Weekly reads: embryonic stem cells, Parkinson’s, Alzheimer’s

Early during my postdoc I was primarily interested in the role of Myc genes both in cancer and in stem cells, work that later included embryonic stem cells. These cells are often called ES cells.

At first I first started studying N-Myc in neural stem cells using a conditional knockout approach. However, soon after I was excited about figuring out what Myc and N-Myc might be doing in ES cells too. This was just before Yamanaka reported his four-factor reprogramming including Myc.

The next few years were an exciting time.

embryonic stem cells
Human embryonic stem cells grown in the Knoepfler lab.

Myc gene in embryonic stem cells

Eventually, we made mouse ES cells that were floxed for both Myc and N-Myc. Addition of an enzyme called Cre could lead to a double knockout of both of these key Myc genes. Our studies led to a better understanding of the role of the Myc family in pluripotency. Myc proteins have key roles in pluripotency and self-renewal. These mechanisms relate to its cancer-causing ability when overexpressed.

This was back in the mid-to-late-2000s. Many people thought that human ES cells would lead relatively quickly to therapies. However, it seemed like a long road ahead.

Now we as a field have reached a quarter century since human ES cells were first reported by Jamie Thomson. Where does the field stand clinically in terms of translation of ES cells to the clinic?

That brings us to our first item.

After 25 years of hype, embryonic stem cells are still waiting for their moment, MIT Tech Review. This is a tough headline for a piece from Antonio Regalado. The article is well-balanced though. There are many potential therapies slowly moving forward. One potential therapy in development highlighted in Antonio’s piece is from Neurona for epilepsy.

A take-home message from the article is just how hard it is to get an approved, safe, and effective cell therapy.

I was surprised that Antonio didn’t specifically discuss iPS cells more.

More recommended reads

Aspen Neuroscience Announces FDA Clearance of Investigational New Drug Application for ANPD001, Autologous Cell Therapy for the Treatment of Parkinson’s Disease, PR. It’s exciting to see an IND for Parkinson’s Disease. Stem cell biologist Jeanne Loring founded Aspen.

Designing persuasive health education for patients seeking unproven stem cell interventions, Stem Cell Reports. Really interesting piece from a team led by Zubin Master. It’s a tough battle out there to educate patients and help them make good decisions in the stem cell clinic space. I get several emails a week from patients with questions about clinics.

Rescue of Alzheimer’s disease phenotype in a mouse model by transplantation of wild-type hematopoietic stem and progenitor cells, Cell Reports. This is interesting work from Stephanie Cherqui and her team.

I’ve been somewhat skeptical over the years of the idea of using blood cells to treat neurodegenerative disorders. Part of my skepticism may have arisen from so many stem cell clinics selling bone marrow cells or even MSCs to supposedly treat dozens of neurological conditions.

This mouse study has some cool data. It proposes that HSCs may use a unique potential mechanism involving microglia. At this point no one should be selling marrow cells for Alzheimer’s treatment. The field needs much more data to consider such therapies.

The promise of banking umbilical cord blood, BBC. This headline had me worried at first. Was this going to be another shallow piece promoting the benefits of specific private cord blood banks?

Fortunately, the answer is no.

The piece digs into this topic in some depth and, for example, explores public vs. private cord blood banking. I support the former wholeheartedly. However, private cord blood banking is more complicated. While there can be benefits of private banks, they are just rare and most families are wasting thousands of dollars as they’ll never need the cord blood units. Still, for some families, it may be worth it.

I wish the BBC had a better title for their piece. Something more nuanced.

Check out: Fact-checking, pros and cons of cord blood banking. I’ve also included my video fact-check on cord blood cells for autism above. If you like our YouTube channel please subscribe.

6 thoughts on “Weekly reads: embryonic stem cells, Parkinson’s, Alzheimer’s”

  1. Paul- blood macrophages are being used as substitutes for microglia in the brain. They are not the same cells. Microglia arise in the yolk sac and migrate into the brain during embryonic development, where they take up residence as a major part of the brain’s innate immune system. Macrophages are a poor substitute. Since microglia can be rather easily made from iPSCs (although make sure you characterize them well), I don’t see why anyone would use macrophages instead.

    1. I agree that is puzzling. Who’s using macrophages as a substitute for microglia? Also, most macrophages live in tissues rather than the blood so what is meant by”blood macrophages”? Can one mobilize macrophages into the blood rather than tissues? Or are monocytes from the blood being used which then turn into macrophages?

  2. Dear Admin:

    As a follow up to my comments about the Antonio Regalado article, you might be interested in sharing a recent TEDx talk that I gave on the challenges of reporting science to the public:

    https://www.youtube.com/watch?v=_Yooeb-yKz0

    As well as my recent book on related problems in COVID science reporting.

    https://www.cambridgescholars.com/uploads/sbpub_sub/resources/Missing-Elements-in-the-Public-Science-Supporting-the-COVID-19-Spread-Narrative-in-the-US.pdf

    James @ Asymmetrex

  3. Dear Admin:

    Shall we agree from your opening history that you may be quite unable to see your own bias when you state the Antonio Regalado’s MIT Tech Review “article is well-balanced though”?

    I have a particular vantage point for insisting that the article is anything but balanced, let alone “well-balanced.” Antonio interviewed me for about about an hour on a Zoom call as he was preparing his report that turns out to be an opinion-editorial, instead of a fair report on what has occurred in the highly-touted and over-promised field of human embryonic stem cell (hESC) medicine in the past 25 years, since the report of the ability to derive hESCs. A more accurate title for his piece would have been “25 Years Later, Still Continuing to Hype Human Embryonic Stem Cells for Medicine.”

    Antonio’s piece does not have a single dissenting quote from his pronounced narrative that hESCs might one day yield effective cellular therapies. Every quote is one of unjustifiable optimism from someone well invested in never admitting the now well-recognized shortcomings of hESCs for developing medical therapies for children and adults. Some of the shortcomings were warned about 25 years ago, while others have emerged over time.

    When I talked with Regalado about them, he expressed unfamiliarity with some of them; and so, I guess he decided to ignore them because they did not fit into his pollyanna narrative.

    hESCs cannot be used directly for cellular therapies for two main reasons. Most people understand the problem that they form tumors when implanted into mature tissues. However, few understand that they are different than adult tissue stem cells; and therefore could never maintain the required continuous renewal of tissue stem cells, even if they didn’t form tumors. They were always going to be incompatible for cell therapies in children and adults as promised.

    So, after stopping the nonsense of solving the hESC tumor problem, promoting scientists’ next promise was that they would differentiate hESCs into needed organs and mature tissue cells. Beyond the intrinsically formidable challenge of this promise, there were earlier hurdles, as well as a fundamental biological flaw from the onset that continues to be ignored. That flaw is the requirement that transplanted cells be able to continuously renew tissue cells in the manner that blood stem cells do after their transplantation. Differentiated cells do not have this property. This problem is the future of current pancreatic beta-cell clinical trials unless those preparations contain asymmetrically self-renewing pancreatic stem cells like those found in islets. Given the source of the treating beta-cells from differentiation of pluripotent cells, the presence of such stem cells is unlikely.

    Some scientists, in particular in the blood stem cell field, have considered trying, with some reported successes, to produce hard to get and expand blood stem cells from differentiation of hESCs. But this strategy is also problematic because of the aforementioned earlier hurdles, which include genetic and epigenetic mutations that occur during the derivation and propagation of hESCs. The question was raised by yours truly 25 years ago of why go through all of these machinations to produce genetically defective hESC-derived adult tissue stem cells, when scarce research dollars could be focused on clinical development of natural donor adult tissue stem cells, which have none of the tumor-formation or mutation problems.

    A final problem that emerged later in failed attempts in the clinical development of hESCs completely thwarted the differentiation strategy. In vitro differentiation of the hESCs yields immature embryonic-like cells that, even if they could be repeatedly transplanted for cell therapies, would not provide the mature cell functions required in the tissues of children and adults. The hESC research field has been years trying to mature hESC-derived differentiated cells. But even if they succeed, as the beta-cell transplanters say they have, the fundamental problem of achieving effective tissue cell renewal still looms.

    In the absence of even a hint of these lurking problems that are now recognized by many in the field, whether they acknowledge them or not, Antonio Regalado’s article is certainly not well-balanced. Not only will it serve to mislead non-experts, but it will also mislead some experts as well.

    James @ Asymmetrex®

    1. James, Antonio was writing about the 25th anniversary of the publication of the first scientific paper on hESCs. Nothing to do with you.

  4. Thanks for this nice compilation. In fact I was surprised by recent interest and reviews on definition of adult stem cells (PMID: 36270939, 36922629). Human ES and iPS have evidently not been successful to enter the Clinics. Eventually tissue-resident stem cells will succeed. But collectively we need to arrive at a consensus on how to define adult stem cells. Cord blood banking has applications limited to blood diseases since HSCs are committed progenitors.

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