Objective
The objective of this project is to develop a safe, effective, and scalable stem-cell–based therapy capable of restoring natural insulin production in people with Type 1 diabetes. The work focuses on building high-quality “islet organoids”, clusters of insulin-producing cells made from human pluripotent stem cells (hPSCs), and preparing them to survive and function long-term after being transplanted into the body.
To achieve this goal, the project combines three cutting-edge technologies:
1. Chemical maturation. Stem-cell–derived beta cells often behave like immature, fetal-like cells and are not yet capable of the rapid, precise insulin release required to control blood sugar. Using a high-resolution platform called ChemPerturb-seq, the investigators screened hundreds of drugs and identified specific compounds that push these cells toward a more adult-like state. These compounds activate essential genes and pathways that give mature beta cells their unique ability to sense glucose and release insulin appropriately.
2. Chemical pre-conditioning. After transplantation, the biggest threat to the cells is the harsh environment they encounter in the first few days, very low oxygen, inflammation, and nutrient stress. The team developed a chemical “pre-conditioning” approach in which organoids are treated with protective molecules before transplantation. This short treatment strengthens the cells, making them more resilient and capable of surviving the critical early phase after implantation.
3. AI-enabled organoid manufacturing. Producing these specialized organoids in a reliable and reproducible way requires advanced technology. The project uses the CellForge platform, which combines automation, real-time cellular monitoring, and artificial intelligence to optimize the manufacturing process. CellForge analyzes the state of the cells during every step and automatically adjusts conditions to ensure that each batch of organoids meets strict quality standards.
Primary Objective. To generate stem-cell–derived islet organoids that are both functionally mature and resilient, and to test whether they can successfully survive, engraft, and restore blood sugar control when transplanted into a safe and minimally invasive subcutaneous site.
The specific components of the objective include identifying and optimizing small molecules that strengthen beta cell identity and insulin-secreting function; determining which combinations of pre-conditioning molecules best promote survival under low oxygen and inflammatory stress; and using scRNA-seq to understand how each treatment alters the molecular state of the organoids. The project will also test organoid performance in both healthy and diabetic animal models, measure long-term survival, insulin secretion, and the ability to reverse diabetes, and establish a scalable manufacturing process suitable for future clinical translation. By focusing on the subcutaneous space, a safer and more accessible site than the liver, the project aims to develop a therapy that could ultimately be delivered through a simple outpatient procedure. The overarching goal is to lay the groundwork for a next-generation T1D treatment that eliminates the need for daily insulin injections, provides consistent physiologic control of blood glucose, reduces long-term complications, and can be produced at scale for widespread clinical use. Collectively, this work aims to advance the field toward a practical, durable cure for Type 1 diabetes by addressing the key biological and engineering challenges that currently limit stem-cell–based beta cell replacement therapies.
Background Rationale
For people living with Type 1 diabetes (T1D), daily life requires constant vigilance. Individuals must monitor their blood sugar, calculate insulin doses, prepare for meals and physical activity, and remain alert to the dangers of both high and low glucose levels. A true cure would require replacing the insulin-producing beta cells that the immune system has destroyed—restoring the body’s own capacity to control blood sugar.
Scientific progress over the past decade has made this vision more realistic. Researchers can now create insulin-producing cells from human pluripotent stem cells, which are capable of becoming any cell type in the body. Early clinical trials have shown that these stem-cell–derived islet cells can survive after transplantation and begin secreting insulin, offering meaningful improvement in glucose control. These promising results demonstrate that beta cell replacement is feasible. However, major challenges still prevent this therapy from becoming widely available and reliably effective.
The first major challenge is that stem-cell–derived beta cells are often functionally immature. Although they can produce insulin, they behave more like fetal than adult beta cells. They may not respond quickly enough to changes in blood sugar, and their insulin secretion can be inconsistent. Achieving full maturation, so that the cells work just like healthy human beta cells, is essential for reliable, physiologic glucose regulation.
The second challenge is poor survival after transplantation. Regardless of the transplantation method, new beta cells face severe stress the moment they enter the body. They encounter extremely low oxygen levels, inflammation, and limited access to nutrients before new blood vessels form. As a result, more than half of transplanted cells typically die within the first few days. This early loss dramatically limits the effectiveness of cell replacement therapy.
The third challenge concerns the transplantation site. Traditional islet transplants are performed in the liver, but this approach carries risks such as bleeding, thrombosis, and liver injury. A safer alternative is the subcutaneous space, a location just beneath the skin. This site is easy to access, allows simple monitoring and retrieval, and avoids many surgical complications. However, it is also biologically harsh: it contains few blood vessels, meaning transplanted cells experience even more oxygen deprivation and inflammation.
This project takes a comprehensive and technologically advanced approach to overcome these obstacles.
First, the team uses ChemPerturb-seq, a cutting-edge screening platform that analyzes how hundreds of small molecules affect beta cells at single-cell resolution. This allows the researchers to identify compounds that promote maturation, strengthen insulin-secreting pathways, and help the cells behave more like fully functional adult beta cells.
Second, to address the problem of early cell death, the project incorporates chemical pre-conditioning. Using an innovative in vivo barcoded screening method, the researchers identified protective molecular cocktails, such as IGF-1, PGE2, and beta-lipotropin (LIP), that significantly improve cell survival and insulin secretion after subcutaneous transplantation. Pre-conditioning helps cells better withstand low oxygen, reduces stress on mitochondria, and activates protective pathways that enhance long-term function.
Third, the project ensures the ability to manufacture these islet organoids consistently and at high quality using CellForge, an AI-enabled automated organoid production platform. CellForge continuously monitors the molecular state of cells and adjusts culture conditions in real time. This ensures that each batch of organoids meets stringent quality standards and can be scaled for future clinical use.
Together, these strategies, chemical maturation, pre-conditioning, and AI-driven manufacturing, create an integrated pipeline designed to produce robust, functional, and clinically translatable islet organoids. By targeting the key biological barriers that have limited beta cell replacement therapy, this project moves the field closer to a practical, durable, and widely accessible cure for Type 1 diabetes.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease in which the body’s immune system destroys the insulin-producing beta cells in the pancreas. Without enough insulin, the body cannot properly control blood sugar, leading to lifelong dependence on insulin injections or pumps. Even with excellent medical care, many people struggle to maintain stable blood sugar levels, placing them at risk for severe complications affecting the eyes, kidneys, heart, and nerves. A long-standing goal in diabetes research has been to replace the missing beta cells so that the body can once again regulate blood sugar naturally.
Recent advances in stem cell biology have made it possible to generate insulin-producing cells from human pluripotent stem cells (hPSCs). These cells can be produced in almost unlimited quantities and have shown promising early results in clinical studies, where some patients demonstrated measurable insulin production after transplantation. However, major challenges still limit the full therapeutic impact of this approach. First, stem-cell–derived beta cells often resemble immature, fetal-like cells and cannot immediately regulate blood sugar at levels comparable to adult human beta cells. Second, transplanted cells frequently die soon after implantation because they face extreme stress—including lack of oxygen, inflammation, and poor integration with blood vessels. Third, the most common transplantation site (the liver) carries risks such as bleeding and thrombosis, while safer alternatives like the subcutaneous space are currently too hostile for fragile beta cells to survive.
The goal of this project is to overcome these barriers by creating fully functional, stress-resilient stem-cell–derived islet organoids, and to evaluate their ability to reverse diabetes when transplanted into a safe and accessible subcutaneous site.
The project integrates two powerful innovations:
1. Chemical maturation of hPSC-derived islet organoids
Using a platform called ChemPerturb-seq, which profiles how individual small molecules alter beta cell gene expression at single-cell resolution, the team has identified several compounds that strongly enhance the maturation of beta cells. These compounds increase expression of critical genes (e.g., MAFA, UCN3) and strengthen insulin secretion.
2. Chemical pre-conditioning to improve cell survival after transplantation
A cutting-edge in vivo barcoded screen uncovered two chemical combinations that protects human beta cells from early post-transplant apoptosis in the subcutaneous space. Pre-conditioned cells survive better, secrete more insulin, and show stronger responses to glucose in animal models.
Together, these strategies will be implemented using the iOrganBio CellForge platform, an AI-guided, automated system capable of producing large numbers of high-quality organoids with real-time monitoring and optimized differentiation control. CellForge ensures consistency, scalability, and clinical manufacturing readiness.
The research will proceed through two major aims:
• Aim 1: Generate highly functional, mature islet organoids using chemical maturation and evaluate their performance both in laboratory tests and in transplanted mice.
• Aim 2: Apply pre-conditioning strategies to enhance resilience to stress and test whether these organoids can survive, engraft, and ultimately restore normal blood sugar in diabetic animals.
If successful, this work will create a scalable, reproducible, and clinically translatable process for producing transplant-ready islet organoids capable of curing diabetes through a minimally invasive procedure. The approach combines modern stem cell biology, AI-enabled manufacturing, and chemical precision medicine to address one of the most important unmet needs in T1D therapy.
Anticipated Outcome
The anticipated outcome of this project is to create a new type of stem-cell–derived islet organoid that is strong, mature, and capable of working like the beta cells lost in Type 1 diabetes. These organoids will be designed not only to produce insulin at the right times, but also to survive the difficult conditions they encounter after being transplanted into the body.
Here are the main outcomes we expect:
1. One major anticipated outcome is the generation of more mature, highly functional beta cells. By identifying and applying specific small molecules that enhance cellular maturation, the project aims to produce beta cells that respond quickly and accurately to changes in blood sugar, express key genes and proteins characteristic of fully mature human beta cells, secrete insulin in a regulated and physiologic manner, and exhibit improved metabolic fitness along with well-formed insulin granules. Achieving this degree of maturity is essential for enabling transplanted cells to assume glucose control as effectively as natural beta cells.
2. Stronger cell survival after transplantation. The early days after transplantation are the most dangerous for beta cells, and pre-conditioning is expected to play a critical role in improving their survival. By reducing early cell death, protecting cells from low oxygen and inflammation, enhancing mitochondrial function, the cell’s primary energy source, and strengthening adaptive stress-response pathways, pre-conditioning should help transplanted organoids withstand the harsh post-implantation environment. As a result, we anticipate a significantly higher number of functioning beta cells in the graft during this critical early window, ultimately improving long-term therapeutic performance.
3. Successful engraftment in the subcutaneous space. A key goal of this project is to demonstrate that the subcutaneous space, a simple, safe, and easily accessible location beneath the skin, can support long-term survival and insulin production when organoids are appropriately conditioned. We expect pre-conditioned islet organoids to promote the formation of new blood vessels around the graft, develop into stable and well-structured islet tissue over months, and consistently secrete insulin in response to glucose challenges. If validated, this site could make islet transplantation substantially more accessible to patients by avoiding the risks associated with liver-based procedures.
4. Restoration of normal blood sugar in diabetic animals. In diabetic mouse models, we anticipate that pre-conditioned islet organoids will rapidly begin producing insulin after transplantation, normalize fasting and post-meal glucose levels, and demonstrate strong responses in glucose tolerance tests. We expect these improvements to be sustained for at least 24 weeks, reflecting durable graft function and metabolic control. Such findings would provide compelling evidence that this therapy could ultimately replace insulin injections in humans and restore natural glucose regulation.
5. Establishment of a scalable, clinically ready manufacturing process. A successful outcome will also include validation of the CellForge platform’s ability to generate islet organoids at large scale with consistent quality, using automated, AI-guided processes that meet the stringent requirements of preclinical and clinical manufacturing. Demonstrating that CellForge can reliably produce uniform, functional organoids is essential for future translation, as widespread clinical use will require reproducible, high-throughput manufacturing systems capable of supporting population-level therapy.
What success means for the future
If all anticipated outcomes are achieved, the research will lay the foundation for advancing this therapy into non-human primate studies and eventually human clinical trials. In the long term, this project could lead to a world where people with Type 1 diabetes receive a simple transplant under the skin that restores natural insulin production—freeing them from daily management burdens and dramatically improving health outcomes.
Relevance to T1D
People with T1D must take insulin every day of their lives to survive, yet even the best insulin delivery systems cannot match the body’s natural ability to regulate blood sugar. This is why complications such as blindness, kidney failure, nerve damage, and heart disease remain common, even among individuals who work tirelessly to manage their disease.
The core problem is simple: the body no longer has functioning beta cells.
The most powerful solution would be to replace those cells.
This project is directly relevant to T1D because it seeks to create a practical, scalable, and minimally invasive beta-cell replacement therapy that restores natural insulin production. The approach addresses several critical needs in T1D research and therapy:
1. Providing an unlimited supply of insulin-producing cells. Cadaveric islets used in conventional islet transplantation are extremely limited and vary widely in quality. Human pluripotent stem cells can produce virtually unlimited numbers of insulin-secreting cells under controlled conditions. This overcomes the biggest supply barrier to making cell-replacement therapy accessible to all people with T1D.
2. Improving the quality and maturity of replacement cells. Current stem-cell–derived beta cells resemble immature, fetal cells and do not match the precision, speed, or stability of real human beta cells. The project’s chemical maturation strategy is designed specifically to correct this problem, making the resulting organoids far more capable of controlling blood sugar.
3. Ensuring cells survive after transplantation. The vast majority of transplanted cells die in the first few days—especially in the subcutaneous space, which is the safest and easiest transplantation site. Pre-conditioning directly targets the stresses that cause this early cell loss, potentially transforming the success rate of beta-cell grafts.
4. Enabling a safe, accessible transplantation method. Subcutaneous transplantation offers a highly accessible and patient-friendly approach to beta-cell replacement therapy because it is minimally invasive, avoids the risks associated with liver-based procedures, allows for repeated or adjustable placement of grafts, and enables straightforward retrieval if needed. By engineering islet organoids specifically to survive and function in this site, the project addresses a major translational barrier and moves the therapy closer to practical real-world clinical implementation.
5. Reducing the burden and risks of T1D. If successful, this therapy has the potential to dramatically reduce the daily burden and long-term risks of Type 1 diabetes by freeing patients from constant glucose monitoring and insulin injections, lowering the likelihood of severe hypoglycemia, preventing progressive damage to vital organs, and improving emotional well-being and overall quality of life. By mitigating both the physical and psychological challenges of diabetes management, and reducing healthcare costs associated with complications, this approach could enable many individuals to live lives much closer to those without diabetes.
6. Moving toward a durable or permanent cure. The long-term vision of this work is to develop a therapy capable of fully replacing the need for insulin by solving the interconnected challenges of beta-cell maturation, survival, and engraftment. By creating a solution that is scalable, reproducible, clinically safe, and accessible to a broad patient population, the project advances the field toward a practical and durable cure for T1D. In doing so, it directly addresses the biological obstacles that currently limit stem-cell–based beta-cell replacement therapies and offers a scientifically grounded path toward restoring natural insulin production and transforming the lives of millions living with Type 1 diabetes.
In summary, this research is deeply relevant to Type 1 diabetes because it tackles the exact biological obstacles that prevent beta-cell replacement therapy from becoming a cure. It offers a scientifically grounded path toward restoring natural insulin production and transforming the lives of millions of people living with T1D.