April Scientiae Contribution: Persistence

This month’s Scientiae is being curated by Candid Engineer, and the topic is “Overcoming Challenges”. Comrade PhysioProf has previously alluded to the fact that in his experience, the most important single character trait required for success in science (or any creative professional pursuit) is persistence. This is because persistence allows one to overcome challenges that seem insurmountable.
Inside the crack, I provide an anecdote from my own career that illustrates this maxim.

When I was a post-doc, I started my research in my mentor’s lab studying the cellular components we were interested in–let’s call them widgets–using reconstituted biochemical and biophysical systems in vitro. During one of our many wide-ranging discussions of our work, my mentor mentioned to me a relatively vague idea that he had for taking the kinds of widgets we were studying in their own right, and deploying them in vivo as a tool for engineering the response properties of particular cells, and thus providing an experimental entry point into understanding how those cells participate in tissue, organ, and organismal physiology.
Well, this sounded like a fucking great idea, so I began thinking really hard about particular species of the genus of widget that we were studying would be a good candidate for deploying in vivo. I scoured the literature, found what looked to be a great candidate widget, got the clone from the discoverer of that particular widget, and started subcloning into DNA vectors for initial in vitro characterization.
At the same time, I needed to figure out what a suitable model system would be for introducing the widget into cells in vivo and then proceeding with tissue, organ, and organismal physiological measurements of the effects of the widget. The lab next door to ours happened to work on a potentially suitable model organism, so I went to talk to the PI.
He was reasonably supportive, and gave me appropriate DNA constructs for introducing the widget into the organism. I scurried back to the lab and subcloned the motherfucking widget into the constructs. I then went to the PI and said, “OK. I’ve got the constructs. Help me get them into the organism.” So he grabbed one of his trainees and asked her to help me.
Well, she was not very enthusiastic or communicative, and I struggled with little real help for months before realizing that without genuine help, there was no way I was going to successfully implement proof-of-principle of our idea in this model organism.
Around this time, a very senior PI had joined the department from a different institution, and I realized that the particular organ system that he studied in a different model organism would also be a suitable context for testing proof of principle. So I went to see him. And he suggested a very complicated approach that required a huge amount of very complicated subcloning. Having no experience working with that model organism before, I had no way to assess the viability of what he was suggesting, so I scurried off and started subcloning.
Well, this fucking subcloning scheme was so ridiculously complicated, that I spent nine months just getting the final correct construct. But I did it!! So I went back to that PI and said, “OK. I’ve got the constructs. Help me get them into the organism.” So he grabbed one of his trainees and asked her to help me.
Well, this trainee was only marginally more helpful than the one in the first collaborative lab, but we did manage to obtain a few strains of the model organism that had potentially incorporated our widget. Unfortunately, by one of our cellular assays, we could not detect our widget in the cells of interest. However, and to my great surprise and excitement, we saw a very dramatic organ-level physiological phenotype in the organ that contained the cells of interest!
So I spent many months characterizing this phenotype, and doing a bunch of control experiments, and FUCKITY FUCK! It was a complete artifact! And the cause of the artifact was the what-I-soon-realized-to-be-totally-fucking-harebrained scheme that the PI had suggested to me, and that *any* of his post-docs would have immediately recognized as totally fucking stupid.
Well, at around this time another new faculty member joined the department, this one an entry-level tenure-track assistant professor who worked ont he same model organism as this latest failed attempt at proof of principle. Being the inquisitive sort that I am, I looked up his publications and was all like “HOLY FUCKNOLY!!! This dude has EXACTLY the technical infrastructure to do EXACTLY what we want with our widget, and GODDAMN how could I have wasted over a year on that crazy-ass scheme suggested by the other PI!?!?!?”
So I went to see the new PI dude, and I was all like, “Dude, this is what I want to do! YOU GOTTA HELP ME!!!!” And he was all like, “OK. Let’s do it!” I scurried back to the lab and made the (very simple) constructs in just a couple weeks, and then the new PI dude and I sat down together side-by-side and performed the procedure to incorporate our widget into the organism, and we ended up with a good number of strains that had potentially incoporated our widget.
As I began the simpler initial assays to see if I could detect our widget in the cells we cared about, I was all like, “HOLY FUCKNOLY!! THERE IT IS!!!” And further physiological assays at the tissue, organ, and organismal level established not only that our proof-of-principle for using widgets as tools in vivo in this way was totally successful, but that we had revealed KICK-ASS NOVEL BIOLOGY!!!111!!!ELEVENTY!11!!!111!!
The moral of this story is to never lose sight of one’s scientific goals, no matter how many obstacles are encountered on the route to achieving those goals, and to persist and persist and persist until one either achieves those goals or it becomes clear that the goals are genuinely not attainable.