The case of the immortal stem cells

March 31, 2016

Dr. Nigro, Filipodia editor

 

Retraction. ReTRACtion. It even sounds like it could be something painful, and well, it is. We like to use the word retraction even less than

 

the word scoop in basic research. Yet, retraction notices still appear at the end of the contents page of even the most prestigious of journals where articles undergo rigorous review. How could this happen when the review process is so thorough? we ask. Because there are things that we would never predict could happen but they do.

 

It is an unpleasant process to retract a paper, even when you watch from the outside. It can feel like a collective failure because as a large group with diverse training we should have a better chance to recognize the potential flaws in the research of our closest colleagues. Nevertheless, there are many lessons to be learned if you are ever close to a group retracting a paper. The first, as is often said, is that challenges are going to occur in life but it is all about how you deal with them that reveals what kind of person you are.

 

A few years ago, our group comprised of around 30 physicians, surgeons, and basic scientists were all called into a mandatory meeting. It was for an official announcement from the group leader; a paper in the group had been retracted.

 

The major finding of the article was that human mesenchymal stem cells spontaneously immortalized with passage in culture. The result was interesting based on the fact that other human cell types such as fibroblasts did not spontaneously immortalize in culture unless transfected with a combination of oncogenes. However, these were stem cells.

 

These experiments were performed in parallel in an independent lab in another country. Unfortunately, neither group tested whether the cells at the end of the experiment were related to the original cells they had put into the experiments. In both groups, technical error led to the contamination of primary cell populations with rigorously growing cell lines that had been used in laboratories for years around the world. Each lab had independently introduced cell lines into the normal stem cell populations. Once the stem cells reached senescence, the contaminating cell lines overtook the culture (this result is actually intriguing).

 

DNA analysis or fingerprinting was eventually performed to establish cellular origin, but only after the paper had been published. The paper was formally retracted shortly thereafter by all authors in all countries, and we all learned firsthand that handling primary cell populations simultaneously with established cell lines was a bad idea. It was not a novel discovery. One PI I had worked with forbade the use of HELA cells because he claimed that they jump. Contamination of cell lines even with other cell lines or the simple act of mislabeling cells in culture was a recognized consequence of in vitro culture, sort of the so-called elephant in the room, but one that was somewhat ignored.

 

At the time, the retracted paper provided further evidence that labs worldwide should be required to demonstrate cellular origin in order to publish. While reproducibility among labs is an underlying issue, in this particular case the conclusion had more critical repercussions-perpetuation of a misguided concept as well as catastrophic consequences for the clinical use of passaged stem cells.

 

Other reasons for retraction are more serious. Clear cases of fraud have hit research headlines. Why the review process fails in these cases is a good question, but it is also our responsibility at our respective institutions to be attentive long before articles even go out for review. And more importantly, speak up about it. It is part of the training process for all of us and supersedes hierarchy.

 

Although the mesenchymal stem cell result discussed above initially seemed plausible based in part on the cells’ connection to the development of cancer, the human cells in the retracted studies did not spontaneously immortalize under standard conditions in vitro. If there could be a good reason for the retraction of a paper, this one was it. The senior author handled the issue brilliantly and demonstrated a good dose of humility. We all learned an important lesson-perform controls-and the error emphasized the caveats in work implementing established cell lines not only in our laboratory but worldwide.

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