Objective
Our goal is to create a new generation of enhanced insulin-producing cells that can sense their environment and protect themselves from immune attack.
Scientists can now make insulin-producing β cells from stem cells, offering hope for a lasting cure. These stem-cell–derived β cells can restore insulin production, but they can still die during transplantation, settling in their new niche, and when exposed to immune attacks.
Our project aims to change that. Instead of suppressing the immune system, we will reprogram the cells themselves so that inflammatory signals no longer lead to damage or death but are used to jumpstart β cell resilinece. We will use artificial intelligence (AI) to find the small DNA “switches” that control how β cells respond to inflammation, then use a precise “search-and-replace” tool for DNA, to rewrite those switches safely and accurately. This approach will create β cells that keep producing insulin and stay healthy even under immune attack.
If successful, it will be a major step toward a true biological cure for T1D and could pave the way for designing resilient, self-healing cells for other diseases in the future.
Background Rationale
Type 1 diabetes is an autoimmune disease in which the immune system destroys β cells that make insulin, a hormone necessary to regulate blood sugar. Without insulin, glucose builds up in the blood, causing serious health problems. Current treatments, like insulin injections or pumps, cannot perfectly mimic natural β-cell function.
Stem-cell technology now allows scientists to make new insulin-producing cells in the lab that could one day readily replace those destroyed by the immune system. Early clinical trials are encouraging, but these transplanted cells remain vulnerable to inflammatory molecules from the immune system. This inflammation damages β cells even when they are protected by capsules. Inflammatory damage happens because the β cell genome responds to cytokines in a harmful way. Short control regions called enhancers act like switches that turn genes on or off when the environment changes. In β cells, some of these enhancers are triggered by inflammatory signals to activate stress or cell-death genes.
Our project is based on a simple but powerful idea: instead of trying to suppress the immune system, we will reprogram β cells to resist inflammation and even be enhanced, by redesigning these regulatory sequences. New artificial intelligence (AI) tools can now predict how small DNA changes alter gene regulatory activity. By pairing AI design with advanced precision gene-editing tools, we can safely and accurately change just a few DNA letters to prevent harmful responses without disrupting normal insulin production. This approach directly targets the underlying DNA code that makes β cells vulnerable, reprogramming the code instead toward enhancing resilience of the cells. This approach offers a fundamentally new way to make cell therapies that survive and thrive in the body.
Description of Project
Type 1 diabetes (T1D) occurs when the immune system destroys the insulin-producing β cells in the pancreas. Without insulin, the body cannot control blood sugar levels, requiring lifelong insulin therapy. While insulin pumps and continuous glucose monitors improve care, they cannot fully replace the natural control provided by real β cells.
Stem-cell technology now makes it possible to grow glucose responsive, insulin-producing stem-cell–derived β cells (SC-β cells) in the laboratory. These cells can sense blood sugar and release insulin, restoring glucose balance in animals and early clinical trials. Unfortunately, transplanted SC-β cells are damaged by stress and inflammatory molecules released by immune cells,reducing their ability to make insulin or causing them to die.
Our project offers a completely new way to protect β cells by teaching the cells new ways to respond to their environment and immune attacks. Every gene in a cell is controlled by short DNA “switches” called gene regulatory or enhancer elements. These switches decide which genes are turned on or off in different cell types and in response to environmental changes. In β cells, certain enhancers are activated in response to stress and cytokines. By redesigning these DNA switches, we can make β cells that resist and even counteract stress while still performing their normal insulin-producing function.
To achieve this β cell enhancement, we use two cutting-edge technologies. The first is artificial intelligence (AI), which analyzes and interprets large genomic datasets to predict how tiny DNA changes alter gene activity. Using AI, we can identify the exact regulatory “letters” that make β cells vulnerable or that contribute to cellular responses. The second technology is PRIME editing, a new, highly accurate gene-editing tool that can rewrite DNA like a “search and replace” function, changing specific bases without cutting both strands of DNA. This makes it safer and more precise than older tools like CRISPR-Cas9.
We will first use AI models to design the best small DNA edits to protect β cells from inflammation. Next, we will introduce these edits into human stem cells using prime editing, grow them into SC-β cells, and test whether they resist inflammatory damage while continuing to produce insulin.
If successful, this project will generate the first inflammation-resistant human β cells through directed rewriting the logic by which the cells respond to their environment, paving the way toward a long-lasting, cell-based cure for T1D. In the future, this same approach could also be applied to other cell types and diseases where inflammation limits the success of regenerative therapies.
Anticipated Outcome
This project aims to create the first human β cells that are naturally resistant to inflammatory damage through AI-guided genome rewriting, eliminating the need for harsh immunosuppression or encapsulation.
By applying AI-guided DNA design and advanced prime editing, we expect to identify a small number of precise DNA changes that make β cells ignore the immune system’s inflammatory “attack signals.” The resulting cells will stay healthy and strive, and continue to make insulin even in an inflammatory environment.
We anticipate that:
Computational modeling will reveal specific regulatory sequences that control how β cells respond to stress and inflammation.
Advanced Prime editing will successfully rewrite these sequences without disrupting other genes.
Lab tests will show that edited SC-β cells remain functional after exposure to inflammatory cytokines.
If successful, this approach will not only produce inflammation-resistant β cells for transplantation but also establish a blueprint for designing cell therapies that are self-protecting and long-lasting.
In practical terms, this could mean that people with T1D who receive SC-β cell transplants might achieve long-term insulin independence without lifelong immunosuppressive drugs. It would be a decisive step toward a true biological cure for T1D. Beyond diabetes, the same technology could help reprogram and enhance other cell types, such as heart, nerve, or blood cells, to resist environmental stresses and limitations, opening a new frontier in regenerative medicine.
Relevance to T1D
The goal of this work is to solve one of the most persistent challenges in curing Type 1 diabetes: protecting new insulin-producing cells from the immune system. People with T1D must manage blood sugar levels manually for life because their immune systems destroy β cells that make insulin. Cell replacement therapy using lab-grown SC-β cells offers real hope, but immune attack and inflammation continue to threaten these transplanted cells.
Our research takes an entirely new approach. Instead of blocking the immune system or hiding the cells, we are reprogramming the β cells themselves so they can survive inflammation. Using artificial intelligence, we can read the DNA “grammar” that tells β cells how to react to stress. Then, with new gene editing approaches, we can rewrite that grammar to remove harmful responses and improve how cells respond to triggers..
For people living with T1D, this means that transplanted β cells could be reprogrammed for enhanced performance, which could help transplanted cells survive for years, perhaps indefinitely, which would end the need for insulin injections.
This project is directly aligned with the Breakthrough T1D mission to deliver curative therapies by combining the latest advances in stem-cell biology, gene editing, and artificial intelligence. It represents a step toward a future where T1D can be cured at its root cause, restoring healthy insulin production without immune suppression, and enhancing β cell function by design.