From the Cosmos to the Clinic: A New Type of DNA Is Created

A, G, T and C are quite possibly the most famous letters of the alphabet (if you are a biologist at least) and make up the key ingredients for life on earth. From school age, we are taught that DNA, the basic building blocks of our genes, consists of four nucleobases that are entwined in an elegant double helix; ready to unravel when life demands replication. DNA is transcribed to RNA which is translated to protein in a neat, self-sustained system that allows organisms to adapt and evolve to their environment, transferring these adaptations to their offspring.

As space expeditions are deployed to far away planets and galaxies, one of humanity’s greatest questions remains unanswered - is there other life out there?

If so, would this life form consist of the same universal DNA and RNA building blocks that are found in organisms living on Earth? This question has encouraged great debate, and recognition that our understanding of DNA and RNA is limited, considering that the discovery of DNA’s structure only occurred relatively recently in the 20th century. The idea that DNA may exist in a form other than that in our very cells was pretty incomprehensible until recently. 

A new kind of DNA

Steven Benner, PhD, and team at the Foundation for Applied Molecular Evolution have constructed a new kind of DNA that is synthetic, created in a laboratory rather than by nature. It has been named “hachimoji” DNA (from the Japanese "hachi" meaning "eight", and "moji" meaning "letter"). Unlike regular DNA, hachimoji DNA contains eight building blocks that pair predictably, meaning it has a greater storage capacity than regular DNA. It can also be copied to make hachimoji RNA, which is able to direct protein synthesis and produce selectable phenotypes, “We can set up in vitro selection systems that will force hachimoji DNA and hachimoji RNA to evolve to have many selectable phenotypes. For example, we have evolved pieces of hachimoji DNA to bind to breast cancer cells, liver cancer cells, and anthrax toxin. We are now evolving pieces of hachimoji DNA that are adapted to selectively cut proteins that are responsible for disease,” Benner comments. The research findings are published in the journal Science.

Creating hachimoji DNA – a collaborative effort

“For hachimoji DNA and hachimoji RNA, the researcher must go into the laboratory and construct by chemical synthesis the building blocks necessary to make hachimoji DNA and evolve mutation enzymes to allow hachimoji DNA to be transcribed to give hachimoji RNA”, says Benner.

He emphasizes that the creation of synthetic DNA is not a simple task and was a collaborative effort: “We had to work hard to get enzymes that replicate hachimoji DNA and transcribe hachimoji DNA to give hachimoji RNA; here, the laboratory of Andy Ellington was very important. We further had to work extremely hard to get methods to determine the sequence of building blocks in hachimoji RNA. We also had to determine the crystal structures of hachimoji DNA, where Millie Georgiadis was key. We then had to determine the rules for binding of hachimoji DNA, where John SantaLucia and his team at Wayne State/DNA Software were key.”

Answering cosmic questions with hachimoji DNA

Benner has previously stated that he believes “alien” life will be created in a laboratory on Earth, rather than in a faraway galaxy. “There is no better research strategy to address "cosmic" questions than to go into the laboratory and try to synthesize alternative genetic systems, to see if they are really possible. Setting a grand challenge of this nature drag scientists across uncharted terrain where they are forced to ask and answer unscripted questions. When the synthesis fails, the theory driving its design must be defective. This drives discovery and paradigm change in ways that scripted hypothesis-based research cannot." 

The researchers are quick to caution that hachimoji DNA should not be considered “alien” on the basis that it is not self-sustaining and cannot survive outside of the laboratory. Hachimoji DNA and RNA require significant attention from the scientist to keep them alive: “We can let hachimoji DNA run overnight unattended as long as we have made sure before we go home that we have given enough building blocks, enzymes, and energy. Without any of these, hachimoji DNA dies immediately” adds Benner.

How can we use hachimoji DNA, and what are the ethical implications? 

Hachimoji DNA possesses a myriad of potential applications from improved diagnostics to the creation of proteins with extra amino acids, and novel pharmaceutical agents. The implementation of hachimoji DNA in modern medicine may occur in the near future, as Mark Poritz, product development director at Firebird Biomolecular Sciences that commercialize the synthetic material used in the creation of hachimoji DNA, says "Parts of this new DNA are already in products to diagnose disease and monitor the environment for disease-causing viruses". 

From an ethical perspective, what issues does hachimoji DNA pose? “Here on Earth, it is fundamentally impossible for a system that is not self-sustaining to influence existing life. Putting a small organic molecule into an ecosystem is more likely to have an impact on existing life by driving bacteria to evolve to handle it, than anybody building a new genetic system from the bottom up" Benner comments. "There are still broader ethical concerns about the creation of new knowledge. Some argue that it should not be done for fear that it will be abused. However, the opposite side, which we find compelling, is that the potential for new knowledge to create good far outweighs the potential for it doing harm.”

Reference: "Hachimoji DNA and RNA: A genetic system with eight building blocks," by S. Hoshika; N.A. Leal; M.-J. Kim; M.-S. Kim; N.B. Karalkar; H.-J. Kim; S.A. Benner at Firebird Biomolecular Sciences LLC in Alachua, FL; S. Hoshika; N.A. Leal; M.-J. Kim; N.B. Karalkar; S.A. Benner at Foundation for Applied Molecular Evolution in Alachua, FL; A.M. Bates; M.M. Georgiadis at Indiana University School of Medicine in Indianapolis, IN; N.E. Watkins Jr.; H.A. SantaLucia; J. SantaLucia Jr. at DNA Software Inc. in Ann Arbor, MI; A.J. Meyer; A.D. Ellington at University of Texas, Austin in Austin, TX; S. DasGupta; J.A. Piccirilli at University of Chicago in Chicago, IL.