We combine chemistry, biochemistry, immunology, and physiology to uncover basic mechanisms in innate immunity and, in parallel, develop therapeutic hypotheses and lead molecules. Innate immune pathways as the first line of defense against pathogens present many exciting opportunities for scientists from many disciplines.
These pathways are a rich source of novel chemistry: they involve diverse molecular patterns in pathogens, little-explored second messengers, and drugs with poorly understood mechanism.
Activation of innate immunity is a proven therapeutic strategy for vaccination, viral infection, and cancer, while inhibition is a strategy for treating autoimmune diseases and neurodegeneration. To date, however, most modulators of innate immunity are broad, non-specific, and poorly characterized, such as killed bacteria, alum crystals, and steroids.
The Li lab seeks to improve understanding of these pathways and facilitate the development of more precise drugs for preventing or treating specific diseases.
The innate immune STING pathway must defend decisively and potently against viruses and cancer by recognizing cytosolic double-stranded DNA (dsDNA) as a danger signal, but tolerate benign self dsDNA. Therefore, understanding how the STING pathway distinguishes between defense and tolerance is of paramount importance. Cytosolic dsDNA activates production of a second messenger cyclic-GMP-AMP (cGAMP). We previously discovered that cGAMP is an immunotransmitter that is secreted by producing cells and detected by various immune cell types and stromal cells. This is a tightly regulated process by various cell type specific cGAMP transporters and hydrolases. We uncover these regulatory mechanisms using our in-house chemical biology tools for target identification coupled with genetic approaches. We screen for checkpoints and enhancers of the STING pathway, with a focus on druggable targets.
We use classic biochemistry, structural biology, and medicinal chemistry to investigate at the atomic level how protein and small molecule immunomodulators of the STING pathway function effectively and how they fall into dysregulation and cause inflammation. In parallel, we develop and refine prototype drugs that bind to targets in the STING pathway and can be used to test therapeutic hypotheses in disease models.
Cancer and autoimmunity are two sides of the same coin of STING physiology. We have strong interest in the balancing act of the STING pathway in whole organisms. We rely heavily on mouse genetic models and are building cutting-edge genetic knock-in mouse strains that selectively perturb regulators that we have uncovered. We use these mouse strains coupled with cancer, infection, and autoimmune disease models to contextualize the roles of each regulator in different disease settings. We also use these disease models to test our therapeutic hypotheses and lead compounds.
Jacqueline A Carozza, Anthony F Cordova, Jenifer A Brown, Yasmeen AlSaif, Volker Böhnert, Xujun Cao, Rachel E Mardjuki, Gemini Skariah, Daniel Fernandez, Lingyin Li
Anthony F Cordova, Christopher Ritchie, Volker Böhnert, Lingyin Li
Lauren J Lahey, Rachel E Mardjuki, Xianlan Wen, Gaelen T Hess, Christopher Ritchie, Jacqueline A Carozza, Volker Böhnert, Merritt Maduke, Michael C Bassik, Lingyin Li
Jacqueline A Carozza, Jenifer A Brown, Volker Böhnert, Daniel Fernandez, Yasmeen AlSaif, Rachel E Mardjuki, Mark Smith, Lingyin Li
Jacqueline A Carozza, Volker Böhnert, Khanh C Nguyen, Gemini Skariah, Kelsey E Shaw, Jenifer A Brown, Marjan Rafat, Rie von Eyben, Edward E Graves, Jeffrey S Glenn, Mark Smith, Lingyin Li
Sabrina L Ergun, Daniel Fernandez, Thomas M Weiss, Lingyin Li
Christopher Ritchie, Anthony F Cordova, Gaelen T Hess, Michael C Bassik, Lingyin Li
Lingyin Li is an Associate Professor in the Biochemistry Department and the ChEM-H institute at Stanford. She received her Ph.D at the University of Wisconsin-Madison with Dr. Laura Kiessling and performed postdoctoral studies with Dr. Timothy Mitchison at Harvard Medical School. The Li Laboratory has pioneered the development of chemical tools to define and manipulate new modulators of the innate immune STING pathway. Dr. Li is the recipient of the NIH New Innovator Award in 2017, the Ono Pharma Foundation Breakthrough Science Initiative Award in 2017, and the 2022 Eli Lilly Award in Biological Chemistry.
Before joining Li lab as lab manager/ LSRP, I was working at different Stanford labs since 2004. At Li lab I maintain all the mouse strains for different projects in the lab. Outside of the lab I enjoy spending time with family and friends.
I trained in chemistry and biochemistry, completing my PhD at Stanford with Lingyin in 2021. Now, I work on identifying druggable proteins in innate immuno-oncology and developing molecules that target them. I really enjoy backpacking in the Sierra Nevada foothills and spending time with my family.
Before joining Stanford I worked at EMBL Grenoble, France, on X-ray structural characterization of plant hormone receptors and their ligands. At Li Lab I supervise protein structural work, training students. Outside of the lab, I enjoy biking and reading books.
I have a PhD in Biochemistry from Stanford. In lieu of a traditional bio, I commissioned members of my lab space to write a descriptive haiku for me:
In my PhD
I found cGAMP transporters
I enjoy biking.
Prior to Stanford, I worked in epigenetics and organic synthesis. At Arc, I work on understanding the regulation of extracellular cGAMP. Outside of lab I enjoy swimming and music.
Prior to Stanford, I majored in Chemistry at the National University of Singapore, where I worked on the organic synthesis of carbohydrate probes and imprinted polymers. At Arc, I use tools in biochemistry, computation and cell and structural biology to study molecular mechanisms of innate immune activation. Outside of the lab I enjoy mahjong, board games and mind games, eating and running so I can keep eating.
I studied Chemical Engineering at Johns Hopkins and spent two years doing stem cell research at USCF before starting medical school at Stanford. I’m currently pursuing a joint master degree where I study ENPP1's role as an innate immune checkpoint in cancer. In my free time I like to cook/eat good foodwith friends and families.
Prior to Stanford, I did my undergrad at MIT, where I worked on a joint project between the labs of Harvey Lodish and Hidde Ploegh to engineer red blood cells and nanobodies for various therapeutic purposes. At Arc, I work on how extracellular cGAMP signals in T cells. Outside of lab I enjoy doing photography, watching basketball games and trying out different food.
Prior to Stanford, I completed my BS in Chemical Biology from UC Berkeley followed by two years of research in Judith Frydman’s lab studying chaperone-huntingtin interactions. At Arc, I work on understanding the cellular and biochemical factors that regulate STING activation. Outside of lab, I enjoy being active outdoors, trying new foods, and bingeing true crime shows.
Prior to Stanford, I worked on biomaterials for drug delivery and chemical probes for studying bacterial glycans. At Arc, I work on mapping the regulation of the immunotransmitter cGAMP in the context of STING signaling. Outside of lab I enjoy playing tennis, squash, soccer, and mini golf
Prior to Stanford, I received my B.S. in Chemistry and Biology from the Massachusetts Institute of Technology (MIT), where I worked in Prof. Laura Kiessling's lab studying structure-fuction relationships of mucins by designing mucin-mimetic polymers with antivirulence properties against cholera toxin. At Arc, I work on STING signaling and regulation in T cells. Outside of lab I enjoy going on road trips, hiking, and attempting to cook Brazilian dishes.
We are accepting post-docs and students! Please email lingyin@arcinstitute.org with your CV and a description of your background and research interests.
We would love to hear from trainees from any scientific discipline and background. In the past, students have joined the Li lab from the Departments of Biochemistry, Chemistry, Chemical & Systems Biology, Biology, Immunology, and Biophysics.
