Researchers race to strip stem cells of cancer risk
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
Genetic modifications in skin cells can induce the cells into what scientists call a pluripotent state a condition that is essentially the same as that of embryonic stem cells.
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."
Obama links scientific research to protecting 'free thinking'
President Obama wiped out another contentious aspect of his predecessor George W. Bush's legacy by removing curbs on federal funding for embryonic stem cell research.
President Obama's orders on science and stem cell research have a symbolic importance that's even greater than their impact on science, say policy experts.
"Promoting science isn't just about providing resources — it is also about protecting free and open inquiry," Obama said Monday at a White House ceremony. The president signed an executive order lifting federal funding limits on human embryonic stem cell research and a presidential memorandum seeking to insulate scientific advisors from political interference.
"We view what has happened with stem cell research as one (example) of the failure to think carefully about federal support of science and the use of science," says Nobel-Prize winning virologist Harold Varmus of the President's Council of Advisors on Science and Technology. Obama seeks to shift science from political football to supporting evidence in upcoming debates over energy, environment and economics, says Varmus.
"The president restated the centrality of science to the issues," said Alan Leshner of the American Association for the Advancement of Science, who attended the ceremony. "I've never seen the scientific community so pleased by a presidential action," says Leshner. "It really is a historical attempt to establish the clear role of science in underlying policy."
The executive order lifts Bush's Aug. 9, 2001 decision to withhold federal support of research on newly collected colonies of embryonic stem cells, the master cells from which all tissues are formed. Bush, decrying the destruction of embryos necessary to harvest the cells, limited funding to research involving 21 stem cell colonies — called lines — already in existence.
Obama has given the National Institutes of Health 120 days to provide guidelines to stem cell scientists for applying for research grants to research the hundreds of human embryonic stem cell lines, many of them marked with genes for diabetes, Parkinson's and other ailments. Varmus said previous recommendations by the International Society for Stem Cell Research and National Academies of Science, which require informed consent from embryo donors and limit any compensation, would ground the guidelines.
In a December ABC News/Washington Post poll, 52% of respondents said Obama should lift the Bush restrictions, with 42% opposed. Opponents of lifting the restrictions, such as Rep. Eric Cantor, R-Va., says Obama should focus on the economy rather than reviving any debate over stem cells. Others, such as Tony Perkins of the Family Research Council oppose the destruction of human embryos needed to create cell lines, seeing it as the destruction of human life.
"I can tell you the controversy has overshadowed and squelched advances that could really help the desperately ill," says stem cell scientist Michael West of BioTime, Inc. in Alameda, Calif., which recently offered nearly 300 new human embryonic stem cell lines to researchers, all of them will now be eligible for funding, West says. In 2008, the NIH provided $938 million to stem cell researchers, but only $88 million went to human embryonic cells. Research is also conducted on adult and animal skin cells.
"Stem cell research pretty clearly has public support, so this is not a hard choice for Obama," says science policy expert Aaron Levine of the Georgia Institute of Technology in Atlanta. But, he cautions, "The opponents will continue to be very vocal."
The U.S. share of stem cell research publications has dropped over the last eight years from half to about a third of the field's output, Levine says. "The Bush decision inspired some nations to invest and others to pursue what they saw as an opportunity to get ahead of us."
Q&A: Stem cell study enters new era
