Brenner, S., Jacob, F., and Meselson, M. 1961. An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Nature (4776): 576-581. [PDF]
Francois Jacob, our hero many times over, died on April 19, 2013. Much has been written about Jacob, including the most inspiring book of all time, his own incredibly-titled autobiography, and many simply jaw-dropping remembrances of his life and career (which didn’t even begin until the age of 30, prior to which point he was fighting against the Nazis as a military doctor). In light of this, we wish to pay our humble respects to Jacob by focusing in on one of his most truly moving papes, in which he helps figure out that mRNA is the intermediate messenger between DNA and protein. As someone who has grown up learning about DNA, RNA and protein from textbooks beginning at the age of 13, it is unspeakably humbling to realize that even such awe-inspiring knowledge as this was unleashed in the form of a single Pape. Given the torrential onslaught of meaningless papes which flood our poor inboxes daily, it is mindboggling to imagine what it must have been like when a pape of this stature and dignity could simply show up in Nature one week. We are all indebted to the True Pape such as this one, and we continue to pray for many more like it. In tribute to Jacob, we heartily recommend you enjoy his wonderful papes first-hand.
By the beginning of the 1960s, it was known that the physical basis of heredity was DNA, and it was strongly believed that the sequence of bases in DNA was co-linear with the sequence of amino acids within proteins. However, it was also known that DNA doesn’t leave the nucleus, whereas protein synthesis takes place in ribosomes, which are in the cytoplasm. The question, therefore, was how does the information get from the nucleus to the cytoplasm, and what is the molecular basis of this process? The best guess at the time was that each ribosome acted as a specialized template for a specific protein. Given that ribosomes are made of RNA, after all, it made perfect sense to imagine that the ribosomal RNA contained sequence-specific information which could encode a specific protein.
[At this point, as an aside, and just out of curiosity, would any of you know how to prove that mRNA is the messenger, even knowing the right answer beforehand? Even if you could go Back to the Future 2 with the book of correct answers to biology, could you figure out how to do these experiments to prove it? I sure couldn’t. There are those who believe that science progresses largely within social constraints, and that the intellectual contributions of specific individuals should not be hero-worshipped, and that somebody else would have figured it out pretty soon anyway. This may or may not be the case (it isn’t - you should definitely hero-worship Jacob and his crew), but I dare you to let this pape wash over your brain and not “need a minute” to collect yourself].
In any case, there is a true story where Jacob visits Brenner and Crick, and he’s telling them about his latest results implying the existence a short-lived molecule between DNA and protein, and they’re all at a party (probably much like the exact opposite of the moon-tower kegger in Dazed and Confused), then someone recalls a recent pape showing that after a virus infects a cell, there is this short-lived species of RNA that arises, which the authors hadn’t known how to interpret in their own pape, and then apparently everybody at the party starts screaming and Jacob doesn’t really speak English but picks it up quickly enough, and later that night they have all of the experiments planned out, and within weeks and they’re headed to Matt Meselson’s lab to use his ultracentrifuge.
The basic set-up is this: grow a bunch of bacteria in heavy nitrogen and carbon, infect them with the virus, and then transfer them immediately to a light medium. Any new products will be light, and any old products will be heavy, and the two can be separated by density in an ultracentrifuge in a cesium chloride density gradient (ground-truthed in Figs. 2 and 3). Using this set-up, they show that upon infection with virus, a new species of RNA is formed (Fig 4), which has a short half-life on the order of 16 minutes (Fig 5), and which associates with the old, heavy ribosomes (Fig 6). That is, the new RNA does not make new ribosomes, but represents a new, previously unknown species of RNA (the messenger!). They then show, using labeled sulfur, that the newly synthesized viral proteins, together with the new RNA, are also found on the old, heavy ribosomes (Figs. 7 and 8), disproving the idea that specialized ribosomes form each protein individually. Hallelujah!
In addition to figuring out one of the basic truths of life, there are two details of this pape which are particularly insane. (1) These experiments, with the exception of the sulfur stuff, were done by Brenner and Jacob in a period of four weeks, in a dirty basement, while visiting a lab that neither Jacob nor Brenner typically worked in. What’s more, the experiments completely failed for the first three weeks and the actual data was gotten in that one final week when no one believed in them. (2) The heavy carbon, which was necessary to separate out old and new ribosomes, was not just something you could buy. According to this great interview with Meselson, it did not exist anywhere in the USA or Japan, and so he got Linus Pauling to directly ask the head of the Soviet Academy of Sciences to make one gram of it for them, which they did by thermal diffusion, over the course of one full year. They delivered it to Meselson as a gas, which Meselson then turned into carbon dioxide that he fed to algae, which photosynthesized the heavy carbon into their bodies, which he then fed to yeast, which he then used to make yeast broth to feed the E. coli. Point is, these people were not kidding around at all, and we are eternally grateful for that.