Sunday brunch buffet of stem cell good news, fun links, & cool papers

Enjoy! A brunch for the brain.

News and links

CBER Director Focuses on Flexibility to Advance Regenerative Medicines

Lab-Grown Blood Stem Cells Produced at Last

Transplanted stem cells become eggs in sterile mice

hair stem cells

Liao, et al Figure 2D

Maryland fund awards $8.5 million for stem cell research

Positively good news from Asterias for CIRM-funded stem cell clinical trial for spinal cord injury

Sergio Canavero: Will His Head Transplants Roll?

Century-old tumours offer rare cancer clues

Papers

Identification of hair shaft progenitors that create a niche for hair pigmentation (see Figure 2D above)

Tip110 Deletion Impaired Embryonic and Stem Cell Development Involving Downregulation of Stem Cell Factors Nanog, Oct4, and Sox2

Modeling Psychomotor Retardation using ipscs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier

Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators

Prc2 facilitates the regulatory topology required for poised enhancer function during pluripotent stem cell differentiation

President Mills Leaving, CIRM Needs New Leader to Navigate Future Challenges

Randy MillsCIRM announced today that its President and CEO, Randy Mills, is soon leaving for a new job as President of the National Marrow Donor Program/Be The Match in Minnesota. Update: Dr. Maria Millan, the CIRM Vice President of Therapeutics, will be its leader starting July 1 until a new leader is chosen.

For this kind of position three years is a relatively short tenure so CIRM will need to scramble a bit to keep continuity and momentum as it searches for and ultimately puts in place a new leader. It’s a critical time for CIRM as it and its allies consider big picture strategy for the future, approaches to future funding such as a possible new proposition for state funding (Prop 71 2.0), and how to continue all those exciting clinical trials and research beyond the current period of its funding.

In general, Mills had a big positive impact on CIRM and helped it go to the next level. About the only thing I wasn’t a fan of in terms of his leadership was my perception of his negativity toward the FDA and toward FDA oversight of stem cells, and how that manifested at CIRM during his time there. But good people can strongly disagree on policy. We’ll have to wait and see how the regulatory experiment of stem cell provisions in the 21st Century Cures Act, which Mills may have helped to make possible, will impact regenerative medicine in terms of changes in FDA oversight. It could also impact CIRM too.

Now CIRM’s Board has an exciting, difficult task ahead. Who do they want as their new leader to tackle CIRM’s challenge? What kind of background and future vision? The priorities, leadership skills, and vision of the new leader are likely to together be a major factor in CIRM’s future success. Who are the top possible candidates out there right now? I’m going to do a follow-up, future post on these questions and CIRM’s future.

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.

Upbeat prospects for some California clinical trial efforts from CIRM

Over at the California Stem Cell Report, David Jensen is reporting on some good news from CIRM for California on the stem cell clinical trial front.

Stem cell biotechs Asterias and Capricor have stem cell trials supported by 20+ million in CIRM funding each and have been hitting milestones. These trials are progressing and so far have good safety profiles. Asterias and CIRM have mentioned some possibly encouraging early hints at efficacy as well in its trial, and apparently there are hopeful hints from the Capricor trial too.

See the posts from CIRM here (a weekly summary kind of post that begins discussing Asterias) and here. For background, also see past posts I’ve done on both companies here and here in the archives, and see especially my interview with Asterias leadership from a few months back.

It’s early days for these trials and at these phases they are not really designed to look for efficacy so a conservative approach to discussing such trials is in order given the stage, but at this phase of the game for early clinical trials the news has been all one could hope for so far in both cases.

asterias-cells

Asterias cells

The Asterias and Capricor trials are for spinal cord injury and Duchenne muscular dystrophy, respectively. The latter trial utilizes the Capricor CAP-1002 product, which is a cool allogeneic cardiosphere technology made from donor human heart tissue. A beating cardiosphere from a different source (IPSCs) can be seen in the video above. Asterias’ trial employs their OPC product made from hESCs, which is also inherently allogeneic. The idea of potentially repairing the injured spine via stem cells is intriguing.

I’m hoping in the next month or so to do a broader update on the stem cell and regenerative medicine biotech arena. By way of disclosure, I do not have any financial stake in either company discussed here.

A TGIF weekend reading list of new stem cell pubs & headlines

In case you have some free time for reading this week, here’s a list containing an assortment of interesting research articles and stem cell headlines. I’ve thrown some oddballs in there too including one article from May 1983, when I was just finishing up junior high. No, I didn’t write it. And no the headline for this current blog post is not referring to stem cell-themed pubs where you can go get some ale made from stem cells, but that’s not a bad idea, right?

Yeah, it’s been one of those long, busy weeks and it’s only Friday. And from the TGIF archives a piece from last year including stem cell soup, Kim Kardashian, and zombies.

And now the list.

PNAS, Butts, Et al. Figure 5H 2017

Newsy pieces

Research & other journal articles

And the one from 1983, Stem Cell is a Stem Cell is a Stem Cell. But is it? This reminds me of a fake journal name I came up with some time ago I imagine someone doing as a knockoff of the real top stem cell journal Cell Stem Cell. The fake journal name?

Stem Cell Stem Cell

My whole crazy list of fake and maybe future real stem cell journals with wacky names is here. Good for a laugh.