The Human Immune System – Part 1

The astonishing complex hidden defense mechanism we inherited from evolution.

I’ve written before that one of the joys of life is just appreciating how beautifully complex and wondrous it is.  A big part of that appreciation comes from better understanding our own immune system, which keeps us alive in the most interesting ways.  This essay series will explore the human immune system, using Philipp Dettmer’s book Immune: A Journey into the Mysterious System That Keeps You Alive.

As Dettmer writes:

Imagine waking up tomorrow, feeling a bit under the weather. An annoying pain in your throat, your nose is runny, you cough a bit. All in all, not bad enough to skip work, you think, as you step into the shower, pretty annoyed about how hard your life is. While you are totally not being a whiny little baby, your immune system is not complaining … [W]hile intruders roam your body, killing hundreds of thousands of your cells, your immune system is organizing complex defenses, communicating over vast distances, activating intricate defense networks, and dishing out a swift death to millions, if not billions, of enemies. All while you are standing in the shower, mildly annoyed … [T]here are not many things that have such a crucial impact on the quality of your life as your immune system. It is all- embracing and all- encompassing, protecting you from bothersome nuisances like the common cold, scratches, and cuts, to life- threatening stuff from cancer and pneumonia to deadly infections like COVID-19. Your immune system is as indispensable as your heart or your lungs.

Understanding the immune system can help reduce fear and anxiety, and (as we’ll explore in a future essay in this series) reducing fear and anxiety can actually boost the immune system’s performance:

Understanding the mechanisms that are keeping you alive as you read this is not just a nice exercise in intellectual curiosity; it is desperately needed knowledge. If you know how the immune system works, you can understand and appreciate vaccines and how they can save your life or the lives of your children, and approach disease and sickness with a very different mindset and far less fear. You become less susceptible to snake oil salesmen who offer wonder drugs that are entirely devoid of logic. You get a better grasp on the kinds of medication that might actually help you when you are sick. You get to know what you can do to boost your immune system. You can protect your kids from dangerous microbes while also not being too stressed- out if they get dirty playing outside … Besides all these practical and useful things, the immune system is also simply beautiful, a wonder of nature like no other … The immune system is the most complex biological system known to humanity, other than the human brain.

Over millions of years, evolution has supplemented the most basic immune system with much more complex defenses:

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 … [W]hile 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 … 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 … 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 … 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.

As Dettmer later emphasizes, the immune system doesn’t really “try” anything, as of course it has no intentionality, and is simply the result of the laws of physics and chemistry and evolution’s process of propagating mutations that help sustain and replicate life.

Dettmer starts with describing humans’ elementary particle of life, the cell:

So what exactly is a cell and how does it work? As we said, cells are the smallest units of life: things that we can clearly identify as something that is alive … The definition of life is a big, complicated, brain- melting affair in itself. We know it when we see it but it is very hard to define. In general there are a few properties that we assign to it: Something alive separates itself from the universe around it. It has a metabolism, meaning it takes up nutrients from the outside and gets rid of internal garbage. It responds to stimuli. It grows and it can make more of itself. Cells do all these things. And you are made almost entirely from them. Your muscles, organs, skin, and hair are made up of cells. Your blood is filled with them. Being as small as they are, they are not conscious, they do not have free will or feelings or goals or make active decisions. In a nutshell, cells are biological robots, driven entirely by myriads of biochemical reactions guided by the even smaller parts they are made up from … Your cells have “organs” that are called organelles, like the nucleus, the information center of your cell— a pretty large structure with its own protective border wall that houses your DNA, your genetic code. There are mitochondria, generators that transform food and oxygen into chemical energy that keeps your cells running.

Water and protein are our friends:

A single human cell is filled up with dozens of millions of individual molecules. Half of them are water molecules … that give the insides of your cells a consistency that is kind of like soft jelly and enable other things to move around easily. Because on this scale water is no longer a thin fluid but viscous and honey-like. The other half of your cells’ insides consists mostly of millions of proteins. Between 1,000 and 10,000 different kinds— depending on the function of the cell and what it needs to get done … [Y]our cells are mostly made from and filled up with proteins … Proteins are the most fundamental organic building blocks and tools of all living things on this planet. They are so useful and manifold that a cell can use them for basically everything, from sending signals to constructing simple walls and structures to complex micromachines.

Proteins are sort of the Lego bricks of life, but very squishy and vibrating Legos.  Different protein configurations enable different puzzle piece fittings to interact differently with other environmental entities based on their own particular configurations:

Proteins are made from chains of amino acids, which are tiny organic building blocks that come in twenty different varieties. All you need to do is to string them together into a chain, in whatever order you like, and voila, you have a protein. This principle enables life to construct a stunning variety of different things. For example, if you wanted to make a simple protein from a chain of ten amino acids, and you have twenty different amino acid types that you can choose from, this gives you a breathtaking 10,240,000,000,000 different possible proteins … How do your cells know in which order to put amino acids to make the proteins they need? Well, this is the job of the code of life: Your DNA, a long sequence of instructions that are necessary for a living thing to be a living thing … In the world of proteins shape determines what they can and can’t do. Shape is everything. In a way, you can imagine proteins like really complex three- dimensional puzzle pieces. Depending on their shape, proteins are the ultimate tool and construction material. A cell can use them to build basically everything. But the magic of proteins goes beyond being merely construction materials. Proteins are used as messengers that convey information: They can receive or send signals that change their shape and trigger intensely complicated chain reactions. For your cells, proteins are everything.

Our bodies are immensely complicated Rube Goldberg devices:

As long as your cell is alive it is always moving and shifting. Wheels spin and tip over dominos, which push switches and pull levers and ferry marbles around on tracks that then spin more wheels, and so on. All these tiny little protein puzzle pieces and structures inside your cells interact in lots of really cool and complex ways. How do they do that? By wiggling around really fast. Proteins are so small, weigh so little, and exist on such a fundamentally different scale that they behave very strangely compared to things on the human giant level. Gravity is not a relevant force for things at this scale. And so, at room temperature, an average protein can move about sixteen feet (five meters) per second, in theory. Maybe that does not sound fast, until you remember that the average protein is about one million times smaller than the tip of your finger. In practice, proteins can’t actually move that fast inside cells, because there are so many other molecules in the way. So they constantly collide and bump into the water molecules and other proteins in all directions. Everybody is pushing around and is getting pushed. This process is called Brownian motion and it describes the random movement of molecules in a gas or fluid. Which is the reason water is so important for your cells— because it enables other molecules to move around easily. Despite, or maybe even because of the chaos of random movements in combination with the speed of your protein puzzle pieces, things get done in cells … Let’s try to simplify a little. To imagine the basic principle cells use to bring things together, a good metaphor is a sandwich. If you were inside a cell and you wanted to make a jelly sandwich, the best approach would be to throw the toast and jelly into the air and wait a few seconds. Because of how fast everything is smashing together, they will come together all by themselves, unifying into a sandwich that you can just pick from the air. In the microworld, the different shapes of a molecule determine which molecules attract and repel each other. And so the shape of your cells’ proteins determines which proteins attract or repel each other and how they interact (while the number of different types of proteins determines how often these interactions happen). This creates the interactions that make up the biochemistry of all cells on earth. These interactions are fundamentally important for biology and are called biological pathways. Pathways are fancy words to describe a series of interactions between individual things that lead to a change in a cell. This can mean the assembly of new special proteins or other molecules, which can turn genes on and off, which changes what the cell can and can’t do. Or it can spur a cell into action and cause the cell to do things we would call behavior, like reacting to a danger by moving away.

Dettmer reminds us again that there is nothing intentional in this process:

Your cells are nothing but bags of proteins guided by chemistry. But together these proteins form a living being that can do a lot of really sophisticated things … As amazing as your cells are, please remember: Cells don’t want anything. Cells don’t feel anything. They are never sad or happy. They just are, right here, right now. They are as conscious as a stone or a chair or a neutron star. Cell robots follow their code that has been evolving and changing for billions of years … This is not to say that our complex human cells are completely reliant on randomness. Cells have a lot of complex and wonderful mechanisms to get things exactly where they need them to be, and that we’ll ignore here. If you do care: There are transport proteins that move along the scaffolding of cells. The best thing about them is that they look like gigantic, ridiculous feet that jump forward by magic and if you have a moment to get distracted, you should look at videos of them on YouTube.

Dettmer is referring to videos like these. which show a sort of mechanical-looking thing walking rhythmically on a track.  However, in reality, simple machine metaphors for these biological processes warrant some qualifications, which can be found here here, and in this paper here, which notes that “these models tend to overlook the fact that proteins operate in an environment that is drastically different from the macroscopic one in which we, and our machines, exist. Motor proteins, like all other molecules, are subject to constant thermal and quantum fluctuations that make carefully synchronized movements along a desired path challenging in the extreme. In fact, the energy of ATP hydrolysis responsible for generating the power-strokes that allegedly propel motor proteins forward is only about an order of magnitude larger than the environmental stochastic forces that are permanently buffeting them. In such conditions, moving mechanically and deterministically is like trying to ‘swim in molasses’ or ‘walk in a hurricane’.”

Back to Dettmer:

Imagine you were the grand architect of the immune system. Your job is to organize the defenses against millions of intruders that want to take it over. You get to build whatever defenses you like, although the accountants remind you that the body is on a tight energy budget, has no resources to spare, and they kindly ask you to not be wasteful. How would you approach this monumental task? What kind of forces would you put at the front and which ones would you hold in reserve? How would you make sure that you could react strongly to a sudden invasion but also prevent your army from exhausting itself too quickly? How would you deal with the massive scope of the body and the millions of different enemies you would have to account for? Luckily, your immune system has found many beautiful and elegant solutions for these problems … [I]t’s helpful to imagine them as empires and kingdoms that, in unison, defend the continent that is your body. We can organize them into two very different realms that together represent the most powerful and ingenious principles that nature found to defend your continent of flesh: The Realm of your Innate Immune System and the Realm of your Adaptive Immune System. The Realm of the Innate Immune System contains all the defenses you are born with and that can be employed mere seconds after an invasion occurs. These are the basic defenses that go back to the very first multicellular animals on earth and they are absolutely crucial for your survival. One of its most central features is that it is the sort of smart part of your immune system. It has the power to tell self from other. And once it detects other it immediately springs into action. Without your Innate Immune System, you would be overwhelmed and killed by microorganisms within days or weeks. The Realm of the Adaptive Immune System contains specialized super cells that coordinate and support your first line of defense. It contains factories that produce heavy protein weapons and special cells that hunt and kill infected body cells in the case of viral infections. Its defining feature is that it is specific. Unbelievably specific, in fact. Your Adaptive Immune System “knows” every possible intruder … [Y]our Adaptive Immune System possesses the largest library in the known universe, with an entry for every current and future possible enemy. But not only that, it also is able to remember everything about an enemy that showed up only once. It is the reason most diseases are only able to manifest themselves once in your life. But this knowledge and complexity come with downsides. In contrast to the Innate Immune System, your Adaptive Immune System is not ready yet when you are born. It needs to be trained and refined over many years. It starts as a blank slate and then gets progressively more powerful, only to get weaker again as you age.

Dettmer adds an aside regarding the unfortunate term “white blood cells”:

So you have probably heard that you have white blood cells and they are your immune cells or something like that. Well, while this name has its use in the right context it just generally means “the cells of the immune system” and I don’t think immunology has done itself a favor with this term. “White blood cells” describes so many different cells that do so many different things that it is sort of useless if you want to understand what is really going on here. So you can forget “white blood cells” again because we are not going to use it.

Dettmer then introduces the two things mostly responsible for making humans sick:

[W]e are mostly talking about bacteria and viruses. Although, in developing countries, protozoa, single-celled “animals” that cause diseases like malaria, which kills up to half a million people each year, are still a serious problem. Any sort of invader that is able to give your immune system a run for its money is called a Pathogen— which appropriately means “the maker of suffering.”  In a pleasant environment, a single bacterium can reproduce once every twenty to thirty minutes by dividing into two bacteria. So after four more hours of dividing, there would already be 8,000 of them. A few more hours and there would be millions. And in a few more days, there would be enough bacteria to fill up the entirety of the world’s oceans. Luckily this math does not quite work in reality because there is neither the space nor the nutrients. And not all species of bacteria can replicate this quickly, but this is what would technically be possible. The point being, their potentially superfast reproductive cycle is a huge challenge for your immune system to deal with. Since they are so omnipresent on this planet, you are positively, absolutely covered by bacteria at all times, and have not even the slightest chance of ever getting rid of them. So our bodies had to arrange with this fact of life and make the best of it. A life without bacteria is impossible. And indeed, most bacteria are not only harmless to us, but our ancestors made a pretty good deal with them that is actually even beneficial to us. Trillions of them act as friendly neighbors and partners in crime and help you survive by keeping unfriendly bacteria away and breaking down certain food parts for you, and in return, they get a place to call home and free food. But these are not the bacteria we are concerned about in this book. There are a lot of unfriendly, pathogenic bacteria that try to invade your body and make you sick.  Before the onset of antibiotics, even small wounds could lead to serious disease or even death … [O]ur grandparents in fact did have it harder in life. We have data from a Boston hospital from 1941 that shows that 82% of bacterial infections of the blood resulted in death. We can barely imagine the horror this number represents— a scratch and a tiny bit of dirt literally could mean that your life was about to end. Today in developed countries less than 1% of these kinds of infections are deadly. The fact that we don’t really think about this stuff too much shows how fast humans forget and move on, and how happy we can be to live in the present and not in the past.

In the next essay in this series, we’ll explore our bodies’ first line of defense from these bacteria and viruses: our skin.