Amazing new research from the University of Calgary explains why immune cells unnecessarily “swarm” sterile injury sites, causing damage and pain with no direct benefit — a biological glitch with profound implications about why some painful problems are so severe and stubborn.1 It’s old news that the inflammatory response often seems like overkill, but we now have a key piece of the puzzle — the precise reason for the overreaction — and confirmation that it is pointless in principle, a lose-lose situation imposed by evolution.
This is a great triumph of microbiology and an evolutionary perspective on medicine.2 The potential to exploit this knowledge for more effective pain medications is great. Meanwhile, while we wait, I can think of no other scientific news in my career that has boosted my understanding of pain more at one stroke than this; for a pain science geek, that’s exciting! This is a fine day to be the author of eight easily-updated books about painful problems.
One of the principle qualities of pain is that it demands an explanation.
Plainwater, by Anne Carson
Pain is a message, a sort of public service announcement from your brain about a credible threat. Supposedly.
In the case of the pain of a burn, the message is simple: “Fire is super-duper dangerous! Don’t mess with it!” But does the message really need to be as loud as it is? Does it have to last for days?
Maybe it does. I always assumed that the explanation for this was that pain has to be extreme to have the desired effect — that the logic of neurology and psychology requires pain to actually be emotionally traumatic in order to ensure that we remain permanently keen to avoid whatever caused it. This rationalization of the severity of pain can be stretched to include basically any kind of pain that has any kind of obvious cause.
But what about pain with no apparent cause? Just what is it that your body is telling you to stay away from when you have an unending case of low back pain or plantar fasciitis? What’s the “information” encoded in that pain?
“Never sleep comfortably again?”
“Never walk again?”
And why does it continue telling you? Permanently, in some cases.
The severity and chronicity of some pain has always been hard to understand in the context of evolution, particularly when it actually interferes with function. Our first experience with being burned tells us to never, ever touch fire again, and we don’t — and (this is the important part) we’re definitely better off for it. But when the message of pain is actually debilitating for long periods, how exactly is that sensation helping? Were cavemen with chronic back pain better hunters or something?
Pain has always presented a bit of a problem for evolutionary biology. In a chapter on “design” flaws, Richard Dawkins states this nicely in his book, The Greatest Show on Earth:
Pain, like everything else about life, we presume, is a Darwinian device, which functions to improve the sufferer’s survival. Brains are built with a rule of thumb such as, ‘If you experience the sensation of pain, stop whatever you are doing and don’t do it again. It remains a matter for interesting discussion why it has to be so damned painful. Theoretically, you’d think, the equivalent of a little red flag could painlessly be raised somewhere in the brain, whenever the animal does something that damages it: picks up a red-hot cinder, perhaps. An imperative admonition, ‘Don’t do that again!’ or a painless change in the writing diagram of the brain such that, as a matter of fact, the animal doesn’t do it again, would seem, on the face of it, enough. Why the searing agony, an agony that can last for days, and from which the memory may never shake itself free? Perhaps grappling with this question is evolutionary theory’s own version of theodicy. Why so painful? What’s wrong with the little red flag?
It turns out that nothing at all is wrong with “the little red flag.” In a wide variety of painful circumstances, a little pain would actually be perfectly adequate to serve the basic evolutionary goal of warning us away from dangers.
But it turns out that we have a system that purposefully takes pain to the next level. It didn’t have to be that way. It was just an accident of biology, another design flaw. If Dawkins had known this when he was writing Greatest Show, I’m sure he would have delighted in pointing it out!
The system to blame here is the infection-fighting system, the immune system, the body’s Hazmat teams — blindingly fast, agile, fierce cells bristling with biological weapons. Their rather wimpy-sounding name — “neutrophils” — should be changed to “badassocytes.” A few billion of these little monsters are your best friends every time there is a genuine risk of infection — which there definitely is every time the skin is broken. They descend on the scene of the injury like a horde of microscopic barbarians and generally beat the tar out of any microscopic invaders stupid enough to try to crash the party that is you. Neutrophils also destroy a fair bit of healthy tissue in the process. They take no chances.
This is all a normal part of inflammation, and it all makes perfectly good sense. As much as the pain is nasty, this kind of pain makes sense: it’s a fair trade. I’m quite willing to put up with the pain, knowing that it’s for a good cause.
But imagine if your local fire department hosed down your house when there was no fire. What if they had no concept of a “false alarm”?
Neutrophils have no concept of a false alarm. None at all.
Internal injury — sterile tissue damage, any injury where there is exactly zero risk of infection — causes exactly the same reaction. Neutrophils rush to the scene and start doing their thing. They attack and kill any cells in the area — ours included — just in case. Better safe than sorry, you know! Except it’s not better, not here, not in this situation.
Here are two remarkable (and short) videos showing neutrophil sieges on sterile wounds:
A dramatic neutrophil response to sterile injury is not news. Dr. Kubes: “We have known how white blood cells find their way to sites of infection for many years, but understanding how, or even why white blood cells go to sites of sterile non-infectious tissue damage has been a real dilemma.”
The problem is that they have a bogus alarm signal, and identifying the nature of that bogus signal is the science news here.
In a well-designed biology, the “badassocytes” would know the difference between injury with a risk of infection and an injury without a risk of infection. Viewed strictly as an engineering problem, this is a no-brainer: there are countless candidate chemical signatures that could do the trick, “smells” that are exclusive to each kind of damage. But the neutrophils are oblivious to those smells, because there is only one signal that does matter to them, just one telltale sign that crops up inside our very own cells, as well as on actual invaders.
That’s because there’s actually an “invader” inside every single cell in our body: a welcome guest providing a critical service, without which we would literally die in seconds. But that guest is still foreign, technically. It still smells like an invader — like bacteria, specifically.
A long, long (long, long, long!) time ago, multicellular organisms started a marriage of convenience with a bacteria. Those bacteria became permanent residents of every cell in our bodies. They became, in fact, cellular organs, vital subsystems. The mitochondria are arguably the most awesome microscropic machines in biology. They produce energy, and a great deal of it. They are the engines of our cells.
Mitochondria have always stayed true to themselves, remarkably autonomous symbionts. They even still retain their own DNA. Our immune systems evolved relatively separately from the mitochondria, which remained safely tucked away inside our cells. As long as the mitochondria stay inside our cells, there’s no trouble. But no one gave them a hall pass … and when cells are damaged and mitochondria spill out into our tissue fluids, the neutrophils attack, because mitochondria look like invaders to stuck-in-their-ways neutrophils. That’s their signal.
Neutrophils react to all unfamiliar bacteria. And mitochondria have managed to remain “unfamiliar” to them for a few billion years now. And so they are treated like invaders.
The neutrophils are merciless. They do not heed the pathetic little mitochondrial protests:
Friend! Friend! Please, no, I just work over there in that damaged cell, don’t spray me with membrane-ripping acid,3 no no no no, nooooooarrrghghAAAACK—!
But neutrophils don’t even mind killing our own cells. In fact, it’s their job. They are indiscriminate better-safe-than-sorry killers that are only too happy to take out a few you-cells in the heat of battle. “It’s the only way to be sure.”4 And so not only is this component of inflammation completely pointless in the absence of any actual infection hazard, but more healthy cells are actually killed. The neutrophils make the situation worse.
This has profound implications.
It means that pain and injury actually get worse for no reason whatsoever. There’s really no upside at all, not in terms of rehabilitation. Nor is this overkill even necessary in principle — which is the next topic.
This is just not fair. It’s like a horror movie monster that gets bigger when you attack it.
As if overzealous neutrophils aren’t bad enough, they actually get even more overprotective5 when you exercise moderately — the holy grail of health and fitness, the single best thing you can do for your health. As nicely summarized by Alex Hutchinson, a 2011 study in the journal of Medicine & Science in Sports & Exercise by Syu et al6 shows that:
Regular, moderate exercise boosts the ability of the neutrophils to get to infection sites quickly (chemotaxis) and attack the bad guys (phagocytosis). And in fact, the neutrophils are still ultra-alert for a couple of months after you stop training. In addition, the researchers found that regular exercise extended the life of the neutrophils.
Busier, more effective, longer-lasting neutrophils sounds great to most people, and this science has been reported widely as “good news.” Put these two pieces of science together, and you have an explanation for one of the great catch-22s of the human condition: exercise is good for you, but it often hurts more than it seems like it should.But a “boost” to immune function is never as simple as it sounds or all good news,7 and the counterintuitive price of better infection-fighting could be vulnerability to repetitive strain injury, slower healing, and pain chronicity — by reacting more strongly to aseptic cellular trauma, as well as real pathogens.
Put these two pieces of science together, and you have an explanation for one of the great catch-22s of the human condition: exercise is good for you, but it often hurts more than it seems like it should. Athletes and active people are prone to many poorly defined aches and pains,8 as well as more serious, common and persistent injuries that significantly restrict performance and competitiveness — and sometimes even drive people away from exercise altogether, because the cost is just too high. And that cost may well be higher for some people than others.9
This is simple but not necessarily obvious: we haven’t evolved out of this one because the only thing worse than neutrophils that over-react is neutrophils that under-react. Given biology as it is, they have to be the way that they are. Evolution does not dare mess with that over-sensitivity. If neutrophils don’t react to mitochondria, then they wouldn’t react to real invaders either. And that would be very, very bad.
So we’re stuck with the situation. Neutrophils: can’t live with ‘em, and (literally) can’t live without ‘em.
Awful catch-22s like this are actually quite common in evolution. There are many trade-offs: adaptations that helps in one way, but sacrifices something else. As long as there is a net improvement in breeding, evolution is happy with the solution, and some of these trade-offs work out amazingly well: elegant optimizations to serve different goals simultaneously as well as possible, exactly the sort of thing you might say must have been intelligently designed. But many other evolutionary compromises are awkward and ridiculous, and could have been avoided entirely by a designer … even a stupid one. Some prominent examples include:
And, of course, neutrophils that cannot comprehend “false alarm” but could if they were designed properly from the ground up.
I doubt that this particular glitch — the neutrophil response to sterile injury — was ever functional in any biological context, for any animal, ever. It’s simply an undiscriminating inflammatory response, unpleasant and problematic, but impossible to evolve out of because the alternative is even worse and natural selection can’t “think” laterally and has no reverse gear. Evolution can only go forward in increments, building on what it has. If a small mutation of an existing system improves your breeding chances, fine, we can do evolutionary business. But every other engineering option is off the table.
Not all pain is the result of sterile inflammation, of course, but a good portion of it certainly is. Here are several ways in which neutrophil over-reaction is probably relevant to common kinds of painful problems:
Finally, and most ominously …
Fortunately, neurology is also our friend. This article has been about some nasty business in the tissues, but the brain is the king of pain. There is no pain without brain. A healthy nervous system can handle just about anything, responding to nonsensical inflammation with minimal “concern.” The brain likely even plays a role in regulating the behaviour of the neutrophils, taming them or getting them more riled up. For instance, brains may be quite capable of understanding that an ankle sprain is not a septic injury and taming the neutrophils to some extent — singing them a little biochemical lullaby. I’m guessing intelligently here — I’m not aware of any direct evidence about this — but the last few decades of pain science have consistently shown that it’s safe to bet on the omnipotence of the central nervous system. There are multiple lines of evidence converging on this kind of thinking. Consider the microglial cells — very similar critters to the neutrophils, but devoted to protecting nerves specifically, certainly responsive to threats and almost certainly also responsive to the brain.
The neutrophil over-reaction is a marvellous way of understanding a key feature of pain — worthy of this whole, big article — but it’s intertwined with a neurological perspective on pain that is even more informative. We are generally wired to over-react to potential threats, and so dysfunctional pain sensation is a common problem. The credibility of any threat to the body is entirely up to your brain. Pain is an entirely brain-generated interpretation of signals from the tissues (nociception) that have no significance in and of themselves, and can even be entirely ignored by the brain, block from ever reaching our conscious mind. We only hurt when the brain actually assigns meaning to the raw data coming from the tissues. If the brain decides the data mean trouble, then (and only then) do the tissues seem to “hurt.” It’s really the brain what does the hurting, though.
There’s no doubt that the unnecessary inflammation in sterile injuries is giving the brain a whole lot more nociception to try to cope with and ignore, and it’s pretty clear that a lot of people ain’t coping with their peripheral inflammation so very well.
Believe it or not, there’s a practical conclusion here. Hopefully it is extremely helpful for patients’ brains to understand the neutrophil factor. It may help them believe that their perception of pain is not “accurate,” that inflammation does not necessarily represent any threat at all, that its bark is far worse than its bite. This is what I have dubbed the “confidence cure” — that informed, rational confidence can significantly blunt chronic pain. Anything that can ethically, truthfully, rationally boost that confidence is valuable.
In the difficult battle to educate public and practitioners about pain science, any specific example of the disconnect between pain and threat is super useful. You can tell people “pain is an opinion” and often a misinformed one, but it’s nearly useless without vivid, specific reasons why.
Other than feel smug about our superior understanding of the biological mechanisms of pain?
Not much, no.
One minor practical implication of the study is that it punctuates the importance of resting injuries and avoiding re-injury (see The Art of Rest). If neutrophil over-reactions drive a vicious cycle of inflammation, than it is clearly wise to be quite cautious not to damage any cells in a troubled area, or, worse, re-injure already-damaged cells. This made all kinds of sense before, but it makes even more sense when you know that a spike in inflammation while healing from a (closed) injury is not actually a functional, helpful process in any way — not a healthy, natural part of healing, as inflammation is often given credit for — but actually a destructive annoyance that significantly postpones full recovery without any compensatory benefits. Thorough and genuine resting has always been an underrated strategy for chronic, slow-healing injuries, and now we have a powerful reason to take it seriously. Avoiding mobilizing your neutrophils!
Otherwise, this science is merely enlightening and does not actually suggest any treatment method let alone self-treatment (not that you should underestimate the power of a well-informed resting strategy for many problems). All we can do is wait for scientists to cook up a new approach to the problem — probably pharmaceutical — which is going to be tricky, because you can’t just shut down neutrophils. You have to stop them from doing something very specific.
Fortunately, it’s not a hollow victory to “merely” upgrade our understanding. Better treatments would be great, but comprehension is a good start.
Ripley: I say we take off and nuke the entire site from orbit. It's the only way to be sure.
Hudson: Fuckin' A...
Burke: Ho-ho-hold on, hold on one second. This installation has a substantial dollar value attached to it.
Ripley: They can bill me.