The Inhabited Body
Companion Primer

Primer Chapter 3: The Code of Life — DNA, RNA, and Proteins

This chapter is part of the companion primer to The Inhabited Body. It explains what DNA is, how cells read and use genetic information, and why understanding these processes matters for the microbiome. If you have ever wondered what mRNA actually does — or why it featured so prominently during the COVID-19 pandemic — this chapter is for you.

A Book Inside Every Cell

Imagine that every building in a city — every house, every office tower, every garden shed — contained a complete copy of the same enormous instruction manual. This manual tells the city how to build every structure, run every service, and respond to every emergency. No building uses every page. A fire station reads the chapters on firefighting; a bakery reads the chapters on baking. But every building holds the entire book, just in case.

This is roughly how your body works. Almost every one of your 37 trillion cells carries a complete copy of your genome — the full set of genetic instructions for building and maintaining you. The genome is written in a molecule called DNA, and it is astonishingly long. If you could unwind the DNA from a single human cell and stretch it into a line, it would extend about two metres. If you lined up the DNA from all the cells in your body, it would cover the distance from the Earth to the Sun more than 40 times over — roughly 6 billion kilometres of molecular thread [piovesan2019?].

But length is not the same as complexity. The genome's real power lies not in how much DNA there is, but in how the information within it is organised, read, and acted upon. Understanding this process — how a chemical molecule becomes a living, functioning organism — is the purpose of this chapter.

What DNA Actually Is

In April 1953, James Watson and Francis Crick published a brief paper in Nature that would transform biology. In barely more than a page, they described the structure of deoxyribonucleic acid — DNA — as a double helix: two strands wound around each other like a twisted ladder [watson1953?].

The discovery did not come from nowhere. It built on decades of work by many scientists, including the X-ray crystallography of Rosalind Franklin and Maurice Wilkins, the biochemistry of Erwin Chargaff, and the earlier demonstration by Oswald Avery and colleagues that DNA, not protein, was the molecule of inheritance. But Watson and Crick's model brought everything together in a single, elegant structure — one whose shape immediately suggested how it might work.

The Twisted Ladder

Think of DNA as a ladder that has been gently twisted along its length. The rungs of the ladder are pairs of small molecules called bases (or nucleotide bases). There are only four of them:

These four letters are the entire alphabet of the genetic code. Every instruction for building and running a living organism — from a bacterium to a blue whale — is written using just A, T, G, and C.

The bases pair in a strict, predictable way: A always pairs with T, and G always pairs with C. These are called base pairs. This pairing rule — known as complementary base pairing — is one of the most important principles in molecular biology. It means that if you know the sequence of one strand of the DNA ladder, you can immediately deduce the other. The two strands are mirror images, like a photograph and its negative.

The sides of the ladder (the vertical rails to which the bases are attached) are made of alternating sugar and phosphate molecules. The sugar in DNA is deoxyribose — hence the "deoxyribo" in deoxyribonucleic acid. Each unit of one base plus one sugar plus one phosphate group is called a nucleotide. DNA is simply a chain of nucleotides — a polymer — and the human genome is about 3.2 billion nucleotides long [international2004].

Why the Double Helix Matters

The double-helix structure is not just aesthetically pleasing. It solves two fundamental problems of biology.

First, it explains how genetic information is stored. The information in DNA is encoded in the sequence of bases along the strand — just as the information in a book is encoded in the sequence of letters on the page. The sequence ATGCCTAA means something different from AATCCGTA, just as "cat" means something different from "act." Change the sequence and you change the instructions.

Second, it explains how genetic information is copied. When a cell divides, it must duplicate its DNA so that each daughter cell receives a complete copy. The base-pairing rules make this straightforward: the two strands separate (like unzipping a zip), and each strand serves as a template for building a new partner. Wherever there is an A on the old strand, a T is placed on the new one; wherever there is a G, a C is placed. The result is two identical double helices where there was one before.

This process is called DNA replication, and it occurs every time a cell divides. In a rapidly growing bacterium like Escherichia coli, it happens once every 20 minutes or so. In your body, it happens millions of times a day. The accuracy is remarkable — the cellular machinery makes only about one error per billion nucleotides copied — but it is not perfect. The occasional mistake that slips through is a mutation, and mutations are the raw material of evolution.

From DNA to Protein: The Central Dogma

Knowing the structure of DNA was a monumental achievement, but it immediately raised a deeper question: how does a cell actually use the information in its DNA? The answer, worked out over the decade following Watson and Crick's discovery, was formalised by Crick in 1970 as the central dogma of molecular biology [crick1970?]:

> DNA → RNA → Protein

This is not a dogma in the religious sense (Crick later admitted the name was poorly chosen). It is a statement about the flow of information in living systems. Genetic information flows from DNA to RNA to protein. Let us unpack what this means, step by step.

The Recipe Book Analogy

Imagine your genome as a vast recipe book locked in a vault (the cell's nucleus — recall from Primer Chapter 2 that eukaryotic cells keep their DNA inside a membrane-bound nucleus). The book is far too valuable to take into the kitchen. So when the cell needs to make a particular dish — say, a digestive enzyme — it does not haul out the entire book. Instead, it makes a temporary copy of just the relevant recipe. That copy is carried out of the vault into the kitchen, where it is read by the cooks and used to assemble the dish. When the dish is done, the copy is discarded.

In this analogy:

This analogy is imperfect — biology always is — but it captures the essential logic. DNA stores the information. RNA carries a working copy. Ribosomes read the copy and build the protein.

Step One: Transcription — Copying the Recipe

The process of making an RNA copy of a gene is called transcription (literally, "writing across"). It works like this:

  1. An enzyme called RNA polymerase binds to the DNA at the start of a gene.
  2. It unwinds a short stretch of the double helix, exposing the bases on one strand.
  3. It reads along the strand, building a complementary RNA molecule one base at a time — much like DNA replication, except that RNA uses the sugar ribose instead of deoxyribose and substitutes the base uracil (U) for thymine (T).
  4. When it reaches the end of the gene, it releases the newly made RNA molecule and the DNA snaps back together.

The result is a single-stranded molecule of messenger RNA (mRNA) — a disposable working copy of one gene. In eukaryotic cells, the mRNA is processed (trimmed, modified, and polished) before being exported from the nucleus into the cytoplasm, where the ribosomes await.

In bacterial cells — which, as we saw in Primer Chapter 2, have no nucleus — transcription and the next step (translation) happen almost simultaneously. An mRNA molecule can begin being read by ribosomes even before it is fully transcribed. This difference in timing between bacteria and human cells has important consequences for antibiotic design, as we will see in later chapters.

A Note on RNA

RNA is chemically very similar to DNA, but there are three key differences:

These differences make RNA less chemically stable than DNA — which is exactly the point. RNA is meant to be temporary. It is the Post-it note of molecular biology: carry the message, deliver it, then get recycled. DNA, by contrast, is the archival copy — built for permanence.

Step Two: Translation — Building the Dish

Once the mRNA reaches a ribosome, the second stage begins: translation (so called because the information is "translated" from the language of nucleic acids into the language of proteins). This is where the genetic code — the set of rules that links base sequences to amino acids — comes into play.

The Genetic Code: A Three-Letter Language

In the early 1960s, a series of brilliant experiments — most famously by Marshall Nirenberg and Heinrich Matthaei at the US National Institutes of Health — cracked the genetic code [nirenberg1961?]. Here is how it works.

The mRNA is read in groups of three bases at a time. Each group of three — called a codon — specifies one amino acid. Amino acids are the building blocks of proteins, rather like beads on a necklace. There are 20 standard amino acids used by living cells, and the sequence of codons in an mRNA determines the sequence of amino acids in the resulting protein.

With four bases and groups of three, there are 4 × 4 × 4 = 64 possible codons. But there are only 20 amino acids, so most amino acids are specified by more than one codon. The codon GCU, for example, specifies the amino acid alanine — but so do GCC, GCA, and GCG. This redundancy is called degeneracy of the code, and it provides a buffer against mutation: a change in the third position of a codon often has no effect on the resulting protein.

Three of the 64 codons do not specify any amino acid. Instead, they act as stop signals — punctuation marks that tell the ribosome "the protein ends here." One particular codon, AUG, serves double duty: it specifies the amino acid methionine and acts as the start signal for translation. Almost every protein begins with methionine.

The genetic code is very nearly universal. With minor exceptions, every organism on Earth — from the bacteria in your gut to the cells of your brain — uses the same code. A codon that specifies alanine in a human cell specifies alanine in a bacterium. This universality is powerful evidence that all life on Earth shares a common ancestor.

How Translation Works: A Factory Floor

Picture a ribosome as a small but precise factory machine, sitting on the mRNA like a train on a track. As the ribosome moves along the mRNA, it reads each codon and recruits the matching amino acid.

The matchmaking is done by a third type of RNA molecule: transfer RNA (tRNA). Each tRNA carries a specific amino acid on one end and has a three-base anticodon on the other — a sequence complementary to the mRNA codon. When the anticodon matches the codon currently sitting in the ribosome, the tRNA delivers its amino acid, which is linked to the growing protein chain. The empty tRNA is then ejected, the ribosome moves forward by three bases, and the process repeats.

A typical protein is between 100 and 1,000 amino acids long. A bacterial ribosome can assemble about 20 amino acids per second — meaning a medium-sized protein takes about 15 seconds to build. Multiple ribosomes can read the same mRNA simultaneously, strung along it like beads on a string, each producing its own copy of the protein. This cluster of ribosomes on an mRNA is called a polysome, and it allows cells to produce many copies of a protein quickly.

When the ribosome encounters a stop codon, translation halts. The newly made protein is released and begins to fold into its functional three-dimensional shape — a process we will return to shortly.

Proteins: The Workers of the Cell

If DNA is the blueprint and RNA is the messenger, then proteins are the workers — the molecules that actually do things. The importance of proteins to life cannot be overstated. Consider just a few of their roles:

Enzymes speed up chemical reactions. Every metabolic process in your body — digesting food, synthesising neurotransmitters, detoxifying drugs — depends on enzymes. Without them, the chemistry of life would be too slow to sustain a cell.

Structural proteins provide physical support. Collagen gives your skin its strength. Keratin makes up your hair and nails. The bacterial cell wall (discussed in Primer Chapter 2) is reinforced by enzymes that build and maintain it.

Transport proteins move molecules around. Haemoglobin carries oxygen in your blood. Membrane channels shuttle ions and nutrients in and out of cells.

Signalling proteins carry messages. Hormones like insulin, cytokines that coordinate the immune response, and neurotransmitters that relay nerve impulses are all proteins (or are made by proteins).

Defence proteins protect the organism. Antibodies, which recognise and neutralise invaders, are proteins. So are many of the antimicrobial peptides that your body deploys against pathogenic bacteria.

Protein Folding: Shape Is Everything

A newly made protein is just a long chain of amino acids — a string of beads. To function, it must fold into a specific three-dimensional shape, dictated by the sequence of its amino acids. Hydrophobic amino acids tend to cluster together in the interior (away from the surrounding water), while hydrophilic ones face outward. The chain twists into local structures — alpha helices (like a corkscrew) and beta sheets (like a pleated fan) — which then pack together into a compact, functional form.

This folding happens in milliseconds, and when it goes right, it produces a molecular machine of astonishing precision. But when folding goes wrong, the consequences can be severe. Misfolded proteins are the basis of diseases like Alzheimer's, Parkinson's, and the prion diseases discussed in Primer Chapter 1. Your cells have elaborate quality-control systems — chaperone proteins that help other proteins fold correctly, and proteasomes that shred and recycle those that fail.

Gene Regulation: Not Every Recipe Is Cooked

Here is a puzzle. Almost every nucleated cell in your body carries the same genome — the same 20,000-odd protein-coding genes. (There are exceptions: mature red blood cells have shed their nucleus entirely, immune cells deliberately rearrange certain genes to produce diverse antibodies, and researchers have documented small-scale somatic mutations that accumulate differently across tissues over a lifetime. But the vast majority of your cells share an essentially identical copy of the master plan.) Yet a liver cell looks and behaves utterly differently from a neuron, which looks and behaves utterly differently from a white blood cell. If they all have the same instruction manual, how can they be so different?

The answer is gene regulation — the system that controls which genes are switched on (expressed) and which are switched off (silenced) in any given cell at any given time. A liver cell and a neuron contain the same recipes, but they are reading different pages.

This insight traces back to the pioneering work of François Jacob and Jacques Monod, who in 1961 described how bacteria regulate gene expression in response to their environment [jacob1961?]. They showed that E. coli only produces the enzymes for digesting the sugar lactose when lactose is actually present — a feat of molecular economy that earned them the Nobel Prize.

Gene regulation is extraordinarily sophisticated. In your cells, it involves a cast of hundreds of specialised proteins called transcription factors that bind to specific DNA sequences near genes and either promote or block transcription. Some transcription factors activate genes; others repress them. The combination of active transcription factors in a cell — determined by signals from the environment, from neighbouring cells, and from the cell's own developmental history — defines the cell's identity.

This is why a liver cell stays a liver cell and a neuron stays a neuron, even though both carry the same genome. They are reading different chapters of the same book.

A Dimmer Switch, Not an On/Off Toggle

It is tempting to think of genes as being simply "on" or "off," like a light switch. In reality, gene expression is more like a dimmer: genes can be expressed at high levels, low levels, or anything in between. The rate of transcription can be adjusted up or down, the stability of the mRNA can be altered, and the efficiency of translation can be tuned. Even after a protein is made, it can be chemically modified, redirected, or tagged for destruction.

This fine-tuning is essential. Consider insulin: your body does not simply make insulin or not. It adjusts insulin production moment by moment in response to blood sugar levels. Too much insulin is as dangerous as too little. The same is true for almost every protein in your body — and, as we will see in later chapters, for many of the proteins produced by your microbial residents as well.

Beyond the Gene: The "Junk DNA" Revolution

When the Human Genome Project published its first results, one of the most surprising findings was how little of the genome actually codes for proteins. Of the roughly 3.2 billion base pairs in the human genome, only about 1.5 per cent consists of exons — the segments of genes that are translated into protein [venter2001?]. The rest was initially dismissed as "junk DNA" — evolutionary debris with no function.

That view has been substantially revised. The ENCODE project, a massive international effort to catalogue the functional elements of the human genome, reported in 2012 that roughly 80 per cent of the genome shows some form of biochemical activity — including regulation, transcription of non-coding RNAs, and other functions [encode2012?]. (The precise interpretation of this figure remains debated among scientists, but the days of "junk DNA" as a default label are over.)

Among the non-coding regions that have turned out to be important:

Promoters and enhancers are DNA sequences that control when, where, and how strongly a gene is transcribed. They do not code for proteins themselves, but without them, the protein-coding genes would be silent.

Introns are sequences within genes that are transcribed into RNA but then cut out before the mRNA is translated. They were once thought to be useless, but many introns contain regulatory elements, and the process of removing them — called splicing — allows a single gene to produce multiple different proteins by including or excluding different combinations of exons. This is called alternative splicing, and it vastly increases the protein diversity that a genome can generate. The human genome has about 20,000 protein-coding genes, but through alternative splicing it can generate a far larger number of distinct protein variants — though exactly how many of these splice variants produce stable, functional proteins remains an active area of research.

Non-coding RNAs are RNA molecules that are transcribed from DNA but never translated into protein. Far from being waste products, many of them play critical roles. MicroRNAs (miRNAs), for example, are tiny RNA molecules — only about 22 bases long — that regulate gene expression by binding to messenger RNAs and preventing their translation or promoting their destruction [schmiedel2015?]. Long non-coding RNAs (lncRNAs) participate in a bewildering variety of regulatory functions, many of which are still being discovered.

Epigenetics: Writing in the Margins

There is one more layer of gene regulation that deserves special attention, because it has profound implications for the microbiome story.

Epigenetics (literally, "above genetics") refers to changes in gene expression that do not involve altering the DNA sequence itself. Think of it this way: if the genome is a book, epigenetics is the system of bookmarks, highlights, and sticky notes that tell the reader which pages to read, which to skip, and which to read extra carefully. The underlying text does not change, but its interpretation does.

The two best-understood epigenetic mechanisms are:

DNA methylation. Small chemical groups called methyl groups can be attached to cytosine bases in the DNA. When a gene's promoter region is heavily methylated, the gene is typically silenced — like placing a "do not read" sticker over a recipe. Methylation patterns are established during development and can be maintained through cell division, ensuring that a liver cell's daughter cells are also liver cells.

Histone modification. In eukaryotic cells, DNA is not floating free. It is wound around spool-like proteins called histones, forming a structure called chromatin. The tightness of this winding determines whether a gene is accessible or hidden. Chemical modifications to the histone tails — adding or removing acetyl groups, methyl groups, phosphate groups, and others — can loosen or tighten the chromatin, making genes more or less available for transcription. Think of this as the difference between a tightly shelved book (hard to read) and one lying open on the desk (easy to read).

Why Epigenetics Matters for the Microbiome

Here is where the story connects to The Inhabited Body. Epigenetic changes are not fixed at birth. They can be influenced by environmental factors throughout life — including diet, stress, toxin exposure, and, crucially, the metabolites produced by your gut microbiome.

Short-chain fatty acids such as butyrate, produced by bacterial fermentation of dietary fibre in the colon, are potent inhibitors of histone deacetylases — enzymes that tighten chromatin and silence genes. By inhibiting these enzymes, butyrate keeps chromatin in a more open, transcriptionally active state, influencing the expression of genes involved in immune regulation, gut barrier integrity, and even cancer suppression. This means that the bacteria in your gut are not merely passive passengers. Through the metabolites they produce, they are actively writing in the margins of your genetic instruction manual — influencing which genes your own cells read, and how loudly.

We will explore this extraordinary dialogue in detail in Chapters 7 and 11 of the main book. For now, the key point is that understanding DNA, RNA, and protein is not just about understanding your own cells. It is about understanding the molecular language through which your microbial residents communicate with you.

mRNA: From Obscurity to Headlines

For decades, mRNA was the quiet middle child of molecular biology — overshadowed by DNA (which stored the information) and protein (which did the work). Then came the COVID-19 pandemic, and mRNA became a household word.

The mRNA vaccines developed by Pfizer-BioNTech and Moderna work by delivering synthetic mRNA into your cells. This mRNA encodes the spike protein of the SARS-CoV-2 virus — the protein the virus uses to latch onto and enter your cells. Your ribosomes read the synthetic mRNA and produce the spike protein, just as they would any other protein. Your immune system then recognises the spike protein as foreign and mounts a defence. When the real virus arrives, your immune system is already primed and ready.

The synthetic mRNA does not enter the nucleus and cannot alter your DNA. It is read, used, and degraded within hours to days — just like any other mRNA. It is the epitome of the disposable messenger.

The key breakthrough that made mRNA vaccines possible came from the work of Katalin Karikó and Drew Weissman, who discovered in 2005 that chemically modifying certain nucleosides in synthetic RNA prevented it from triggering a dangerous inflammatory response [kariko2005?]. This finding — which earned them the Nobel Prize in Physiology or Medicine in 2023 — solved a problem that had stymied mRNA therapeutics for years: the immune system's tendency to attack foreign RNA as if it were a sign of viral infection.

This detail circles back to the microbiome in an interesting way. The innate immune system distinguishes self from non-self RNA in part by detecting the presence or absence of nucleoside modifications. Mammalian RNA is heavily modified; bacterial and viral RNA typically is not. This means that when bacterial RNA leaks from damaged microbes in the gut, it can trigger immune responses through Toll-like receptors (TLR3, TLR7, and TLR8) — the same receptors that Karikó and Weissman's work was designed to evade. The conversation between microbial RNA and the immune system is an active area of research that we revisit in Chapters 12 and 13 of the main book.

How Bacteria Do It Differently

Everything described so far — the nucleus, the introns, the histones, the elaborate processing of mRNA — applies to eukaryotic cells. Bacteria and archaea, as we saw in Primer Chapter 2, are prokaryotes, and they handle their genetic information differently. These differences are not merely academic curiosities. They are the reason many antibiotics work, and they are essential for understanding how the microbiome functions.

No Nucleus, No Waiting

Bacterial DNA sits in the cytoplasm, not locked away in a nucleus. This means there is no barrier between where mRNA is made (transcription) and where it is read (translation). In bacteria, ribosomes begin translating an mRNA while it is still being transcribed — the ribosome latches on to the leading end of the mRNA even as RNA polymerase is still extending the trailing end. This coupling of transcription and translation gives bacteria extraordinary speed. A bacterium can go from receiving an environmental signal to producing a new protein in under a minute.

Operons: The Bacterial Efficiency Trick

Bacteria organise many of their genes into operons — clusters of genes that are transcribed together as a single mRNA. The genes in an operon typically encode proteins that work together in the same metabolic pathway. For example, the lac operon in E. coli contains three genes needed for digesting lactose, all under the control of a single promoter. When lactose is absent, a repressor protein blocks transcription of the entire operon. When lactose appears, the repressor releases, and all three genes are transcribed together. It is an elegantly efficient system — like printing all the pages of a multi-step recipe on a single sheet of paper.

Eukaryotic cells, by contrast, almost never organise their genes into operons. Each gene typically has its own promoter and is transcribed independently. This gives eukaryotes more precise control over individual genes, but at the cost of the streamlined efficiency that operons provide.

Fewer Introns, Faster Processing

Bacterial genes almost never contain introns. The mRNA produced by transcription is the mRNA that gets translated — no splicing required. This is another reason bacterial gene expression is so fast. It also means that bacterial genomes are far more compact than eukaryotic ones. The E. coli genome has about 4,300 genes packed into 4.6 million base pairs. The human genome has about 20,000 protein-coding genes spread across 3.2 billion base pairs. Gene for gene, bacteria use their DNA about 70 times more efficiently.

Different Ribosomes, Different Targets

As mentioned in Primer Chapter 2, bacterial ribosomes (70S) are structurally different from eukaryotic ribosomes (80S). This difference is the basis for several classes of antibiotics. Drugs like erythromycin, tetracycline, and chloramphenicol bind specifically to the bacterial 70S ribosome and block translation, killing the bacterium or halting its growth. Because these drugs do not bind to the human 80S ribosome, they do not directly harm human cells — a crucial application of the principle of selective toxicity introduced in Primer Chapter 2.

However — and this is a point we will return to repeatedly in The Inhabited Body — these antibiotics cannot distinguish between pathogenic bacteria and beneficial ones. When you take an antibiotic for a throat infection, the drug also disrupts protein synthesis in the trillions of helpful bacteria in your gut, on your skin, and throughout your body. The collateral damage can be profound.

Horizontal Gene Transfer: Sharing the Recipe Book

In animals and plants, genes are passed vertically — from parent to offspring. Bacteria, however, have a second trick: horizontal gene transfer (HGT), in which genes are passed between unrelated organisms, even across species boundaries. If vertical gene transfer is like inheriting your grandmother's recipe book, horizontal gene transfer is like a stranger at a bus stop handing you a recipe they tore from a magazine.

There are three main mechanisms, all introduced briefly in Primer Chapter 2 and explored in depth in Chapter 2 of the main book:

Transformation — a bacterium picks up free-floating DNA from its environment (often released by dead cells nearby).

Transduction — a bacteriophage (a virus that infects bacteria) accidentally packages a fragment of one bacterium's DNA and injects it into another.

Conjugation — two bacteria form a physical bridge (a pilus), and one transfers a plasmid or other DNA directly to the other. This is sometimes called "bacterial sex," although it involves gene transfer rather than reproduction.

Horizontal gene transfer is how antibiotic resistance spreads so rapidly through bacterial populations. A single bacterium that acquires a resistance gene — whether by mutation or by receiving a plasmid — can share that gene with its neighbours in hours. This is why antibiotic resistance is one of the most urgent public health challenges of our time, as we will discuss at length in Chapter 19 of the main book.

Tying It All Together

The flow of genetic information — from DNA to RNA to protein — is the central process of all cellular life. But understanding the code of life is not just about memorising the steps. It is about appreciating the system as a whole: a dynamic, regulated, responsive network that allows cells to adapt to their environment, communicate with their neighbours, and maintain their identity.

For the microbiome, these molecular details are not abstractions. They are the mechanisms through which:

Every one of these processes depends on the molecular machinery described in this chapter: DNA storing the instructions, RNA carrying the message, ribosomes building the protein, and regulatory systems deciding which instructions to follow and when.

Where This Matters in The Inhabited Body

Chapter References

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