Using skin cells taken from children with a rare heart defect, U.S. researchers have created beating heart cells in the lab with the same heart defect, allowing researchers to test new drugs in human cells instead of mice.
While most heart drugs had no effect on the cells, a cancer drug being studied by Cyclacel Pharmaceuticals Inc appears to help, the team led by Ricardo Dolmetsch of Stanford University reported Wednesday in the journal Nature.
The study is among the first to use powerful new technology to create human models of disease by reprogramming ordinary cells to behave like embryonic stem cells, the body's master cells that can give rise to any tissue in the body.
"Because every cell in our body has the same genetic programming, that means we can take skin cells and reprogram them to generate stem cells, and we can take those cells to make heart cells," Dolmetsch said in a telephone interview.
Discovered in 2006, induced pluripotent stem cells or iPS cells can be collected from people with genetic diseases and grown in batches that live for months and years in the lab.
Dolmetsch's team collected skin cells from children with Timothy syndrome, a rare genetic disorder that causes autism and long QT syndrome, a defect in the timing of the heart's contractions that makes the heart beat out of sync.
People with long QT syndrome have irregular heart beats and are vulnerable to ventricle fibrillation, a potentially deadly heart rhythm in which the heart beats chaotically.
"We generated these reprogrammed cells from these kids and over the last four years or so we developed these methods for converting these cells into cardiac cells," Dolmetsch said.
The team reprogrammed skin cells from two Timothy syndrome patients and five normal people, then coaxed these cells into becoming cells that form the atrium and ventricle of the heart and nodal cells — cells that make up the heart's electrical system. The three cell types spontaneously clumped together to form miniature one-chambered hearts.
While heart cells from normal patients beat at an average of 60 beats per minute, those from patients with Timothy syndrome beat much more slowly — at 30 beats per minute.
"We knew right away there was something wrong with the cells from these kids. They would beat and they would stop and they would flutter," Dolmetsch said.
Next, the team tested several heart rhythm drugs to see if they corrected the problem. None worked, but they did have success with the experimental cancer compound roscovitine, now being tested in phase 2 trials.
Dolmetsch said the drug would need to be altered to be used in heart disease, but he said the findings show the promise of using iPS cells as a way to study human diseases, especially for conditions in which there are no good animal models.
"The potential is really large," he said.
Several drugs, including Merck's withdrawn painkiller Vioxx, cause long QT syndrome and Dolmetsch said the cells could be used to screen drugs for toxic side effects.
His team is also working on genetic forms of heart failure, and they have created a lab dish model of ventricular fibrillation, a chief cause of cardiac death, which accounts for more than 400,000 deaths each year in the United States.
Stanford has applied for patents on the technology and Dolmetsch said several drug companies, including Pfizer, Roche and Amgen, have expressed interest in licensing some of the lines.