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In August 2000, the potential for finding a type 1 cure was championed when the National Institutes of Health (NIH) issued guidelines concerning the use of federal funds for research using stem cells from frozen human embryos.
Despite not foreseeing any practical use for stem cells in treating people with diabetes for another five years, many experts regard them as being the solution to the islet-shortage problem. Since two pancreases are necessary to get the necessary number of islets required for a transplant procedure, the prospect of an unlimited pool of islets created from stem cells is most intriguing to the diabetes community.
At this point in time, however, experts can only speculate that stem cells create islets. If it is in fact true that they can, stem cells may very well be the answer to a lot of prayers. Standing in the way, however, is the controversy surrounding the ethics of using "embryonic" stem cells instead of adult stem cells.
What do the Guidelines Say?
The NIH guidelines insist that federal research be conducted only on cells taken from frozen embryos that remain undeveloped. The guidelines will allow research with a particular type of human stem cell called an embryonic stem cell.
The guidelines will not allow payments to embryo donors and will preclude donors from specifying who should receive their embryo's stem cells. This is aimed at discouraging the creation of a "market" for embryonic cells and blocking any incentive for a woman to create and abort fresh embryos just to provide a potential treatment for a relative or friend with diabetes or any other disease.
NIH stresses that donors need to understand embryos will not survive the procedure.
Solving the Islet-supply Shortage
The announcement of the NIH guidelines garnered praise from President Clinton, who said stem-cell research offers "potentially staggering benefits" and may unlock clues to treating diabetes, as well as Alzheimer's, Parkinson's, spinal-cord disorders, heart disease, cancer and burns.
At the October 28, 2000 Diabetes Research Institute Foundation Research Update in New York City Luca Inverardi, MD, associate director of the Diabetes Research Institute's Cell Transplant Center, gave a discussion called "Challenges of Islet Supply." Inverdi said that among all the ways to solve the islet-supply shortage, the use of stem cells seemed the most promising for people with diabetes.
The Juvenile Diabetes Research Foundation (JDRF) said the NIH guidelines offer hope to the millions of Americans who suffer from diabetes. On September 14, 2000, Mary Tyler Moore, international chairman of the JDRF, testified before the Senate Appropriations Subcommittee on Labor, Health and Human Services, and Education in support of the government allowing federal funds for stem-cell research.
"We owe it to the 16 million Americans with the disease to pursue all promising research avenues, including stem-cell research, within the ethical framework established by the federal government," said Moore.
In January 1999, Doug Melton, PhD, chair, department of molecular and cellular biology at Harvard University, presented testimony before the Senate Subcommittee Examining Stem Cell Research. Melton, whose nine-year-old son Sam has type 1 diabetes, also called the use of stem cells a potential cure for diabetes.
"One of the most promising ways of curing diabetes is to restore biologically the function of [islets]," said Melton. "This could occur either through islet-cell transplantation or through engineering of cells to restore the insulin-secreting function. In both instances, the availability of stem cells would significantly expedite research progress."
How Will Stem Cells Help People with Diabetes?
There is an almost universal consensus among experts that using stem cells will cure all people with diabetes.
Ammon Peck, PhD, department of pathology, immunology and laboratory medicine at the University of Florida in Gainesville, says there are already too few pancreases to meet the demand for most islet-transplantation procedures.
"Stem cells offer a new approach to generate abundant islets for future implant demands," says Peck.
Melton, in his January 1999 testimony, said if and when scientists can specialize stem cells to become islets, cell lines could be developed to produce an unlimited number of islets.
"This would effectively solve the islet cell supply problem," said Melton.
James Shapiro, MD, FRCS, director of surgery at the University of Alberta, Edmonton, is a member of the revolutionary Edmonton Protocol team whose transplant protocol weaned several type 1s off insulin after receiving transplanted islets and a novel regimen of anti-rejection drugs. Shapiro says stem cells are "a potential cure for the entire 130 million patients with diabetes worldwide," which, he says, is predicted to increase to 300 million within the next 25 years. Shapiro feels the use of stem cells would allow patients to receive transplants without having to rely on scarce organ donors.
"With a limitless source [of islets], even patients with type 2 diabetes would be good candidates," Shapiro adds, "[Using stem cells] will entirely replace a need for organ donors."
Fred Levine, MD, PhD, associate professor of the Cancer Center at the University of California, San Diego School of Medicine, says the NIH guidelines are promising because they will allow embryonic stem-cell research to go forward. He says stem-cell research would advance the recent findings of the Edmonton Protocol team.
Alberto Hayek, MD, of the Whittier Institute for Diabetes in La Jolla, California, says stem cells will enable the Edmonton Protocol procedure to possibly be repeated as often as the patient requires it, "since the source of cells will be plentiful."
Levine also says stem cells could potentially be used in the treatment of some forms of diabetic complications where tissue replacement would be valuable.
Shapiro says that in addition to creating a limitless supply of islets, stem cells can repopulate the immune system to make it less susceptible to immune attack.
Do Stem Cells Grow Islets?
At this time, stem cells are not used to grow islets. Peck cautions "only in theory" does one stem cell multiply into many more stem cells.
According to Hayek, the capacity for stem cells to replicate "needs to be investigated in tissue-culture systems." Hayek, who has been conducting research on islet transplantation for over 17 years, agrees with Peck that stem cells are capable of originating islets only in theory. In addition, he is uncertain as to how many islets grown from stem cells are needed to cure a person with diabetes, but speculates that it is probably the same amount as now-10,000 islets per kilogram of body weight.
According to Shapiro, if the islet source were limitless, then one stem cell should probably deliver 50,000 islets per kilogram, based on the recipient's body weight.
Levine says, "nobody has definitively identified a stem cell in the normal human pancreas." He adds that pancreatic duct cells may in fact have properties of pancreatic endocrine stem cells and cites research by Susan Bonner-Weir, MD, of Harvard University. Weir has shown that duct cells can be induced to form a small number of islets, including beta cells.
"To be broadly applicable, this would have to be coupled with a technology to grow large numbers of the duct precursor cells," says Levine, whose lab is working to optimize just that.
Peck says stem cells have been used to grow immature islets in a test tube and can give rise to "hundreds, perhaps thousands, of islets."
Last year, according to a study published in the March 1, 2000 issue of Nature Medicine, type 1 diabetes was reversed in mice after Peck and colleagues manipulated stem cells from the pancreases of eight diabetic mice. Peck grew the islets in the lab, then implanted them back into the mice on a section of the kidney. Five days after the implantation, Peck weaned the mice off insulin. Within one week, the mice's average blood sugar levels had dropped from 400 mg/dl to between 180 and 220 mg/dl. The mice appeared healthy and no longer required insulin. Blood sugar levels in a control group of eight non-implanted mice rose to an average of 400 to 800 mg/dl and all eight died of diabetes-related complications.
Will Stem Cells Help Reduce the Cost of Islet Transplantations?
Shapiro speculates that the greater abundance of islets grown from stem cells will reduce the cost of islet transplantation.
"If less drugs are needed and if pancreases don't have to be flown for urgent processing by research teams in the middle of the night, this is likely to have a big cost-benefit impact," says Shapiro.
As of now, the cost of a procedure such as the Edmonton Protocol is around $100,000 per person, with anti-rejection drugs costing around $57,000 per person per year.
Levine says one appealing aspect of using stem cells grown in a lab is that they can be manipulated to allow them to avoid immune responses. If that goal can be achieved, it is possible that stem cells could eliminate or reduce the need for anti-rejection drugs.
Shapiro says whether stem cells make any difference in the amount of anti-rejection drugs a person needs to take after a transplant depends on whether the stem cells are taken and grown from the same individual, or whether they come from another person.
"If they can be genetically altered to make them less susceptible to immune attack, they may be less susceptible to rejection," speculates Shapiro. "The concern remains that they could be destroyed by the same autoimmune process that caused diabetes in the first place. So some drug therapy might be required, but likely at much lower doses than is needed now to stop rejection."
A Hot-button Issue-To Use Adult or Embryonic Stem Cells?
Several anti-stem cell scientists and politicians are opposed to the funding of embryonic stem-cell research, arguing that it involves dead fetuses.
On September 8, 2000, pro-life scientists urged Congress not to fund embryo stem-cell research. Representatives from the group Do No Harm testified before the Senate subcommittee responsible for funding NIH. The group argued there are alternatives to using embryonic stem cells.
Shapiro agrees. He says scientists have to find ways to deliver a supply of stem cells that do not lead to the injury of an embryo. He suggests using adult, rather than embryonic, stem cells.
"They don't need to come from an embryo," Shapiro argues. "There are believed to be stem cells actually found within the adult pancreas. This would get around the ethical dilemma of having to rely on an embryo source."
Levine creates genetically engineered cells derived from adult beta cells that have properties of pancreatic endocrine stem cells. He says these can be grown in unlimited quantities and induced to form cells that exhibit glucose-responsive insulin secretion.
"Adult stem cells have the advantage that they completely avoid the moral and ethical issues that have been raised with embryonic cells," says Levine. "However, adult stem cells may have a more limited lifespan than embryonic cells, which give rise to all of the different types of cells in the body."
Hayek says there are stem cells in adults, "But, so far nobody has been able to make insulin cells out of stem cells from bone marrow." Hayek says if such a thing is accomplished, "it will advance the field tremendously."
Levine says stem cells from adults are probably limited in the number of different cell types to which they can give rise. He says the advantage of using embryonic stem cells is that one cell line could in theory be used to give rise to any desired cell type for any disease.
"Many opponents of stem-cell research are opposed because they believe that it will encourage abortion or the harvesting of embryos for research," says Levine. "However, under ideal circumstances, an unlimited number of stem cells could be grown from a single embryo and a continuing use of embyros will not be necessary.
Levine understands that some individuals are opposed to the use of any embryonic tissue for any reason.
"I think that those individuals will remain opposed to stem cell research under any circumstances."
Peck says it is not absolutely necessary to use fetus-derived stem cells to generate islets from stem cells.
"But, we must investigate if there are differences between fetal and adult stem cells in terms of function, behavior, etc..." says Peck. "Both fetal and adult stem-cell research should proceed, ensuring, of course, the rights of all. [At this point], we do not know enough about this area to draw conclusions."
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