is something that has long been the dream of geneticists.
Avery is almost there, but he is still thinking along chemical lines. ‘All life is chemistry’, said Jan Baptista van Helmont in 1648, guessing. At least some life is chemistry, said Friedrich Wöhler in 1828 after synthesising urea from ammonium chloride and silver cyanide, thus breaking the hitherto sacrosanct divide between the chemical and biological worlds: urea was something that only living things had produced before. That life is chemistry is true but boring, like saying that football is physics. Life, to a rough approximation, consists of the chemistry of three atoms, hydrogen, carbon and oxygen, which between them make up ninety-eight per cent of all atoms in living beings. But it is the emergent properties of life – such as heritability – not the constituent parts that are interesting. Avery cannot conceive what it is about DNA that enables it to hold the secret of heritable properties. The answer will not come from chemistry.
In Bletchley, in Britain, in 1943, in total secrecy, a brilliant mathematician, Alan Turing, is seeing his most incisive insight turned into physical reality. Turing has argued that numbers can compute numbers. To crack the Lorentz encoding machines of the German forces, a computer called Colossus has been built based on Turing’s principles: it is a universal machine with a modifiable stored program. Nobody realises it at the time, least of all Turing, but he is probably closer to the mystery of life than anybody else. Heredity is a modifiable stored program; metabolism is a universal machine. The recipe that links them is a code, an abstract message that can be embodied in a chemical, physical or even immaterial form. Its secret is that it can cause itself to be replicated. Anything that can use the resources of the world to get copies of itself made is alive; the most likely form for such a thing to take is a digital message – a number, a script or a word.5
In New Jersey in 1943, a quiet, reclusive scholar named Claude Shannon is ruminating about an idea he had first had at Princeton a few years earlier. Shannon’s idea is that information and entropy are opposite faces of the same coin and that both have an intimate link with energy. The less entropy a system has, the more information it contains. The reason a steam engine can harness the energy from burning coal and turn it into rotary motion is because the engine has high information content – information injected into it by its designer. So does a human body. Aristotle’s information theory meets Newton’s physics in Shannon’s brain. Like Turing, Shannon has no thoughts about biology. But his insight is of more relevance to the question of what is life than a mountain of chemistry and physics. Life, too, is digital information written in DNA.6
In the beginning was the word. The word was not DNA. That came afterwards, when life was already established, and when it had divided the labour between two separate activities: chemical work and information storage, metabolism and replication. But DNA contains a record of the word, faithfully transmitted through all subsequent aeons to the astonishing present.
Imagine the nucleus of a human egg beneath the microscope. Arrange the twenty-three chromosomes, if you can, in order of size, the biggest on the left and the smallest on the right. Now zoom in on the largest chromosome, the one called, for purely arbitrary reasons, chromosome 1. Every chromosome has a long arm and a short arm separated by a pinch point known as a centromere. On the long arm of chromosome 1, close to the centromere, you will find, if you read it carefully, that there is a sequence of 120 letters – As, Cs, Gs and Ts – that repeats over and over again. Between each repeat there lies a stretch of more random text, but the 120-letter paragraph keeps coming back like a familiar theme tune, in all more than 100 times. This short paragraph is perhaps as close as we can get to an echo of the original word.
This ‘paragraph’ is a small gene, probably the single most active gene in the human body. Its 120 letters are constantly being copied into a short filament of RNA. The copy is known as 5S RNA. It sets up residence with a lump of proteins and other RNAs, carefully intertwined, in a ribosome, a machine whose job is to translate DNA recipes into proteins. And it is proteins that enable DNA to replicate. To paraphrase Samuel Butler, a protein is just a gene’s way of making another gene; and a gene is just a protein’s way of making another protein. Cooks need recipes, but recipes also need cooks. Life consists of the interplay of two kinds of chemicals: proteins and DNA.
Protein represents chemistry, living, breathing, metabolism and behaviour – what biologists call the phenotype. DNA represents information, replication, breeding, sex – what biologists call the genotype. Neither can exist without the other. It is the classic case of chicken and egg: which came first, DNA or protein? It cannot have been DNA, because DNA is a helpless, passive piece of mathematics, which catalyses no chemical reactions. It cannot have been protein, because protein is pure chemistry with no known way of copying itself accurately. It seems impossible either that DNA invented protein or vice versa. This might have remained a baffling and strange conundrum had not the word left a trace of itself faintly drawn on the filament of life. Just as we now know that eggs came long before chickens (the reptilian ancestors of all birds laid eggs), so there is growing evidence that RNA came before proteins.
RNA is a chemical substance that links the two worlds of DNA and protein. It is used mainly in the translation of the message from the alphabet of DNA to the alphabet of proteins. But in the way it behaves, it leaves little doubt that it is the ancestor of both. RNA was Greece to DNA’s Rome: Homer to her Virgil.
RNA was the word. RNA left behind five little clues to its priority over both protein and DNA. Even today, the ingredients of DNA are made by modifying the ingredients of RNA, not by a more direct route. Also DNA’s letter Ts are made from RNA’s letter Us. Many modern enzymes, though made of protein, rely on small molecules of RNA to make them work. Moreover, RNA, unlike DNA and protein, can copy itself without assistance: give it the right ingredients and it will stitch them together into a message. Wherever you look in the cell, the most primitive and basic functions require the presence of RNA. It is an RNA-dependent enzyme that takes the message, made of RNA, from the gene. It is an RNA-containing machine, the ribosome, that translates that message, and it is a little RNA molecule that fetches and carries the amino acids for the translation of the gene’s message. But above all, RNA – unlike DNA – can act as a catalyst, breaking up and joining other molecules including RNAs themselves. It can cut them up, join the ends together, make some of its own building blocks, and elongate a chain of RNA. It can even operate on itself, cutting out a chunk of text and splicing the free ends together again.7
The discovery of these remarkable properties of RNA in the early 1980s, made by Thomas Cech and Sidney Altman, transformed our understanding of the origin of life. It now seems probable that the very first gene, the ‘ur-gene’, was a combined replicator–catalyst, a word that consumed the chemicals around it to duplicate itself. It may well have been made of RNA. By repeatedly selecting random RNA molecules in the test tube based on their ability to catalyse reactions, it is possible to ‘evolve’ catalytic RNAs from scratch – almost to rerun the origin of life. And one of the most surprising results is that these synthetic RNAs often end up with a stretch of RNA text that reads remarkably like part of the text of a ribosomal RNA gene such as the 5S gene on chromosome 1.
Back before the first dinosaurs, before the first fishes, before the first worms, before the first plants, before the first fungi, before the first bacteria, there was an RNA world – probably somewhere around four billion years ago, soon after the beginning of planet earth’s very existence and when the universe itself was only ten billion years old. We do not know what these ‘ribo-organisms’ looked like. We can only guess at what they did for a living, chemically speaking. We do not know what came before them. We can be pretty sure that they once existed, because of the clues to RNA’s role that survive in living organisms today.8
These ribo-organisms had a big problem. RNA is an unstable
