We are semantic apes. We love categorizing things. Even in Genesis, God seems to be amused by Man’s propensity to name things, bringing “all the wild animals and all the birds in the sky” to “see what the man would name them.” We love to classify and differentiate. But it’s easy to see why this exercise might amuse God. Nature is happy to challenge us with annoying exceptions to all of our beautiful categories. It seems that Nature is unwilling to behave even in our core physics, foiling notions like the separability of waves and particles or space and time. I am a neuroscientist, and in biology, we have our own nuisances. One of these annoying problems is answering, “when is death?”
It sounds like it should be an easy question. Obviously, there are dead people and alive people. Dying seems inevitable because so far, everyone’s done it. But defining the point of death has historically been a moving target. Until the mid-20th century, death was conveniently defined by when any measurable vital function, like the heartbeat, ceased. But it turned out that mechanically shoving air in and out of the lungs and restarting the heart were relatively easy hurdles to overcome. Think of how crazy this is! If you could go back in time to a century ago, you could say, without lying, “oh yeah, in the future, people die and rise from the dead all the time. It’s pretty normal.”
We sort of have a working definition for “brain death” now, although it’s defined differently in different places. Usually, there is some objective element to this, like that the patient cannot sustain vital functions without assistance, which generally requires them to have a functional brainstem. There is also usually some subjective part, like that a medical professional believes that the brain can’t recover. Is brain death real death in a way that the heart-stopping is not? I don’t think so. Besides finding the topic interesting, I’m also interested in inspiring people to consider that some physiological limitations are not set in stone. Once Roger Bannister broke the four-minute mile, everyone started doing it. If we start changing our attitude to think of brain death as a challenge rather than an inevitability, then maybe it will more quickly join heart death and lung death as health events that one can recover from.
Let’s think about the core ideas around what death is. For one thing, the absence of consciousness seems to be necessary. No one seems to be too bothered by the notion of fingernails growing on a corpse, even though that implies that some metabolic process is still occurring. (This is a myth, by the way.) The idea of it is sort of creepy, but not many people would feel the need to keep the corpse around because the fingernails seemed to be alive.
On the other hand, if the corpse occasionally complimented the outfits of its family members at its funeral, everyone would be alarmed. That leads to the second core idea, which is that not only is there no consciousness — we can pull off that feat in our sleep — but that this lack of consciousness is impossible to come back from. But that caveat is tricky because what you can and can’t come back from changes as medical technology improves.
It used to be that if the heart stopped, then you wouldn’t become conscious again. But after learning techniques to restart the heart, it did become possible. So what makes us so sure that “brain death” is final? Our assurance is two-parted. The first part is that we don’t get any new neurons after very early development in most of the brain. We do get some in the hippocampus and maybe some other small areas, but for the most part, if a neuron dies, we just have to do without it. We’re surprisingly good at this. There is remarkable plasticity in the brain, and the organ seems to be good at reallocating what cells are left to make up for lost ones. But sometimes, small populations of cells that control essential functions are killed, and we can’t replace them. Sometimes we lose vast swaths of tissue at once. So one issue is that just keeping someone’s blood pumping won’t rebuild a brain, in the same way that our skin can grow back if damaged.
On top of that, the main issue is that there is extensive damage in the brain that occurs when blood flow ceases. Through my education, this fact perfectly exemplified the Dunning-Kruger effect in psychology. According to this cognitive bias, we over-estimate our expertise when we know a little bit about something. When we learn more, we start underestimating and questioning our knowledge. Early in my biology studies, it made perfect intuitive sense that the brain would be damaged quickly by a lack of blood flow. But as I learned more, it started to make less sense. For instance, muscle tissue can go hours without blood and then is just dandy when you bring blood back. Some other animals, like some turtles, can hibernate for weeks in the winter in environments devoid of oxygen. What gives? Why do brain cells in humans become irrevocably damaged after just a few minutes without oxygen?
Our turtle friend has given us a clue by hibernating. There seems to be some relationship between the damage and metabolism, which refers to the chemical processes that help living beings do everyday life things. When the turtle goes into this state of dramatically reduced metabolism, the lack of oxygen doesn’t cause permanent damage. But why? Let’s get into the weeds!
But first, I just want to mention something here because stuff like this always gets me psyched about science. One of the most fantastic things to me about this topic is that nearly all of our collective human understanding about this question, “what in the world does metabolic rate have to do with brain damage when there is no blood flow,” was discovered within my lifetime! The science isn’t some old classic result from the 1800s. Someone else was confused, just like me, and was trying to figure it out around the same time that I was pretending to be a Power Ranger.
The story begins with calcium. Calcium is well known in biology for being important for fortifying bones. Lesser well known is that it is also important for everything. In the 1970s, some researchers had observed that calcium concentration in the liver increased during bouts of restricted blood flow. Weird. Other groups noticed that the same thing happened in the kidney. Super weird. Still other groups saw that it happened in the heart. There seemed to be a pattern. Increases in calcium appeared to be generally correlated to organ damage during restricted blood flow. An obvious question was whether damage to the tissue was causing the increases in calcium or if the accumulating calcium contributed to the damage. This type of question is what experiments were made for!
By the early ’80s, some people found a way to inhibit the accumulation of calcium in tissue. If they inhibited calcium accumulation in the liver during restricted blood flow, there was less damage than when they didn’t. Same thing with the heart. Another pattern. It looked like the calcium accumulation accompanying the lack of blood flow was not good. It wasn’t a massive leap of creativity to say, “Hey, maybe calcium is also involved in all that damage that we see in the brain.” That also turned out to be true. So at this point, an answer was starting to form. When there is no blood, there is too much calcium, which seems to be bad. But I often compare scientists to toddlers who keep asking “why” no matter what answer you just gave. Why does calcium cause damage? Why is it worse in some places than others?
I’m focusing here on results instead of methods, and I always feel a bit hesitant to do this as a scientist because I’m choosing a narrative, and you might interpret an experiment very differently. I think most humans love stories, and we feel very comfortable operating within narratives, but you learn as a scientist that these stories change all the time. All the knowledge you learn in the textbooks is the most popular story at the time. The experimental results don’t vary, but we constantly revise how we interpret them and the narratives we attach to them.
So zooming out even more, I will share the current narrative for why a lack of blood flow damages the brain so badly.
Step 1) Blood flow stops, which prevents our brain from acquiring oxygen and glucose.
Step 2) Oxygen and glucose are essential for creating energy for the metabolic processes in our cells. They are used to make a molecule that acts as the legal tender currency of all cellular operations, called ATP. Since there is no more oxygen and glucose, all of the ATP gets used up.
Step 3) Running out of ATP is terrible everywhere, but it’s particularly bad in the cells in the brain. Brain cells function by maintaining electric potentials on their cell membranes. That way, cells can communicate with each other through chains of depolarization. But those electric potentials don’t just come for free. They are very expensive! There are ion pumps all over the cells that pump in and out charged elements to control the cell’s electric potential. But those pumps require ATP to work.
Step 4) This is the exciting part. You might expect the cells just to relax and shut down operations if these ion pumps stop working. But actually, the membrane losing its polarization (a process called depolarization) is the same important mechanism that brain cells use to “communicate” with other cells via action potentials. The neuron is running out of gas, but the result is paradoxically to frantically tell all the downstream cells to activate! The worst thing that happens when the ion pumps stop working has to do with calcium. Calcium is usually pumped out of brain cells, and then it’s let back into brain cells when the neuron is “firing,” but then quickly pumped out again. When properly regulated, calcium plays a significant role in multiple, unrelated signaling pathways. These functions depend on precise control and timing of when it appears where. With the pumps not working, calcium accumulates inside the cell and starts wreaking major havoc, including initiating signaling cascades that tell the cell to kill itself. It also makes the cell “fire” again more easily, which then tells the downstream cell to let in more calcium, and so this creates a kind of vicious cycle that results in increasing damage in a process called excitotoxicity.
It’s a challenging problem but seems approachable. One strategy is to find a way to safely control these channels that are letting in all of this calcium or other dangerous cations to prolong the time it takes for damage to occur. There are also cell populations in the brain that seem naturally resilient to excitotoxicity that people are researching to figure out why. Finally, if you could turn off metabolism during bouts of lack of blood flow, that could also go a long way to giving healthcare professionals time to fix the problem. Currently, the issue is that if you freeze cells to arrest metabolism, it tends to damage tissue in other ways. Ice crystals mess up the connections between cells and organs fracture. If you use cryoprotectant chemicals to prevent ice crystals from forming, you get excellent structural preservation, but there is damage at the molecular level. So while this avenue is exciting for the future, as far as I know, we have a ways to go.
I imagine that in the future, the issue of death will become even more complex. I suspect that the idea of “brain death” will stay with us. Our conception of death has everything to do with consciousness, and all the evidence points to consciousness being a function of the brain. But how we define the point of death and the subjective determination of when someone has no hope of coming back will change. For now, I think it makes sense to look to the lessons of restarting the heart and maintaining respiration. We need to think ambitiously about how to protect and bring the brain back from ceased function. Why can’t we regrow brain? Can we overcome that hurdle? Can we stop excitotoxicity from happening? Can we freeze someone until the future when we have a better chance of addressing the health issue that caused their brain to be unconscious?
If we solve problems like freezing and thawing humans, the issue of death will become even hairier. You might currently have no hope of coming back to life, but maybe in 100 years, you could. The open question of what medical problems will be solvable in the future would leave defining the point of death ultimately ambiguous. There will likely be an additional level of inequality in determining who gets a chance to come back from the dead in the future.