Chardin’s philosophy seemed to offer a way to have your cake and eat it too: You could embrace evolution and all the findings of science, and at the same time, believe in a higher guiding force, although somewhat invisibly. Yet, despite his compromising stance on the big questions of our existence, few were happy with his ideas. The Church felt they were too far removed from traditional theology, and scientists didn’t appreciate the addition of unknown forces just to satisfy a need to place humanity in the center of all being.
One of the scientists who regarded Chardin’s ideas with disdain was the French biochemist and Nobel Prize–winner Jacques Monod. In “Vitalisms and Animisms,” a chapter in his book Chance and Necessity, Monod critiqued Chardin’s logic as “hazy” and his style as “laborious.” But most of all, he was “struck by the intellectual spinelessness of [his] philosophy.” There seemed to be a “willingness to conciliate at any price, to come to any compromise.”
Yet, even for Monod, the problem of how to reconcile the blind motions of atoms and their lifeless laws with the complexity of life was a deep, central mystery. Allergic to any vitalistic or animistic explanations and unable to see how physical laws by themselves could lead to the complexity of life (which was Thompson’s idea), he resolved the dilemma by placing randomness front and center. The origin of life, according to Monod, was an incredibly improbable event. Once it happened, evolution took over, infused with a healthy dose of randomness. While both Thompson and Monod rejected the introduction of guiding principles, such as Chardin’s spiritual energy, they greatly differed on the roles of chance and necessity.
The problems of how life came to be, how life operates (metabolism, growth), and the history of evolution can be answered in many ways. However, we could organize most answers to these questions along two dimensions. There is the dichotomy of “mere physics” versus higher forces (life forces, the soul) along one dimension, and then the question of chance versus necessity along the other. Figure 2.2 shows schematically how we could visualize these various views. Why are there so many views on the origin and nature of life? Undeniably, it is difficult to see how simple physical laws can lead to life’s complexity, but at the same time, scientists have repeatedly found that yesterday’s ignorance about certain biological phenomena have turned into today’s knowledge—knowledge based on those same simple physical laws. Thus we should heed both Monod’s and Thompson’s warning: When we feel the need to invoke extraneous principles to assuage our ignorance, it is wiser to hold off. Rather, we should continue our search for explanations within known science. So far, this has served us astonishingly well. Chardin knew that the “connection of physics and biology” had to lie in the cell. However, he believed that the cell was “still a closed book” and “an impregnable fortress.” Since Chardin’s time, much of this fortress has been penetrated, the depth of our explanations has greatly increased, and the cell is not quite as enigmatic as it used to be. And in all of this, physics and chemistry have been our guides.
FIGURE 2.2. A simplified view of how various scientists and philosophers have explained life with respect to chance versus necessity and vital forces versus physical forces.
Variation and Atomic Physics
Vitalism was discredited by physics by the end of the nineteenth century, and the Origin of Species had discredited purpose—but many scientists could not yet accept the idea that randomness might play an important role. Darwin’s theory provided a plausible explanation for the variety of life forms and the biological history of our planet, an explanation that did not involve purpose or teleology. But physics and evolution made strange bedfellows. Physics of the nineteenth century was based on natural laws. It was based on necessity. By contrast, evolution needed variation and novelty—chance—to function. How could the two be reconciled?
Reconciliation came slowly and happened through the express help of physicists. By the end of the 1800s, the holistic laws of thermodynamics— the laws that describe the behavior of matter using properties such as pressure, volume, or temperature—were reduced to a more fundamental theory. This theory explained these holistic properties in terms of the motions of atoms. The new theory, which we will explore in more detail in Chapter 3, was at first called kinetic theory, but as it grew and encompassed more and more phenomena, it became known as statistical mechanics. Randomness became an accepted part of physics, and tamed by statistical averaging over large numbers, the random motions of atoms could now be described by well-defined probability distributions.
Early in the twentieth century, the study of atoms and light led to another theory that explicitly included the concepts of chance and probability: quantum mechanics. The iron-clad model of necessity, classical physics, was now replaced by a fundamentally statistical picture of nature— a picture in which we could never state with certainty where a particle would go or how much energy it had. All we could calculate were probabilities. Quantum mechanics arose from a need to explain startling new experimental results. For example, throughout the late 1800s into the early 1900s, experiments revealed a plethora of new and mysterious radiations: X-rays; cathode rays; and alpha, beta, and gamma radiation. The study of these new types of radiation provided impetus for the new science of the quantum. And by the 1920s, these mysterious rays would also prompt a sea change in biology: Physicists were starting to study the effect of radiation on biological matter.
Chromosomes, bundles of DNA, were discovered in 1882 by German biologist Walther Flemming (1843–1905) and others, but their significance was not immediately clear. Although they were duplicated during cell division, the part they played in heredity was not recognized, because Mendel’s work had fallen into obscurity. By 1900, however, his work had been rediscovered and the German biologist Theodor Boveri (1862–1915) and his American counterpart Walther Sutton (1877–1916) made the connection between chromosomes and Mendel’s hereditary traits. By 1909, the American embryologist Thomas Hunt Morgan (1866–1945) had begun his famous genetic experiments on the fruit fly Drosophila, a fast-reproducing animal. The momentum of biological research now shifted across the Atlantic. Morgan discovered that not all traits were independent, as Mendel had thought, but that there were various degrees of linkages. This suggested that traits were contained in some kind of linear arrangements on chromosomes, with nearby traits more likely to be inherited together. The mixing of traits was assigned to a crossing-over of linear molecules. During the crossing-over process, the progeny received a mixture of the genes from both parents. If two traits were located close to each other on the hereditary molecule, it was less likely that they would be separately inherited during the reshuffling. However, crossing-over only explained some aspects of variations in populations. It could not explain how brand new traits could arise, but these new traits were needed for evolution.
By 1920, through the tireless work of several pioneers in genetics, it became clear that hereditary information was lined up along linear molecules, wound into chromosomes. The proof came from the new science of radioactivity, and with the understanding of radiation came a new idea on how novelty and variation were introduced into a species beyond a mere reshuffling of existing traits. One of these pioneers was the American geneticist Hermann Joseph Muller (1890–1967), one of Morgan’s Ph.D. students. Muller became interested in the effects of X-rays and radioactivity on the mutation rates of fruit flies. He had been studying mutations; these rare and significant changes in the hereditary material are generally harmful. He was hoping that X-rays could induce mutations in a controlled manner. After three years of false starts (the X-rays sterilized the fruit flies, and they produced no offspring he could study), a breakthrough came in 1926. By controlling the dose of X-rays, Muller was able to find a direct relationship between X-ray dose and the probability of mutation. This work established that radiation increased the probability that new genetic traits would be created in a species—chance was finally coming into its own.
Muller obtained definitive results in 1932, worki
ng in Berlin with Russian geneticist Nikolai Timoféeff (1900–1981), but the molecular nature of the hereditary substance remained a mystery. At this point, a young atomic physicist joined Timoféeff’s lab. Max Delbrück (1906–1981) was able to explain Muller and Timoféeff’s data theoretically using his knowledge of atomic physics. Although the nature of the genetic substance was unknown, Delbrück argued that if we assumed the genetic substance to be a molecule, it should be subject to the laws of atomic physics and of thermodynamics. In the now famous green pamphlet of 1935, published in the obscure Transactions of the Scientific Society of Göttingen, Delbrück, Timoféeff, and Karl Zimmer (1911–1988) presented data on the dependence of mutation rates on temperature or X-ray dose. The results were clearly compatible with current knowledge of atomic and thermal physics.
Thus, a remarkable story unfolded throughout the first half of the twentieth century: Previously mysterious biological processes, such as heredity and variation, became connected to measurable physical entities. By contrast, Helmholtz’s achievement had been essentially restrictive—it subtracted vital forces from the list of possible explanations. However, Helmholtz and his fellow nineteenth-century scientists could not explain how the business of life was conducted. This business was conducted on the molecular scale, which had been inaccessible to nineteenth-century science. For the first time, through the work of Muller, Timoféeff, Delbrück, and others, some of the deepest mysteries of life were connected to physical, molecular entities. Molecular biology was born.
What Is Life?
As an alumnus of Johns Hopkins University, I can appreciate an anecdote I found in Walther J. Moore’s biography of Erwin Schrödinger (1887– 1961), 1933 Nobel laureate and founder of wave mechanics—the most widely used formalism for quantum mechanical calculations. Schrödinger, a scientific refugee from Nazi Austria, was offered a position at Johns Hopkins. In accordance with time-honored tradition, faculty members of the host university wanted their distinguished guest to have a good time. In true Baltimore fashion, they gathered at a seafood restaurant to sample the famous Maryland crabs. I am not sure if they already had Old Bay seasoning at the time, but Schrödinger enjoyed his seafood very much and felt a nice glass of beer would go very well with it. Unfortunately, it was the height of prohibition. The hosts apologized, but no beer was to be had. Schrödinger decided to take a position in Dublin, Ireland, instead.
Delbrück’s work would have lingered in the obscure journal in which it was published had it not been brought to Schrödinger’s attention in the early 1940s by another émigré from Nazi rule, Paul Peter Ewald (1888–1985), a pioneer in X-ray physics. Schrödinger was fascinated when he first read the green pamphlet, which was titled “On the Nature of the Gene Mutation and the Gene Structure.” For Schrödinger, the green pamphlet by Delbrück, Timoféeff, and Zimmer was a revelation.
Schrödinger worked the technical paper into a series of inspiring lectures at Trinity College, Dublin, attended by over four hundred listeners and, later, into his famous book What Is Life? In the book, he placed Delbrück and his colleagues’ findings into the context of contemporary science and made daring speculations based on the rather more careful conclusions of these scientists. Although many of Schrödinger’s speculations were wrong, the book provided an inspiration to many physicists entering biology.
The book was quite short (only ninety pages in the edition I own), but Schrödinger touched on many of the puzzling aspects of life, especially the nature, size, and surprising stability of the hereditary substance. Schrödinger was familiar with rough estimates of the size of the hereditary substance from microscopic observations of chromosomes, which had placed the size of a gene at about 30 nanometers cubed—still large for a molecule. Schrödinger wanted a closer estimate. Delbrück, Timoféeff, and Zimmer had estimated that if X-rays were strong enough to ionize about one in every thousand atoms, then mutations would occur with near certainty. Assuming that gene mutations were due to atomic changes in a gene-carrying molecule, Schrödinger took Delbrück’s work one step further: If ionizing one in a thousand atoms caused a mutation with (almost) certainty, then the size of a gene had to be about one thousand atoms, which was about 3 nanometers cubed.
This conclusion, which Delbrück and his collaborators had wisely avoided, did not make much sense, even to contemporary molecular biologists. Mutation happens due to the creation of so-called radicals (molecules with a missing electron), which can diffuse over much larger distances than 3 nanometers. Moreover, today we know that there are molecular machines, so-called repair enzymes, that can repair the genetic material (which we now know to be DNA). Thus, mutations are really the result of chemical damage, which is subsequently not repaired correctly by the cellular machinery. Nevertheless, Schrödinger’s estimate, although based on false premises, spurred the imagination. What could fit into a 3-nanometer cube? What kind of molecular units would consist of one thousand atoms?
Using his estimate of the size of a gene, Schrödinger wondered how such an assembly of atoms could be stable. Molecules in a living body are subject to violent thermal motion—at the elevated temperatures of a living body, atoms rattle, shake, and bump into each other at high speeds. Only a very stable chemical bond could survive such abuse. Schrödinger became convinced that genes must be molecules. He envisioned the genetic material to be like a crystal, but with one unexpected condition. To hold the complex information needed to operate a cell, the crystal had to be aperiodic, that is, nonrepetitive. Real crystals are quite boring on an atomic scale—they are repetitions of the same atomic arrangement over and over. Such a repetitive arrangement cannot contain much information. It is like writing a book, but you are only allowed to use one letter: eeeeeeeeeeeeee. To convey information, you need different letters, which can be arranged into sentences, such as “The cow jumped over the moon.” You need an aperiodic sequence of letters. Schrödinger believed that the letters of the genes were written in the language of atoms and molecules. Here, Schrödinger was closer to the mark than with his estimate of the size of the letters, although this idea was not original with him. We now know that the genetic material is not an aperiodic crystal, but an aperiodic polymer: a floppy, long, linear molecule, called DNA.
Schrödinger’s puzzlement over how the molecules in our cells escape thermal motion led him to conclude that everything in our cells was made stable by strong chemical bonds. For him, thermal motion was the enemy, to be overcome by fortifying the bonds of our microscopic nature. As we will see throughout this book, Schrödinger was fundamentally wrong on this point. There are no solids in our cells. Everything is squishy and moving. Far from being the enemy, thermal motion is the key to the activity in our cells.
Schrödinger also commented on the value of statistical mechanics, the science of averaging large numbers of randomly moving molecules to arrive at precise macroscopic laws. An example is the ideal gas law, a law that relates the density, pressure, and temperature of a gas. This law emerges from averaging vast numbers of gas molecules. Schrödinger called this process “order from disorder.” In biology, by contrast, Schrödinger saw a different class of laws at work, laws that made “order from order.” Undoubtedly, that is what living organisms do, but deep down, they still have to contend with disorder and must first make order from this underlying chaos. Schrödinger could not see how this was possible. The numbers of atoms in life’s molecules seemed to be much too small, and expected random changes (or “fluctuations”) much too large. In a stunning reversal of Helmholtz’s insights, Schrödinger claimed that biology had to encompass new laws of physics not previously seen in inanimate matter. According to him, statistical mechanics could not, by itself, explain living matter. Instead, the “most striking feature” of life was that it seemed to be based on an “order-from-order principle” rather than an order-from-disorder principle as in statistical physics. Schrödinger’s solution was to imagine life as clockwork, in a throwback to La Mettrie two hundred years previously. However, he a
dmitted that the idea of life as clockwork had to be taken “with a very big grain of salt.” A big grain, indeed.
We are now close to a solution of Schrödinger’s conundrum. A living organism is not based on a solid. It is not clockwork. And statistical mechanics can teach us a lot about how it works.
The Rules of the Game
As we’ve seen in this chapter, randomness is here to stay. Far from the destructive force it has been made out to be through the millennia, it is good for us—or at least good for life as a whole. In the chapters that follow, we will learn how randomness is part of every aspect of life—even in the simple act of lifting an arm or converting food into motion.
How can we visualize the relationship between necessity, the laws of nature, and randomness? One way was suggested by biochemist Manfred Eigen in his 1975 book The Laws of the Game: How the Principles of Nature Govern Chance. Eigen won a Nobel Prize for the study of ultrafast chemical reactions and realized that the interplay of necessity and chance resembles games. Different games can represent different phenomena we may encounter in the principles that govern life: chemical reactions, population growth, the regulation of enzymes in cells, or evolution. A good game combines elements of necessity (it must have rules), chance (there must be surprise), and sufficient complexity. Chess has simple rules, but the totality of all chess games ever played and the variety of chess strategies used show that chess is a game full of subtle complexity. Games are models of emergence—the appearance of unexpected features arising from the interactions of many different parts, rules of the game, chance, and space and time. Life can best be understood as a game of chance—played on the chessboard of space and time with the rules supplied by physics and mathematics. To gain a physicist’s understanding of life, we need to begin with the rules the game of life obeys. To start, let us learn about the kind of games atoms play.
Life's Ratchet: How Molecular Machines Extract Order from Chaos Page 8