In his TEDMED 2015 talk, Scripps Chemistry Professor Floyd Romesberg shares his enthusiasm for developing artificial DNA and its implications for novel protein therapeutics. We caught up with Floyd to learn more about the exciting work of his lab.
TEDMED: What has your lab been up to since you spoke at TEDMED?
FLOYD: Since I spoke at TEDMED, my lab has continued to nurture and optimize our semi-synthetic organism. The nascent organism I described in my talk was the first to replicate DNA containing a third base pair, but only a single pair, and the poorly growing organism rapidly lost the unnatural base pair under all but the most controlled conditions. It was an incredible proof of principle, but lacked the fortitude of real life. The newly improved organism still relies on the same protein to take up the unnatural nucleotide precursors of our unnatural base pair, but we have engineered the protein to be less toxic and are now utilizing a newer, chemically optimized unnatural base pair. In addition, we have optimized the host cell. The result is a semi-synthetic bacterial organism that can be grown like any other laboratory strain and that retains multiple unnatural base pairs in virtually any sequence context – the first semi-synthetic form of life that stores genetic information using a six-letter, three base pair alphabet.
TEDMED: What’s next for you?
FLOYD: We’re continuing to push forward with the semi-synthetic organism. Since we reached the milestone of unrestricted storage of increased genetic information, the next step has been to focus on information retrieval in the form of messenger and transfer RNA transcribed from the six-letter DNA. The unnatural base pair will be one third of a new amino acid codon, and we’re also working on engineering the components to decode the new codon into a novel amino acid during protein synthesis. There are a lot of moving parts to coordinate, and we have to get each part to work but we also have to make sure the parts all work together. It might sound like an insurmountable problem, but that’s what people thought about our efforts to expand the genetic alphabet. It may take some time, but getting bacteria to produce unnatural proteins should be possible. When we accomplish this, we will have created the first form of synthetic life that stores and retrieves increased information and which can access forms and functions not otherwise possible in the fully natural world.
TEDMED: What does the future of medicine look like with protein therapeutics?
FLOYD: Protein therapeutics have revolutionized medicine, but their potential activities and uses are limited by their being composed of only the natural twenty amino acids and in the challenges of their specific modification. The future of protein therapeutics lies in methodologies to include any chemical functionality into their composition, thereby imparting novel or optimized activities and properties. With development of our semi-synthetic organism, we will be able to produce the unnatural proteins directly during their synthesis within the cell. In this manner we should be able to extend the potential application of protein therapeutics to diseases that have been difficult to target, such as infectious diseases and cancer. The possibilities are essentially endless.
TEDMED: What kind of impact do you want your research to have?
FLOYD: I would like our research to impact our conceptual understanding of life– what it can be and how it might have evolved– and also influence our practical uses of it, by producing modified proteins to treat disease.