A Brief History of Creation

by Bill Mesler

  Schrödinger deduced that the basis of genetic inheritance must lie in a molecule he called an aperiodic crystal. He chose a crystal because he believed that this molecule had to be ordered and stable, and thus able to persist over generations, which would not be true for a coacervate-like suspension. The crystal had to be aperiodic because he believed it would have to be able to store limitlessly variable information to allow for mutation and evolution. In other words, it had to be a single molecule structured in a way that atoms could store information.

  Since the complexity of the first living thing must have stopped well short of a full-fledged cell, it stood to reason that some part of a cell had come first. The first half-living thing—what would come to be called a protocell—would have to have been able to do both of two things: metabolize using components of its environment and replicate with modification. Metabolism and replication were the same factors that Oparin and Haldane had singled out in their own hypotheses for the origin of life. The problem that would eventually arise was that these two functions are handled by different but mutually interdependent subsystems within the cell itself.

  In later years, it would usually be described as the chicken-or-the-egg paradox of the origin of life. But in the mid-twentieth century, when Miller and Urey had reinvigorated the field with their experiment at the University of Chicago, it was a problem that hadn’t yet reared its head. Though the workings of enzymes that govern metabolism were becoming well understood, little was concretely known about chromosomes. Since Thomas Hunt Morgan’s elucidation of the chromosome’s role in genetic inheritance, it had been clear that chromosomes play a central role in the functioning of genetics. But no one yet understood what they were actually made of. It was reasonable to assume that replication was handled by the same part of the cell that governed metabolism, that the chicken and the egg were the same thing. The reality was that scientists didn’t yet really know all that much about cells.

  THE CELL PROVIDES one of the strongest pieces of evidence of the deep evolutionary connection between all life on Earth. Just as Geoffroy Saint-Hilaire had seen the similarities in such seemingly different appendages as a bird wing and a human hand, microbiology, as it became more sophisticated, revealed equally compelling similarities in the structures of living cells of diverse organisms. The structures, the functions, even the language of genes, are too similar for cells not to have originated from the same cellular ancestor.

  There are only two basic types of living cells: prokaryotes (from the Greek for “prenucleus”) and eukaryotes (those containing a “true nucleus”). Single celled and lacking a nucleus, the prokaryotes are the simplest organisms. All multicellular organisms—plants, animals, fungi—are eukaryotic. Every multicellular species is like a colony of cells, each of which is programmed to perform specialized tasks and depends on the functions of other cells for its survival. The human body has so many cells that it is difficult to say how many there are. Some estimates have put the number as high as 100 trillion, but most guesses are about one-third that number.

  The first person to actually see a living cell was Antonie van Leeuwenhoek, although it is his seventeenth-century contemporary Robert Hooke, who usually receives credit. In his book Micrographia, Hooke described microscopic structures that made up a piece of cork. These were not actually cells, but the remains of cell walls, made up of leftover cellulose and lignin. The name he used to describe them—“cell,” a derivation of the Latin word cella, for “small room”—stuck. Thus, cells were named after the part that was easiest for the first microscopists to observe, the protective lipid layer known as the cell membrane.

  At its most fundamental level, a cell is nothing more than a few basic elements. But the way these elements are organized is enormously complex, coming together to form a dynamic factory with complex machinery, most of which is made up of proteins. There may be tens of thousands of types of proteins, each carrying out a specific task in the cellular assembly line. Pretty much everything living organisms do—respiring, eating, growing, reproducing—is accomplished by or with their help.

  In some ways, the cytoplasm, the viscous protein and nucleic acid solution housed within the confines of the cell membrane, came to be seen by scientists as a modern version of the protoplasm, the enigmatic essence of living things that gave them all their lifelike properties. Proteins were seen as particularly important. In the first half of the twentieth century, it was easy to assume that proteins carried genetic information as well. The importance of proteins in cellular metabolism was well established, although some scientists were beginning to have doubts about their role in heredity.

  LIKE MOST SCIENTISTS who were focused on the origin-of-life question at the time, Sidney Fox was firmly in the camp of those for whom the protein reigned supreme. At Caltech, Morgan, one of the fathers of modern genetics, frequently told him, “Fox, all the problems of life are problems of proteins.” That message was reinforced after Fox left Caltech for a position in the lab of one of the world’s greatest authorities on proteins, the chemist Max Bergmann, a German Jew who had fled Nazi Germany and established a laboratory at Rockefeller University in New York.

  The start of World War II sidetracked Fox for a while. He returned to California, joining the war effort at a private lab where he helped invent a process to isolate from shark livers vitamin A that could be used by Allied pilots to enhance their night vision. After the 1953 Miller-Urey experiment had generated so much excitement in the scientific world, Fox returned to the “big question” that had intrigued him since his days at Caltech, the question of the origin of life.

  The Miller-Urey experiment triggered a rash of similar experiments seeking to duplicate the formation of amino acids. Many involved modifications of Urey’s vision of the early-Earth environment. Some used different gas combinations to simulate the early atmosphere. Various energy sources were substituted for the lighting Miller had used. But Fox wasn’t interested in retreading the same ground Urey and Miller had walked. The question of how amino acids had appeared on Earth may not have been firmly settled, but it appeared to be nearly so. The origin of organic molecules no longer felt like an insurmountable mystery, and certainly not the obstacle it might once have seemed. Instead, Fox turned to the next step in the development of living organisms. He wanted to understand how amino acids could form some type of early prototype of the cell that would have represented the “half-living” stage Haldane had once referred to. For Fox, that next step had to have been the formation of a protein, or something close to it, from amino acids.

  This was a more difficult problem than Miller and Urey had confronted. Even the smallest of proteins contain a long string, or polymer, of amino acids that have to be arranged in a precise sequence. Thus, the term “sequencing” in proteins refers to establishing the exact order in which the amino acids are arranged. Later, the term “sequencing” became more commonly associated with the search for the order and placement of genes in chromosomes, and for the order of individual nucleotides within genes.

  To get from the simple amino acids Miller and Urey had found in their experiment to full-fledged proteins was an exceedingly complicated proposition. Yet Fox seemed to stumble upon what he saw as the answer rather quickly. After the Miller-Urey experiment had invigorated the study of the origin of life in academic circles, Fox turned in earnest to the problem of how simple amino acids could be built into more complex structures. While away from the lab giving a series of lectures, he had an epiphany: what would happen, he wondered, if amino acids were evaporated in an environment resembling Darwin’s warm little pond?

  Fox and his research team found that purified amino acids heated to 175°C organized themselves in a seemingly nonrandom way into chains of amino acids similar to protein polymers. These strings of amino acids were short compared to real proteins, but they did exhibit signs of catalytic activity similar to that of proteins. Convinced he had discovered the next step on the road to life from nonlife, Fox named these sho
rt amino acid strings proteinoids. By 1959, he had found that when his dry proteinoids were reintroduced to hot water, they spontaneously formed tiny microspheres that he increasingly described as “lifelike.” In May of 1959, Fox announced his discovery in a paper published in Science. His experiment, he claimed, was the basis of what he called “a comprehensive theory of the spontaneous origin of life at moderately elevated temperatures.”

  As his study of proteinoid microspheres continued, Fox became more and more convinced that he had discovered the precursors of modern cells. They had an outer shell that in some ways mimicked a cell membrane, such as by being selectively permeable to certain biological substances. They acted as catalysts, speeding up chemical reactions much the way proteins do. The microspheres were even capable of absorbing other microspheres, allowing them to grow, bud, and divide into new microspheres. Later, he would discuss his microspheres as if they were alive in some primitive way.

  Many scientists were skeptical from the outset. Miller was one of the most prominent of these critics. In a letter published in Science following Fox’s first claims, Miller and Urey questioned the plausibility of the geological conditions that would have been necessary for Fox’s proposed scenario. Even in a laboratory setting, proteinoids required a precise series of very specific steps, heating and cooling coupled with drying and rehydration. Fox hypothesized a tidal basin next to a volcano as the setting where the geochemical creation of proteinoids might have taken place. Miller and Urey doubted that such steps could have occurred on the early Earth and downplayed the idea that a volcano would have been a conducive place for life to arise. Fox, they argued, had discovered a fascinating chemical phenomenon, but not a phenomenon relevant to the origin of life. Fox’s proteinoids were certainly not alive, nor were they capable of evolving into something that was alive.

  It was this last criticism, coupled with the burgeoning science of molecular biology, that eroded the significance of Fox’s work in the eyes of most scientists. In the years following the Miller-Urey experiment, scientists had acquired a greater understanding of the roles of the complex molecules found in biological cells—an understanding that was steadily undermining the idea of the protein being key to every life process. Proteins were gradually losing their preeminence among those trying to understand the origin of life, and the search for the ancestor of the modern cell was slowly but surely drifting toward other cellular components. The focus was steadily turning to nucleic acids, long misunderstood and underappreciated.

  ON A SPRING DAY in 1953, a tall, sandy-haired young man with a bit of a stoop walked into the Eagle Pub in Cambridge and boasted loudly that he and his companion had just discovered the secret of life. It was a bold claim, considering it was being made by a scientist who had not yet completed his PhD. But then, Francis Crick was never shy about sharing his high opinion of his own abilities. James Watson, the man who shared pints with Crick at the Eagle Pub and later a Nobel Prize in Stockholm, would eventually write a book about the discovery of the structure of DNA titled The Double Helix. The book’s first line was, “I have never seen Francis Crick in a modest mood.”

  It would take the rest of the world another decade to appreciate just how important Crick and Watson’s discovery truly was. Eventually, though, their discovery of the structure of DNA would indeed come to be seen as one of the most important scientific advances of the century, and Crick’s would become one of the most famous names in science.

  A SHOEMAKER’S SON from Northampton, then the shoemaking capital of Great Britain, Crick was old for a doctoral student. And although his grandfather, Walter Drawbridge Crick, was, in his spare time, a naturalist and an acquaintance of Charles Darwin, and even coauthored Darwin’s last submission to Nature, Crick had scant experience in biology. He spent his undergraduate years at University College London, where Robert Grant had once instructed Henry Charlton Bastian. Like Bastian, Crick was most intrigued by two important but little-understood biological problems—the phenomenon of consciousness and the origin of life—yet he had settled on what to him was the largely unsatisfying pursuit of a degree in physics. When World War II broke out, Crick had been working on what he later described as the “dullest problem imaginable,” the measurement of the viscosity of water at temperatures between 100°C and 150°C. He was rescued from this fate when a German airplane dropped a sea mine on the laboratory where he worked and destroyed his experimental apparatus.

  Crick then found himself designing sea mines of his own for the British Navy’s Admiralty Research Laboratory. He came up with a rather ingenious design for a mine that could be triggered only by extreme magnetic fields of the sort used by German minesweepers.

  At the end of the war, Crick was still a student in search of a PhD. Like a generation of young physicists inspired by Schrödinger’s book What is Life?, Crick was determined to move into biology. In 1949, he found a research position at Cambridge’s Cavendish Laboratory. “The Cavendish,” as it was known, was the most prestigious physics laboratory in Great Britain, as well as the site of some of the most revolutionary discoveries that were unlocking the secrets of the inner workings of cells.

  In 1912, not long after the discovery that X-rays were, in fact, waves, a twenty-five-year-old Cambridge student named William Lawrence Bragg had hit upon the idea of using the diffraction patterns of X-rays to obtain a picture of the arrangement of atoms of crystals. Soon, scientists had found ways to crystallize isolated samples of the components of living cells, enabling them to get a glimpse at their atomic-level structure and learn the intricate details of how they actually worked. The discovery would lead to a revolution in the understanding of biochemistry and turn Bragg into history’s youngest Nobel laureate.†

  By the time Crick arrived, Bragg was running the Cavendish. Under his leadership, the Cavendish had become the center of some of the most advanced crystallography research being conducted in the world. Most of the work centered on proteins, and Crick was initially assigned the task of critiquing the research of one of Cavendish’s brightest stars, the Austrian microbiologist Max Perutz, who was diligently trying to establish the molecular structure of hemoglobin. Perutz hoped that the structure of that protein would unlock the secret of how genes are transmitted, but Crick found himself unconvinced by Perutz’s hypothesis. Crick had begun to lean toward the view that the secret to genetic inheritance lay elsewhere in the cell, in the oft-overlooked nucleic acid called DNA.

  Back in 1871, a Swiss-German chemist named Friedrich Miescher had isolated a new biochemical substance from cells that he had extracted from the pus-soaked bandages obtained from a nearby hospital. Miescher was puzzled that the substance contained nitrogen and phosphorus but not the sulfur that would have established it as a protein. Because the substance had been drawn from the nucleus of cells, he named it “nuclein,” which was eventually changed to “deoxyribonucleic acid,” or simply DNA.‡ But nobody really knew exactly what DNA did or that it had any relationship at all to the purely theoretical things known as genes.

  More than half a century after Miescher’s discovery, the world was treated to a vital clue that DNA played a more important role in genetic inheritance than anyone had previously thought. In 1943, a Canadian-born physician named Oswald Avery began a series of experiments on viruses at the Rockefeller Institute in New York. Chemical analysis had by then become sophisticated enough to show that viruses, like cells, were composed of both proteins and nucleic acids; the two components could even be separated in the lab. Working with the pneumonia virus, Avery found he could change harmless viral strains into virulent strains simply by exposing them to the pathogenic DNA. The lesson was that DNA by itself—completely free of the presence of proteins—had the power to pass on genetic traits.

  Joshua Lederberg would one day call the experiment “the historical platform of modern DNA research,” but it took a great deal of time for most scientists to accept its full significance. Everybody knew about Avery’s findings, but too many great minds ha
d invested themselves in the centrality of protein. The idea of DNA as the carrier of genetic information represented a fundamental paradigm shift in the understanding of biochemistry and the working of cells. There was a great deal of resistance in the scientific community, even within the Rockefeller Institute. As late as 1951, in an essay marking the half-century anniversary of the rediscovery of Mendel, the great geneticist Hermann Muller—the first to realize that genes were subject to mutations—would write, “We have as yet no actual knowledge of the mechanism underlying that unique property which makes a gene a gene—its ability to cause the synthesis of another structure like itself.”

  For a growing number of scientists, however, the implication of Avery’s experiment was clear: DNA was indeed the central agent of genetics. Crick counted himself cautiously among this group. By the time he and James Watson met, though, Watson was outright convinced. A blunt American with a crew cut that stood out like a sore thumb at the Cavendish, Watson had been sure of the primacy of DNA since his undergraduate days at the University of Chicago. He was angered by the reluctance of more established scientists to recognize DNA’s importance. Later, in The Double Helix, he railed against the resistance he had faced from “cantankerous fools who unfailingly backed the wrong horses,” adding for good measure that “a goodly number of scientists were not only narrow-minded and dull, but also just stupid.”

  After Watson arrived in 1950, he and Crick were drawn together by a crystallographer named Maurice Wilkins, who had produced some of the first X-ray diffraction images of DNA. Wilkins soon recruited both men to help him make sense of his raw data.

  At the time, prominent labs around the world were racing to discover the structures of proteins. Protein research made up the bulk of the crystallography work being done at the Cavendish. As for solving the structure of DNA, the most serious competition Watson and Crick faced was from a team led by Linus Pauling at Caltech, but Pauling was handicapped by his lack of access to the state-of-the-art X-ray data being produced in Cambridge. By 1953, Watson and Crick were accessing increasingly detailed data provided by a researcher who had taken over the lead role in much of the Cavendish’s DNA work: Rosalind Franklin, a chemist and the niece of former home secretary Herbert Samuel. Drawing upon the raw data provided by Franklin’s increasingly sophisticated crystallographic work, Crick and Watson were finally able to deduce the structure of DNA.§