Life's Ratchet: How Molecular Machines Extract Order from Chaos (12 page)

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.

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, working 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.

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 admitted that the idea of life as clockwork had to be taken “with a very big grain of salt.” A big grain, indeed.