The story of the immune system begins with the story of life itself, almost 3.5 billion years ago, in some strange puddle on a hostile and vastly empty planet. We don’t know what these first living beings did, or what their deal was, but we know they very soon started to be mean to each other. If you think life is hard because you need to get up early in the morning to get your kids ready for the day, or because your burger is only lukewarm, the first living cells on earth would like a word with you. As they figured out how to transform the chemistry around them into stuff they could use while also acquiring the energy needed to keep going, some of the first cells took a shortcut. Why bother with doing all the work yourself if you could just steal from someone else? Now, there were a number of different ways to do that, like swallowing someone else whole, or ripping holes into them and slurping out their insides. But this could be dangerous, and instead of getting a free meal, you could end up as the meal of your intended victim, especially if they were bigger and stronger than you. So another way to get the prize with less of the risk might be to just get inside them and make yourself comfortable. Eat what they eat and be protected by their warm embrace. Kind of beautiful, if it wasn’t so horrible to the host.
As it became a valid strategy to become good at leeching from others, it became an evolutionary necessity to be able to defend yourself against the leeches. And so microorganisms competed and fought each other with the weapons of equals for the next 2.9 billion years. If you had a time machine and went back to marvel at the wonders of this competition, you would be pretty bored, as there was nothing big enough to see other than a few faint films of bacteria on some wet rocks. Earth was a pretty dull place for the first few billion years. Until life made, arguably, the single largest jump in complexity in its history.
We don’t know what exactly started the shift from single cells that were mostly on their own to huge collectives working closely together and specializing.*
Around 541 million years ago, multicellular animal life suddenly exploded and became visible. And not only that, it became more and more diverse, extremely quickly. This, of course, created a problem for our newly evolved ancestors. For billions of years the microbes living in their tiny world had competed and fought for space and resources in every ecosystem available. And what are animals really to a bacteria and other critters if not a very nice ecosystem? An ecosystem filled top to bottom with free nutrients. So from the very start intruders and parasites were an existential danger to the existence of multicellular life.
Only multicellular beings that found ways to deal with this threat would survive and get the chance to become even more complex. Unfortunately, since cells and tissues do not really preserve well over hundreds of millions of years, we can’t look at immune system fossils. But through the magic of science we can look at the diverse tree of life and the animals that are still around today and study their immune systems. The farther separated two creatures are on the tree of life and still share a trait of the immune system, the older that trait must generally be.
So the great questions are: Where is the immune system different, and what are the common denominators between animals? Today virtually all living beings have some form of internal defense, and as living things become more complex, so do their immune systems. We can learn a lot about the age of the immune system by comparing the defenses in very distantly related animals.
Even on the smallest scale, bacteria possess ways to defend against viruses, as they can’t get taken over without a fight. In the animal world, sponges, the most basic and oldest of all animals, which have existed for more than half a billion years, possess something that probably was the first primitive immune response in animals. It is called humoral immunity. “Humor,” in this context, is an ancient Greek term that means “bodily fluids.” So humoral immunity is very tiny stuff, made out of proteins, that floats through the bodily fluids outside of the cells of an animal. These proteins hurt and kill microorganisms that have no business being there. This type of defense was so successful and useful that virtually all animals around today have it, including you, so evolution did not phase this system out, but rather, made it crucial to any immune defense. In principle, it hasn’t changed in half a billion years.
But this was only the start. Being a multicellular animal has the perk of being able to employ many different specialized cells. So it probably did not take animals too long, in evolutionary terms, to get cells that did just that: Specialize in defense. This new cell-mediated immunity was a success story right from the start. Even in worms and insects we find specialized soldier immune cells that move freely through the tiny critter bodies and can fight intruders head-on. The further up we climb the evolutionary tree, the more sophisticated the immune system becomes. But already, on the earliest branch of the vertebrate part of the tree of life, we see major innovations: The first dedicated immune organs and cell training centers, together with the emergence of one of the most powerful principles of immunity—the ability to recognize specific enemies and quickly produce a lot of dedicated weapons against them, and then to remember them in the future!
Even the most primitive vertebrates, jawless fish, who look ridiculous, have these mechanisms available to them. Over hundreds of millions of years, these defense systems got more and more sophisticated and refined. But in a nutshell, these are the basic principles, and they work well enough that they were probably around in some forms around half a billion years ago. So while the defenses you have at your disposal today are pretty great and developed, the underlying mechanisms are extremely widespread and their origins reach back hundreds of millions of years. Evolution did not have to reinvent the immune system over and over again—it found a great system and then refined it.
Which finally brings us to humanity. And to you. You get to enjoy the fruits of hundreds of millions of years of immune system refinement. You are the height of immune system development. Although, your immune system is not really inside of you. It is you. It is an expression of your biology protecting itself and making your life possible. So when we are talking about your immune system, we are talking about you.
But your immune system is also not a singular thing. It is a complex and interconnected collection of hundreds of bases and recruitment centers all over your body. They are connected by a superhighway, a network of vessels, similarly vast and omnipresent as your cardiovascular system. Even more, there is a dedicated immune organ in your chest, as big as a chicken wing, that gets less efficient as you age.
On top of organs and infrastructure, dozens of billions of immune cells patrol either these superhighways or your bloodstream and are ready to engage your enemies when called. Billions more sit guard in the tissue of your body that borders your outsides waiting for invaders to cross them. On top of these active defenses you have other defense systems made up of quintillions of protein weapons that you can think of as self-assembling, free-floating land mines. Your immune system also has dedicated universities where cells learn who to fight and how. It possesses something like the largest biological library in the universe, able to identify and remember every possible invader that you may ever encounter in your life.
At its very core, the immune system is a tool to distinguish the other from the self. It does not matter if the other means to harm you or not. If the other is not on a very exclusive guest list that grants free passage, it has to be attacked and destroyed because the other might harm you. In the world of the immune system, any “other” is not a risk worth taking. Without this commitment you would die within days. And as we will learn later, sadly, when your immune system under- or overcommits, death or suffering are the consequences.
While identifying what is self and what is other is the core, it is not technically the goal of your immune system. The goal above all things is maintaining and establishing homeostasis: the equilibrium between all the elements and cells in the body. Something that can’t be overemphasized enough about the immune system is how much it tries to be balanced and how much care it puts into calming itself down and not overreacting. Peace, if you so want. A stable order that makes being alive pleasant and easy. The thing that we call health. The basis for a good and free life where we can do what we desire, not held back by pain and disease.
How crucial health is becomes the most apparent when it is missing. Health is really an abstract concept because it describes the absence of something. The absence of suffering and pain, the absence of limitations. If you are healthy, you feel normal, you feel right. Once you witness your health go away, even for a brief time, it is hard to forget how fragile you are and how much you are living on borrowed time. Disease is an unavoidable fact of life. If you have been lucky, you have not had to face it up to this point. If you or one of your loved ones has had to deal with it already, you know that nothing is more elemental for a pleasant life than being healthy. To the immune system, this means homeostasis. While the battle to stay healthy is ultimately futile and will be lost in the end, we still fight it to carve out more years, months, days, and hours. Because, overall, it is pretty good to be a human and it is worth it to have this experience a little bit longer.
But health is a hard thing to maintain because every day of your life you are in contact with hundreds of millions of bacteria and viruses that would love to make your body their home, as we saw in those single-celled organisms billions of years ago. For a microorganism you are an ecosystem waiting to be conquered. An endless continent full of resources, breeding grounds, and opportunities to thrive, a really nice home. Arguably at some point they will succeed, as when you die, the decomposition of your body will be immensely sped up by an army of unhinged microbes no longer kept in check by your defenses.
And not only do you need to worry about the plethora of life trying to get inside, but also about your own misguided self that can cancel the social contract of the body: Cancer. Making sure that doesn’t happen is one of the most important jobs of your immune system. In fact, while you were reading the last few pages, somewhere inside you a young cancer cell was quietly eliminated by your immune cells.
But the part meant to protect you also can go wrong and be corrupted. When it is tricked, your immune system can help diseases spread or protect cancer cells from detection. Or if the system is out of tune or flawed, it can get confused and decide that the body itself is the enemy. It can decide that self is other and literally start attacking the cells it exists to protect, resulting in any number of autoimmune diseases that need constant calming by medication, sometimes with harsh side effects.
Or take allergies, which are a very intense reaction of your immune system against things it should not be concerned about. An allergic shock shows strikingly how truly powerful your defense system is and how horribly it can go wrong: it may take a disease days to kill you—your immune system can do so in minutes.
Oh, and even if your immune system works as intended, it can be as much of a burden as it is helpful: Many of the unpleasant symptoms you feel when you are sick are the consequences of your immune system doing its job when activated—in some diseases the most crushing damage or even death are caused by an unhinged response to an intrusion. For example, many deaths from COVID-19 come from the immune system doing its job with too much enthusiasm.
The collateral damage your defense networks dish out against you can build up over time and today it is thought that many deadly diseases start with your immune system working as intended. So as important as it is for your health to have an immune system that is fast and brutal, it is just as important to keep it in check and prevent it from becoming unhinged and destructive. Just like in the human world, if you need to go to war, you at least want your wars to be over quickly and end with a clean victory. You don’t want decades of occupation or conflict that eat up resources and leave destroyed infrastructure.
So in the hands of your immune system lies an enormous responsibility to keep you well for as long as possible. Even if the battle will certainly be lost in the end, it matters to you today, right now, that it is fought well and with the necessary responsibility.
To summarize, distinguishing between self and other is core, homeostasis is the goal, and there are seemingly infinite ways for it to all go wrong.
What makes the immune system so fascinating is that all of this complex work has to be done by parts that are mindless and, individually, pretty dumb. And yet they are able to coordinate and react to dynamic and quickly developing situations. Imagine the Second World War happening, but ten times as large and without generals. Only mindless immune soldiers on the ground trying to figure out if they need tanks or fighter jets and where they need to go. And it all happens within days. That’s what it is like for you to battle even a common cold.