STAP cells (stap細胞) are real deal says new Vacanti patent declaration

STAP is back?vacanti-stap-figure-2017

Really?

No, I don’t believe so, but there’s an interesting development and twist on the STAP cell front.

Just a few days ago on January 4, 2017 Dr. Charles Vacanti, the originator of the STAP cells concept, submitted a declaration to the USPTO affirming the belief that STAP cells are real and requesting that the patent office allow the rejected STAP patent application to be reconsidered.

I find a number of aspects of this development notable:

  • The declaration says they have generated new data supporting STAP, but the two figures shown are in my opinion unconvincing. More specifically, just showing some floating spheres and an image of a single cell (not even stained for a marker) doesn’t really prove anything. You can see a snapshot of Figure 1 above. Note that in May 2016 an Obokata-associated website posted some supposed STAP validation data as well, but in my view it too wasn’t at all convincing.
  • qPCR results on induced expression of pluripotency genes are mentioned, but I didn’t see that actual data in the document or other related documents so as far as I can tell it can’t be evaluated at this point. Update: I’m still searching to see if I can find a patent document that shows the new qPCR and it may be in there somewhere. Stay tuned. BTW, you can look at the patent documents directly yourself at this USPTO website. Plug in patent application #14/397,080 and click on the tab at the top that reads “Image File Wrapper”. I’m not a patent expert so there may be other useful tabs at the top as well where for instance the qPCR data could be found or other information.
  • The declaration expresses concern with how Nature handled the STAP cell situation with the retractions, indicating that in the view of some of the authors there should have been an indication that the authors believed the concept was real.
  • Why do some of the STAP authors believe in it still but many others in the stem cell field don’t? Apparently, according to the declaration, the other labs who tried the STAP method just didn’t use the proper technique. I have doubts about that explanation. For instance, Vacanti’s own Harvard/B&W’s colleague George Daley and other top stem cell scientists published two BCA pieces in Nature refuting the existence of STAP. Reportedly they even did some of this work in Vacanti’s own lab with someone who was an author on the STAP papers.
  • The STAP cell patent application has been transferred to a private company called Vcell Therapeutics, Inc., which seems somewhat obscure. A Japanese blog has dug into this situation and mentions a J. Kelly Ganjei, a name I’m not familiar with, as a leader of Vcell. There’s even some speculation that Vcell may be short for “Vacanti cell”, but I don’t know about that. Given the sound of the company’s name I can’t help but think of VSELs, another controversial kind of stem cell, when reading the word “Vcell”.

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STAP cell top 10 list of predictions

rp_STAP-stem-cells-hope-or-mirage-201x300.pngNow that it appears that the authors have all consented to eventually have both of their STAP cell Nature papers retracted, what’s next for STAP?

Who knows, but below is my attempt at a top 10 list of STAP predictions looking ahead. I hope I’m wrong about several of them.

  • 10. No insight will come from Nature on the STAP review or editorial process and there will be no indication from them that anything went wrong at their level.  I predict the journal will never open up about the editorial and review process behind the STAP debacle. If the papers are finally retracted (keep in mind that they have not yet been actually retracted) by authors as seems most likely at this point, I figure that for Nature that will be the end of the story. I hope I’m wrong.
  • 9. Obokata does not sue RIKEN. She and the institution make a private agreement/settlement (perhaps already a done deal given how things are shaping up with her rejoining the STAP validation team at RIKEN).
  • 8. STAP patent gets approved. Despite all the problems with the STAP scientific story, the US Patent Office approves the STAP cell patent anyway. Crazy, huh?
  • 7. Someone somewhere claims to get STAP to work, but the data are very weak.
  • 6. No news from Brigham and Women’s or Harvard Medical School regarding any potential institutional reactions related to STAP at least until 2015 and perhaps never.
  • 5. At least one person leaves RIKEN related to STAP. This happens either because of their links to STAP or conversely because they find the whole thing too ugly to bear.
  • 4. More retractions or corrections of other papers from at least one or more of the STAP paper authors.
  • 3. More top tier journal stem cell paper problems unrelated to STAP, despite STAP as a potential learning experience. Few lessons will be learned from STAP at the stem cell publication level. One or more likely more stem cell papers in a high-impact, top tier journal will have serious problems (e.g. be retracted, be on a possible path to retraction, have major data manipulation, etc.) in the next 12 months.
  • 2. No convincing reports published in 2014 that STAP cells, as they were portrayed in the Nature articles, really exist.
  • 1. No imminent Obokata departure. Obokata stay at RIKEN at least through the end of 2014. There may even be rumors that she can help the RIKEN team get STAP to work again.

Analysis: Why Obokata OKs Retraction of Nature STAP Cell Letter, But Not Article

Haruko ObokataJapanese news media are reporting that Haruko Obokata and other key authors have agreed to retract the Nature STAP cell letter, but not the Nature article.

This is a major development and a peculiar one because to many in the  field it is the Nature STAP cell article that is the more flawed of the two Nature papers on STAP.

Why would Obokata and her colleagues agree to retract the STAP letter from Nature, especially after for so long categorically rejecting the idea?

I suspect they are under pressure from other co-authors, from RIKEN, and probably from Nature. Just yesterday I wrote an editorial calling on Nature to retract both articles and more broadly there have been a lot of calls for Nature to do something about STAP so I imagine the journal may be hoping that the authors will retract the papers so they do not have to do so themselves editorially.

Why would the authors retract the STAP letter but not the article?

It appears, at least from the Japan Times story, that there may be some effort to place blame for STAP on Dr. Teru Wakayama:

“Of the three researchers, her lawyer said University of Yamanashi professor Teruhiko Wakayama is responsible for the paper Obokata has agreed to retract. He was engaged in all experiments, and Obokata wrote the paper under his guidance, lawyer Hideo Miki said.”

This seems unfair to me.

It is also worth nothing that RIKEN is currently determining a punishment for what it called Dr. Obokata’s misconduct and RIKEN asked Obokata to retract the other STAP paper (correction on which STAP paper RIKEN requested be retracted via new Cyranoski Nature News piece on today’s development):

“Ironically, the paper that Obokata has agreed to retract was not the one found by RIKEN to contain  manipulation. Obokata still stands by that paper, which establishes the basic technology for creating STAP cells.”

I’d also imagine that to Obokata and others including her postdoc mentor Dr. Charles Vacanti that the Nature article is far more important to keep unretracted. It is the heart of the STAP cell story. I have emailed them both asking for clarification.

If I was a Nature senior editor (and of course I’m not), I’d figure this is the end of the road for STAP and we should editorially retract the STAP article at this point since the authors will clearly not do so. This is in fact the perfect time for Nature to retract the STAP article what with the authors apparently OK’ing retraction of the other STAP paper. Get both STAP retractions out of the way at once during roughly the same news cycle.

The fact that the STAP letter is now likely to be dead only further supports the idea that the whole STAP story is fundamentally flawed and the STAP article cannot survive much longer either.

Editorial: Past Time for Nature to Retract STAP Cell Papers & Open Up On Review Problems

nature's misstapTwo stem cell papers riddled with errors, with figures that resulted from potential misconduct, with plagiarism, and with other serious problems remain uncorrected and unretracted in the prestigious journal Nature.

It is well past time for the journal to editorially retract them.

It was about four months ago that Nature published the two astonishing STAP papers reporting the supposed creation of super-powerful stem cells (known variously as STAP cells or STAP stem cells) via simple methods such as weak acid treatment.

Since their publication, it’s been all down hill for these papers.

As soon as they came out I posted a review raising key questions about them related to puzzling issues.

Within a week I was the first scientist to publicly raised serious doubts about the papers. I gave the top 5 reasons to doubt the papers.

Within a few more weeks there were signs that the STAP papers were seriously compromised and one senior author, Teru Wakayama, himself called for their retraction.

To this day, nobody has gotten the STAP method to work and perhaps even more importantly, it is clear that both papers are irredeemable due to many serious and unfixable problems.

And yet they still remain uncorrected and unretracted in Nature.

Why?

Could the journal be holding out some hope that someone somewhere will get the STAP method to work? If so, the journal leadership should realize that it’s too late for that to save the papers.

Is the journal going through some slow process of investigation that it wants to finish before retracting the papers? I don’t know, but time is ticking away and there is no apparent reason for further delay.

Are they just hoping that as months go by fewer people will care about STAP?

Whatever the reason, it is well past time for Nature to editorially retract these tainted papers. There is nothing more to be learned that could save the papers and every day that passes with them still in the Nature portfolio is a shame.

Making matters worse, there is no apparent sign that Nature is taking the STAP problem to heart as it pertains to its own role in the debacle and the flaws in its own manuscript review process. For example, Nature recently published an editorial harshly criticizing Japan for its science related scandals and in that piece Nature mentioned the STAP scandal as an example, but it did not mention a role for Nature itself in the STAP mess that might need discussion and action. And of course the STAP papers included America’s Brigham and Women’s Hospital, not just Japan.

It’s time for Nature to get real on STAP.

Retract the STAP papers and publicly discuss what went wrong.

The journal of course cannot and should not be directly blamed for any potential author misconduct, but clearly Nature has some major responsibility for the train wreck that is STAP.

You can only get so much mileage out of blaming others outside the journal as much as that blame may be appropriate.

Time for action and openness by Nature. That’s the only way for the journal to move on in a positive way.

In a pickle over STAP stem cells: top 5 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.

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.