Objective
The overall goal of this project is to develop stem cell–derived islet (SC-islet) implants that are more durable and function more effectively after transplantation, bringing us closer to a practical, long-term cure for type 1 diabetes.
Objective 1: Improve insulin-producing cell function
This part of the project focuses on improving the core machinery inside insulin-producing cells. We will use a cutting-edge method called mammalian directed evolution, which mimics natural selection in the lab, to strengthen key proteins called transcription factors. These proteins control how cells grow and function, especially in making insulin. By evolving more powerful versions of these proteins, we aim to boost the ability of SC-islets to produce insulin reliably and respond to blood sugar levels just like natural β-cells.
Objective 2: Make transplanted cells more resilient to stress
After implantation, SC-islets must survive in an environment that can be highly inflammatory. This stress often damages or kills the implanted cells before they have a chance to fully mature and function. In this objective, we aim to make the cells tougher, specifically by engineering key transcription factors so the cells can still function under inflammation. This will help more cells survive the transplant process, stay healthy over time, and continue to support normal blood sugar control.
Together, these two objectives are designed to enhance the performance and longevity of SC-islet implants, moving one step closer to a safe, scalable cure for people living with type 1 diabetes.
Background Rationale
For people living with type 1 diabetes (T1D), everyday life involves constant monitoring of blood sugar levels and regular insulin injections. This is because the immune system mistakenly destroys insulin-producing cells in the pancreas. While insulin therapy helps manage the condition, it is not a cure, and many people still face serious long-term complications such as kidney failure, heart disease, and vision loss.
One promising treatment is islet transplantation, in which insulin-producing cells from a donor pancreas are implanted into the body to take over blood sugar regulation. This approach has been shown to work. In fact, the Edmonton Protocol, one of the first successful procedures, helped nearly 80% of participants achieve insulin independence within just three months. However, this treatment is limited by a major obstacle: a shortage of suitable organ donors. On top of that, even when donor cells are available, many of them don’t survive long after being transplanted, due to the stress of inflammation and low oxygen in the body.
To overcome the donor shortage, researchers have turned to stem cell–derived islets (SC-islets). These lab-grown clusters of insulin-producing cells offer a renewable source of transplant material. Early clinical trials, including those based on protocols developed by our collaborator Prof Timothy Kieffer, have shown promising results. Some patients using SC-islets have been able to reduce and even eliminate, their need for insulin injections.
Despite these advances, challenges remain. The implanted SC-islets often experience significant cell loss shortly after transplantation, and the insulin-producing β-cells inside them don’t always fully mature or function as they should. Analyses of transplant tissue reveal a mix of outcomes: some areas where the cells survive and work well, and others where the tissue becomes scarred or lacks the blood vessels needed for survival. Researchers also find that the β-cells (the cells that produce insulin) are often outnumbered by other cell types, suggesting that the therapy needs to produce not just more cells, but the right kinds of cells.
To make SC-islet therapy a realistic, lasting solution for people with T1D, researchers must now focus on improving cell survival, maturation, and long-term function. This project addresses these key issues by developing stronger, more stress-resistant insulin-producing cells, helping bring us closer to a durable and scalable cure for type 1 diabetes.
Description of Project
Type 1 diabetes (T1D) is a lifelong autoimmune condition in which the immune system mistakenly destroys the pancreas’s insulin-producing cells. Without insulin, people with T1D must carefully manage their blood sugar using injections or pumps, an ongoing burden that, even when well-managed, can still lead to serious complications such as vision loss, kidney failure, and heart disease.
One of the most promising potential cures for T1D is stem cell–derived islet (SC-islet) implantation. This treatment involves implanting lab-grown insulin-producing cells into the body to replace those lost to the disease. Early clinical trials have shown encouraging outcomes, with some recipients able to reduce or even stop taking insulin for at least a year.
However, widespread use of SC-islet therapy faces challenges. A major barrier is that the implanted cells are highly sensitive to stress, especially the inflammatory environment they encounter in the body after transplantation. This stress can disable key proteins, called transcription factors, that help insulin-producing cells mature and function properly. As a result, many implanted cells fail to survive or do not become fully functional.
This project addresses that problem by making insulin-producing cells more resilient to inflammatory stress. The focus is on enhancing transcription factors, “master switches” that control how these cells develop and operate. Using a cutting-edge method called mammalian directed evolution, we will evolve stronger versions of these proteins that remain active even under stress. This could result in more effective, long-lasting SC-islet implants capable of offering a scalable, curative treatment for people with T1D.
Anticipated Outcome
This project aims to tackle a major unmet need in type 1 diabetes (T1D) by developing improved stem cell–derived islet (SC-islet) implants that last longer and work more effectively after being placed in the body. Unlike current treatments, which only manage the symptoms of T1D, this approach targets the root cause, the loss of insulin-producing β-cells, offering a potential path toward a true cure.
The research team has already helped lead a first-in-human clinical trial showing that SC-islets can significantly reduce or eliminate the need for insulin injections. They have also developed a powerful new technology called the PROTEUS platform, which allows researchers to evolve key proteins inside β-cells to make them stronger and more resilient. A key innovation in this project is the creation of specially designed proteins that can resist the damaging effects of inflammation, one of the main causes of cell failure after transplantation.
The expected outcomes include the development of a new type of therapeutic SC-islet, capable of surviving and functioning more effectively in the body. This work will also generate advances in synthetic biology and stem cells that will be shared with other researchers, helping to advance scientific progress through international collaborations.
In the long term, this research could lead to a first-of-its-kind treatment for T1D, and the methods developed here may also be adapted for use in treating type 2 diabetes. The project will strengthen an interdisciplinary collaboration, train an emerging T1D scientist, and open the door to future commercial opportunities. Most importantly, it aims to improve the lives of people living with diabetes by offering safer, more effective treatments and reducing the long-term burden on patients and the healthcare system.
Relevance to T1D
This research takes a bold step toward solving one of the biggest challenges in type 1 diabetes (T1D): how to restore the body’s ability to naturally produce insulin. While current treatments help manage blood sugar, they don’t address the root cause of the disease: the loss of insulin-producing β-cells in the pancreas. People with T1D must rely on daily insulin injections or pumps, which come with ongoing risks and complications, including dangerous episodes of low blood sugar and long-term organ damage.
Our project offers a new kind of solution. Instead of simply replacing insulin, it aims to restore the body’s own ability to make it, through lab-grown stem cell–derived islet (SC-islet) implants. These implants are designed to replace the missing β-cells and take over the job of regulating blood sugar.
What makes this project especially innovative is the use of directed evolution, a cutting-edge technique that allows researchers to improve the key proteins that control how β-cells function. Using a new platform that we developed called PROTEUS, we’re engineering these proteins to better survive and work in the harsh environment that typically damages cells after they are implanted in the body.
For people living with T1D, this research could lead to treatments that are safer, last longer, and potentially eliminate the need for insulin injections altogether. It may also lower the risk of severe blood sugar swings and improve overall health and quality of life. In the long term, this approach could also benefit people with other forms of diabetes, expanding its impact even further.