iPS cells are similar to cancer cells paper, part 2: unsettled reviewers

I’m a fan of iPS cells, but my lab has been concerned about the similarities between induced pluripotency and cancer formation for many years. We just now published a paper that directly addressed the similarities of cancer and iPS cell transcriptomes. These are cause for concern and need to be faced as we contemplate clinical trials using iPS cell-based therapies.

Not surprisingly, however, there are certain members of the stem cell field who would rather focus away from the idea that iPS cells are similar in some respects to cancer. However, we need to understand iPS cells fully to consider their potential clinical use.

Once we had a manuscript together comparing iPS cells to cancer cells, we sent it to several high profile journals without much luck. We thought that the fact that our data indicated that iPS cells are similar to cancer cells might make reviewers and editors excited. We thought that the paper was novel and thought provoking in a number of ways. At the same time I realized the theme of the paper would be controversial.

I would say two general things about the review process at the two journals that turned down the paper. First, the reviewers at these journals were enormously helpful with their suggestions and helped us improve the paper substantially. Second, they were clearly very uncomfortable with the notion that iPS cells are related in some ways to cancer so unsettled in fact that I believe it influenced their reviews.

At one journal a reviewer said (emphasis mine):

this paper is not sufficiently novel as most of the findings have been addressed before, or are trivial….Therefore publication in a more specific journal is recommended.

In fact, to our knowledge, no one else has addressed in a published form and in a direct manner the relationship between iPS cells and malignant cancer cells….and of course we don’t believe our findings to be trivial. Sure people talk at conferences and email each other about how they seem to get cancer-like cells as a “by product” when they make iPS cells, but no one has published on it.

Regarding the above reviewer comment, it’s nice that we got that dreaded “a more specific journal is recommended” comment, huh? Reminds me of my piece “Dirty Dozen Easy Steps to Kill a Paper” at #10.

Another reviewer:

this study offers little useful insights to the fields of stem cell and cancer biology.

Really? I disagree.

At another journal, like at the first one, the reviewers also had some helpful suggestions during two rounds of review and we addressed almost every point in a revision, but the paper was still somehow rejected. One review just felt very uncomfortable with iPS cells and cancer cells being similar. S/he said:

Many unsettling results….

Yeah, it may be unsettling that iPS cells share traits with cancer cells, but if that is the reality, isn’t it important that people know that and think about it, talk about it, and address the issue with eyes open?

Another reviewer, based on their comments, seemed flustered by the idea that iPS cells could be like cancer cells, plus  threw in #6 from my dirty dozen steps to kill a paper:

The manuscript is generally poorly written.

Ouch. Nobody is perfect, but I like to think we are pretty good writers in my lab.

In the end, forgetting all the reviewing and publishing issues…..I believe the reality is that iPS cell formation and cancer formation are similar, but distinct processes. The cells that one gets out of each–iPS cells and cancer cells–are also highly related in some important ways. It doesn’t matter who the messenger (author) is, this is reality.

Even Jaenisch said in his recent Cell paper (discussed here and here), somewhat incidentally it seemed, that many of the cells that come out of the iPS cell production process in his lab are in fact “transformed”, presumably cancer cells. But astonishingly he doesn’t discuss that or include that in his model.

I’m not naive enough to be surprised by the road that this paper took to get published. I’m just glad it is out there. Also, I hope the paper stimulates more discussion and more publications in the very important area of the relationship between iPS cells and cancer as well as the similarities more generally between pluripotent cells and cancer.