Why is the human body so crap except for the liver?

[Epistemic Status: Speculative unifying theory of biology.]

I don’t know about you, but I greatly resent having to be a biological organism and subject to all the poor engineering and design decisions that entails. This has many manifestations. A recent one is often wondering, why is the entire body such garbage except for the liver?

Take the kidneys. Once you reach adulthood, they start to slowly decay. You can damage them through not-obviously-dangerous stuff like taking too much vitamin D or taking ibuprofen while dehydrated. Significant damage typically leads to scarring and a permanent reduction in function. Or take the gums. If you brush too hard or don’t floss enough, they may retreat down your teeth, never to return. Most of the body is like that.

But the liver. My friends, the liver! If it’s injured, it will usually heal without scars. As you age, it typically maintains near full strength. You can give half of your liver to someone else and it will regrow to full size and function in a few months. I’d like to find whoever designed the liver and have them make me a full body.

Except here’s a theory: It’s good that most of the body is fragile crap. It would be better if some parts of the body were more fragile.

Menopause. We’re still struggling to reconcile modernity with the short human reproductive interval. But did you know that menopause is almost unknown outside of humans? Even the other great apes remain fertile for almost their entire lives. The only known exceptions are (1) killer whales, (2) pilot whales, (3) beluga whales, (4) false killer whales, (5) narwhals, and (6) one specific population of chimpanzees in Uganda.

Inuries. If your leg gets chopped off, that’s it, no more leg. Your body will try to grow scar tissue over the wound and then you’re on your own. But if you chop off the leg of a salamander it… grows a new leg. Isn’t that the obvious to do? Why don’t we do that?

Telomeres. The ends of your chromosomes have a little repetitive sequence called a telomere. When cells divide, the body tries to copy the DNA, but good-old DNA polymerase can’t quite copy all the way to the end, meaning the telomeres slowly get shorter. After dividing 50-70 times, the telomeres are gone, and the cells stop dividing and then slowly stop working. This is one of the many ticking clocks of aging.

Transplants. If you need a new kidney, and someone is nice enough to give you one of theirs, your body will respond by trying to kill it, meaning you have to take horrible immunosuppressants for the rest of your life. And even after taking them, there’s a 30% chance the kidney will be rejected within 10 years. This is not helpful.

Diabetes. Some day, your immune system may decide to attack your pancreas. After a while, your pancreas will stop making insulin, meaning that unless you reorient your entire life around keeping your blood sugar in check, your eyes, kidneys, nerves, and heart will constantly accumulate damage. Your immune system should not attack your pancreas.

Brains. After you reach adulthood, neurons don’t divide. If some of your neurons die—which happens every day—then they’re gone. If you get a brain injury, the other neurons will try to “learn around” the injury, but the neurons themselves are never replaced.

Junk. All cells build up various “junk” over time. As they divide, the junk is diluted. But some cells (neurons, various cells in the eyes) never divide, so the amount of junk (e.g. lipofuscin) just goes up and up. This is another ticking clock.

Blood. Your flesh needs blood, which your body delivers through blood vessels. Over time, these can get clogged with plaque. The thing to do in this situation is to sprout new blood vessels. Your body knows how to do that. But by default it maintains high levels of various inhibitors (angiostatin, endostatin, THBS1) that tell your cells not to do so. If your heart or brain get starved of blood, your body will try to reverse all this inhibition, but the process is slow and clumsy and can only produce tiny blood vessels.

As always in biology, the correct answer is: A lot, it’s complicated. But I think there’s a common thread.

The clearest case is probably telomeres wearing down as you get older. At first glance, you might ask, why does this problem exist at all? Bacteria—because they aren’t idiots—have circular DNA, which doesn’t have ends or telomeres. Eukaryotes like us evolved from bacteria. Who decided to replace circular DNA with linear DNA?

Or, you might ask, why doesn’t the body re-lengthen the telomeres? Well, actually it does! We have an enzyme designed specifically for that purpose, called telomerase. But, after embryonic development, the body doesn’t bother to use it, except in stem cells, reproductive cells, and certain parts of the immune system. Huh?

The reason we have linear DNA instead of circular DNA is contested.1 But whatever. If the body wanted to re-lengthen the telomeres, it could easily do that. Your cells already have DNA to make telomerase. They just don’t use it. Instead, they let the telomeres get shorter until they stop dividing and stop working. Why?

(That’s our answer to the question in the title of this post: The human body is so crap except for the liver because cancer. As we’ll see, this answer is only semi-correct, and even then only with several caveats. But what do you expect from biology?)

Letting the telomeres get shorter is not a mistake. It is a deliberate design decision.2 Often, in your body, the following happens:

(If you’re a biologist who is outraged at the above description, I’ve written a footnote which I beg you read before yelling at me.4)

Having telomeres that wear down is good, because it slows down cancer. It’s also bad, because it means our bodies slowly stop working. Evolution decided the good outweighed the bad, and I expect that evolution was right.

Several of the other ways in which the human body is “crap” can be explained in the same way. Why can’t you re-grow your leg if it gets chopped off? Well, that would require that all your cells have a “begin rapid growth mode” button on them, with some external trigger. In a sense, it would require your body to leave your cells sitting around in a state that’s closer to being cancer. Not doing that is good, because it slows down cancer, and bad, because you can’t grow a new leg. Evolution apparently doesn’t like that tradeoff, and again I assume evolution is right.5

Fragile kidneys are much the same. We could have kidneys that try harder to repair themselves. That’s probably biologically possible. But it would likely mean more kidney cancer. Arguably, the question isn’t, “Why are the kidneys such fragile crap?” but rather, “Why is the liver so weirdly regenerative?”

That question has two standard answers. Answer #1 is that the liver has a hard job. It sits directly downstream of the gut. If you eat toxins or bacterial products or viruses or parasites, the liver sees them at high concentrations before the rest of the body. Not only that, it’s the liver’s job to detoxify stuff, and detoxification chemistry is often self-damaging: The liver breaks toxic stuff down into even-more toxic stuff, and then deals with that stuff recursively. The liver is constantly getting damaged, as part of its job description, so it must be able to regenerate. Evolution designed it to do that, and it just pays the cancer tax.

Answer #2 is that the liver isn’t unusual. Your skin can survive wounds. And your intestines can survive exposure to digestive enzymes, bile, and bacteria. The surface layers of both of these are constantly turning over. And, lo and behold, skin cancer and colorectal cancer are both very common.

At the other end of the spectrum, neurons and cardiac muscle cells don’t reproduce after childhood. If they die, they’re gone.6 As a result, “heart cancer” is almost unheard of. (The very term “heart cancer” almost sounds ungrammatical.) Brain cancer is a thing, but it’s essentially always in other types of brain cells, not neurons.

So maybe we can think of different parts of the body as making different tradeoffs between regeneration and cancer risk:7

At first glance, we seem to have a cute little story: Evolution pays the cancer tax for organs that need to interface with the environment, because it’s a harsh world out there. And it pays the fragility tax for organs that can be tucked away so that regeneration isn’t as necessary.

Wouldn’t that be nice? Let’s formalize that as a theory.

One problem with the above theory is that it isn’t clear that regeneration is always an option. The skin and guts are pretty homogeneous (at least in each layer). The liver can be approximated as a big blob of repeated functional units. If you give half your liver away, those functional units get larger, which is how your liver grows back to near full size and function.

But other organs are highly “structured”. Your neurons are a complex circuit encoding all your memories and learned behaviors. If neurons were reproducing, that circuit might be unstable.

Your heart is also highly structured. And even if your heart could re-grow, if you lost half of it, you wouldn’t survive long enough to do so. (Do not attempt to donate half your heart.) In principle, it’s surely physically possible to design a heart where you can remove half and it will still pump enough blood to keep you alive while it re-grows. But evolution either didn’t figure that out, or didn’t think it was worth the trouble. Either way, with the current heart design, high regeneration doesn’t look like an option.

So it’s not as simple as evolution choosing to pay the cancer tax for some organs and choosing to pay the fragility tax for others. Some organs need to maintain a stable complex structure to keep working, meaning there may not be much of a cancer/fragility knob to turn.

Fine. But there are several organs I didn’t include in the above table. For example, look at this:

The lungs are the worst of all possible worlds, with low regeneration and high cancer. As far as I can tell, this is a consequence of the physical fact that gas diffusion is slow. To work around that, your lungs have a delicate fractal geometry that crams ~100 square meters of surface area into a ~5 liter volume. That’s impressive, but it makes regeneration hard. At the same time, the lungs need to interface with all sorts of random toxins and pathogens in the air, meaning lots of ways for mutations to happen.

And now, ladies and gentlemen, the stupid pancreas:

Superficially, this looks less exceptional than the lungs, with low-ish regeneration and merely moderate cancer risk. But the pancreas is more problematic for our theory, because that moderate cancer risk exists despite not being exposed to the outside world.

Biologically, the reasons that the pancreas sometimes develops cancer seem understood, although complex. But as far as I can tell, there is no convincing explanation for why the pancreas is designed that way. Is it an evolutionary fluke? Is there some other subtle tradeoff? It’s unclear. So there’s no satisfying big-picture evolutionary trade-off to point to.

But we still need to face the final boss, the strangest organ of all.

Bad news for our theory, good news for you as a biological organism. The small intestine does interface with the environment, and it replaces all its surface-level cells every few days. Yet it very rarely develops cancer. That’s despite the fact that it’s quite similar to the cancer-crazed colon. It’s also despite the fact that the “small” intestine makes up ~90% of the digestive tract’s surface area. What the hell?

Biologically, the main explanation seems to be that the small intestine uses an ingenious defense strategy. My new favorite part of the body:

While the surface cells of the small intestine are continuously being replaced, they aren’t themselves reproducing. Instead, carefully protected stem cells tucked into the valleys between