CAREER: Reconstructing Primordial Life of the Lost RNA World

Understanding the earliest chemical reactions and molecules involved in the first living cells is a long standing question in biology. Early life is thought to have used RNA as its genetic material as well as its enzymes. Therefore, it is important to understand how RNA molecules could have facilitated the emergence of the first self-replicating cells. This project addresses this fundamental question by building simplified models of primitive cells, or protocells, in the laboratory. These protocells contain enzymes made of RNA that can help them grow and divide, and even compete with other protocells. This project will advance the understanding of the chemical events that led to the emergence of the first living cells. This research will also lead to the creation of self-replicating synthetic cells which could be used to manufacture sustainable materials, therapeutics, and other goods. In parallel, the project will also support workforce development through training of students and engage the public through an integrated education and outreach program that connects early life research with science communication and art. These efforts include science communication through a popular science blog, a series of popular science writing workshops, a new course on public engagement in science, and the creation of a full-length graphic novel on the early life. Together, these activities will reach local and global communities to advance scientific discovery, inspire public curiosity, and cultivate the next generation of scientists and science communicators. This project advances NSF’s priorities in Biotechnology and Advanced Materials and Manufacturing. The project aims to construct model protocells that exhibit life-like properties such as growth, division, competition, and ultimately Darwinian evolution – a defining feature of life. Because early life is thought to have been powered largely by catalytic RNA molecules, or ribozymes, this project will use in vitro evolution to generate a suite of ribozymes that provide evolutionary benefit to the protocells that contain them. First, ribozymes will be evolved to copy RNA sequences inside prebiotic lipid protocells. This will establish a protocellular system capable of sustaining ribozyme-catalyzed RNA replication using building blocks that enter from the extracellular environment. Second, ribozymes will be evolved that stabilize protocell membranes, testing whether improved protocell survival due to membrane stabilization can drive their competitive growth and division. Third, this study will examine how RNA evolution is influenced by the RNA’s immediate microenvironment, including variations in UV exposure, temperature, and pH, and the presence of minerals, molecular crowding, and confinement – conditions relevant to life on the early Earth. The expected outcome is a set of experimentally grounded models for how Darwinian evolution could have emerged in primitive cell-like chemical systems, along with new insights into RNA function, RNA evolution, and the physicochemical conditions that shaped early life. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2540950 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT,01003031DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Saurja DasGupta | Institution: University of Notre Dame, NOTRE DAME, IN | Award Amount: $925,937 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2540950 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2540950.html