Arc Institute

Interested in how Lingyin Li and postdoctoral researcher Chris Ritchie unlocked the secrets of PELI2, a new player in autoimmunity? You can learn more at the Arc blog: https://lnkd.in/gyvjsBhi

Introducing a powerful, programmable new mechanism for genome design: DNA recombination with bridge RNAs, discovered by Arc’s Patrick Hsu lab. As the first natural RNA-guided DNA recombinase, this system enables insertion, excision, or inversion of any two DNA sequences. CRISPR has revolutionized gene editing. But for true large-scale genome design, scientists need a precise and programmable way to rearrange large segments of DNA. The bridge recombinase programmably joins two DNA molecules without exposing DNA breaks, overcoming key limitations of existing approaches. How does it work? The recombinase enzyme relies on a noncoding bridge RNA with two loops. One loop binds the donor DNA and the other loop binds the target DNA – the first example of a bispecific guide RNA. The two loops can be independently programmed to control the directionality of the DNA rearrangement. The new discovery is the result of two and a half years of collaboration with scientists across disciplines, institutes, and continents. The research was led by Patrick Hsu Matthew Durrant Nicholas Perry, with significant contributions from Arc Core Investigator Silvana Konermann’s lab, and the Nishimasu lab at the The University of Tokyo, led by Hiroshi Nishimasu. It is an early example of scientific output from Arc Institute’s collaborative model, which blends expert scientific staff with graduate students from Arc’s partner universities–UC Berkeley, Stanford University, and UCSF–in an interdisciplinary research environment across computational and experimental science. “We are excited to explore new applications that stem from our team’s interdisciplinary research across computation, genetics, biochemistry, bioengineering, and structural biology—the deep synergistic work that Arc was specifically designed to accelerate," said Hsu. Read more: https://lnkd.in/gipcKrFn First study in @Nature: https://lnkd.in/g6RwBQGE Second study in @Nature: https://lnkd.in/gHSh9tSb Learn about job opportunities at Arc: https://lnkd.in/gyfgqR3n Video by Visual Science

🎧 Exciting new discovery from Lingyin Li and postdoctoral researcher Chris Ritchie on PELI2: a protein that functions like noise-canceling headphones for the cGAS-STING pathway. cGAS-STING is a crucial immune defense mechanism for the human body that’s triggered in response to threats like viral and bacterial infections and cancer. But how does it know when to fight and when to stand down? Lingyin and Chris found that PELI2 acts like a sensor, filtering out cellular “white noise” that could chronically trigger STING—and lead to inflammatory conditions like lupus and neurodegeneration. At the same time, PELI2 turns into an amplifier when interferon levels grow above a certain threshold, ensuring that STING turns on at the right time. As Lingyin explains, “This research was highly interdisciplinary, combining “hardcore” biochemistry with immunology, genetics, and computation, but likely would not have received funding under traditional models. It’s the kind of curiosity-driven, interdisciplinary work that we’re uniquely positioned to do at Arc.” Read the full study in MolecularCell: https://lnkd.in/gmj6VDHK

🛠️New CRISPRi tool from Dr. Luke Gilbert and lab! Until now, scientists have been limited to targeting fewer than 3 genes at a time with CRISPRi. But what about when we want to study more complex combinatorial biology? Chris Hsiung in the Gilbert Lab has developed an Acidaminococcus Cas12a variant that can knock down 3+ loci simultaneously – meaning researchers can study complex genetic interactions and map regulatory biology more effectively. Check it out in Nature Biotech: https://lnkd.in/g3Nk7-kR

Early career scientists explore their most curious + innovative ideas at Arc as Science Fellows. New Fellow Uche Medoh, PhD joins us with a background in investigating the molecular mechanisms of anti-aging metabolites for human health and disease. Uche will drive important subcellular metabolism and aging exploration to develop treatments for age-related diseases (e.g. Alzheimer’s) in a dynamic, collaborative, and interdisciplinary community of scientists tackling complex disease. Welcome to Arc, Uche!

After discovering the role of the ENPP1 enzyme in masking cancer from the immune system, Dr. Lingyin Li and lab have found a new enzyme, ENPP3, that inhibits the cGAMP-STING pathway and the body’s  anti-tumor immune response, preventing immunotherapies like Keytruda from working effectively. Lab researcher Dr. Rachel Mardjuki first confirmed in mice that turning down both ENPP1 and ENPP3 combats metastasis better than just removing one or the other. She found that ENPP1 and ENPP3 have non-overlapping expression patterns in both normal tissue and tumor cells and compensate each other to degrade cGAMP. Then, in collaboration with Arc Investigator Dr. Hani Goodarzi, the Li lab explored ENPP3’s impact on melanoma patients treated with Keytruda: patients with low ENPP1+ENPP3 had 60% chance of no metastasis, but patients with high ENPP1+ENPP3 just 20% chance of no metastasis. This finding creates the opportunity to develop a single inhibitor treatment to block both ENPP1 and ENPP3 to make patients more receptive to Keytruda’s benefits – offering greater hope for impactful cancer treatment. Check out the findings in Cell Reports: https://lnkd.in/g63qHbCN And learn more about Dr. Li’s ENPP1 paper here: https://lnkd.in/gXptTaQ5

This afternoon, Arc’s Patrick Hsu and Brian Hie welcomed Sir Tony Blair and Tony Blair Institute for Global Change to Arc to see our institute in action, including the research we’re doing to accelerate biomedical progress with AI foundation models. Thank you Tony and Benedict Macon-Cooney for visiting Arc – we enjoyed discussing global health and change!

New from Cell Chemical Biology: Arc Core Investigator and Stanford University Biochem Professor Lingyin Li explores the future of cancer therapy using cGAMP-STING 🧬 The Li lab works to investigate how the signaling molecule cGAMP is passed between different cell types to activate the STING pathway and how cancers escape detection through cGAMP degradation — which controls how immune cells are recruited to a tumor to fight cancer. The perspective piece from Dr. Li outlines the successes + setbacks of cGAMP analogs as STING agonists, as well as new strategies for boosting endogenous cGAMP-STING signaling for cancer therapy while avoiding toxic side effects.👇 https://lnkd.in/gaaD2ZME

Delighted to see Arc Innovation Investigator and Stanford University Professor Zhenan Bao inducted into National Academy of Sciences. Her lab works to treat neurological disorders through skin-inspired bioelectronics – the kind of bold research Arc was created to fuel. Congratulations to Dr. Bao!"