In this business, I have begun to learn to let go of mysteries.
In graduate school, my lab studied a large family of signaling proteins. We were particularly focused upon one particular subunit of a heterotrimeric signaling complex. The “gamma” subunit comes in many flavors or isoforms—twelve different isoforms, the last time I checked. Why? This was the burning preoccupation of my PI. Why so many isoforms? These subunit variants have little amino acid sequence similarity (between 15-30%) and are all exquisitely conserved across mammalian evolution. That suggests that there are important functional differences between these isoforms. But what the hell are those differences? What are these protein subunits really doing in the cell? Why, my PI would frequently say with exaggerated frustration, are there so many of them?
It’s been over ten years since I left that lab, and the answer is still unknown. My old lab has made important progress on the function of some of these proteins, but my old PI’s question is essentially unanswered. It was a question that preoccupied me for a while, but I long ago left that field. The answers will not come from me.
During my first postdoc, I became absorbed by a different set of questions. And in the year before I left that lab, I made some interesting observations. Overexpression of a certain gene in a certain cell line led to striking changes in cell morphogenesis: the cells were suddenly able to form long branching tubules that could invade through extracellular matrix. Why? How the hell did they do that? Interesting, my PI at the time commented, and then remarked that he had no clue what it meant or how to pursue the finding. My time in that lab was limited; my fellowship funding had just run out, and I would be out the door in a few months. There was simply no time to follow up on my discovery. It was a mystery that would be left unpublished, unanswered.
The image of those branching tubules from my first postdoc has stayed with me. When I joined my current lab, I decided to make use of the cell system I had learned during my first postdoc. And I realized that some of the cell lines I had made during that first postdoc would be perfect controls for experiments I was planning for my second postdoc. I further realized that this was a chance to solve old mysteries: the assays I had planned for my new project could also be applied for that old project I had abandoned. I would crank all my cell lines (old and new) through the assays together; I’d get two papers for the price of one! I told my new PI my idea, and he gave me his enthusiastic support. I wrote my old postdoc PI a long e-mail, catching him up on my career transitions, asking him for my old cell lines, and outlining a collaboration and project proposal. In response to my one-page letter, he sent these exact lines: “Great to hear from you. Happy to send the cells.”
Well, you may have guessed how this ends. In theory it sounds easy to process multiple cell lines together through complicated assays; it sounds easy to balance different projects. It is, most of us find, not that easy. Especially when my primary project began taking on intriguing new dimensions. The work from my first postdoc did indeed serve as useful controls, but they have not served for anything more.
“We need to look over your goals,” my current PI said shortly after the new year. He’s big on making goals in writing and revisiting them regularly. We looked over the list of goals I’d written in the fall. One of the first was to complete that project from my first postdoc lab, and get out a minor publication on it. “I think we’ll going to have to drop this one,” I said regretfully.
“You don’t want to do it anymore?” he asked.
“I would LOVE to do it,” I answered. “But I just don’t think we can.”
“It would benefit you more than me,” he said honestly. “I think you’re right. I don’t like having my people drop their goals, but you’re right.”
I don’t like it either, but my primary project, the R01-funded project that funds me and this lab, is the one of primary importance. It’s the project that will help determine, in a few year’s time, whether or not this assistant professor gets his R01 renewed and this lab survives. And that primary project has taken off. It’s soaring. And it’s in a wide open field—I have no competitors (that I know of). That side project I dreamed of, an old observation of branching cells? It’s in a competitive area, and the work involved to bring it to publication would be a risky commitment, and far more than I can afford.
So I find myself again saying goodbye to a past mystery, even while the mysteries of my current project deepen. I wonder if anyone will follow up on that long-ago observation I made in my first postdoc? Nothing has been published on it. Perhaps no one has yet noticed the effect?
That old mystery may someday be solved. But—like the mysteries of my grad school lab--it will not be by me.