Scientists use AI-designed proteins to generate immune cells
The scientists engineered a synthetic activator of a key cellular pathway called Notch signalling, which plays a crucial role in cellular differentiation and is essential for transforming human immune progenitors into T cells.
Notch signalling is a cell-to-cell communication system vital for various developmental processes and tissue homeostasis in multicellular organisms. Homeostasis is the body's way of keeping everything balanced and stable, despite what is happening around it.
'In response to viral infections or cancer, the body requires a higher production of T cells to mount an effective immune defence. However, this process depends on the activation of the Notch signalling pathway, for which no effective molecular activators have been available,' Rubul Mout from Assam, the principal scientist of the study, said.
Associated with the Harvard Stem Cell Institute and the Stem Cell & Regenerative Biology Program at Boston Children's Hospital, he is one of 24 scientists involved in the collaborative effort. They include George Daley, the Dean of Harvard Medical School, and Nobel laureate David Baker.
Improved method
According to the study, an earlier method of activating Notch signalling in laboratory settings by immobilising Notch ligands on tissue culture dishes is not applicable for therapeutic use in humans. The quest for a viable, soluble activator of Notch signalling that could work in vivo (inside a living body) made the team develop a library of custom-designed soluble Notch agonists and systematically test their ability to activate the Notch pathway and support T cell development and function.
AI-driven protein design technologies, an innovation that contributed to Dr Baker receiving the 2024 Nobel Prize in Chemistry along with Demis Hassabis and John Jumper, were used to address the challenge.
Using the agonists, the researchers demonstrated the large-scale generation of T cells in a laboratory bioreactor, an important advancement given the growing demand for T cell production in hospitals worldwide for Chimeric Antigen Receptor (CAR) T cell-based cancer immunotherapies.
Furthermore, when the agonists were injected into mice during vaccination, the animals displayed significantly improved T cell responses, indicating an enhanced immune response. The treatment resulted in increased production of memory T cells, which are crucial for the long-term impact of vaccines.
'Being able to activate Notch signalling opens up tremendous opportunities in immunotherapy, vaccine development, and immune cell regeneration,' Dr Mout said.
'What excites me the most is using this technology to engineer synthetic proteins that simultaneously bridge T cells and cancer cells, boost T cell-mediated killing, and neutralise the immunosuppressive tumour micro-environment. Our goal is to develop next-generation immunotherapies and cancer vaccines,' he added.
The other collaborators of the study include Urban Lendahl of the Stockholm-based Karolinska Institutet and a former Chairman of the Physiology and Medicine Nobel Committee, Stephen C. Blacklow, the Chair of Harvard Medical School's Department of Biological Chemistry and Molecular Pharmacology, and R. Grant Rowe of Boston's Dana-Farber Cancer Institute.
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