The Weissman laboratory studies how cells ensure that proteins fold into their correct shape, as well as the role of protein misfolding in disease and normal physiology. They are also widely recognized for building innovative tools for broadly exploring organizational principles of biological systems. These include ribosome profiling, which globally monitors how proteins are synthesized, and CRISPRi/a for turning the expression of genes. The Weissman group has also pioneered the use of genetic interaction maps (pairwise descriptions of the extent to which the loss of one gene will aggravate or buffer the effect of the loss of a second one) to define gene function and to search for cancer vulnerabilities. The ability to bridge large-scale approaches and mechanistic investigations is a key focus of the lab. Beyond the immediate payoff of these efforts, this work seeks to contribute to the broader goal of developing more principled, less ad hoc approaches for defining gene functions.

Tuning Gene Expression: While the catalog of mammalian genes and when and where these genes are turned on is rapidly expanding, our understanding of their function lags behind. The Weissman lab and collaborators developed robust technologies that enables the systematic investigation of the cellular consequences of turning on or off individual genes. The group has designed and validated genome-scale CRISPRi and CRISPRa libraries that enable systematic analysis of gene function. They have also adapted this approach to allow the largescale analysis of double knockdowns enabling the systematic search for synthetic lethal interactions that will inform the rational design of combination drug therapies. The Weissman group is broadly applying the CRISPRi/a approach to understanding disease mechanisms, defining drug targets, and even potentially treating disease by reversibly regulating gene expression without permanently altering patients’ DNA. Most recently, they have developed a variant of CRISPRi/a termed CRISPRoff and CRISPRon that allow for the heritable and programable turning off or on of the vast majority of genes.

Mapping the Cancer Evolution: The Weissman lab has designed, built, and optimized molecular recorder technologies, which makes it possible in principle to capture critical features of a cell’s life—environmental insults, developmental decisions, external and internal signals, ancestry and progeny—in a defined and compact region within its genome. These recordings can then be read out in a massively parallel manner using droplet-based single-cell RNA-sequencing technology. Just as the flight recorder of a plane provides critical forensic information about the normal operation of a plane and how these operations failed, molecular recorders provide an unprecedented view of normal biology and disease. They have built upon their molecular recorder technology in several ways that make it both more easily deployable to study various biological contexts of interest and more information-rich for larger, longer, and deeper recording experiments. A major focus of the Weissman lab is to use these molecular recorder technologies to study critical aspects of different stages of cancer progression including tracing the rate, routes and drivers of cancer metastasis as well the evolutionary process by which a cell containing oncogenic mutation develops into an aggressive tumor and evades therapeutic challenge.

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