In a pickle over STAP stem cells: main reasons for skepticism

in a pickleIf you take an ordinary cucumber and soak it in a mild acid solution of vinegar for a few weeks you get a pickle, which is where we find STAP stem cells.

Recently, some scientists reported in Nature that if you take ordinary cells and soak them in a mild acid solution for 30 minutes, often the cells transformed into the most powerful type of stem cells known to science.

These newly incarnated pluripotent or totipotent stem cells, which they termed “STAP” stem cells, reportedly can make any known type of cell and maybe even an entire embryo along with its own placenta.

Now that’s no pickle.

The authors reported that it doesn’t even have to be acid, but any number of stresses will do the trick.

Just how amazing is this? It’d be like putting your cucumber in vinegar to make a pickle and instead finding the cucumber had changed into a living, swimming goldfish in the jar.

We’ve seen some amazing things in the stem cell field turn out to be completely true such as iPS cells, but somehow from day 1 I had no doubt about iPS cells.

Extraordinary claims require extraordinary evidence and independent replication. STAP stem cells aren’t there…at least not yet.

Five more specific reasons make me skeptical of STAP stem cells at this point.

  • 1. The STAP method & results are illogical. I’m not a Vulcan like Spock on Star Trek, but I believe logic and common sense are keys to science. To me STAP defies common sense. Illogical doesn’t necessarily mean wrong, but it raises doubts. STAP just seems too good to be true.
  • 2. The STAP team previously reported “spore” stem cells, which to my knowledge have not been independently replicated. They reported in 2001 the discovery of “spore stem cells” that are a micron or two in size, behave kind of like fungal spores, can take a beating, and may have a “minimal genome” contained in an atypical, tiny nucleus. Dr. Vacanti recently told me that STAP stem cells and spore stem cells are believed to be the same thing.
  • 3. The team also previously reported adult pluripotent stem cells. Drs. Vacanti and Obokata also published a surprising paper in 2011 reporting to have found pluripotent stem cells in adult tissues. I’m not a believer in such cells, but other folks do believe in such cells and call them VSELs or MUSE.
  • 4. Evolution should have selected against a hair trigger for conversion to pluripotency or totipotency. A process for any ordinary mature cell to go back in developmental time easily trigged by any one of a host of different stressors would be harmful, even deadly to organisms. In that reality, we should see teratoma or teratocarcinoma tumors–the kind that arise from pluripotent or totipotent stem cells–sprouting up all over the body after injuries or even just spontaneously, but that doesn’t happen. The key concept here is that in the wrong developmental context (in a child or an adult rather than in an embryo), embryonic-like stem cells would not behave normally just to fix tissues and then stop. Rather they’d make tumors. Evolution should select against that. Now if the authors had reported STAP stem cells as multipotent tissue specific stem or progenitor cells that might have made sense as a mechanism for tissue repair. But they didn’t.
  • 5. Why the delay to make human STAP cells?  The team says they made mouse STAP stem cells successfully in 2011, but only now in 2014 are they just starting to try to make human STAP stem cells. What the heck? Wouldn’t trying to make human STAP stem cells have been something they should have done immediately in 2011 or even done at the same time as trying to make the mouse ones? There may well be a good reason for this delay, but again it’s just something that is puzzling.

What’s the bottom line? In the end, right now we cannot be 100% sure either way about STAP stem cells. However, we’ll know if STAP cells are the real deal within as short as two months because quite a few labs are now trying the technique. Again, I believe the odds are it won’t work, at least not in a reasonably close fashion to what was reported in these Nature papers. Sure, we might see some people say to the media or even publish papers indicating that they can kinda sorta almost make STAP-like cells with certain stressors sometimes, but my prediction is that it still won’t be very convincing.

I really hope I am wrong and if I am you’ll read my happy mea culpa right here.

For additional background see my review of the STAP Nature paper here and more STAP-related thoughts here.

19 thoughts on “In a pickle over STAP stem cells: main reasons for skepticism”

  1. Hi Dr. Knoepfler,

    Thanks for your blog, very informative!
    I have listened to I do not know how many news bulletin here in Japan and I almost never heard the name of Charles Vacanti or the other corresponding co-authors. It seems this discovery -whether true or false is not the point here I guess- was made by a one women’s team, despite Dr. Vacanti being a corresponding author as well.
    Then, I saw there is already a Wikipedia page on Dr. Obokata’s biography that I think is unfair since, again, it gives the impression she was on her own.
    Been trying to edit the page saying things like “in collaboration with…” but they always have been edited back….by Japanese users.
    I believe it is an important issue, since fair-play and good faith are the tennents of scientists, just like publishing solid and reproducible results…
    I am not sure what Dr. Vacanti thinks about this.
    Anyway, it may just be a meaningless rant of a foreigner in Japan. In that case, I apologize for using your time. Please judge and feel free to join the Talk page on Dr. Obokata’s biography.

    1. Hi John,
      I think what you are observing is a real phenomenon where Dr. Obokata is being portrayed in the Japanese media as a solitary, heroic figure of sorts. On some level it is understandable as we are all looking for heroes, even in science. Perhaps when all is said and done on STAP, we will realize she was/is a hero or perhaps not. At this point who knows? There sure seem to be a lot of complex layers to this story both in terms of the science and the people involved.
      I do get the impression that there is tension at this point between the US researchers and the Japanese researchers involved.

  2. Catherine Danielson

    Well, we’re having quite the debate on this topic over at the Seeking Alpha board, but from a very different POV. Basically, the author of an article there is claiming that this discovery torpedoes Advanced Cell Tech’s planned work with a much more standard method of delivering iPSC’s. Because almost everyone over there is hoping to make money from ACT’s stock, you can probably guess how passionate this is getting. But what really strikes me is that the reports in the popular press about this study are even nuttier– the irrational enthusiasm is really taking a vacation from reality. I have an MSW, I’ve done qualitative research in the social sciences, and I’ve seen this kind of thing before… but not usually in hard science. It all kind of reminds me of cold fusion and George Bray’s thigh cream.

    Basically, even if every single claim made is 100% true, the gap between theory and practical application is staggering. And it’s very hard to believe that every claim is true, for the reasons discussed in this article, and for many others. I think that everybody needs to calm down.

  3. The pictures shown in the NewScientist article resemble mouse es cells… and human es cells in its primed form don’t look anything like that; maybe they use naive conditions, but somehow I doubt it.
    Also, I’m one week in with my own pilot test with human neonatal fibroblast, and the combination of acidic shock and serum free media makes the cells to form aggregate, but a live staining indicates that they are not Tra-1-60 positive… and other than that; the culture looks pretty boring, no MET or anything interesting going on. It’s still possible that they need more time, but based what on what I’ve seen so far I’ll put a big red flag on this one.

  4. i 100% agree with u on #4, evolutionary point of view, but I know that experiment on monkey is underway. Also they filed their patent 2 years ago.

    1. You are right. There are reasons to believe in this and there are reasons not to believe in this. In the end we’ll have to see if other labs can do it…

  5. Just seems a shame that so many people go straight for the researchers necks. Very very negative reaction, seemingly mostly due to the fact that the lab isn’t one of the “big” labs. If all research came out of a small number of labs, revolutions couldn’t or wouldn’t happen. Lets ask questions and be thorough but lets get rit of the negativity and belittlement that has surrounded ideas such as this.

    1. No, to me it doesn’t matter if a lab is big or small. It boils down to the data, the way it is communicated, and its validation.

  6. Time will give us the answer. This is a simple and quick procedure, I am sure that many capable labs will test this method in the upcoming weeks and months.
    Science is an open community. Positive critique is healthy, yet any negative comments or critique will bite you back. What makes me uncomfortable is your analogy to pickle making, which is totally inappropriate. You need a much acidic environment (typical vinegar has pH around 2) and much longer time (a few weeks), yet the STAP method exposes the cells to a pH 5.7 solution for 30 minutes. There are several order of magnitude difference in acidity. Secondly, just because the idea is unconventional, we should not automatically reject it. There are so many anecdote stories in the history of science that defy the unconventional wisdom.
    Based on the story on this young researcher, Dr. Haruko Obokata, she didn’t receive much support to carry out her idea in the last five years, instead she had to fight off the same type of criticism like yours to continue her work. I can only imagine that she didn’t have the resource to carry out the “ideal” experiments as you suggested. The good news is that this idea is now in the public domain. Many labs will jump in to reproduce and extend this idea. Time will tell.
    I can’t make a judgment on the outcome yet. However, this new idea will for sure stimulate a new wave of studies and move the field forward.

    1. Hi Stan,
      Thanks for your comment. I have a somewhat different view about the potential outcomes. If STAP is proven correct then that’s fantastic, exciting, and a big advance for the field, However, because of the very dramatic nature of the claims in the papers and by the team to the media as well as the media’s intense reaction, if instead they are proven largely incorrect (again, we don’t know that yet and they could be proven true) I think this will not have moved the field forward and there is a significant risk of negative fallout to the stem cell field as a whole.

  7. Point #1: Exactly how is it illogical?

    Point #5: STAP cells make perfect evolutionary sense.

    1. Regarding making evolutionary sense: stressing a plant is a good way to switch it into reproductive mode. Could this be a similar thing?

      Excuse me if it’s a silly question. I’m not a cell scientist.

      1. Brian, that’s a great question and comparison. I’m not sure we have a good answer yet though. Stress is a really powerful force.

  8. Vacanti seems to have a bunch of unpublished results on this up his sleeve. There’s his claim that he asked a collaborator to try to initiate a pregnancy with a cluster of mouse STAP cells, which apparently developed in to an abnormal fetus. Abnormal or not, if that kind of thing is possible with STAP cells that would make for a big ethical hullabaloo.
    But like gareth was saying, it sounds like Vacanti is making some unpublished claims about human STAP cells. Maybe he was waiting on the results of whether mouse STAP cells could be used for cloning before starting with human cells, and was satisfied by the failure of the mouse STAP cell pregnancy to develop normally? He did say that “There was some sort of glitch – which is probably a good thing due to the ethical issues that would occur if we were able to create a live clone”.

    Anyway though, do we know when Vacanti actually started trying to make human STAP cells? Maybe he’s been working on them for a while and just decided to talk about in light of the news about the two papers?

    1. Thanks for the comment, Brendan.
      I’m not sure how much unpublished data there is on the human STAP front. There are a lot of claims bouncing around though in the media. I do not know when they started working on the human STAP stuff, but my impression (which could be wrong) was just recently.
      If embryos can be made via STAP, all hell could break loose.

  9. Hi Paul:
    Very nicely worded issues. I am more cynical than you are, and I didn’t immediately accept Yamanaka’s results. But after the greatest cynic of them all, Rudolf Jaenisch, repeated the work, I, like the rest of the world, had a more positive view. Reprogramming human cells is now routine in my lab, as well as hundreds of other labs. But a lot of high profile studies in the stem cell field have not been reproducible as published, so I’m skeptical until my lab can make the cells and we can analyze the hell out of them.
    As an old friend asked recently: “How can you tell when a stem cell researcher is exaggerating their results?” Answer: “Because they’re moving their lips.”
    It would be fun to have a sort of crowd sourcing approach to testing out the STAP idea- I hope you can convince everyone to share their experiences.


    1. Hi Jeanne,
      Thanks for the kind words. I wanted to express my concerns and yet at the same time not go over the top. It can be a fine line to walk. I like your crowd sourcing idea. I was thinking to offer people the opportunity to share their experiences on this blog if they want to quickly indicate to a large audience what they’ve found on the STAP front.

  10. Hi Paul, on point 5 it appears that it has been done …rumours see link:
    This all does seem a bit fairytale like to me but I may be wrong. I just worry if indeed it is true, will it be a game changer. Not sure ? Worry that the cells have been through so much stress, in a short time, that looking for trouble, may be more like a cancer, i.e. barretts oesaphagus produced by acid reflux!
    I will stand on the fence and still make iPSC the ol´fashioned way til this is vindicated. gareth

    1. Gareth, you make some good points. Regarding human cells, my impression is that that work has just begun rather than being done. I’ll be very curious to see how this all plays out.

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