Cambridge Healthtech Institute recently interviewed Dr. Floyd Romesberg of The Scripps Research Institute about synthetic biology and developing unnatural base pairs for protein therapeutics. He will present on “A Semi-Synthetic Organism with an Expanded Genetic Alphabet” at the 9th Annual Engineering Genes and Hosts conference, taking place January 9-10, 2017 as part of the 16th Annual PepTalk event which runs from January 9-13, 2017 in San Diego, CA.

Q1: Can you tell us about your projects at The Scripps Research Institute and the resources that support them there?

The projects in our lab are multi-disciplinary, spanning physics, synthetic chemistry, and molecular biology, all with a focus on understanding the molecules of life and how they might be manipulated. We study how antibodies are evolved to fight infections and the role that their flexibility might play. We study how antibiotics developed in nature and use this information to help identify candidates for development as drugs. We use laboratory evolution to evolve DNA polymerases to make modified DNA for different applications. Finally, we have developed an unnatural base pair and are using it to create semi-synthetic organisms that store and retrieve increased information. All of these are or have been funded by the NIH, the NSF, the Office of Naval Research, and internationally through the A*STAR fellowship.

Q2: How did you come to research the production of novel proteins via living factories? What are your goals with this work?

Protein therapeutics have revolutionized medicine, but they are limited by being composed of only 20 natural amino acids. We have been motivated by the possibility that proteins that can access additional, unnatural amino acids, perhaps with interesting functionality, would allow them to be developed as even better drugs. Our group has been developing unnatural base pairs for 17 years, initially motivated by the physiochemical properties driving DNA replication, but the long-term goal was always to use them as the basis of a semi-synthetic organism that stores, transcribes. And translated them, allowing for the semi-synthetic organisms to produce proteins with new amino acids.

Q3: What challenges persist in your field, and what progress has your team – or other peers – made in overcoming them?

The field of synthetic biology has been incorporating unnatural amino acids into proteins for a couple of decades now. With the introduction of a third base pair to the bacterial genome, more new codons are available than would ever be needed. The number of available orthogonal tRNA synthetase/tRNA pairs is now the limitation field-wide. We are currently investigating ways to solve this issue using the unnatural base pair as well.

Q4: You’ve attended PepTalk as a speaker before. Why are you returning and what do you intend to get out of the 2017 programs?

The talks are a great mix of new science and practical applications, which appeals to me.


Floyd_RomesbergFloyd Romesberg, Ph.D., Professor, Chemistry, The Scripps Research Institute

Floyd Romesberg’s research combines the tools of chemistry, molecular biology, microbiology, genetics, and modern spectroscopy to study different aspects of evolution. Projects include the identification and development of novel antibiotics, the development of tools to apply steady state and time-resolved UV/vis and IR spectroscopy to understand how proteins are evolved for biological function, the artificial evolution of DNA polymerases with novel activities, the investigation of the cellular response to DNA damage in prokaryotic and eukaryotic cells, and the development of unnatural base pairs with which to expand the genetic alphabet and code. Recently Floyd’s lab succeeded in generating a semi-synthetic organism that stably propagates six-letter DNA, paving the way to living factories to produce novel proteins for biotechnological and medical applications. Floyd is also a co-founder of Achaogen Inc. (IPO 2014, NASDAQ AKAO), and RQx, Inc. (acquired by Genentech/Roche in 2013), two companies working to develop novel antibiotics, as well as Synthorx, Inc., a new synthetic biology company.


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