Romesburg. "Efficient and Sequence-independent Replication of DNA Containing a Third Base Pair Establishes a Functional Six-letter Genetic Alphabet." PNAS. Proceedings of the National Academy of Science, 6 June 2012. Web. 23 May 2014.

Service, Robert F. "Designer Microbes Expand Life's Genetic Alphabet." Science/AAAS. American Association for the Advancement of Science, 7 May 2014. Web. 23 May 2014.

          Scientists from the Scripps Research Institute in California have developed two additions to life's four known nucleotides- adenine, thymine, guanine, and cytosine- known as X and Y. X and Y bases were developed after over three hundred failed base formulas and structures that simply did not work as well. The new bases are drastically different from the typical ATGC bases used by natural life. The bonding between base pairs of A-T and G-C is based on hydrogen bonds- hydrogen molecules bond strongly with nitrogen, oxygen, and fluorine molecules, pulling the bases together. However, the new X and Y bases utilize hydrophobic interactions and complementary shapes, allowing them to have similar bond strength and stability to A-T and G-C pairs. Incredibly, when an E. Coli cell was modified to include X and Y bases and supplied with free floating X and Y nucleotides, the DNA Polymerase enzyme which replicates DNA, was able to successfully copy the X and Y bases with an error rate of just .1%. The team is currently attempting to decrease the error rate to .01% using a variety of polymerases, at which point the transcription error rate would be indistinguishable from the error rate of the natural bases. However, without externally supplied X and Y nucleotides, the cell became depleted and the X and Y nucleotides were replaced with other bases. Though developing a mechanism for cells to synthesize their own X and Y nucleotides is a complicated undertaking, Stephen Benner, a researcher at the Foundation for Applied Molecular Evolution in Florida is attempting to solve the problem. Meanwhile, the Scripps research team is using a protein from algae that takes nucleotides from the material around the cell, allowing them to artificially supply X and Y nucleotides. Researchers are encouraged by the finding that due to the stability of the X-Y pair, DNA repair enzymes do not recognize the pair as damaged. This means that the DNA will not try to get rid of the unnatural X-Y pairs, silencing concerns that X-Y pairs would be excised due to their abnormal effect on DNA's double helix shape (the X-Y pairs cause the double helix shape to become slightly deformed, as seen here. Not only do the repair enzymes not harm the X-Y pairs, but the low error rate of X-Y transcription implies that the enzymes are actually repairing the X-Y pairs just as they would with A-T or G-C pairs. The researchers have not yet attempted to transcribe altered DNA into mRNA, however when they do they plan to also insert artificial tRNA which is able to recognize the X and Y bases and release a predetermined amino acid, creating all new natural proteins.

Top- X-Y bases. Bottom- C-G bases, with visible hydrogen bonds.

          At this point, the team's primary goal is getting cells to transcribe the DNA into mRNA, synthesizing tRNA that can read the new bases, and actually creating proteins coded from the new bases. Their addition of two bases to DNA's repertoire quadruples the amount of information that DNA can carry, and the team, which has since formed their own company, Synthorx, hopes to use this newfound storage capacity to expand life's typical library of twenty amino acids to a theoretical maximum of a hundred and seventy two. More amino acids would allow cells to create new proteins with vastly different functions from those available to cells today. Scientists hope that the new pair may be utilized in beneficial viruses. The requirement of externally-supplied X and Y nucleotides means that cells containing X-Y pairs in their DNA cannot accurately reproduce without a constant supply of the nucleotides. This would allow scientists to create a virus which could be used against diseases or to repair cells, then die as supplies of X and Y nucleobases are cut off, alleviating concerns that the virus could stay alive, mutate, and do damage. Advancements in this area would allow for whole new classes of revolutionary medicine- instead of slowly synthesized artificial drugs, cells could rapidly create evolving proteins to combat disease in the body. Additionally, research with the new nucleotides may allow scientists to find out why all modern life uses the four traditional bases instead of other bases. Were there originally other bases at the dawn of life? Is a four base system more efficient, or is it just how life happened to evolve? However, the research also raises ethical and legal questions. The field of synthetic biology is not heavily regulated, and lacks oversight and restrictions. This raises ethical issues as to how far researchers should go. For now though, the research is limited to the cellular level, as are most of its implications.

         Though the main New York Times article by Andrew Pollack was fascinating and inspired me to look more into the subject, the article did not include enough details. This isn't the author's fault; the complexity of the research and all the implications are difficult to summarize in a short article, and none of the other articles I looked into were able to condense everything relevant into a few paragraphs of text. The article was able to effectively summarize who did the research, exactly what was and what was not accomplished, and some of the implications of the research. However, the title of the article, "Scientists Add Letters to DNA's Alphabet, Raising Hope and Fear" seems to imply more risks than actually exist. Outside of their X-Y nucleotide rich cultures, the modified E. Coli cells will not stay modified long. Fortunately, other articles from CNN, NPR, AAAS, and more were able to fill in other details that the New York Times article missed, and the missing details forced me to look deeper into the subject than I might have otherwise.