In a healthy body, the insulin-producing beta cells of the pancreas are responsible for maintaining normal blood glucose levels. In type 1 diabetes, however, these beta cells die as a result of an autoimmune attack, and in type 2 diabetes, beta cells can become overtaxed and begin to die off. A crucial part of a diabetes cure, therefore, will be replacing any lost beta cells with a source of insulin for the body.
Right now, we imitate a diabetes cure by replacing insulin from the outside with injections. Injected insulin must be dosed by an individual and acts regardless of whether or not there is sugar in the body. Beta cells, however, produce insulin in precise amounts, and only in response to glucose.
For a diabetes cure, then, we will need more than injected insulin; we will need beta cells, or a close imitation of them. Many researchers around the world are working on different approaches to allow us to produce steady, sustainable supplies of insulin-producing cells. Some are starting with embryonic stem cell lines, some are starting with gut cells, some are starting with pigs, and Dr. Sarah Ferber is starting with liver cells.
Dr. Sarah Ferber runs a lab in Sheba Medical Center near Tel Aviv, and has founded the company Orgenesis in order to turn a dozen years worth of her research into a cure for insulin-dependent diabetes, whether type 1 or type 2. Like many researchers, she sees the benefits of islet transplantation: patients given islet cells, which include beta cells, from donor pancreases can produce insulin in response to glucose, just like non-diabetics. However, she also sees significant drawbacks: islet supplies are limited, and, as with other organ transplants, patients must take immunosuppressive drugs to prevent the destruction of the transplanted beta cells.
So how can we replace beta cells without requiring immunosuppression to prevent transplant rejection? Dr. Ferber’s approach is to use autologous liver cells that are transdifferentiated in vitro into beta cells. In other words, Dr. Ferber wants to take a patient’s own liver cells, turn them into beta cells in the lab, and then put them back in the patient just like an islet cell transplant. Because the starting cells are the patient’s own cells, important protein markers on the cells would “match” what the patient’s immune system expects, and the cells would in theory not induce an immune reaction like an organ transplant would.
Dr. Ferber and Orgenesis are currently working towards developing the technology to extract liver cells from a patient with a biopsy, expand the liver cells in culture in the lab, and then turn the liver cells into functional beta cells. The first two steps are straightforward, and the third step is one they are making good progress on using science’s growing understanding of transdifferentiation.
Transdifferentiation is the process by which a cell is switched from one kind of tissue cell– say, a liver cell– to another kind– say, a beta cell. This process is similar to taking a stem cell and turning it into any kind of tissue cell (ViaCyte is trying to make beta cells from stem cells in this manner), but instead of starting from a stem cell that can by its nature turn into many kinds of cells, transdifferentiation starts from a cell that is already committed to being a certain kind of cell.
In order to turn a liver cell into a beta cell, Dr. Ferber must tell the liver cell, “Stop acting like a liver cell, and start acting like a beta cell.” For many years, scientists have been studying the question of what makes a certain kind of cell do what it does, and for decades research has been building that shows that certain proteins within cells, called transcription factors, are responsible for binding to DNA and turning genes on and off within cells. A liver cell acts like a liver cell because it has liver transcription factors, and those keep liver genes turned on. A beta cell acts like a beta cell because it has beta cell transcription factors and not liver transcription factors.
So, scientists have found that in order to turn a liver cell into a beta cell, we need to make the liver cell use beta cell transcription factors. In the last ten years, there has been a renaissance in this sort of transdifferentiation by replacing transcription factors, and, luckily for diabetics, beta cells are one of the big areas of focus in this field. A number of groups are working to transdifferentiate alpha cells and gut cells, as those are close to beta cells on the developmental tree. Dr. Ferber has chosen liver cells, which are also developmentally similar to pancreatic cells. Whatever the starting material, the strategy is similar: take the genes for beta cell transcription factors, put them into the target cell, and force the target cell to make the beta cell transcription factors. Then, grow the cells and watch to see if they start acting like beta cells.
In the case of beta cells, many years of research have gone into determining that one of the most important beta cell transcription factors is a protein called PDX1. This is not the only important factor, and in fact transcription factors are not binary, but maybe what makes beta cells beta-cell-like is the particular mix and balance of all sorts of transcription factors, but PDX1 is a very good start, and might be enough to tip the balance of the cell.
Dr. Ferber takes liver cells from a patient, grows them in a dish, and then adds a viral vector with the gene for PDX1 to the liver cells. The vector enters the cells, and forces the cell to start making the PDX1 protein from the gene. PDX1 then begins to turn off liver genes and transcription factors, and to turn on beta cell genes. Thus far, Dr. Ferber has been able to take patient cells, turn them into insulin producing cells with PDX1, and then put the transdifferentiated cells into mice, curing the mice of diabetes.
Dr. Ferber is now progressing towards the point of being able to run human clinical trials, one step at a time. The successful generation of insulin-producing cells that work in mice is the first step on a long road, but she is optimistic that she can repeat the results in larger mammals and soon enough, humans.
Of course, there are concerns. Autologous cells may get around the problem of transplant rejection, but not necessarily the problem of autoimmunity for type 1 diabetics. Dr. Ferber has early evidence in mice that the trandifferentiated cells, though beta-cell-like, are sufficiently different from actual beta cells that they seem to slip by the immune system. However, this is still to be tested in humans.
Further, cell therapy with virally transduced cells is still the Wild West, from a medical perspective. There are a handful of FDA approved cell therapies, but no approved gene therapy products outside of clinical trials to date, and no approved transdifferentiated cell therapies.
Can Orgenesis cure diabetes? The next step to finding out is getting regulatory approval for clinical trials. Once those are in place, the answers should start rolling in.