Hello and welcome to 10 craziest things cells do. My name is Wallace Marshall and I teach at UCSF, the University of California, San Francisco. In today's talk, we're going to tackle the myth that cells are small, simple, and stupid. Why do we all tend to think that? It arises from the idea of cell theory. And so cell theory is built on two premises, one is that cells are small, simple building blocks, similar to atomictheory. And also the second part of cell theory is that cells are separate compartments of living matter, and that's why they're called "cels." So typically when we learn about cells in school, we learn some picture like this shown here, where it's a relatively simple bag or box full of watery enzyme with a few parts in it, but pretty simple and kind of boring. And the general view about cells is that they're not very exciting, they're relatively simple, like the lego block. And the only way to build anything interesting is to have lots and lots of cells. It turns out, though, when you look at real cells, they're not necessarily simple at all. They can be very complicated and make beautiful shapes. So I've just shown here a few examples of cells, both free living cells and also cells from the bodies of animals and plants, in which the cells are much more complicated than just a little bag of enzymes. No one knows where all the shape comes from, but it makes you think that maybe cells could do much more complicated things than just sit there and be building blocks. So today's lecture, we're going to talk about 10 crazy things that cells can do. One thing that cells can do that's crazy is get really big. It's not crazy that you get big, but it's crazy how big they can get. Here's one example, Gromia sphaerica. It's a round amoeba that lives on the ocean floor, and a single cell can be 1.5 inches in diameter, the size of a large grape or small ping pong ball. And as you can see here, they're comparable in size to an animal, here are several Gromias shown next to a shrimp. And I love this picture, because it looks as though the cells are actually chasing the shrimp down and trying to kill it. They aren't really doing that, but it just gives you that impression. But another nice thing about this image is that you see how the cells can leave behind trails in the dirt. And there's an ongoing controversy now in people who study trace fossils, who want to know when did hard-bodied animals first evolve. They've often based those arguments on seeing traces and tracks in the dirt that have been fossilized, and it's now thought some of those tracks could be things like Gromia that were big enough to leave trails, even though they were just single cells. Gromia's big, but it's not the biggest cell we know. One really big kind of cell is Acetabularia, it's a green algae. And this is a clump of them. Each individual cell looks like a plant, it's got a root at the base, a stalk, and then this flower-like cap, you see. Each single cell could be 10cm long. You could hold these cells in your hand like little flowers and even make a bouquet out of them. So this is extremely large, these are among the largest single cells we know that have just one nucleus. If you let cells have lots of nuclei, then there's even bigger examples. This is an example of Caulerpa, which is a multinucleate syncytial cell. This bush-like plant here, is actually one single cell that makes many branches and fronds and leaves, but it's all just one cell. And it can be larger than a human being. And just one cell. So cells can be crazily large, so that's crazy thing number 10 that cells can do. Some cells, though, can be extremely small. And this example is Ostreococcus tauri, which is only about a micron in diameter and is so small that it only has one of everything. So the entire cytoskeleton is just one microtubule. Number 9, cells that walk. We're used to thinking about cells moving by crawling along a surface like an amoeba, or we think about cells that can swim through pond water. But cells have many other ways that they can move, for example, this kind of cell here, Stylonychia, is a type of ciliate that's able to walk. It walks using clusters of cilia on the bottom surface of the cell. And as shown in the picture on the right, it can actually walk along leaves and branches inside the pond. So this is one remarkable way the cell can walk. And if you didn't know better when you see these things moving, you would think they were little insects like cockroaches, but it's just one cell. But there are other varieties of motile behaviors that cells can do beyond just walking. For example, there are cells like Dileptus shown here, that are basically vampire cells. They have a sharp little needle they can poke into other cells and then drink their cytoplasm. There's also cells that can open up mouths that they have, into gigantic mouths that can swallow other cells whole. For example, here is Didinium swallowing a Paramecium whole. So there's a wide variety of movements that cells can do, moving and also attacking other cells. Number 8, cells that go left. So I've talked about weird ways that cells can move by walking and by opening their mouths, but even among cells that crawl the normal way, there's very strange things that certain cells do. For example, there was a beautiful paper by Xu et al, showing that white blood cells tend to move left. So what they did was they looked at cells in the absence of any chemical attractive signal, just sitting on the dish. And they drew a line from the nucleus to the centrosome, basically giving you an idea of the axis that the cell is oriented in, and so they show that line in these graphs here with this red arrow. They then added a chemoattractant everywhere in the media, so the cell has to pick a random direction to start moving in. And the remarkable thing, as shown by the blue dots, is that most of the cells will move to the left of their original direction. So these cells know left from right. How does a watery bag of enzymes know which way is left and which way is right? It's really not clear. The one structure in the cell that does have a left and right handedness to it, though, is the centriole. So as shown here, the centrosome contains a pair of centrioles, that are basically barrel like structures made of microtubule triplets. And those microtubule triplets have a certain handedness as they go around the centriole. So you could imagine that this might be a source of left or right handedness in a cell. And in fact, in this paper, when they ablated the centriole, they were able to eliminate the leftward bias of the motion. So this just tells us that the ability of cells to move and the decisions that they make while they're moving are probably a lot more complicated and crazier than we ever would've thought. Number 7, tunneling nanotubes. A fundamental part of cell theory is that each cell is a totally separate entity disconnected from all the others. That's why they were called cells in the first place. But in fact, we know that cells are often connected with each other. This is well known in plants, you've probably heard about plasmodesmata, shown at the bottom. Which are tubes connecting plant cells after they divide. But it's also true in animal cells, so one thing that we've discovered in the past decade is that many animal cells can be joined by very narrow connections called tunneling nanotubes. Which allow cells to join to each other and exchange various chemicals and maybe even organelles. So even though they look separate, the cells are really connected at a small enough scale. Tunneling nanotubes are a specific case of the more general idea that cells are not as separated from each other as one might think. And there are many different examples that have come to light. For example, shown on the top here is the phenomenon of leukocyte transcellular migration. In this case, white blood cells or leukocytes in the bloodstream want to escape from the blood vessel and attack invading organisms in your tissue. So they have to get through this epithelial layer, but the epithelial cells are very tightly connected to each other. And actually, the leukocytes cannot squeeze through them. So instead, they just dive right through the cells. So you can have a leukocyte crawling inside another cell, and this is happening all the time right now in your bodies. So you can have cells inside of other cells. You also can have cells that let go of membrane vesicles which can then be taken up by other cells and passed from one cell to another like a bucket brigade, and these are called argosomes, shown here on the bottom. An even more weird example, which I feel is weirder than argosomes, is kleptoplasty. This is a phenomenon whereby the cells of one organism can eat another cell and digest it and then save the organelles from that cell and put them inside of itself. So here we see a sea slug, the reason why the sea slug is green is because the cells of these sea slugs contain chloroplast that they stole from green algae that this organism was feeding on. So that's why they call it kleptoplasty, the stealing of plastids or organelles. So all these examples just show that cells really are not as disconnected as one tends to believe and they're constantly exchanging material in ways that we're only now beginning to understand. Number 6, cytoplasts. What a cytoplast is, is under certain conditions, for example, by heat shock, a piece of the cell -- a piece of the cytoplasm will just decide to take off by itself. And that's shown here, you have a little piece of cytoplasm that's just crawled away from the rest of the cell. These cell fragments can move by themselves, they leave behind the nucleus, the centrosome, the golgi, most of the components of the cell are left behind. But yet, this little fragment of cytoplasm is still able to move and it can still do chemotaxis. The main reason why researchers study these is because it allows you to ask what behaviors can a cell do without the other organelles? And in particular, you can show that you don't need the nucleus or genes to do chemotaxis. So it's been very useful to rule out transcription as an important factor in many behaviors. But on some level, formation of cytoplasts is still a laboratory artifact. However, it points to the ability of other cell types to naturally fragment. The really classic example being platelets. So platelets are structures that float in your blood that are important for wound healing, for promoting a blood clot. But what platelets actually are is tiny fragments of a much larger cell called a megakaryocyte. And as shown in this cartoon, the megakaryocyte grows and grows, sends out long, long fibrils, which then fragment to make lots of tiny little pieces, and those are the platelets. So this again speaks to the exceptions to cell theory that we need to think about. Normally, we think about the cell as being the minimal unit of biological function. But here's an example where the important unit of function is actually a tiny little fragment of the cell that's been shattered and is now freely moving around in the blood. Number 5, cells that can sense electricity. So now we're starting to get into the realm of the truly crazy. So when you look at a mitotic spindle, just visually, the microtubules of the spindle look an awful lot like the lines of magnetic force around a bar magnet. Now there's absolutely no similarity between these two phenomena whatsoever, they just look similar. Nevertheless, the fact they look similar tends to make you want to think about, could there be electric fields doing something important in biology, in cell biology? And in fact, this has led to a variety of proposals and inventions, including several patents for equipment that would use electric fields to change the behaviors themselves. It's not entirely clear whether these would actually work. They're considered a little bit on the fringe of what we know, but nevertheless, there is one very clear case where electricity is affecting what cells do. And that's the phenomenon of galvanotaxis. So this is illustrated in this slide here, where we see keratocytes from a fish, which are moving in the direction of an applied electric field. And this is a well known phenomenon, galvanotaxis. Why would cells care about electric fields? Well, it turns out, epithelial layers like your skin, have an electric potential across them. So the cells in the skin are constantly pumping ions back and forth, and if you were to punch a hole in your skin, for example, if you get cut or wounded, that would now produce an electric field that varies from position to position across the skin. This then gives an electrical cue for the keratocytes to move towards the site of the wound, so they can fill in the hole. So galvanotaxis is not only a real phenomenon, it's actually really important for your ability to heal wounds. Number 4, cells that can solve mazes. Part of cell theory is that we think cells are relatively stupid, because they're so simple and they need to be used as building blocks. So therefore an individual cell probably can't do that much. That's not necessarily true, and in fact, we really don't know how much computation one cell can perform. People have done various interesting experiments to ask whether cells can do problem solving, one classic example, is can cells solve mazes? So here I'm showing two examples of maze solving by cells. One is Physarum, which is a syncytial slime mold. So a single cell will fill up a maze and it will eventually grow such that the fibers of the cell will find the shortest path between the entrance and exit of the maze, between two chunks of food. So, in this sense, Physarum is able to solve the maze. Filamentous fungi can also solve mazes, as shown on the bottom. They can send little filaments into the maze and those filaments make choices about which way to move when they hit a corner or intersection. And it's been shown that the choices that the single cell makes are better than just random. So it is somehow solving the maze. Cells can also solve a well-known problem in computer science called the "traveling salesman" problem. So the traveling salesman problem is, if you're a salesman and you want to visit a number of cities in defined locations, how do you decide which order to visit those cities so you minimize the total traveling that you do? It's known from computer science theory that many different problems can be shown to be equivalent to traveling salesmen. So if you can solve this problem, you can solve many problems in computer science. Turns out that single cells can solve this problem of traveling salesmen. Here's an example of the Physarum, and again this is syncytial slime mold. And what the experiment done here was researchers put chunks of food in a pattern that mimics the location of cities and villages surrounding Tokyo. They then let a single cell of physarum grow until it built various filaments connecting these food sources. They then found that the pattern of these food sources, not only is optimal, in terms of matching the traveling salesman problem, it also very closely mimics the actual railway map of the greater Tokyo area. Arguing that the single cell can do the same kind of problem solving that human engineers would do when they plan out a railway map. So this all shows that cell are probably a lot smarter than we think they are. And we probably are only beginning to scratch the surface of what kind of problems they can solve. Cells can also learn, and they can show simple types of learning. Here's an example, where we see Stentor coeruleus, this is a pond-dwelling ciliate that normally stretches out into the shape of a cone. And as it's stretched out as a cone, it can filter feed. So it's eating bacteria and algae. But while it's stretched out, it's vulnerable to other organisms eating it. So something touches it, it contracts down into a ball, shown here. Once it's contracted though, now it can't feed anymore. So the cell has to decide when something touches it, is it really dangerous or not? How does it know it's dangerous? It does the same way human does, by experience. If something happens all the time, you learn that it's safe. For example, if you live near a railway track, you don't get scared when the train goes by anymore. So that's habituation. It's a common form of learning that all animals do. And actually, the Nobel prize was awarded to Eric Kandel for studying this exact kind of learning in Aplysia, the sea slug. As shown in the graph here, if you tap Stentor cells again and again and again, they will gradually learn to ignore the tap, showing that they do in fact do habituation. So this shows the cells not only can solve problems like mazes, they can also learn like animals. It really raises the question, how much thinking can a cell actually do? Number 3, cells that can see. In a series of controversial papers, Gunter Albrecht-Buehler argued that cells possess some kind of eye that allows them to detect information at a distance. Several experiments he did showed that cells can move toward infrared light sources, and perhaps more controversially, that cells can align to each other, even if they're on opposite sides of the glass coverslip. Now this is not something that everyone necessarily thinks is true, I'm not aware of any careful attempts to reproduce this by anyone. Because I think most people think this is just so unusual, unexpected, and crazy. But doesn't mean it's not true, however. And in fact, there are clear cases where cells are able to sense and use light, and effectively see. This is quite common in algae, so Chlamydomonas is a green alga that swims with two flagella, as shown here. Has a eyespot that can detect light coming from particular directions. So as it swims, it's scanning for light and it can go directly toward the light source very quickly. This is just a very simple eye spot, it's just a patch of photoreceptors. But there are more complex eyes, for example, dinoflagellates form a reflecting lens that actually focuses light outside of the cell body, right onto the interior of its flagellum, where the photoreceptor molecules are located. Other dinoflagellates like Warnowia, form actually a clear lens just like the human eye has, and it uses the lens to focus light onto its photoreceptors. So cells definitely do have eyes, what we don't know yet is how much information they get from that light, whether it's just the intensity of the light or just the spatial information. That's still, I think, an open question. Number 2, exploding cells. There's nothing more extreme that you can do than to explode. And there are cells that do just that. Here's an example, this is Magnaporthe grisea, also known as the rice blast fungus. It causes the disease that destroys rice crops. And the way it infects a plant cell is, it has to get through the tough wall of the plant cell. How does it do that? It does it by forming this structure here called the appressorium, and shown in high-mag down here. Where it's a protrusion of the cell that becomes surrounded by a thick cell wall and it fills up with melanin, creating a very strong osmotic pressure. Actually, the pressure that builds up inside this thing is 10 Mpa, the same pressure of a bullet. When the cell builds the appressorium on top of the plant surface, it then suddenly ruptures at just one point, releasing this massive pressure into a tiny little spot on the plant cell, punching a hole into it. Like shooting it with a bullet from a gun. So by exploding, this cell produces a breach in the defenses of the plant and allows the fungus to invade that plant. This is a relatively extreme example. Most cells do not explode in this dramatic manner, but many cells do actually take advantage of hydrostatic pressure in order to move. And this is a phenomenon called blebbing. So as shown here, cells will sometimes have the cell membrane let go from the actin cortex, and then hydrostatic pressure will then push out this bleb of the membrane, which can then fill in with more actin. And that allows the cell to then move a little bit forward. And cells can move forward progressively by these blebbing events, and there are beautiful theories showing how the hydrostatic pressure is enough to provide the force for this motion. So this shows that even very extreme phenomenon like cells exploding, often point to very fundamental and universal cellular behaviors that most cells actually do. Number 1, the craziest thing that I'm aware of is cells that can eat your brain and control your mind. The cells we're talking about are Toxoplasma, shown here in this image, they have this conoid organ that they can use to puncture and move inside of other cells. And if they get into your brain, they will actually eat holes in your brain. Now it turns out, this isn't really that bad for you. Many people, many of us, have toxoplasmosis. We have these organisms that have eaten holes in our brain, you can get it from your cats if you're pregnant or immunocompromised. Or if you eat a lot of raw meat like carpaccio or beef tartare, you can get toxoplasma infections. It doesn't cause really overt symptoms, it doesn't kill you, but interestingly enough, a researcher called Jaroslav Flegr, shown here, has combined personality tests with immunoassays for toxoplasma infection. And what he finds is that individuals who have had toxoplasma infect their brain, tend to have a variety of personality traits. So for men, it tends to correlate with dressing sloppily. For women, it tends to correlate with dressing overly neatly. For both men and women, it tends to correlate with suicide, reckless driving, and introverted personalities. So this is a case where a single cell is somehow able to get into our brains and not just eat random holes, but somehow actually control the way our mind works. And if that's not crazy, I don't know what is. So I hope you've enjoyed today's lecture. I hope it shows you that cells are not as simple as we think they are. They're incredibly complex, they can do crazy things, and I believe we've only scratched the surface of what cells are capable of. Thank you.
