Alien DNA… created in a laboratory

© Shutterstock
© Shutterstock

For billions of years, life’s history has been written with just four letters; A, T, C and G, designating the DNA subunits contained in all living organisms.

 

In May 2014 a big change occurred in this dogma.

 

New dogma, …

 

Floyd Romesberg, associate Professor of Chemistry at the Scripps Research Institute in California, and his colleagues published an article in Nature magazine in which they declare accomplishing something once thought to be impossible. After a 15-year effort, they have managed to create a « semi-synthetic organism » whose genetic material includes an added pair of DNA bases, not found in nature. The new unnatural base pairs (UBP) is formed between d5SICS and dNaM (d5SICS-dNaM), and have the capability to replicate in the presence of the right enzymes.

 

Throughout their synthesis and application in a living cell, 4 main challenges had to be overcome in order to have the UBP recognised, integrated and used by the cells:

  1. the UBP must be available inside the cell
  2. endogenous polymerases must be able to use the UBP to faithfully replicate DNA containing them within the complex cellular milieu
  3. the UBP should not be efficiently excised by DNA repair pathways
  4. Neither the presence of the unnatural triphosphates nor the replication of the UBP introduces a notable growth burden.

 

… new potentials

 

Hailed as a breakthrough by the scientific community, the work is a step towards the synthesis of cells able to churn out drugs and other useful molecules. “If you read a book that was written with four letters, you’re not going to be able to tell many interesting stories,” Romesberg says. “If you’re given more letters, you can invent new words, you can find new ways to use those words and you can probably tell more interesting stories.” A rough analogy: Just think how many crazy new words you could spell with 39 letters instead of the usual 26.

 

Further refinements are needed, but the major next step would be demonstrating the in-cell transcription of the new expanded-alphabet DNA into the RNA, which would feed the cell’s protein-making machinery. Several applications are possible, which include research (development of glowing amino acids that could help scientists to track biological reactions), diagnosing disease, or creating new tailored protein therapies (incorporation of a toxic amino acid into a protein to ensure that it kills only cancer cells). But that’s still a ways off. In this purpose, Romesberg has started a company, “Synthorx”, to explore these possibilities.

 

And safety?

 

The greatest difficulty, at this stage, may be to reassure to those who fear the uncontrolled release of a new life form that can affect the environment and ecosystem. The molecular building blocks for d5SICS and dNaM are not naturally present or synthesised in the cells. Thus, to get the E. coli to replicate the DNA containing these unnatural bases, 2 conditions are essential :

  1. Providing the UBPs. For that, a continuous pool have to be supplied artificially by adding them to the fluid solution outside the cell.
  2. Getting the UBPs into the cell. In order to get the building blocks, known as nucleoside triphosphates, into the cells, special triphosphate transporter molecules had to be expressed by the cells.

According to Romesberg’s team, an important thing to note is that these two conditions/limitations constitute an important control over the system. The new bases can only get into the cell when the ‘base transporter’ protein is ON. Without this transporter or when new bases are not provided, the cell will revert back to the natural bases; A, T, G, C, and the UBPs (d5SICS and dNaM) will disappear from the genome. The requirement to keep feeding the cell with the UBPs’ precursors is actually an important safeguard: If some of the ‘new life form’ ever escape from the lab, they’ll quickly revert to making natural four-letter DNA.

 

Epilogue

 

This change in one of the fundamental dogma in Genetics raises an important question. Is it possible to create a wholly synthetic organism? According to Romesberg, “That’s just not going to happen, because there are too many things that recognize DNA. It’s too integrated into every facet of a cell’s life”.

 

The fact that human minds can take the cell’s literature and edit it by inserting new letters or seeking new outputs powerfully supports the suggestion that the original code was intelligently designed. Nature, during the numberless evolution processes, has selected a unique and powerful method to store and transmit the genetic information.

DNA expanded alphabet

DNA expanded alphabet

 

Sources