Wednesday, February 2, 2011

Letting go of mysteries

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 It was a mystery that would be left unpublished, unanswered.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.


ruchi said...

I miss your regular writing (though I understand that it hard to keep up.) But you write so beautifully ... I may not understand your mystery, but I hope it is solved anyhow.

Cloud said...

I love this post!

I, of course, know this feeling well, since I work in industry and my work gets directed by company priority. Priorities change, companies fail, jobs end, I move on... but I've left a long list of interesting things behind.

It is nice to remember that this happens in academia, too.

Cath@VWXYNot? said...

Sorry the side project isn't working out... but it sounds like it's for the right reasons, i.e. excellent progress on other projects!

Have you thought about submitting your original finding to a journal like, um, BMC Thingummyjig (Googles) BMC Research Notes? They're into publishing scientifically sound "snippets" that aren't enough for a full paper. That way you'd get a publication, and credit if/when someone else builds on your finding to solve the mystery.

Alternatively, you could pass the results on to a lab that's working on something similar with the understanding that they can take them and run with them as long as you're an author on the resulting paper?

Just a couple of thoughts!

The unsolved mysteries do still niggle, don't they? My PhD lab was working on why the mutated viral version of a transcription factor causes cancer when the original cellular version doesn't. I was trying to determine what made the viral protein activate some promoters that the cellular protein repressed, and vice versa, but never got a satisfactory answer. Others in my group and elsewhere were using microarrays and other tools to try and identify new target genes... there were a couple of interesting leads, but none of them provided a full explanation. AFAIK, no-one's managed to solve the mystery yet, and my old lab now focuses on DNA damage checkpoints (something that they'd just started as a side-project when I first joined the lab).

I have automated PubMed searches set up for both my PhD and postdoc fields, so hopefully one day I'll see an answer!

The bean-mom said...


Thank you. I've missed both blog-writing and reading of late...trying to get back on that horse =)

Cloud--yup, happens in academia all the time! Maybe not as bad as industry, but getting worse from where I stand. More and more it seems that it's about chasing funding rather than pursuing the ideas that really drive you. I know so many people of late who have had to drop promising projects, or even switch fields, because they couldn't get the funding needed... sigh.

Cath--you describe it perfectly--those loose ends just niggle at you, don't they? And thanks for the link to BMC Research Notes! I'd actually never heard of the journal before. Sounds like a great premise.

Anonymous said...

Sounds like you are back in the swing of things Bean-Mom. I didn't understand the details but my sense is you are enjoying your work.

So I decided to give a try at the ole blogging thing again. I've become a pissed off assistant professor half way through the tenure track ready to spout foul language that would do CPP proud. So I'm going the humor and sarcasm route. My new blog is at
Have you read the Dr. Seuss story "Sneeches on Beeches"?
--- your blog friend who has tried blogging several times and failed.

Anonymous said...


There's a t there.

Clearly I've lost my spelling ability too. That's what tenure-track does I suppose.

The bean-mom said...

Good to see you back, Dr. Sneetch! I left a comment on your blog, but it didn't show--can't remember if it was moderated or not? Anyway, I look forward to reading more of your posts (and hope you will soon have occasion to write more positive poetry about your department chair! =) )