The Joy of Why - How Is Cell Death Essential to Life?

Episode Date: December 5, 2024

Death might seem like a pure loss, the disappearance of what makes a living thing distinct from everything else on our planet. But zoom in closer, to the cellular level, and death takes on a different, more nuanced meaning. There is a challenge in simply defining what makes an individual cell alive or dead. Scientists today are working to understand the various ways and reasons that cells disappear, and what these processes mean to biological systems. In this episode, cellular biologist Shai Shaham talks to Steven Strogatz about the different forms of cell death, their roles in evolution and disease, and why the right kinds and patterns of cell death are essential to our development and well-being.

There's tons of people online making these huge claims about how you should live your life. On Science Versus, we take those claims on. This season, we're finding out. Are microplastics as scary as they sound? Microplastics have now been discovered in human testicles. Is social media rotting your brain? Have we hit the climate tipping point? Is it Waterworld? Is it Kevin Costner Waterworld?

New episodes of Science Versus, that's Science VS, are out now. In the second that it took you to hit play on this episode, a million cells in your body died. Some were programmed to expire in natural regulated processes, such as apoptosis. Some terminated their own lives after infection to stop viral invaders from spreading. Others suffered physical damage and went through necrosis, their membranes splitting open and their contents

spilling out. We know there are nearly a dozen different ways for our cells to kick the bucket and learning how to control these processes can make all the difference in the world to a sick patient. I'm Steve Strohgatz and this is The Joy of Why, a podcast from Quantum Magazine where I take turns at the mic with my co-host, Jan 11, exploring some of the biggest unanswered questions in math and science today. In this episode, we ask cellular biologist Shai Shaham,

how can the death of a cell help other cells around it? And how do these insights help us understand life itself? Shai is a professor at the Rockefeller University, where he studies programmed cell death during animal development and the complex role that glial cells play in the nervous system. Shai, welcome to The Joy of Why. Thank you for having me, Steve.

Thank you for joining us. I'm very curious to learn more about cell death, so I thought maybe we could start by talking about the lives of cells. What are the sorts of things that cells do that tell us they're alive? So that's actually a fairly complicated question. It really depends on the specific assay that you use to ask whether the cell is alive or not. So for example, if a cell is moving from

one place to another, you might say the cell is alive. But if the cell is sitting and not going anywhere, you have to ask, what does it mean to be alive? Is it metabolizing food? Is it producing signals to other cells? But others would say that these sorts of things can also be the hallmarks of cells that are just chemically active but not performing any biological function.

The whole field of cell death is plagued by this question of defining what a dead cell is. And really the best definition that at least I've been most comfortable with is if the cell is just completely gone, then I know it's dead. Otherwise, it's very difficult to say. It's interesting that it's so subtle. I think many of us think of cells as dividing, and I'm wondering is that a crucial aspect of being alive? Does a cell have to divide to be considered alive? You would say certainly that if a cell is dividing, it is alive.

The question is though if it's not dividing, is it not alive? And I think that the answer to that is really dependent on context. So for example, you can have bacterial spores that survive for years without dividing. And then when the time is right, they emerge from the spore configuration that they're in and start dividing and replicating themselves. And so for all of that period of time, which could be even decades, was the cell dead or alive? There was an example near and dear to my heart since we work on C. elegans, which is a nematode

worm. And there was a recent description of a nematode that was extracted from permafrost in Siberia, where it froze about 40,000 years ago and was revived back in the lab. And so you ask yourself, was that whole organism alive or dead for 40,000 years? Unbelievable. That's so interesting. I mean, we have this concept in ordinary language of suspended animation, the spores that you talked about. They're waiting to come back to life

would be the common sense way of saying it. But what are they when they're in suspended animation? So that brings up this question of irreversibility. Yeah, absolutely. I mean, I think you're struggling with something that we in the field struggle with a lot. At the end of the day, it all boils down to the assay. So let's say that you had that spore that was sitting around for 100 years waiting to start dividing. If you observed the spore, let's say, at year 30

and decided to spend a few weeks looking at it, it would look dead for all intents and purposes. And it's only if you waited the full 100 years and then saw it emerging that you would say, ah, actually it was alive. But if we have another assay where we're looking at metabolism or we're looking at the ability to accumulate mutations in the genome or the ability to signal to other cells. If the cell is doing stuff in terms of your assay, then you would consider it

alive, but it's a very operational definition. I don't think there's much point in involving the mystical here. It's clean, isn't it? To say that it's sort of operationally alive relative to certain assays, that seems fairly clear-cut. We could measure, is it metabolizing or not? Is it dividing or not? In trying to circumscribe life and death, let me bring in a few other categories of things to think about, like parts of a cell.

Can parts of a cell die? Or does it have to be in the nature of death that the whole cell has to die? So certainly not. If you recall what I said earlier, I'm most comfortable defining a dead cell as a cell that's just not there at all. And certainly we have situations where parts of a cell disappear. And this can be either programmed event, which is supposed to happen, or it can be due to injury or some mishap. There are cases in development where axons grow out of a neuron.

So an axon, it's a long thin process that comes out of a neuron, whose job basically is to connect to other neurons to make our brain work. These axons, during a normal part of development, might decide to start retracting. And this retraction, in fact, is given the name dying back. during a normal part of development might decide to start retracting. And this retraction, in fact, is given the name dying back. So operationally here, the axon has no function, and physically it's actually disappearing. And so you would argue that part of the cell is actually dying. So you mentioned something about programmed cell death, which is the area I want to start

getting into with you next. For instance, I read about something called necrosis. What happens if a cell becomes necrotic, or what is that kind of death? So let me distinguish between two kinds of cell death. So there's a cell death, which is a consequence of a genetic program which is present in the DNA, in the genes of a cell, which is dedicated to executing the demise of the cell. So this is a process which has been evolutionarily selected and which has been passed on from one generation of a cell to the next generation. And the job of this pathway is specifically to allow a cell to commit suicide.

Then there's another category of cell death, which I would put in the category of what happens to a cell when you step on it. And there are myriad ways, as you can imagine, of hurting a cell in a non-natural way. Necrosis is one of those ways. It's a very ill-defined term, but when people usually talk about it, they refer to an unregulated type of cell death that's not encoded in our genes

and involves swelling of the cell, often formation of membrane whorls or substructures within the cell that are abnormal, and eventually leakage of the content of the cell into the environment. And I suppose that provokes a reaction from the immune system? Yes, so the difference generally between the genetically programmed death events and the foot stepping on the cell type of events is that the former are designed in a very clean way to not perturb the surrounding environment. In fact, they do everything they possibly can to minimize any damage to surrounding

cells when they die. The other type of death, though, often elicits harsh reactions, either from neighboring cells or, if the animal has an immune system, from immune cells that try to cope with the damage that the exploding cell has unleashed on its environment. I mentioned this term apoptosis earlier, this genetically programmed style of death that's relatively clean. Am I getting that right? That's what we're talking about now. I would say that people in the field often equate programmed cell death with apoptosis,

but actually that's not entirely accurate. Apoptosis is one form of programmed cell death with apoptosis, but actually that's not entirely accurate. Apoptosis is one form of program cell death. We've discovered one in our own lab, a different one, called linker cell type death or LCD. And there's at least one other type of cell death that I know of which has been studied by a colleague of mine in Drosophila melanogaster, the fruit fly. So we know of basically three bona fide examples of genetically programmed cell death pathways. You want to give us a picture of them? What should we visualize if a cell is undergoing any of those three?

So apoptosis, that term was actually first coined by Kerr and Wiley in a paper in the early 1970s. It's related to a Greek word which has to do with the falling of leaves from the tree to make the connection to some sort of a death process. And so it's characterized by the condensation of chromatin or of the DNA inside the nucleus. It becomes very compact and it cannot carry out its functions because it is so compact. In addition, the cell cytoplasm, so the bulks of the cell seems to shrink.

Often, the organelles like the mitochondria that are present in the cytoplasm will rupture but this happens generally fairly late in the process. Overall the whole thing happens very rapidly. So only if you sit there and count the number of cells over time that are undergoing this process that you realize how prevalent it is. So overall you have a very compact demolition process which gets rid of the cell and then these cells that have died on their surface have special signals that are known in the field as eat me signals and they signal to neighboring cells or to specialized phagocytic cells to come and

literally eat them up and degrade them. And so most programmed cell death follows that path. And apoptosis in particular has the features that I mentioned. The linker cell type death is in some sense almost like a mirror image of apoptosis. There's very little chromatin condensation. In fact, the hallmark of this cell death is that there's very open chromatin condensation. In fact, the hallmark of this cell death is that there's very open chromatin and then organelles, rather than waiting till the end of the death process to exhibit defects right from the beginning, tend to swell. But importantly, this type of cell death still presents eat-me signals on its surface, and these cells are still cleared by either

neighboring cells or specialized phagocytes that degrade it. I'm curious to hear a little more about this second one because number one I never heard of it before and number two my first scientific paper in my own career was about applying math to the structure of the chromatin fiber. So when you mentioned linker, are you referring to the linker DNA between nucleosomes? Actually, I'm not. This cell death, we actually discovered it in the nematode C. elegans, and it's the death of a single cell in the male

of the animal that's called the linker cell. And the reason it's called the linker cell is because it connects the developing male gonad to the exit channel, which will allow sperm to be released from the male during mating. This cell basically stands as a plug in between the gonadal tube and the exit channel. The animal eliminates it using this novel linker cell death program. And that allows these two tubes to fuse together so that sperm can exit. And what we've discovered is that what you can see by electron microscopy, which allows you to view cells at very high

magnification and with specific types of contrast, this type of cell death actually is not relegated only to this one cell in nematodes, but it's also extremely prevalent in developing mammals and in humans. In fact, much of the cell death that happens in our nervous system has this shape. And in addition to the features that I mentioned, one other prominent feature that the cell death has

is that the nuclear envelope acquires these indentations, or crenellations as we call them, where it just looks very wavy. And this is really a hallmark of a lot of cell death that happens in human disease also. And so we're very curious about the possibility that linker cell death might play a role in human disease, where in the disease state you're inappropriately activating this type of cell death when you're not supposed to. I do want to come back to this question about cell death and its implications for human disease.

But if it's okay, I'd like to keep enumerating various pathways of cell death, because there are a few that have to do with defensive functions. I'm thinking of cases where viruses or other pathogens are causing infections or other sorts of problems and cell death is happening in response to attack. So, many of these actually have a lot in common with apoptosis, and the name signifies just the context. So, for example, pyroptosis is a type of apoptotic cell death that happens during an inflammatory response. And so the pyro is supposed to allude to the inflammation or this fiery kind of state. And the idea there basically is that you might have a situation where a cell is infected with a virus or a bacterium and

it's to the benefit of the host organism that the cell off itself so that the rest of the organism doesn't get exposed to the bacterium or to the virus. There's many pathways that are dedicated towards eliminating cells that are infected. Besides what you might consider apoptotic type cell death, for example, when a particular form of T cell called a cytotoxic T cell recognizes a cell that has been infected with a virus, it will release proteins called

perforins, whose name is exactly what they sound like. They basically make pores. And so they release these perforin proteins that make holes in the membranes of the target cell. And that will trigger either an apoptotic response or just leakage in general out of the cell and eventually the cell just disintegrates and gets eaten by circulating phagocytes. So this type of response is similar to the type of thing that happens in complement mediated cell death, another type of reaction that our body has in response to a cell that has been invaded by a foreign organism. And often it's a very complicated cascade of proteins that are circulating in the blood

that will eventually lead to a coding of an infected cell with a certain type of protein which is an eat-me signal for phagocytes. So the cell itself is not destroyed from within, as in some of these other examples that we've been talking about, but it's just marked as a bad seed so that the phagocytes can come and take care of it. So the impression I'm getting from all of this discussion

is that when cells either carry out these programs or allow themselves to be marked as eat me cells, it's for the greater good that this is to help other cells around them or other tissues. It feels like this is something that is multicellular. If you were a single cell, you wouldn't have the same incentive to do this sort of thing. It's in the context of being in a multicellular organism that these processes happen. Is that wrong? You're on the right track. I wouldn't necessarily restrict it to a multicellular organism. You just need to be in a situation where

you have a conglomeration of cells that need each other in order to survive. So it's true that in a multicellular organism, you need to exercise this principle of, I might need to die for the greater good, but it's also true in bacteria. So for example, bacteria tend to form what are known as biofilms, basically sheets of many bacteria lined up next to each other. Under starvation conditions, when the biofilm doesn't have enough foods to

feed everybody, a subset of the bacteria there decide to just destroy themselves and serve as nutrients for the other bacteria that are surviving. Often there's wars between the bacteria and they will invoke killing mechanisms in your gut. So I think the principle that you hit on that you need to be in a multicellular environment is important, but it doesn't necessarily have to be within a single organism. All right. So multicellularity broadly construed then, not necessarily in a multicellular organism, but multicellular life in its various forms,

these issues come up. In the context of animals, there are examples where the general principles that we found could be very meaningful. So one place to look, for example, are ants. So in an ant colony, it's essentially what's called a superorganism, where each ant plays an important role within the colony. And often it's true that ants have to die in order to generate an interesting structure that's important for the survival of the colony or to even just provide nourishment. So there's these wonderful movies that you can find on YouTube and on National Geographic where you can see ants forming a bridge so that other ants can travel across this bridge. And often those ants

that are on the bridge will die and their exoskeleton is what serves as the part of the bridge on which other ants march. So there are example where individual animals die as a way to better the entire collective. That's interesting. One other thing that I was wondering about, because you did mention C. elegans, the wonderful little worm only about a millimeter long that has taught us so much about biology from development, genetics, behavior, neuro, biology, aging, it's incredible, neuro, biology, aging. It's incredible what we've learned from this little critter.

And some of our listeners may not be familiar with this creature. Can you just tell us a little about C. elegans and also how it has helped us learn about processes involved in cell death and their significance? Sure. If you want to study cell death, it would be really useful to know that at a given moment in time, at a given location within the animal, a cell is going to die. Because if you have that predictability, you are able to manipulate the system ahead of time to ask all sorts of questions. That predictability is absent in most model systems.

However, in nematodes and specifically in the nematode C. elegans, this is precisely what we can do. So C. elegans has the remarkable property that the pattern of cell divisions from the fertilized egg all the way to the adult is entirely identical, except for a very small number of exceptions, between individuals of the species. And superimposed on this cell division pattern is also a pattern of cell death, which is exactly the same.

The way we can demonstrate that the pattern is the same is that we can give cells names in C. elegans. So we can say this cell is called Mo and this one is called Curly, but actually we give them much more boring names like ASE or NSM or CEP sheath. Whereas in us or in other vertebrates, you really can't name cells and have them be the same cell in every animal. We can tell you with precision that the cell called curly will die four hours and 20 minutes after the fertilized egg began dividing, and we can tell you for sure that it's going to take 25 minutes for that death process to occur. This detail was worked out in the late 1970s and early 1980s by two extraordinary scientists,

Bob Horvitz and John Sulston, and they determined the entire pattern of cell divisions from the fertilized oocyte all the way to adulthood. And as they were watching these cell divisions unfold, they realized that there were cells that would eventually disappear. And those were the dying cells. And so we know that in, for example, a developing C. elegans hermaphrodite worm, 1090 somatic cells precisely are generated, and of those exactly 131 cells will die, living the animal with a complement of 959 somatic cells. And based on this precision, we can now do all sorts of genetic studies and cell biological

studies where we can look at the same exact cell over and over and over again to try to understand what drives the cell death process. And really, I think this is the biggest advantage of using C. elegans to study cell death. So in case anyone is wondering, they're not hard to capture, right? They're just like if you pick up a handful of dirt, there's a lot of these C. elegans in there. So nematodes and C. elegans in particular is found all over the world and in fact when I started my laboratory at Rockefeller, the first thing that I decided to go and do was to see if I could isolate the Rockefeller version of C. elegans.

So I went out and I got a bunch of dirt and I put it on petri plates that have agar, that's how we grow the worms, and just waited for them to emerge and indeed we found them and I put it on Petri plates that have agar, that's how we grow the worms and just waited for them to emerge. And indeed we found them and I was very excited to find the Rockefeller isolate only later to find out that Rockefeller actually imports its dirt from upstate New York. So in fact, they were not local C. elegans, they were upstate New York C Seattle, I guess. Steve McLaughlin Country worms coming down to the city. So the story you've just told is so remarkable and amazing. The machine-like development of this creature from the time it's

fertilized oocyte to an adult. And then you mentioned that for a mouse or for us, it's not as predictable. I'm sure some people must be wondering, aren't they very special in the whole zoo of life? Convince us that studying this strange worm was really relevant to us. First, I should start out by saying that they are very special. So there is something that they do that other organisms don't. And I think it's important not to gloss over that. But in terms of the relatedness to other animals, you need to look no further than

the DNA of the animal and the genome. So the sequence of DNA nucleotides, which code for genes in our genome, are essentially the same in C. elegans as they are in us. For example, the process of apoptosis is executed by a protein called a caspase. It's a protein whose job is to cleave other proteins. And the protein is encoded by a gene. And this gene is pretty much the same gene in worms as it is in people. If you want to follow Nietzsche's line of thought, man is worm. I'm not familiar with that quote. Is that the real quote? It is. It's in German, but this is the translation of it.

Okay. I never thought of him as a cell biologist, but maybe he was onto something. We'll be right back after this message. Welcome back to the joy of why. So I wanted to explore a variety of laboratory systems for looking at cell death from say a bacteria in a plate to C. elegans up to more complex organisms. So what is the right scale for us to be studying these questions of cell death? I think it is important to look at all different scales. I guess the smallest scale is the cell itself. And certainly there are examples of bacteria where cells die and those are very important to understand for health reasons, but also just as basic questions of curiosity.

How does a bacteria decide that it needs to die? Working in bacteria is a wonderful system. Working in a cell culture might also tell us a lot. So if we take cells from, let's say, a human or from a mouse and put them in culture and let them divide and die within the culture, we might not learn about the context in which they're executing the cell death, but we might be able to learn a lot about the molecules and about the signals that are involved

in telling cells whether to die or not to die. And once we've established some principle in this simplified cell culture, we can then try to move our understanding into an organism where we could, for example, explore the role of a gene that we discovered in cell culture and see what effect it might have on the organism. In an organismal level, there are aspects of cell death that you can't really explore in other settings, which has to do with collective phenomena of cell death. So not just a single cell dying, but aggregates of cells. And that's probably most beautifully demonstrated in the field of developmental biology, and particularly the process of morphogenesis. So that is the process by which animals or any living

organism that's multicellular get their form, their shape. Rodin is famous for saying that he was trying to reveal the statue that was within the slab of stone that he's carving and it's the same principle in terms of cell death. We have this mass of cells and in many cases some of them die to be able to form a particular shape. And perhaps the most famous example is the development of the digits in vertebrates. So in embryogenesis, all vertebrates have very prominent cellular webbing that connects the digits.

In vertebrates like us, for example, there's massive cell death that happens in that interdigital webbing that eliminates those cells and that's why we have well separated digits. So you're talking about formation of fingers or toes here. Yes, exactly. But in the duck, for example, a lot of that cell death doesn't take place and that's why they have webbed feet.

That's amazing. Not that they were growing the web, it's that the other creatures were sculpting away their web. Aren't there genetic variants? Or I think some of my relatives have said, look at my toes, I have webs between these toes. So those are probably vestigial structures that did not completely get eliminated during embryogenesis.

Well, let's move on to this more of a human-centered point of view here about cell death, maybe related to healthcare issues, medical care. For instance, would knowing more about cell death help us reverse organ failure or anything else in which lots of cells in a tissue might be dying? So cell death is associated with virtually every disease state in humans. And broadly, you can categorize them into two kinds of problems. One group are diseases where there's too much cell death going on, diseases like organ infarction, like for example, when you have a heart attack, cells in your heart will die, or in neurodegenerative conditions where cells in the brain will die

and then you develop Alzheimer's or Parkinson's disease. And then there's the opposite side of the spectrum, diseases where cells that should be dying are not dying. And that's essentially what all cancers are. Cancers are cells where somehow the programs that allow the body to eliminate these harmful cells have stopped doing this, and the cells are inappropriately surviving. So really, this in principle could touch every major disease. Now, this is not to say that cell death is the root cause of every disease, but certainly there are cases where if we could block the cell death from happening,

it might at least give us a fighting chance to treat the cells that otherwise would be completely gone. In terms of utility, there's been a number of drug studies looking at compounds that can either inhibit or promote cell death in various disease contexts. For example, in the clinic now there are drugs whose job is to trigger cell death in specific tumor settings. And these drugs arose from our understanding of how cell death happens and the specific molecules involved. It makes me wonder with your earlier mention of markers on cell surfaces that say eat me,

whether that can be used on cancer cells, maybe in a kind of cancer immunotherapy or something like that. At the moment, there isn't anything that's specifically in trials to look at these eat me signals, but what you can do is you can create your own eat-me signals. So if you can discover something on the surface of a cancer cell that marks it uniquely from all other cells, because you only want to eliminate the cancer cell, you don't want to get rid of all the other cells in your body. So if you can identify this, you can generate a specific antibody which would trigger, for example, an apoptotic response in the cell to which it binds.

And in fact, there is really an incredible revolution afoot in the treatment of cancers using what's known as immunotherapy. And this is precisely what this is based on. So the idea here is to allow the body to identify specific unique markers for tumor cells, generate an immune response towards those, and then immune cells will go to these cells and destroy them using a variety of different ways that we mentioned already in our conversation. We've been focusing a lot on what is known or what we've discovered in the past few decades

about cell death. I wonder if you have a few questions that you'd love to see answered in your lifetime or where you think the great exciting open areas might still lie in this field. Yeah, I think there's an enormous amount for us to learn. So as you alluded in the beginning of our conversation, a very commonly studied cell death process

is called apoptosis. And we, for many years, thought that this process was sufficient to explain many of the types of cell death related events that happen during the development of animals. But work over the last couple of decades has demonstrated that you can completely eliminate this cell death program from the genome of an animal. And yet, the animal can still survive just fine. And so what that means is that there must be other ways to kill cells that are out there.

Now, one way might be this linker cell type death, which I mentioned, but it may not be the only way. There may be other ways. And so that whole black box of what other programs are out there is an incredibly fascinating direction that will definitely deserve our attention, particularly if we wish to make cell death an important angle of attack in disease.

There is another big question that we would like to understand. So I told you in C. elegans, we know precisely which cells are going to die at any given moment. We don't know this in vertebrates, but we would love to be able to understand how if you have two neighboring cells in a human, why one will undergo cell death and another will not. And we don't at all understand that. So I think this becomes a much bigger question. It's a question that has to do with how cells respond to their environment and cell death in this case would just be a readout, but certainly still an incredibly fascinating question and wholly unanswered.

Wonderful. Those are some great directions. Finally, you as an individual scientist in this great enterprise, is there something about your own research that particularly gives you joy? I love discovering stuff. I have always been interested in finding new things that no one has found out before. And in some sense, the specific details of what it is that I'm finding are not even that important,

because I think once you get into the details, everything seems interesting and exciting. As long as there's a question to be asked and a way that I can imagine to solve it, that will bring me into work every day and it still does. I know that feeling and I sometimes will tell my own graduate students that it almost doesn't matter what the question is. The process of discovery is so fulfilling and everything becomes interesting once you start looking at it deeply enough. Absolutely. Rare, but fulfilling. But what about something that Francis Crick said one time that it's just as easy to work

on an important problem as a trivial or uninteresting or unimportant problem. Do you ever think about that aspect, that you want to work on things that matter in some external sense? I've often thought of that quote in trying to decide what my next goal should be. But I will tell you that in my opinion, I lack the hubris to decide what's important and what's not. And I think science has proven over and over how discoveries that seemed unimportant and fringe at any moment turn out to be all the rage just a couple of decades later.

And this could be true in biology, this could be true in physics, this could be true in mathematics. And so I think that by narrowing myself to this particular scheme that Crick suggested, I might be excluding areas of discovery that could be even more exciting than what I can imagine. And I just think my imagination, good as it is, is just not good enough to be able to foretell the future like that. I'm getting a great deal of joy personally from that answer. The virtue of modesty, it may actually be a very practical thing,

for exactly the reason that you described, that we don't really know. I could talk to you all day, Shai. This has been wonderful. Okay, Steve. I really enjoyed it. We've been speaking with cell biologist and neuroscientist Shai Shaham. Thanks so much for joining us here on The Joy of Why. We've been speaking with cell biologist and neuroscientist Shai Shaham. Thanks so much for joining us here on The Joy of Why. Thank you, Steve. Thanks for listening.

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