Barely 30 years old and already leading her own laboratory at the RIKEN Center for Developmental Biology in Kobe, Japan, Haruko Obokata shot to scientific stardom in January 2014 when she and her colleagues published two breakthrough papers in Nature, one of the world’s top science journals, demonstrating a surprisingly simple way of turning ordinary body cells into something very much like embryonic stem cells.
All Obokata did was drop the mouse cells into a weak bath of citric acid for 1/2 hour to wash away their developmental past, and the cells emerged like cellular infants, able to multiply abundantly and grow into different types of body cells – a power known as pluripotency.
Published online January 29 (in print January 30), with an almost supernatural title, “Stimulus-triggered fate conversion of somatic cells into pluripotency”, Obokata phrased the scientific question as follows:
“In the canalization view of Waddington’s epigenetic landscape, fates of somatic cells are progressively determined as cellular differentiation proceeds, like going downhill. It is generally believed that reversal of differentiated status requires artificial physical or genetic manipulation of nuclear function such as nuclear transfer or the introduction of multiple transcription factors. Here we investigated the question of whether somatic cells can undergo nuclear reprogramming simply in response to external triggers without direct nuclear manipulation. This type of situation is known to occur in plants—drastic environmental changes can convert mature somatic cells (for example, dissociated carrot cells) into immature blastema cells, from which a whole plant structure, including stalks and roots, develops in the presence of auxins. A challenging question is whether animal somatic cells have a similar potential that emerges under special conditions”.
(“Stimulus-triggered fate conversion of somatic cells into pluripotency”, by Haruko Obokata, Teruhiko Wakayama, Yoshiki Sasai, Koji Kojima, Martin P. Vacanti, Hitoshi Niwa, Masayuki Yamato & Charles A. Vacanti, online January 29, in print January 30, 2014, Pages 641-647, Volume 505, Nature)
The answer was yes, cells could become supernatural in a sense – pluripotent to be accurate – when given unusual stimulus:
“Collectively, these findings show that the differentiation state of a committed somatic cell lineage can be converted into a state of pluripotency by strong stimuli given externally. Hereafter, we refer to the fate conversion from somatic cells into pluripotent cells by strong external stimuli such as low pH as ‘stimulus-triggered acquisition of pluripotency’ (STAP) and the resultant cells as STAP cells. …
…
This study has revealed that somatic cells latently possess a surprising plasticity. This dynamic plasticity—the ability to become pluripotent cells—emerges when cells are transiently exposed to strong stimuli that they would not normally experience in their living environments.”
(Haruko Obokata, Teruhiko Wakayama, Yoshiki Sasai, Koji Kojima, Martin P. Vacanti, Hitoshi Niwa, Masayuki Yamato & Charles A. Vacanti, January 29, 2014, Nature)
It would be a faster and easier way to reprogram cells, much less likely to damage them or make them cancerous, than the genetic manipulation pioneered in 2006 by another Japanese scientist, Shinya Yamanaka, who was awarded a Nobel Prize for it.
It was Haruko Obokata’s turn to become an instant media sensation. As Britain’s The Guardian newspaper reports, the media wondered when she would be given a Nobel Prize, curiously finding out and reporting more about her: she painted her laboratory pink and yellow, sticking cartoons everywhere; at work she wore a kappogi – a cooking apron – her grandmother had given her; and in her leisure time she fed her pet turtle, took baths, shopped and went on dates.
(“What pushes scientists to lie? The disturbing but familiar story of Haruko Obokata”, by John Rasko and Carl Power, February 18, 2015, The Guardian)
But within days of the Nature papers’ publication, disturbing allegations emerged in science blogs and on Twitter: some of the papers’ images looked doctored, and chunks of her text were lifted from other papers.
The RIKEN research institute, of which the RIKEN Center for Developmental Biology is a part, conducted an investigation in February and March, confirming there was at least some research misconduct; in the Nature paper quoted above, some of the text may have been copied from a paper by other researchers, and some images were copied from Obokata’s doctoral thesis on a very different subject:
“The Paper 1 Methods section in question consisted of 17 lines copied from the paper by Guo J., et al., without citing the source. This is absolutely not allowed, and this is something that is strictly taught at research institutions and universities. Appropriate quotation and citing of all sources is a matter of course for all researchers. Dr. Obokata’s explanation that she did not possess a copy of the Guo paper, did not remember where she had copied the text from, and that it was simply oversight, is highly questionable.
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On February 20, the committee was presented by Drs. Sasai and Obokata with a request for correction and with supporting documentation. They brought up two points: One was that some of the immunofluorescence images of in vitro differentiated cells and teratoma … actually were derived from STAP cells created out of bone marrow hematopoietic cells but not spleen hematopoietic cells; and the second point was that they were thinking of replacing the incorrect images. The supporting documentation they provided consisted of these image files. Dr. Obokata explained that she mistook the images because both the spleen and bone marrow hematopoietic cell samples had the same “hemato” (hematopoietic) label.
Later, it was discovered that the images in Paper 1 very closely resembled images she had used in her doctoral dissertation for Waseda University. …
Paper 1 presents STAP cells created by subjecting the spleen cells of a 1-week old mouse to an acid bath, while in Dr. Obokata’s doctoral thesis she describes acquiring “sphere” cells (sphere-shaped cell clusters) by forcing the bone marrow cells of a 3 to 4-week old mouse through a narrow pipette in a process of applying mechanical stress to the cells. The two experimental conditions are quite different. …
… It is hard to believe that Dr. Obokata was unaware of the different experiment conditions when she prepared the images. Also, there are traces around the images in Paper 1 that suggest they were cut out of an identical arrangement of images in the doctoral thesis. This makes it very difficult to accept Dr. Obokata’s assertion that she cut and pasted the images from the thesis to Paper 1 without realizing that they represented completely different experimental procedures. …”
(“Report on STAP Cell Research Paper Investigation”, by Research Paper Investigative Committee, March 31, 2014, RIKEN)
Also in March, co-author Teruhiko Wakayama of Yamanashi University, Japan, a cloning expert, reviewed data of the tests he had conducted for the Nature papers, and found a mismatch between a line of mouse reported in the Nature papers and the lines for which experiments were actually done by Obokata.
The Nature paper had reported the success of converting mature cells to STAP cells for 3 strains of mice:
“We tested the following three different genetic backgrounds of mice for STAP stem-cell establishment from STAP cell clusters, and observed reproducible data of establishment: C57BL/6 carrying Oct4-gfp (29 of 29), 129/Sv carrying Rosa26-gfp (2 of 2) and 129/Sv × C57BL/6 carrying cag-gfp (12 of 16).”
(Haruko Obokata, Teruhiko Wakayama, Yoshiki Sasai, Koji Kojima, Martin P. Vacanti, Hitoshi Niwa, Masayuki Yamato & Charles A. Vacanti, January 29, 2014, Nature)
Wakayama’s test data revealed that results published for the mouse strain 129 had actually been from the other 2 strains:
“On 25 March, Wakayama told Nature News that his preliminary analysis of the STAP cell lines on which Obokata worked alone showed that they were genetically distinct from the ‘129 strain’ of mouse said to have been used to derive them. Instead, he says, they came from two other strains, known as B6 and 129B6F1 hybrid. “This discovery was a shock,” says Wakayama.”
(“Mismatch alleged in acid-bath stem-cell experiment”, by David Cyranoski, March 27, 2014, Nature)
RIKEN’s investigation findings of “research misconduct” were announced on April 1. Haruko Obokata’s short-lived scientific stardom was now a scandal, and public shaming of her followed. On live television, Obokata tearfully apologized for her mistakes, but calling them “benevolent”:
“The news media, having built her up, was more than happy to tear her down. A tearful Obokata faced a gruelling press conference, broadcast live on TV. Standing amongst a battery of microphones, strobe-lit with camera flashes, she apologised, bowed, answered questions, bowed, apologised some more, and bowed.
Obokata apologised for many things that day. She apologised for “insufficient efforts, ill-preparedness and unskilfulness”, for errors of methodology and sloppy data management. They were all, she said, “benevolent mistakes”, due to her youth and inexperience.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
Obokata insisted that her STAP cells exist, that she had created them “over 200 times”, and would be willing to go anywhere to reproduced them with other scientists:
“This is the first statement in public by Dr. Obokata since the problems with the articles emerged in February. Her lawyers said she was hospitalized Monday because her “mental and physical condition” was unstable.
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“The STAP phenomenon has been confirmed on many occasions. Since I encountered the STAP phenomenon, I’ve dedicated myself to experiments with a sense of mission to explore the phenomenon. I sincerely hope that the STAP phenomenon won’t be denied due to presentational mistakes, and that scientific research on it continues.”
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Dr. Obokata says she has created STAP cells over 200 times.
“If anyone wants to watch me create STAP cells, I’ll go anywhere” to work with others to replicate the data, Dr. Obokata says.”
(“Live: Obokata Speaks About Stem Cell Research Probe”, April 9, 2014, The Wall Street Journal)
But despite her method’s simplicity, other scientists were unable to reproduce the results. One by one, Obokata’s co-authors expressed doubt and asked to retract the papers, and in June so agreed Obokata. Online on July 2 (in print July 3), 2014, the two Nature papers were retracted.
At RIKEN, Haruko Obokata’s supervisor was co-author Yoshiki Sasai, a deputy director of the RIKEN Center for Developmental Biology. Sasai stood by Obokata as indicated in the investigation report quoted earlier, but the investigation brought him tremendous mental stress that saw him hospitalized for nearly a month in March; then in early August 2014, Sasai was found dead at the Center, hanged from a stairway handrail, to the end still determined to get Obokata to “reproduce STAP cells”:
“Sasai, 52, deputy director of the Riken Center for Developmental Biology in Kobe and an adviser to scandal-hit Riken scientist Haruko Obokata, 30, was confirmed dead after being found hanged from a stairway handrail at the center, the police said.
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Satoru Kagaya, head of public relations at Riken, said at a news conference that at least one apparent suicide note was found on the desk used by Sasai’s secretary, as well as three other notes left near the body.
One of the notes, addressed to Obokata, read, “Be sure to reproduce STAP cells,” sources revealed later in the day.
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Sasai supervised Obokata’s writing. A Riken investigative committee has said Sasai bore heavy responsibility for not confirming data for the STAP study and for Obokata’s misconduct.
Obokata is now engaged in experiments at Riken to verify the findings of the research.
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Retractions of papers in major scientific journals are rare, and the scandal was a major embarrassment to Japan’s scientific research.”
(“STAP paper co-author Sasai commits suicide”, August 5, 2014, The Japan Times)
A major embarrassment to Japan’s scientific research led to the suicide of the man who supervised the writing – but not the end of the saga as the woman at the center of the research work continued to insist that STAP cells exist.
Finally in December 2014, after months working with a research team assembled by RIKEN to assist her, Haruko Obokata conceded that she could not produce STAP cells under the stricter conditions and was “extremely perplexed”, and resigned from her job:
“Obokata submitted her letter of resignation to Riken, dated Dec. 21, on Dec. 15, the institute said. Riken plans to accept her resignation.
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“I regret that I had to conduct my work (for verification tests) within limitations that were much greater than I had anticipated and therefore was not able to do the examination to the fullest,” Obokata, 31, said in a statement issued through Riken. “But, under the given circumstances, I tackled the work to the limit of my soul. Now, I am exhausted. I am extremely perplexed by such a result (of my verification tests).””
(“Obokata resigns as Riken reports her failure to re-create STAP cells”, December 19, 2014, The Asahi Shimbun)
RIKEN then released its second investigation report. Its genetic analysis showed that Obokata’s so-called STAP cells had been derived from regular embryonic stem cells, and so there was no other choice but to conclude that the mix-up with embryonic stem cells “refutes all of the main conclusions of the two papers”, and that the contamination – involving 3 different types of embryonic stem cells – was unlikely accidental, although persons responsible could not be pinpointed:
“Investigation of samples from the Obokata and Wakayama laboratories
The following conclusions were reached based on analyses of SNP distribution, specific deletions, inserted GFP gene, and other factors.
a) The three STAP stem cells, FLS, GLS, and AC129, were actually derived from the three ES cells FES1, GOF-ES, and 129B6F1-ES1, respectively.
b) The FI stem cell CTS was actually derived from an ES cell FES1.
c) It is highly probable that the chimera mice claimed to be developed from STAP cells were actually developed from ES cells FES1.
d) It is highly probable that the teratomas claimed to be developed from STAP cells were actually developed from ES cells FES1.
e) The STAP cell samples given to GRAS for Chip-seq analysis were actually 129B6F1-ES1 cells.
Opinion
It is unlikely that there was accidental contamination by three different ES cells, and it is suspected that the contamination may have occurred artificially. However, given the difficulty of identifying who might have contaminated the cultures, it is not possible to conclusively determine that it was artificial contamination.”
(“Summary Report on STAP Cell Research Paper Investigation II”, RIKEN)
Clearly there had been persistent, even systemic, contamination with embryonic stem cells in Obokata’s over 200 experiments successfully producing the STAP cells, which under the verification conditions imposed by the RIKEN investigation she was unable to produce even once.
In its recent comprehensive reporting of the Obokata scandal – a feature article dated February 18, 2015, written by John Rasko and Carl Power – The Guardian has solemnly informed the public that the phenomena of published scientific research results incapable of verification by independent reproduction, i.e., replication, have been widespread and could even be in the majority.
Firstly, scientists would rather produce new results than reproducing others’ work:
“But before we start to congratulate ourselves on the ever-upwards path of science, we should bear in mind that most experiments are never reproduced. There are simply too many of them. Besides which, researchers often don’t have much interest in repeating the work of others. Scientists may be truth-seekers, but they generally prefer new truths. They want to be the first to make a discovery. That’s where all the glory lies; that’s how to get a name for yourself, attract more funding and advance your career. Confirming – or failing to confirm – someone else’s discovery is unlikely to get you very far. It’s unlikely to even get you into print since science journals tend to favour novel research.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
Secondly, those who find it important to verify others’ published results, such as some pharmaceutical industry researchers do, may find to their horror that even most of the so-called “landmark experiments” in their field can not be reproduced:
“Not only are most experiments not reproduced, most are probably not reproducible. This statement will shock only those who have never worked in a wet lab. Those who have will already suspect as much.
A few years ago, Glenn Begley put this suspicion to the test. As head of cancer research for pharmaceutical giant Amgen, he attempted to repeat 53 landmark experiments in that field, important work published in some of the world’s top science journals. To his horror, he and his team managed to confirm only six of them. That’s a meagre 11%. Researchers at Bayer set up a similar trial and were similarly depressed by the results. Out of 67 published studies into the therapeutic potential of various drugs (mostly for the treatment of cancer), they were able to reproduce less than a quarter.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
And thirdly, if the public haven’t known about it, researchers know “in their heart of hearts” that for various reasons, fraud being one, “reproducibility is the exception rather than the rule”:
“The Amgen and Bayer studies were too small to tell us how bad the problem really is, but they do illustrate something that biomedical researchers already know in their heart of hearts: reproducibility is the exception rather than the rule. There are probably many reasons for this. Apart from outright fraud, there are all those “benevolent mistakes” that scientists make more or less unwittingly: poor experiment design, sloppy data management, bias in the interpretation of facts and inadequate communication of results and methods. Then, of course, there is the devilish complexity of reality itself, which withholds more than it reveals to the prying eyes of science.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
But how do The Guardian article’s writers know what biomedical researchers know in their “heart of hearts”? Researchers certainly would not say anything like that to contradict the credibility of their own work.
These two writers appear to be medical and academic insiders: John Rasko is a professor at Sydney Medical School, and leads both the Cell and Molecular Therapies at Royal Prince Alfred Hospital and the Gene and Stem Cell Therapy Group at the Centenary Institute, University of Sydney, while Carl Power is a researcher and editorial coordinator at the Centenary Institute and University of Sydney.
Still, the incredible speed at which Haruko Obokata shot to scientific stardom, and the same amazing speed at which it unravelled – I note that it was quite unlike the pet turtle she kept at home – made her case a glaring one. It has brought her to the rank of notorious fraudsters in biomedical research history, according to Rasko and Power who refer to two other such personalities in history.
One of the two was South Korean scientist Hwang Woo Suk:
“In 2004, this charismatic, square-jawed scientist from Seoul National University became the pride of South Korea when he claimed he had created the first human embryonic stem cells by means of cloning. His smiling face was on the front page of newspapers worldwide, and Koreapost issued a commemorative stamp in his honour. Since cloning is a form of cellular reprogramming, Hwang’s work generated the same kind of excitement as Obokata’s. Both promised the holy grail of regenerative medicine: patient-specific stem cells capable of repairing any damaged tissue or organ in the body. But an investigation by Hwang’s university proved his results were as bogus as Obokata’s. None of his 11 “cloned” stem cells matched their supposed donors.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
In fact, the Hwang Woo Suk scandal loomed large in the minds of other scientists, like Shinya Yamanaka of Japan’s Kyoto University who was pioneering reprogramming mature cells into stem cells, and who felt it prudent to repeat the experiments as he later recalled in his 2012 autobiography for the Nobel Prize in Physiology or Medicine:
“In 2005, we succeeded in generating ES-like cells with the four factors, and I named the resulting cells “induced pluripotent stem cells or iPS cells.” I was anxious about whether they were really the pluripotent cells that we were looking for because the method used to generate the iPS cells was much simpler than I had expected. In addition, after hearing about a big scandal involving a Korean researcher who falsely reported the successful generation of human ES cells by cloning at around that time, I thought we should repeat our experiments to make sure of the result so that no researcher could cast doubt on our findings.”
(“Shinya Yamanaka – Biographical”, 2012, Nobelprize.org)
But even Yamanaka noted that competition was fierce and publishing papers “as quickly as possible” was critical:
“In 2006, we published a paper in Cell on the successful generation of mouse iPS cells using the four factors. Some researchers seemed surprised at the finding that only four genes are needed to reprogram somatic cells into the embryonic state. But in the following months, a few labs at MIT and Harvard demonstrated that they had been able to produce mouse iPS cells using our protocol, and an increasing number of researchers have since started working on the new technology.
Right after we generated mouse iPS cells, my team began to work on reprogramming human somatic cells. In November 2007, we reported the generation of human iPS cells from human fibroblasts by introducing the same quartet of genes via viral vectors. On the same day, Thomson’s lab announced in Science that they had also succeeded in making human iPS cells using a different set of four factors … I remember that I worked day and night to publish our paper as quickly as possible after I heard a rumor in the summer that a U.S. group had submitted an article on the successful generation of human iPS cells.”
(2012, Nobelprize.org)
The Hwang Woo Suk saga, a recent development of which I cited on a Facebook community page, “Science, Education Progress, and New Millennium Bugs”, was intriguing not only in his fast rise to stardom and fall – like Obokata but in a much more brilliant fashion – but also in his apparent scientific research ability and resilience, which have brought him recovery from criminal fraud conviction to founding a research company that leads the world in the nascent field of commercial dog cloning, and launching a major joint project with a company in China sponsored by the Chinese government.
(Facebook posting, March 3, 2015, Science, Education Progress, and New Millennium Bugs)
So I wouldn’t be surprised if her present disgrace isn’t the last the world hear from, or about, Haruko Obokata, either.
The reported prevalence of published scientific experiments that are actually irreproducible, and thus suspect in the forms presented, if indeed known in the hearts of researchers can make it more likely for the ambitious among them to take bolder steps, catapulting themselves on the back of falsehood to a higher plateau for greater fame and power. But contrary to the rejuvenated pluripotent trajectories of the fairy-tale STAP cells, ethically such is fraud on a downhill path, as John Rasko and Carl Power remarked:
“While some stem cell researchers may indeed possess that “vaulting ambition” characteristic of Shakespeare’s tragic heroes, from what we have read and witnessed firsthand, scientific fraud rarely springs from a heroic, all-or-nothing decision. It is more like a bad habit you acquire, a gentle slope you descend without realising how deep you’re getting.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
An acquired habit may likely have been peer influenced. The reality that some of the notorious frauds in science history took a long time to be uncovered, or settled, may well have given some of the ambitious researchers of the modern generation a sense of rightfulness, namely that they, too, deserve greater fame and power, based on scientific half-truth at best, than their own solid accomplishments could bring them.
The other example of a notorious fraud in biomedical research history discussed by John Rasko and Carl Power was one that occurred a century ago, that pioneered the right methodology leading to modern cell science, but with overly optimistic claims that were untrue but were not debunked during the lifetime of the perpetrator – Nobel Prize winner Alexis Carrel:
“Over the past century, the “wet lab” (where scientists carry out biological experiments) has seen more than its share of scandal. Indeed, modern cell science emerged from a terrible debacle.
The man in the middle of it all was Alexis Carrel, a brilliant and rather dapper Frenchman working at the Rockefeller Institute in New York. Carrel discovered that, if you remove some cells from the body, sit them in a nutritious broth and handle them correctly, they can not only survive, but thrive and multiply. Also, if you take some cells from one culture, you can start a new one and, with that, a third, and so on. The importance of this technique – know as cell “passaging” – can’t be overstated. With it, Carrel literally opened a new era in cell research. Unfortunately, he did so with an experiment that, while earning him international superstardom, proved to be a complete and utter train wreck.
On 17 January 1912, Carrel removed a chick embryo from its egg and cut out a small fragment of its still-beating heart with the aim of keeping it alive as long as possible. He had hardly begun this experiment when he announced to the world that his chicken heart culture was immortal, that immortality belonged potentially to all cells, and that death was only the consequence of how cells are organised in the body. In other words, the secret of eternal life is within us all, an attribute of our basic biological building blocks. It captured the public’s imagination and was soon accepted by the scientific community.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
I note that Alexis Carrel’s grandiosely optimistic claim of potentially eternal life for a cell culture, published in May 1912 a few months after the start of his experiment, bore remarkable resemblance to the kind of claim made by Haruko Obokata and her co-authors in January 2014 that mature cells could be bathed to re-emerge as youthful stem cells. Carrel wrote:
“The purpose of the experiments described in this article was to determine the conditions under which the active life of a tissue outside of the organism could be prolonged indefinitely. It might be supposed that senility and death of the cultures, instead of being necessary, resulted merely from preventable occurrences; such as accumulation of catabolic substances and exhaustion of the medium. The suppression of these causes should bring about the regeneration of old cultures and prevent their death. It is even conceivable that the length of the life of a tissue outside of the organism could exceed greatly its normal duration in the body, because elemental death might be postponed indefinitely by a proper artificial nutrition.
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Of sixteen cultures of heart and blood-vessels made on January 17, 1912, five were still very active in March, 1912, and of the five active ones, two heart cultures previously described grew slowly, but pulsated, and another heart culture, which pulsated from time to time, produced a large growth of ameboid and fixed cells which covered an extensive area of the medium. …
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These facts show that experiments made with these or with more perfect techniques and followed over long periods of time may lead to the solution of the problem of permanent life of tissues in vitro, and give important information on the characters acquired by tissues liberated from the control of the organism from which they were derived.”
(“On the Permanent Life of Tissues Outside of the Organism”, Alexis Carrel, May 1912, Pages 516-528, Number 5, Volume 15, The Journal of Experimental Medicine)
I should comment that the world must have been so excited by Alexis Carrel’s good news of eternal life in the horizon, as the Nobel Prize in Physiology or Medicine was awarded to Carrel, for his earlier work as a pioneer of organ preservation and transplant, by the end of 1912 – exactly a century before its awarding to Shinya Yamanaka:
“The new ways he has opened up of protecting threatened tissues and of replacing damaged or harmful tissue with tissue that is healthy and alive are so remarkable and the results obtained so marvellous that the Caroline Institute considers itself to be acting in complete conformity with the fundamental purpose of the great benefactor’s will in awarding Carrel the greatest distinction of present-day medicine, the Nobel Prize. ”
(“Award Ceremony Speech”, J. Akerman, December 10, 1912, Nobel Committee for Physiology or Medicine of the Royal Caroline Institute)
Carrel’s optimistic claim of potential permanent life seemed to bear out as one of those chicken cell cultures continued to live and grow for 34 years. Other scientists tried in vain, none could reproduce Carrel’s results, but they dared not question his scientific statue:
“Carrel and his assistants kept – or claimed they had kept – that culture alive for 34 years, which is five times longer than the average chicken. For many years, around 17 January, journalists wrote birthday stories on the chicken heart and wondered how large it would have grown had Carrel nurtured every one of its ever-multiplying cells. (According to calculations, it swiftly dwarfed the Earth and filled up the entire solar system.)
The problem was, no one else could keep a cell culture alive indefinitely. Lab after lab tried and failed, decade after decade. Because Carrel was a giant in the field of cell research and a Nobel Prize winner, few dared to doubt him. Scientists blamed themselves when their cells died. They assumed that they lacked the master’s skill, that his lab had higher standards than they could reach, that they had somehow exposed their cells to infection or failed to keep them properly nourished. …”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
Long after Carrel and his famous chicken culture had died, scientific research finally proved that his success was scientifically impossible, that the same chicken culture can live no longer than 35 times of multiplying, which would take several months only:
“It was only in the mid-60s – half a century after Carrel established his chicken heart culture – that the dogma of cell immortality came crashing down. That’s when Leonard Hayflick, an ambitious young researcher at the Wistar Institute in Philadelphia, discovered that ordinary body cells have a finite life span – or, more precisely, an average number of times they can multiply in vitro. This is their Hayflick number. For chickens, it is 35. In other words, a population of chicken cells can double about 35 times before they die, which usually takes several months.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
But how did Carrel’s chicken cell culture live for 34 years when the cells could only multiply 35 times? There is no direct answer:
“By the time Hayflick proved this, Carrel was long dead and his “immortal” chicken cells discarded. Which means that we know Carrel’s most famous experiment was a sham, but not why.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
The first scientific paper on such limits, by Leonard Hayflick, was written in May 1961, and published in December 1961 – 17 years after Carrel had died in November 1944 (his longest-running chicken cell culture created on January 17, 1912, must have outlived him but died before January 17, 1947).
(“Alexis Carrel – Biographical”, 1912, Nobelprize.org; and, “The serial cultivation of human diploid cell strains”, by L. Hayflick and P.S. Moorhead, December 1961, Pages 585-621, Issue 3, Volume 25, Experimental Cell Research)
Carrel’s chicken fame was either a fraud, or a result of continual contamination by live chicken cells as it went along, according to Rasko and Power:
“If it was fraud, it was one of the most outrageous cases in the history of science. However, the cause may have been carelessness rather than dishonesty. Carrel and his staff used “embryonic juice” as a culture medium and, if they prepared it badly, it might have contained live chick cells. In that case, instead of just feeding their culture, they re-seeded it. It’s an easy enough mistake, but to make it consistently enough to keep their chicken heart cells alive for 34 years suggests an astonishing degree of negligence.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
Such persistent luck was more likely fraud, i.e., “artificial contamination” as termed by the RIKEN investigators on STAP cells in 2014.
According to John Rasko and Carl Power, the entire scientific community should share the blame for upholding such a false dogma for so long:
“… The entire scientific community shares some of the blame because it upheld the dogma of cell immortality for more than 50 years despite the fact that it was based on a single, sensational, irreproducible experiment.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
My view, though, is that those with the understanding and the influence should share the blame for upholding an untrue claim as scientific maxim for 49 long years, but that not everyone in science was in the know, or could openly go against the dogma even if disagreeing with it.
A century after Alexis Carrel, Haruko Obokata had the same persistent luck of contamination, but not the fortune of permanent scientific glory like that bestowed on Carrel, and instead disgrace.
Well, Obokata hasn’t been a successful pioneer of cutting-edge organ science, with medical applications, has she?
She hasn’t; but intriguingly some of her co-authors have been accomplished in that field and harbor great ambitions for laboratory growing of transplantable human organs.
In the list of authors for the earlier-quoted Nature paper dated online January 29, 2014, are Martin P. Vacanti and Charles A. Vacanti, two of the well-known Vacanti brothers, accomplished medical scientists in Boston, Massachusetts.
The four Vacanti brothers had been touted for their accomplishments by The New York Times over a decade earlier:
“Jay, 55, more formally known as Dr. Joseph P. Vacanti, is the chief of pediatric surgery at Massachusetts General Hospital, the director of pediatric transplantation, the director of the laboratory of tissue engineering and organ fabrication, and a surgeon in chief of MassGeneral Hospital for Children.
Chuck, the second-oldest brother, is Dr. Charles A. Vacanti, 53, chairman of the department of anesthesiology, perioperative and pain medicine at Brigham and Women’s Hospital and director of the laboratory for tissue engineering and regenerative medicine.
Marty, third in line, is Dr. Martin P. Vacanti, 51. He is a pathologist at Mass General and a research scientist in Chuck’s and Jay’s labs.
And Frank, Dr. Francis X. Vacanti, a 49-year-old self-described “gizmo guy,” is an anesthetist at Massachusetts General who, working mostly independently from his brothers, is developing a coated breast implant.
Together, the brothers hold 88 patents, a vast majority of them Jay Vacanti’s. They have a total of 11 children and have been father figures to nearly 1,000 graduate students or doctors in training. The brothers have also written more than 300 scientific papers, 189 of them attributable to Jay Vacanti.”
(“SCIENTISTS AT WORK — JOSEPH, CHARLES, MARTIN AND FRANCIS VACANTI; From Old Cars to Cartilage, Brothers Like to Tinker”, by Judy Foreman, December 30, 2003, The New York Times)
As fate had it, among the 1,000 or more graduate students and doctors mentored or trained by the Vacantis would be Japanese graduate student Haruko Obokata, led in 2008 by Charles Vacanti onto a research career path that would eventually see the short-lived stardom and then shame.
Besides each working in the medical fields, the brothers had tissue engineering laboratories, led by Joseph and Charles as reported in the New York Times, where they produced world-leading pioneer work, reported as early as 2001:
“Joseph (Jay), Charles, Martin, and Francis Vacanti work together as researchers in the new field of tissue engineering, a discipline they practically invented. What they are trying to create is nothing less than lab-grown human organs, produced from a patient’s own tissue. Their work is urgently needed— roughly 100,000 patients in this country die each year because not enough people donate organs, and many of those who are saved by transplantation ultimately die because donor organs are rejected.
… Imagine a world, say the Vacantis, in which diseased pancreases, lungs, and spinal cords can be replaced as easily as the transmission in an old Chevy. Imagine a world in which salvation grows in an incubator. Imagine a world in which hope is a given.
… It was only in 1996 that Chuck and Jay Vacanti held the first conference of their fledgling Tissue Engineering Society. Today two of their former colleagues, Anthony Atala, a pediatric urologist at Children’s Hospital in Boston, and Laura Niklason, a Duke University researcher, have already performed what seem like miracles— Atala successfully implanting lab-grown bladders in beagles and Niklason growing fresh pig arteries in her lab. This year there are more than 50 laboratories in the United States alone racing to create people-made people parts. And the researchers in all of those labs are indebted to five breakthroughs made by the four Vacanti brothers.”
(“Brothers with Heart”, by Joseph D’Agnese and Chris Buck, July 1, 2001, Discover Magazine)
One of the five breakthroughs made by the Vacanti brothers was the discovery of “spore-like cells”, unusually tiny cells that lie dormant in animal tissues, so tiny that fellow researchers at first dismissed as “debris”, “junk”:
“In 1996 Chuck had convinced Marty, the pathologist, to leave Nebraska and join him in Worcester. Chuck had grown increasingly frustrated with the fragile adult-tissue cells he had been working with. Most cannot last more than 30 minutes without an oxygen supply. Fetal stem cells are hardier, but harvesting them is controversial.
Chuck told Marty to find an alternative: “Look for stem cells in adult tissue.”
He instantly replied: “They don’t exist.”
“They have to exist,” Chuck insisted, intent on driving his point home. “If the human body is constantly trying to repair itself, it must have immature cells somewhere. Find them.”
“You’re nuts,” Marty told him.
“Just do it.”
… Marty decided to give it a try. For 15 months he drew cells from living animals, only to watch them die. He scrounged lab animals other researchers had sacrificed for their work. He scraped flesh with scalpels and dissolved it in enzymes. He peered into the resulting broth, magnified 200 times, to no avail. At every staff meeting, Marty had nothing to report. It became embarrassing.
Then one day, peering through the microscope, he spotted tiny circular shapes. Adult-tissue cells are about 15 micrometers wide. Marty saw cells only 3 micrometers wide. He began showing them around. They’re too small to be stem cells, everyone said. Just debris. Junk.
Tired and depressed, Marty stood in his lab staring at flasks of the cell soup, thinking, “Wastebasket or incubator?” For reasons he does not comprehend, he stuck them in the incubator. Three days later, those little specks of junk had multiplied. What’s more, they had gone without oxygen for more than an hour before he put them in the incubator, an ordeal adult stem cells could not have survived.
At staff meetings Marty took center stage. Eventually someone asked: What do you call these cells? Privately, Marty had begun to call them “sporelike cells.””
(Joseph D’Agnese and Chris Buck, July 1, 2001, Discover Magazine)
These spore-like cells turned out to be among every animal tissues, with the ability to survive tough physical conditions, some stem cell ability and the ability of fast growth when activated:
“Weeks later, Chuck phoned with a suggestion, but Marty cut him off. Obsessed now, he had been examining every scrap of tissue he could lay his hands on and had isolated sporelike cells in every one. He’d bought a tray of chicken livers at the grocery. Even there, he found them.
Chuck was agog but, being Chuck, couldn’t wait to up the ante. Freeze ’em and cook ’em, he said. Marty took them down to -121 degrees Fahrenheit. The cells survived. He left them at 187 degrees Fahrenheit for 30 minutes. They were still alive.
Marty tried to keep a lid on his excitement. He’d learned early that it was prudent to get the data in the bag before you crowed over a new discovery. His confidence soared the day he showed his work to Guido Manjo, an eminent Italian-born pathologist who lectures at UMass. Manjo’s advice: Test those cells for DNA— and publish as soon as possible. Then came the ultimate compliment: “Dr. Vacanti,” said the senior scientist, “you may have discovered a fundamental process of nature that has not yet been described.”
Manjo was correct. DNA was present in the cells, and no one in the history of biology had ever identified such minuscule formations living in mammalian tissue. They were the kind of cells that the Vacantis had been dreaming about: They could live in the body without oxygen for days until blood vessels grew to supply them. Marty’s most recent research shows the cells may actually be able to differentiate into tissues other than those of the organs from which they originated.
Properly incubated, they grow like grass on a prairie. The team in the lab at Worcester has used them to grow everything from retinal rods and cones to liver, bone, fascia, skin, and heart tissue. They have pulled sporelike cells out of a diabetic pancreas and grown insulin-producing islets in 12 weeks. They have cut a golf-ball-sized section from a living sheep’s lung, stuffed the wound with a scaffold seeded with pulmonary sporelike cells, and watched as the lung incorporated the new tissue in eight weeks. Everyone was in awe: A lung is perhaps the most complex organ in the body, possessing at least half a dozen different types of tissue.”
(Joseph D’Agnese and Chris Buck, July 1, 2001, Discover Magazine)
The Vancanti brothers were not trained cell scientists. Yet Chuck’s great leap of logic and imagination and Marty’s hard work led to the discovery of the versatile spore-like cells and their omnipresence.
But his colleagues were so skeptical that Chuck Vacanti moved himself to a different institution in order to avoid them. Then in 2008, graduate student Haruko Obokata came to work under him, reproducing Marty Vacanti’s results with much more professional rigor:
“The initial, tiny seed cells seemed to be very hardy and resistant to harsh conditions, so he and his brother dubbed them spore-like cells and published their results in 2001 in a respectable, though not prominent journal.
Other UMass scientists were extremely skeptical of the results. Eventually, tired of having to defend his work internally, Charles moved to Brigham. He made a conscious choice during the job interview not to mention the research.
“I didn’t want to tell them about my little flop on spore-like stem cells,” Vacanti recalled.
Martin eventually moved back to the Midwest, and Charles’s research went in other directions. But he was still interested in the strange cells he and his brother had isolated. He asked Koji Kojima, a thoracic surgeon and researcher in his lab, to try to see whether he could isolate the same tiny cells.
Kojima started by trying to find them in lung tissue. Eventually, he found the right protocol. Another scientist in the lab found them in muscle.
But Vacanti had learned his lesson. Maybe his lack of training had been an asset when he was trying an unconventional approach and following his intuition where few others would have gone. But he now knew he had to build a rock-solid case that these cells were what they seemed to be.
…
“Older scientists were never going to abandon what they were taught. We needed someone who was flexible enough to explore different possibilities,” Vacanti said. They needed a student.
In 2008, a Japanese graduate student, Haruko Obokata, took up the project, and succeeded in much more rigorously replicating the 2001 work that had attracted so much criticism.”
(“Ignorance led to invention of stem cell technique”, by Carolyn V. Johnson, February 2, 2014, The Boston Globe)
Perhaps other scientists’ skepticism played a role. Charles Vacanti began to think that the spore-like cells had not been present everywhere in the organ tissues but were created by the lab process – a thinking Obokata’s Japanese teacher also harbored:
“Two years later, at a conference in Florida, Vacanti met with Obokata and her mentor from Japan, Masayuki Yamato, from Tokyo Women’s Medical University. He asked them not to make fun of him. Then, he proposed that maybe the isolation procedure was actually creating the cells. He wondered if Obokata would return and see whether this was true.
“I was completely convinced that the cells we described . . . were being ‘created’ during the isolation process, rather than simply being isolated,” Yamato wrote in an e-mail. “I was so surprised to find that Chuck and I had independently reached the same conclusion.””
(Carolyn V. Johnson, February 2, 2014, The Boston Globe)
Then somewhere in this second great leap of logic and imagination, the laboratory stress became more than producing the spore-like cells, but converting the mature cells to pluripotent stem cells – as phrased in the January 2014 Nature papers.
In February 2014 Paul Knoepfler, a biomedical scientist and blogger at the University of California, Davis, conducted an interview with Charles Vacanti, who stated “our belief” that the STAP cells and the spore-like cells “are one and the same”; however, Vancanti’s explanation that the lab process killed mature cells and allow the “stem” cells to survive, obviously did not match Obokata’s notion of “conversion” in their newly published Nature papers:
“You have published some revolutionary findings and outside the box hypotheses in the past such as spore stem cells. What’s your thinking today on spore stem cells? Is there any connection between the STAP cell stress reprogramming concept and spore stem cells, which you reported were able to resist great stress like desiccation and freezing?
Vacanti: It is our belief that they are one and the same. The report demonstrates that we were making these cells rather than isolating them. It may be a subtle, but we feel very important difference. We feel that many reports describing stem cells may indeed represent reports of how to make stem cells. It has been believed that the harsh environment associated with the isolation process killed mature cells, allowing the hardier “stem” cells to survive, and be selected out.
We were not dumb enough to again call them “spore like cells”, since almost no one read that paper. For several years, we believed that to be the case, but were fairly “gun shy” about being roasted again. But it seems that the time has come.”
(“Interview with Charles Vacanti on STAP Cells: Link to Spore Stem Cells & More”, by Paul Knoepfler. February 2, 2014, Knoepfler Lab Stem Cell Blog)
In a slightly different version of the history as in a Nature report, Obokata first proved the “pluripotency” of spore-like cells, then both Charles Vacanti and she felt that the spore-like cells were created in the lab process, and after that came her notion of “conversion”:
“Vacanti told Nature’s news team in January that by 2006 his laboratory could grow the cells in large numbers, but that they still “were not exceptionally well characterized by us”. That is, the team had not demonstrated pluripotency. This was a job he gave to Obokata, a graduate student who had joined his lab in 2008.
Proving pluripotency is often done by injecting cells into a developing mouse embryo — creating a ‘chimaera’ — and tracking their fate. It is a difficult experiment, and Obokata needed help. “I was looking for the god’s hand of chimaeric-mouse generation,” she said back in January. A Google search led her to famed mouse cloner Teruhiko Wakayama at the CDB, whose lab she entered in 2011 as a visiting professor. After hundreds of failures to get cells derived from adult mice to show up in chimaeras, she and Wakayama switched to newborn mice as the source of the cells — and the process worked.
By that point, both Vacanti and Obokata were convinced that the stress of the isolation process was creating the pluripotent cells. Obokata said that the idea had come to her while she was taking a bath and reflecting on the stress in her own life.
In the experiments at RIKEN, she used acid to stress spleen cells from newborn mice, and she carried out further experiments to characterize their conversion with Yoshiki Sasai and Hitoshi Niwa, two highly regarded stem-cell biologists at the CDB. With the two key characteristics of STAP cells now demonstrated — they were pluripotent and were created using stressful conditions — she had enough data to publish two papers in Nature on 30 January.”
(“Research integrity: Cell-induced stress”, by David Cyranoski, July 3, 2014, Nature)
It still appears unclear why the creation of the pluripotent cells was a “conversion” – something supposedly demonstrated in the now discredited Nature papers:
“Through real-time imaging of STAP cells derived from purified lymphocytes, as well as gene rearrangement analysis, we found that committed somatic cells give rise to STAP cells by reprogramming rather than selection.”
(Haruko Obokata, Teruhiko Wakayama, Yoshiki Sasai, Koji Kojima, Martin P. Vacanti, Hitoshi Niwa, Masayuki Yamato & Charles A. Vacanti, January 29, 2014, Nature)
John Rasko and Carl Power wonder if Obokata was “cooking” data to “please” Charles Vacanti:
“Vacanti’s role in this scientific debacle is especially intriguing because Stap cells originally sprang from his fertile imagination. For well over a decade, he had been working on a hunch that pluripotent stem cells exist in all mammalian tissue, ready to swing into action whenever needed. It was a big, bright, potentially career-defining idea which for a long time Vacanti couldn’t sell. He lacked conclusive proof. He also lacked credibility. After all, he was not a stem cell scientist but an anesthesiologist and tissue engineer best known for grafting an artificial ear on to the back of a mouse (the infamous Vacanti earmouse).
Then, in 2008, Obokata joined his lab as a graduate student, bringing with her the skill set and credentials he sorely needed. Thus began a partnership that continued after Obokata returned to Japan. With her help, Vacanti repeated his earlier experiments and revised his hypothesis: mammalian tissue doesn’t so much maintain a reserve of pluripotent stem cells; it creates them when put under stress by injury or disease. Stap cells were supposed to confirm this hunch, being the laboratory equivalent of stem cells spontaneously produced by the body.
Did Obokata begin cooking data in order to please her supervisor? Did Vacanti ever suspect that her results were too good to be true? Whatever the case, the Stap cell scandal is their monster child.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
Whatever the truth had been, when other scientists were unable to reproduce the results and expressed their doubts after the Nature papers’ publication, Vacanti defended his brainchild more vigorously than even Obokata defending her work, claiming that he was able to create the STAP cells, and even posted a “special recipe” online for doing it, which, like Obokata’s work, others were unable to reproduce:
“This charming, silver-haired midwesterner, who headed the anesthesiology department at Brigham and Women’s Hospital in Boston, did almost as much to confuse the issue of replication as Obokata herself. From the start, Vacanti claimed that he had been able to create Stap cells, including human ones, though he offered no evidence. What he did offer, however, was his own special recipe, which he posted online in mid-March (around the time that Riken first declared Obokata guilty of misconduct), assuring the scientific community that if he could make Stap cells, anyone could.
Unfortunately, that humble boast backfired. No one else could get his recipe to work.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
Then when co-author Teruhiko Wakayama, who found mix-up of test data as discussed earlier, went public with his request to retract the Nature papers, both RIKEN and Vacanti continued to defend the STAP cells:
“Wakayama told NHK he has requested that his co-authors retract the studies and then would like outside experts to do verification studies. He said he is “no longer sure about the credibility of the data used as preconditions for the experiments,” NHK reported.
A Riken official told The Japan News that “the basis of the articles” — the fact that STAP cells were produced – “is unshakable.”
…
Dr. Charles Vacanti, a study co-author, said in a statement that he stands by the research.
“I firmly believe that the questions and concerns raised about our STAP cell paper published in Nature do not affect our findings or conclusions,” said Vacanti, who is director of the Laboratory for Tissue Engineering and Regenerative Medicine at Brigham and Women’s Hospital in Boston.”
(“Scientist wants to withdraw stem cell studies”, by Elizabeth Landau, March 12, 2014, CNN News)
After RIKEN’s release of its first investigation report, finding research misconduct on Obokata’s part, Vacanti continued to defend the Nature papers and opposed retracting them:
“Harvard researcher Dr. Charles A. Vacanti, head of the department of anesthesia at Brigham and Women’s Hospital in Boston, was the senior author of one of the papers but was not named in an English-language draft of the RIKEN report provided to the Globe.
Vacanti said he continues to stand behind the main findings of the research he did with Obokata, who worked in his Brigham lab for several years.
“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,” Vacanti said in an e-mailed statement. “It is imperative to correct the errors, but absent any compelling evidence that the overall scientific findings are incorrect, I do not believe that the manuscripts should be retracted.””
(“Fraud alleged in findings on stem cells”, by Karen Weintraub, April 2, 2014, The Boston Globe)
The Nature papers were retracted in July, and in August came the death of Obokata’s RIKEN supervisor and co-author Yoshiki Sasai. Then, Vacanti decided to step down from his chairmanship at Brigham and Women’s Hospital in Boston for a one-year sabbatical, but doing so without mentioning the scientific fraud scandal, only that his resignation was 2 years overdue after 12 years on the job:
“When I accepted the position in 2002, I anticipated serving as Chair for a period of 10 years, having a vision of what I hoped to accomplish during that time. I approach the age of 65 next year having served as Chair of two anesthesia departments – UMASS then BWH – over the last two decades. I have always felt that a leader is most effective during the first decade of service, after which time there can be diminishing returns on the energy invested in the challenges faced. I feel that is certainly true in my case, and that by this measure, I am two years past due in making this decision.”
(“STAP News From Harvard? Vacanti Stepping Down as Chair & Going on Sabbatical”, by Paul Knoepfler, August 13, 2014, Knoepfler Lab Stem Cell Blog)
As a fellow biomedical scientist, University of Sydney’s John Rasko expressed his indignation at Charles Vacanti’s unaccountability, and unwillingness to retract the Nature papers even after Obokata’s expression of consent:
“Fellow scientists question the explanation, given the controversy erupting around the Nature papers. “(It) certainly seems to coincide with recent events,” said Sydney University stem cell researcher John Rasko.
“Vacanti was reluctant to accept that the study should be retracted, and maintained that the observations were real,” Professor Rasko said. “This was even after Obokata had said she supported the retraction — and it took a long time for her to capitulate.””
(“Science can keep its house in order”, by John Ross, August 19, 2014, The Australian)
As Rasko and Carl Power later pointed out in their The Guardian article, while leaving for sabbatical Vacanti posted another “special recipe” for creating STAP cells, stating that his laboratory was able to use it to reproduce them through “conversion”, with “profound” results:
““In recent months, our lab decided to re-explore the utility of a low pH solution containing ATP in generating STAP cells,” Vacanti writes in the revised protocol. “We found that while pH alone resulted in the generation of STAP cells, the use of a low pH solution containing ATP, dramatically increased the efficacy of this conversion. When this acidic ATP solution was used in combination with mechanical trituration of mature cells, the results were even more profound” (emphasis original).”
(“STAP co-author offers yet another recipe for stem cells” by David Cyranoski, September 12, 2014, Nature)
Just like with his previous online recipe, others were unable to make it work.
Given Charles Vacanti’s leadership role and status in medical research and education at Brigham and Women’s Hospital, a leading U.S. hospital affiliated with Harvard Medical School, his lack of scientific accountability in the face of efforts by the Japanese RIKEN institution to conduct a thorough investigation into fraud, questions naturally arose about institutional responsibilities on the part of Brigham & Women’s/Harvard.
In March 2014 when the controversy grew intensely public, Harvard Medical School issued a general statement emphasizing its “highest standards of ethics”:
“We are fully committed to upholding the highest standards of ethics and to rigorously maintaining the integrity of our research. Any concerns brought to our attention are thoroughly reviewed in accordance with institutional policies and applicable regulations.”
(Elizabeth Landau, March 12, 2014, CNN News)
When Charles Vacanti decided to resign from his chairmanship, the contrast between RIKEN’s active investigations and inaction on the part of Brigham & Women’s/Harvard was noted by researcher and blogger Paul Knoepfler:
“What’s the deal with Brigham and Women’s Hospital or Harvard Medical School when it comes to the retracted STAP cell papers?
I was just writing yesterday in part about how we haven’t really heard anything (news, statements, etc.) from those places about the whole STAP cell mess.
In contrast, in Japan and at RIKEN there has been a non-stop flood of news and developments involving STAP.”
(“Paul Knoepfler, August 13, 2014, Knoepfler Lab Stem Cell Blog)
By December 2014 when Obokata resigned her job and RIKEN’s second investigation report completely discredited the retracted Nature papers, the inaction of Brigham & Women’s/Harvard became the focal point as Knoepfler pointed out:
“With its final report released today (also a powerpoint of images were released including the one showing a figure posted here of reportedly made up data published in a STAP paper), RIKEN seems to now have handled this complicated mess in a relatively rigorous, scientific manner that paves the way for moving on from it.
…
Harvard and Brigham and Women’s Hospital may or may not be conducting STAP investigations of their own. However, certainly at this point relatively speaking key unanswered questions remain on the Harvard side of STAP.”
(“Perspectives on final RIKEN report on STAP cell scandal & what comes next”, by Paul Knoepfler, December 26, 2014, Knoepfler Lab Stem Cell Blog)
In their February 2015 The Guardian article, the Australian researchers John Rasko and Carl Power observed that in the United States scientific misconduct investigations are usually carried out “under a veil of secrecy”; they further opined that “in all likelihood Brigham has begun its own inquiry”:
“It makes you wonder why Vacanti hasn’t been dragged over hot coals like Obokata and her Japanese colleagues, and why Brigham hasn’t followed Riken’s example by publicly flogging itself.
The answer is simple: in the US, investigations into scientific misconduct usually take place under a veil of secrecy. In all likelihood, Brigham has begun its own inquiry but, in stark contrast to the one carried out by Riken, we probably won’t learn anything about it – even the fact of its existence – until after a verdict is reached.”
(John Rasko and Carl Power, February 18, 2015, The Guardian)
It had better be, because scientific accountability has become a serious issue. Now in other parts of the world like Japan in this case, and also Taiwan, a Nobel Prize laureate or a government cabinet minister would have to shoulder the appropriate responsibility for a scientific scandal.
The Scientist magazine in December 2014 named the Haruko Obokata story No. 1 on its list of “The Top 10 Retractions of 2014”.
(“The Top 10 Retractions of 2014”, by Adam Marcus and Ivan Oransky, December 23, 2014, The Scientist)
At No. 2 on the list was an Iowa State University researcher who spiked rabbit blood samples with human blood to make it look like his HIV vaccine was working. The fraud led to serious penalties not only for the researcher, Dong-Pyou Han, who resigned and is facing criminal charges, but also for the institution, Iowa State University, which must reimburse the National Institute of Health nearly $0.5 million in funding spent on Han’s employment, and also lose nearly $1.4 million in cancelled funding for the remainder of the project:
“Federal officials are rescinding nearly $1.4 million in grant money for an Iowa State University research team that was besmirched by a colleague’s alleged fraud.
The National Institutes of Health decision comes on top of ISU’s agreement to reimburse the federal agency $496,000 for salary and other costs related to Dong-Pyou Han’s employment. The former ISU scientist is accused of faking experiment results to make it look like a vaccine was protecting rabbits against the AIDS virus.
Han, who resigned from the university last year, faces four federal criminal charges that could bring prison time if he’s convicted.
The National Institutes of Health is the leading source of federal money for medical research. A spokeswoman told the Register on Monday that the agency has decided not to make the final, $1.38 million payment on a grant to the ISU team. The team, which includes researchers at other universities, was awarded $14.5 million in such grants over several years, officials have said. Much of that money was awarded because of the team’s dramatic reports of vaccine success, which turned out to be bogus.”
(“ISU loses $1.4 million in fraud case”, by Tony Leys, July 8, 2014, The Des Moines Register)
As RIKEN’s second investigation report has concluded that the contamination with embryonic stem cells in the STAP cells experiments was unlikely accidental, the main difference between the fraud in the Obokata case and Dong-Pyou Han’s fraud is that no one has been caught for “artificial contamination” leading to the STAP cells.
Like the Dong-Pyou Han case in the U.S., the Hwang Woo Suk case in South Korea nearly a decade earlier also saw the perpetrator face criminal charges, and Hwang was held criminally accountable for fraud in spite of his solid scientific research ability.
Given the illumination by John Rasko and Carl Power that the contemporary scientifically disgraced Hwang Woo Suk and the early 20th-century Nobel Prize laureate Alexis Carrel were top examples of scientific fraud in biomedical research history, and given that the ramifications during the two’s respective career and life times were polar opposites – criminal conviction versus lifelong glory – I have to wonder if the inaction on the part of Brigham and Women’s Hospital and Harvard Medical School in the Haruko Obokata/Charles Vacanti case has been due only to the absence of a concrete allegation of intentional fraud, or also to a sense of elite impunity – when compared to the Iowa State University case.
Next down on the No.3 spot of The Scientist’s top-10 retractions of 2014 was Taiwanese researcher Peter Chen and his fraudulent peer-review ring, a connected circle of researchers who peer-reviewed and approved one another’s papers for publication – often relying on false identities.
The unraveling of the Peter Chen case led to the retraction of 60 published papers deemed to have been accepted due to fraud, Chen’s departure from his university professorship, stepping down of a U.S.-based scientific journal’s editor-in-chief, and the resignation of the Taiwanese government’s education minister in 2014. A former president of the National Central University, the Taiwanese education minister Chiang Wei-ling had advised Chen’s twin brother on his Ph.D. thesis 10 years earlier, and was named by his former student as a co-author on 5 of those fraudulent papers. On the Facebook community page, “Science, Education Progress, and New Millennium Bugs”, I have posted some facts from press articles on this case:
“The case came to light in May 2013 when Ali Nayfeh, then editor-in-chief of the Journal of Vibration and Control, learned from an author that he had received e-mails from two people claiming to be reviewers, e-mails that came from generic-looking Gmail accounts rather than the professional institutional accounts that many academics use.
Nayfeh alerted SAGE, the company in Thousand Oaks, California, that publishes the journal. The editors there e-mailed both the Gmail addresses and the institutional addresses of the authors whose names had been used; one scientist responded that he had not sent the e-mail and did not even work in the field.
This sparked a 14-month investigation that came to involve about 20 people from SAGE’s editorial, legal and production departments. It showed that the Gmail addresses were each linked to accounts with Thomson Reuters’ ScholarOne, a publication-management system used by SAGE and several other publishers, including Informa. The investigators tracked every paper that the person or people behind these accounts had allegedly written or reviewed, and also ferreted out further suspicious-looking accounts, a total of 130 of such accounts.
After the scandal was exposed, ring leader Peter Chen resigned from his teaching post in February 2014. In May, Nayfeh resigned at his journal. And in July, Taiwan’s education minister Chiang Wei-ling (蔣偉寧), whose name had appeared on 5 of the papers, resigned “to uphold his own reputation and avoid unnecessary disturbance of the work of the education ministry”, according to a public statement.
Those 5 papers were authored by Chen Chen-wu (陳震武), twin brother of Chen Chen-yuan (陳震遠), i.e., Peter Chen. The papers bore Chiang’s name as a co-author, and also listed Peter Chen as one of the authors — without Chiang’s knowledge — according to Chen Chen-wu.
Chiang, a 56-year-old civil engineer, was president of National Central University before he was appointed education minister in February 2012. He said he did not know Peter Chen personally, but had advised Chen’s twin brother Chen Chen-wu in his doctoral thesis about 10 years earlier.”
(“Facebook posting”, March 28, 2015, Science, Education Progress, and New Millennium Bugs)
In comparison, even if he had not been a party in the fraudulent experiments conducted by Haruko Obokata, Charles Vacanti was a senior author of the now retracted Nature papers, an academic and scientific mentor of Obokata, and the intellectual father and leader of this whole framework of spore-like cells and STAP cells. His acts of posting special recipes online, claiming creation of STAP cells in his laboratory as described but providing no evidence, already were much more involvement in activities of questionable scientific honesty than the former Taiwanese education minister Chiang Wei-ling.
In Japan, developments continue in relation to the Obokata scandal. In early March 2015, Japanese media reported the decision to step down by RIKEN president, Nobel Prize in Chemistry laureate Ryoji Noyori:
“Ryoji Noyori, longtime president of the Riken research institute, has decided to step down as the head of the government affiliate, which has been mired in a scandal involving the creation of so-called STAP cells, sources said March 6.
In expressing his intention to resign, the 76-year-old Nobel Prize-winning chemist has cited his advanced age and the fact that his term has already extended for nearly 12 years.
…
Ministry officials said that he is not resigning to take responsibility for the recent scandal over the groundbreaking discovery of a new stem cell mechanism called “stimulus-triggered acquisition of pluripotency” (STAP).”
(“Nobel laureate Noyori to resign as president of embattled Riken, citing age, long tenure”, March 6, 2015, The Asahi Shimbun)
There were remarkable similarities to Charles Vacanti’s resignation as department chairman at Brigham and Women’s Hospital in August 2014, I note, that both had been on the helm for 12 years, and both resignations were said to be unrelated to the Obokata scandal.
But Ryoji Noyori wasn’t even in a science field related to Obokata; still, he voluntarily returned part of his salary to RIKEN as a gesture of taking responsibility for the debacle:
“Riken will announce later this month the results of an evaluation by a panel of outside experts on the progress of the institute’s organizational reform to prevent similar instances of misconduct from occurring. Noyori is likely to have decided to resign as the announcement is approaching.
…
Noyori voluntarily returned a portion of his salary to take responsibility for the STAP scandal last October. But he has appeared in only one news conference to discuss the scandal, triggering criticism that has not fulfilled his accountability as head of Riken.”
(March 6, 2015, The Asahi Shimbun)
Then on March 24, Japanese and international media reported on Noyori’s imminent departure and the Japanese government’s naming of his replacement, former Kyoto University President Hiroshi Matsumoto:
“Former Kyoto University President Hiroshi Matsumoto will replace Nobel laureate Ryoji Noyori as head of the Riken research institute, the science ministry decided Tuesday.
Noyori, 76, will leave the post on March 31, halfway through his third term through March 2018, after a difficult year caused by a researcher’s highly publicized misconduct in a stem-cell study.
The 2001 Nobel winner in chemistry has served as head of the leading government-backed research organization since October 2003.
…
Matsumoto, a 72-year-old expert on space plasma physics, was president of Kyoto University for six years until last September. He is a member of the government’s Committee on National Space Policy.”
(“Former Kyoto U. chief to take helm at scandal-plagued Riken”, March 24, 2015, The Japan Times)
So the Japanese government has moved a top academic executive from the institution where Shinya Yamanaka had done ground-breaking, Nobel Prize-winning research on cell reprogramming for stem cell creation, to RIKEN’s helm.
Foregoing the remaining 3 years of his third term, the timing of Ryoji Noyori’s resignation was highlighted in his official announcement, that he was departing a day before the commencement of RIKEN’s new status as a National Research and Development Institute, and that his efforts to reform RIKEN following the Obokata scandal had received a positive assessment in the prior week:
“As of April 1, 2015, RIKEN will have a new status as a National Research and Development Institute. With the consent of the Minister of Education, Culture, Sports, Science and Technology, I have decided to take this opportunity to step down from my position as RIKEN president, effective March 31, 2015.
Over the 11 years and 6 months since my appointment in October 2003, I have dedicated my efforts to making RIKEN the bedrock for the launching of many of Japan’s advances in science, technology and innovation. Fortunately, RIKEN has attracted numerous outstanding scientists from inside and outside Japan, and these people have achieved creative and outstanding results, not least of which has been the discovery of element 113. RIKEN has also successfully completed two of Japan’s key technology projects—the SACLA X-ray Free Electron Laser and the K computer—and most recently, has launched the world’s first clinical trial in regenerative medicine using iPS cells. …
Despite this, however, because of a most unfortunate case of research misconduct that has severely tarnished RIKEN’s good reputation, I have had to implement major RIKEN-wide organizational and managerial reform directed at rectifying this situation. Last week, the Management and Action Plan Monitoring Committee commended these efforts in its report, and it is with some relief that I am assured the measures are proving to be effective and will be carried forward.”
(“Ryoji Noyori to step down as RIKEN president”, March 24, 2015, RIKEN)
Clearly, this Nobel Prize winner has displayed appropriate senses of conscientiousness, pride and humility.
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