Life's Ratchet: How Molecular Machines Extract Order from Chaos

by Hoffmann, Peter M.

  We can also think about the competition between liquid and frozen water in the language of the molecular storm. At low temperatures, the forces between atoms are stronger than the shaking of the molecular storm and draw atoms together to form structures; at high temperatures, the forces between atoms are no match for the more violent molecular storm, and snowflakes melt. The concept of free energy captures the tugof-war between deterministic forces (chemical bonds) and the molecular storm—or in other words, between necessity and chance, in one elegant formula, F = E − TS.

  FIGURE 3.1. Free energy of liquid water (black) and ice or snow (gray) plotted against temperature. Because liquid water has higher entropy, it is represented as a steeper line in the diagram. At low temperatures, ice has lower free energy than liquid water, and water freezes. At high temperature, liquid water has lower free energy (because of the higher entropy), and ice melts.

  Driving the Molecular Storm

  According to the second law, free energy will eventually be degraded and reach a minimum. If this tendency holds for all natural processes, then the universe must have started out with an abundance of free energy at the time of the big bang. This is clearly the greatest gift of the universe: Without this gigantic amount of free energy, the universe would be a cold, uniform, and very boring place. How does the universe share its bounty? The big bang started out as pure energy and very little entropy (a single point cannot have much entropy). Shortly after the big bang, energy congealed into energetic particles that whizzed around near the speed of light. The particles collided, annihilated, or appeared out of the expanding fireball, creating chaos where formerly there was simple order. In this expanding fireball, the newborn universe started to create entropy (as well as degrade some of its free energy). As free energy was degraded, new structures were brought into existence—according to Einstein’s equivalence of mass and energy (E = mc2), featureless energy became quarks, electrons, muons, neutrinos, photons, and all their tiny brethren.

  After three hundred thousand years, the universe had cooled enough to form the first atoms: Quarks bound together in threesomes called protons and neutrons. Protons and neutrons clustered into nuclei, which captured electrons. Again, the entropy of the universe increased with the release of atomic binding energy (which turned into heat), and something new was created in the process.

  The universe continued to cool and became less and less dense. Empty, cold, and no longer able to form nuclei of atomic mass higher than hydrogen and helium, the universe filled to more than 99.9 percent with just these two elements. There is a joke among astronomers that the periodic table really only needs those two entries. All the other elements are so rare, we may as well neglect them (of course, there would be no astronomers if that were truly the case).

  Filling the universe with hydrogen and helium was like filling it with fuel. When light nuclei combine in a process called nuclear fusion to form heavier nuclei, they release large amounts of energy (this is what happens in a hydrogen bomb). To make heavier nuclei, two lighter nuclei must collide at very high speed. High speed implies high temperature; as the difficulty of building a nuclear fusion reactor demonstrates, the needed temperatures and densities are difficult to achieve.

  This is where gravity lent nature a helping hand. In the early universe, some regions (just by chance) had slightly higher densities than neighboring regions. These denser regions gravitationally attracted more atoms, gained more mass, and continued to attract more atoms. A once-almost-even distribution of atoms became increasingly clumpy. Atoms clustered together in giant nebulae, separated by giant voids. The nebulae began to collapse under their own weight and, with their continued collapse, became hotter and hotter. Finally, densities within the nebulae became so great and the collisions between nuclei so fast that nuclear fusion began to create heavier nuclei. Hydrogen and helium were cooked into heavier elements, and stars were born.

  Stars are the furnaces that “burn” the overabundance of fuel in our universe. Deep within stars, nuclear fusion creates heavier and heavier nuclei, all the way up to iron (even heavier elements are created in large stellar explosions, called supernovae). In fusion, energy is released and streams outward in the form of radiation. Our sun bathes the Earth’s atmosphere in electromagnetic radiation, or light, which is absorbed by molecules and atoms. When molecules absorb this light energy, it is ultimately converted to kinetic energy, making the molecules shake, rotate, or move faster. As these faster molecules collide with slower, less energetic molecules, the faster molecules give up some of their energy in the collision. Soon, this gift of energy from the sun is distributed among many molecules, heating up our atmosphere. The molecular storm, and the abundance of free energy on our planet, come forth from the universe, carried to us by our sun.

  Open Systems

  This short history of the universe has shown that the degradation of free energy is not all bad. As free energy is dissipated, and the entropy of the universe increased, new structures are born, from quarks to nuclei to atoms to . . . life. The universe continues to share its free energy with abandon. The continual flux of energy is a fact of life—a fact that keeps living systems out of thermodynamic equilibrium. Equilibrium is the state in which all available free energy has been degraded and no usable energy remains. Equilibrium means death. Living beings must avoid equilibrium. As long as we are alive, energy continues to flow through us. In thermodynamics, systems through which energy and matter flow from and to the environment are called open systems.

  Recognizing that living organisms are open systems is an important step toward our understanding of life—but it is not enough. A small volume of gas within a larger one is also an open system; new molecules enter this volume all the time, while others leave. If left alone, the volume will tend to a state in which, on average, the same amount of molecules enter and leave at any point in time. Moreover, the molecules are not transformed. The molecules that enter are the same as the ones the leave. Consequently, there is no degradation of free energy. Although such a volume is open, it is at equilibrium.

  Living systems are different: What enters is not the same as what leaves the system. Living beings gobble up low-entropy energy, degrade the energy, and expel high-entropy energy into the environment. We call such systems dissipative systems, because they continuously dissipate free energy into high-entropy energy.

  Thus living organisms are open, dissipative systems. But there is still more. Nature is full of open, dissipative systems that we would not consider alive. A hurricane is an example. It takes a low-entropy source of energy (the large temperature difference between the ocean and the upper atmosphere) and continuously dissipates this energy in a display of awesome power. It dissipates the energy by moving the heat of the ocean to the cool upper atmosphere by convection (air-mass movement due to differences in temperature). The motion of huge masses of air, coupled with forces originating from the Earth’s rotation, soon organize the moving air into a giant rotating storm. As long as there is a supply of warm ocean air, the storm continues to rage, dissipating the heat energy of the ocean as it sweeps across the water. What is most striking about the hurricane is its structure: the rotating swirls of clouds, the eye of the storm in the middle. Many open, dissipative systems show spontaneous emergence of structure, in seeming violation of the second law. But we already know there is no contradiction here. The hurricane increases entropy overall far more than it locally decreases it.

  The study of far-from-equilibrium systems, and their spontaneously created “dissipative structures,” has led many scientists to speculate that living systems are similarly built. But that would be misleading. A close look at life at the microscopic level shows that it is a tightly controlled dance of sophisticated molecules, designed by evolution. It is not a spontaneous, wasteful system like a hurricane. Life is a highly efficient process. Efficiency is best achieved when we do not stray too far from equilibrium, because large movements cause friction and, consequently, rapid degradatio
n of low-entropy energy. Life chooses the middle road: By staying away from equilibrium, we stay alive. By staying close to equilibrium, we increase efficiency.

  Life is a near-equilibrium, tightly controlled, open, dissipative, complex system. Such a system can only work if its parts are “designed” (by evolution) to push thermodynamics to its limits. Life does not exist despite the second law of thermodynamics; instead, life has evolved to take full advantage of the second law wherever it can. But how can it do this? Life’s engines operate at the nanometer scale, the tiny scale of molecules. But what is so special about this scale that chaos can become structure, and noise can become directed motion?

  4

  On a Very Small Scale

  There is no excellent beauty that hath not some strangeness in the proportion.

  —FRANCIS BACON

  A biological system can be exceedingly small. Many of the cells are very tiny, but they are very active; they manufacture various substances; they walk around; they wiggle; and they do all kinds of marvelous things—all on a very small scale.

  —RICHARD FEYNMAN, “THERE’S PLENTY OF ROOM AT THE BOTTOM,” LECTURE AT AMERICAN PHYSICAL SOCIETY MEETING, 1959

  I had been impressed by the fact that biological systems were based on molecular machines and that we were learning to design and build these sorts of things.

  —K. ERIC DREXLER

  IN MARCH 2011, I ATTENDED THE BIOPHYSICAL SOCIETY meeting to learn what the veterans of this field have been up to and where I should take my own research. Biophysics deals with the physical underpinnings of living systems and the use of physical methods to explore life. When biophysics was founded in the 1800s by researchers such as Helmholtz, it dealt with the parts of living organisms one could easily handle and see. It was a macroscopic science. Today, when you attend the largest meeting of biophysics on the planet (sixty-five hundred participants, over seven hundred posters, every day, for four days), absolutely everything deals with structures only found at the nanoscale. Biophysics today is nanophysics.

  The biomolecular world is filled with exquisite structure and a mysterious drive for change and motion. In several talks, people presented motility assays, a fancy term for attaching protein molecules called myosins to a surface and then seeding fibrous proteins, called actins, on top of the myosins. All these molecules are so tiny that they cannot be easily seen in an optical microscope. To make them visible, the researchers attach little molecular flashlights, fluorophores, to them, which turn the actin filaments into molecular fireflies. Immerse the myosin and actin filaments in a liquid buffer solution, and not much happens, but add an energy storage molecule, called ATP, and all over the surface, actin comes “alive.” Like little nanometer-scale worms, the actin filaments start moving in almost straight paths. Sometimes they hit an invisible obstacle and curve in a new direction. As long as enough ATP is provided, they just keep going and going. What moves them? According to the researchers, it’s the myosin molecules. They act like molecular motors, pushing actin forward with their two molecular “hands” and passing each actin filament from one myosin molecule to the next, like a rock star crowd-surfing.

  In other talks, researchers explained how cells change their shapes by polymerizing filaments such as actin or the sturdier microtubules. Filaments are made of small units, which spontaneously form by assembling themselves (polymerization) or by being actively assembled and disassembled by molecular machines. As the filaments grow, they push on the cell surface, creating protrusions. This is how cells move. Yet another set of talks dealt with the intricate structures of cell membranes, the thin shell that surrounds each cell and separates the inside of the cell from the outside environment. Riddled with specialized pores, the membrane only admits desired molecules into the cell, while undesired molecules are kicked out. Floating on the membrane are the cell’s “TV antennas”: cell receptors waiting for a chemical signal from the outside world. Once a signal arrives, it is transmitted through the membrane, setting up a cascade of activity that may lead to cell motion, cell division, the secretion of a compound, or cell suicide. This is the nanoscale world of our cells.

  Life must begin at the nanoscale. This is where complexity beyond simple atoms begins to emerge and where energy readily transforms from one form to another. It is here where chance and necessity meet. Below the nanoscale, we find only chaos; above this scale, only rigid necessity.

  Nano

  How do you tell a bunch of sixteen-year-olds how small a nanometer is? I was standing in front of eighty high school juniors from the Macomb County Math and Science Center, trying to explain my research. I needed to get them to imagine the unimaginable. “A nanometer is to the size of a human, as the size of a human is to ten times the distance from the earth to the moon,” I began, but quickly realized that the distance from the Earth to the Moon is not something many of us have experienced firsthand. Little pearls of sweat started forming on my forehead. I tried again: “A nanometer is so small, you would need to slice the width of a human hair one hundred thousand times to reach a nanometer.” Better. But how about translating distance into time? “If I would shrink you to one nanometer in height, you could walk about twenty-five hundred nanometers in one hour. At this speed, it would take you eighty-two years (!) to walk the length of a full-sized human, from his toes to the top of his head.” Gasps. They started to realize that a nanometer is not just small—it is so small that the nano-realm is utterly removed from anything we could ever hope to experience. Yet, we can measure this stuff.

  Fifty years before my little lecture to future scientists, Richard Feynman, the famous Nobel Prize–winning physicist, gave a groundbreaking lecture to fellow physicists at the 1959 American Physical Society meeting. In typical Feynman fashion, the lecture was simply titled “There’s Plenty of Room at the Bottom.” The “bottom” was the microscopic scale, from micrometers (one thousand nanometers) down to atoms at just a few tenths of a nanometer in diameter. Feynman’s point was that no law of physics should keep us from creating machines that are just a few nanometers large. It’s simply a question of engineering.

  It took a while for Feynman’s vision to become reality, but by the late 1980s, nanotechnology was starting to take off. With the invention of tools to image objects only a few nanometers in size and to measure and manipulate them in various ways, it was now possible to compress data to nanoscale bumps or to build ever-more-complex nanostructures. These advances led to a kind of frenzy of wild predictions in the 1990s and into the 2000s, some overhyped (nanotechnology as the savior for all our energy, medical, and environmental problems) and some doomsday (gray goo of nanorobots eating everything in sight—as in the remake of The Day the Earth Stood Still or in Michael Crichton’s book Prey).

  At least in the media, the nanotechnology craze has died down a bit. The early promises of nanorobots (or nanobots) cleaning plaque out of our trans-fat-challenged arteries have not materialized as fast as expected. The dangers of nanotechnology are there (small nanoscale fibers can possibly cause cancer—think asbestos), but the gray-goo idea seems highly overdrawn. The media have moved on. But in science, nanotechnology and nanoscience are alive and well. Scores of physicists, engineers, chemists, and medical researchers are engaged in nanotechnology research, from nanobatteries to nanomedicine.

  Personally, I prefer to speak of nanoscience rather than nanotechnology. Nanotechnology is the next step, after the science has been worked out. What is nanoscience? In short, it is the production, measurement, and understanding of systems where at least one spatial dimension is in the nanometer range. Sometimes, this broad definition has led to trouble, as many old areas of research, such as thin-film technology and some branches of chemistry, suddenly became nanotechnology research, only because they dealt with things smaller than one micrometer. Thus there is a joke about nanotechnology—that it is simply a ruse to get money out of funding agencies. While there was some truth to this charge—at least in the early days—there is something genuinely
special about the nano-scale: Systems, once shrunk down to this “magic” scale, exhibit new and rather unexpected properties.

  Feynman’s talk at the 1959 American Physical Society meeting is often credited as having jump-started the nanoscience revolution. The truth, however, is a bit more complicated. When he gave his famous talk, the assembled listeners did not take the topic very seriously. One attendee of the meeting recalls: “The general reaction was amusement. Most of the audience thought he was trying to be funny . . . It simply took everybody completely by surprise.”* Feynman’s talk was rediscovered twenty-five years later, when many of his predictions had come to pass. By then, technology had caught up with many of Feynman’s visionary ideas, and they were finally taken seriously.

  Feynman took his inspiration from living systems, as have many recent nanotechnology visionaries. He was taken by the way information was written “on a very small scale” in biological cells, and how cells used the information to “manufacture substances,” “walk around,” and “do all kinds of marvelous things.”** Indeed, if today’s nanotechnologists are dreaming of building nanosize machines, they have to accept that nature beat them to the punch by a mere three billion years! Living cells are teeming with molecules that perform amazing feats at a nanoscale with almost uncanny precision.

  Feynman envisioned that nanoscale miniaturization would allow us to store whole books on the head of a pin, build tiny motors, move single atoms around, or build powerful pocket-size computers. All of these things have come to pass. Some of his other predictions are still not feasible, such as the creation of a nanosize surgeon, an idea we now know as the nanobot. A nanobot would be a tiny device that could be swallowed like a pill or injected into the bloodstream. The device would perform nanosurgery, such as cleaning plaque from arteries or performing search-and-destroy missions on cancer cells. However, in a field called targeted drug delivery, or nanomedicine, researchers have already made remarkable progress in creating nanostructures which will specifically seek targeted cells (for example, cancer cells) and then deliver their payload (deadly drugs to a cancer cell, or a piece of DNA to repair gene damage) only to the targeted cells. Another one of Feynman’s predictions, which he took from a science fiction story by Robert Heinlein, was the possibility of building a machine that could construct a smaller version of itself. The smaller version, in turn, could build an even smaller version. Like a set of Russian nesting dolls, the machines would build smaller and smaller versions of themselves, all the way down to the last, nanometer-size machine.