Investigating Pancreatic Beta Cells

Understanding how cells fail in diabetes

Diabetes is a metabolic disorder that affects over 150 million people worldwide and is a leading cause of death in many countries. Despite current treatment regimens of several insulin injections per day, blood glucose levels still fluctuate significantly in diabetic patients, making diabetes the sixth leading cause of death in the United States. Further, diabetics are at a higher risk of developing pancreatic cancer; only around 5% of patients with pancreatic ductal adenocarcinoma (PDAC) will survive longer than five years. Dr. Maike Sander, Professor in the Departments of Pediatric & Cellular and Molecular Medicine at the University of California, San Diego, is leading one of the premier laboratories worldwide for advancing our understanding of pancreatic cell differentiation. Dr. Sander is studying the properties of beta cells in the hope of enabling the body to regenerate its own beta cells or to produce large numbers of functional beta cells from human pluripotent stem cells (hPSCs) for implantation into the human body. Her lab has played a significant role in providing the preliminary research that initiated the first-ever stem cell based phase 1/2 clinical trial for type 1 diabetes, led by the San Diego-based biotech company Viacyte, Inc, which implanted stem cell-derived beta cell precursor into human diabetic patients. The first patient was implanted with generated beta cells in December 2014.

The goal of Dr. Sander’s laboratory is to develop therapies for the treatment of pancreatic diseases, such as diabetes mellitus and pancreatic cancer. Research in her lab is focused on understanding the molecular mechanisms that underlie the formation and function of the diverse cell types of the pancreas, most notably the insulin-producing beta cells, which fail in diabetes. She is interested in understanding how they are made in the adult human body, how can they regenerate, and how the embryo makes them initially. Currently, the only treatment that offers some hope as a cure for type 1 diabetes is islet transplantation, which is greatly limited by the lack of available transplantable islets, harvested from cadaver tissue. Current treatments are limited in scale, but Dr. Sander’s approach could offer wide-scale therapy options to a vast population of patients suffering from diabetes and other pancreatic diseases. Understanding the embryonic creation of beta cells is essential to generating them in a dish from stem cells, as it follows nearly the same process. Novel genetic mouse models developed in her laboratory have allowed Dr. Sander to identify fundamental mechanisms by which beta cells are generated and kept functional.

Current research projects fall into four areas:

  1. Development of replacement beta cells from human pluripotent stem cells (hPSCs)

    a. Dr. Sander is investigating ways to differentiate stem cells into beta cells for implantation in the hope of restoring insulin production in afflicted individuals. The ability to produce beta cells in the culture dish will also facilitate studies aimed at understanding the disease mechanisms of diabetes. Her laboratory has invested significant effort into establishing a highly efficient, hPSC-based in vitro system for beta cell differentiation. Using this differentiation platform, she has begun to dissect the mechanisms that drive beta cell development. Her laboratory is also involved in the development of strategies for facilitating engraftment of hPSC-derived pancreatic cells after implantation.

  2. Beta cell regeneration during adulthood

    a. In diabetes, it is the pancreatic beta cells that fail, leaving a person unable to produce sufficient amounts of insulin to meet the dietary needs of that person. A major hurdle in the development of therapies for this is a poor understanding of how beta cells normally regulate their capacity to replicate and expand. Dr. Sander is asking, how do we cure this, how can we improve glucose homeostasis in patients with diabetes? One possible strategy is to increase already existent and functional beta cell mass by stimulating beta cell replication. There is evidence that despite the autoimmune attack on beta cells, patients with type 1 diabetes still harbor a few residual beta cells in the pancreas. In patients with low beta cell count, expanding these cells could improve blood glucose control. Dr. Sander is working toward this goal by identifying factors that she could target with drugs to improve beta cell function and stimulate the expansion of beta cells.

  3. Causes of diabetes

    a. The genetic causes of diabetes are poorly understood. It is known that diabetes has a huge genetic component, and certain sequences of nucleotides may make an individual predisposed to acquiring diabetes. Identifying the disease genome will shed light on the genetic causes of diabetes, and once discovered, Dr. Sander can study how those disease-associated mutations affect the function of beta cells that she produces from stem cells.

  4. Pancreatic cancer

    a. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. There is currently no cure and early detection is difficult. To gain a better understanding of this type of cancer, Dr. Sander’s lab has developed unique genetic mouse models that reiterate the pathological features of human PDAC. She is currently utilizing these mouse models to define the genetic changes associated with the initiation and progression of this lethal cancer. Results from these studies will identify novel diagnostic markers for early detection as well as reveal novel pathways to target for drug discovery and treatment.

Bio

Dr. Sander always knew she wanted to be scientist, but she also had strong desires to explore the medical field as a doctor. Really, she was torn between the two, and settling for only one was a very difficult decision. Ultimately, she chose to attend medical school, rather than pursuing a Ph.D., because she wanted to understand human diseases from a medical angle, and then approach science from that same perspective. She figured medical school would expose her to a number of human diseases, and from there she could identify which disease(s) she wanted to pursue as a scientist. The ability to help people has always been a driving motivator, and a medical degree guaranteed the ability to work on human diseases.

While in medical school at the University of Heidelberg, Germany, her educational interests gravitated toward understanding the mechanisms that control endocrine and metabolic homeostasis. In consideration to her medical training and interest in endocrinology, she chose the field of diabetes research.

Dr. Sander’s laboratory is located in the Sanford Consortium for Regenerative Medicine Building situated next to the Salk Institute and within walking distance to other buildings of the UCSD Medical School. The Sanford Burnham Medical Research Institute, Scripps Research Institute, and numerous biotechnology companies are located within a mile of her lab. This proximity, along with the cohesiveness of the La Jolla research community, provides her with an extraordinary variety of nearby intellectual and technical resources. Her lab maintains collaborative relationships with scientists in the areas of stem cell research, islet biology, proteomics, genomics, and computational biology at UCSD and many other academic institutions. She also has close partnerships with local biotech companies, including the Genomics Institute of the Novartis Research Foundation (GNF) and San Diego-based biotech company Viacyte, who are the first to launch a stem cell-based diabetes clinical trial. Studying diabetes requires a multidisciplinary approach and Dr. Sander’s collaborators provide her with the skills, knowledge, and resources her lab needs to reach their scientific goals.

When she is not in the lab, Dr. Sander is likely working out, spending time riding her bicycle, running around her neighborhood, swimming in the ocean, or participating in her own personal triathlon, participating in all three activities in one day! She finally spends quiet leisure time reading or watching movies.

Publications

Postnatal beta cell proliferation and mass expansion is dependent on the transcription factor Nkx6.1

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Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells

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Dynamic chromatin remodeling mediated by Polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells

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Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal..

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Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or...

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Awards

Appointed Director of the Pediatric Diabetes Research Center, 2012

Elected member of the American Society for Clinical Investigation, 2011

Grodsky basic research scientist award, 2008

from the Juvenile Diabetes Research Foundation

Career development award, 2001-2006

from the Juvenile Diabetes Research Foundation

Patents

U.S. Patent No. 6,127,598: "Nkx2.2 and Nkx6.1 transgenic mouse models for diabetes, depression, and obesity."

German, Michael S., Rubenstein, John L.R., Sussel, Lori, Sander, Maike, Hartigan-O’Connor, Dennis, Pedersen, Roger A., Meneses, Juanito J. Oct. 3, 2000.

U.S. Serial No. 09/654,462: "Requirement for Nkx6.1 and Nkx2.2 in ventral neuron generation."

Jessell, Thomas M., Briscoe, James, Ericson, Johan, Rubenstein, John L.R., Sander, Maike. filed September 1, 2000 continuation in-part of U.S. Serial No. 09/569,259, filed May 11, 2000 – CIE Ref. 1046m.