Scientists Develop Biological ‘Artificial Intelligence’ System for Molecular Design in Mammalian Cells
Researchers at the University of Sydney’s Charles Perkins Centre have created a novel system called PROTEUS (PROTein Evolution Using Selection), which applies biological artificial intelligence to engineer molecules with new or enhanced functions directly within mammalian cells. This breakthrough tool accelerates the evolution of proteins and other molecules, offering a practical path to developing more precise research tools and gene therapies.
PROTEUS leverages directed evolution, a laboratory technique that simulates natural evolution to generate molecules with desired traits. Unlike traditional approaches that can take years, PROTEUS completes multiple cycles of mutation and selection within weeks. This rapid process enables the discovery of molecules that could improve treatments such as gene editing technologies like CRISPR.
Directed Evolution Enters Mammalian Cells
Directed evolution has historically been performed in bacterial cells, but PROTEUS extends this capability to mammalian cells, which are more relevant for human health applications. According to Professor Greg Neely, co-senior author and Head of the Dr. John and Anne Chong Lab for Functional Genomics, this advancement allows for the creation of molecules finely tuned to function effectively in the human body—something difficult to achieve with existing methods.
PROTEUS works by programming mammalian cells with a genetic problem, for example, how to efficiently switch off a disease-causing gene. It then explores millions of potential molecular solutions, identifying those best adapted to solve the problem. This approach can drastically reduce the time and uncertainty involved in molecular design.
Applications and Validation
The system has been used to develop improved proteins that respond better to drug regulation and nanobodies capable of detecting DNA damage, a key factor in cancer development. However, its potential extends to optimizing a broad range of proteins and molecular tools.
One of the main technical challenges addressed by the team was maintaining cell stability through many cycles of mutation without allowing the system to find trivial or unintended solutions. They overcame this by using chimeric virus-like particles—combining the outer shell of one virus with the genetic material of another—to control the evolutionary process effectively.
Lead researcher Dr. Christopher Denes emphasized that PROTEUS runs continuously, allowing researchers to monitor and understand how solutions evolve over time. The system’s stability and effectiveness have been confirmed by independent laboratories, and it has been made open source to encourage widespread adoption.
Future Directions
The team hopes PROTEUS will accelerate the development of new enzymes, molecular tools, and therapeutics, including enhancing gene-editing technologies and optimizing mRNA medicines for improved potency and specificity.
Note: Alexandar Cole, Christopher Denes, Daniel Hesselson, and Greg Neely have filed a provisional patent application related to this technology. Other authors declare no competing interests.
For more on the science behind directed evolution, see the 2018 Nobel Prize in Chemistry summary.
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