ABSTRACT
My lab has focused on developing methods to understand the causes and consequences of biological
heterogeneity. Examples of heterogeneity include differences between the traits of individuals in a population,
between cells in an organism or between proteins in a cell. Heterogeneity defines the phenotypic landscape at
the organismal, cellular and molecular levels, shaping how biological systems respond to short-term
perturbations and how species and tumors evolve. Heterogeneity can be encoded by genetic variants or it can
arise from environmental perturbations or stochastically.
My lab’s past successes include a plethora of new approaches to understand phenotypic heterogeneity arising
from genetic variation. In particular, I developed deep mutational scanning, which can measure the
consequences of tens or hundreds of thousands of genetic variants on different aspects of protein or cell
function. Using deep mutational scanning, my lab has gained fundamental insights into protein structure and
function, enhanced computational variant effect prediction and reshaped how human genetic variants are
interpreted. Moreover, hundreds of labs around the world have taken up my methods and, collectively, the
methods have been used to measure the effects of millions of genetic variants in hundreds of genes.
Now, I am investigating the causes and consequences of non-genetic biological heterogeneity. For example, I
am fascinated by questions like “how do isogenic cells in a population, each with a different transcriptomic,
proteomic and metabolomic state, respond differently to a perturbation? How does the initial state of a cell
determine its eventual fate? What, if anything, does cellular morphologic heterogeneity mean either in terms of
cell state or fate?” However, answering these questions requires developing new methods. Thus, in this MIRA
application, I am seeking funding to extend my work probing the basic biology of non-genetic cellular
heterogeneity by developing a slate of new methods and using them to answer fundamental questions like
those highlighted above.