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: https://www.ncbi.nlm.nih.gov/pubmed/25714340  and https://www.ncbi.nlm.nih.gov/pubmed/27888558.  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.

Lorenz Studer named 2015 MacArthur Fellow for stem cell work

The annual selection of MacArthur Fellows highlights creative leaders in a variety of fields. The fellows receive $625,000 with no strings attached.

Stem cell biologists have been selected on a regular basis over the years as MacArthur Fellows including Kevin Eggan (2006), Sally Temple (2008), and Yukiko Yamashita (2011).

This year’s group of two-dozen 2015 MacArthur Fellows includes stem cell biologist Lorenz Studer (see video above). You can learn much more about Dr. Studer’s work on his lab’s home page here.

Lorenz Studer

Screenshot from MacArthur video

The announcement highlights Studer’s work on creating dopaminergic neurons (the type lost in Parkinson’s Disease) from stem cells including in particular from IPS cells, and broader implications of his work to neuro conditions:

“Lorenz Studer is a stem cell biologist pioneering a new method for large-scale generation of dopaminergic neurons that could provide one of the first treatments for Parkinson’s disease and prove the broader feasibility of stem cell–based therapies for other neurological disorders.”

Big congrats to Dr. Studer!

This is good news for the overall stem cell field as well.

Top 6 recent stem cell good news stories

IPSC arrayIt can be difficult at times in a cutting edge field like stem cells in terms of keeping upbeat about hopes of rapid translation to help patients with real, proven therapies. It takes a long time, money, dedication, and even a bit of luck for the researchers and biotech companies out there. It’s a challenging path with many possible roadblocks and landmines. For instance, I recently wrote about how many stem cell stocks are not doing well. I also have to admit at being a bit discouraged at the events related to the first IPSC clinical study recently going into a hold pattern.

At the same time there continues to be much good news as well and below I’ve highlighted some of the top recent encouraging stories out there. What other good news is out there in the stem cell world?

Stem cells Transdifferentiation from the top. I love direct reprogramming and there’s some cool new data from multiple groups.

NYSCF Publishes Details on Automated Global Stem Cell Array Production Process. Very cool. A top stem cell scientist Susan Solomon, who was part of the team, describes it as “Affymetrix for stem cells”. Great analogy. IPSC on a chip. Check out the paper here and Figure 4b above.

Sanofi links with Evotec to tap stem cells for diabetes care. Big pharma interest in stem cells.

Embryonic cell power increased. Is induced totipotency possible?

Liver Stem Cells‘ Source Discovered By Scientists. Liver disease is a huge and growing problem.

Grant awarded for HIV clinical trial using stem cells. This could make a transformative difference for HIV patients. Way to go UC Davis researchers.