Stem Cells: Developing New Cures

Although stem cells hold promise as direct therapy for human diseases, many researchers are even more enthusiastic about the opportunity to use stem cells to study disease fundamentals. Learn how clinicians and researchers are involving diabetes patients in the search for a cure by developing new stem cell lines from their DNA. 

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Diabetes in a Dish: Using Stem Cells to Study Disease

Alan Altschuler, a trim, tall 60-year-old, estimates that he’s given himself 40,000 insulin shots in the last 40 years. He was diagnosed with diabetes in college and was squeamish about needles then. “My doctor said, ‘If you don’t give yourself shots, you’ll die,’” recalls Altschuler. “A bit heavy-handed, but it was effective.”

Now Altschuler wears an insulin pump attached to his abdomen by a narrow tube. Several times a day, he adjusts his body’s blood sugar manually: He pricks a finger with a lancet, dabs a test strip to the blood, and reads his glucose levels on a handheld meter. He mentally calculates the quantity of insulin his body needs to process the sugars in the apple or sandwich or whatever it is he’s eaten. Then he programs the insulin pump to administer this quantity under his skin. While technological advances are making it easier for the 21 million diabetics in the United States to manage healthy lives, diabetes is still a disease that requires vigilance. And it’s still a disease without a cure.

Altschuler himself is contributing to diabetes research by donating the very thing responsible for his disease--his genetic code. Scientists from the New York Stem Cell Foundation (NYSCF), Columbia University’s Naomi Berrie Diabetes Center, and Harvard University’s Stem Cell Institute are using DNA from patients like Altschuler to culture stem cells, early-stage cells that can develop into all kinds of body tissues. Because the patients’ DNA genetically programs the resulting stem cells to get sick, these cells can offer an unprecedented medium to explore the mechanisms and development of disease. Knowing these cellular fundamentals might provide new drug targets for diabetes, Alzheimer’s, Parkinson’s, and other serious illnesses.

The Black Boxes of Disease

Diabetes is the country’s sixth-leading cause of death. Stem cells offer promise, in particular, for Type 1 or “early-onset” diabetes, which Altschuler has. Type 1 diabetics have immune systems that destroy their beta cells, the insulin-producing cells of the pancreas. Insulin is a hormone that alerts cells all over the body when to uptake glucose from food as well as the reverse, when to release the glucose as energy. Diabetes, if untreated or ill-managed, can bring about kidney failure, amputations due to poor circulation, blindness, heart attacks, and other life-threatening conditions.

Researchers would like to monitor how a diabetic’s beta cells malfunction and become immune targets, but they can’t directly. One roadblock is that it is impossible to remove beta cells from a patient for culturing and analysis: the surgery would unleash pancreatic enzymes that would digest the internal organs. Furthermore, there’s the quandary of disease presentation, which Harvard stem cell scientist Kevin Eggan likens to a plane crash. “By the time the person comes into the clinic, they’re already sick. That’s like the moment when the plane hits the ground.” he says. “But something went wrong at 35,000 feet to cause the crash. Disease is like that. For the scientist, everything that you want to understand has already happened. Everything you want to study is already gone.”

Stem cells could operate as the flight recorder for that crash--as “black boxes” for diabetes and other human diseases. This is because stem cells are pluripotent: in the developing embryo, they differentiate into the many cell types in our body such as nerve cells, liver cells, pancreatic cells, and so on. “Embryonic stem cells are remarkable cells,” says Eggan. “They have the ability to self renew indefinitely in culture. Over a period of weeks we could go from a single cell in a dish to an entire room full of cells.” By coaxing this “line” of stem cells to develop into beta cells, researchers would be able to watch the development of diabetes as it presumably unfolds from embryo to adult.

Somatic Cell Nuclear Transfer

To produce stem cells that are genetically identical to a disease patient, the Columbia/NYSCF/Harvard partnership is banking on a still-experimental technique called somatic cell nuclear transfer (SCNT). So far, stem cells from SCNT have been achieved only in mice and macaque monkeys. The partnership hopes to be the first to successfully implement the technique in humans.

Doctors at the Naomi Berrie Diabetes Center begin the process by taking 3 mm biopsies of skin cells from diabetes patients. In the nearby laboratory of the New York Stem Cell Foundation, researchers use a microscopic glass pipette to extract the 46 chromosomes of DNA from the nuclei of these skin cells.

Then, researchers at Eggan’s lab at Harvard remove the 23 chromosomes from an unfertilized egg donated by a woman for research. (Eggs and sperm have half the number of chromosomes of the body’s other cells). The patient’s 46 chromosomes are then inserted into the donor egg’s empty cytoplasm.

If these steps meet success, the egg, sensing that it has achieved a complete chromosomal set as if fertilized by sperm, would begin to divide as an embryo. After about four and a half days, the egg is called a blastocyst. This is a mass of about a hundred cells that resembles a microscopic soccer ball. The stem cells would be extracted from the interior lining of the blastocyst and placed into a petri dish with a growth medium. The blastocyst would be discarded, but the stem cell line would go on.

The Potential of Stem Cells

Over the last five years, Eggan’s lab, in collaboration with that of fellow Harvard researcher Doug Melton, has derived about 50 new lines by extracting stem cells from surplus embryos in fertility clinics. While these lines are shared with biomedical scientists around the world, most of them don’t have genetic markers for disease. Disease-specific cells produced through SCNT would have more therapeutic value. For example, by monitoring how diabetic stem cells develop into beta cells, researchers could microanalyze the pancreatic malfunctions and immune deficiencies that transpire in patients. Scientists could identify the chemical signals that cause a person to get sick, which could provide new targets and better testing platforms for drugs that might slow or reverse those signals.

These approaches may also benefit Type 2 or “adult-onset” diabetes. The beta cells in Type 2 diabetics produce insulin, but not enough to meet that person’s metabolic demands, which are often elevated as a result of obesity. Type 2 patients represent perhaps 95 percent of the diabetics in the United States, a percentage that is growing.

What about the more futuristic scenarios of using stem cells for direct disease treatment, where healthy cells are created anew and transplanted in the body to replace diseased cells? While researchers have had some success replacing tissues for diseases like Parkinson’s, “for diabetes, this is a ways off,” says Rudolph Leibel, co-director of the Naomi Berrie Center. “It turns out it’s not easy to coax stem cells into beta cells that adequately produce insulin.” But the benefits of successful transplantation could be enormous. Insulin regulation aside, stem-cell derived beta cells would be genetically identical to the patient, thus eliminating immune rejection.

“Although [transplantation] is the universal promise of these cells, I think, for diabetes, it is actually better to understand the biology of this disease,” says Leibel. “We don’t understand the biology well enough. We could intervene in ways that have been undreamt of heretofore.”