A puzzle worth a Nobel Prize.

flickr image by M0nniOnce again, it’s Nobel Prize time. The first prize to be awarded, as expected, was for Physiology and Medicine and went to Craig Mello and Andrew Fire. Mello and Fire were awarded for their discovery of

a fundamental mechanism for controlling the flow of genetic information

namely what is now known as RNA interference or RNAi. Uncommonly for a Nobel Prize, this year’s award came relatively soon after the discovery to which is referred. The paper describing Fire’s and Mello’s work was published in 1998 on Nature. This has been interpreted as a sign of the outstanding importance of their discovery since usually it takes decades for a work to be recognized valuable of such an award. Now, the very fact that someone is publishing a work that is so important to inaugurate a brand new field from scratch is definitely rare and it is something that every scientist dream about. It does happen periodically and many times is, indeed, well recognized for instance with a Nobel Prize. What is very rare, though, it’s the discovery to come out of the blue, completely unexpected. Was this the case for Fire’s Work (he was the corresponding author in the paper)?

At first glance it might seem so. On the same issue of Nature, for instance, the paper was accompanied by a News and Views kind of article, discussing the discovery and explaining why it was so important to people not familiar with that field. In that news and views the authors ask themselves “What kind of mechanism have Fire and colleagues uncovered?” and they answer in this way:

Fire and colleagues have uncovered a complex and intriguing mode of regulation in C. elegans. Does dsRNA perform a biological function in C. elegans (and is this function titrated out by the microinjected dsRNA)? Does a similar phenomenon exist in other organisms? What would happen if transgenic animals or plants were generated expressing both the sense and antisense strands of a transgene? A similar mode of action would not be suspected to occur in mammals, because injection of dsRNA is often used as a control for antisense experiments, albeit at the individual cell (and not organism) level. Nevertheless, perhaps specific ‘knockouts’ can be generated this way, for organisms in which genetic material cannot be delivered by microinjection. Whatever the mechanism might be, dsRNA-mediated inhibition of gene expression will provide a useful alternative for working out gene function in C. elegans and, maybe, in other animals and plants.

There is no doubt that Fire’s and Mello’s paper was outstanding: not just a breakthrough discovery but even all based on an extremely simple experiment, so easy to do but that nobody tried before (see Fig.2 of that paper, that is *the* experiment). In other words: originality! This is what Science should be.

On the other hand, although Mello and Fire’s was indeed a brilliant one, it did not completely come out of the blue. RNAi has a longer history.

Birth of the whole RNAi story can be pointed to two particular papers: one from researchers at University of California titled Introduction of a Chimeric Chalcone Synthase Gene into Petunia Results in Reversible Co-Suppression of Homologous Genes in trans and a second one from researchers at the University of Amsterdam with the more explicit title Flavonoid genes in petunia: addition of a limited number of gene copies may lead to a suppression of gene expression. Both teams of scientists wanted to create darker petunia flowers; to do so they overexpressed by means of transgenesis more copies of the gene involve in the metabolism of the pigment: the Chalcone Synthase (or CHS). Unexpectedly what they obtained was the opposite effect: more than half of the resulting flowers were completely white and the remaining ones had significantly lost their pigmentation:

We have shown, unexpectedly, that the introduction of a CHS transgene resulted in a dramatic reduction in the expression of a homologous gene in a large proportion of independent transgenotes in three different genetic stocks.

What is the phenomenon behind? Well, Alexander Van Der Krol and colleagues, authors of the second paper, offered an enlightening explanation to the phenomenon. It’s 1990, first example of such an event and they write:

The mechanism of suppression by sense genes may involve interference of RNA strands with the transcription process itself. The transcription process may be blocked by interaction of RNA with duplex DNA, resulting in a triple helix structure (Hogan and Cooney, 1989). Alternatively, interaction may occur with the DNA strands when they are separated during the transcription process. DNA modification processes, such as a cytosine methylation, could subsequently silence the gene permanently.

It’s surprising to see that not only they introduced the name of RNA interference but also that they could foresee what has started to emerge only in recent time, years after that moment: the effect of epigenetics on permanent silencing of the gene. Most of the early discoveries of RNAi happened in the following years in that very same biological system: petunia flowers and CHS gene. Plant biologist get very close to the solution of the puzzle: in 1998, one year before Fire and Mello’s paper, Richard Flavell published a work in Cell in which he proposed a mechanism of action of that phenomenon, involving double strand pairing of RNA molecules! He got it right, but it didn’t look outside the box. Sticking to the very same system has been the fortune and the mistake of plant biologists! Many people wondered whether the Nobel prize should have been awarded to some of these plant guys too, given the fundamental role they had in the early phase.

As a matter of fact the explosion of RNAi arose after Mello and Fire’s paper. They took a problem from a different organism (year before), studied it in C. elegans showing that it was not really peculiar to plants and they did the experiment: that very simple experiment that was to be done, and that nobody had thought before. They solved the puzzled and won the prize.

Press Release: The 2006 Nobel Prize in Physiology or Medicine

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