Some human stem cells growing in labs that researchers have used in experiments to treat serious diseases contain serious cancer-causing mutations, scientists reported on Wednesday. The discovery raised alarms that patients could be treated for one disease, such as macular degeneration, only to develop another, cancer.
Harvard scientists obtained samples of most of the human embryonic stem cell lines registered with the National Institutes of Health for use in both basic research and in developing therapies for patients with diseases including diabetes, Parkinson’s, and macular degeneration. They found that five of the 140 lines had cells with a cancer-causing mutation.
At least two of the five lines have been used in experimental treatments tested in clinical trials in an unknown number of patients. None is known to have developed cancer.
You’re probably asking:
It’s been 18 years since scientists got stem cells from human embryos, launching the “regenerative medicine” revolution. No one noticed this before?
Actually, a 2011 study found the same cancer-causing mutation, in a gene called TP53. But the study examined a single embryonic stem cell line, said biologist Jeanne Loring of the Scripps Research Institute, who led that research.
Wait, what’s a cell line?
You start with cells from a days-old human embryo, a hollow ball of 200 or so cells. You remove the stem cells, which are genetically identical, and grow them in lab dishes. The cells divide and proliferate. All of these progeny constitute a cell line. In 2009, President Obama approved the use of federal funds for research on newly-created cell lines from embryos that were going to be discarded by fertility clinics or were donated by couples and met ethical criteria.
How did the new study go beyond the earlier one?
Scientists led by Kevin Eggan and Steven McCarroll of Harvard University zeroed in on the 182 supposedly healthy human embryonic stem cell lines that meet Obama’s criteria and were registered with the NIH, they reported in Nature online. They obtained those they could (the NIH registry is just a list; you have to get the actual cells from the labs that made and own them) and did DNA sequencing on 114. They also did DNA sequencing on another 26 lines that had been prepared for human experiments. Of these 140, five had cancer-causing mutations in the TP53 gene.
Is that dangerous to people who receive the cells?
Patients do not receive embryonic stem cells; they get cells that those stem cells turn into, like pancreas cells or neurons or heart cells. The problem, Eggan said, is that as stem cells grow in lab dishes “they have a propensity to acquire the same kind of genetic mutations found in human cancers. The final type of cell — liver, lung, pancreas, and anything else — will inherit the mutations, conferring a very real risk” of causing cancer in the patient who received the cells.
Five cell lines out of 140 doesn’t sound so bad.
You might think otherwise if you received cells from any of the five. In fact, some cell lines have been used more than others, so five out of 140 might understate the risk. Two of the lines most widely used in research, called H1 and H9, both have the cancer-causing mutations. H1 was used in a famous clinical trial by the biotech company Geron (GERN) for spinal cord injury. That study was abandoned in 2011, after five patients received cells, but picked up in 2014 by Asterias Biotherapeutics. H9 is the source of cells in a clinical trial for macular degeneration. Other stem cell lines with TP53 mutations are in line for use in other trials. No one knows how many patients have received cells from lines with TP53 mutations.
Is anyone keeping an eye on the patients to see if they develop cancer?
A spokesman for Asterias told STAT that Geron and now Asterias have followed the original five patients and have seen “no evidence” of tumor formation. Asterias is giving all participants in the ongoing trial frequent MRIs to look for tumors. WiCell, a nonprofit associated with the University of Wisconsin that owns and supplies the H1 line, said it was unaware of the new findings. “We always want to do what is best for the research community,” said Robert Drape, executive director of WiCell. “Once we have an opportunity to review [the] publication, we will consult leading researchers in the field and determine the appropriate next steps.”
Shouldn’t the Harvard scientists have sounded an alarm sooner?
They started seeing cancer-causing mutations in stem cells about 10 months ago, McCarroll said, “and we shared the results ahead of publication,” including telling stem cell scientists about the problem at a meeting last fall. Scientists who control some of the lines have begun their own DNA testing, he said.
What do other experts think?
Scripps’s Loring said there was no reason “to say the sky is falling.” There are ways to ensure cells are healthy before they’re implanted in patients. But NIH cancer geneticist Dr. Stephen Chanock suggested that TP53 mutations might be just the tip of the iceberg: “We cannot rule out the possibility of additional, less frequent acquired [mutations] in other cancer genes,” he wrote in Nature in a commentary.
What about the type of stem cells that more and more scientists are using instead of embryonic ones?
Those are called induced pluripotent stem cells; they come from the cells of already-born people. Unfortunately, any such cells that grow in the lab long enough can accumulate cancer-causing mutations, Loring said. Perversely, cells that do acquire cancer mutations survive better than cells that don’t.
What’s the solution?
Neither the Harvard scientists, nor Loring nor Chanock, believe the discovery of cancer-causing mutations in stem cells should derail stem cell therapies. But the Food and Drug Administration does not require researchers to sequence the DNA of cells before putting them into people, mandating only testing for abnormal chromosomes. That’s a mistake, Loring said. “We need to use the tools we have to make sure we don’t screw up somebody we’re trying to cure, by giving them cancer.” In her own research testing iPS cells as a treatment for Parkinson’s disease, “we are doing tons of quality control to be sure nothing bad slips into people,” she said. “You have to check your cells even though the FDA does not require it.”
DNA sequencing to catch cancer-causing mutations in stem cells costs about $1,000 per genome. Regulators in both Europe and the US are considering making that mandatory, said Pete Coffey of University College London, who is studying the use of stem cells to treat eye diseases. Although a 5-in-140 risk may seem small, “regulators are going to ask [researchers who propose clinical trials] what are you going to do when it goes wrong, not if.”
If stem cells can develop cancer-causing mutations before they’re put into people, can they also do so after?
McCarroll and others think not.“There is something very different about the environment of cells growing in a lab dish versus the body,” he said. But suddenly discovering cancer-causing mutations in cell lines that have been around for nearly two decades is nevertheless enough of a surprise to “underscore the need for regenerative medicine to proceed with care,” Eggan said.