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Who Watches the Watchers?

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Although my posts are usually concerned with strange medical puzzles or odd diagnoses, every once in a while I like to shift gears and talk about something from the research aspect of clinical epidemiology and medicine. This is one of those times.

For those unfamiliar, the institutional review board or IRB is a person or a small committee that reviews research proposals, papers, or articles to help the author or the researcher produce a quality manuscript or study. In my previous experience as a senior assistant editor, I worked as a peer reviewer examining submitted manuscripts for publication. Seldom if ever did these research studies make it through to publication on the first submission. Often it would take 2 or 3 attempts and much editing for the work to republication. However, in this final form it is a significantly better read and stronger argument for the authors work.

Although it is rare, sometimes a study or a research paper makes it through only to be shown to be mistaken or outright fraud. Andrew Wakefield and associates were found to be complicit in significant fraudulent study concerning vaccination and autism; the damage of this admittedly false research is still being experienced. The direct relationship between Wakefield’s blatant misdeeds and outright lies and the drop in childhood vaccination and resulting increase in preventable infectious diseases are obvious. This study appeared in the Lancet, and within a few weeks was being questioned by other researchers. Eventually, the Lancet was forced to retract the article and Wakefield lost his license to practice in the UK. Interestingly enough, he currently practices in the United States. In Texas I believe.

Recently another IRB failure made its way to publication, this time in the journal Nature. Over the past decade or so, researchers have sought a viable replacement for embryonic stem cells. Stem cells have become politically dangerous to discuss. However, their potency and plasticity made them extremely powerful in the research of disease treatment. Stem cells are pluripotent, in other words, they can become virtually any cell necessary, with few exceptions.

Because of the political association, stem cell research has taken a beating by a largely uneducated population, and replacements have been sought for some years. Enter the Jellyfish genes.

So the excitement concerning stimulus-triggered acquisition of pluripotency or STAP cells was well-founded. Here at last was a replacement for the stem cell research. Although the discovery was made under the best of circumstances, last year’s sensational article explained the process in remarkably simple and elegant processes. Stressed cells, it was claimed, sometimes emit a greenish glow under fluorescent lighting. This is key to the discovery, and the resulting retraction of the research. Researchers in the US and Japan found that treating cells from newborn mice with acid or forcing them through thin pipettes somehow transform them into pluripotent stem cells. Recall that pluripotent cells can become anything, and, therefore, are the Holy Grail in medical research. Pluripotent cells, which form naturally in early embryos, lose their plasticity in fetal development. So you can imagine the excitement that these same cells could be easily produced through chemical or physical stressing of ordinary cells. You are probably thinking that this sounds a little too good to be true. Moreover, you’d be correct. The claims rapidly collapsed as researchers around the world attempted to reproduce the experiments, and failed. Soon an investigative committee at the Japanese research organization where the lead author had worked and published some of this data in other journals found evidence of misconduct. The researcher resigned in December 2014. Her supervisor and co-author committed suicide in August 2014.

So what happened? How could well-trained expert researchers have made such a simple mistakes? That answer is complicated and at the same time quite simple. If you are bent on finding a particular result, you may very well find it. The team had used mice that carried a particular reporter gene that made the cells will green under fluorescent light.

In fairness, the STAP cells that the researchers observed did glow with a similar greenish hue, called an artifact, just as the mouse embryo stem cells did when exposed to fluorescent light. The difference is that the signal emitted from the STAP cells was significantly fainter than the bona fide stem cells. However, if you look hard enough for what you expect to see, you will see it. In the several months since the original paper was published, several researchers have made similar observations but saw distinct differences between the stem cells and the STAP cells. Yes, the same artifacts existed when cells were stressed, however, these were not found to be pluripotent. It hopes to avoid such a fiasco from occurring again; some researchers have laid out particular criteria for first future claims of reprogramming advances, suggesting a series of tests to avoid misleading results.

In my experience the IRB has been both an annoyance and a lifesaver. When my most recent doctoral dissertation found its way to the IRB, I was forced to rewrite much of my chapter 3 (methodology), and while I was more than annoyed at the prospect of rewriting 30 pages of statistical testing protocols, in the end, the dissertation was better and begrudgingly, the IRB was correct in his requirements. As a doctoral advisor, I have worked with PhD candidates who saw their chairperson as obstructionist and viewed the IRB with such disdain that vulgarities were often used to address the person. I always attempt to explain that the IRB is the students or the researcher’s best defense against retraction and best, or at worst, looking like a fool. It is the IRB’s job to make sure that what you say, and what you do is both legitimate and expands upon the field. If your technical brief comes back covered in red ink, then it is your job to read the comments and to make the adjustments. He or she is not trying to give you a hard time. In fact, they are protecting you from the world of detractors who will be far less kind if you make a mistake. Science is ultimately a self-correcting process, and the IRB plays a crucial role, and if they fail, be assured that the scientific community, in a collective role, will point out your errors.

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