Self & Other · The ID Check

A Strange Aside About Smell

The MHC variation is, in essence, a bet against pandemics. It is the species saying, in genetic language, that we will not all be vulnerable to the same things. The cost of the bet is that none of us is perfectly protected against everything. The benefit is that no single pathogen can erase us.

This explains, by the way, why the same illness affects different people so differently. When a new virus arrives, some people’s immune systems handle it almost effortlessly; others struggle; a few die. Behavior matters, age matters, dose matters, luck matters. But MHC variation matters too, and it has been quietly shaping who lives through which disease for as long as humans have existed.

A Strange Aside About Smell

We can’t quite leave this chapter without one of the strangest findings in MHC biology, because it’s the kind of thing that makes the whole subject feel less like cellular accounting and more like something genuinely peculiar about being alive.

In the 1990s, a Swiss researcher named Claus Wedekind ran a study that has since become famous in popular science books. He had men wear plain cotton T-shirts for two nights in a row, then sealed the shirts in boxes. He had women, in the days around their most fertile point in the menstrual cycle, sniff the boxes and rate the smells.

The result, replicated in various forms since, was that women tended to rate as more attractive the smell of men whose MHC genes were most different from their own. The effect was small but consistent. Something about the bodily smell of a person carries information about their MHC profile, and something in another person’s nose, at least under certain conditions, can detect it.

Why this would be the case is biologically reasonable, in a slightly unsettling way. A child whose biological parents had very different MHC profiles would inherit a wider variety of MHC molecules and, therefore, a more flexible immune system — better able to display fragments from a wider range of pathogens. From an evolutionary point of view, “be drawn to mates whose immune systems are different from yours” would produce more resilient children. Whether this is actually a meaningful force in human relationships is much debated and probably overstated in the popular telling. But the underlying observation — that MHC genes affect bodily smell, and that other humans seem to detect it without knowing they are detecting it — is real.

We don’t fully understand it. We don’t know how much it matters. But it’s a useful reminder that the immune system, for all its molecular precision, is woven through the rest of you in ways that don’t stay in their lane. The flashcards your cells hold up are, indirectly, also part of why one person smells like home to another.

The MHC and Disease

One last thing about MHC, which we’ll return to in Chapter 10.

Because different MHC versions display different sets of fragments, different MHC versions also have different relationships with disease. Some MHC versions are protective against certain illnesses; others are associated with vulnerability.

This includes autoimmune diseases. The strongest known genetic risk factors for many autoimmune conditions are particular MHC variants. People who carry the variant called HLA-B27, for instance, are far more likely to develop a kind of inflammatory arthritis called ankylosing spondylitis. People who carry certain HLA-DR variants have higher risk for type 1 diabetes, for celiac disease, for rheumatoid arthritis, for lupus, for multiple sclerosis. The associations are statistical, not deterministic — most people with the risky variants never develop the disease, and many people with the disease don’t carry the riskiest variants. But the link is real and consistent.

Why? Because if you happen to inherit an MHC molecule whose groove is very good at displaying a fragment that looks suspiciously like one of your own proteins, your T cells may, in certain circumstances, be tricked into responding to that self-fragment as if it were foreign. The same molecular feature that protects you from one set of infections leaves you vulnerable to a different kind of error.

This is one of the genuinely sad ironies of immunology. The variation that protects the species from pandemics is the same variation that makes some individuals more prone to fighting themselves. Every benefit, somewhere, has a cost.

We’ll come back to this. For now, the thing to remember is that the MHC system is not just an engineering detail of how T cells see their targets. It is one of the deepest sources of biological individuality humans have. It is also, to a degree we’re only starting to map, woven into who gets which diseases and who doesn’t — in ways that are not anyone’s fault, that have nothing to do with effort or willpower or what you ate, that were largely settled the moment you were conceived.

So now we have, finally, the molecular answer to the question we asked at the very beginning of the book. How does your body know what counts as you?

The answer is: every cell in your body wears a molecular badge — the MHC molecules — that is almost unique to you. Inside the badge, the cell holds up a constantly refreshed sample of what it currently contains. Other cells walk by and read the samples. If they see only normal you-fragments, nothing happens. If they see anything else, an enormous response begins.

This is the system that told Medawar’s pilot, on day eight after the skin graft, that the borrowed skin had to go. This is the system that finds viruses hiding inside your liver cells. This is the system that, in some people, in ways we are still working out, eventually makes a mistake — reads a normal you-fragment as foreign, and starts attacking it. The system is breathtaking. The system is fallible. The system, in your body, is running right now.

There is one more piece we need before we can talk about what goes wrong. The MHC system explains how T cells see their targets. It does not explain how T cells learn, in the first place, which targets to leave alone. Every T cell is born with a randomly generated receptor, thanks to V(D)J. Most of those random receptors will recognize foreign things. Some, by sheer chance, will recognize bits of you. What stops those self-reactive T cells from killing your own cells the moment they leave the bone marrow?

The answer is that they don’t leave the bone marrow, exactly. They go somewhere first. They go to a school. The school is harsh, and most of the students don’t survive, and the ones who do come out trained — mostly — to leave you alone.

That school is the next chapter.

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