[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. Some other ways the body would appear to be poorly designed 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. What’s going on here? 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? Because… … Cancer. (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: Some cells get a mutation that causes them to start reproducing too fast. Your immune system decides they’re suspicious and kills them. You’re fine. 👍 But sometimes this happens: Some cells get a mutation that causes them to start reproducing too fast. They grow for a while, but then (for complicated reasons3) they stop increasing in number. But they aren’t just sitting there, they’re constantly reproducing and dying, much faster than normal cells. Eventually, they develop another mutation that allows them to overcome whatever was stopping them from growing. This continues for a while, with the cells gradually acquiring more of the mutations they need to grow to a large size. But wait! With all this reproduction, at some point the mutated cells ran out of telomeres and stopped being able to reproduce. Ha! Screw you, mutated cells! 👍 To be clear, this also sometimes happen: (Steps 1-6 above) With all this reproduction, at some point the mutated cells figured out how to turn telomerase back on. This re-lengthens their telomeres, so they can reproduce indefinitely. They either stop growing for other reasons (👍) or you use our modern technological civilization to kill/remove them (👍) or they grow so slowly that something else kills you first (🤌) or there is a less desirable outcome (👎). (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?” OK, so 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 Organ Regeneration Cancer risk Colon / rectum Extremely high High Bone marrow Extremely high High Skin High High Liver High High-ish Bladder High High-ish Thyroid Medium Medium? Kidneys Low Low-ish Cardiac muscle Near zero Very low Neurons Near zero Near zero 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. Theory: More regeneration implies more cancer risk. Evolution tunes organs that encounter the environment for more regeneration and more cancer. It turnes organs that don’t for the opposite. Of course, it’s not that simple. Complexities 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. Revised theory: More regeneration implies more cancer risk. Evolution tunes organs that encounter the environment for more regeneration and more cancer. It turnes organs that don’t for the opposite. But for highly structured organs, regeneration might not be an option. Fine. But there are several organs I didn’t include in the above table. For example, look at this: Organ Regeneration Cancer risk Lungs Low-ish High 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. Revised theory v2: More regeneration implies more cancer risk. Evolution tunes organs that encounter the environment for more regeneration and more cancer. It turnes organs that don’t for the opposite. But for highly structured organs, regeneration might not be an option. And if highly structured organs encounter the environment, cancer risk is still high. And now, ladies and gentlemen, the stupid pancreas: Organ Regeneration Cancer risk Pancreas Low-ish Moderate 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. Revised theory v3: More regeneration implies more cancer risk. Evolution tunes organs that encounter the environment for more regeneration and more cancer. It tunes organs that don’t for the opposite. But for highly structured organs, regeneration might not be an option. And if highly structured organs encounter the environment, cancer risk is still high. And the pancreas is weird. But we still need to face the final boss, the strangest organ of all. The small intestine Organ Regeneration Cancer risk Small intestine Extremely high Very low 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 the intestinal villi slowly produce “transit-amplifying cells”. Those transit-amplifying cells divide 4-6 times as they migrate to the surface, each eventually yielding 16-64 mature epithelial cells. Those spend a few days doing epithelial stuff, meanwhile sliding along with their siblings from the bottom to the top of whichever villus they happen to be on. When they reach the tip, they’re ejected into the digestive stream to die, merry Christmas. So, even if a mutation arises somewhere, it doesn’t really matter, because the cells are all on a conveyor belt towards death anyway. Clever, no? Turns out, the real hero isn’t the liver. It’s the small intestine. (The small intestine also uses a few other tricks: The surface cells are programmed to commit suicide if damaged even a little bit. The immune system is tuned to kill anything that looks even slightly funny. And it hosts huge amounts of detoxifying enzymes. But villi seem to be the really unique bit.) This is a huge challenge for our theory. Not only does the small intestine have low cancer and high regeneration, it has low cancer because of high regeneration. If the small intestine can do that, then why not the rest of the body? One answer is that it takes a ton of energy. Your guts shed ~40 billion epithelial cells every day, amounting to ~⅓ kg of tissue every week. Like the brain, your guts consume ~20% of total energy, despite making up only ~2% of body mass. Evolution doesn’t want to do that everywhere, because evolution doesn’t want you to starve to death. So, there isn’t just a trade-off between regeneration and cancer. There’s a three-way tradeoff between regeneration, cancer, and energy usage. But even if energy weren’t an issue, other organs couldn’t easily copy the small intestine’s strategy. For example, the colon is similar in many ways to the small intestine, but the colon doesn’t have villi. It needs to be flat, because the colon’s job is to extract water. If there were villi dangling everywhere, they’d be ripped off by the solid waste. The colon also hosts far more bacteria that produce toxic byproducts, meaning the colon’s cells need to be tuned to try to resist damage, instead of committing suicide. This also means that the immune system needs to be more relaxed about killing foreign entities. So even though the colon also replaces the epithelial cells (a bit more slowly) cancer is still common. (Or, imagine your skin was covered in tiny fragile villi. You’d look awesome, but they’d be constantly getting ripped off. If you wanted that to work, you’d need to make the villi stronger and more disposable, and… we just invented fur.) Revised theory v4 final (actually final) updated (2): More regeneration implies more cancer risk. Evolution tunes organs that encounter the environment for more regeneration and more cancer. It tunes organs that don’t for the opposite. But for highly structured organs, regeneration might not be an option. And if highly structured organs encounter the environment, cancer risk is still high. And the pancreas is weird. And actually, it’s not just a trade-off between regeneration and cancer, it’s a three-way trade-off between regeneration and cancer and energy usage, and various parts of that space may or may not be available depending on the job an organ has to do. So, a cancer vs. fragility tradeoff definitely doesn’t explain everything. But it does explain some things, somewhat, sort of. In biology, that’s pretty good. Is this bad? We’ve discussed various ways in which the body might appear to be crap. Let’s revisit those, and ask if the right tradeoff is being made for the modern world. Injuries. Your skin is calibrated for constant wounds, which most of us today don’t get. This leaves lots of repair pathways sitting around to be hijacked by skin cancer. Similarly, your bone marrow is calibrated to be able to recover from catastrophic blood loss. Today we don’t experience as much catastrophic blood loss, and we have blood transfusions, but all that generative capacity is still there to be used by leukemia and lymphoma. And whatever benefit there might have been to re-growing a limb is probably lower today, when we less often lose limbs. Best guess: It would be better if the body tried less hard to recover from injuries. Brains. Do modern people suffer fewer brain injuries than our evolutionary ancestors? It’s hard to say for sure, because brains are soft tissue. But the fossil record for upper paleolithic humans suggests between 2% and 34% suffered skull fractures, more than modern people. So you might think it would be better if the brain was tuned more towards fragility rather than cancer. But brain injuries are still common today. Around ⅓ of people experience a concussion sometime in their lifetime, because we love to drive cars at high speed, play dangerous sports, and survive to old age where stairs and bathrooms pose a risk. Also, for whatever reason, the brain is already tuned quite strongly towards fragility. Best guess: Maybe the current tradeoff is about right? Telomeres. Should the body re-lengthen the telomeres? On the one hand, we’re more likely to survive to ages where this is actually an issue. On the other hand, we’re also more likely to survive to ages where cancer is a danger, which is precisely where telomeres not getting re-lengthened is an issue. Best guess: Maybe the current tradeoff is about right? Livers. It seems that the liver is so regenerative because it needed to be. Ancestral humans were constantly dealing with parasites and bacteria and rotting food. When I started writing this essay, I figured this meant the liver was “over-specced” for the modern world. Today we have refrigerators and food inspectors and pasteurization. Our lives are much less harsh and involve fewer toxins than our ancestors. So, if calibrated for the modern environment, I figured that it would be better if the liver was a bit more fragile, but also marginally less prone to cancer.8 But… it’s not clear that this is actually true. Liver failure remains extremely common today. While we don’t ingest nearly as many toxins, we eat diets that lead to metabolic dysfunction, and we consume tons of alcohol, and many of us live in dense conditions where hepatitis can easily spread. We’re also more likely to live to an age where liver failure is an issue. Best guess: Unclear. We should stop doing stuff that causes liver failure. Menopause. Why do humans have menopause, unlike almost all other mammals? The most common theory is the grandmother hypothesis. The general idea is that reproducing becomes more and more risky as you get older. For most animals, evolution doesn’t care, because evolution’s goal isn’t to make you happy, it’s to maximize reproductive fitness. So, screw it, try to reproduce and let the dice fall where they may. But even after reproducing, humans can help the survival of their genes by providing resources for their offspring. So, for humans, evolution decided to turn reproduction off, so you can spend more time with your grandkids. In particular, with cancer, some theorize that continued cycles of estrogen cause damage to the ovaries, womb, and breasts. Menopause shuts this down,which may decrease the odds of ovarian / uterine / breast cancer. It’s a cute theory. But again: Menopause: Humans, killer whales, pilot whales, beluga whales, false killer whales, narwhals one group of chimps in Uganda. No menopause: Everything else, including elephants, other whales, lions, horses, zebras, dogs, rats, wolves, birds, reptiles, amphibians, fish. Some of this makes sense. Unlike toothed whales, Blue/Humpback whales are mostly solitary or live in loose groups. Mice don’t babysit for their grandkids. But what about elephants? Or hyenas? Or bonobos? Or orangutans? Or lions? Or sperm whales? All of these have social organizations where females contribute to the survival of their offspring, and yet they don’t have menopause. Anyway, is menopause the right tradeoff for the modern age? It’s hard to say. On the one hand, modern people live much longer, meaning the marginal cost of cancer is higher. On the other hand, people want to reproduce more at older ages, meaning menopause has a higher cost. (Both “to evolution” and “to us”.) Also, an ancestral woman began menstrating in her late teens, and then likely underwent many pregnancies, each followed by years-long periods of breastfeeding (which suppresses menstruation). An average modern woman experiences 3-5 times as many menstrual cycles. It’s very confusing. Best guess: No idea. Cell junk / diabetes / transplants. As far as I can tell, these are mostly unrelated. TLDR Cancer is bad because cancer is bad. Cancer is also bad because evolution made gruesome realpolitik compromises in the design of every part of the body to try to hold cancer in check. If we lived in a universe where cancer was impossible, we wouldn’t just not get cancer, our bodies would also be enormously more regenerative and longer lasting. In a sense, even if you don’t get cancer, cancer still hurts you, because your body was forced to take costly preventative actions. (Even if the barbarians never get over your city wall, you still had to build the wall.) Even if we someday completely defeat cancer, its legacy will live on in our genes until the point that we re-design ourselves. Screw cancer. Some people think linear DNA is easier to copy. Others think that linear DNA just happened by accident, but when it happened it was survivable because we happened to have retrotransposons, i.e. bits of DNA that build little machines to create new copies of their DNA and insert it into the genome. After the break in the circular chromosome, those machines started putting copies of their DNA on the end, because that’s what they do, and this made the break survivable. Those retrotransposons later became telomerase. ↩ This is teleological; let’s not let it come between us. ↩ This could happen because your immune system contains them. Or because oxygen and nutrients can’t diffuse inside the clump of mutated cells. Or because they run into a barrier of different cell types that they can’t outcompete. Or for other reasons. ↩ Hello biologists! You might be thinking, “Well actually, 90% of cancers turn telomerase back on; clearly telomeres don’t help that much; Dynomight why are you so bad?” That is approximately what the Dynomight Biologist thought, when pressed into service to review this post. True, having telomeres that wear down is not a magic bullet that makes cancer impossible. And yes, most cancers figure out how to turn telomerase on. But that is a linguistic fact. Your body has lots of mutated cells all over the place, most of which will never hurt you. Conceivably, we could have defined all mutated cells as “cancer”, with subcategories of “low risk to health” and “significant risk to health”. Then, telomeres would seem great, because it’s hard for cells to move from “low risk” to “high risk” without figuring out how to turn telomerase on. That’s hard to do through blind random mutation, which is one reason most of your mutated cells are in the “low risk” category. Cells do sometimes succeed in turning telomerase on, but it’s still a useful layer in body’s layered cancer defense strategy. We didn’t happen to define our words that way. Instead, we defined “cancer” to mean approximately “mutated cells that pose a significant risk to health” and we’ve invented other categories for other mutated cells (benign neoplasm, clonal expansion, hyperplasia, etc.) The “cancer” category excludes most cells that don’t turn telomerase on because telomere shortening is a good (albeit leaky) barrier between mutated cells and risks to your health. Just because Vikings sometimes get past your city wall doesn’t mean that a city wall is not worth having. Thank you for visiting my footnote. ↩ The precise reasons that salamanders can regrow limbs but most species can’t is somewhat unclear. You could speculate that salamanders tend to lose limbs more frequently, so it’s more worth it for them to pay the “cancer tax”. Or you could speculate that cancer isn’t as much of an issue due to their short lifetime. But do they actually have an unusually high frequency of needing to regrow limbs? And are they paying some kind of cancer tax? What would we even look at to determine that? Cancer rates vary in different animals for all kinds of reasons. ↩ Dead cardiac muscle is replaced with scar tissue. Dead neurons are replaced with a “brain scar” made of glial cells. ↩ Thyroid cancer risk is hard to rate, because it’s common but has a very low fatality rate. ↩ You wouldn’t want to make the liver unable to regenerate, but there are several “knobs” that might be tuned. Broadly speaking, the liver could be designed to regenerate more slowly, with more careful “proofreading” and slower/stricter cell-cycle checkpointing. Then liver injuries would take longer to heal, but would result in fewer mutated cells. ↩

It might seem a bit out of character for a powerful general—a fierce warrior—to go everywhere with a book tucked under their arm. But in ancient Rome, that was the figure that the great Scipio Aemilianus cut. He was known for training in philosophy as arduously as he trained at arms. Flash forward to General […] The post No One Is Excused From This appeared first on Daily Stoic.

Thoughts on surrendering to the here and now and doing the best with the information we have in any given moment

A Much Cheaper, Almost-as-Good Alternative

cohort four starts sept 28