Bret Weinstein is a fun one to watch. He gained some notoriety for his role in the public meltdown of Washington state’s Evergreen State College in 2017, and I was a college student myself when I discovered him via this fortuitous catastrophe. He has courted more and nastier controversy since then, but frankly most of his haters have proven to be absolute lightweights where the relevant scientific questions are concerned, and what public fuss there is about him mostly serves to distract from his most important idea.
Weinstein is an evolutionary biologist, and, as far as I can tell, he understands his subject well and is able to apply its fundamental insights to a wide range of situations. His podcast is one of my favorites, and I’m especially grateful for the series he and his wife began producing in 2020 as we were all coming to grips with the COVID-19 global emergency. I consider him an excellent thinker (and I would know), and he’s certainly had an impact on my own ideas, so here I’d just like to write up my thoughts on his big idea about the biological inevitability of death.
This stellar sleeper-hit of a hypothesis first found a home in a 2002 issue of Experimental Gerontology under the title, “The reserve-capacity hypothesis: evolutionary origins and modern implications of the trade-off between tumor-suppression and tissue-repair” (thanks, Gwern!) and was not picked up on in any serious way by the scientific community. The reasons for its tepid reception are sordid and complex and even fun in a gossipy way, and he discusses the whole situation on his brother’s podcast here. But make no mistake, the idea itself is a banger.
The basic idea is that telomeres limit our cells’ capacity for multiplication in order to reduce the risk that they will multiply out of control and become cancerous, meaning there is a fundamental limit on our ability to repair damaged tissue.
We are repairing damaged tissue all the time, whether from illness, injury, or everyday wear and tear, and it’s remarkable the degree to which a person can, for instance, regrow a damaged liver. On the other hand, each time a cell divides, there is a small but real risk that it will “go rogue” and use its reproductive capacity to grow itself into a tumor instead of saving itself for tissue repair. Thus, even assuming no injury or infectious disease cuts anyone’s life short, each of us is naturally fated to die from either the over- or under-reproduction of our cells.
A cell’s “reserve capacity” for self-replication exists in a tradeoff space between the potential benefit of using it to rebuild damaged tissue and the potential harm of misusing it to build a tumor. This is of course different for different cell types throughout the body, so there is a genetic mechanism for endowing cells with the appropriate level of reproductive potential, and it is found in the telomeres at the ends of each chromosome.
If you’re as well-versed as I am in the Greco-Latinate argot of science, it should be clear to you that “telomere” means “end-part”, and indeed the telomeres in a cell are the repeating nucleotide sequences comprising the end parts of each chromosome. Like the plastic aglet at each end of a shoelace, telomeres buffer a strand of DNA against the messiness of life, but they also play a central role in regulating cell division.
The structure of the telomere lets it bind to certain protective proteins, marking themselves as the legitimate ends of whole chromosomes rather than the broken ends of DNA fragments in need of repair. Each time a cell divides, its telomeres shorten because the molecular mechanism that copies DNA cannot copy the entire strand, so telomeres also act as a non-coding buffer against information loss in the protein-coding parts of the chromosome. This means, however, that a cell can only make so many copies of itself before its telomeres become too short to serve their protective function. When a telomere can no longer effectively bind the protective shelterin complex proteins, the cell’s DNA repair proteins respond as they should to DNA damage and trigger internal shutdown mechanisms that cause the cell to stop dividing and potentially wait for repair or just straight-up die.
(Incidentally, the nucleotide sequence that makes up the telomeres of humans and other vertebrates is ‘TTAGGG’ which is significant not because of the information it carries but because it gives the end of the chromosome certain structural properties that allow it to function as it does. This is a great example of the interplay between form and content that seems to me like God’s signature on creation.)
The role telomeres play in cell division imposes a limit on the number of descendants a cell can spawn, known as the Hayflick limit, and Weinstein argues that while this results in the degradation of our tissues with age, it also provides a failsafe against the growth of tumors. Any cell that turns traitor and begins to multiply out of control can only go so far before it hits its Hayflick limit and finds that it can no longer count on its own molecular machinery to aid its insurrection against the life of the body as a whole.
Skin cells actually do this all the time, ending up as moles or skin tags, and there’s a good reason why skin is more liable to this than most tissues. Skin is our first line of defense against the world, and even without the commonplace cuts, scrapes, and bruises life deals us, we are shedding and replacing skin cells in untold numbers every day.
Skin may be the most obvious surface through which our body makes contact with the outside world, but I can think of two others hidden away in our holes. The first is the lungs, which I think we all know by now are especially liable to cancer if you burn through their reserve capacity by keeping them irritated with smoke, for instance. Cancers of the mouth and throat, likewise, result from their tissues’ front-line positions necessitating a great deal of reserve capacity.
The third and in some ways most important major bodily boundary is the lining of the gut, which is not only exposed to whatever toxic crap you cram into your maw but also constantly subject to the corrosive action of digestive fluids. These tissues need a lot of repair and so are high in reserve capacity, making them also relatively likely to produce polyps.
(One condition that illustrates the reserve-capacity hypothesis well in the digestive system is known as Barrett’s esophagus, in which the lining of the lower esophagus undergoes a metaplastic transformation into a tissue type more closely resembling the lining of the intestine. This is often associated with esophageal damage from chronic acid reflux, and it is a precursor to esophageal cancer, which conjunction I think shows both sides of the reserve-capacity coin. An esophagus damaged by chronic acid reflux functions better if its tissues can increase their reserve capacity to deal with corrosive conditions as the intestines do, but a tissue with an increased capacity for repair is at greater risk of cancer, which is observable in the case of Barrett’s esophagus.)
Other tissues, however, are much less expendable and require far less replication of their cells. Neurons, for instance, mostly don’t multiply once we’re done growing. This means they should have precious little reserve capacity, making them hard to replace when damaged but also at little risk of turning tumor. And, indeed, neural tumors are extremely rare — most brain tumors come from other cell types — but brain damage is more likely to have long-lasting effects, cell for cell, than damage to virtually any other organ.
Another quite vital organ that sits alongside the brain at the low-reserve-capacity end of the tissue/tumor tradeoff space is the heart. The heart never produces tumors, but its lack of reserve capacity leaves it with little ability to repair itself if damaged. Its function as a pump depends on a particular internal structure (much more than, say, the liver) that would be radically disrupted by any excess growth of cells deforming its shape.
(On the basis that the heart is minimally resilient to damage, Weinstein has argued that Vioxx and other drugs that became infamous for causing “heart damage” really cause more general tissue damage throughout the body, which shows up first in the heart because it has the least reserve capacity.)
So, to recap, our tissues differ in their reserve capacity based on the ability of the cells that compose them to replicate themselves, which is determined by the length of the cells’ telomeres. Tissues with greater reserve capacity are more capable of repairing themselves but by the same token more capable of developing tumors, while those with less reserve capacity have reduced cancer risk but likewise reduced ability to recover from damage. Thus, our lifespans are inevitably limited by the fundamental tradeoff between various tissues’ potential for healthy self-repair and their potential for malignant growth.
Following Weinstein’s argument, there are two truly natural ways to die, assuming we avoid early death from infectious disease, toxic chemicals, and physical injury. Either some tissue produces a tumor that grows beyond what the body can handle or some organ fails because it exhausts its capacity for self-repair via cellular reproduction.
The organ most likely to suffer the latter fate is the heart, and indeed heart disease kills more people each year than any other single cause, with cancer a relatively close second. The next two slots go to COVID (!) and accidental injury, both external causes largely irrelevant to reserve-capacity considerations, while stroke rounds out the top five.
I’m getting into more speculative territory here, so please bear with me. If we lump heart disease and stroke together under the more general category of “circulatory system failures,” it runs away with the top spot, body-count-wise. I think it’s worth looking at circulatory system failures as a category, because it seems plausible to me that the reserve-capacity tradeoff that limits the heart’s ability to heal applies to the circulatory system more broadly. A mole on your face might not look pretty, but a growth of the same size inside an artery would be fatal. Based on the huge potential downside of a tumor, it’s likely that the cells lining our arteries have very little reserve capacity, meaning that instead of getting replaced by new cells when they die, arterial cells are more likely to be replaced with cholesterol, the Big Bad of cardiology.
It was from YOU: The Owner’s Manual by the pioneering cardiologist Dr. Oz that I first learned about the relationship between blood pressure and cholesterol. It seems counterintuitive at first: shouldn’t higher blood pressure leave arteries less likely to clog by flushing material through them with greater force?
The key to this mystery is the role played by cholesterol in repairing damaged arteries. Higher blood pressure increases the frequency and force with which blood cells strike the arterial wall, damaging more cells and degrading the tissue at a greater rate. Because the circulatory system has little reserve capacity, it cannot adequately replace its dead cells as it ages, so it increasingly has to fill in the gaps with artery-clogging lipoprotein sludge or else risk an aneurysm wherever cell-line death leaves a weak spot.
The relevance of the reserve-capacity hypothesis to cancer should be clear, and I hope I’ve also shed some light on how it relates to heart disease and other circulatory system failures, so I’d like to take my reasoning a step further and speculate about its relevance to psychology.
(We’re getting deeper into the weeds now, so feel free to take a massive bong hit or something before reading on.)
I was in high school when I learned about Type-A personality as a risk factor for heart attacks, and I don’t know how well this model holds up to the latest psychometric methods, but I was intrigued by the suggestion that people with different personality types are more likely to suffer different deaths. Traditionally, “Type-A” people were held to be more likely to die of heart attacks, while “Type-C” (which doesn’t appear on the above-linked Wiki page, but I swear it was in the textbook) people were more likely to get cancer. The textbook confabulated some pop-Freudian explanation in terms of emotional coping strategies affecting bodily health, but I’m intrigued by the possibility that the causality runs the other way.
Let’s assume that, just as different cell types in the body have different levels of reserve capacity, the average or baseline level of reserve capacity across all cell types varies among individuals. If this were the case, then some people with more reserve capacity overall would be more prone to cancers of any type than the average person, but they would have a more robust circulatory system and thus be less likely to suffer heart failure. Those with less global reserve capacity, on the other hand, would be more protected against cancer, but their cells’ relatively limited potential to proliferate would leave their circulatory systems especially vulnerable.
The implication of this for psychology is that people who are more prone to different causes of death face different risk profiles in the world and might benefit from different life strategies and overall attitudes. If individual variance in reserve capacity really is a biological factor in why different people are prone to different pathologies, it makes sense that our intuitions and emotional biases would naturally be attuned to helping us deal with the different kinds of risks we face.
I don’t take this line of thinking seriously enough to speculate about why different Type-A traits might be advantageous to people with less reserve capacity, but it’s worth thinking more generally about how different kinds of risk trade off against each other. A family history of cancer, for instance, might mean you don’t have to worry much about high cholesterol, but you should still watch what you eat so that you don’t load your guts with carcinogens.
Of course this is confounded by the fact that people who are generally unhealthier are at greater risk of death for any reason, but it makes sense to me that in general different people’s bodies would be likely to fail in different ways. Given that people do in fact die in a number of different ways, I’d like to think my presentation of the reserve-capacity hypothesis here offers some explanation of how and why.
Cut. Print. Let’s go eat.