Friday, March 25, 2005

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!


Anonymous Anonymous said...

For me, the frequency of revertants- 10%- sounds hard to ignore.
But my first response also would have been to shelve that experiment and try it a way that didn't yield suprises. 

Posted by gaw3

3/26/2005 08:36:00 AM  
Anonymous Anonymous said...

I agree with gaw3. The problem is, sober experiments used to confirm such phenomena are often seen as boring in many academic circles... 

Posted by Vavoom

3/29/2005 12:32:00 AM  
Anonymous Anonymous said...

Yea, I agree also that 10% is hard to ignore - I should have mentioned that in my post...  

Posted by Andrew

3/31/2005 09:36:00 AM  
Anonymous Anonymous said...

Very interesting from a psychological point of view (I don't know enough about genetics to know what the hell is going on). There's a cognitive psychologist named Kevin Dunbar who's doing research on scientific cognition. He goes around to molecular biology labs, spends three months to a year observing and interviewing them, collecting all sorts of data, and then goes back to his own lab to analyze it. One of the more interesting of his findings is the way in which scientists handle unexpected results: through analogy. The analogies are almost always to similar results in previous experiments. Thus, when you get an unexpected result, like the one you describe in the post, the first explanation that you will inevitably come up with is that the results are due to the same factors that caused similar results in previous experiments. Only when the analogy breaks down will you be likely to look for alternative explanations. In this way, explanations for unexpected results are self-perpetuating: they act as schemas for understanding future unexpected results, and as humans, we have schema-driven minds (this also explains why paradigms are so important in the first place).

Anyway, great post. It raises some of the issues that we cognitive psychologists are working really hard to explain right now - within the computationalist paradigm, of course. 

Posted by Chris

4/04/2005 12:51:00 AM  
Anonymous Anonymous said...

For anyone reading this comment thread, Chris has a great post here  following up his comment above. 

Posted by Andrew

4/04/2005 10:49:00 PM  
Anonymous Anonymous said...

I heard Thomas Cech speak years ago about the discovery of catalytic RNA. He was frustrated for a long time by the failure of his students and post-docs to get RNA preps that were free of protein-they all had this enzymatic activity. He said when the light come on it was blinding. 

Posted by Jim Wallis

7/05/2005 05:36:00 PM  
Anonymous Anonymous said...

Yes, catalytic RNA is a great example! I believe there was a similar puzzlement when someone (I forget who) discovered that the lac operon in E. coli is positively regulated as well as negatively regulated.

Recently, I heard that one of John Gurdon's early students discovered cyclins years before Tim Hunt - but that all he saw was this protein coming and going on his Western blots and didn't know what to make of it. He must have been pretty annoyed when Tim Hunt's paper came out! (Meanwhile, let it never be said that major new discoveries are taken easily: Tim Hunt said that one of the reviewers on his now-classic cyclin paper said it was "wild speculation based on shoddy evidence" or something similarly scathing.) 

Posted by Andrew

7/05/2005 10:09:00 PM  
Blogger M.C. said...

Hi Andrew. Speaking of not ignoring anomalies, I'd welcome your thoughts on this evidence that Lamarkian-style effects occur in evolution.

Also this paper by the co-discoverer of retrovirii is very interesting.

You might also enjoy this discussion of how anomalies tend to be received when they contradict the favored model du jour.

This is relevant to the discussion as well.

Then after reading all that stuff, you might be open to this.

3/08/2006 02:53:00 PM  
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