Extending Luria and Delbrück's legacy by quantifying mutations and phenotypic transitions

by Marco Cosentino Lagomarsino (IFOM and Dip. Fisica Università di Milano)

Wednesday 15 Jan 2025, 11:00 → 12:00 Europe/Rome

Aula 3 (Dip. di Fisica - Edificio E. Fermi)

In 1943, Luria and Delbrück’s fluctuation test, later worth a Nobel prize, revealed that bacterial resistance arises from random mutations occurring before exposure, establishing a foundational framework for quantifying mutation rates, and proving the power of using a physics approach based on mathematical models in biology. Today, as we confront drug resistance from bacteria to cancer, similar principles apply, but with the added complexity that cells not only acquire mutations but can also undergo reversible phenotypic transitions that enhance survival. In this seminar, I will discuss how we extended Luria and Delbrück’s legacy in two directions. First, we showed that in colorectal cancer lines, drug-induced "persister" cells exhibit elevated mutation rates, accelerating resistance. Second, we combined fluctuation assays with deep sequencing to track mutational processes across systems ranging from yeast to patient-derived organoids, offering a powerful alternative to (and a cross-validation with) mutation-accumulation experiments. This work may help advance our fundamental understanding of resistance evolution as well as providing tools to predict and potentially prevent therapeutic failure.