Mind reading, big pictures and little details

The one thing about being a postdoc is that you’re no longer green behind the ears, and have developed somewhat of a decent bullshit detector. You’re also a little less in awe of your boss or most other independent investigators. And hopefully most postdocs become rather good at reading between their lines when discussing projects or experiments with their bosses. At least, when the boss says “this won’t work”, or “just go and do this”, you don’t just take their word for this.

Here’s my thumb rule for those statements. If your boss has this really nice but far fetched idea, and is really excited about it, he/she will say “these experiments are easy, you need to go for it. All you need to do is purify a couple of proteins, throw in some reaction mixtures and read your data”, you can almost be sure that the experiments will involve about two years of backbreaking work involving 16 hour workdays that go on for months, and plenty of labor in the 4 degree cold room. On the other hand, if you go up to your boss and discuss a proposal/idea you have come up with and the boss says “that’s way too hard, and I don’t think it’s going to work”, it means (a) the boss isn’t really interested in that idea but wants you to work on his/her crazy idea (see above) or (b) hasn’t really thought much about it since you are the one who has come up with the idea or (c) both.

One sometimes wishes for those early days as a rookie graduate student, in awe of the boss, naïve, gullible and completely willing to try the most insane or undoable experiments possible as a thesis project, only because the boss is such a famous scientist, he/she has to be right.

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On a related note, you can safely assume the thumb rule that any senior investigator who is exceptionally creative with big picture ideas (and who hasn’t done benchwork for 20 odd years) is going to propose the maximum number of “that’s easy” experiments that hang on a slender thread of a hypothesis (the kind that goes “if this were true, then this and this and this will be true, and so this story will be awesome”. Except that the very first “if this were true” is a big if). You’re also certain to be doomed to some years of crazy and hard experiments that are going to tell you that the first “if” is false.

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The phenomenal growth of molecular biology through the nineties and now the past ten years has made many biological experiments amazingly easier, and I’m very grateful for that. But I think it has done enormous damage to good, quantitative biochemistry (and biology in general).

The beauty about a lot of modern molecular biology is that it is carried out using kits made by companies, which the average trained monkey can execute. You don’t need to know most of how it works. Also, the reagents and kits have been made so good that you don’t even have to worry too much about being quantitative in your experiments. They’ll usually work (somewhat). You can throw in a little bit of an enzyme or lots of it, or a little bit of salt or lots of it, use approximate concentrations and approximate conditions and still the experiment works. Here’s a real example. Set up a PCR reaction with a Taq polymerase kit, good primers and a plasmid template. Now spit into that reaction tube, double the volume of the reaction with your saliva, and then start the reaction. I can pretty much guarantee that the reaction will still work.

What this oversimplification of molecular biology has done is it’s created (or is creating) a pretty large number of extremely sloppy biochemists. I see far too many undergraduates or graduate students who (a) don’t really understand the concept of molarity, normality, salt concentrations, pH, metal or buffer effects and (b) also think that just because they think it doesn’t matter, it really doesn’t matter. For example, they think that they can purify a protein on an ion-exchange column using either a 100 mM sodium chloride solution or a 200 mM sodium chloride solution and it won’t matter much. Or their buffer can be at a pH of 6 or 7 or 8 and their protein will show the same activity. And most of them don’t think pH meters need to be calibrated (and don’t know how to calibrate it anyway).

All of this, combined with the extreme confidence of today’s kids, makes for very interesting presentations in student seminars where they show rubbish experiments, and then authoritatively state “I think our hypothesis is wrong” followed by “this company that supplies us with X reagent sucks. My experiment didn’t work because I think the reagent has gone bad”.

If you’re going to make a statement like that, you need to back it up with data. But who needs data these days?

We need some more hardass investigators, who won’t be scared to crack the whip.