Research Roundup: December 13, 2019

Seeking success predictors for cancer immunotherapy, probing protein structure through evolution, and mulling mapping methods for single-cell biology.

Erik Jacobs
Credit: Erik Jacobs

Welcome to the December 13, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Helping patients with better predictions for immunotherapy 

Most patients with cancer who are treated with immune checkpoint blockade (ICB), a type of immunotherapy, either develop resistance or do not respond to it. The predictors of response to ICB are not fully characterized. To solve this problem, an interdisciplinary team of clinical and computational investigators led by David Liu (postdoctoral scholar) and Cancer Program associate member Eliezer Van Allen, along with Keith Flaherty, Livnat Jerby-Arnon, and core institute member and Klarman Cell Observatory director Aviv Regev, analyzed tumor samples collected from a cohort of 144 patients with advanced melanoma and undergoing ICB. By integrating genomic, transcriptomic, and clinical data collected from the patient cohort, the researchers were able to discover biomarkers of response and resistance to ICB, and develop clinically applicable predictive models. Read more in Nature Medicine and a blog post from Dana-Farber Cancer Institute (DFCI).

Proteins get into shape

The natural evolution of proteins yields clues about their structure. A team including Nicholas Gauthier, Michael Stiffler, Frank Poelwijk, and Cancer Program associate member Chris Sander, collaborating with Cell Circuits Program associate member Debora Marks, hypothesized that proteins evolved over several weeks in cell culture hold structural clues as well. Their approach, known as 3Dseq and described in Cell Systems, takes an individual gene through multiple cycles of mutagenesis and functional selection. Deep sequencing of the resulting variants reveals sites that evolve together and likely interact in physical space, allowing them to compute the proteins’ 3D structure. Read more about this new technology, demonstrated using two antibiotic resistance proteins, in a DFCI press release.

A new anatomical cartography

In order to create truly robust single cell-level atlases of organs and tissues, scientists working in different labs and with material from different individual donors need a common coordinate framework (CCF): a reference map that allows them to spatially plot their data gathered from many individuals to the same relative location in the human body. In a Perspective in Cell, Jennifer Rood, Tommaso Biancalani, Regev, and colleagues in the Human Cell Atlas consortium describe prior mapping approaches, outline the features that should go into a CCF, and consider the challenges in creating and using one.

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