Mutations in pluripotent stem cells: No, the sky is not falling

Figure 3 Merkle et al.

Figure 3 Merkle et al. Nature 2017

By Jeanne Loring

“Mutation” and “cancer” are eye-catching words for a headline; add “stem cells” and there is a good chance that a lot of people will hear about it. These words have been liberally used in the press to describe the results of a recent publication: “Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations.”

Every time a scientific report suggests that human stem cells are dangerous, I feel the need to reassure both scientists and non-scientists that we should not panic.  The sky is NOT falling (contrary to Henny Penny), and pluripotent stem cells remain valuable for cell replacement therapies.

Human embryonic stem cells (hESCs) have been around for 20 years, and the NIH has registered 384 different hESC lines that meet ethical guidelines and are eligible for use with NIH grant funding.  The cell lines are held by their owners, and Kevin Eggan, the senior author on the mutation publication, spent years convincing the owners to give him samples of 140 of them for genomic analysis.

His research group sequenced all of the protein coding regions of the genomes of these cells, looking for errors that might affect their suitability for both clinical and research use.  They found many differences among the cells, but focused on one particular gene, TP53, because of its association with many kinds of cancers.  The protein, called p53, is a tumor suppressor. This means that having two healthy copies of the TP53 gene protects cells from becoming cancerous.  The publication reported that about 5% of the cell lines tested had only one good copy of TP53. This means that they are less protected and more likely to form tumors.

Problems with TP53 in hESCs have been reported before by two papers from my research group:  and  But the current study went to the heart of the potential problem:  scientists who provided the cells to Eggan DID NOT KNOW that they carried TP53 mutations.  This is definitely something to be concerned about.

Why didn’t the scientists know?

Allow me to have a small rant…I have been on this soapbox since 2000, when I received my first NIH grant for genomic analysis of human stem cells  (NIH). I’ve been telling anyone who will listen that they need to use genomic and epigenetic methods to ensure the safety of stem cell derivatives used for transplantation.  Our cell replacement project to treat Parkinson’s disease with autologous dopamine neurons has numerous quality control steps, including whole genome sequencing (WGS), epigenetic profiling, and gene expression analysis. These measures go far beyond what is required by the FDA, but we want to use all of the tools we can to make sure that the transplanted cells won’t harm the patients.

But stem cell scientists without a background in DNA sequencing can often find the huge datasets to be daunting and some researchers are concerned that they won’t be able to understand the results. I’ve been lucky that I have a background in genomics and close colleagues who specialize in bioinformatics.  And I’ve had my own genome sequenced (three times, but that’s another story), which makes me more comfortable about the normal variations among different people and the significance of disease-causing mutations.  Luckier still, CIRM has funded my lab for 9 years to perform extensive genetic analysis of human pluripotent stem cells and their derivatives.

What can a stem cell scientist do now (instead of panicking)?  I can’t invite everyone to collaborate with me, but I can recommend that researchers look around them to find scientists down the street or across campus who can analyze WGS datasets.  WGS costs about $2,000, a tiny fraction of the cost of developing a bank of stem cell-derived cells for cell replacement therapy or of potentially stopping an actual trial that inadvertently used insufficiently validated cells later found to contain functionally important mutations.

Last year my lab reported ways to identify dangerous mutations that might occur in induced pluripotent stem cells, using WGS.  Once a bioinformaticist agrees to work on stem cell sequences, this would be a good place to start.

Don’t panic!  Check your cells instead.

About the author. Jeanne Loring is a professor in the Department of Molecular Medicine at The Scripps Research Institute in La Jolla, CA.  Her lab focuses on stem cell applications for Parkinson’s disease, multiple sclerosis, Fragile X Syndrome, and rescue of endangered species.