Paradigms, anomalies, and ground-breaking discoveries

When I first read Kuhn's "The Structure of Scientific Revolutions," I was deeply disturbed. I'd grown up believing that scientists are dispassionate collectors and analyzers of data who don't allow anything to stand in the way of The Truth. Kuhn argued instead that scientists work within models ("paradigms") that structure the way they interpret data - including what data they toss out as "experimental error." Scientists are largely trapped within their paradigm until the number of anomalies increases to the point that the cognitive dissonance is too much, and someone eventually comes up with a new (often incommensurable) paradigm that solves the problem. Kuhn was careful to say that this was not a limitation of science - rather, it is the key to science's fantastic success, in that it focuses our attention on questions that can actually be answered. Still, I was not too happy with this idea - it seemed to cast doubt on the objectivity, and therefore the validity, of science.

Then I started doing actual research.

In fact, the uncertainties involved in actual experiments are so huge that there is no way you can make sense of anything without a paradigm. For anything beyond the most simple of experiments, you have to take a lot of things for granted. And the truth is that experiments fail so often that it is quite sensible to dismiss experiments that don't work as expected as unexplainable failure rather than a blow to the reigning paradigm, and to pursue more productive lines of research instead. But sometimes the paradigm really is wrong, and we just hope that Kuhn was right and eventually people get bothered enough by all the anomalies to toss out or revise the old paradigm.

I bring this up because of the finding reported in Nature that there may be inheritance of genetic sequence information outside of the DNA genome (or as the paper's title says, "genome-wide non-mendelian inheritance of extra-genomic information"). (The Nature article requires a subscription; NYTimes reports here.) Plant geneticists found that in the standard plant genetic model (Arabidopsis thaliana), parents that had both copies of a certain gene mutated sometimes produced offspring that inexplicably recovered the wildtype version of that gene.

This is the kind of bizarre finding that, if you are too stuck within a paradigm, you just toss out as some weird error. I used to work in a fruit fly lab, and we constantly worried about contamination of fly lines (i.e., if a stray fly sneaks its way in while you are transferring flies from one bottle to another). If you had a bottle full of fly mutants with white eyes (the wildtype is red), and suddenly one day some red eyes (or orange eyes, which is the heterozygous color) appeared, you'd think the stock got contaminated, and you'd just throw out the red-eyed flies (or, more likely, the entire stock).

Now, the genetic anomaly in the Arabidopsis case is not as severe - for example, contamination is less likely because plants don't move, and Arabidopsis can be self-fertilizing. But still, I imagine that if I had discovered this, my first thought would not have been "wow! this is something new and exciting!" but "oh God, what the hell went wrong this time?" When I read the paper, I got this sense a little - as if the researchers were frustratedly trying to find out what was going wrong with their experiment, only to find that every possible conventional explanation within a traditional Mendelian paradigm failed. (It wasn't an epigenetic modification, or a suppressor mutation, or contamination, or outcrossing, or high mutation rates in that part of the genome; nor is there any additional sequence for that gene in the DNA genome.) And that's when you get really excited.

You get excited because this finding reveals yet another hole in the so-called "Central Dogma" of molecular biology, that sequence information flows from DNA to RNA to protein. Now, the Central Dogma has been full of holes for a long time (retroviruses 'reverse transcribe' RNA into DNA; prions transmit information from protein to protein). But for eukaryotes, DNA has always been the permanent repository of genetic information - RNA is thought to be too unstable. Yet here you have the fixing of a mutated gene, clearly being fixed from a wildtype template, where the DNA genome does not contain another wildtype copy of the gene. The researchers have proposed double-stranded RNA "holdovers" from previous generations that can be used as templates for gene conversion if the plant is under stressful conditions. Multigenerational RNA stability is totally mad - but this is the least mad explanation there is. I'm excited to see what happens next.

Just imagine if the researchers had written it off as some unexplainable experimental mishap and moved on to a more productive (read: more conventional, understandable) line of research. Kuhn's paradigm theory relies on the willingness to escape the paradigm to explore the anomalies that become ground-breaking discoveries. And we should be thankful that people do take risks like this - it keeps science self-correcting, and interesting!