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from the a-long-but-thought-provoking-story dept.
In January, a team of scientists from the RIKEN Institute in Kobe, Japan, and Harvard University published two high-profile papers in the prestigious scientific journal Nature (paper 1, paper 2), in which they reported the discovery of a simple method for reprogramming somatic cells (e.g., skin cells, blood cells, etc.) to a totipotent state (i.e., like an early-stage embryo, capable of forming a new copy of the donor organism (a.k.a., a "clone")). The method, which they termed "STAP" (for Stimulus-Triggered Acquisition of Pluripotency) involves using a mildly acidic solution to stress cells taken from any of a variety of tissues (skin, blood, etc.). After stressing, the cells are grown under standard culture conditions for several days, at which point, with no further intervention, the cells become totipotent.
The discovery was celebrated for its broad clinical potential (the resulting cells have all of the capabilities of embryonic stem cells they can be directed to differentiate in culture into any cell type (neurons, bone cells, cardiac cells, etc.)). However, unlike therapies that use embryonic stem cells, because STAP cells are patient-derived, STAP-cell therapies would not carry a risk of transplant rejection. Also, STAP cells are free of the ethical and logistical (i.e., limited supply) issues that plague embryonic stem cell methods.
The reported technique is amazingly fast, shockingly efficient, astoundingly simple, and... wait for it... completely unreproducible. Both papers have now been formally retracted (retraction 1, retraction 2).
However, the bottom line is that this entire episode has affected research elsewhere:
Scientists in the stem-cell field (like this submitter) will recognize that the news here is not (i) that papers purporting to demonstrate a new method for producing stem cells were rushed through the peer-review process (the Nature editor handling these manuscripts could easily have requested evidence of independent replication before publishing), nor (ii) that a new high-efficiency and supposedly simple cell-reprogramming method is, in fact, irreproducible (high-profile protein-based reprogramming method: yet to be reproduced, high-profile microRNA-based reprogramming method (paywalled, sorry): yet to be reproduced, high-profile (one of Science Magazine's Top-Ten Breakthroughs of 2010) messenger RNA-based reprogramming method : yet to be reproduced (PDF)).
What makes this story unusual is the ferocity of the public's response (in Japanese) to what are, quite frankly, levels of data falsification, data fabrication, and plagiarism that are not atypical in this field (see below). As a direct result of this public outcry, the lead author of both papers, Dr. Haruko Obokata (who, since questions about her work first arose in February, has been hospitalized because, according to her lawyer, "her mental and physical condition is unstable") was formally investigated by a committee established by RIKEN comprising senior scientists. In May, the investigative committee found Dr. Obokata guilty of three counts of scientific misconduct. As a telling, and also borderline-farcical aside, during the investigatory committee's investigation of, among other things, alleged image manipulation in one of the papers, an investigative committee was formed to investigate alleged image manipulation in published papers authored by the chair of the original investigative committee, who, unsurprisingly, was forced to step down from his chairmanship as a result. As perhaps the clearest reflection of the overall state of the field, the committee chair was replaced, not by another scientist, but by a lawyer, as apparently no trustworthy scientists could be found.
To restore public trust, the RIKEN Institute tasked an outside panel of experts with (i) investigating the culture at the Center for Developmental Biology (CDB) at RIKEN, where the STAP-cell work took place, and (ii) recommending any policy or structural changes that could be made to help ensure that the science produced at the CDB meets an acceptable level of integrity moving forward. The panel recently concluded that the best course of action would be for the CDB to be "dissolved as soon as possible".
Furthermore, the STAP-cell fiasco has placed in jeopardy RIKEN's bid to be named a Special National Research and Development Corporation by the Japanese government (as well as the increased funding that comes with that special designation).
The aforementioned public outcry has so far been largely limited to Japan. There has yet been no indication of whether Harvard will initiate its own investigation or take any other action in this matter (Dr. Charles Vacanti, of ear-mouse fame, who is affiliated with Harvard, is an author of both retracted papers).
There are many other interesting and relevant aspects of this story that shed light on how things went so wrong, including (i) many pages of Dr. Obokata's doctoral dissertation appear to have been copied and pasted from the website of the U.S. National Institutes of Health, (ii) requirements normally associated with RIKEN's hiring practices (e.g., interviews conducted in English) were disregarded in the hiring of Dr. Obokata, (iii) RIKEN will allow Dr. Obokata to attempt to replicate her experiments, but she will be monitored by video surveillance.
This episode has cast a spotlight on the shortcomings of publicly funded biomedical research, and raises a number of important questions. Starting from the assumption that the primary goal of biomedical research is to improve peoples' health (as opposed to fundamental biology research, which has as its primary goal the generation of knowledge):
1. In light of the following three points, is it a good idea to devote public resources to biomedical research at nonprofit institutions (e.g., universities and research centers like RIKEN)?
a. While researchers at for-profit companies can face financial incentives to generate positive results, researchers at nonprofit institutions also face financial incentives to generate the positive results required to publish high-profile papers (tenure, revenue from patent-licensing, opportunities to engage in outside commercial activity (e.g., consulting, start-up companies, etc.) are all often directly linked to the publication of high-profile papers).
b. While regulatory authorities (such as the Food and Drug Administration in the U.S.) provide strict oversight of clinical research (which constitutes the vast majority of research conducted at for-profit bio-tech and pharmaceutical companies), there is little or no meaningful independent oversight of non-clinical research (which constitutes the vast majority of research conducted at non-profit institutions).
c. There is generally no requirement attached to public funding of non-clinical biomedical research that the funded research be advanced to the point of actually improving anyone's health (e.g., clinical trials). Instead, a successful endpoint is defined as a high-profile publication in a prestigious journal.
2. Can we decouple public funding of biomedical research from potentially corrupting influences, perhaps by avoiding performance-based metrics that are highly susceptible to gaming/fraud (number of publications, publishing in high-impact journals, etc.) when determining the allocation of funding? If so, what metrics, if any, should we use to determine which scientists get public funding, and how much they get (again, focusing on biomedical research, but recognizing that the same principles likely also apply to other fields of applied/commercializable research)?
3. Can we improve the peer-review system, perhaps by requiring independent replication as a matter of course, and/or by requiring papers that have not been independently replicated to carry a disclaimer to that effect (like the albeit often disregarded requirement of a conflict-of-interest disclosure statement)? Would a scientific journal that unilaterally adopts these practices thrive?
4. To disincentivize scientific misconduct, should we try to help the public understand the importance of adhering to the following basic tenets of scientific publication: a. all authors share responsibility for the entire paper, b. irreproducibility of a published method is grounds for retraction, independent of the integrity of the data (i.e., whether or not there is specific evidence of misconduct; think Fleischmann and Pons' cold fusion), and c. fabricated or falsified data in a publication are grounds for retraction, independent of the purported reproducibility of the published method.
Finally, before someone says: "Papers were published, the scientific community couldn't reproduce the results, and the papers were retracted, all within six months. The peer-review process worked! Hugs all around!", please consider the following:
Last December, this submitter's lab submitted a grant application to the U.S. National Institutes of Health, in which we proposed work on a new cell-reprogramming method. Our application was rejected in March (after the publication of the STAP-cell papers, but before the integrity of the papers had been seriously questioned) because, as one reviewer put it, "The [...] field continues to move fast [...] A case in point is the recent successes in reprogramming cells just by stressing the cells in culture" (referencing the now-discredited STAP-cell papers). The point here is that, in our current system, scarce public research funding is allocated before erroneous and/or fraudulent papers can be identified, investigated, and retracted. (btw, our resubmission application just received a great score and will hopefully be funded :), but we (and the patients who may eventually benefit from our work) still lost six months due to the initial rejection :(
(Score: 0, Offtopic) by BlackHole on Saturday July 05 2014, @11:09AM
A recent SN poll asked: "What is your favo(u)rite topic for articles?" http://soylentnews.org/pollBooth.pl?qid=28&display=full [soylentnews.org]
"Science" won with more than twice as many votes as the #2 choice. The problem is that SN is about the discussion, and hard science stories seem to generate little discussion.
At the same time, there has been community interest in more original content on SN (see this comment, for example: http://soylentnews.org/comments.pl?sid=2408&cid=56223 [soylentnews.org]), and the vision for SN includes: "bring[ing] us up to standards on par with ArsTechnica, Engadget, and other large names in this field": http://soylentnews.org/article.pl?sid=14/03/24/080215 [soylentnews.org]
So, in that spirit, this submission was a piece of original reporting on a hard science topic with a special discussion-promoting SN-flavo(u)r (and it was not co-submitted to any other sites which shall not be named). Of note, it was submitted at 10:58am on Wed., July 2, roughly the same time that the story was picked up by most major English-language news outlets:
http://www.nytimes.com/2014/07/03/business/stem-cell-research-papers-are-retracted.html?_r=0 [nytimes.com]
http://online.wsj.com/articles/science-journal-nature-retracts-stem-cell-research-studies-1404308718 [wsj.com]
http://www.bostonglobe.com/news/science/2014/07/02/controversial-stem-cell-creation-method-retracted/NiScjZhcPcaopw7ziGvWaN/story.html [bostonglobe.com]
I thought it would be cool if this was posted at the same time that it was hitting the other big sites, so we could link into our discussion from those sites, and possibly help bring some more people to SN. So, a question for the editors: Do you want submitters to preface their subject with "Breaking:" if they think it is time-sensitive or would that just be annoying?
Anyway, what do you think?
A) Good, want more.
B) tl;dr.
C) This comment was tl;dr.
D) Other (please specify).
(Score: 1, Offtopic) by tynin on Saturday July 05 2014, @12:08PM
I would say A) Good, want more. However as this topic is highly specific, and deeply seated in a profession I have only superficial knowledge on, so I suspect the number of comments for this will be limited. Still, I always enjoy delving into the comments on these to find those from someone within the field that has a gestalt viewpoint, and can articulate it well.
(Score: 1, Offtopic) by kebes on Saturday July 05 2014, @02:20PM
The advantages of such a summary are well known: readers want a way to know whether they should bother reading the detailed article (some readers can skip it because they are already experts and agree with the thesis; others can skip because they realize they aren't interested). It is also easier to read something when you already know what the author is trying to convince you of (some authors hate 'giving away the punchline', but for non-fiction it's usually best to lay out the conclusion right away).
The downside of an executive summary is that you will comments nitpicking things you said in the summary, even though you addressed them fully in the detailed section. But, I think this is okay, because: (1) it's inevitable (no matter what, some fraction of readers will skim and yet feel qualified to comment); (2) it's okay since misguided comments will get shot-down by others, and may spur useful discussion in any case.
(Score: 2) by janrinok on Saturday July 05 2014, @02:56PM
I am the editor responsible for releasing this story. Your story presented me with several problems - the type I am more than happy to have - and I would like to respond to your comments personally. Most stories reach us with a small summary and a link or two. Yours was a well written article, considerably longer than we usually receive and, although there were links, none of them summed up the article as well as your own work did. The links did what they were supposed to do - they supported what you had written. Additionally, you provided exactly what we had been hoping to receive - original and thought-provoking material. Furthermore, I feared that, had I released the same story during the week when there are more people to read it but when most of them have less time to spend digesting a long article, the story would not have received the same exposure or generated the same level of interest.
I tried to write a concise summary that would compel someone to want to continue to read what you had written - I was unable to do your article justice. There would also have been the problem then of where to place your article so that I could subsequently link to it in my summary. Should I put it in the first comment? After my summary? Eventually, I decided that your article would speak for itself.
You mentioned timeliness in your own comments, pointing out the the story 'broke' on the 2nd July. It was not, in my opinion, time critical to the degree that we should have interrupted other stories to publish yours and, as I have mentioned, it required handling differently to how we normally approach things. It was edited by me on 4 July which, in SN terms, is not at all unusual and placed in the next available release slot. It is perhaps unfortunate, because of the holiday celebrations in the US, that all stories over about 36 hours have been released by 3 editors 'across the pond' to enable our US colleagues to enjoy some time with their families and friends. We worked hard and were having to queue stories to go out over the period that we would normally be enjoying our own weekend and sleeping. It added, perhaps, another 8 hours to the release time. That is the explanation and I can only apologise if you consider that I did not treat your story in the manner it deserved. Another weekend and it might have been different, but even so perhaps not as much as you would have wished.
Finally, you asked for constructive criticism of your story. I can only suggest, if it is at all possible, to try to shave a few words off subsequent submissions but I cannot see how you could have done so in this instance. As I stated at the start, you provided an excellent example of original material presented at the right level for the target community, and included your own personal experiences to make the points stick. We would strongly encourage the submission of more material of this standard, not to replace the usual much shorter items that are more reliant on the material to which they link, but as stories that will engage many on this site and cause a high quality discussion to ensue.
Thank you for your submission - I am genuinely sorry if you feel I should have handled it differently.
(Score: 1) by BlackHole on Saturday July 05 2014, @04:36PM
First, to keep this comment on-topic for our exacting moderators, here is a great summary of the fallout that has occurred over the last couple of days since the retractions: http://retractionwatch.com/2014/07/05/weekend-reads-fallout-from-stap-stem-cell-retractions-confessed-hiv-vaccine-fraudster-pleads-not-guilty/#more-21331 [retractionwatch.com]
Second, to janrinok, thank you so much for the detailed (and very timely) response :) I was hoping that SN would like something of this nature, and it seems from your comment, and from the others so far that it does. Regarding the timeliness issue, I did not mean to suggest for one moment that I thought this submission should have been handled differently. Really, I was just wondering if you felt that there was anything more that _we_ the submitters could do to help _you_ the editors, say by pointing out the "breaking" nature of a story in some way. A comment on the recent "How to Get Better Stories onto Soylent" story suggested one possible method: http://soylentnews.org/comments.pl?sid=2408&cid=56943 [soylentnews.org] Again, the quality of the discussion is key, so I fully acknowledge that timeliness is less critical at SN than it would be elsewhere. However, it does seem that there could be some benefits to SN having its discussion at roughly the same time everyone else is. In the case of this story, for example, we could drop a comment with a link to our discussion in the stem-cell blog that is frequented by the experts in this field (http://www.ipscell.com), which could help draw some of them here. Just my $0.02.
(Score: 2) by janrinok on Saturday July 05 2014, @05:39PM
Noted - thank you.
(Score: 2) by c0lo on Sunday July 06 2014, @12:35AM
Let me try
<cynical mode='on'>
You know about how important stem cells are, right? Well (in case you lived under a rock last years, we'll tell you now) obtaining stem cells for research on personalized medicine have been quite challenging - the typical source, the umbilical cord, may not be available.
Ok, now hear this: two bastard - one from Kobe Japan, the other from Harvard US - claimed they manage to convince normal cells to become stem cells with inexpensive and simple procedures, and so they published two papers. Problems?
big problem - my lab didn't get the money last grants round in March, because of these bloody clowns that made it look simple.
We knew and we told them so: it is not that simple and one need money to look into it; but did they listen to us?
Well, yeah, now we are getting those money we asked (and maybe something extra) but we still wished they'd came our way earlier: its for the patients, you see?
(sure thing, it's stating-the-obvious that research is a risky business, many a-time we come back empty handed from our journeys. But... look at this shiny pendulum and think like this: if we would be successful, wouldn't it be in your interest that we succeed 6 month earlier?)
</cynical>
https://www.youtube.com/watch?v=aoFiw2jMy-0 https://soylentnews.org/~MichaelDavidCrawford
(Score: 1) by cubancigar11 on Saturday July 05 2014, @10:53PM
A. Good good extremely good. I felt I am at the right place reading this article.