Stem cell debacle déjà vu

Michael Cook
8 Apr 2014
Reproduced with Permission

Once again, a major advance in stem cell science has been tainted by allegations of fraud. A leading research centre in Japan, the RIKEN Institute, has apologised for "research misconduct" by a young scientist who had found an astonishing new method for producing pluripotent stem cells.

The researcher was a 30-year-old woman, Haruko Obokata, and her paper, published in January in Nature, the world's leading science journal, seemed to be an astonishing breakthrough. When ordinary skin cells were placed under stress, somehow they reverted to a pluripotent state - they could become any cell in the body. In fact, she believed that they might even become totipotent, that is, they could even form the placenta which nourishes an embryo. It was so simple that it seemed almost too good to be true.

The paper described two methods. Obokata's method involved chemical stress by bathing the cells in an acid solution. The method used by one of her American co-authors, Charles A. Vacanti, of Harvard Medical School, involved physical stress by forcing the cells through a tiny pipette.

A straightforward technique for producing pluripotent stem cells is the Holy Grail of modern biology. Made from a patient's own cells, they will not be rejected. Success could usher in a whole new era of medicine. Embryonic stem cells - the first to be studied -- are pluripotent, but they are hard to control and are ethically problematic. Another Japanese scientist, Shinya Yamanaka, won the Nobel Prize for discovering in 2007 that even ordinary cells can become pluripotent, but his method is complex.

Unfortunately, Obokata's "stimulus-triggered activation of pluripotency" (STAP) cells were too good to be true. The news was so exciting that scientists rushed to their workbenches and to replicate her results. All attempts failed. Then troubling problems emerged, reviving painful memories of the notorious Hwang Woo-suk and the fraudulent stem cell papers that he had published to great fanfare in 2005 in the journal Science.

Haruko Obokata now stands accused of misusing and manipulating images which she used to document the creation of her STAP cells. She admits that there were mistakes but denies the charges of misconduct. She still insists that the method does work. But from being the pin-up girl of Japanese science she is being reviled as an unethical adventurer who has brought shame on her colleagues. According to the Asahi Shimbun, a Japanese newspaper, Waseda University now also suspects that some portions of her 2011 PhD thesis may have been plagiarised.

A six-member committee set up by the RIKEN Institute was quickly set up to investigate six errors in the paper. Four were found to be innocent mistakes but two were branded "misconduct". "Dr Obokata's actions and sloppy data management lead us to the conclusion that she sorely lacks, not only a sense of research ethics, but also integrity and humility as a scientific researcher," was its brutal conclusion. Nature is conducting its own investigation.

The president of RIKEN, Nobel laureate Ryoji Noyori, issued an apology both for Obokata's behaviour and for the carelessness of her co-authors. If the misconduct is confirmed after the appeals process, he said that the paper should be retracted and that the authors would be disciplined. RIKEN is going to conduct a "rigorous scientific re-evaluation" of STAP which will take about a year to complete.

The flawed research could still be vindicated or at least it could give insights into pluripotency. Harvard's Dr Vacanti maintains that his method works. "While the investigation determined there were errors and poor judgment in the development of the manuscript, I do not believe that these errors affect the scientific content or the conclusions," he told the Boston Globe. A Hong Kong researcher said last week that Vacanti's protocol seemed to work.

So the story is not over yet. But, as MIT stem cell expert Rudolf Jaenisch told the Globe, "It's embarrassing; it's not good for the field."

Over the past 20 years, it would be hard to name a patch of science which has involved more medical potential, scientific excitement, ethical controversy and research misconduct than stem cells. So how could a 30-year-old junior researcher have reported an incredible breakthrough without incredibly rigorous scrutiny?

There are several areas that scientists ought to look at.

Deficient education in research ethics. In his apology, Dr Noyori promised to "fundamentally rethink our provision of ethical education". Apparently young researchers are not being steeped in a culture of scientific rectitude. The director of RIKEN's Center for Developmental Biology, Masatoshi Takeichi, admitted that "our systems for supporting the young scientists we have appointed into leadership positions were not effective in this case". And the chairman of RIKEN's investigating committee, Shunsuke Ishii, declared that, "I have never experienced this kind of carelessness" among junior researchers.

Pressure and competition. In the wake of the story, New Scientist conducted its own survey of 1000 stem cell scientists, of whom 110 replied. The respondents painted a picture of a highly competitive environment in which people were sorely tempted to take short-cuts. "There is a tremendous pressure to publish, in order to receive funding. Shortcuts are, therefore, not unusual," said one researcher. "I know of numerous instances where fellows with, at times, the knowledge of their mentors, have published falsified data," said another.

The peer review process. Headlines that "peer review is broken" are exaggerated, but its status as a warranty for the reliability of research results - at least in the eyes of the public - must be questioned. Scientists agree. "The review process has become a playground of promoting personal opinions, rather than evaluating the actual science," one researcher complained in the New Scientist survey. In 2011 the UK Parliament published a thought-provoking report on peer review which stressed that it is an important tool but not a guarantee of truthfulness. In fact, Richard Horton, the editor of The Lancet, a leading medical journal, has written, "We portray peer review to the public as a quasi-sacred process that helps to make science our most objective truth teller. But we know that the system of peer review is biased, unjust, unaccountable, incomplete, easily fixed, often insulting, usually ignorant, occasionally foolish, and frequently wrong."

Reckless editorial practices in leading journals. Stem cell biology has been plagued by fraud and error for years. So amazing claims ought to be subjected to an amazing level of scrutiny. Given that critics found holes in the paper by Obokata and her colleagues so quickly, it's dismaying that Nature allowed itself to be stung. It's hard to escape the suspicion that science journals, just like other media, are so eager to scoop the competition that they sometimes lower their guard. As one publisher told the UK Parliament's inquiry, "If you have a very conservative editorial board, the journal will suffer. It is a market; the more proactive entrepreneurial editorial teams will win out and build better, more successful journals. It is a very dynamic market. A conservative editorial board wouldn't last long."

The magical spell of stem cell alchemy. "Stemness", or the ability of cells to develop into an integrated organism, is close to the secret of life itself. In the minds of many stem cell researchers, more is at work than curiosity; their ultimate goal is to dominate and control what it means to be human, perhaps to escape our mortality. "The Promethean prospect of eternal regeneration awaits us, while time's vulture looks on," wrote one scientist. With so much at stake, researchers and editors are easily tempted to throw caution to the winds.

The latest instalment of the stem cell saga need not tarnish the credibility of the scientific method. Only if an experiment can be replicated will a hypothesis be accepted by the scientific community. And in this case, suspicions arose precisely because no one could replicate it. This shows that "the scientific process of checks and balances actually works," as Jonathan Garlick, a stem-cell expert at the Tufts University, told the Boston Globe.

However, non-scientists could be forgiven for feeling a bit less confident in the credibility of stem cell science after seeing its dirty linen hung out to dry.