The overall goal of the Sherwood lab is to advance genomic and precision medicine applications through high-throughput, multi-disciplinary science. In this talk, I will review a suite of high-throughput genomic and cellular perturbation platforms using CRISPR-based genome editing that the lab has developed to improve our understanding of genetic disease, gene regulation, and genome editing outcomes.

This talk will focus on recent efforts using combined analysis of rare coding variants from the UK Biobank and genome-scale CRISPR-Cas9 knockout and activation screening to improve the identification of genes, coding variants, and non-coding variants whose alteration impacts serum LDL cholesterol (LDL-C) levels. Through these efforts, we show that dysfunction of the RAB10 vesicle transport pathway leads to hypercholesterolemia in humans and mice by impairing surface LDL receptor levels. Further, we demonstrate that loss of function of OTX2 leads to robust reduction in serum LDL-C levels in mice and humans by increasing cellular LDL-C uptake. Finally, we unveil an activity-normalized base editing screening framework to better understand the impacts of coding and non-coding variation on serum LDL-C levels, altogether providing a roadmap for further efforts to dissect complex human disease genetics.

Cell fate decision-making is responsible for development and homeostasis, and is dysregulated in disease. Despite great promise, we are yet to harness the high-resolution cell state information that is offered by single-cell genomics data to understand cell fate decision-making as it is controlled by gene regulatory networks. We describe how we leveraged joint dynamics + genomics measurements in single cells to develop a new framework for single-cell-informed Bayesian parameter inference of Ca2+ pathway dynamics in single cells. This work reveals a mapping from transcriptional state to dynamic cell fate. But no cell is an island: cell-internal gene regulatory dynamics act in concert with external signals to control cell fate. We developed a multiscale model to study the effects of cell-cell communication on gene regulatory network dynamics controlling cell fates in hematopoiesis. Specifically, we couple cell-internal ODE models with a cell signaling model defined by a Poisson process. We discovered a profound role for cell-cell communication in controlling the fates of single cells, and show how our results resolve a controversy in the literature regarding hematopoietic stem cell differentiation. Overall, we argue for the need to consider single-cell-resolved models to understand and predict the fates of cells.

We formulate and sketch the proof of the K-theoretic Farrell-Jones Conjecture for
for the Hecke algebras of reductive p-adic groups. This is the first time that
a version of the farrell-Jones Conjecture for topological groups is formulated. It implies that
the reductive projective class group of the Hecke algebra of a reductive p-adic group
is the colimit of these for all compact open subgroups. This has been proved rationally by
Bernstein and Dat using representation theory. The main applications of our result
will concern the theory of smooth representations
In particular we will prove a conjecture of Dat.

The proof is much more involved than the one for instance for discrete CAT(0)-groups.
We will only give a very brief sketch of it and the new problems occurring in the setting of
totally disconnected groups. Most of the talk will be devoted
an introduction to the Farrell-Jones Conjecture and the theory of
smooth representations of reductive p-adic groups, and
discussion of  applications.

This is a joint project with Arthur Bartels.

Lattice homology is a combinatorial invariant of plumbed 3-manifolds due to Nemethi. The definition is a formalization of Ozsvath and Szabo's computation of the Heegaard Floer homology of plumbed 3-manifolds. Nemethi conjectured that lattice homology is isomorphic to Heegaard Floer homology. For a restricted class of plumbings, this isomorphism is known to hold, due to work of Ozsvath-Szabo, Nemethi, and Ozsvath-Stipsicz-Szabo. By using the Manolescu-Ozsvath link surgery formula for Heegaard Floer homology, we prove the conjectured isomorphism in general. In this talk, we will talk about aspects of the proof, and some related topics and extensions of the result.

I will outline a new algorithm for unknot recognition that runs in quasi-polynomial time. The input is a diagram of a knot with n crossings, and the running time is n^{O(log n)}. The algorithm uses hierarchies, normal surfaces and Heegaard splittings.

The unknotting number of a knot is the minimum number of crossing changes needed to untie the knot. It is one of the simplest knot invariants to define, yet remains notoriously difficult to compute. We will survey some basic knot theory invariants and constructions, including the satellite knot construction, a straightforward way to build new families of knots. We will give a lower bound on the unknotting number of certain satellites using knot Floer homology. This is joint work in progress with Tye Lidman and JungHwan Park.

In rational conformal field theory, the sewing and factorization properties are probably the most important properties that conformal blocks satisfy. For special examples such as Weiss-Zumino-Witten models and minimal models, these two properties were proved decades ago (assuming the genus is ≤1 for the sewing theorem). But for general (strongly) rational vertex operator algebras (VOAs), their proofs were finished only very recently. In this talk, I will first motivate the definition of conformal blocks and VOAs using Segal's picture of CFT. I will then explain the importance of Sewing and Factorization Theorem in the construction of full rational conformal field theory.

Studying quasi-isometries between groups is a major theme in geometric group theory. Of particular interest are the situations where the existence of a quasi-isometry between two groups implies that the groups are equivalent in a stronger algebraic sense, such as being commensurable. I will survey some results of this type, and then talk about recent work with Daniel Woodhouse where we prove quasi-isometric rigidity for certain graphs of virtually free groups, which include "generic" cyclic HNN extensions of free groups.

I will give an overview of the interactions between chromatic homotopy theory and the algebraic K-theory of ring spectra, especially around the subject of Ausoni-Rognes's principle of "chromatic redshift," and some of the recent advances in this field.