by Matthew Cobb

I have just sent off the final version of my book Life’s Greatest Secret: The Story of the Race to Crack the Genetic Code (to appear in 2015 with Profile Books, and Basic Books in the USA). The book is mainly history, covering the period 1943-1961, but the final four chapters bring the story up to date, describing things like the sequencing of the Neanderthal genome, the development of genetic engineering, and epigenetics.

To celebrate, I thought I’d give readers a condensed version of one of the sections dealing with that exotic-sounding entity, the RNA World.

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Proteins and DNA, which are so important to life today, have not always existed on our planet. The RNA machinery that exists in every cell of every organism on Earth, and the ability of RNA molecules to act as enzymes, catalysing biochemical reactions without the involvement of proteins, all indicate that another form of life existed before DNA-based life-forms: the RNA world. RNA is a molecule that resembles DNA except it has only one strand, rather than two, and it uses a slightly different set of chemical bases to code information: whereas DNA uses A, C, G and T, RNA uses U in place of T.

Exactly what the first replicating molecules were, and how they made the transition from merely replicating to also interacting with the world, we do not know – they may have been RNA molecules, or perhaps even simpler compounds, such as peptides. They appeared perhaps 4 billion years ago, probably in the microscopic pores of rock around a deep-ocean hydrothermal vent (although Jack Szostak argues they appeared in small vesicles made of fatty acids, and no one actually knows).

Wherever they were found, those early replicating systems would have had to speed up the chemical reactions that define life. If left to their own devices, the kind of reactions that take place in our cells would need billions of years to occur spontaneously; in the presence of RNA they take a fraction of a second.

At some point, perhaps after a period of evolution and competition between various biochemical types of life, the RNA world came into being. There are no direct traces of this world, so our views are based on strong suppositions rather than physical evidence.

This was a very different kind of life to the one we know. In the RNA world, RNA molecules were the basis both for reproduction and for biochemical interaction (that is, they acted as enzymes, speeding up and favouring chemical reactions).

In a world without DNA or proteins, the genetic information contained in an RNA molecule coded simply for that piece of RNA. Reproduction involved the copying of RNA molecules that acted as enzymes to direct chemical reactions. These RNA molecules provided the raw material for natural selection to begin its long work of sifting between variants, eventually leading to the DNA-based life that now covers the planet.

The idea of the RNA world was first been put forward by Oswald Avery’s colleague, Rollin Hotchkiss, at a symposium organised by the New York Academy of Sciences in 1957. Struck by the fact that some viruses use RNA and others use DNA, Hotchkiss suggested that:

[As] a genetic determinant, RNA was replaced during biochemical evolution by the more molecularly and metabolically stable DNA. Cell lines have preserved the RNA entities which, evolutionwise, were primary to DNA and may have allowed them to store their information in DNA and thereby become subservient to it metabolically.

In the late 1960s the idea was taken up by Francis Crick, Leslie Orgel and Carl Woese; Wally Gilbert coined the phrase ‘RNA world’ in 1986.

Although the RNA world no longer exists (but who knows what secrets lurk in the deep ocean?), we all carry its legacy within our cells. When our DNA-based life appeared, evolution did not redesign life from scratch: it used what was to hand, adapting existing RNA biochemical pathways and turning them into something new and strange.

This explains why RNA is not simply a passive messenger between the two apparently fundamental components of life – DNA and proteins. It plays many roles, shuttling genetic information around the cell and shaping how it is expressed, just as it did in the RNA world. As the RNA biochemist Michael Yarus has put it: ‘Without RNA, a cell would be all archive and no action.’

RNA is involved in almost all of the cell’s machinery for getting the genetic information out of DNA and either creating proteins or controlling the activity of genes. In its many forms, RNA performs essential functions within the cell, even if it has lost its role as the embodiment of genetic information, replaced by the semi-inert double helix of DNA. The double helix – iconic, rigid and fixed – contrasts with the many physical forms that RNA can take, enabling it to carry out such a wide range of functions, which would have been such an important feature of the RNA world.

Just as we do not know when the RNA world appeared, so we also do not know when it finally disappeared. All we can do is trace the ancestry of modern, DNA-based organisms back to the Last Universal Common Ancestor (LUCA), a population of single-celled DNA organisms that lived perhaps 3.8 billion years ago. LUCA evolved out of the RNA world, eventually – perhaps rapidly – out-competing and replacing it.

The replacement of RNA as the repository of genetic information by its more stable cousin, DNA, provided a more reliable way of transmitting information down the generations. This explains why DNA uses thymidine (T) as one of its four informational bases, whereas RNA uses uracil (U) in its place.

The problem is that cytosine (C), one of the two other bases, can easily turn into U, through a simple reaction called deamination. This takes place spontaneously dozens of times a day in each of your cells but is easily corrected by cellular machinery because, in DNA, U is meaningless. However, in RNA such a change would be significant – the cell would not be able to tell the difference between a U that was supposed to be there and needed to be acted upon, and a U that was a spontaneous mutation from C and needed to be corrected.

This does not cause your cells any difficulty, because most RNA is so transient that it does not have time to mutate – in the case of messenger RNA it is copied from DNA immediately before being used. Thymidine is much more stable and does not spontaneously change so easily.

The new DNA life-forms would have had a substantial advantage because they involved proteins in all their cellular activities. Although we do not know when or why protein synthesis developed, it seems unlikely that it occurred instantaneously – there was probably no protein revolution. Initially the interaction of RNA and amino acids (the building blocks of proteins) would have enabled RNA life-forms to gain some additional metabolic property, before eventually the appearance of strings of amino acids – proteins – created the world of protein-based life.

At some point DNA supplanted RNA as the informational molecule, keeping the genetic sequence safe, using RNA to produce rapid translations of that sequence into the patterned production of proteins, as the RNA enzymes were co-opted and turned into bits of cellular machinery such as transfer RNAs and ribosomes. Proteins can carry out an almost infinite range of biological functions, both as structural components and as enzymes. In both respects, they far surpass RNA. The appearance of proteins therefore opened new niches to life, spreading DNA and protein across the planet, creating and continually altering the biosphere.

These new DNA-based life-forms would have out-competed the RNA world organisms in terms of their flexibility and the range of niches that they could occupy. They would also have been able to grow much more quickly: a modern DNA-based cell can replicate itself in about 20 minutes. Experiments suggest that it would have taken days for an RNA-based life-form to reproduce. The RNA world was slow, limited and probably confined to the ocean depths.

The evolutionary and ecological advantages gained through the use of proteins by DNA-based life show that the appearance of translation from a sequence of RNA bases into a sequence of amino acids was a decisive evolutionary step. The evolution of the genetic code was essential for life as we know it. It truly is life’s greatest secret.

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Further reading:

If you want to know more, I strongly recommend Michael Yarus’s book Life from an RNA World.

This article by Cech is also excellent, though at a higher level:  Thomas R. Cech (2012) The RNA Worlds in Context Cold Spring Harb Perspect Biol