Understanding how an individual will respond to a drug, or the effect of a mutation on some phenotype, is the major goal of modern biology.
The ability to predict the outcomes of genetic and environmental perturbations is necessary for everything from personalized medicine to building designer organisms.
Our high-throughput quantitative systems biology research group combines mathematical modeling with measurements of thousands to millions of genotypes and single cells to understand drug resistance and cell growth at the single-cell level.
Our goal is to be able to predict the of a drug or mutation in single cells, and to understand why seemingly identical cells respond differently to the same treatment.
To do so we use high-throughput time-lapse microscopy, flow-cytometry, single-cell RNA & DNA sequencing, machine learning and quantitative data-driven mathematical models to generate novel hypotheses and to draw conclusions from complex high dimensional biological data.
The following are some examples of questions we’re working on:
- Why do mutations and drug treatments have different outcomes in different individuals? Within a single population of cells, not all cells will be killed by a drug, and identical mutations can have no effect in some individuals but result in a severe disease phenotype in others. Why are only some individuals and single cells affected by a drug or mutation?
- Machine learning to predict mutational impacts in heterogeneous genetic backgrounds. The effect of each mutation depends on the genetic background in which it occurs. To discover fundamental principles that govern how genotype determine phenotype we build large libraries containing millions of genetic variants, measure the phenotype of each variant, and develop novel computational approaches to quantify and predict the impact of each mutation on phenotype.
- What mechanisms result in the predictable evolution of drug resistance during treatment? Some tumors, fungi and bacteria strains consistently and reproducibly acquire multidrug resistance in both patients and in lab experiments, while other genotypes do not. How is the ability to evolve a phenotype encoded in DNA?