Women and research fraud – the case of Haruko Obokata
In a previous post , I have discussed the large imbalance in the sexes amongst scientists who have committed research fraud. Major cases of research fraud involving women are rare. In this previous post I promised that my next post would be a case-study of research fraud involving a female perpetrator.
Choice of subject for this case-study
Haruko Obokata was the first female found guilty of research fraud that I investigated and a number of other features of this case make it an ideal case-study. The tainted research was published in the world’s premier science journal, Nature, and if true it would have had a huge impact upon research and potentially a huge impact upon the treatment of a number of incapacitating or life-limiting conditions. The wide publicity that the case attracted and the publication of the results of detailed institutional investigations into the affair meant that information about the case and its main characters was readily available.
I briefly considered the two other cases outlined below before settling upon Obokata as the subject of my case-study.
Kristin Roovers was a postdoctoral fellow at the University of Pennsylvania who in 2005 was discovered by an editor of the Journal of Clinical Investigation to have extensively manipulated an image (of a western blot) by one of the journal’s editors during a spot check. The journal notified the US federal Office of Research Integrity (ORI) and she was subsequently found to have extensively manipulated images in three published papers. Image fraud has become a major problem and a majority of accusations of research fraud dealt with by the ORI involve some form of image manipulation or falsification. The ORI banned Roovers from working for any US government agency for five years. She returned to Canada and in June 2008 she was dismissed from a position at the Ottawa Health Research Institute when they found out about her previous fraudulent activities at the University of Pennsylvania which she had not made known before her appointment.
Anna Ahimastos was an experienced postdoctoral researcher at the Baker IDI Heart and Diabetes Institute in Melbourne Australia. In 2015 she admitted fabricating clinical trial data which suggested that a drug widely used to treat high blood pressure and heart failure, ramipril, also improved the walking ability of patients with intermittent claudication (pain in the legs when walking due to peripheral artery disease). Two papers with Ahimastos as the first and corresponding author were retracted and the retraction notices make it clear that Ahimastos was responsible for the fabrication. Initial news reports said that other papers authored by Ahimastos were under investigation and seven papers by her have now been retracted. In 2010, Dr Ahimastos was awarded the Young Tall Poppy Science Award by the Australian Institute of Policy and Science.
Obokata was a Japanese stem cell scientist based at the RIKEN institute in Tokyo and in January 2014, Obokata was first author of two papers published in Nature Obokata et al 2014a and 2014b in which it was claimed that stem cells could be produced by subjecting ordinary skin cells to a mildly acidic environment. These papers have now both been retracted after an initial enquiry at the RIKEN institute in Japan found that she committed acts of research misconduct including image manipulation. A later statement from the RIKEN institute confirmed that her work could not be repeated and she resigned from the institute. As a result of this affair one of her research supervisors hanged himself in his laboratory in August 2014.
A reported major scientific advance attracts worldwide publicity
This case is a very recent example of what appears to be serious research misconduct affecting an apparent scientific breakthrough that would have had major practical benefits both for researchers and for the practical treatment of patients. The work reported by Obokata and her colleagues suggested that they had found a very simple, inexpensive and ethically non-controversial way of producing pluripotential stem cells from ordinary skin cells. The research was conducted in mice but there seemed every reason to hope and maybe even to expect that it would work in people.
If verified this procedure could have allowed researchers and clinicians to easily produce stem cells that were specific for an individual. These stem cells and any resulting differentiated tissue cells would have been recognised as “self” by the individual’s immune system and so would not have triggered the rejection process. Stem cells are undifferentiated or primitive cells that have the potential not only to reproduce themselves but also to differentiate into a variety of other cells. This raises the possibility that stem cells could be used to stimulate the regeneration of damaged tissue in a range of human diseases like liver cirrhosis, heart failure and blindness caused by macular degeneration.
There are different categories of stem cells that are classified according to the range of cell types that they can produce. Cells from newly formed embryos have the potential to develop into any cell type in the body and are called totipotential stems cells. Pluripotential stem cells have the capacity to develop into most other cell types and these are the ones that Obokata et al claimed to be able to simply produce from ordinary skin cells. Because of their versatility these are scientifically and medically extremely useful. Human pluripotential stem cells can currently be obtained from blood from the umbilical cord and they can also be harvested from aborted foetuses or even from human early stage embryos that have been created solely for that purpose. The use of aborted embryos and still more the use of embryos created solely to be a source of stem cells raise many ethical and emotional objections and dilemmas. Obokata et al’s findings seemed to make these ethically sensitive procedures unnecessary. Bone marrow is a rich source of haematopoietic stem cells which can develop into red and white blood cells. Bone marrow transplants that are used to treat radiation sickness and leukaemia rely on the transplantation of stem cells in the donor bone marrow. If a patient’s own bone marrow (or that of an identical twin) is used as the source of bone marrow then there is no need for anti-rejection drugs and this would also be true of stem cells produced from the person’s own skin cells as claimed in Obokata’s papers.
In 1962 Sir John Gurdon showed initially in frogs that stem cells can be also be produced from ordinary cells but this is a complex technique in which the nucleus of an ordinary (intestinal) cell is removed and transplanted into an egg cell from which the nucleus has been removed. It was shown much later in 2006 by Shinya Yamanaka and colleagues that introducing just a few genes from mouse embryo stem cells could convert ordinary cells back into pluripotential stem cells. In 2012 Gurdon and Yamanaka were jointly awarded the Nobel Prize for Physiology or Medicine:
“For the discovery that mature cells can be reprogrammed to become pluripotent”
This award highlights the scientific and medical significance of the claims made in the papers of Obokata and her colleagues.
The two Nature papers published on 30th January 2014 claimed that ordinary skin cells could be converted into pluripotential stem cells by simply exposing them to weak acid for 30min. They were thus claiming to have found a very simple way of producing essentially unlimited supplies of patient-specific stem cells for research use and ultimately for clinical treatments. Obokata et al called them STAP cells because they were produced by Stimulus-Triggered Acquisition of Pluripotency. This apparent breakthrough was quickly relayed to a worldwide audience by the scientific and general media e.g. a report with the headline Stem cell “major discovery” claimed appeared on the BBC web-site on 29th January 2014. Several senior British clinical researchers are quoted in this BBC article; the general tone of these responses is one of astonished excitement at the mouth-watering prospects for improved treatments:
“I thought – my God that’s a game changer! …..It looks too good to be true, but the number of experts who have reviewed and checked this. I’m sure that it is” Professor Chris Mason (UCL)
“A major scientific discovery……..It will make a fundamental change in how scientists perceive the interplay of environment and genome”. Dr Dusko Ilic (King’s College London)
“Remarkable”………”…and why does it not happen when we eat lemon or vinegar or drink cola?” Professor Robin Lovell-Badge (MRC)
Within a few weeks of the publication of these articles, questions started being asked about the veracity or accuracy of what had been reported. On 18th March 2014 an article in the news section of Nature indicated that just days after publication, the RIKEN institute had reported “serious errors” in the papers’ methodology and that questions were also being asked about the integrity of the first author’s doctoral thesis. Six problems with the papers had been noted; two had been dismissed as unintentional mistakes but four of them were regarded as serious and were still under investigation. This same issue suggested that 20 pages of Obokata’s PhD thesis had been plagiarised and an image from a commercial web-site used without attribution. There were also suggestions that Obokata might have contacted a professor at Waseda University in Japan about the possibility of retracting her thesis.
On April 1st 2014, the results of a formal investigation by a RIKEN institute panel were released and a press conference was given. This report concluded that fraudulent actions were apparently carried out to deliver the STAP results. Obokata was held to be solely responsible for the misconduct and that misconduct was deemed to be deliberate. At this news conference it was revealed that Obokata had admitted to copying and pasting images from other sources as she “wanted to make results of the team’s research look beautiful”. The committee reported that they could only find two laboratory note-books kept by Obokata over a three year period and that the information in them was fragmentary and not dated. The other three co-authors from the RIKEN were deemed to be not involved in any wrongdoing but they were criticised “for submitting articles without confirming the data”. It is acknowledged that discovering problems with data is not easy unless it is looked at with sceptical eyes i.e. unless you consider the possibility that your colleague is deliberately trying to deceive you. In a statement issued in immediate response to the report, Obokata admitted to making some errors but denied fabrication and acting with any malicious intent.
It was reported on April 7th 2014 that Dr Obokata had been hospitalised because her “mental and physical condition is unstable” just before she was due to speak at a news conference of her own. On July 3rd 2014 the two papers were both formally retracted from Nature by the original authors. The same retraction notice is used for both papers and it acknowledges the critical errors identified in the RIKEN report and makes it clear that some of these errors had been categorized as misconduct. They list a further 5 errors that were not listed in the RIKEN report. They apologize and say that the errors impair the credibility of the study but they are unable confirm whether or not the STAP phenomenon is real and that this is still being investigated.
News of the retraction was reported on the BBC web-site on 2nd July 2014. It is interesting to read the comments of the three experts who were interviewed by the BBC when it reported the original “breakthrough”:
Professor Chris Mason who expressed some disbelief in the earlier report as noted above – “If you’re a reviewer you can only review the material you are given. You have to take it on trust. You’re not a detective looking for fraud.”
Dr Dusko Ilic – “The technology sounded too good to be true., though I still find it fascinating how a 30-year-old scientist could pass scrutiny of her co-workers and multiple reviewers in Nature with a complete fabrication.”
Professor Robin Lovell-Badge – “This story illustrates how the stem cell field can rapidly detect bad science and reject it”…”…..it was hyped far beyond reality, by some of the authors and perhaps their willing victims, the media.”
In relation to the last quote, it is unfortunately not always the case that bad science is rapidly detected once it is subject to scrutiny and potential replication by other scientists. Some scientists publish fabricated data for decades before being found out and the most common way in which they are found out is by the actions of a whistle-blower. Wolfgang Stoebe and his colleagues (2012) who analysed the ways in which 40 notorious cases of scientific fraud had been unmasked went so far as to entitle their article “Scientific misconduct and the myth of self-correction in science”.
What has happened to Obokata?
In March 2015 Obokata refunded 600,000Yen (about £4500) to the Riken to cover the costs of publication of the two retracted STAP papers which pales into insignificance in the light of the estimated 145million Yen (about £1.1million) spent by the Institute on the original study, the subsequent investigation and attempts to repeat the work. Waseda University announced in November 2015 that it had stripped Ms Obokata of her PhD. Obokata has apparently written a book in which she tells her side of the story and puts much of the blame for the affair on one of her ex-colleagues and co-authors Dr Wakayama. Obokata still seems convinced that she has made a real discovery. She has set up a web-site where on the home page she apologises for her past careless mistakes and tells of her problems with depression brought on by her involvement in the affair. She also gives her protocol for making STAP cells “in the hopes that another scientist will be able to bring them to reality”. Another of Obokata’s papers was retracted in early 2016 . This paper was published in 2011 when she was still affiliated with Waseda University in Tokyo. The retraction of this paper from a different institution, with different co-authors and different project seems to suggest a pattern of research misconduct.
Sad footnote to the STAP affair
There is a very sad footnote to this story; in August of 2014 it was reported that Professor Yoshiki Sasai was found dead in his laboratory at the RIKEN after having apparently committed suicide by hanging himself. Professor Sasai was exonerated from any misconduct in the RIKEN report into the affair but was criticised for his supervision of Dr Obokata and for not spotting inconsistencies in the publications. The BBC report suggests that Professor Sasai was deeply ashamed of his part in this affair. His suicide note made it clear that his association with this case and the ensuing press harassment were the reason for his suicide.
I have not linked to references for every recent development in the continuing STAP story but an archive of articles about Obokata affair from The Japan Times gives a chronological account of the main and continuing developments.