EP45: Sperm Capacitation: Intelligent Motion with Dr. Meisam Zaferani

This episode, the conclusion of our mini-series on sperm capacitation, features physicist Dr. Meisam Zaferani discussing sperm motility through the lens of search theory and active matter physics. Dr. Zaferani explains how the sperm, which he calls an "autonomous natural robot," overcomes the massive challenges of movement at the microscopic scale, where movement is dominated by fluid viscosity rather than inertia. To maximize their chance of reaching the egg, sperm constantly adapt their swimming strategies—a process physically evident as hyperactivation—to the geometrically complex and viscoelastic environment of the female reproductive tract.

Transcript

And I was talking to a couple of friend of mine, and we were talking about like how sperm could be seen as, as an autonomous natural robot because it doesn't have gene expression. But it's so fine tuned during the process of gametogenesis so that it can go outside the body and perform a very complicated task.
Hey there listeners, welcome to another episode of The Future Conceived, the official podcast of the society for the Study of Reproduction. I'm Cam Schmidt, assistant professor in the Department of Biology at East Carolina University. Imagine you accidentally drop your car keys on a dimly lit street. How would you search for them? You could get down on your hands and knees, slowly and methodically searching the ground around you. But this might take a while. Alternatively, you might simply walk in a systematic zigzag over the area where you think they fell, hoping to accidentally kick them with your feet. But with this strategy, you might miss the keys altogether. Every search process from foraging animals looking for food to motile sperm searching blindly for an egg must make a trade off between traversing distance and covering searchable area. We've long known that mammalian sperm undergo pattern transitions in their motility. Sometimes sperm move nearly in a straight line, or rarely they move vigorously in tight circles, a pattern known as hyperactivation. What these phase transitions are for, however, remains a mystery. Today we'll be chatting with Doctor Meisam Zaferani, a research fellow in The Omen Darling Bioengineering Institute at Princeton University. Doctor Zaffaroni is a physicist who's working to understand how the animate motion of biological systems differs from the inanimate motion of nonliving systems. In this fascinating conversation, Doctor Zaffaroni reframes sperm motility in the context of searching and finding, helping us better understand what we know and don't know about sperm motility. Welcome to the show. My son. Thank you for joining us.
Thank you for having me.
As I mentioned, it's a three part series, and in the other episodes we discuss how cell signaling pathways control change in sperm during fertilization that enhances their overall fertility competence. Um, and and then we talked about metabolic systems that underpin the energy requirements of Uh, motility. So I'm excited in this episode to talk a little bit more about how sperm move. Um, and more importantly, maybe how understanding how sperm move helps us understand bigger questions, both in reproductive science and also maybe in physics more generally. To start, can you kind of summarize what sperm do?
Yeah, that is a very good question. So basically the whole purpose of sperm migration within the female reproductive tract is they have to migrate a very long distance. So if you actually divide the distance they have to travel until they reach the oocyte by their length. The problem is somehow like the scale is similar to how Titanic, um, traveled between US and UK and, and and I and I should say it's not just a regular ocean. It's it's a mucous ocean. So they have to actually travel this long distance and, and withstand the selective pressure so that they eventually, um, get nearby the oocyte and receive all the signals that are coming from the oocyte so that they can find it and penetrate it and so on. Um, so that's that's how they do. But, but, but the whole question is how they adapt their motion and how they change motility during this process. Because we all know that, that in order to to migrate in a very complex system, you have to constantly adapt your, your swimming strategies. And I should mention that the geometrical complex, um, the geometrical complexity that we have in the female reproductive tract requires this constant, um, adaptation. And at the same time, um, um, we all know that, that the fluid properties, rheological properties of the mucus Ucas are different at different um, um, functional regions within the female reproductive tract. So, so um, the big question that I'm concerned about, and I try to understand is how how sperm cells constantly change their motion and motility strategy, um, to, to enhance their, their chance of reaching to the fertilization site.
So I know the way that fertilization, I think is kind of often conceptualized is as though the sperm are navigating to the egg, and that kind of seems as though the sperm know where the egg is. But the way that sperm moves seems to support the idea that they really don't, and that they have to search around and find it. So on a scale of dumb as a rock to smart as a brain, how smart does a sperm have to be to find the egg?
Yeah, that is a very, very hard question. I really don't know, like what is the scale? But what I know is that there definitely is smarter than a rock. They're not as complicated as brain. Um, they're somewhere in between. You know, the way we can think about this question is that what they do in order to maximize their chance? Are they using their maximum capacity? They have just a flagellum, and they have one head, and the head is slightly tilted out of the plane. So they roll around the longitudinal axis. What can you do with it? If I give someone like this limited amount of tools and say, do this very complicated task, how good they can be considering the fact that they have their limitations, right? Um, we should always be careful when we talk about all these constraints. And as far as I know, based on this limitations, they're super smart. And when I say super smart, I'm not talking about a brain. I'm And talking about billion years of evolution that shaped all these different parameters, so that now they have a chance of winning the game. And that's that's how I describe their the level of intelligence.
Or one thing I think we should talk about so that we can get our heads around the, the forces that the sperm have to work against is that at the the scale of sperm, uh, movement is different than it is at people size scale.
Yes.
Can you compare and contrast those two things a little bit?
Yeah. So the way the movement is happening at macro scale is dominated by by inertia. We have mass and this mass and weight, um, controls a lot of aspects of our motion. But as you start to decrease the scale, um, and people usually use um. Um, a number called Reynolds number to describe this effect. Especially in the fluids. The viscous effects become more dominant than inertial effects. And the whole physical laws, like the entire system that we use to describe motion, changes significantly. So the way the sperm cells are moving is completely different. The way that we can swim in the ocean. There are some similarities as long as symmetry allows. But the fundamental principles are significantly different. So as you actually go down and just smaller scale, the the, the, the mechanics of life become change. It's completely different. And there is this beautiful article, um, life at low Reynolds number that I, um, um, I encourage everyone, everyone in your audience to, to just read that article because it explains very simply and also very elegantly that, But how how this change, um, shapes life and also help these micro organisms or every swimmer or every, um, biological agent that is moving at this scale to, to perform a task.
With that in mind, then the environment has a different effect on the way that the sperm moves than it would for macroscale movement. So I know some of the work that you've done has been related to how sperm move near a barrier versus further away from a barrier. Can you talk a little bit about that?
Yes, absolutely. So one thing that we should always consider is that when we talk about sperm locomotion, it should be always careful about this geometrical constraint they have. We should always be careful that this migration is happening inside a confined environment. It's not in the ocean. And then the next question that pops out is how does geometry influences sperm migration? How does confinement influences this migration? So I did a very simple experiment back when I was in grad school. I said, okay, let's have a microfluidic chip whose height is like two hundred microns, and another microfluidic chamber whose height is around thirty microns, which is much more similar to the to the passages inside the female reproductive system. And what you realize is that depending on this confined geometry, sperm manifests its motility in a very different forms. So it is important, and it is crucial to understand how these geometries and the way we call it in physics, like boundaries, how these boundaries shape sperm migration. And you should always be consistent. Always try to do your best to mimic the conditions, physical conditions in vivo and and then observes for emotion in that moment. One thing that that has people have discovered it before us that when sperm cells hit a boundary, this physical boundaries are capable of rectifying and directing sperm motion in a certain way. Okay. But and one of our studies, what we did was that how, how combination of fluid flow and different geometries could lead to a selective behavior that can happen potentially within the female reproductive tract. And especially we were thinking about the Uterotubal junction. One very interesting aspect of studying sperm interacting with the physical boundary is that when they undergo this process of capacitation and by capacitation. I just want to focus on its physical manifestation, which is hyperactivation. So when you have a very simple plain physical boundary and a progressive sperm that is, that is in its activated mode. It hits the boundary, collides with the boundary, and it becomes rectified by the boundary. And it's usually thought that that this rectification is responsible for, for directing sperm motion, especially in the lower part of the tract. But what happens is at some point, sperm cells become hyperactivated. And we demonstrated that Hyperactivation regulates this this boundary following navigation. So when sperm is not hyperactivated, they collide the boundary and move along it. Ballistically. But when you make them hyperactivated, they start to perform some random motion along the boundary, which we call a random walk.
A random walk would be like if you have a particle at a position, and then it's going to kind of like toss a coin or something and choose to go left, right, forward or backward. Yes. And then just keep doing that over and over and over again. And you've got, uh, let's say this is a person. The person is kind of wandering around in this random pattern, and if they were to restrict the number of directions they could go, like they could only go maybe, uh, forward, maybe just a little bit left or a little bit right. They can't turn around, they can't go backward. Then the walk will become correlated with the direction that they're moving at the previous steps. So in other words, it's kind of a fancy way of saying that they kind of wander along in a, in a progressively straighter line.
Exactly.
So then a progressive sperm is is doing a persistent random walk. Is that the right.
Absolutely highly persistent random walk. So there is actually a quantitative way of measuring that. There's this length that is called persistent links. People in the field of polymer physics and polymer chemistry have used it in the past to to describe polymer chains, but at the same time we can use it for promotion. So if they're moving progressively, it means that the persistent length is in the order of millimeters. So what what does it mean is that if you want to see sperm changing its direction on its own, you have to wait for like several millimeters until it changes direction, okay. Because this gradual changes in the direction eventually leads to change in the direction, right? If you sum them up, eventually it's going to lead to a change in the direction. But if you if you induce hyperactivation this persistent links reduces. So they keep changing their swimming direction. After much shorter distance they travel. And this change in the persistent links is a is a very interesting characteristics of search behavior. So when sperm cells are far from the oocyte or from far from egg is released there, moving with like a very high persistent length. But as as they gradually reach to the vicinity of the oocyte. The persistent lungs become shorter, which means that the search is much more local. Okay, I'm going to tell you a story, which is very interesting. So a few years back, I went to, um, ascb American Society for Cell Biology conference, and I went to this session that was about animal migration, where it was bird migration, and the speaker was talking about long distance migration of birds. And they used this, um, framework to describe long distance migration. Every long distance migration in birds have three phases. The first phase is called long distance phase, in which they actually receive very long distance navigational cues from the environment. For instance, if they want to come from, like, I don't know, Europe to North America, he would use coast coastal guidelines to find their direction. But when they get closer to their distance, they transition into this homing phase, which means that they're trying to find the proximity of of the target. And eventually, when they find the proximity of the target, they transition into pinpoint mode, which means they're trying to locate the exact location. And if you imagine, like in a world without any maps or like very limited maps, we would do exactly the same thing. If you're coming from, um, um, if you're coming to Princeton, the first thing that you have to do is you come to new Jersey, right? And there are specific highways to new Jersey. So you come to new Jersey. So you you travel over long distances in this very directed highways. Okay. And when you come to new Jersey, then the next question is Where's Princeton? Now you start to wander around until you find Princeton. And eventually when you come to Princeton, you transition into this pinpointing mode, and you're trying to locate molecular biology department. And I, I think is something of a very similar picture, could be true for sperm migration in the female reproductive tract in the first phase. Um, they're swimming progressively, which means the persistence length is very high. They're in the highway. So the only purpose is to migrate over long distances. And they will get when they, um, go inside the oviduct. Now, during the homing phase. Now the persistence length is much shorter because they're wandering around and doing all those sorts of, like, intermittent search strategies. And when they eventually become close or like a like like in a nearby area of of of the oocyte. They're trying to receive. Pinpointing signals from the oocyte so that they can locate it, um, with high precision.
So there's a kind of famous saying in random walk literature, uh, that, uh, a drunken man will always find his way home, but a drunken bird may be lost forever. And that refers to, uh, sort of a mathematical quirk of random walks that on two dimensions, meaning, uh, the model of the drunken man is he's, I guess, leaving the bar or something, and then, uh, walking down the city street and then deciding to go left, right, forward, backward. And you can calculate, uh, how often that person might stumble across a particular intersection or accidentally make it back to the bar or accidentally make it home. But when you make that problem, three dimensions. So imagine like, you know, taking those streets and expanding them into a big three dimensional lattice. There are many, many, many more points to visit now. And so it makes finding any given point much less likely to happen. Uh, do you think that's related to the tendency of sperm to track along surfaces? Yeah. Um, does that give them a search advantage? Yes.
I think that what you said was fantastic. I think reducing the dimensionality of search is a very powerful tool for biological systems to increase their chance of finding a target. But at the same time, I should tell the the environment of the female reproductive tract, especially in the oviduct. Some people may think it's three dimensional, but I don't think it's three two dimensional. I would call it like quasi two dimensional. Because one dimension is significantly much bigger than the other dimension. And that's why we need to use microfluidics to observe all these behaviors, because you have to have a control over height of the channels versus their area surface area.
The luminal fluid and the female reproductive tract is not necessarily the same as viscous or non-viscous culture, media or things, especially things that we often capacitate the sperm in actually for, for research studies. Um, what effect does viscosity. Well, let me let me ask this question. What are the differences between viscosity and visco elasticity? And how do each of those affect the way that sperm move?
So um, there are many reports in the literature that are somewhat contradictory, but in my experience, I realized that increasing the viscosity per se do not change sperm motion significantly, so maybe some swimming speed changes a little bit. And given the fact that we have like a very large variations between sperm cells, it's always difficult to decipher what's actually going on. But when you change the swimming media to viscoelastic, which is something mucus like, um, by adding this long chain, long chain polymers, what you would see is that indeed sperm motion hugely depends on their swimming media. Especially like the rheological properties of swimming media. For instance, I talked about, um, hyperactivation. So the very first question we had when I was in grad school, um, um, Hong Kong, um, in, in, in vet school, he asked me this very, very simple, but very, very intriguing question. And that was how are you going to quantify Hyperactivation. I said I don't know. And he said, because in clinics, the way we are characterizing hyperactivation quantifying it, it's not it's not a quantification. We just watch them. It's just very it's subjectively determined. And how are you going to quantify that? I had no answer for that. So I started to observe sperm cells for a long time in different swimming medias. And I realized that when the swimming media is viscous, um, very similar to the, to the standard medium, what you would see is sperm showing this display, this erratic behavior moving in random trajectories. And because I'm a physicist, I always look at this, these stochastic trajectories as random walks. And I did the analysis I extracted the trajectories and I realized that they're indeed random ones. But the way you can do that is that you can plot the mean square displacement and see if they transition from the ballistic to the diffusive behavior. And if you see that, it means that you have a random walk. And I was so excited and I said, wow, I found I now have um, a quantitative framework, i.e. random walk to describe Hyperactivation. But then later on I started to observe hyperactivation in visco elastic medium, and I realized that they're not showing the the random walk behavior anymore. They're swimming in tight circles depending upon the rheological properties of the media. They can show either random walk or the circling motion. And a year after that, I said, what happens if I watch sperm cell in a viscoelastic fluid for a very long time, let's say minutes or like twenty minutes. And in order to actually keep them in the same area, I had to make this microfluidic chambers so I could watch them for an extended extended period of time. And I realized that in viscoelastic fluid, they showed this behavior that I call circling and wandering. So they both both circling and wandering behavior with a stochastic switch between these two modes. So now I know that Hyperactivation shows itself in very different ways depending on the rheological properties of the media. If you have if your if your if your medium is viscous, then they're doing random walk. But if the media if the medium that you're observing them in is viscoelastic, half of them will display pure circling and the other half displays circling and wondering. And the question is which one of these behaviors are more relevant in the context of search processes, and and which one of these modes of hyperactivated motility is more suitable for for effective transport in scientists geometrically complex environment. So, to answer your question, yes, this elasticity is crucial. You have to make the fluid visco elastic and then um, do all the measurements you want.
Are typical devices that sperm are measured in, say for computer assisted sperm analysis or semen analysis. Do you think those are the right kind of way to measure sperm?
I don't I don't know if I should say this, maybe cut it later, but I hate those measurements because they don't mean anything. So if you actually keep doing measurement in different channels with different rates, you would measure different things. I did all these experiments the same speed. Everything would change significantly, even persistent length. So you have to be very careful, like what conditions you are using to, to, to make all these measurements. So in fact, I'm, I really want to talk to people like outside this field of physics and reproductive biology. So like people who are interested to turning all all these fundamental studies we are doing into practical applications. I'm actively looking for people who can help me in this regard, because I believe all these measurements that we are doing using microfluidics and other control behavior should be they should they will actually revolutionize the world of reproductive medicine, because now we can we can have actual biomarkers to assess male and female infertility. So it's not just about male. It's also about capacity of fluid coming from female to induce hyperactivation. And then see if the circling and wandering behavior, all these random processes we talk about if they exist or not, if a sperm is not is is not capable of doing all these random walks, then what will be the chance of fertility? Very low. So I think we can in the future come up with ideas to revolutionize assisted reproductive technologies for sure.
Do we track them long enough?
No. People actually use this automated tracking stuff, um, which is subject to significant errors. And when you increase the time of observing them, the errors become much more significant, and there's no way that you can overcome that. So there are multiple things that we should be very careful in the future. First, we should observe sperm cells for a long enough time. Order of minutes, several minutes like thirty minutes to see what's going on. And then we should come up with ideas to track them in a very efficient way. Like a very precise way. As I said, the circling and wondering, sperm circling and wondering, does it serve? I have to observe sperm cells for like twenty minutes to observe this behavior. So if you watch them for like 20s, you're not going to see any changes. But if you wait and be patient long enough, you will see that they switch between different modes of motility.
So it sounds like there's kind of an intrinsic movement behavior that sperm will experience by just kind of actively propelling themselves and then kind of running into different things in the environment. And then there's also external information, maybe in the form of chemical or biochemical signaling pathways or fluid flows that can also influence maybe kind of fine tune the, the timing or the direction that they move. Um, how do you think those two things work together? Maybe both in a kind of biological and physical context.
The chemical signal and also the fluid flow.
Yeah. Well, okay. Let me let me clarify what I mean there. I guess I think sperm can maybe do sort of complicated things without really having to actively get information from the environment. Or they can also get information from the environment through cell signaling. What are they capable of doing without cell signaling. And then what does cell signaling add to their capabilities?
I think it's really difficult to separate these two forms of information. But as far as I know, and I understand from the physical perspective, the response to the fluid flow is just that. It's just a physical phenomenon. We don't actually need cell signaling for that. And also every swimmer that that that swims is a constant velocity at that scale when it encounters a boundary. The boundary can rectify its swimming direction and and direct its swimming direction. That is the physical part. But the chemistry part, the biochemical pathway, as you said, it's to me, I only think about it in the context of Hyperactivation. I know Capacitation has many different aspects, and it's crucial for fertilization. But I only think about it in the context of like hyperactivation, where I know the swimming pattern changes and even the transition from progressive motility to hyperactivated motility changes all these physical behaviors that I just described. So basically, at some level, when they're not hyperactivated physical cues like the rheological properties of the swimming media, um, the boundaries, the fluid flow, the direct sperm motion in a certain way. But as a sperm gradually undergoes hyperactivation, all these physical cues influences for motion in a much different way.
I think that's a really good segue into selection. I know you've done some work on that. Monitoring them longer may help, because I don't know if there are things that that that become clear unless you monitor them for a while. But I guess. Can you talk a little bit about selection? Yes.
Um, so I think there are several important things that we have to select for. The first thing is that when they're activated, when they're not hyper activated, you have to select for progressive motility. And at the same time, sperm capacity or sperm ability to respond to fluid flows. Do they perform this upstream motion behavior that has been reported in several papers? Um, that is number one. And number two, is that what happens when when you add some hyperactivation agonist. Do they hyperactivate. And if they do, what kind of hyperactivation hyperactivated motility you would observe in them. Are they doing just random walk. Do they circle or do they circle in wonder? I think we should select for circling and wondering. And the reason I have for that is because we did some simulations, and we have realized that when they are performing, exhibiting the circling and wandering motion, they can effectively migrate in complex geometries very similar to the environment of the female reproductive system, especially in the oviduct, which is geometrically complex. So I think that's that's what we should select for.
Do you think that because that kind of behavior has kind of a high level competence. Is that what's under selection in natural fertilization that it takes multiple different things to be able to do that kind of a complex behavior?
Yes, one hundred percent. In fact, we do have a I have a patent right now about the circling and wandering, and I'm thinking about, like commercialization in the future and how we can build devices to select for those sperm cells. And, you know, like the transition between we actually don't know how they transition between these two states, like what drives this transition. It could be something fluid, mechanical. But I think maybe, maybe the transition between circling and wandering could be somehow relevant to sperm centriole. Because we know for wandering behavior, sperm head needs to be tilted with respect to the flagellar beating plane. And if the head is not tilted, which means that the dynamic basal complex is not flexible enough, they do not have mechanosensation. And that's why they do not switch between behaviors and the viscoelastic fluid. So observing, circling, and wandering is relevant to, uh, to flexibility of dynamic basal complex. Which could somehow be relevant to to Centriole. And there are actually reports in the literature saying that there's this huge possibility that many unexplained infertility are due to centrioles, but that's just wild speculation. I do not have any evidence for any of these claims.
You've studied search and sperm, and now you're working on microtubules and how microtubules assemble and bounded environments. And I realized that this is getting a little bit away from the the reproductive science. But this is relevant to the listeners, I promise. I'm interested in that idea that there's a through line between these two things, that sperm are active matter that will fill the space that they're in. And it seems like microtubules also do something similar. So do you also think there's a through line there?
Yes, absolutely. So here's the thing. When I wanted to do my postdoc, I said, I'm going to work on something different to diversify my level of expertise, my expertise in different things. But after a while, I started to appreciate the similarities between these two systems. For instance, one of the one of the key questions I'm working on right now is that how emergent properties in microtubule networks are coming from this simple interaction between microtubule themselves and the motor proteins that drives this self-organization, and this diverse form of microtubule architecture in different systems. But now, one question about Hyperactivation is that when you induce hyperactivation, a simple thing actually changes. And that's the asymmetry in the beating pattern. So as you induce hyperactivation, the flagellar beating pattern becomes highly asymmetric. But how. So we know that the sperm cells have this this array of microtubules inside their tail and their dyneins flagellar dyneins actively bending this, this microtubules inside that architecture. But but but how they can actually make it asymmetric. It requires a highly advanced level of coordination between dynein arms and microtubules, so that some molecular interaction can lead to emergence of this asymmetric flagellar beating pattern. So the way I see similarity is that how molecular interaction can give rise to a biological phenomenon that is crucial for their function. So indeed, this this work that I'm doing on microtubules is how we can control this simple interaction to build cellular structures and how we can use it for. For nanotechnology.
So it sounds like one of the measures of success from from your point of view. And maybe this is because you've worked in a materials science background, is being able to create materials that behave in biological ways.
Absolutely. It's it's not just me. Many, many engineers and physicists are now trying to think about biology and come up with solutions for for practical applications, and they call it bioinspired technologies and materials. So you know that there is this field of active materials, and people are trying to harness the power of molecular motors and microtubules, or people working on DNA origami. So, so that they can come up with ideas for, for new materials at nanoscale, uh, with the capacity of of doing a task at that scale. So biology is also a source of inspiration for for physicists and engineers to come up with solutions. But yeah, looking at a biological system from materials perspective is, is is very, very intriguing. And it's not just about materials. It's also about, I don't know, robots. We can also think about robots building like microswimmers or like synthetic, um, agents that can do like an elevated form of optimization or computation, as you described it. Right? It has its own technical, um, difficulties. I know how it's hard to fabricate materials. Um, but for instance, the most, I think established method, like most established framework for like bioinspired materials at that scale would be this metal surfaces with cilia on it. So they have this metal surface so that they can actuate this artificial cilia with electromagnetic waves. Um, and they can claim that it's a, it's a surface that that acts like this ciliary surface, for instance, in the oviduct that is responsible for transporting the oocyte.
I know some of the things that I've seen at that scale, robots and things like microswimmers require sort of a top down control, like you're applying an electric field or you're using magnetism or something. Do you think in the near future we'll see self propelling particles that do more complicated things?
Yes. So that is actually a very remarkable question. I the answer is I don't know, but I, I can tell you something about the world of microtubules that I'm working on. So there is actually this top down approach. So you can use external fields, external light electric fields, whatever magnetic field to to control the behavior of agents at this nano and micro scale. But at the same time we can we can use the, the, the intrinsic properties of these materials, which is the ability to self-organize. So what if I can, um, build a surface or build a microfluidic chip and I use a cell free system like Xenopus egg extract that I'm using right now, and add a bunch of proteins like, um, recombinant proteins to mimic some aspect of the cell cycle and induce a pattern formation in them like a motion, so that I can later on use this self-organized emergent motion for useful purpose. So it doesn't have to be always top down. Sometimes you try to Um, borrow some tools from the cells toolkit and try to use that for, um, for engineering and building new technologies and materials. It doesn't have to be always top down. We would be very smart if we come up with solutions so that we can use cells, but not the entire cell like some part of it, and then try to activate it artificially.
It seems like there's a common thread there as well that you have, you know, in sperm, in a reproductive tract or in, in any environment, they will move away from their initial position and then they will run into boundaries depending on the shapes of the boundaries. They get channeled. And it seems that microtubules also do something similar. So even though those are two completely different processes, that two completely different scales. Do you think search is fundamental to biology and maybe physics more broadly.
So here's the thing you ask a question about, like on a scale of stupid as a rock to like, human brain, how do you rate sperm cells? And I said, they're better than a rock. So what if I ask the exact same question about microtubules? So I think you would agree that they're closer to rock than sperm cells are to rock, right? It shouldn't be as smart. Smart as smart as sperm cells because they're molecules. So basically the the collective behavior at molecular scale builds emergence of intelligence in in a higher scale. So basically you build up, you come from microtubules, build sperm cells or other different type of cells. And these cells actually collectively build tissue. And these tissues collectively build an organ. And this organ builds up an animal. Right. So this hierarchy, as you actually move from I'm not working on complex brain. I don't work on brain, I don't work on animal. I work on like this. This limit of intelligence at molecular and cellular scale. I'm working on this. And and as you said, the fundamental question is like how search processes change as you move toward less intelligent systems. So how how bacteria or how sperm cells search for something. And you can ask the same question how how microtubules actually search for boundaries so that they can coordinate their self-organization according to those boundaries. That's a very that's a very smart question. So if I ask the same question about Iraq, you would say. They don't search for anything, right? But. But how come microtubules can build a spindle? It's a it's a very complicated architecture. We can't do that in vitro. It's very hard to reconstruct the spindle machinery. So, so the idea of of intelligence and emergence are somehow entangled to each other. So small items, small molecules start to interact with each other, and they form a, another system with a higher level of complexity. And hence a more sophisticated search for much more sophisticated tasks. So, so when when looking at looking at the problem through this lens, microtubules and sperm cells, they both should respond to boundary and coordinate their behavior accordingly. sperm cells are doing like a very complicated form of navigation in response to the boundaries. But microtubules, they self-organize differently by changing the kinetics of their reaction. That's how they do it.
How was your experience been working at the boundary between physics and biology, especially communicating between the two? I know physicists are interested in their own thing. Sometimes biologists are interested in their own things and they don't necessarily do things the same way.
It is really, really I'm saying it from from the deepest part of my heart. It's really exciting. Interacting with biologists and physicists are remarkable. Both communities are fantastic, very smart people working on very, very beautiful. And both physics and biology, as it's evident by the rich history of interaction between physics and biology. There are tons of opportunities of gluing ideas from physics and biology, but it's really, really hard. So you have to be very patient and develop a thick skin because the mindsets are different, even though they're passionate about collaborating. The language and the kind of framework they're looking at, the problem is different. So every postdoc or grad student or a faculty who want to actually bridge ideas between physics and biology, they should interact with both physics physicists and biologists. But at the same time, I think they should be very careful. Yeah, there are other like, problems, I don't know, challenges associated with these things. For instance, um, sometimes people may find your ideas not interesting. Maybe your ideas are not interesting, but maybe that person is also wrong because they don't look at the problem the way you are looking at it. And for a grad student, unlike for a postdoc, it's a it's a challenging phase to convince everyone that I'm right. This this idea is worth it. And it consumes a lot of energy because you actually belong to two communities and you have to talk to two communities. It's like having two advisors, right? It's always hard. You have to work really, really hard. You have to be patient. But the reward is so big because the questions are interesting. The way you're looking at them is interesting. And at the end, both failed will have respect for you.
What do you think the biggest thing or the best thing that each add to each other might be? Like what does biology bring to physics and what does physics bring to It's a biology.
So I think biology brings remarkable questions to physics, and physics provides remarkable tools and ideas to understand biological systems. It's so amazing that how a biologist can can work with this complicated systems, and the way biologists can manipulate these systems and have control over, like, all different elements of biological system. That's remarkable. And every physicist would love to work with a biologist. And at the same time, there are qualitative descriptions in biology that a physicist can help to quantify them. And at the same time, there are tools that we can provide, um, and make connection between biological findings and their purpose.
Is there something about biology that physicists like that kept physicists away? I mean, I know physicists have for a while been tackling biological problems, and some of them in really influential ways. You know, thinking back to Schrodinger even. Right.
Of course. Yeah, yeah. What is life? Right?
Yeah.
Um, so in general, I don't know how to answer your question, like in the best way possible, but like, in general, the way I see the the world of biological physics right now is that there are two different types of attempts in understanding biological systems. One is this through the lens of emergence. So basically the idea is how this simple interactions at microscopy at microscopic scale can lead to emergence of of of behaviors and patterns that are meaningful, um, for, for specific biological functions. Um, which is very interesting. Um, especially like I'm working on microtubule right now. And the question is like how simple interaction of microtubule with the neighbors through nucleation of microtubules or through like some molecular motor complexes, how this lead to something as complicated as the spindle. Right. And this is not just the question we have in biology. We have a rich tradition of condensed matter physics. And people did a lot of effort to understand how a group of electrons or like whatever particles can form collective states, um, which they called quasi particles, how how can they form this collective states? Um, and how these collective states can be used to understand the properties of material. But now we are using a very similar approach to understand biological systems, um, through this and and There's this remarkable opportunity to learn how how merchant mechanics, for instance, um, can help a biological system to do a specific task. But another theme that I keep seeing is this, this, this framework of optimization. Okay. We know what drives a biological behavior. For instance, we know what drives let's say we know all the molecules that are responsible for, um, inducing hyperactivation. It could be anything, right? There are tons of ways like thermotaxis chemicals, metabolic pathways. But how hyperactivation can lead to a better search. That is where physics can help, right? Um, and how how this behavior leads, um, the higher order of of of of optimization. Other than these two themes, there are also tons of like tool development. Um, like an optics or, I don't know, different kind of microfluidic systems, optofluidic systems that help understanding the system with much, much more precision. Because when when there are no numbers or like Quantifications, it's really hard to understand. This is this is my interpretation of the world. I don't understand the world when I don't see numbers. Maybe that's my problem, but I think it's, uh, it's it's kind of a problem that most physicists are interested in. Just put numbers first and then try to think how to interpret those numbers.
Do you think it's challenging to find optimization in biological systems from a point of view of analysis, because it seems like biological systems optimize on a lot of things at once?
Yeah, that is the big challenge. That is the grand challenge. Because, you know, when we think about, like, sperm finding an egg, the problem is well defined. So we have one sperm cell that is trying to find an oocyte. So we can somehow find an optimal solution for this problem under some specific conditions. But when you think about sexual selection or let's say post-copulatory sexual selection, the question becomes much more harder because now you have two individuals, two males that are competing. And when we think about two males, we should also think about society. So if one sperm coming from one individual is very successful in finding the oocyte, let's say it's optimal, then what about other males. So there's always this component of trade off that start to emerge at different levels. So, so having a system like a mathematical system or like, I don't know, any logical system that can show all these hierarchies working at the same time and trying to solve a question in an optimized way. It becomes super complicated. And I've never seen someone doing something like that. So we'll always try to to find solution like locally. But we can't argue about this global optimization. Never like this is good for that purpose. That's it. That's all the claim we can we can do.
What counts as a satisfying explanation for how a biological system works for you. Coming from a physics background.
If we can write a good comprehensive mathematical equation for that, that's it. That's the end of the story. If we can write out math for it, it means that we understand it. That's good. That's very satisfying. Which is actually hard. So you have to have a lot of experimental data before writing out an actual mathematical description. Of course, you can propose models. But the question is are people convinced with your model? So if you write a mathematical description of a biological system and the community accept it, and you convince everyone, it means that you have enough data, enough experimental data to validate all these hypotheses and validate this mathematical expression. And by the way, I'm an experimentalist. I'm an experimental physicist. Even though I talked about this mathematical descriptions, it doesn't it. Even though you need to work with like theorists to come up with theoretical ideas like every mathematical equation have decades of experimental work behind. So it's not just a theory, it's it's meaningful physics. So what I said is not just about like, they're looking for math. They're looking for theories. No, we're we are looking for theories supported by experimental evidence.
Yeah, I totally agree with that. Um, well, unfortunately, we've reached our time limit for today's show, so I just want to say that this has been a really, really fascinating conversation with you, Meysam. And I really appreciate you joining us today on the Future Conceived.
Sure. Absolutely. Thank you for having me.
Well, listeners, that officially wraps up our first three part mini series on the mechanism of sperm capacitation. Stay tuned for our next mini series as we shift our focus toward the egg and the key events that activate embryonic development. This podcast was sponsored by PSERs. Virtual Education Committee, whose mission is to develop virtual programs that aid in education, highlight the lives and careers of society members, and bring updates on the latest scientific advancements in reproductive biology. If you're not a member of SSR, now is the perfect time to join this incredible network of researchers and professionals in shaping the future of reproductive science. For more information, please check out our website at. If you enjoyed this discussion, please like and subscribe wherever you get your podcasts and join us for our next episode in this series, when we learn from Doctor Mariana Wolfner of Cornell University about egg activation in fruit flies. Until next time.