What is mRNA? Solving a molecular mystery
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You don’t have to have a degree in genetics to have heard of DNA - or deoxyribonucleic acid, to give it its full name. The three letters, and the iconic image of the twisted double helix, are found everywhere from news stories and advertising to films, fiction and pop songs.
We’ve talked about the discovery of the structure of DNA and the genetic code before, back in episode 9 of series 3 - Twisted History - and episode 16 of series 1, Genetics by Numbers. And I’m pretty sure that by now you’ve picked up enough knowledge from all our podcasts to know that DNA is the genetic code containing the instructions for life found inside all cellular organisms from bacteria to blue whales (as far as we know).
By 1944, scientists working with bacteria had figured out that DNA was responsible for transmitting inherited characteristics from one generation to the next and was in all likelihood the stuff that genes were made of. However, this was still viewed as a hypothesis rather than confirmed fact for a further decade or more, and many researchers still believed that genes were actually made of proteins - the molecules that make up the structure of cells and carry out all the chemical reactions of life - rather than DNA.
One of the biggest stumbling blocks was the fact that while researchers working through the late 40s and 50s knew that DNA existed and probably contained genetic instructions telling cells to do stuff like build proteins, they couldn’t see the link between the two.
Even once James Watson, Francis Crick, Rosalind Franklin and Maurice Wilkins figured out the double helical structure of DNA, it still wasn’t clear how it actually worked. How on earth did the information within genes get interpreted by the cell and turned into proteins, when the two seemed completely unrelated and unconnected? It was a real headscratcher.
Nonetheless, there were plenty of ideas. The notable physicist George Gamow, thought that proteins might directly assemble on DNA, directed according to the specific sequence of the four molecular ‘letters’ of the DNA alphabet, A, C, T and G (the molecular building blocks, or bases, adenine, cytosine, thymine and guanine). But while it was a neat hypothesis, there was a problem.
DNA is found in the nucleus - a biological bag in the middle of the cell. But most proteins are outside the nucleus, and were probably made there too. So, Gamow’s idea was a non-starter.
Instead, scientists began to focus their attention on another component that they’d discovered inside cells, along with proteins and DNA: RNA.
Meet RNA
RNA - ribonucleic acid - is far less famous than its deoxy relative, although it’s chemically very similar. While DNA is double-stranded, forming that famous twisted ladder, RNA is single stranded - imagine just one half of the ladder, as if it were cut straight down the middle of the rungs.
Like DNA, RNA made of a long chain of chemicals known as nucleotides, with the main difference being that the sugary molecule that makes up the ‘strut’ of the ladder is ribose, rather than deoxyribose, and the chemical ‘letters’ spelling out the sequence are A, C, G and U - adenine, cytosine, guanine and uracil, rather than the adenine, cytosine, guanine and thymine of DNA.
Importantly, RNA was found outside the cell nucleus in the cytoplasm (that’s basically the gloop that contains all the stuff that isn’t the nucleus), and levels of RNA seemed to go up a lot when genes were active and lots of proteins were being made. So, was this mysterious molecule the missing link between DNA and proteins?
The mystery deepens
Adding to the intrigue, researchers had discovered an abundance of tiny, complex particles in the cytoplasm made of protein and RNA bound together, which they called ribosomes. Clearly this was another piece of the puzzle, but there was still something missing.
They had DNA, RNA, proteins and ribosomes, but no clear path of connection between them. How was the genetic information encoded within DNA ‘read’ then ‘translated’ into proteins? At this point, you may wish to imagine the meme of the guy standing in front of a board plastered with pictures and red string.
How on earth did it all fit together?
It was Francis Crick, one of the co-discoverers of the double helical structure of DNA, who had a flash of insight that illuminated the path towards a solution.
He suggested that there might be two types of RNA inside cells - a kind of ‘template RNA’ inside the ribosome, which contained the unique instructions to make a particular gene, and something he referred to as an ‘adapter’ RNA, which brought the building blocks of proteins, amino acids, to the ribosome and helped to connect them together. As we’ll see, this wasn’t quite correct, but it got people thinking about the different jobs that RNA might be doing inside cells.
There were some other clues, too. Throughout the 1950s, at least six research groups identified relatively short-lived RNAs inside cells that seemed to appear when genes were active. But nobody spotted the significance of these findings at the time due to the technical difficulty of studying RNA, or simply drew incorrect conclusions from what they were seeing.
Then, on the 15th April 1960 - Good Friday, as it happened to be, a meeting occurred that changed everything.
A Good Friday for science
The scene is King’s College Cambridge, in the rather cramped room of Sydney Brenner, a talented South African scientist who had been recruited to Cambridge by none other than Francis Crick himself. Gathered together are a small gang of the leading lights of molecular biology at the time, who are hanging out after a conference the previous day for a bit more hot science chat.
As well as Crick and Brenner, there’s also Francois Jacob, who’s come over from his lab at the Pasteur Institute in Paris. Jacob starts explaining to the assembled group the results of his latest experiments with his colleagues Arthur Pardee and Jacques Monod, nicknamed the ‘PaJaMo’ experiments (not PaJaMa, as sometimes appeared).
Apparently, Pardee has discovered that a gene in bacteria encoding the enzyme beta-galactosidase seems to make a mysterious transient ‘messenger’ RNA molecule, referred to only as ‘X’ (or ‘eeks’, by the French team). Brenner suddenly lets out a loud yelp as a flash of insight hits him. Jacob later wrote,
“Francis and Sydney leaped to their feet. Began to gesticulate. To argue at top speed in great agitation. A red-faced Francis. A Sydney with bristling eyebrows. The two talked at once, all but shouting. Each trying to anticipate the other. To explain to the other what had suddenly come to mind. All this at a clip that left my English far behind.”
The insight that so exercised the two men was the realisation that this mysterious messenger ‘X’ was the missing link between genes, ribosomes and proteins.
The solution was crystal clear, making sense of all the tantalising experimental clues that had been piling up over the past decade. Francis Crick described this transient messenger RNA - what we now usually refer to as mRNA - using the most advanced technology that was available at the time: audio tapes. If you’re under 30, ask your parents to explain this bit...
Crick described mRNA as a kind of ‘tape recording’ that was copied from the genetic instructions encoded within DNA, kept safe within the cell nucleus.
The mRNA then goes out into the cytoplasm where it’s ‘played back’ by ribosomes, analogous to a tape player, which follow the recorded instructions to the letter in order to put together the relevant protein. Then this mRNA recording is destroyed - hence its transient nature.
Straight away, during that April afternoon in King’s College, Jacob and Brenner began planning experiments that would prove this idea to be correct, carrying on their discussions that evening at one of Crick’s legendary Cambridge parties. Jacob writes,
“A very British evening with the cream of Cambridge, an abundance of pretty girls, various kinds of drink, and pop music. Sydney and I, however, were much too busy and excited to take an active part in the festivities…It was difficult to isolate ourselves at such a brilliant, lively gathering, with all the people crowding around us, talking, shouting, laughing, singing, dancing.
“Nevertheless, squeezed up next to a little table as though on a desert island, we went on, in the rhythm of our own excitement, discussing our new model and the preparations for experiment…A euphoric Sydney covered entire pages with calculations and diagrams. Sometimes Francis would stick his head in for a moment to explain what we had to do. From time to time, one of us would go off for drinks and sandwiches. Then our duet took off again.”
Proving the existence of mRNA
A flurry of experimental work followed as Brenner and Jacob set about searching for mRNA, with help from geneticist Matt Meselson at Caltech in Pasadena, who had a fancy ultracentrifuge that was capable of separating out the different molecules inside cells, including mRNA. In less than a year they had done it - isolating transient RNA messages that associated with pre-existing ribosomes to produce proteins, writing up their findings in a paper they submitted to Nature.
But they weren’t the only people on the trail. James Watson - the other half of Watson and Crick - had assembled a team of molecular biologists in the US and France who also discovered mRNA, even going as far as to send a cheeky telegram to Brenner in February 1961 asking him to hold back publication of their Nature paper so that Watson and his colleagues could get theirs in the same edition of the journal. Amazingly, Brenner agreed and the two papers came out back to back in May 1961.
Other research groups were also making similar findings at the same time, notably Marshall Nirenberg, who went on to play a key role in deciphering the three-letter code of DNA, suggesting that even without the Good Friday meeting/party in Cambridge, sooner or later mRNA would make itself known.
Yet despite the importance of the discovery of this molecular messenger, and the multitude of Nobel Prizes awarded through the 1960s for similar key advances in unravelling the mysteries of molecular biology, there has never been a Nobel for the discovery of mRNA. Brenner, Crick, Jacob and Monod are often held up as the ‘discovers of mRNA’ but, as we’ve heard, the true story is more complicated than a flash of insight in a Cambridge college and a few frenzied experiments.
Seeing as most of this story has come from Matthew Cobb’s excellent piece about the discovery of mRNA, which I’ve linked to in the show notes and the page for this podcast at GeneticsUnzipped.com, and his book, Life’s Greatest Secret, I’ll leave it to him for the last word:
“Textbook authors, students and Wikipedia editors generally like simple stories. A simple view of the history of mRNA would claim that Jacob and Monod named it, while Brenner, Jacob and Meselson subsequently isolated it. The complexity of what actually took place is much more in keeping with what we know about science — a series of different groups attack a problem, using slightly different techniques, seeing the problem from different angles, before eventually a breakthrough makes clear what was previously problematic.
“Who discovered mRNA? It is complicated. No wonder the Nobel Prize committee did not try and reward the discovery. Naming just three (or even six) people would be invidious — mRNA was the product of years of work by a community of researchers, gathering different kinds of evidence to solve a problem that now looks obvious, but at the time was extremely difficult. But that is the nature of history — it straightens out what at the time was tangled and unclear.
“We have the advantage of looking backwards, knowing the answer; the participants were peering into a foggy future, trying to reconcile contradictory evidence and imagine new experiments that could resolve the problem. Their collective insights and imaginations laid the basis for today’s understanding and tomorrow’s discoveries.”
References:
Matthew Cobb - Who discovered messenger RNA?
Matthew Cobb - Life’s Greatest Secret
Genetics Unzipped - Twisted history - the true story of the double helix
Genetics Unzipped - Genetics by numbers
