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.

Nominations open for Stem Cell Person of the Year 2016 Award

Nominations are open starting today for the Stem Cell Person of the Year Award for 2016. Please email me your nominations: knoepflerATucdavisDOTedu.stem-cell-person-of-the-year-award

This is a unique award as it is given to an individual who has taken risks to help others within the stem cell field and they based their actions on outside-the-box thinking.

Another unusual aspect is that anyone is eligible for the prize whether you are a scientist, physician, patient, writer, student, etc. There are also no geographic restrictions.

The winner receives recognition as a positive leader in this arena and a $2,000 cash prize that I award myself out of pocket.

Nominations will close one month from today on October 15th.

The nominations I receive will then be subject to an Internet vote and the top 50% will be the finalists, from which I will choose the winner. While I alone choose the winner, I often get feedback from leaders around the globe in the stem cell and regenerative medicine field.

Previous winners include these stellar stem cell leaders:

Who will win the Stem Cell Person of the Year Award for 2016? Send me your nominations.

At #ISSCR2016, $2,000 donation to Summit For Stem Cell patient group

Summit for Stem Cell

Screenshot from Summit for Stem Cell website

Something very unusual and positive just happened at this year’s ISSCR meeting.

Every year in December I give out an award for the Stem Cell Person of the Year to the individual with the strongest positive impact in the stem cell field generated specifically from outside-the-box thinking and actions.

Dr. Jeanne Loring was the recipient in 2015. The award comes with a $2,000 prize that I pay myself. Jeanne declined it, but that money is now going to support an innovative Parkinson’s patient research group called Summit for Stem Cell.

Jeanne and her lab work with Parkinson’s Disease patient advocates together as the overall Summit for Stem Cell team toward the goal of IPS cell-based therapies for Parkinson’s. This is a very exciting area of research. Part of the reason Jeanne got the Stem Cell Person of the Year Award is her unique combination of great translational science and a bigger picture sense of how to make stem cell therapies become a reality.

Putting our heads together regarding the $2,000 prize from last year, Jeanne and I decided along with Summit for Stem Cell leader Jenifer Raub that the money would go to that group to support their outstanding efforts.

Knoepfler Loring Raub

The three of us just met up a few hours ago at ISSCR 2016 for me to give a $2,000 check to Jenifer (see picture above with me, Jeanne, and Jenifer from left to right).

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Stem Cell Person of the Year 2015: Jeanne Loring

Jeanne LoringCongratulations to Dr. Jeanne Loring, the winner of the Stem Cell Person of the Year Award for 2015.

Facing steep competition from a very tough field of competitors of finalists, Jeanne came out as the winner for her exceptional contributions in 2015 and throughout her many years in the field. She not only has made numerous advances scientifically, but also gone the extra mile in many respects as an advocate and educator.

Her scientific contributions include outstanding research on human stem cells and in particular in stem cell epigenetics. See her publications on GoogleScholar.  She has been a great mentor to her trainees. You can visit her lab page here.

She has also been a creative leader in producing IPS cells from endangered species, an area with huge potential ecologically and at a societal level in terms of preventing extinctions.

Jeanne has mobilized patient advocates and catalyzed exciting work in the clinical pipeline in a number of areas including most prominently in the last few years for Parkinson’s Disease.

For instance, the patient organization Summit for Stem Cell that Jeanne works on is doing amazing things.

More broadly, Jeanne has often led the way on important, but difficult issues such as on the WARF patent challenge. In addition, she has been a fierce advocate for evidence-based medicine and has been unafraid to challenge predatory stem cell clinics. A video of Jeanne talking about stem cell tourism is pasted above.

Overall, Jeanne has had a transformative positive impact at least in part via taking risks and thinking outside the box, important criteria for the Stem Cell Person of the Year Award.

Jeanne has declined the $2,000 financial component of the Award. I’m currently considering whether to donate the funds to a charity or put them towards a novel educational outreach project in the stem cell field.