As we think about how much of a role belief should play in the hard sciences such as cell biology, a supposed cell type called VSEL or very-small embryonic stem cell-like cells comes to mind. For these guys it seems to me that the ratio of data to belief isn’t great.
VSELs have nine lives.
I thought the idea of VSELs was pretty much dead years ago. This was after Irv Weissman’s lab published a paper showing the cells, also sometimes called VSEL stem cells, don’t exist. Others chimed in to agree.
Overall, only a few labs in the world have published regularly on VSELs.
But it’s hard to 100% prove a negative, right? VSEL fans just keep plugging away even now.
New VSEL paper
The latest on VSELs is a review article in the great journal Stem Cells. The paper is pushing the usual about VSELs along with a new angle on cancer. Here are the authors: Deepa Bhartiya, Nripen Sharma, Shruti Dutta, Piyush Kumar, Ashish Tripathi, and Anish Tripathi. Bhartiya has been a regular commenter here on The Niche where she has weighed in about VSELs, MUSE cells, and others. For example, here’s a comment she made on a post I did on STAP cells.
I’m surprised that Stem Cells published this piece for several reasons.
First, the VSEL review doesn’t even mention that there’s any controversy about VSELs. It doesn’t cite literature that goes against the authors’ views.
Second, the overall VSEL literature and some of its proponents/authors have had some issues in the last few years (see image above and more info on this below).
Third, the review article seems kind of promotional in nature to me. It pushes a purported early cancer diagnostic test somehow related to VSELs. As some of the authors disclose, they have a company marketing this. This recent piece from the NCI on early cancer detection tests gives some helpful context on this area more generally.
VSELs don’t form tumors but are connected to cancer?
The other thing about this review and its main hypothesis is that it seems to look for the best (most useful) of both worlds in an almost contradictory way.
On the one hand, some VSEL researchers say that although VSELs are pluripotent they do not form teratomas or other tumors. (Generally by definition pluripotent cells can form teratoma).
On the other hand, now the review article is saying that VSELs can be an important source of cancer stem cells.
Could both be correct?
I suppose so but I do think there are convincing data on this.
Sometimes a discovery comes along that, if true, would revolutionize medicine. Imagine being able to detect cancer before it's even cancer? https://t.co/sqCVizvOmo? #CancerResearch #dnajourney
— David Sinclair (@davidasinclair) March 29, 2023
Belief vs. data
Of course, belief has a role in science but we have to be careful about it.
Scientists can want their hypotheses to be true and even sometimes believe they are true before the data are all there. It’s not that hard to get attached to an exciting hypothesis.
Some of the VSEL researchers at times seem surprised that there are skeptics. The long-time VSEL mantra is that most of the stem cell field just doesn’t know how to find VSELs, but that they are real. If only all the other labs would do the research properly.
Much of this tension boils down to the data. I don’t think the data are there consistently to support the existence of VSELs in the body.
As I said, there have been some serious issues reported on key VSEL papers.
For example, Elizabeth Bik reported issues with 28 VSEL papers from leading proponent Marius Ratajczak. Some of the authors of the Stem Cells review had a paper retracted recently too. Further, some of their other papers have popped up on PubPeer too for what seem to be image issues.
This all makes me view VSELs overall more skeptically.
Looking ahead
Contrast VSELs to another type of pluripotent stem cell: iPS cells. I’m trying to imagine a hypothetical scenario of working so extensively with iPS cells, as my lab does, while much of the stem cell community says iPS cells aren’t real and reprogramming didn’t actually work for them. That wouldn’t be a comfortable place to be. Of course, iPS cells are real and hundreds of labs routinely have been doing reprogramming successfully.
A final note on this is that a tweet from well known anti-aging researcher David Sinclair is how I found out about the new VSELs paper in the first place. He tweeted about it in an exuberant kind of way. Earlier this month I noted that Sinclair had seemed excited about some iffy anti-aging stuff on Twitter too. As I’ve said before, he publishes great research so what’s with the tweets?
The key part of his VSEL tweet is the “if true” qualifier.
If despite everything, I’m wrong and VSELs can be real, then I still think the most likely explanation is that they do not exist naturally but are created inconsistently and rarely by experimental conditions.
Is there something in science you believe in that goes against prevailing opinion?
Dr. Bhartiya directed me to this post, interestingly enough. It was quite interesting to read, as I recently posted on the subject to Real Clear Politics:
https://doctorbuzz.substack.com/p/bs-alert-a-blood-test-claims-100
Your take on the scientific concerns surrounding VSELs were not something I had come across while researching the article. I think you tread too lightly on their research, though; their findings require a suspension of disbelief, as I detail in my post.
A part of me feels compelled to nudge Stem Cells a bit for publishing this piece, for all of your criticisms as well as mine. I find it disconcerting to read about impossible findings in a respected journal without any acknowledgment that the findings are, indeed, absurd.
Buzz Hollander MD
Half a century ago my PhD supervisor believed saturable transport kinetics for intestinal folate transport were an artefact caused by the anomalous solubility characteristics of folates in a hypothetical acid microclimate. The microclimate was shown to exist, but I generated data consistent with carrier-mediated transport. I was not allowed to publish them. We eventually compromised by publishing papers describing and evaluating both hypothetical models, but the correct carrier-meditated mechanisms were established by other groups. This was a salutary lesson for me on the pernicious effects of dogmatic beliefs in the conduct of scientific research.
Dear Paul
Thanks for the write up on our article published in Stem Cells
[DOI: 10.1093/stmcls/sxad015].
My group had challenged Irv Weisman and his findings when their study was published. Yes, it is indeed very difficult to undo negative data published by one of the leading labs on stem cells. I have learnt this the hard way. Negative data from his lab took Science back by decades.
One will appreciate VSELs, if one is willing to delve into their biology with an open mind. VSELs are pluripotent stem cells, developmentally connected to primordial germ cells and are different from embryonic and induced pluripotent stem cells (ES, iPS) since they do not readily divide in vitro, nor they form teratoma, nor compliment a developing embryo. Recent studies have shown that it is possible to expand VSELs in vitro by using epigenetic modifiers.
The controversy on VSELs surfaced in 2012-2013, almost a decade ago and the Science has moved ahead since then. Our Stem Cell article in 2023 (besides being promotional), discusses hard core science. We discuss that epigenetically altered VSELs (due to various extrinsic insults) get transformed into cancer stem cells (CSCs). Role of VSELs being the possible embryonic remnants that initiate cancer was first discussed by Prof Ratajczak’s group [doi.org/10.1038/s41375-018-0294-7].
VSELs do not form tumors but are connected to cancer?
This is correct. Normal VSELs remain quiescent and epigenetically locked in G0 stage of cell cycle. They are responsible for regular turnover of cells in adult tissues and get activated in case of chronic injury to restore homeostasis. Upon exposure to extrinsic insults, VSELs undergo epigenetic changes, enter cell cycle and increase in numbers. This results in cancer initiation. One may refer to these links which support this [DOI: 10.1186/s13287-022-02784-5; DOI: 10.1007/s12015-022-10424-x, DOI: 10.1530/REP-22-0337]. Only VSELs, being immortal, have the potential to carry various early-life insults to adult life (other cells are regularly replaced) and initiate pathologies.
Belief vs data
Paul- I am so happy you wrote this post. But wonder why you did not take up our studies where we reported how VSELs initiate cancer. We believe in what we see under a microscope- and we regularly see VSELs under a microscope. There is no scope for disbelief. VSELs are pluripotent stem cells that exist in the body and do all the magic. On all the 3 fronts of regenerative medicine, aging and also cancer – VSELs have the potential and we recently discussed this [DOI: 10.3389/fcell.2022.1061022].
Looking ahead
Paul – please remove VSELs/MUSE cells from your initial skin cells in culture and then try to do reprogramming to make iPS cells. I think you will not succeed [DOI: 10.1073/pnas.1100816108, DOI: 10.1093/carcin/bgab042]. VSELs exist naturally in normal tissues. My basic research at NIRRH was focused on this. [doi: 10.1007/s12015-020-09993-6, doi: 10.1007/s43032-020-00250-2, doi: 10.1007/s12015-021-10284-x].
Now at Epigeneres, after my retirement, I am excited to see how my 2 decades of basic research translates to the Clinics. VSELs are superior to CTCs and ctDNA for early detection of cancer. We at Epigeneres see cancer as a stem cells dysfunction. Sincere thanks to Stem Cells for considering our article for review and eventual publication and Prof Sinclair for his interest.
Willing to discuss this further
Best
Deepa Bhartiya
Research Director
Epigeneres Biotech
Mumbai, India
Hi Deepa. Thanks for your comments.
Truly interesting story..thank you for the update
These vsel are only seen on darkfield, correct ? (Kidding)