Tirrell Lab

My laboratory closed in the spring of 2025. I'm no longer accepting new research students or postdoctoral scholars.

Between 1978 and 2025, my students, postdoctoral coworkers and visitors, often in collaboration with the laboratories of faculty colleagues, explored a small number of problems in macromolecular chemistry. We started out working in radical polymerization and ring-opening polymerization, reflecting my experiences as a graduate student and as a visiting researcher at Kyoto University. This early work revealed an unusual polymer rearrangement and provided strong evidence for the importance of penultimate effects in radical copolymerization and against concerted addition of charge-transfer complexes to propagating radicals.

An unexpected result in the early 1980s opened a new line of research in my laboratory. Salicylic acid copolymers I had prepared as a graduate student had shown interesting antimicrobial activity, with the activity dependent on the identity of the comonomer. This observation prompted us to investigate the interactions of polyelectrolytes with cell membranes and model membrane systems. We found such interactions to be highly sensitive to the pH of the membrane suspension. While this was not unexpected, we were surprised to learn that poly(2-ethylacrylic acid) and its derivatives behaved as tunable membrane "switches," leaving lipid membranes largely unperturbed at physiological pH but opening them rapidly and completely upon reduction of the pH by a few tenths of a unit. This behavior provides a foundation for a variety of controlled delivery technologies.

Until the mid-1980s, research in my laboratory focused on polymers made via chemical synthesis. That changed when recombinant DNA methods became widely available. The prospect of using artificial genes to direct the biological synthesis of novel macromolecules opened the door to addressing one of the most fundamental characteristics of synthetic polymers – the fact that they always consist of complex molecular mixtures, heterogeneous with respect to chain length, sequence and stereochemistry. We wondered – and still wonder – what kind of macromolecular chemistry could be accomplished by combining the design flexibility available to the synthetic polymer chemist with the architectural control provided by protein biosynthesis. We've used that approach to explore the design of crystals, liquid crystals and macromolecular networks (including some that retain the cells that made the artificial proteins), and we've demonstrated some of the promise of encoding macroscopic materials behavior into artificial genetic information. But much more remains to be done.

As we started our work on artificial proteins, we realized that the approach would be more interesting and useful if we could expand the set of amino acids that cells use to make proteins. This line of research proved to be productive, both in our hands and in those of investigators in other laboratories. Non-canonical amino acids are now used not only in macromolecular design but also as powerful tools in chemical biology. The BONCAT method for time-resolved and cell-selective analysis of protein synthesis has been especially widely adopted.

I would like to express my deepest appreciation to the students, postdoctoral scholars, visitors, staff members and faculty colleagues who have made my participation in research so enjoyable and rewarding.