Overview
Our research explores the origins of the DNA–RNA–Protein system and the expansion of existing genetic systems through chemical and biological engineering. We investigate how functional nucleic acids, genetic replication, and protein translation could have emerged, and develop artificial genetic materials capable of participating in information transfer and translation.
Origins of the DNA–RNA–Protein System
How did the complex molecular machinery of modern biology emerge from relatively simple chemical systems? Our research investigates the chemical processes that could have given rise to functional nucleic acids, genetic replication, and protein translation, focusing on three fundamental questions.
I. How could a self-sustaining, evolving RNA system have emerged?
The RNA world hypothesis proposes that RNA once served as both a genetic material and a functional catalyst. However, the emergence of a self-sustaining RNA system would have required chemical processes capable of assembling functional RNAs and replicating genetic information. We investigate how prebiotic chemical energy could have been harnessed to drive RNA assembly and replication, and how these processes could have supported the emergence of self-sustaining, evolving RNA systems.
II. Could DNA have played a role in the earliest stages of RNA-based life?
DNA is generally considered a later evolutionary innovation that enabled more stable storage of genetic information. We explore the possibility that DNA emerged much earlier and facilitated the formation and replication of functional RNAs. In particular, we investigate whether DNA could have stabilized primordial genetic information and alleviated template inhibition during nonenzymatic RNA replication. We also explore how distinct DNA and RNA polymers could have emerged from potential ancestral nucleic acids containing both deoxy- and ribonucleotides. These studies aim to shed light on the evolutionary origins of the distinct biological roles of DNA and RNA.
III. How did protein translation emerge, and how was the chiral relationship between D-nucleic acids and L-proteins established?
The emergence of protein translation enabled genetic information encoded in RNA to direct protein synthesis, establishing a fundamental connection between nucleic acids and proteins. We investigate whether the peptidyl transferase activity of the modern ribosome could have originated from simpler, proximity-driven chemical processes that facilitated peptide bond formation.
We also explore how the specific chiral relationship between D-nucleic acids and L-proteins became established. Was this relationship dictated by intrinsic chemical preferences, or did it emerge through evolutionary selection among alternative chiral combinations?
Expanding the Genetic System
Why does all known life rely on DNA, RNA, and proteins as the principal macromolecules for storing, transferring, and expressing genetic information? Could this system be expanded to incorporate artificial genetic materials with novel chemical structures and functions? We explore the chemical space beyond natural DNA and RNA to develop alternative genetic polymers capable of participating in genetic information transfer and protein translation. In particular, we aim to engineer artificial genetic materials that can be synthesised, replicated, and used as templates for protein synthesis, with the ultimate goal of integrating them into the genetic and metabolic machinery of living systems.
I. Enzymatic Engineering for Artificial Genetic Materials
Engineering enzymes involved in genetic information processing, including polymerases, ligases, and the ribosome, is essential for expanding the chemical diversity and evolutionary potential of artificial genetic materials. We aim to develop enzymatic tools that enable the synthesis, replication, and evolution of noncanonical nucleic acids, both in vitro and in vivo. Our research focuses particularly on engineering enzymatic pathways for the biosynthesis of noncanonical nucleotide building blocks, including dNTP and NTP analogues, and developing polymerases and other genetic machinery capable of processing artificial nucleic acids.
II. Evolution and Applications of Artificial Genetic Materials
Can artificial genetic materials evolve to acquire new functions and participate in biological information transfer? We investigate the functional potential of chemically modified nucleic acids, with particular interest in their ability to serve as templates for protein synthesis. A central question is whether artificial messenger RNAs (mXNAs) can be recognized and translated by the ribosome, thereby expanding the repertoire of genetic messages accessible to the translation machinery. Ultimately, we aim to develop functional artificial genetic materials with novel chemical properties and explore their potential applications, including new opportunities for mRNA-based therapeutics.