In a groundbreaking development, researchers at Rice University have successfully engineered living cells to utilize a 21st amino acid that illuminates protein changes in real time. This innovation offers a novel method for observing cellular changes, proving effective in bacteria, human cells, and live tumor models. The findings, set for publication in Nature Communications on October 23, promise to enhance the study of complex diseases like cancer in a more ethical manner.
This breakthrough addresses a persistent challenge in biology: tracking subtle protein changes, known as post-translational modifications (PTMs), within living systems. These modifications function as on/off switches for various biological processes, including growth, aging, and disease. By engineering cells to produce a glowing version of lysine, researchers can now observe these switches in action without disrupting the cells, providing a new perspective on the inner workings of life.
Revolutionizing Protein Observation
“This system lets us see the invisible choreography of proteins inside living cells,” stated Han Xiao, the study’s corresponding author and a professor of chemistry, bioengineering, and biosciences at Rice University. “By equipping cells with the tools to produce and sense a new amino acid, we unlock a direct window into how PTMs drive biological processes in living animals.”
Chromophoric Proof of Concept
The initiative began with the hypothesis that enabling cells to autonomously produce and utilize a 21st amino acid would surpass traditional methods that rely on feeding cells synthetic labels. The research team identified and harnessed enzymes to produce acetyllysine within the cells, then genetically engineered bacteria and human cells to incorporate it into proteins at specific sites.
Reporter proteins, such as fluorescent proteins or enzymes, emit light when PTMs are added or removed, validating the system’s effectiveness for real-time tracking. “This innovative method goes beyond previous approaches by eliminating the need for external chemicals and allowing us to watch protein changes happen naturally inside living cells,” Xiao explained.
Implications for Cancer Research
The researchers demonstrated the capability of their sensors by studying the deacetylase SIRT1, a post-translational regulator involved in modulating inflammation and cancer biology. Inhibiting SIRT1 blocked its enzymatic activity but, contrary to some expectations, did not impede tumor growth in certain cell lines.
“Seeing a glow in response to acetylation events inside living tissue was thrilling,” Xiao remarked. “It makes the invisible world of protein regulation vividly observable and opens new possibilities for studying disease mechanisms and drug actions.”
Broader Applications and Future Outlook
The engineered cells could transform how scientists study PTMs in areas such as aging and neurological disease. Their ability to function in living organisms allows for real-time tracking of disease or treatment, and their light-based signals are well-suited for large-scale drug screening targeting PTM-regulating enzymes.
Future enhancements may extend this approach to other types of PTMs or human-derived organoid systems, increasing the platform’s relevance for personalized medicine and providing deeper insights into cellular regulation.
“With this living sensor technology, our research offers an innovative tool that illuminates the dynamic world of PTMs, promising to reshape our understanding and treatment of diseases rooted in protein regulation by transforming invisible molecular signals into visible biological narratives,” said Yu Hu, the study’s first author and a postdoctoral researcher at Rice.
Support and Collaboration
Co-authors of this study include Rice’s Yixian Wang, Linqi Cheng, Chenhang Wang, Yijie Liu, Yufei Wang, Yuda Chen, Shudan Yang, Yiming Guo, Shiyu Jiang, and Kaiqiang Yang. The research was supported by the SynthX Seed Award, National Institutes of Health, Robert A. Welch Foundation, U.S. Department of Defense, and Robert J. Kleberg Jr. and Helen C. Kleberg Foundation.
As the scientific community eagerly anticipates the publication of these findings, the potential applications of this technology continue to expand, offering hope for more ethical and effective research methods in the study of complex diseases.
