>> Amy Draves: Thank you for coming, especially today. We really appreciate that. I name is Amy Draves and I'm here to introduce Peter Hoffman who is joining us as part of the Microsoft Research visiting speaker series. Peter is here today to discuss his book Life’s Ratchet, How Molecular Machines Extract Order from Chaos. Science tells us that living beings are merely sophisticated structures of lifeless molecules, yet life emerges when the random motions of atoms are harnessed into ordered activity by molecular machines in our cells. Peter Hoffman is a professor of physics and associate Dean at Wayne State University in Michigan and the founder and director of the University's biomedical physics program. Please join me in giving him a very warm welcome. [applause] >> Peter M. Hoffmann: Thank you. Can you hear me? It's working? Okay, great. Thanks very much for coming. This is only my second time in Seattle. The last time was 17 years ago, so it's been a while. As you can tell from my accent I am from Germany originally but I came to this country 20 years ago to do my graduate studies and ended up in the end at Wayne State University as professor of physics. And today I want to talk you about my first book, which interestingly is about biology which I took the last formal class in 11th grade, you know, so that's a bit strange. Physicist typically are little bit repelled by biology because we think of it as some kind of vast collection of things to memorize or something like that which physicists don't like. We like everything to be reducible to some simple principles. So for a long time I didn't pay that much attention to biology either, but I started reading about evolution and found it pretty interesting. Then some years ago, just by chance, I inherited a research collaboration. I do research using a technique called atomic force microscopy and somebody asked me if I could study proteins, single molecules with that, and so I started doing that and a couple years later I started an undergraduate program in biomedical physics. I started teaching my first biophysics course for that. I had read up on all of those things and I learned actually that we already do know how physics can explain how life works, at least on a very fundamental level. I realized there was no book that actually brought that knowledge to the greater public, so I decided to write one, so four years later [laughter] I'm here to talk you about it. The first thing I have to put out is a disclaimer. This comes from Erwin Schrodinger which is one of the founders of quantum mechanics and he wrote a little book in 1945, in 1940 I think, What Is Life? So he was one of the first physicists to venture into the realm of biology and just to excuse himself for venturing into someone else's turf, he said "a scientist is supposed to have a complete and thorough knowledge, at first hand, of some subjects and therefore is usually expected not to talk about topics of which he is not a master. This is regarded as a matter of noblesse oblige. For the present purpose I beg to renounce noblesse, if any, and to be freed of the ensuing obligation." So I want to say the same thing. I'm going to talk about biology but remember I am a physicist. And here then is the challenge that I want to talk about and that the book is about, and this goes really back to, everything goes back to the ancient Greeks, I suppose. But it didn't take an ancient Greek to talk about it 2000 years later. Here is Immanuel Kant and he said, "that crude matter should have originally formed itself according to mechanical laws, that life should have sprung from the nature of what is lifeless, that matter should have been able to dispose itself into the form of a self maintaining purposiveness,” which is a tough word to say actually, “that is contradictory to reason." So what I'm going to talk about is how can matter that that I study as a physicist as a material scientist which is made of atoms that are randomly swirling around, how can that create something like me that is walking around and talking like you that are listening and understanding what I'm saying. How can that even fundamentally be possible and then we are going to go to the bottom of how it could work. So here's something living, taken out of the front window of my house and this something is looking for food, manipulating food, eating food, paying attention to its surroundings. So we asked the question like throughout this book what is life? And really it's a difficult question to answer, what is life because when you ask the question what is life we actually think of life as some thing that is added to something to make it a life, right? And that's really the problem in philosophy; it is always like what is life, but life is really not a thing. Life is a process, so really the question we should ask is what do we mean when we say an object is a life or living? And there are many definitions of that. You can go to Wikipedia or your favorite encyclopedia; this is kind of what I came up with, living things are self-contained entities with some kind of purposeful directed motion, regulated self renewal and high complexity. I want to focus on the purposeful directed motion and purpose, I don't mean like what's the meaning of life. I I'm not going to answer that question today; I'm sorry. If you came for that, sorry. What I mean with that is that everything in the body has a purpose. The molecules in your cells have a certain purpose to do certain things. Your liver has the purpose of cleaning up your blood or something. Your brain has the purpose of thinking, I suppose. Things like that, so how does that set purpose come from? And everything in your cells has some direction to do things in a certain way. They don't randomly go back and forth and that's the question we want to answer. So where does this purpose then begin? We go to atoms, and these are atoms of silicon to molecules to organelles to cells to organisms; that's our dark shadow by the way. Where on this continuum does this purpose arise? One answer people have given is that they have postulated that there is some extra ingredient somewhere along this continuum that turns these lifeless molecules, random molecules into something that has a purpose and they have called this thing by various things, but a lot of times they call it the life force. So this is something like a life force there, something that we add like dash of life force to a bunch of molecules and then they make a living being. And this question is pretty old. I'm not going to go through the whole history of it right now, so I'm just going to jump in increments of 2000 years. But let's just start at the beginning because I do want to come back to this fellow here. Democritus, we all know, is the guy who came up the idea of atoms and he said something interesting. He said "everything is the fruit of chance and necessity." Another fellow Aristotle didn't like that and he said "Democritus says that atoms owing to their ceaseless motions produced the bodies motions … it is not in this way that the soul appears to originate motion in animals -- it is through intention or process of thinking." So for him it was the idea that everything is sort of top-down. We got the soul which produced the thinking and the thinking controls how the atoms and molecules move. Whereas, for Democritus it was from the bottom-up. We've got the molecules and they follow the laws of chance and necessity and somehow this builds up to everything else. So who is right? This back-and-forth really has continued through thousands of years and the reason that it wasn't really resolved for a long time is because we simply didn't have the tools to figure it out. So fast-forward 2100 years and the first real scientific proof that something like a life force may not actually be there came through the law of the conservation of energy, because if there were something like a life force it would be something that adds energy at some point. But we know that all of the food we eat and the activity that we do and the heat that we radiate follows a very tight balance sheet. Whatever we take in is what we get out. And actually the whole idea of conservation of energy came to defeat the idea of the life force. If you actually go back and you read Hermann von Helmholtz and Julius Robert von Mayer which were the German physicists that figured that the general law of conservation of energy out, they specifically say if there was a life force it would allow for the possibility of a perpetual motion machine because it would add some energy out of nowhere that just is not there. And of course the complexity part I want to mention is on the side of mechanism, of course, we have Darwin and Wallace which explained that part also. So that's where we are today then. Modern science is pretty heavily on the side of mechanism, but that doesn't mean that the life force is really dead. It really survives in the popular imagination. Here is a quote that I took out of a film that was made in conjunction with the book The Secret, you may have heard of, from the books sold. I mean, I wish I could just sell a 10th of those books. I would be retiring now probably. Here's what this person said, "human beings are an incredible source of power and could use the power in their body to illuminate a whole city for nearly a week." So supposedly there is this like this untapped Energy source inside of us that if you just tap into it you could illuminate a whole city for a whole week. Well if you apply the laws of energy conversation, how many light bulbs could one human being really light up? One [laughter]. So the power that the human being runs off of is about 100 watts. That's kind of the baseline power, which is actually kind of amazing when you think about all of the things that we do. I mean a light bulb is pretty boring. They just get hot, shine a bit of light and that's it. We do a lot of stuff on 100 watts, but we definitely can't light up like whole city. So there is no life force, but that still doesn't really help us because we still have to explain where does this purpose originate from those random motions of the atoms? And so the history of science then is a history of reductionism. It's looking at smaller and smaller pieces from the early books on anatomy to the discovery of cells by Robert Hook, the cell theory in the 1800s, the x-ray picture here of Roseland Franklin of DNA which let for Crick and Watson figure out the DNA structure. Here's Perutz and Kendrew Nobel prize winners figuring out the structure of proteins to modern times when we use atomic force microscopes to -- this is a 10 nanometer bar here to get pictures of proteins at the scale of one or two nanometers. So we have looked to smaller and smaller scales, but the question is have we found the answer as we look to these smaller and smaller scales? You probably are going to expect a no. We keep looking and there is nothing there. Well, not really. We did find the answer and it did happen to be at the nanometer scale. Just real quick, you all know what a nanometer is. But it's always nice to just get a feel for what it is. Nanometer is 100,000th the width of a human hair. A nanometer to the size of human is the same as a human to 10 times the distance from the Earth to the sun. A nanometer is so small if you are shrunk to the size of a nanometer it would take you 82 years to walk the length of a human being, of a full-sized human being. So that's kind of, and yet as you can see our bodies are filled with trillions of little machines that walk around all the time. As a matter fact, when I lift my arm there are just thousands, trillions, millions of machines pulling little ropes and pulling up my arm. And they are of this size, of ten hundred nanometers. They are constructed like all biomolecules as polymers. They are constructed as little units that are strung together and by the laws of physics fold into intricate shapes. This happens to be a protein that I work on and this is the basic idea. You have units and a protein which most of the molecular machines are made of proteins. Not all of them, some are made of RNA. They are units that are strung together per instructions in the DNA but then physical laws make them fold into certain shapes depending if some of the site groups here like water or hate water or whatever. To study these things one of the techniques -- there are many techniques. I'm just going to talk about one. There are many things that people use fluorescence microscopy, laser tweezers, and I talk about all of those in my book. The one I use in my lab; this is how and [inaudible] lab would be built. Its home built as we say. People think I built it in my home, but that's [laughter] it's built in the lab. But the basic idea is to have a sharp tip that can interact with a surface. You can scan that tip over the surface just like an oldfashioned record player where you have a needle scanning your record and the forces between that tip and the surface can then create an image of the surface and if the tip is sharp enough you can create images as fine as atoms. Each [inaudible] is a silicon atom. You can even see atoms in the second row and in a third row below. This is an AFM in my lab that can actually do an image like this. This is an AFM that works for biology because it has a liquid cell. You can also measure forces between molecules. You can attach molecules to the tip. You can attach molecules to the surface. You can put a cell on here and probe a cell. You can do all kinds of neat things with this. I'm a little bit envious, but there is a professor at Kanazawa University in Japan who built basically the fastest of these AMFs ever built. Typically when you are trying to get an image in an AFM you gotta have a lot of patience. When I was a graduate student I would sit for hours in front of the screen just seeing these little images come up, and then they wouldn't look any good and then I would do it again and then, you know, it would take me two years to get any decent images that I can actually publish and it was pretty painful. These people spent six years to build this AFM. This can create an image in 100 milliseconds and that is amazing because they are trying to scan biomolecules which are very fragile and you have a hard tip and if you do it too fast and didn't regulate the distance between that tip and the surface it would just shred everything, right? It would just go like this and just shred everything. This has very, very fast electronics so it can scan within 100 milliseconds this whole picture. This whole picture is 100 x 100 nanometers. What are we looking at? We are looking at, which I may call a road, a molecular road. This is a molecule called actin. It's what we call a track. And this thing here that looks like a tripod I want you to really keep attention to that one. This is a molecular machine. You can find this on, okay, keep watching it. It made a step. Here's another one. Saw that? I mean let's just play it one more time. It's like a little walking man that is 50 nanometers high. These things are in your cells right now. There are trillions of them in your cells moving cargo around. Typically there is cargo attached on the top moving them in a fixed direction. They don't go back and forth randomly. Some of them move only from the center of the cell to the cell membrane. Some of them move only from the cell membrane to the center of the cells. Some are specialized to pull DNA apart when the cell separates. There's some in your ears that attach tension in some of the structures in your ears so you can hear better. They do all kinds of stuff. All of these little machines running around in yourselves doing these kinds of things. So what makes them move first of all? When you see a molecule and it moves, what makes them move? I mean it seems weird, right? Well, actually what makes them move interestingly as a first order. I mean, we will see that that's not the whole answer, is simply the noise, the randomness in our cells. Our bodies are 37°C, roughly 98°F or something like that and that means, temperature means that your molecules in your body move at a certain speed. If you make it hotter they move it higher average speed, right? Every biomolecule, the one you just saw, collides 10 to 13 times a second with water molecules. It's bombarded by water molecules. These collisions provide 10 to the eight, that's 10 million times more energy to this molecule than the molecule itself actually generates. Now of course it's completely random, so on average it wouldn't move the molecule anywhere. It would be like, it would translate to a microscopic situation it would be like you are trying to drive a car through 70,000 mph wind. Of course that wind would change direction 10 to 13 times per second. [laughter]. So that's actually what makes everything dynamic, everything moving in yourselves, but of course, that cannot generate any directed motion clearly, right? And it comes down to a famous law of thermodynamics which you all have heard of and here are Morpheus and Neo kind of given us an introduction to it from the matrix. You probably have seen this movie, right? Here is Morpheus explaining to Neo that the machines, these are the molecular machines. These are big machines that control humans and the matrix. Discovered a new form of fusion. "All that was required to initiate the reaction was a small electric charge. The human body generates more bio electricity than 120 volt battery and over 25,000 BTUs of body heat. We are as an energy source, easily renewable and completely recyclable. The dead liquefied and fed intravenously to the living." Neo, "no! I don't believe it! It's not possible!" At least Neo paid attention in physics class. [laughter]. I could go on; every line has some nonsense that doesn't make any sense. But the main one is that humans are an energy source and that they are easily renewable; that doesn't make sense. That could mean humans make energy out of nothing. We are not an energy source. We are an energy sink if anything. And it comes down to the second law of thermodynamics which may have heard of and this concept of entropy. And here is just a simple summarizing of the second law, there can be no process whose only result is to convert high entropy, which is randomly distributed, energy into low entropy which means simply distributed or concentrated energy. So if you liquefy a human or something that's pretty simply randomly distributed energy. That's not much content in it anymore. You feed it to another human, you know, they radiate heat, but they don't really generate energy because heat itself is a random type of energy, so you can't generate an ordered energy out of this without having another input of more ordered energy. It's just like refrigerator. Your refrigerator actually does lower entropy and your ice cream has lower entropy than your melted ice cream, your frozen ice cream has, but it does that by taking an enormous amount of low entropy energy out of your socket and heating up your kitchen. That's why you can't cool your room down by leaving the refrigerator door open, right? So this would never work. Well, so how do the molecular machines work? They clearly take random energy and turn it into directed energy. And I just told you that they are animated by the molecular storm of the random energy, but how do they not violate the second law? Maybe they do use this special fairy dust or something, right? Well, let's ask this guy. Well, not that guy on the left. You know who that is. The guy on the right. That is Sir Arthur Stanley Eddington who was the first to do an experiment to actually prove general relativity by seeing the bending of the light around the sun, but he said something else which is a quite famous quote. "If your theory is found to be against the second law of thermodynamics, I can give you no hope. There is nothing for it but to collapse in deep humiliation." So when somebody is called Sir, you should take very seriously what he has to say. This brings us to this little critter here. This problem about violating the second law left all kinds of what we call in German the Duncan experiments, meaning fraud experiments. And one of those famous ones is Maxwell's Demon. And the idea was that well, maybe we can come up with a situation where disordered energy can turn into ordered energy without violating any second law of thermodynamics. So what's the situation? We created a little nanometer sized demon which controls a little trapdoor. And we have gas on both sides which have some fast molecules, hot molecules and some slow molecules, cold molecules. And he opens the door just to let the hot molecules into the left chamber and the cold molecules into the right chamber. And when he does that for a while this is what we get. We get all of the hot molecules over here that move fast and the slow molecules over there. Well now he has created the random situation and he has ordered it. Now we can actually take this and just stick a little turbine in there and the hot molecules are going to want to go back in here and they drive the turbine and I can extract energy from this. So where is the problem? Why does this not violate the second law? This is actually created lots of headaches for physicists. Of course, you could say well, he has a demon here to open doors and he has to maybe think and measure and maybe one of those things, you know, needs some extra, creates entropy basically. Well, we can automate the Demon. To get away from this little creature and we just create a ratchet, a little machine that can do the same thing and this comes down to Richard Feynman, actually goes back to a fellow called Smoluchowski in the beginning of the 1900s and Richard Feynman picked it up in his Feynman lectures to illustrate the second law of thermodynamics. And he said like well, let's assume we have a ratchet that is like a wheel with asymmetric teeth and a pawl with a spring and we have the water molecules falling around it the just hit this wheel and the wheel kind of randomly turns back and forth but because this pawl is there it really can only move counterclockwise. It cannot go counterclockwise because there is too much of a steep incline here, so we could actually make this little ratchet and it would only turn one direction and it would take energy out of the heat bath, turn into ordered energy we will be all done. That's how our molecular machines work. Well, wait a minute. You’re violating the second law here completely. That can't be. So what he actually did he studied a little bit more detail and he showed that wait a minute. The pawl itself is also going to be hit by water molecules. It's also going to get just as hot as the wheel, and it's going to randomly open and close and it's going to do that just enough that it sometimes will allow the wheel to rotate in a clockwise direction. And it's even more likely to rotate in a clockwise direction because the pawl is already kind of bunched up to this edge, so if it opens it doesn't have far to go to end up over here and then I will just push down and turn the wheel that way. And you can do the bands of equation. What's the probability for to go clockwise and how far counterclockwise and you can show mathematically without a doubt that no matter how tough you make the spring up here it will just would go back and forth randomly and it will never make any headway in any direction. It does not work. It's a very nice demonstration of the second law of thermodynamics. Still, there's something to this asymmetry there and so we want to keep that in mind. We want to keep in mind we have the molecular, random molecular motion. We have asymmetry there. How can we make it work? So to figure that out we're going to enlist the help of another legendary figure, Sisyphus which was this fellow who was King of Corinth which was forced by the gods to roll a boulder up a steep hill and as soon as he would make it up hill he would, the boulder would roll back down again and he would do it all over again. So it's kind of like doing, going to work. So he's trying and trying and oh, it's really heavy and it's no fun. So he made a request to the gods. This is not in your usual Greek mythology, but I'm telling you that this is what happened. He asked them just shrink me down to the nanoscale, okay? So they granted his wish and here he is at the nanoscale. It seems like the same problem as before, but now this boulder gets hit by random motions of molecules biggest around. He gets an idea. Well, let's them wiggle. If it wiggles uphill, I'll just step right behind it and keep it from falling back down. If I let it wiggle up I step right behind it. I keep doing that and finally I can drink a beer. So this is the way to go. You let the molecular storm do the work but you have to reset the situation by always keeping the distance the same behind it, so it has to be like what you would call a reset step. It turns out that even when they analyzed over many years Maxwell's demon a little bit more and this was maybe interesting especially talking here, was that the energy again comes from a reset step but Maxwell's demon the reset step is that he forgets his previous measurement. It's in erasing of his memory that we need energy, so if you can ever build a computer built out of superconducting wire that doesn't dissipate any energy, with perfect transistors that don't have any impurities in them and all of that other kind of stuff, it's still going to cost energy as soon as you erase memory. And you always have to erase memory to make place for a new measurement. So it's this reset step that makes it work. How does it work with a ratchet? Again, reset step. Whoops. So we have a ratchet. What would be the reset step? Well let's from time to time weaken the spring or take the spring out. Sounds weird. And then we put the spring back in. We never take it out. Why would that make it work? Well, let's think about it for a moment. Right now as the spring pushes down the pawl here spends most of its time right on the edge of this tooth. It's a further distance to go to the tooth to the right. Well, if you weaken the spring it's more likely, not always happening, just a probability that the wheel will just happen to turn this way. When the spring’s put back in it will push on this incline and push it back down and turn it even more that way. If you add it all up, probability, actually take the spring out, put it back in, take it out you can actually calculate that on average it will turn clockwise, which is actually opposite of what you thought it worked like. Right? Because we were hoping it was going to go counterclockwise. Again, it's this reset step. We actually in a sense erased the memory of where the pawl was located for a moment and then do another measurement and then that -- so this kind of this interesting connection between how this works and information theory. Of course we need energy to do this, so Sisyphus needs energy to step behind the boulder. Maxwell's demon needs energy to forget. We need energy to take the spring out and put it back in, and all it says is that energy is provided by this molecule called ATP, adenosine triphosphate which is basically from breaking down our food it goes through these things called mitochondria which I'm not going to go into detail because we don't have time. But this is how our energy currency and by splitting off one of these phosphate groups it releases quite a bit of energy and turns it into ATP, so just remember that because we need that in a moment. Energy is the other key that we need, and there's an interesting thing about energy in the nanoscale. This is a plot we took out from Physics Today. It's one of -- really, I love this plot, what these people did is they plotted different types of energy, mechanical energy like bending and breaking something, electrostatic energy like putting charges on a sphere, chemical bonds and all of these kinds of things, and they put them on a plot that's a scale, where if you make things bigger how much energy does it take to do these things. And they found that they all merge more or less at a certain scale here that also it seems to match the thermal energy that we have in our bodies. The energy contained in the random motion of atoms, and that scale is a nanometer. So what does that mean? That means that that is the one scale at which you can very easily convert one type of energy into another without any problems. You can take chemical energy and turn it into electrical energy or mechanical energy or thermal energy or all of those things are very easily convertible because they are all of the same magnitude. It's the ideal scale if you want to make a molecular machine is the nanoscale and that's where they are. Here is an example of how chemical energies turn into mechanical energy. There's something that biochemists talk about that's called allostery and it's the idea that the molecule combined to enzyme which is a protein and it can deform that molecule and that's usually used for regulation. You can imagine your cells everything has to be regulated. Your cell is actually the computer; it's a [inaudible] computer and this is how logic is built into your mechanical computer. You have, basically it says if control molecule binds here, then stop creating this product. And you can imagine very complicated feedback loops and connections through all of these different cells, but for our story here that is in itself already a very interesting subject. For our story the important thing is you have the chemical binding and the mechanical motion. So can I make a molecular machine like that? Well, I could put a molecule on a molecular track; I bind the molecule and it propels it to the left. But then what? If the molecule comes off again, it propels it back to the right, so the molecule combines, comes off; it would back-and-forth but it wouldn't go anywhere. So again, what's needed? What's left? What's needed is this reset step. So here is the reset step. You want to detach the molecule from time to time, let it freely move and then reattach. And if the track has an asymmetric which we call energy landscape then this will actually move to the left on average and this is shown here in probabilities down here. To detach we need energy, so this is where the energy input comes in. This is where the second law is not violated. We stick on the surface -- this is really strange so -- we don't violate the second law because we need an energy input to create, provide the reset step and this reset step actually a lot of times simply detaching from a track. Hopefully the music works here. So I'm going to show you how this molecule that you saw in this little movie in the beginning actually moves. And we have the Sorcerer's Apprentice to help us with that. Remember Mickey Mouse trying to control the walking brooms? Well, that's what we have here. So here's another molecule. The one I showed you in the movie was myosin but this is kinesin; they work similar. It has ATP attached to the left foot. ATP breaks down. The foot detaches. Then it goes back and forth by some motion. The ATP on the right attaches to the front foot. By allosteric change it makes the leg bend. This biases the foot forward. The foot goes down. ATP is released and another allosteric change makes it attach to the track. Here we are the same situation as before. ATP breaks down, foot comes loose and so on. That's how it works. Here, we will go through it real quick again because it's just, because it's fun [laughter]. Here we go. How have people figured this out? They have figured this out by using fluorescent techniques, by using AFM, by using laser tweezers, by all kinds of tricks. By doing mutation, by kind of disabling a certain part of the molecule and see what it does then and very, very painstakingly. This is how it all works. It's a complicated diagram and I'm not going go through all of it, but the point is we have allostery which creates an asymmetric energy landscape which converts chemical to mechanical energy. We have random motion and we have a generous supply of ATP. You always have to have more ATP there. It has to be out of equilibrium. That's another key issue I didn't address. That's why we have to keep eating. If we starve, we die, right? And that's where, why the second law is not violated because as soon as your ATP in your ADP levels become the same, then everything stops moving, because this whole machine can go backwards too. If you have more ADP than ATP it will actually move backwards. If they are the same it will move randomly back and forth, so the biasing is done in a very subtle way during this reset step just by having more ATP than ADP in your cells. I'm going to finish up here. This is a diagram of all of the myosins that are known for now and the evolutionary relationships. There are 17 I think different groups of them. Myosin two is the one that moves your muscles. Myosin five is the one that I showed you earlier in the movie. Evolution itself, I want -- one last thing I want to drive home is the idea of the ratchet. It's very universal. The idea is that we have randomness in nature and we have some kind of ordering component and together they create order out of chaos, and evolution itself is the ratchet. When you think about it, you have something, an old structure and maybe a not quite as efficient myosin molecule and by noise which is mutations, many, many new structures are created but then they are filtered and you get a better adapted structure. It's a ratchet. It ratchets up complexity. Even thought and this is speculative now. You can think about it now. How does new innovation happen? Maybe a bunch of guys, some of you work on artificial intelligence and how do you get a computer to come up with new ideas? You're going to have to put some randomness into it. Without randomness in there, without just randomly generating things and then filtering them through something that you already know, you cannot create novelty. I don't think it would work, because if you are just combining stuff that is already there, it's kind of like you are not making a new car by turning it red instead of blue, right? That's not really a novelty, right? When we think, when we have new ideas, when we have intuition that basically comes from the fact that there's all of this random stuff going on in our heads subconsciously and some of it comes to our consciousness because it's filtered through what we already know. So even that is a ratcheting mechanism, so I think it's a very general thing. So I would say the last laugh goes to this guy, Democritus. Really, truly "everything is the fruit of chance and necessity." Thank you very much. [applause] >> Peter M. Hoffmann: Questions, yeah? >>: I have a question. I enjoyed on your slide where you had the [inaudible] just because you were visually showing that. I come from design and [inaudible] opportunity. One aspect, I love this as a layperson this topic, but one problem I have on the visualizations and I was looking forward to in your book or in your talk. They say everything was brought in motion because it gets it by water molecules? >> Peter M. Hoffmann: Right. >>: But whenever you see these visualizations, you never actually -- I have no sense of what the scale is from a water molecule hitting say adensosine triphosphate because nobody ever visualizes a water molecule. So it's floating in some like ether of life, you know, and it's walking, so is there any -- it's just bugged me for a very long time. Can you tell me this thing that's bugged me, what scale are we talking about when it's a water molecule, say and adenosine triphosphate or a protein? >> Peter M. Hoffmann: That's a great question especially the visualization question. I was trying to do this for this talk. I was trying to figure out how to get, I mean, I could've taken a long time to do all that random [inaudible] like check the [inaudible] let alone the water molecules, but it was just too much work. I was trying to think how to do that, you know. I had one, but it looks really lame so I took it out. [laughter]. >>: What was the problem? [inaudible] >> Peter M. Hoffmann: It's tricky, you know, but the water molecules are -- two different sizes I should say because some of my research I do and you will see it in the book if you actually look at the structure of water, what actually assumes the structure when it comes too close to a flat surface. And the difference between water molecules and the size of molecules is roughly .25 nanometers or 2.5 angstrom as we like to say in physics, so it's a lot smaller than some of these molecules of 50 nanometers. So, you know, it's 100 times smaller, so they are tiny little things but there are so many of them and they hit it, they hit these molecules so many times every second. So it makes everything just jitter. So think of is just jittering. You got the molecules because they just jitter all the time, shaking all the time because they get hit by all of these little water molecules. >>: It's kind of more like basketballs and active pebble spread. >> Peter M. Hoffmann: Yeah, yeah. >>: For some of those who are intuitive problem solvers then we think what is the liquid [inaudible] there is no liquid. >> Peter M. Hoffmann: [inaudible] like sandblasting. Just stick something in there and hit it with sand grains or something and it makes everything kind of shake and jitter. And shake and jitter allows it to get over this -- I didn't talk about it, but in chemistry we have this thing called activation barriers because every time you want to walk from one place to another you have to, there is an awkward moment in between for, you know, you go from one low energy to another low-energy state. All of this shaking and jittering helps to get over all of these activation barriers, and that's what finally makes it move. >>: Another question. So rather than depending upon ever faster AFMs and most destructive ones how are you doing on [inaudible] lower-level processes well enough to model and predict and look for new machinery in that way? >> Peter M. Hoffmann: Yeah, people actually do these tests besides just figure out how they work which I said is very painstaking because you have to do many different ways, so the AFM is pretty nice, but it is way tricky to do. I mean these are still the only people who ever managed to do this, I have to say. And even they can't do it every day. But for people who are already figuring this out by attaching little fluorescent labels on the lake or on the top and seeing how they move. But the next step would be to make your own molecular machines. I think that would be the way to do it in and that's happening now. I mean people have taken inspiration from nature and have made their own machines out of DNA or these kinds of, finally now out of DNA; that's a lot of those. Although in nature molecular machines are not made out of DNA, but you can. If you make it small enough and you build asymmetry into it and you have that hit motion and you have a supply of energy which can be anything, even shining a light on something, you can make a little molecular machine and I think that's really where the future is. >>: [inaudible] >> Peter M. Hoffmann: Pardon? >>: They meant in Drexler's style work is not at all ruled out. >> Peter M. Hoffmann: Oh no, I don't think so. I think [inaudible] now Drexler, it's interesting because he is mostly talking about making silicon-based machines and I think that's going to be really difficult. You can see underneath that floppiness. I think to really make it work that's why it works in biology, you need floppy machines. They need to be floppy enough that they can be jittered around and then you know, so I think they have to be black biology. >>: So that was actually leading to my question, I was just wondering, Drexler doesn't concentrate on just blowing up silicon. He's got [inaudible] chemical [inaudible] >> Peter M. Hoffmann: Yeah, other organic molecules. >>: Well, for nanosystems he's interested in all sorts of things [inaudible] and graphite and [inaudible] >> Peter M. Hoffmann: Right. >>: But one of the things he seems to think is that we will improve on nature by being essentially dry, getting rid of the sloppy wet stuff. It sounds like your thesis would be no, he's barking up the wrong tree, that actually the floppy wet stuff is crucial. >> Peter M. Hoffmann: I would think so. I'm not going to, as a scientist and not going to say that the other thing is impossible because you could imagine the dry stuff, if you had to have certain temperature, of course the atoms inside the dry stuff are also shaking so it may be shaking, jittering all by itself without having the outside molecules having to hit it. I think it's much easier and nature has shown us that. When you think of evolution we have a whole universe of silicon-based materials out there. They are called rocks. They don't move around. They just don't too much. They just lay around, right? So it seems to me that nature kind of has hit on the way to do it, but… >>: [inaudible] that there's kind of a barrier that there was no way for natural systems to overcome. If we could get beyond that then you would go [inaudible] possibly what he tried to do [inaudible] goes a lot with strength and things like that, but possibly in getting the strength he's going to lose the randomness which can lead to the more intelligent side of things? >> Peter M. Hoffmann: Yeah. I talk about in my book little bit. How do you withstand this thermal motion you can make something very strong, but then it wouldn't really move much. Or you can make it too floppy and it would just be swept away. You've got to find that old sweet spot right in the middle to make it work and I think that applies to all of these things. >>: What is biological machines [inaudible] essentially different from catalysts [inaudible] chemical [inaudible] to [inaudible] things to bias it in one direction? >> Peter M. Hoffmann: I think there is a lot of overlap. Obviously, the whole chemical background of that which I skipped over because I'm a physicist, is basically yes, a nonequilibrium thermodynamics. If you have a reaction and you have too much of the input of the reactants, you're going to bias it throughout the products. And that's a direction, right, so chemically how do you create your direction in this case, of course including all of the coupling to mechanical motion of that kind is by having this extra large amount of ATP around at all times and as soon as ADP is produced by breaking down the ATP, you pull the ADP out. You recharge it to ATP [inaudible] and you always have this nonequilibrium situation. So you try your reaction from, you know, high-energy state to low-energy state and that gives a direction. It's very much related to those kinds of chemical ideas. All those things kind of -- what I find kind of pleasing about the whole thing is like all of these things come together. My research I consider nano mechanics, so I like the mechanical idea of it but the mechanics and chemistry and when you look at mitochondria, even the electricity, as I said, it works all by separating charges. Thermal motion, all those things come together at the nanoscale and they all kind of become almost interchangeable with each other. >>: [inaudible] bacteria [inaudible] >> Peter M. Hoffmann: Bacteria are active [inaudible] well that's a cytoskeleton thing. Is a good question but that's why my biology knowledge goes a little bit. >>: They caught the [inaudible] and that's one kind of ratchet but I don't recall reading the bacteria about anything with the… >> Peter M. Hoffmann: You know you may be right because bacteria their shape is mostly determined by the cell wall and the actins and all that stuff are actually are used to change the shape of the cell and that starts really with eukaryotic cells that do a lot of that, but I'm not entirely sure. We would have to look that one up. But a lot of things that -- we have bacteria that have two sets of ribosomes that I didn't talk about. We use this machine that translates RNA into the proteins that's like the factory floor in our cells. Bacteria already have that so there's a lot of overlap, but then there's a lot of stuff that bacteria don't have. They don't have mitochondria, for example, because they were bacteria themselves at some point. >> Amy Draves: We have an online question that is where is did the machines come from? >> Peter M. Hoffmann: Okay. That's a great question. This is always the big question, of course where scientists don't have a good answer, is once we have the machines how do we get the variety of them? That's evolution. Where the first machines start from, that goes back to the origin of life and basically I would say we have no idea at this point. There is a lot of origin of life research. People have found out that you can make all kinds of organic molecules in a situation like a [inaudible] on mineral surfaces. Some even pretty complex molecules, but nothing that approaches like a molecular machine, so there has to be some way of initially creating a replicator, something that can replicate itself, like an RNA molecule that then eventually hit on these molecular machines, but that's, you know, all of these things that were the precursor to that are gone for like billions of years. Trying to go back in time and trying to figure out how it actually happened is very hard work. I think we will figure it eventually out but it could take 100 years. It could take 1000 years it could take 10 years; maybe some genius will figure it out in 10 years. But nobody has an answer for that. Once they are there we know how they evolve and we know how they work. Any other questions? >>: At the close of your talk you were saying that you are comparing sort of a ratcheting mechanism used [inaudible] with a larger [inaudible] evolution in saying that there has been ratcheted up being true and then there is a… >> Peter M. Hoffmann: I think I know where you are going but go ahead. >>: Okay. You tell me where you think I'm going [laughter]. >> Peter M. Hoffmann: Improve is a kind of charged word. They change and they become more adapted to whatever, because people don't say like we evolve from bacteria to humans and humans are better than bacteria are. The fact our there are zillions of different bacteria and they are very successful. In some sense, they have been around a lot longer than we have and so they are extremely successful, so you can't say that just because they are primitive that they are less evolved than we are. But it means that you have a flexible structure that can solve problems. Bacteria solves problems very well. They are extremely good at that. So are we in a different way, but I think that channel idea of a ratcheting mechanism is useful there. >>: So you're saying that the general notion of flexibility and adaptability there in the book that's present in that you are [inaudible] more than the idea that there is an advancement [inaudible] >> Peter M. Hoffmann: Right, right. That's the adaptability part. They need a bit of randomness in there and they need some kind of linkage to some filtering mechanism to filter that space in the ratchet. >> Amy Draves: Thank you so much. [applause] >> Peter M. Hoffmann: Thank you, thanks.