A Mystery Result Caused a Hypothesis Reckoning

In the 1970s, I was at Michigan State University, studying mutations in DNA repair that led to skin cancer in people with xeroderma pigmentosum. At that time, researchers hypothesized that carcinogenesis happened in three stages: an initiation stage where a mutation occurs, a promotion step where non-mutagenic factors allow the mutated cell to grow into a benign tumor, and then a progression phase where the tumor becomes invasive. Researchers couldn’t explain what occurred during the promotion step, but I believed that all cancers arose from some factor inhibiting the DNA repair process which led to mutations.

Around this time, I read a paper that hypothesized that this second phase involved non-mutagenic tumor promoters, such as a compound called TPA, to inhibit DNA repair to allow mutations to occur.¹ Since I was convinced that all cancer mutations involved errors in DNA repair, I wanted to test how TPA affected this process.

I had my graduate student set up an in vitro assay to explore the mechanism of TPA. Initially, because some of my previous work showed that TPA was not a mutagen, I didn’t think that it would inhibit DNA repair and thus would not rescue cells if we exposed them to UV light. However, after running the experiment, my graduate student told me that, in the presence of TPA, the cells survived!

My initial thought was that this couldn’t be. I watched him repeat the assay to make sure he wasn’t doing something wrong, and I couldn’t find an error. All of my work pointed to tumor promoters not inhibiting DNA repair, but the results of this experiment suggested TPA did just that.

I can’t remember how I came across the concept of intercellular communication through gap junctions, but once I did, we quickly realized one mistake in our experiment: my graduate student accidentally used too many cells. This meant that normal cells and enzyme-deficient cells touched one another.

Indeed, when we repeated the experiment with a different model, cells that were in contact with each other died, but TPA prevented this. It appeared that this compound shut down intercellular communication.²

Of course, convincing researchers in the field of our findings was challenging. Confronting prominent scientists can be difficult because their critiques can feel like they are attacking you as a person instead of just your ideas. I would try to remind my students of this: when you are facing these criticisms, you have to separate your findings and ideas from your personality.

Moreover, this apparent failure led us to finding a new mechanism in the tumor promotion process. Looking back, I also remember how my graduate student watched me struggle with my hypothesis and previous findings being challenged and also the experience of reviewing our data, techniques, and other explanations to finally come to the correct explanation. I think that as a result, this “failure” allowed my student to become a great scientist, and me to be a better one.

This interview has been edited for length and clarity.

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