Blueprint for a Diabetes Cure: Stem Cells Offer a Path to Replacing Spent Beta Cells
What decides the fate of a cell? In the earliest stages of embryonic development, what tells it to become a muscle or a nerve cell; or to go on to form a liver or a heart?
These questions are at the core of the research of Jim Wells, PhD, and his team in the Division of Developmental Biology.
Wells has spent his career studying where organs come from during embryonic development. His particular focus is on the pancreas, and one of the most prevalent pancreatic diseases in children, type 1 diabetes.
In type 1 diabetes, the body’s immune system attacks insulin-producing beta cells in the pancreas. In most cases, by the time the disease is diagnosed, most of the beta cells are destroyed or beyond repair.
After years of research by his lab and others around the world, Wells believes they now have what he calls a “blueprint” of how insulin-producing beta cells develop. His goal is to use this information to treat children whose beta cells have been depleted.
Giving Cells Direction
Wells and his group have applied their blueprint to the “directed differentiation” of stem cells in a Petri dish, meaning that they’ve figured out how to spur malleable stem cells to head in one developmental direction versus another. In this case, they’re directing them to become insulin-producing beta cells.
“A cell in the embryo that’s trying to find its way toward the end goal of becoming a pancreatic beta cell is bombarded with signals in the form of small molecules, proteins or different types of chemicals,” he explains. “Depending on what that combination is, the cell will say, OK, I’m supposed to become a pancreas cell.”
Wells and his team imitate nature by bombarding the cell with signals of their choosing, guiding it step-by-step in the direction they want.
“We do exactly what the embryo does, only in a much more contrived and directed fashion,” he says. “We’re trying to recapitulate the steps that a stem cell needs to take to become a beta cell.”
Wells and his team have had significant success in identifying the signals that guide this development; they’ve used the information to push stem cells to become pancreatic. He is quick to note that his lab is just one of many around the world contributing to the blueprint of beta cell development. Several labs have been using this embryonic blueprint to get stem cells to produce insulin, a step that he refers to as a “remarkable milestone.”
Not Quite There…Yet
He cautions, however, that the Petri dish still falls short of the embryonic environment. Unlike beta cells in nature, Wells says, those produced in the lab are “not quite there yet” in sensing how much insulin to make in response to their surroundings. He explains that insulinproducing cells have to figure out how much sugar is in the environment, then make just the right amount of insulin so blood sugar doesn’t go too high or too low.
Getting the stem cells to this same level of therapeutic quality, and overcoming the risk of rejection by the body, are significant hurdles to overcome before they can be considered for human use.
Changing the Program
Wells points to what he believes is a promising new approach to overcome rejection: reprogramming, which takes an individual’s own cells and converts them to an embryonic, pluripotent state.
“If you’re dying from a degenerative disease, you could have a skin or other easily accessible tissue biopsy,” he explains, “then we’d convert those cells back to an embryonic state and grow them in a Petri dish.”
This approach would avoid the thorny ethics of embryonic stem cell research and offer a way around rejection.
This type of reprogramming approach was first reported last year in Japan, and has changed the way scientists think about the future of regenerative medicine. However exciting, the technology is still in its infancy – and not without its problems. The newly converted stem cells can potentially turn cancerous, a drawback heightened by the fact that one of the four genes responsible for the reprogramming is an oncogene.
A Revolutionary Idea
Still, Wells says, “This technology is going to revolutionize cell replacement therapies. Looking at the trajectory of this technology, and what’s been published, we’re going to be able to reprogram cells safely. I say that with a fair degree of certainty.”
This idea is so promising that Cincinnati Children’s has established a facility for this type of stem cell research, run by Chris Mayhew, PhD, that uses the reprogramming technology. The center collaborates with a number of research labs throughout the medical center in the use of human stem cell technology.
Wells’ wife, Susanne Wells, PhD, a researcher in the Division of Experimental Hematology at Cincinnati Children’s, has collaborated with Mayhew and Jim Wells to successfully reprogram adult human keratinocytes (skin cells) into a pluripotent embryonic state. They have used reprogramming to develop several cell lines that are indistinguishable from embryonic stem cell lines. These reprogrammed cells have now been redirected toward the pancreatic fate. This work suggests that in the future it might be possible to treat a child with Type 1 diabetes by replacing the child’s own beta cells with ones grown in a Petri dish.
The next step for this research team will be to test the cell lines to see if the reprogrammed skin cells can be further manipulated into becoming insulin-producing beta cells.
From a clinical standpoint, Jim Wells says, this success means that in time, “A kid with diabetes could come in and walk out with his own beta cells. That’s the goal.”
It’s a goal that he believes is well within reach. “It’s not unreasonable to expect that we would have transplantable material in five to ten years.”
