By a stroke of genius and by change

In the last few months we have found out that we are facing a new epoch-making change. The rule called, “a gene, a protein”- that is all DNA information transferred in one direction only to molecoles which transcribe and translate it as amino acids – has now been questioned once and for all. Transcriptome (RNA) has not only the function of transporting and translating information but also the function of coordinating the complex work to make those thousands and thousands of components active in a cell, helping regulate DNA expression.
These secrets of RNA have been discovered by an international association made up of 190 scientists, called Fantom Consortium 3, whose leader is from Italy, Piero Carninci. We asked him to continue talking about this extraordinary discovery and the new horizons set.
We asked him to do so but from a particular point of view, that perspective related to the model called serendipity which, as written by Robet Merton, “refers to the quite common experience of observing an unpredicted, anomalous and strategic datum, which paves the way to the development of a new theory or improves an existing one” (Bologna, 2002).
To us, the point of view is important for at least three reasons: because it adds another element to a story, that story related to the discovery occurred by a stroke of genius or by chance, which refers to numerous and well-known people -including Francis H. C. Crick and James D. Watson who, as they themselves said, would have never discovered the double helix model related to DNA molecular structure without the help of Jerry Donohue, a young U S crystallographer.
Because it exceeds all usual logical terms related to scientific discoveries, it sees the study developed by a researcher as it really is and highlights what has been done to reach that discovery, as said Richard P. Feynman during his opening speech for the awarding of the Nobel Prize (Science, n°13, 12th August 1966, pgs. 699-708), ” when we write an article published in a scientific journal we usually refine our work as much as possible, hiding all traces, not making things complicated or describing as wrong the first idea occurred to us and so on [… so we end up losing our point of view …], what has been really done to reach that aim”.
Because it helps understand the reasons why in an atmosphere full of socio-cognitive interactions it is more likely that chance will pave the way to that particular discovery.
So, due to the collaboration with Mr Carninci, here we are summarising the new frontier of science related to RNA in the light of the definition of unpredicted, anomalous and strategic event given by the well-known U S sociologist.

Unpredicted event : Merton says that “a study directed to verify an hypothesis paves the way to a chance by-product, to a disregarded observation which is important related to theories which weren’t in doubt at the beginning of the process.
Was this the case occurred to you?

Yes, it was. We started from the idea that the genome produced mRNA (messenger RNA) which in turn produced proteins, that is what is stated by the central dogma related to molecular biology. At that time, late 1990s, it was understood that there were 70 to 100 thousand different genes which code themselves as proteins and these estimates derived from quite complex measurements of the number of RNAs inside a cell.
Our data of cDNA (complementary DNA), that is DNA copied by mRNA, gave consistent results with existing theories which in fact referred to 70-100 thousand but they were in contrast to the number of genes, around 22000, found in the human or murine ( of mice) genome. At the same time we began the analysis of our cDNAs and found out that half of them did not code as any proteins. However it took us a very long time to understand that these cDNAs were not fragments of a genome, cloned by mistake, but they were, in fact, a lot of different RNAs which did not code as proteins.

Anomalous: Meron writes that “the observation is anomalous, surprising because it seems inconsistent with the prevailing theory or with facts already stated. Either way the seemingly inconsistency arouses curiosity, so a researcher is given the opportunity of making sense of that new theory, and he or she puts it in a wider horizon in knowledge”.
What was your anomalous thing, your surprise?

As already suggested, from the analysis of these cDNAs we found these RNAs which did not have anything to do with the “central dogma”, in other words they did not code as proteins. At first we did not know what to do with these objects which seemed undesired and useless. I also had some problems with colleagues who thought that those RNAs were an artificial version of my experiments before taking into consideration something outside the dogma. At a meeting in August 2000 one of them maintained that those RNAs were only junk.
It is meaningful how long it takes you before observations which now seem logical can change the old dogma and how we as scientists are also not so much flexible, in one word it taught us a lot.

You found yourself in the same situation described by Herbert Butterfield. To him, “the most difficult form of mental activities to induce is the art of using the same handful of data as you had before, and placing them in a new system of reciprocical relations by giving them a different basic structure, and that means thinking it over again” (The Origins of Modern Science, 1300-1800, London, G. Bells & Sons, 1949, p.1).

Exactly. Fortunately after a while we started to think about what these RNAs could do and if their presence could help understand some regulating processes related to genes or differential splicing (splicing refers to a process which cuts and put together eukaryotic mRNAs into shorter pieces, which are then utilised by the cell in that form in order to produce proteins. We also noticed that these RNAs are expressed in various tissues, have different regulations and we, finally, decided to see their function, but this is the part already published in Science of September 2.

Strategic: Merton remembers that “when saying that an unpredicted event must be strategic, that is it must have the sort of implications which affect the general theory, we are obviously referring more to what the observer adds to the datum than to the datum itself. It goes without saying that the datum wants an observer to be sensitive from a theoretical point of view, in other words he or she must be capable of finding a rule from single things”.
What can be developed from your discovery?

The basic discovery is that there is a new world made up of RNAs which operate regulating various activities in a cell. Fortunately, working with a genome or transcriptome, all data are filed into public databases, for this reason every lab can improve its research using the Internet, which means universally.
The main observation is that the transcription and production or the presence of certain RNAs operate regulating other types of RNAs. Once understood the detail and specific features, these RNAs may be used as a means to control the expression of other RNAs. If, for instance, one of these RNAs to control were responsible for a desease – e.g. cancer, the possibility of regulating its expression procuces positive results. We know, for example, that drugs modulating gene activities or their products – that is proteins – create side effects and often toxicity. On the contrary everyone of us has RNA, for this reason finding RNA effectors can have huge advantages.

As we will partially see, we will now leave Merton and go to the point called “brain drain”, a situation which affects us all more and more when we meet people like you, who can demonstrate his value only leaving Italy.
It’s been written a lot about your “running away” to Japan in the last few weeks after publishing your discovery in Science. But is it really so? or did you, too, like Troisi (a famous Italian actor-director) – who in the movie called “Ricomincio da tre” must accept the idea of always being an immigrant, as people use to say, and not just a person who is travelling – leave Italy by choice and join the “brain drain” sort of club, not wanting to?

At first I would suggest everyone going abroad for a while, whatever can be his or her field or subject, because learning how to adapt yourselves to different cultures and languages gives you a lot of advantages apart from being an important way to improve yourselves from a personal and cultural point of view. Then I would like to add that unfortunately I did not have the chance to work as a researcher in Italy, even trying to do so for several years, either at a University or for the biotechnological industry.
I had a lot from Italy in terms of education and first work experiences. However just when I could have given something back to my country, there were no organizations collaborating in a productive way, at least in Trieste.
To be sincere before leaving, the idea of going to Japan seemed to me a very complicated and difficult thing. However once landed at Tokyo airport, things immediately changed for the best.
What at once stroke me was the end of the frustration I felt in Italy where questions I usually put to myself were: Will I be paid next salary? Am I supposed to change my job? If I don’t buy meat and only eat spaghetti will I have the money to buy petrol I need to go to the lab?
When in Tokyo I suddenly asked myself how to understand genome function or how to develop new types of technology to analyse many genes in parallel.

Something very different from Italy!

Of course. The fact is that in Japan, like in the USA, research organizations are well-organized (as Merton suggests, not in the interview). To research means to invest in knowledge. Working as a researcher is a real job, meaning that a researcher is not seen as a parasite but one that must produce knowledge (and licences) for the developing of the country.
So it is easy to understand that life in Japan is paradoxically easier than in Italy.

Will you ever get back to Italy?

A lot of people have already asked me this question. I don’t know. You never know! I can say that I dream of a situation where I can live between two different worlds and let them interact, that I’m still collaborating with great pleasure with Italian associations and researchers. But I can’t give up living in a country like Japan and in a city like Tokyo. I am probably too lazy to think of leaving everything here in Japan, get back to Italy and struggle in a University, only to have opportunities which are far smaller than here in Japan.



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