|Scientists Grow Insulin-Producing Liver Cells|
Discovery could lead to major advances against type 1 diabetes
By Amanda Gardner
"For me, this is one of the most exciting things to come across in terms of a cure," says Dr. Henry Anhalt, director of the division of pediatric endocrinology at Infants and Children's Hospital of Brooklyn at Maimonides Medical Center.
"Taking care of kids with diabetes is all about the cure. No matter how good we do managing them, ultimately we can't do as good a job as a cell that is capable of sensing glucose and responding," adds Anhalt, who was not involved with the new research.
Those with type 1 diabetes -- formerly called juvenile-onset diabetes -- have an autoimmune disorder that destroys the insulin-producing beta cells of the pancreas. As a result, the body's ability to produce insulin, which is essential for transporting and storing glucose, or blood sugar, is shut down. There's no cure for the disease and patients have to manage their condition by injecting insulin before they eat.
For a longer-term solution, researchers are pursuing ways to get the body to start producing insulin again. One approach would be to transplant healthy beta cells, a nice idea but one that is hampered by the severe shortage of donated pancreases. As a substitute, scientists are looking for ways to actually create their own cells through, for example, genetic manipulation.
Scientists have already shown that inserting certain genes into liver cells prompted those cells to produce insulin. The liver and pancreas are closely related organs and come from the same type of cell during embryonic development.
In the new study, the researchers used fetal human progenitor liver cells (FH), a type of stem cell obtained from fetuses that had been aborted due to medical necessity. The cells were "precursor" cells, meaning they were on their way to becoming a specific type of cell -- in this case liver cells -- but had not fully developed yet.
The researchers first added a gene called pdx-1, which is essential for beta cell development. Once the gene was inserted into the liver cells, it caused the cells to switch on other genes that are normally found in pancreatic beta cells. The gene then prompted the liver cells to secrete insulin in response to glucose.
To produce large quantities of the cells, the researchers "immortalized" them by inserting a gene for telomerase, which repairs the ends of chromosomes and prevents chromosomes from shortening and being unable to divide.
When the cells were transplanted into diabetic mice, the cells brought blood-sugar levels down within the normal range and kept them there for several months.
"There's been a lot of interest in trying to use stem cells to make a variety of mature products, one of which is insulin-producing cells to treat diabetes," says the study's co-author, Dr. Norman Fleischer, director of endocrinology and co-director of the Diabetes Research Center at the Albert Einstein College of Medicine in New York City.
"Here we are taking cells that are much further along. They're already differentiated and are on their way to becoming [liver cells]," he says.
"Other people have shown that you could get some expression of insulin in [liver cells]... but what's new here is combining a developing cell line which, because it has been expressing two genes, made it develop into a functional cell line," Fleischer adds. "It took on a number of characteristics of beta cells, including the production of insulin."
Part of the excitement surrounding the discovery, which appeared in a recent online edition of the Proceedings of the National Academy of Sciences, lies in the fact that the cells actually work within a "context." In other words, they respond to glucose within a living creature. "Being able to insert genes into strange cells and make them make insulin is incredible," Anhalt says.
One big advantage of this technique is that the cells used are human ones. Also, the "immortalization" procedure didn't lead to the development of tumors, which has happened in other cases of genetic engineering with mice. Finally, the liver cells had a higher insulin content than cells produced in different ways, the researchers say.
One big disadvantage is that the research is still in its early stages. "It's not the first time somebody has found cells to correct diabetes in mice," Fleischer says. "[But] there's a long way to go before these are available. This is just a beginning."
Another potential drawback is a political one. "The biggest fear is that these [liver cells] are obtained through 'medically necessary abortions,' " Anhalt points out. "That's the political hot potato that's going to make a difference as to whether the technology blossoms."
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SOURCES: Norman Fleischer, M.D., director of endocrinology, and co-director, Diabetes Research Center, Albert Einstein College of Medicine, New York City; Henry Anhalt, D.O., director, division of pediatric endocrinology, Infants and Children's Hospital of Brooklyn at Maimonides Medical Center, New York City; May 19, 2003, Proceedings of the National Academy of Sciences