Researchers at the Massachusetts Institute of Technology’s Whitehead Institute and Mount Sinai’s Samuel Lunenfeld Research Institute in Canada have each discovered novel lab techniques to create pluripotent stem cells from an adult cell.

“Pluripotency means that the cell has the potential to become any type of cell in the body,” says Knut Woltjen, a senior postdoctoral fellow at the Samuel Lunenfeld Research Institute. “Unlike a skin cell that can only make more skin cells, a pluripotent stem cell can make everything from liver to heart to hair follicles to retinal cells.”

Stem cells have the potential to help scientists better understand and treat myriad diseases, including neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease. Previously, the only known source of such cells was human embryos. But the legal, social and ethical concerns associated with embryonic stem cells have made their use problematic and stalled research in some areas. The ability to create stem cells from adult patients could lead to faster development of more accurate disease models and better therapies.

Viral delivery methods

Rudolf Jaenisch and colleagues at the Whitehead Institute demonstrated that they could not only “reprogram” an induced pluripotent stem (iPS) cell from a skin cell but that they could then change it into a dopamine-producing neuron.  But taking things a step further from previous work in pluripotent stem cell creation, the researchers were then able to remove the genes that made these changes possible. Using lentiviruses, which can deliver genetic information into the DNA of a cell, they transferred four new genes into the DNA of skin cells from people with Parkinson’s disease. They reported their work in the March 5 issue of Cell.

“There’s nothing really fancy about the [lentivirus] approach,” says Dirk Hockemeyer, a postdoctoral fellow in Jaenisch’s lab. “It’s been done by many researchers all over the world. But that’s one of the strengths of the method. It’s highly efficient to derive these kinds of cells.”

The group then went a step further, applying basic molecular principles to remove the new genes after the cell reached a stable pluripotency. Hockemeyer argues that this is a critical step for using these type of cells for basic research.

“Until now, people always assumed that if you wanted to use the cells for basic research that leaving the transgenes [transferred genes] is not a problem,” he says. “But we show that this is not the case. If you leave the genes in the cell, even if there is a very low expression of those genes, it alters the properties of the cells.”

Their new method could help researchers better understand the molecular causes of neurodegenerative disease. Frank Soldner, another postdoc in Jaenisch’s lab, says that studying these cells from Parkinson’s patients may also suggest new ways to treat such diseases.

“To date, basic research into these diseases is all done in animal models or in basic cell culture models. The brain is not accessible. We cannot work on the primary tissue of the brain or even grow primary cells in a dish,” he says. “But we can take a cell from a Parkinson’s or Alzheimer’s patient to make a pluripotent stem cell and then create a dopaminergic neuron,” a type that starts to fail in these diseases. “Then we can take a look at exactly what is going wrong in these specific cells.”

Alternatives to viral transduction

Elsewhere, the new technique developed by Andreas Nagy and colleagues at Mount Sinai’s Samuel Lunenfeld Research Institute in Toronto to create iPS cells does not rely on viruses to transfer genes into the cell. Instead, they use DNA from a cabbage loper moth to change skin cells to iPS cells in mice. This may make for a safer approach, says Woltjen, a senior post-doctoral fellow at the Samuel Lunenfeld Research Institute and first author on the paper, published April 9 in Nature.

“Using a retrovirus can make permanent changes to the DNA of a cell. And though Jaenisch’s group removes the genes that did the work, part of the retrovirus may remain and could still have the potential to be reactivated,” he says. “We’re using four genes as tools to change a skin cell into a stem cell, but introducing them in a removable fashion.”

This nonviral method allows the genes to be removed from the cells without leaving a trace. Woltjen likens it to removing “software” that reprograms a cell. Nagy’s group now is trying its technique with human cells; Woltjen says the preliminary results look very promising.

“It’s a great thing. If we can take these cells directly from the patient and then reprogram those cells into stem cells in the lab, we can then use them as therapeutic cells. The best part is, the benefit comes directly from the patient, so there should be no issue with that patient taking those cells in,” he says.

Years away from cell replacement techniques

Both groups of scientists caution that although these techniques have great potential, clinical cell replacement treatments are still years away.

“There is still a lot of work to do before we can use cell derivations as therapeutics,” says Woltjen. “We need to make sure they are truly equivalent to embryonic cells. It looks like it, but we need to be sure.”

In the short term, though, Hockemeyer and Soldner say, these iPS cells could serve as models for faster drug development.

“These techniques open a tremendous number of experiments that can be done,” says Hockemeyer. “If we can establish a model where we can find out what is wrong with an affected tissue in a patient, then we can look at what we have to do in order to make it behave in a non-pathologic way. We could start screening for drugs that could help do that.”