April Scientiae Contribution: Persistence

March 30, 2009

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.

No Responses Yet to “April Scientiae Contribution: Persistence”

  1. Will be incorporating “Holy Fucknoly” into my everyday language. Thank you. And way to be fucking awesome, btw.


  2. Thanks PhysioProf – I totally needed that just about now.


  3. Dr. Feelgood Says:

    My main problem often comes from dead-ends where the techniques available to me (or to anyone for that matter) are not sufficient to get to the next stage of the research in my model organism. I need smarter people to invent new techniques I can use…Or I need to switch all of my work from rats to mice. That would involve an entire recharacterization of my model though….The thought makes me cry.
    Also, I really need to start vectoring/electroporating in widgets….I only just started qPCRing for widgets.
    Doc F


  4. Beautiful, PP. That “Holy Fucknoly” moment can sustain me for quite a while.


  5. Dave Says:

    It looks to me like the lesson is ‘Carefully screen all advice before potentially wasting time on a wild goose chase’. I always tell my students that it’s worth forgoing one-hundred half-ass experiments for one right experiment.
    I have no great personal anecdotes that demonstrate persistence. Except maybe ones that include lots of rewriting and making voodoo dolls. It’s hell getting bits of fingernails from anonymous reviewers. But you gotta do it right, says Houngan Pete, or it no work.


  6. I always tell my students that it’s worth forgoing one-hundred half-ass experiments for one right experiment.

    HAHAHAHAHAH! That’s a good one! “Buy low, sell high!” HAHAHAHAHAHAH!!!! Good advice!


  7. Dave Says:

    I also tell my students to eat right and exercise. And plan ahead.


  8. qaz Says:

    It’s worth doing one-hundred half-ass experiments as long as you keep your eyes open. It will set you up to do that one right experiment you never would have expected.


  9. Dave Says:

    Half-ass experiments are only for fools who don’t know what the results will be ahead of time. ‘Exploratory science’ is passe, dude. The best results are all generated by Photoshop. I ran a gel in 1997, and have been using it ever since.


  10. S. Rivlin Says:

    Wll, nw w ndrstnd why ths pstdc f CPP, wh hs spnt 5 yrs n hs lb nt knwng wht th hll sh s dng, s s prsstnt. Sh fllws n th ftstps f hr hly fcknly mntr.


  11. Anonymous Says:

    when I was a postdoc I once made a bet (with other members of my group as witnesses) that i would forego all coffee – I was a caffiene addict – until I had achieved a certain important result in my experiment. Of course I expected this result to only be a couple weeks away when I made this declaration. Turns out it was TWO YEARS before I was able to have coffee again. And no I didn’t cheat in the interim or try to find loopholes in the bet.


  12. “‘Exploratory science’ is passe, dude.”
    Hahahahaha. I love you people working on humans who think we know everything there is to know in biology. ‘Exploratory science’ isn’t quite disco, my friend. I bet you think that we know all of the species in the world too, and that “Eukaryotes” = animals, fungi and maybe plants.
    Looks like Sol gave up vowels for lent.


  13. Dave Says:

    Why the hell should we want to catalog all the species in the world? I mean, seriously, people can’t even agree on the definition of a species! There are more important things to fund than camping trips to exotic locales!
    And what’s this about eukaryotes being plants and fungi? What the hell is a eukaryote? I thought there was only vertebrates and non vertebrates (e.g. model organisms). Next you’ll be trying to tell me that mice aren’t humans and gut biota aren’t just an infestation in dire need of antibiotics.
    Sheeesh. I hate people who think we need to know shit. Grad school is for cranking out papers in prep for becoming a postdoc and cranking out more papers, dude. Not for learning shit. We have wikipedia now.


  14. S. Rivlin Says:

    &qt;Wll, nw w ndrstnd why ths pstdc f CPP, wh hs spnt 5 yrs n hs lb nt knwng wht th hll sh s dng, s s prsstnt. Sh fllws n th ftstps f hr hly fcknly mntr.&qt; thnk DM nsrtd prgrm tht tk ll th vwls t f my cmmnts. Hr’s (hpflly) th cmmnt n fll: Wll, nw w ndrstnd why ths pstdc f CPP, wh hs spnt 5 yrs n hs lb nt knwng wht th hll sh s dng, s s prsstnt. Sh fllws n th ftstps f hr hly fcknly mntr.


  15. Amanda Says:

    Totally needed to hear this right now. I’ve spent a good amount of time following random leads to do this particular experiment right. I think I’m getting close, but… damn can this get discouraging.


  16. Hum Says:

    CPP, that’s all fine and well, but most of us these days do not have 5 years or however many years of postdoc funding available. Case in point, despite being in a lab that publishes only in Glamourmags, 4 of our postdocs’ 2 or 3-year fellowships are expiring this year. No one is quite ready to leave yet (publish). Were you able to publish other things in the meantime while you were working on your widget project?


  17. Were you able to publish other things in the meantime while you were working on your widget project?

    Of course. Every scientist should be pursuing a mixture of high-risk/high-reward and lower-risk/lower-reward projects. Had the high-risk/high-reward widget project not ultimately succeeded, however, I would not be sitting where I am now.


  18. Nat Says:

    Persistence goes a long way, and that’s some impressive persistence you got there Comrade.


  19. drdrA Says:

    There is a second very important lesson there- finding the right person to help you can be laborious, but once you find that person you can do awesome things together. Never let them go once you find them.


  20. Jim Thomerson Says:

    I think this is an original comment, but maybe not. Persistance is not the only virtue; however, lacking it, none of the other virtues are worth much.


  21. My PI recently told us the story of the first couple of years of his postdoc, also squandered on a project that went nowhere. These stories are amazingly heartening to everyone who knows that their PI has glamourMag publications every few months. They give us hope for the future…Thanks CPP.


  22. Scicurious Says:

    subcloned the motherfucking widget
    I must use this phrase in the lab today.
    And a good lesson, evaluate very carefully your experiments. A little help with this and I would not be where I am today…sigh…


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