How does our immune system work?

Each day of our lives is a battle for survival against an army of invaders so vast in size that it outnumbers the human population hugely. Yet, despite its vastness, this army is an invisible threat, each individual so small that it cannot be seen with the naked eye. These are the microbes – among them the bacteria and viruses – that surround us every day, and could in one way or another kill us were it not for our immune system, an ingenious defence mechanism that protects us from these invisible foes.

Our immune system is a multi-layered operation, much like the fortifications mounted to protect medieval castles. Our first line of defence – the equivalent of a castle moat – is our skin, a physical barrier that separates the hordes of microbes in our environment from the cells of our bodies that lie beneath. However, our skin does not keep us sealed off completely from our surroundings; indeed, some gaps in our defences are essential for our survival. And two gaps are very obvious: our nose and mouth. 

Every minute of every day we inhale air deep into our lungs. But along with the oxygen molecules we so desperately need come other less desirable particles, including viruses and fungal spores. Fortunately, we have another barrier in place to prevent these less desirable particles getting where we don’t want them. The lining of our lungs is covered by a layer of mucus, which traps many of these particles. Under this layer of mucus lie millions of tiny finger-like protrusions that bend from side-to-side, generating a Mexican wave-like movement that wafts this detritus-laden mucus up and out of our lungs, to be expelled (to put it as delicately as I can) every time we cough up phlegm or blow our noses.

Our requirement for food also leaves us exposed to the threat of invasion, this time via our digestive system. Once again, though, we are primed to defend ourselves. The inside of our stomach isn’t the most hospitable of places: it is highly acidic – perfect for aiding the digestion of food, but not a great place for many bacteria to set up home.

Despite the best efforts of these first lines of defence, however, the most determined invaders succeed in their mission and infect us. But this isn’t the end of the fight as far as our bodies are concerned: when our outer defences are breached a whole army of cells are in place to protect us. These cells are our white blood cells. 

The white blood cells operate as two separate battalions. One battalion is on the constant look-out for any general signs of trouble. In this respect, it acts a bit like a bouncer in a nightclub, who is primed to respond quickly and decisively to any one of a number of general ‘alarm’ signals - be it signs of a scuffle on the dance floor, or signs of inebriation from a late-night reveller. Whenever the alarm is raised inside the body, our first battalion is called to arms, and responds equally quickly and decisively, often simply by ‘eating’ whatever intruder first raised the alarm. 

This approach lacks what one might call any refinement: it is a fairly indiscriminate one-size-fits-all strategy. By contrast, the second battalion acts in a much more specific way, more akin to a group of snipers, each waiting for their particular target. This second battalion has two regiments – the B cells and T cells: B cells police the areas of the body outside of individual cells, including the blood; by contrast, T cells monitor the inside of cells. So how is the specificity of this second battalion achieved?

To answer this question, let’s focus on the B cell. B cells produce special Y-shaped molecules called antibodies. An antibody is like one half of a two-piece jigsaw: its specific shape allows it to recognise – and bind to – something with a complementary shape (just like neighbouring pieces of  a jigsaw fit together because their shapes are complementary). In the case of antibodies, however, the other piece of the jigsaw is a foreign object, such as a bacterium. The binding of an antibody to a foreign particle is one of the general alarm signals that call our first battalion to arms. So, the two battalions of white blood cell work together, with the second ‘sniper’ battalion often helping to focus the activity of the first on a particular invader.

Of central importance to the operation of our immune system is the fact that each B cell produces a uniquely-shaped antibody. Consequently, each antibody will recognize something different. This is important when we consider that our bodies face many different sources of danger, including many thousands of different microbes: we need lots of different antibodies to recognise them all. 

When we get infected by a specific type of bacteria, however, our bodies won’t be facing just one or two cells, but a whole army. We need lots of antibody to tag all of these invaders for destruction – but there’s no way we can always keep in circulation enough B cells to produce all the antibodies we need to destroy all the different microbes we might ever encounter. Instead, our immune system has a clever way of ensuring that large numbers of a particular antibody are only produced when actually needed. So how does this happen?

B cells circulate throughout our bodies in a continual surveillance mission, waiting until they encounter a foreign particle that can bind to their particular antibody (which, at this point in time, is protruding from the B cell like a probe). As soon as recognition happens, the B cell rapidly proliferates, stimulating the production of many copies of its particular antibody, which is now available in sufficient quantities to ‘tag’ many members of the invading army. This rapid proliferation is the reason why it feels like our ‘glands are up’ when we’re fighting infection: these ‘glands’ are our lymph nodes, specific areas around our bodies where B cells accumulate while they undergo proliferation; this accumulation occurs to such an extent that the lymph nodes actually swell.

The ingenuity of our immune system doesn’t end with the way it can detect many different foreign particles: it ‘remembers’ if it has encountered a particular invader before, and responds all the more rapidly (and effectively) if it encounters the same invader again. This memory is exploited by various vaccines, which ‘trick’ the immune system into thinking it is being attacked by a fully-fledged threat (when, in fact, it isn’t). When the body is subsequently exposed to the real threat, however, our immune system can mount a full-scale attack on the invader much more quickly than it could have done if encountering the invader for the first time. Indeed, the priming of our immune system by vaccines is essential to defend us against particularly nasty invaders, which could kill us if the immune system hadn’t already been primed.

This post leaves a number of questions unanswered. For example, is there a difference between bacteria and viruses, and what does this mean for how we defend ourselves against them? We’ll explore these questions in my next post.

How do organisms evolve?

The world around us has been in a state of constant change for millions of years: mountains have been thrust skywards as the plates that make up the Earth’s surface crash against each other; huge glaciers have sculpted valleys into the landscape; arid deserts have replaced fertile grasslands as rain patterns have changed. But the living organisms that populate this world are just as dynamic: as environments have changed, so too has the plethora of creatures inhabiting them. But how do creatures change to keep step with the world in which they live? The answer lies in the process of evolution.

Many organisms are uniquely suited to their environment: polar bears have layers of fur and fat to insulate them from the bitter Arctic cold; camels have hooves with broad leathery pads to enable them to walk on desert sand. These so-called adaptations – characteristics that tailor a creature to its environment – do not develop overnight: a giraffe that is moved to a savannah with unusually tall trees won’t suddenly grow a longer neck to be able to reach the far-away leaves. Instead, adaptations develop over many generations. This process of gradual change to make you better suited to your environment is called what’s called evolution.

So how does this change actually happen? In previous posts I’ve explored how the information in our genomes acts as the recipe for the cells, tissues and organs from which we’re constructed. If we are somehow changing to suit our environment, then our genes must be changing too. But there isn’t some mysterious process through which our genes ‘know’ how to change: if an organism finds its environment turning cold, its genome won’t magically change so that it now includes a new recipe for the growth of extra fur to keep it warm. Instead, the raw ‘fuel’ for genetic change is an entirely random process: the process of gene mutation.

In my last post, I considered how gene mutation alters the DNA sequence of a gene, and so alters the information stored by that gene. If you change a recipe when cooking, the end product will be different. And so it is with our genome: if the information stored in our genome – the recipe for our existence – changes, then we must change in some way too. 

I mentioned above how the process of mutation is random. A mutation may be introduced when an incorrect DNA ‘letter’ is inserted into a growing chain as a chromosome is being copied: instead of manufacturing a stretch of DNA with the sequence ATTGCCT, an error may occur at the second position, to give AATGCCT. But it’s just as likely that an error could have been introduced at the sixth position instead of the second, with ATTGCCT becoming ATTGCGT. Such mutations are entirely down to chance.

And this is where we encounter something of a paradox. Though the mutations that occur in our genes to fuel the process of evolution do so at random, evolution itself is anything but random. So how can we reconcile this seeming conflict?

To answer this question, let’s imagine a population of sheep, all of whom have a woolly coat of similar thickness. Quite by chance, a gene in one of the sheep in the population picks up a mutation so that offspring of that sheep develop a slightly thicker coat. However, the thick-coated sheep is in a minority: most of the population carry the normal, non-mutated gene, and so have coats of normal thickness. Now, the sheep population live in a fairly temperate environment in which a slightly thicker or slightly thinner coat makes little difference to an individual’s chance of survival. So, it’s just as likely that our thick-coated sheep will reproduce – and pass on its mutated gene to the next generation – as it is that the normal-coated sheep will reproduce, and pass on their non-mutated gene. When we look at the population as a whole, we don’t see any real change, as the balance between normal-coated and thick-coated sheep is staying firmly tipped towards coats of a normal thickness. 

However, over a period of years, the climate grows chilly. As this change occurs, the thick-coated sheep – a minority in the population as a whole – find themselves at a distinct advantage. Their thicker coats keep them warmer than their thinner-coated cousins, who find themselves increasingly susceptible to cold-induced disease; in other words, in the population as a whole, the thick-coated sheep have a greater chance of survival. Vitally, this increased chance of survival makes it more likely that they, rather than the thinner-coated sheep, will pass their genes on to the next generation. And so we see the prevalence of the mutated ‘thick coat’ gene increasing as time goes on, and see a greater proportion of the sheep population sporting thicker coats. 

Over time, what started out as a little quirk – a thicker woolly coat – goes from being an anomaly to being the norm, a defining characteristic of a species. When this happens – when a change becomes pervasive – the species is said to have evolved.

Charles Darwin is famed for introducing the world to the process of evolution in his book On the Origin of Species by Natural Selection; what we have seen here is the process of natural selection in action: in a population with different coat thicknesses, environmental conditions are favouring those sheep with the thicker coat. As a consequence, it is more likely that their genes are passed on to the next generation. We’re seeing a random event – the mutation that generated the ‘thick coat’ version of the gene – having a non-random consequence, all thanks to environmental pressures.

This exploration of evolution shows how life is driven by an elegant interplay between the recipe for our existence – our genomes – and the environment in which we live. In biological terms, nothing much happens in a single lifetime: it seems almost as unchanging as a single frame in a film. It is only by playing the film of life through many frames, over many generations, that the real beauty of this interplay is revealed.

What is a gene mutation?

In my last three posts I’ve introduced you to the world of biological information, taking you from the storage of biological information in libraries called genomes, which house information in individual books called chromosomes (themselves divided into chapters called genes), to the way the cell makes use of that stored information to manufacture the molecular machines called proteins.

But what happens when the storage of information goes wrong? If we’re reading a recipe and that recipe contains a mistake, chances are that the end-result of our culinary endeavour won’t end up as it should. And so it is at the level of cells. If the information the cell is using is somehow wrong, the end result will also be wrong – sometimes with catastrophic results.

I’ve mentioned in previous posts how biological information is captured by the sequence of the building block ‘letters’ from which DNA is constructed. The sequence of letters is ultimately deciphered by a molecular machine called the ribosome, which reads the sequence of letters in sets of three, and uses each trio to determine which amino acid – the building block of proteins – should be used next in its mission to construct a particular protein. It should come as no surprise that, if the recipe for the protein is changed – if the sequence of DNA ‘letters’ is altered – the protein that is manufactured will probably contain errors as a result. And if a protein contains errors, it won’t be able to function correctly, just as flat-packed furniture will end up being decidedly wobbly if you construct it from the wrong parts.

Imagine a snippet of DNA has the sequence GGTGCTAAG. The ribosome would ‘read’ this sequence, and would use it as the recipe for building a chain of three amino acids: Glycine-Alanine-Lysine. Now imagine that we alter just one letter in our original sequence so that it becomes GGTCCTAAG. All we’ve done is swap a G for a C at the fourth position in the DNA sequence. However, this change is sufficient to affect the composition of the protein that is produced when the sequence is deciphered: the ribosome will now build a chain with the composition Glycine-Proline-Lysine. 

Surely such a small change won’t actually cause significant problems in a cell, though. Right? Wrong. Amazingly (and perhaps unnervingly) the tiniest error can have really quite significant consequences.

Let’s take just one example. Sickle cell anaemia is a condition that affects the red blood cells of humans.  Red blood cells fulfil the essential role of transporting oxygen from our lungs to all the living cells of our body: they continually circulate through our arteries and veins, shuttling oxygen from one place to another. A healthy red blood cell looks a bit like a ring doughnut (though it doesn’t actually have a hole right through the middle); by contrast, the red blood cells of individuals with sickle cell anaemia become warped into crescent-like shapes (like a sickle, the grass-cutting tool, after which the disease is named). These sickle cells no longer pass freely through our arteries and veins. Instead, they tend to get entangled with each other. As a result, the flow of oxygen round the body is impeded, and the individual afflicted with the disease can suffer breathlessness, dizziness, and sudden pain throughout the body as a result.

So what has this to do with changes in the sequence of a gene? Almost unbelievably, this debilitating disease is caused by just a single error in the sequence of a particular gene. The gene in question (one particular ‘chapter’ in one of our chromosomes, the genetic ‘books’ that make up our genome ‘library’) is constructed from a total of 625 building block letters. Yet, a change in just one of those letters – from the letter A to T – results in the amino acid valine being added in place of the amino acid glutamic acid at a particular point in the protein haemoglobin - the part of the red blood cell to which oxygen actually attaches - as it is constructed from the recipe that the gene spells out. This change is all that’s needed to affect the structure of the haemoglobin, which, in turn, affects the shape of the red blood cell in which it is found, causing it to adopt the distorted sickle shape.

Why do such errors happen in the first place? In short, because cells have to make copies of their genomes – and no process of copying is completely error-free. Almost every cell in our body must possess a full library of biological information – a complete copy of our genome. So, every time a cell divides to produce two daughter cells (when our skin cells divide to repair a cut or graze, or the cells of our stomach lining are replenished, for example) it must first make a copy of its genome so that each daughter cell ends up with a full genome. But as the cell copies its genome – literally letter by letter – mistakes creep in. (If you were to re-type this post without using the delete key as you typed, how many errors do you think there would be in the end result? I’m writing this on a laptop that’s just a few months old, and I can already see that the delete key is the most worn key on the keyboard!) These mistakes are what we call mutations.

Fortunately for us, however, the introduction of errors during the genome-copying process is a rare event: the cells of our bodies do a truly remarkable job of keeping things error-free. Indeed, they copy DNA with an accuracy of 99.999% - this means that only one error is introduced for every 100,000 letters that are copied. That’s no mean feat - and is thanks to a particular molecular ‘editor’ that proof-reads the DNA as it is being copied, spotting errors and correcting them as it reads.

Hiccups in the copying of DNA by our cells are not the only cause of gene mutations: various environmental factors can cause them too. The most prevalent of these is ultra-violet light, a natural component of sunlight – but a component that can cause unwanted changes in the chemical structure of DNA when it comes into contact with our cells. The effect of ultra-violet light on our DNA is the reason why we’re encouraged to wear sunscreens when we’re out basking in the sun: you might think a tan will make you look healthy, but the cost might be the creation of an error in the DNA of some of your skin cells that triggers the formation of a skin tumour. Is that a price worth paying for a few weeks of looking bronzed?

Despite this, gene mutation itself isn’t necessarily a bad thing. Indeed, if mutations weren’t to occur, we’d not see around us the remarkable diversity of life that we do. For gene mutation is the molecular ‘fuel’ for the process of evolution, as I’ll explore in a future post.