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Scientists grow working human beta cells that can end diabetes in mice

Researchers from the Salk Institute have announced an exciting new breakthrough that could lead directly to a cure — not a treatment — for diabetes in humans. It’s the culmination not only of decades of research into diabetes, but of tireless research into stem cell science, developmental biology, and direct genetic manipulation. There are very few caveats to make about the results and implications of this study — from top to bottom, it’s an exciting, practical piece of medical science.

Diabetes, in a broad sense, comes from the loss of functioning beta cells in the pancreas. This can happen because the cells themselves actually die (Type I diabetes) or because they become insensitive to the chemical commands that are supposed to control them (Type II diabetes). In either case, the upshot is the same: Your population of beta cells, large or small, does not produce and release the right amount of insulin to regulate glucose levels in the blood. This can lead to everything from dizziness to severe circulatory problems to coma to death. According to the CDC, about 30 million people suffer from diabetes of one form or another, and over 80 million are classified as pre-diabetic.

Since we know that diabetes has to do with defective or missing beta cells, we have a very obvious candidate for treatment: Put in functioning beta cells to replace the bad or missing ones. The problem has always been growing those replacement cells properly, directing early-stage stem cells with the ability to “differentiate” into most possible cells to become specifically fully adult pancreatic beta cells. Researchers have failed to direct stem cells to become true, glucose-sensitive beta cells that can release insulin as required.

That’s what these Salk researchers have achieved: properly directing an induced pluripotent stem cell to become a fully functioning pancreatic beta cell. Different teams have gotten different levels of beta cell functionality in the past, but this team got them all working at once.

When they transplanted these new human beta cells into Type-I diabetic mice, the mice were cured of their diabetes symptoms. Note that the “cure” only would have lasted as long as the researchers were depressing the mouse immune system to prevent rejection of the human tissue.

Remember, the pancreatic cells in this case are human cells, though they were transplanted into mice. It would be one thing if growing mouse beta cells could cure mouse diabetes; that would be exciting but, ultimately, limited. But if these human beta cells can cure diabetes symptoms in a different species, as they seem to be able to do, then there’s every reason to expect they could achieve the same results in their own species.

Stem cells

Additionally, note that this study did not use embryonic stem cells, the controversially harvested “ultimate progenitor” cells that offer such power to researchers, but induced pluripotent stem cells, which can be grown from regular skin cells harvested from adult patients. Right off the bat, that makes this study much more practical and applicable to the real world. It not only gets around troublesome legal and ethical barriers, but makes the treatment itself potentially affordable to the mass market.

The actual innovation in this case is a fascinating glimpse into how our bodies develop in the earliest stages of development. Normally, a fetus relies on its mother’s generosity to live. Its fetal version of hemoglobin has a higher affinity for oxygen than the adult kind, allowing the fetus to steal enough oxygen from the mother’s blood to stay alive. A similar process exists for blood sugar; the fetus’s new pancreatic beta cells can produce insulin, but they are not responsive to glucose levels and simply accept the sugar level present in the mother’s blood. In essence, the mother’s pancreas is regulating the fetus’s blood — which obviously can’t be the case after birth.

This team discovered that previous attempts to create fully functional beta cells in the lab had not been moving those cells out of the fetal stage — that is, they had the ability to create insulin, but were not using that ability in response to environmental glucose levels, which is the whole point. They identified a protein complex called Estrogen Related Receptor-gamma (ERRγ) as the “energy switch” for these pre-beta cells in regular human development, and theorize that it normally gets flipped on at the instant of a baby’s first breath. As the blood gets oxygenated, it triggers the final elements of fully independent human metabolism. This is when pre-beta cells become beta cells. A similar study from earlier this year achieved something similar, by a different path.

The study basically picked up where many, many researchers had left off — and added ERRγ to the mix. This “secret sauce” activated the beta cell colonies and sensitized them to glucose. The team has also created ERRγ-deficient strains of mice, all of whom are glucose-insensitive, proving that the protein switch is involved in proper beta cell development.

Okay, so we do have to throw in a couple of small caveats at this point. For one, simply adding healthy, properly functioning beta cells won’t necessarily always cure diabetes in all cases. For instance, some genetic problems that cause beta cell death persist into adulthood and could simply re-attack newly transplanted cells and kill those too, restarting the disease in short order. And Type II diabetes will be harder to treat, because you have natural beta cells to compete with. Whenever you’re adding a population of cells to a living organism, you have to think about the ongoing fate of the cells in that organism.

MouseHowever, there’s also good reason to believe that the cells will be broadly accepted by patients’ bodies. Unlike these chimeric mice with half-human pancreatic cell populations, human patients would receive transplants grown from their own genome. This personalized approach should eliminate the vast majority of immune-rejection issues, since the transplanted tissue will literally be the patient’s own, lowering the possibility that it will be identified as invading foreign biology.

This study is at the absolute cutting edge of biomedical research, taking the sorts of highly focused breakthroughs we regularly cover at ExtremeTech and applying a wide variety, all at once. The Evans lab took the cutting edge in stem cell science and combined it with its own research into ERRγ, and even more cutting edge transplantation science. It did this with human cells, immediately making the results more interesting for eventual human testing.

In principle, this is the sort of study that can invigorate a whole field of research. ERRγ itself is unlikely to unexpectedly unlock any great new disease, but its success in this case shows the power of new experimental techniques. It shows how the incredible pace of small-scale breakthroughs in biomedical technology really can lead to applications that were previously impossible. Tech writers haven’t been lying — step by step, the future is coming on faster than ever before.

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