Researchers have unveiled a flurry of advances in recent months in the development of "induced pluripotent" stem cells. "The induced pluripotent stem cell field is probably one of the most fast-moving areas in all of biology," says researcher Leonard Zon of Children's Hospital in Boston.
Andras Nagy, left, at Mount Sinai Hospital in Toronto, is working on ways to create "induced pluripotent" stem cells free of cancer genes.
RIDDING STEM CELLS OF CANCER
Induced pluripotent stem cells photographed through a microscope at Mount Sinai.
The induced cells have previously been created by taking an adult skin cell and adding four cancer-related genes. These are the only genes that can return the cell to an embryonic-like state, but they come with a deadly risk.
This year ...
1. Researchers unveiled several ways to create cancer-free versions of the induced cells by adding various factors:
a. Removable viruses with the cancer genes.
b. Removable DNA.
c. Free-floating "plasmid" genes that never
enter the nucleus of the cell.
d. Proteins from the cancer genes that also
don't enter the cell nucleus.
2. Once the cancer genes have done their work and the cell has returned to its unspecialized state, the viruses or DNA are removed.
3. Future generations of this cell grow into ones that mostly lack cancer genes.
Source: University of Wisconsin-Madison, Mount Sinai Hospital of Toronto, University of Edinburgh, Whitehead Institute for Biomedical Research, Harvard Medical School
Grown from adult skin, these cells are genetically transformed to have the same unspecialized function that makes embryonic cells so important. Embryonic stem cells are master cells that can grow into blood, brain, bone and every type of tissue, raising researchers' hopes of a "regenerative medicine" era in which physicians could grow organs for transplant candidates or tissue to treat spinal injuries.
In January, the Food and Drug Administration approved an experimental paralysis regimen that is the first clinical trial of an embryonic stem cell treatment. But the cells have been surrounded by controversy for the past decade because they are collected by destroying an early-stage human embryo, a reality that in 2001 led President Bush to limit federal research spending. President Obama reversed that decision in March.
Induced pluripotent stem cells sidestep that controversy but have one of their own. The only genes that can change the skin cells' function are cancer genes, so any benefit would carry a deadly risk. "What the investigators have accomplished is to discover the reset button for the cell, but the way they currently press it is by hitting it hard with a ball-peen hammer," wrote University of Wisconsin biologist P. Z. Myers in 2007 in his popular science blog, Pharyngula.
Four different methods, same result
So far this year, researchers have revealed four ways to remove the cancer genes:
•Two international teams, one led by Keisuke Kaji of the U.K.'s University of Edinburgh and the other headed by Andras Nagy of Mount Sinai Hospital in Toronto, separately announced ways to insert raw DNA containing the cancer genes into the cells and then strip the DNA out once the genes have done their work, a process that leaves behind a few mutations in the cells.
•A group led by Rudolph Jaenisch of the Whitehead Institute in Cambridge, Mass., used removable viruses to deliver the cancer genes. Once the viruses were taken out, only traces of the cancer genes remained.
•A group led by embryonic stem cell pioneer James Thomson of the University of Wisconsin attached the cancer genes to free-floating plasmid genes that don't enter the nucleus of the cell. Because the cancer genes aren't in the nucleus, they disappear when the cells reproduce, neatly removing them from subsequent generations of cells.
•Last week, a group headed by Kwang-Soo Kim of Harvard Medical School reported that skin cells treated with proteins from the cancer genes, not the genes themselves, created two induced cell lines, or colonies.
About 100 times less efficient at starting the cell lines than the other methods, the process should be improved by purifying the proteins, says study co-author Robert Lanza of Advanced Cell Technology. "These cells should be completely safe because we didn't use genes to create them," he says.
Even if the cancer risk is eliminated, the scientists acknowledge there will be other questions.
"We are moving into a time for looking hard at these cells, and seeing if they really are identical to embryonic cells. We are seeing some signs of what may be subtle differences," Thomson says.
"I predict in coming months we will see a series of reports showing (iPS cells) are not quite exactly the same as embryonic stem cells in ways that might be meaningful for their therapeutic value," Zon says. "That's why it is very important to continue the embryonic stem cell work, the gold standard point of comparison for the field."
Potential for genetic errors remains
The real worry is the possibility that mutations will spring up in replacement tissues grown from induced cells that have reproduced too quickly, Thomson says. The potential for genetic errors grows with each reproduction cycle, he says.
But Zon is optimistic.
"Reprogramming cells is moving very swiftly," Zon says. "Before too long, I think we will have a very nice cocktail of factors that will create these cells without permanently changing them."
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