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Breakthrough in stem-cell research


A colony of stem cells (above). Gustavo Mostoslavsky (below), a MED assistant professor of medicine, who runs a lab in the gastroenterology section. Photos courtesy of Gustavo Mostoslavsky

What’s up?
Embryonic stem cells are capable of developing into any tissue in our body, from lung to skin to heart. But the use of human embryonic cells in research is controversial, because harvesting them results in the destruction of human embryos.

About two years ago, Japanese scientists working with mice found a way to genetically reprogram fully formed adult cells back into an embryonic-like state. This discovery, known as induced pluripotent stem cells (iPS), was a boon to stem-cell research that might one day enable the regeneration of human organs damaged by injury or disease. The method used by the Japanese researchers had at least one major drawback, however: it used four separate genetically modified viruses to introduce four new genes into host cells. This multiplicity poses a safety risk because at least one of the genes, if improperly activated, can cause cancer. Indeed, at least 20 percent of the mice bred with iPS developed tumors.

Now, a research team led by scientists from the Boston University School of Medicine has found a safer and more efficient way to create iPS cells by combining all four genes into a single “stem cell cassette” that can then be introduced into a host cell with a single genetically modified virus.

What was found
The six-member research team was led by Gustavo Mostoslavsky, a MED assistant professor of medicine, who runs a lab in the gastroenterology section. The researchers worked mainly with cells from the tails of mice. They transferred the four reprogramming genes (Oct4, Klf4, Sox2, and cMyc) into these cells by encoding them into the messenger RNA of a virus that was purged of the genes that make it cause disease, but was still capable of inserting its genes into a host cell.

Collaborating with Darrell Kotton, a MED assistant professor of medicine in the pulmonary section, Cesar Sommer, a MED postdoctoral fellow in gastroenterology, and researchers from Massachusetts General Hospital and Harvard Medical School, Mostoslavsky was able to create mice with the resulting iPS stem cells. In addition, a single cassette could be used to generate cloned iPS cells with a single integration, further reducing the risk of improper gene activation and also making the procedure 10 times as efficient as the one pioneered in Japan.

An article on their findings was published online last December in the journal Stem Cells.

Why it matters
The discovery will greatly improve the speed and reliability of progress on stem cell research. “It makes things easier for labs,” says Mostoslavsky. “It will be easier for them to have more reproducible data, because until now there was so much variability due to the inefficiency of the system.” He says several labs are already using the new method to produce stem cells. More important, in addition to speeding up the research, Mostoslavsky says that “this puts us a step closer to iPS stem cells that could be used in clinical applications.”

Word to the wise
Mostoslavsky cautions that we are still a long way from being able to use these cells to regenerate our diseased organs. “These are all long-term dreams, and we are all basic scientists,” he says. “We are only now doing the basic part of it, which is to understand really how pluripotent these cells truly are and how we can differentiate them into specific cell types.”

What’s next?
The researchers are currently working on a means of removing the genetic cassette from the stem cells after it’s done its reprogramming work, thereby enhancing the safety of the resulting cells. They are also attempting the same genetic reprogramming techniques on human cells.

Where to find out more
More information on iPS cells can be found on Mostoslavsky’s lab Web site.

Chris Berdik can be reached at cberdik@bu.edu.

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