Recently, University of Sydney scientists published a groundbreaking study in Nature Communications, successfully developing a bio-artificial intelligence system called PROTEUS. This system enables the direct design and evolution of molecules with novel functionalities within mammalian cells, providing a revolutionary new tool for gene therapy and research tool development.
This research, a collaborative effort between the Charles Perkins Centre and the Centenary Institute at the University of Sydney, innovatively applies directed evolution technology to mammalian cells. The PROTEUS (Protein Evolution Using Selection) system mimics the natural evolutionary process, shortening what would typically take years, even decades, to just weeks.
This means we can use PROTEUS to generate entirely new molecules with high functionality within the human body, thereby developing novel drugs that are difficult or impossible to produce with existing technologies,” said Professor Greg Neely, Head of the John and Anne Zhang Laboratory of Functional Genomics at the University of Sydney and co-author of the paper. Researchers describe PROTEUS as an AI-like platform. Its innovation lies in shifting directed evolution from primarily bacterial cells to mammalian cells. Moreover, the PROTEUS system can explore millions of naturally non-existent molecular sequences using directed evolution based on a defined problem—for example, efficiently silencing a highly active disease-causing gene in the human body—and identify the molecule best suited to solve the problem. This allows research that might previously have taken years, or even been impossible, to be completed within weeks.
“Directed evolution technology, first implemented in bacteria, was awarded the 2018 Nobel Prize in Chemistry. This technology’s invention revolutionized the development trajectory of biochemistry. Building upon this, the PROTEUS system allows us to further address unsolved genetic problems in mammalian cells,” said Dr. Christopher Denes, principal investigator at the Charles Perkins Centre and the School of Life and Environmental Sciences, University of Sydney. The PROTEUS mechanism involves continuously running mammalian cells, allowing scientists to periodically observe how the system solves genetic problems. Researchers have already used PROTEUS to develop improved proteins more easily regulated by drugs, and nanobodies capable of detecting DNA damage—a crucial process in cancer development. However, PROTEUS’ applications extend far beyond this; it can be used to enhance the functionality of the vast majority of proteins and molecules.”
Currently, the team’s greatest challenge is maintaining the stability of mammalian cells throughout multiple rounds of evolution and mutation, while preventing the system from “cheating,” i.e., circumventing the real problem in an ineffective yet seemingly plausible manner. The researchers made a breakthrough by introducing “chimeric virus-like particles,” which combine the capsid of one virus with the genetic material of another, thereby preventing the system from cheating. This design combines the advantages of two virus families, achieving complementary strengths. Ultimately, the system can process multiple solutions in parallel, with superior solutions gradually becoming dominant and ineffective solutions being eliminated.
“The PROTEUS system’s stability and reliability have been independently verified by other laboratories. We encourage other research institutions to adopt this technology to advance the development of next-generation enzymes, molecular tools, and therapeutic approaches,” said Dr. Denes. The PROTEUS system will be made freely available to the research community to improve gene-editing techniques or optimize mRNA therapeutics for enhanced efficacy and specificity.