Mutant Stem Cells Flee Time's Winged Chariot

An expiration date means new lines are needed.

New research shows that human embryonic stem cells acquire mutations and other genetic changes over time as they grow and divide, according to a new study in Nature Genetics. Opponents of human embryonic stem cell research have seized on this finding and are already arguing that it calls the whole embryonic stem cell research project into question. "The discovery is another bonus for adult stem cell research, touted as a more ethical and more effective alternative. Such cells come from non-controversial sources like umbilical cord blood and bone marrow rather than by destroying days-old unborn children," declares a report from LifeNews.com. But is that so?

Human embryonic stem cells have the ability to transform themselves into all the tissues of the human body. They are derived from three to five day old blastocysts of around 150 cells or so and grown in tissue culture. The hope is that these cells can some day be used as transplants to repair and rejuvenate damaged and diseased organs and tissues, e.g., curing diabetes, spinal cord injuries, and damaged heart muscle.

However, it turns out that many current stem cell lines may have expiration dates. An international team of scientists headed by Aravinda Chakravarti at Johns Hopkins University, using a series of highly sensitive genetic and molecular tests, checked nine of the available 22 federally approved human embryonic stem cell lines and found that older batches of cells experienced changes that look a lot like the transformations that scientists see in cancer cells.

As stem cell colonies grow, researchers divide them and put the divided colonies into different Petri dishes. Each such division is called a "passage." Typically, some cells in a line will continue to be grown while others will be frozen for later use. The team of researchers matched early passage stem cell lines (ones that had undergone only a few divisions before being frozen) with cells from the same lines that undergone more passages. For example, some stem cells might have undergone ten divisions, whereas later stem cells might have been passaged fifty times.

Dan Arking, one of the researchers at Johns Hopkins University, offers one interpretation of what may be happening. As researchers divide growing stem cell colonies, they could be selecting for those cells that have experienced changes that promote their ability to proliferate, giving themselves a growth advantage over more quiescent cells. An alternative explanation, according to Chakravarti, might be that current tissue culture methods are introducing pervasive genetic changes that promote growth in nearly all of the cells simultaneously.

Of course, cells that grow uncontrollably in the body are cancerous. In fact, the Chakravarti research team found that 90 percent of the later passage stem cell lines had developed changes that amplify the effect of cancer-causing genes or disable genes that normally suppress the development of cancer. Some later passage lines also had duplicated large segments of DNA, and some were missing whole chromosomes.

Embryonic stem cell opponents are right that adult stem cells have been used successfully to treat some diseases and repair some tissues. However, Arking points out that adult stem cell lines grown in tissue culture are likely to suffer as much and perhaps even more from mutations and the other genetic changes that embryonic stem cells are subject to. Arking remains a firm booster of embryonic stem cell research, declaring, "I have no doubt that human embryonic stem cells will revolutionize how we do therapy some day." .

One worry for stem cell researchers who are constrained by federal funding is that the supply of early passage stem cells from federally approved lines will be depleted. "We don't know what stocks of frozen early passage cells suppliers have, which means that they might run out of them," said Arking. And even if the federally approved lines are never used for therapies, mutated late passage cells would be undesirable because they could distort research results. "The science tells us that stem cells go bad in tissue culture and if researchers want to use them for research or therapy, they will need a continual supply of early passage stem cells," concluded Arking. The good news is that many new embryonic stem cell lines have been created around the world and are available to privately funded researchers.

Michael West, president of Advanced Cell Technology in Worcester Massachusetts, does not see the new finding as a show stopper. According to West, these kinds of genetic changes have been seen in mouse embryonic cells for years and are no big deal. He believes that the new Johns Hopkins research will become a part of a standard quality control regimen that identifies and isolates genetically normal stem cells that can be safely used in therapies.

The Johns Hopkins research confirmed that early passage stem cells look good, showing no evidence that they suffer from possibly deleterious genetic changes. If their research holds up, it would mean, according to Arking, that "we don't send out cell lines beyond a certain number of passages." Stem cell lines, like any other drugs, will have expiration dates. This is not the death knell of embryonic stem research as some opponents might fondly hope, it's just another problem to be solved.