On Definitions: They Matter

Most of my favorite long-standing discussions with friends and family tend to resolve around definitions. My good friend Paul and I have had hours upon hours of discussion about the nature of the universe - he calls his perception of the order of the universe "god," and I call myself an atheist (interestingly, that picture was taken by Paul), though in practical terms I don't think our beliefs are really that far apart. He says his definition allows him to engage with religious people, I say it just causes confusion. In my first year of graduate school, I used to argue endlessly with my class-mates that viruses are alive. I did this not because I think viruses are alive (though I do), but because I think it's facinating the way we humans give an arbitrary definition of a word, "life," and then dogmatically exclude anything that doesn't fit into that definition. The real answer isn't that simple, viruses aren't the same as cellular organisms, but they're also not the same as unambiguously non-living things. Richard Dawkins (from A Devil's Chaplain):

This way of thinking characterises what I want to call the discontinuous mind. We would all agree that a six-foot woman is tall, and a five-foot woman is not. Words like 'tall' and 'short' tempt us to force the world into qualitative classes, but this doesn't mean that the world really is discontinuously distributed. Were you to tell me that a woman is five feet nine inches tall, and ask me to decide whether she should therefore be called tall or not, I'd shrug and say 'She's five foot nine, doesn't that tell you what you need to know?' But the discontinuous mind, to caricature it a little, would go to court (probably at great expense) to decide whether the woman was tall or short.

The use of language forces us to place boundaries on things. In order for words to have meaning, they must necessarily encompass some concepts and not others. Most of the time, it doesn't really matter - arguments about whether or not a couch is a chair or a machine gun is a robot can be entertaining, but not necessarily important or enlightening.

But this is a post about immunology. Enter NK cells: NK stands for "Natural Killer." They kill stuff, naturally. They look kinda like cytotoxic T-cells, and they kill cells in the same way (by punching holes in their membranes and injecting proteins that force them to commit suicide), but they don't need to be primed by an antigen-presenting cell. Once they develop, they wander around inspecting cells to make sure they're behaving, and if they look screwy, the NK cell bumps them off.

Immunologists like to classify the cells of the immune system into either "innate" or "adaptive," and up until the last year or two, NK cells were unambiguously considered innate. The innate system is usually defined as those cells that respond immediately to infection, recognize non-specific signatures of pathogens, and respond the same way to each subsequent infection. The adaptive immune system (basically T cells and B cells), on the other hand, have a delayed response (they have to be activated by the innate immune system and divide), recognize very specific determinants of very specific pathogens, and generate a memory response that is stronger the next time that specific pathogen rears its head.

But in last month's Nature Immunology, there's a paper showing pretty conclusively that NK cells have features that look an awful lot like memory. But is it really memory? If so, does that mean that NK cells are really adaptive? Does it mean other innate cells could have memory too? If you're an immunologist trapped in the discontinuous mind, these questions are really hard to answer. But I think if you realize that, "innate-" and "adaptive-immunity," as well as "immune memory," have definitions that are assigned by humans, it's a lot easier to swallow.

I don't claim to be immune from this. In my first year of grad school, we discussed the precursor to this paper, and the argument (in which I played no small role) got pretty heated. My position (for that previous paper) was that they hadn't conclusively demonstrated memory, and even if they had, that doesn't mean NK cells are adaptive. Looking back, I think my first point was correct, but I think I got more worked up because I was stuck on a solid boundary between innate and adaptive immunity, and this paper was trying to challenge that.

Definitions matter, but not for their own sake. They allow us to categorize, improving our understanding and our ability to communicate, but we would be remiss to give those definitions power over our ideas. The world is what it is, and if we close our minds around a word and refuse to let our definitions wander, we may miss out on the truth.

I'll leave you with some great lines from the News and Views on this article:

There are many examples in immunology of the assignment of names before function is thoroughly understood. As a result, the words or their definitions can get in the way of the field's ability to incorporate radical new information[...]

The characterization of antigen-specific memory NK cells is important, but the experimental results have difficulty both fitting into old definitions and conclusively showing new major adaptive functions for the cells. The observations support extension of the borders of the definitions of innate and adaptive immunity, but the evidence is not yet sufficient to justify discarding the existing terminology. The main defined functions for NK cells in the context of the fullness of complete immune responses are still innate, with innate immunoregulatory effects on adaptive responses[...] Clearly, much remains to be learned, but for now it is important for immunologists to remember that "There are more things in heaven and earth...than are dreamt of in your philosophy."