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Disrupting Type One Diabetes

(interview with Dr. Jeff Millman)

Tell Us About Yourself

Jeffrey R. Millman, PhD
Jeffrey Millman, PhD
Associate Professor of Medicine
Division of Endocrinology, Metabolism and Lipid Research

My name is Jeff Millman, PhD, and I am a bioengineer within the Division of Endocrinology, Metabolism and Lipid Research in the Department of Medicine here at WashU. My bioengineering expertise uniquely positions me to pioneer research in a laboratory environment, with a steadfast commitment to bridging these innovations to clinical applications. For over eight years at Washington University in St. Louis, I have spearheaded a groundbreaking research program centered on the utilization of stem cells to study and combat diabetes.

Central to my research are pluripotent stem cells, a remarkable category of stem cells we generate from patient-derived skin or blood cells through a specific genetic process. Unlike other stem cells, pluripotent stem cells boast the unparalleled ability to transform into any cell type within the human body, given the proper guidance and stimuli. This versatility not only underscores their potential in regenerative medicine but also illuminates their pivotal role in our quest to understand and eventually cure diabetes.

A big part of my research is determining the correct instructions for telling these stem cells to become insulin-producing pancreatic cells. We have reached the point where we have figured that out.

Our current strategy generates clusters of approximately 2,000 pancreatic cells in the laboratory. Most of these cells can sense sugar and secrete insulin to mimic the normal functions they perform in the body. This is important because patients with type 1 diabetes can no longer produce insulin because their immune system has destroyed these insulin-producing cells.

islet clusters
Clusters of stem cell-derived islets that we generated in the laboratory imaged with a microscope. They have a similar size and shape as islets that come from the body, and we think their three-dimensional nature is important for them to control diabetes

Due to the death of the body’s insulin-producing cells, the current standard of care is for patients to measure their blood sugar levels and inject themselves with insulin. In other words, patients are trying to manually do the job that insulin-producing cells in the body usually do because they no longer have those cells. If we manufacture these cells in the laboratory, we can implant them into patients as a cell therapy allowing the engineered cells to restore the functionality lost in the native cells. This means that patients no longer need to prick their fingers to measure their sugars or administer insulin to themselves.

Tell Us more about Your Background and How You Came to Study Diabetes

I received my PhD in Chemical Engineering from MIT in 2011. While I was doing research for my dissertation, I had the opportunity to be a visiting scholar at a biotech company in San Diego, ViaCyte for a month through a project funded by the Juvenile Diabetes Research Foundation (JDRF), which is the largest private funder of type 1 diabetes research. Before this experience, I had very little understanding of what type 1 diabetes was, let alone the potential of stem cells to address the unmet patient need for a functional cure. This ended up being a transformative experience for me, as I learned much about the disease, including its large impact on the lives of patients and their loved ones, and the power of cell therapy.   

Upon my return to MIT, I couldn’t help but think about why the field wasn’t doing more about this, as it was clearly one of the most pressing biomedical challenges.

That is what prompted me to go to Harvard University with Dr. Douglas Melton, a well-regarded stem cell and developmental biologist known for his work, attempting to figure out how to make stem cell-derived pancreatic cells for diabetes cell therapy. I wanted to train and work with him to disrupt the field by bringing my different perspective in engineering. There, I approached the problem of how to generate stem cell-derived pancreatic cells as a chemical engineering process rather than a more spontaneous developmental process and was successful in generating the first-generation differentiation protocol to make these cells – capable of reversing diabetes in pre-clinical models. These cells are being used in current clinical trials by Vertex Pharmaceuticals, with some patients with type 1 diabetes no longer requiring insulin injections instead receiving all their insulin from the transplanted cells.

Tell us About Your Experiences with the Environment at WashU

Cross section of transplanted stem cell-derived islets. These cells were transplanted into diabetic mice. These have been immunostained, with green showing insulin and red showing another glucagon, another hormone produced by islets. Blue is showing the nuclei of all cells.

My research program has greatly benefitted from collaborations and relationships with physician-scientists. Since coming to WashU, I have had a very productive relationship with Dr. Fumihiko Urano, and we have published a couple of paper together. His work on rare diseases and Wolfram syndrome is fascinating, and combining our expertise was a no-brainer.

We have been able to take cells from his patients, turn those into special pluripotent stem cells, and then using CRISPR gene editing, to correct the mutation that causes Wolfram syndrome. Then, we could take the uncorrected and corrected cells, turn those into insulin-producing cells, and then compare them head-to-head. We can see what is happening inside the cell and what that mutation does to the cell. When we did that, we discovered that these cells had many problems in terms of their ability to correctly generate, process, and secrete insulin, which is corrected with gene editing. What is even more incredible is that we are now able to take those patient-derived, genetically corrected cells, transplant them into an animal model of diabetes, and cure the animal model. This is the first demonstration of taking patient cells combined with gene editing, to cure diabetes in an animal model. Our work using this model has led to an ongoing clinical trial, AMX0035, with patients that have Wolfram syndrome.

Achievements at Harvard led to Clinical Trials

Dr. Millman shares that he was the first to discover how to make these cells while he was at Harvard. That technology he discovered is now in clinical trials being conducted by Vertex Pharmaceuticals, though he is not directly involved. Vertex gave an update at the American Diabetes Association meeting last year saying, that it had transplanted at least six patients that time.

Cross section of stem cell-derived islets. These have been immunostained, with green showing insulin and red showing another islet marker.

So far, two are now cured of diabetes, meaning they no longer need to inject themselves with insulin.  In other words, all the patients’ insulin comes from bio-manufactured cells transplanted into these patients using Dr. Millman’s Harvard-developed process. The other patients have only recently received the cells, so more information still needs to be shared. He explains that it takes about half a year for it to transplant to kick in and be able to do its job thoroughly. The patients are showing improvements but have not yet reached a reversal of their insulin.

Dr. Millman notes that it has took seven years since he and the rest of the Harvard team published the original report before, the first patient received the transplant. Seven years may seem like a long time in most people’s minds, but for this type of work, it is amazingly rapid progress for any drug to make it into the clinic. This is particularly true in this case, as this is a new category of drug; cells for regenerative therapy made from an extensive laboratory biomanufacturing process.

“A lot of my research is trying to connect the dots there, with the hope being that if we understand more about why a stem cell chooses to be an insulin-producing cell, then we would be able to refine the process and make it better, make more cells that secrete more insulin, and then be more effective in therapy.”


The next frontier is to do the work necessary for this technology to become a standard option, like continuous glucose monitors (CGM’s) and pumps, which are already familiar. Dr. Millman is developing large-scale biomanufacturing strategies to generate enough cells to be put into many patients at once and approaches to improve the survival and function of the cells after they have been transplanted.

About 60,000 people are diagnosed with type 1 diabetes each year in the US. Dr. Millman’s goal is to make his process scaled and robust enough that it can help at least treat that many patients, if not more worldwide. As commonplace as CGMs and pumps, ultimately leading to a future without diabetes. However, there is still much scientific research and technological development required to achieve this goal.