Figure 3 Merkle et al. Nature 2017

By Jeanne Loring

“ Mutation” and “ cancer” are eye-catching words for a topic; add “ stem cells” and there is a good possibility that a lot of people will hear about it. These words are already liberally used in the press to describe the results of a current publication: “ Human pluripotent stem tissues recurrently acquire and expand dominant negative P53 variations. ”

Every time a scientific report shows that human stem cells are dangerous, I feel the need to assure 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 cellular replacement therapies.

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

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

Problems with TP53 in hESCs happen to be reported before by two papers from my study group:   https://www.ncbi.nlm.nih.gov/pubmed/25714340  and  https://www.ncbi.nlm.nih.gov/pubmed/27888558.   But the present study went to the heart of the potential problem:   researchers who provided the cells to Eggan DID NOT KNOW  which they carried TP53 mutations.   This is definitely something to become concerned about.

Why didn’ t the researchers know?

Allow me to have a small rant… I have already been on this soapbox since 2000, when I received my 1st NIH grant for genomic analysis of human come cells  (NIH). I’ ve been telling anyone who may listen that they need to use genomic and epigenetic methods to guarantee the safety of stem cell derivatives used for hair transplant.   Our cell replacement project to treat Parkinson’ s disease  with autologous dopamine neurons has numerous quality control steps, including entire genome sequencing (WGS), epigenetic profiling, and gene manifestation analysis. These measures go far beyond what is needed by the FDA, but we want to use all of the tools we are able to make sure that the transplanted cells won’ t harm the particular patients.

But stem cell scientists with no background in DNA sequencing can often find the huge datasets to be daunting and some researchers are concerned that they won’ big t be able to understand the results. I’ ve been lucky which i have a background in genomics and close colleagues that specialize in bioinformatics.   And I’ ve had my very own genome sequenced (three times, but that’ s one more story), which makes me more comfortable about the normal variations amongst different people and the significance of disease-causing mutations.   Luckier still, CIRM has funded my lab for nine years to perform extensive genetic analysis of human pluripotent stem cells and their derivatives.

So what can a stem cell scientist do now (instead associated with panicking)?   I can’ t invite everyone in order to collaborate with me, but I can recommend that researchers look around these to find scientists down the street or across campus who can evaluate WGS datasets.   WGS costs about $2, 500, a tiny fraction of the cost of developing a bank of stem cell-derived cells for cell replacement therapy or of possibly stopping an actual trial that inadvertently used insufficiently authenticated cells later found to contain functionally important variations.

Last year my lab reported ways to identify dangerous mutations that might occur within induced pluripotent stem cells, using WGS.   Every bioinformaticist agrees to work on stem cell sequences, this could 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 Medication at The Scripps Research Institute in La Jolla, CALIFORNIA.   Her lab focuses on stem cell applications designed for Parkinson’ s disease, multiple sclerosis, Fragile X Symptoms, and rescue of endangered species.

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