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Has Mariusz Ratajczak Found the Holy Grail of Stem Cells?

The views expressed are those of the author and are not necessarily those of Scientific American.

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Credit: NIH Stem Cell Unit

So many controversies about stem cells have flared and died away over the past decade that it can be hard to keep track of them all. The most recent contretemps, as evidenced by reports in the scientific press here, here and here, is about an exceedingly rare (and perhaps non-existent) group of diminutive cells called Very Small Embryonic Like cells, or VSELs (pronounced vee sells) for short.

Depending on whom you believe, VSELs could be a dogma-busting game changer for stem cell therapy or, as a scientific report published in Stem Cell Reports yesterday strongly implied, just another fanciful claim that cannot be reproduced and so deserves to be forgotten. We could all wait a few years for the science to mature to get a satisfactory answer, but neither government funders nor impatient biotech venture capitalists are likely to tarry that long before choosing whether to back VSELs or move on to something else that is also, maybe, perhaps, someday, possibly going to work.

So what’s all the fuss about this time? In 2006, Mariusz Ratajczak and his colleagues at the University of Louisville published a report claiming that they had found very small cells in the bone marrow of adult mice that had some of the properties of adult stem cells but didn’t quite look or act like the hematopoietic stem cells normally found in the bone marrow. (Hematopoietic stem cells, like all adult stem cells, normally give rise to a limited number of tissues, in this case, red blood cells, platelets and the various kinds of white blood cells or lymphocytes  that are found throughout the body.) For one thing, these new cells were very small—on the order of 3 microns, which is indeed minute, especially when compared to the smallest white blood cells, which are about 8 to 10 microns.

Another puzzling feature of VSELs, according to Ratajczak and his team, is that they don’t divide and create more copies of themselves the way normal stem cells do—even after investigators dumped a bunch of growth factors on them that have been shown to push other stem cells into recreating themselves. Indeed, you could hardly think of VSELs as stem cells at all—since regenerating themselves is one of the most important hallmarks of stem cells.

But, Ratajczak says, further research in his lab hinted at an intriguing possibility—evidence that VSELs contain certain molecules on their surface that indicate that they are quiescent stem cells (think long-term stasis) left over from the earliest stages of embryonic development. You would expect to have a tough time waking  these cells and getting them to regenerate, he notes.

Imagine if leftover cells from when you were an embryo, which kept the potential to become any type of tissue, randomly started becoming active in your body. How could you stop them from taking over? Any evolutionary pathway that permitted VSELs to easily regenerate would quickly turn into a fast track to a lethal tumor. For these and other reasons, Ratajczak says, it’s entirely possible that VSELs may not be able to grow outside the body. Or perhaps they are only active in childhood, giving rise to some of the tremendous recuperative powers of youngsters. If so, they might prove fascinating but not terribly commercially valuable.

If, on the other hand, a scientist could figure out how to prod VSELS in adults to regenerate themselves—and to differentiate into different cell types—he or she would have found the proverbial Holy Grail—fully functional embryonic stem cells that come from adults instead of embryos. Not only would such an accomplishment avoid a lot of the ethical problems that some people have with the current sources of embryonic stem cells—namely embryos—but fully functional VSELs would eliminate the sorts of rejection problems that clinicians always have to look out for when transplanting bone marrow or other solutions made up of stem cells.

For a while there, it looked as though Ratajczak’s lab was the only one capable of isolating VSELs from mice—never a good sign if you want to convince other researchers that you’ve found something new and different.  Besides being quite small, the cells are very rare, Ratajzak says, making them very difficult to isolate.

Then the Vatican donated $1 million through a foundation to fund work being done on VSELs by a company called NeoStem—which is also not necessarily the best PR if you’re trying to win over skeptical stem cell scientists who have been repeatedly battered by church-state fights over the morality of harvesting stem cells from embryos.

Indeed, more than one stem cell researcher has suggested the interest in VSELs has more of an ideological rather than a scientific underpinning. “I don’t understand this,” Ratjczak told me when I asked him about the possibility. “I am very far from any Vatican people. I am an atheist actually.”

Although two groups have reported in the past two years that they could not replicate Ratjczak’s work, two other groups have now claimed to have found VSELs. After sending a post-doctoral fellow to Louisville to master the technique, Diane Krause, a stem cell researcher at Yale University, led a team of investigators who managed to isolate their very own VSELs from the bone marrow of mice. “It was very challenging,” Krause says. “We had to keep checking with Mariuscz on how to do things.”

The Yale team was subsequently able to coax these cells into becoming more specialized cells (called epithelial cells) of the sort that line the various passageways of the lungs. If their results can be verified, it would lend crucial support to the special nature of VSELs since stem cells from bone marrow don’t usually give rise to epithelial cells.

In addition, Russell Taichman, a professor of dentistry at the University of Michigan, says he has found a very similar kind of cell. Later, when he met up with Mariusz Ratajczak at a conference, Taichman says, “we shared our experiments and it looks like we’re looking at the same thing.”

Credit: Niels Geijsen, Massachusetts General Hospital/National Science Foundation

Irving Weissman, a pioneer in the field of hematopoietic stem cells and the director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University, is having none of this.  “What it really comes down to is when you do evidence-based research and publish evidence-based research, is it reproducible in independent hands?” says the co-author of the recent research paper in Stem Cells Report. “We tried to be as careful as we could to see if we could reproduce the findings and we can’t. We’re a pretty good lab at sorting cells. We’re a pretty good lab at hematopoiesis. Part of the responsibility of a scientist is to publish things so that any lab competent in the art can reproduce it and we couldn’t.”

When I playfully suggested that lack of evidence wasn’t the same as proof of a negative, Weissman nimbly switched gears. “Send us VSELs for us to test, so that we don’t make the mistake of isolation. We’d be happy to evaluate them.”

Naturally, I then repeated Weissman’s words to Ratajczak, who was in Poland to attend a meeting. “Why didn’t Dr. Weissman’s people contact us three or four months ago when they were having trouble?” Ratajczak said. “And now he wants to collaborate?” And then in a less frustrated tone of voice: “Okay, he can come and see me any time.”

Weissman is not the only skeptic. “They [Ratajczak and colleagues] are obviously measuring something. But it’s difficult to say what,” Christine Mummery, a professor of developmental biology at Leiden University in the Netherlands told a reporter for Cell Stem Cell.  “As long as these cells remain rather odd and the experiments that are published seem slightly less than robust, I think they’re open to question.”

So who to believe? Do VSELs exist or not? “I trust Mariusz Ratajczak’s papers and I trust anything that Irv Weissman is doing,” Krause says. “I know there has to be some objective explanation for the difference but I don’t know what that explanation is.”

“We are right and you will see,” Ratajczak says. “The truth will prevail.”

“We’re in this endless round of having to test these things,” Weissman says. When I ask him if VSELs are a distraction, he replies, “I know it’s a distraction.”

Stay tuned. I don’t think we’ve heard the end of VSELs.






About the Author: Christine Gorman is the editor in charge of health and medicine features for SCIENTIFIC AMERICAN. Follow on Twitter @cgorman.

The views expressed are those of the author and are not necessarily those of Scientific American.

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  1. 1. pknoepfler 6:03 pm 07/25/2013

    Thanks for the very interesting piece.

    I think perhaps the amusing title of your article is a bit too generous for VSELs, however, even when posed as a question.

    My sense is that there is far more skepticism about VSELs relative to belief in them in the stem cell field. It’s not really a question of whether they are the “holy grail”, but rather are they even real at all? Assuming for a moment that VSELs are real, they still would not be the holy grail. They are too rare and hard to find to be really useful.

    I published a piece on VSELs yesterday that asked the flip side question of what you asked in your title. My title was “Are VSELs the Sasquatch of the Stem Cell Field?” ( ).

    I also included a poll in that piece, which while non-scientific, up to this point reflects substantial doubt about VSELs with only 31% of respondents indicating their belief that the cells are even real let alone some saving grace kind of super hero heaven-sent cell.

    Paul Knoepfler
    Associate Professor
    UC Davis

    Link to this
  2. 2. djwilson 11:26 pm 07/25/2013

    Isn’t that a lot of ‘ifs’?

    Link to this
  3. 3. Christine Gorman 11:14 am 07/26/2013

    Paul, Thanks for your comments–and the results of your poll. Part of the reason I wrote this as a blog piece with a light-hearted tone is that I wanted to accurately reflect the skepticism and the ardor and the fact that when all is said and done, VSELs might not be good for much oustide the body even if they do exist.

    DJ, Yes, it’s a lot of ifs. That’s the whole point.

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  4. 4. Christine Gorman 11:16 am 07/26/2013

    P.S. The “Holy Grail” is a legend.

    Link to this
  5. 5. ClevelandKF 3:42 pm 07/26/2013

    Unfortunately, I’ve heard this before. It’s at the point of the boy who cried wolf. We need to stop giving in to this sensationalism.

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  6. 6. William_W 8:18 pm 07/26/2013

    VSELs sound intriguing, as most things so mysterious. But I also don’t see any way they are more prolific than those cells we already know about, Christine. And we are already pretty far behind the ball in proving the validity of physiological stem cell methods – though many people believe it’s there.

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  7. 7. R Johnson 1:41 pm 07/27/2013

    I’m definitely one of those people in the court of physiological methods. I’d suggested reading Kevin Xu’s new article on his Wired Blog. It’s a piece on the duality of physiological and pathological models:

    Link to this
  8. 8. William_W 2:19 pm 07/27/2013

    Of course, but the potential is huge. And articles have to get their readers.

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  9. 9. ScientificGal 9:24 pm 07/29/2013

    Do you think there is any hope for VSELs, Christine?

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  10. 10. ClevelandKF 9:57 pm 07/29/2013

    Doubtful, there is nothing so far to support the term “holy grail” for something so unproven, as our author pointed out. We haven’t even identified it yet.

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  11. 11. RW1955 12:33 am 08/3/2013

    Like the post, Raymond.

    Link to this
  12. 12. R Johnson 1:20 am 08/3/2013

    Thanks all, and thanks Christine for the well executed article.

    Link to this

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