It seems almost magical for a molecule to make copies of itself. Nevertheless, these self-replicating macromolecules do not meet the minimum requirements for life on at least two counts. First, such systems require a steady input of smaller highly specialized molecules—synthetic chemicals that must be supplied to the system from somewhere. Under no plausible natural environment could sufficient numbers of these component molecules have arisen independently. Furthermore—and this is a key point in distinguishing life from non-life—self-replicating molecules do not change and evolve, any more than a photocopy can evolve from an original.
SELF-REPLICATING MOLECULAR SYSTEMS
More relevant to metabolism are systems of two or more molecules that form a self-replicating cycle or network. Such systems are now the subject of intense research, and a variety of strategies for molecular self-replication have been identified. In the simplest so-called “cross-catalytic” system, two molecules (call them AA and BB) form from smaller feedstock molecules A and B. If AA catalyzes the formation of BB, and BB in turn catalyzes the formation of AA, then the system will sustain itself as long as researchers maintain a reliable supply of food molecules A and B.
It's easy for theorists to elaborate on such a model. Rather than two cross-catalytic molecules, imagine a system with 10 or 20 molecules, each of which promotes the production of another species in the system. Santa Fe Institute theorist Stuart Kauffman points to such “autocatalytic networks” as the most likely form of metabolic protolife, since that's exactly what modern life does. Given the complexity of living cells, he proposes that the molecular repertoire of the first autocatalytic network might have to be expanded to as many as 20,000 different interacting molecular species. Accordingly, Kauffman drafts complex spaghetti-like illustrations of hypothetical reactants, each playing a key role in the integrated network.
In a cross-catalytic system, two different molecules (in this example designated AA and BB) catalyze the formation of each other. More complicated cross-catalytic systems with numerous molecules may have been the first self-replicating cycle on the early Earth.
Kauffman sees an important payoff in the behavior of such elaborate catalytic networks. Unlike a single self-replicating molecule, such vast networks of reactive molecules have the potential to increase in complexity and efficiency through numerous different interactions among molecules. The large number and variety of molecular interactions foster the emergence of new metabolic pathways and nested cycles of synthesis. Like a living metabolic cycle, Kauffman's networks incorporate a certain degree of sloppiness. Through such variations, the system can change by shifting to new, more efficient reaction pathways and in the process display a defining trait of life—the ability to evolve.
THE GAME OF METABOLISM
Kauffman's theory provides an intuitively appealing model for the emergence of primordial metabolic life. For one thing, if molecules in a complex autocatalytic system efficiently catalyze each other, then there's no need, at least at first, for a genetic mechanism. Accurate replication of the entire system is, in effect, intrinsic to the network. At the same time, the system has the potential to vary and gradually evolve. Growth, reproduction, evolution—the autocatalytic network would appear to meet the minimum criteria for life.
Kauffman's model sounds good on paper, but there's a dramatic gap between plausible theory and actual experiment. For example, what exactly is the chemical “A”? What is “B”? When asked, Kauffman shrugs and says, “That's for the chemists to figure out.” And that's what chemists have done.
If you want to make protolife in the lab, it's best to start by designing a simple metabolic cycle. Metabolism is a special kind of cyclical chemical process with two essential inputs. First you need a source of energy—preferably chemical energy, since that's what all known simple living cells use. (Photosynthetic cells use sunlight, to be sure, but these advanced organisms possess layers of chemical complexity far beyond those of more ancient, simple cells.) Second, you need reliable supplies of simple molecules, such as carbon dioxide and water, to provide the raw materials.
Living cells undergo chemical reactions not unlike burning, in which two chemicals (oxygen and some carbon-rich fuel) react and release energy. However, the objective in metabolism, unlike in an open fire, is to capture part of that released energy to make new useful molecules that reinforce the cycle. So metabolism requires a sequence of chemical reactions that work in concert.
Three basic rules govern this game of metabolism:
Rule 1—The Cycle: Describe a cycle consisting of a sequence of progressively larger molecules. The largest of these molecules should then be able to split into two smaller molecules, both of which are also in the cycle. In this way you end up with two sets of molecules, where before there was only one set and the cycle keeps on reproducing itself.
Rule 2—The Environment: Identify a plausible prebiotic environment that provides a reliable supply of raw materials (i.e., small molecules made up of carbon, nitrogen, sulfur, and other essential elements) and energy (preferably the chemical energy of unstable minerals). Furthermore, all of the different types of molecules in the cycle have to be able to survive in that environment long enough to keep the cycle going. Extremes in temperature, pressure, or acidity, for example, may stabilize some kinds of molecules, while destroying others.
Rule 3—Continuity: An unbroken chemical history must link Earth's earliest metabolic cycle with the metabolism of today's cells. Deep within the metabolism of all of us, there are likely to be “fossil” biochemical pathways that point to life's simpler beginnings. So any plausible model must conform to this “principle of continuity” and use molecules and energy sources that lie close to the basic metabolism of modern organisms.
Experimental evidence provides the ultimate test of any chemical theory. Each chemical step in a hypothetical metabolic cycle is a potential experiment, so you get bonus points if these crucial experiments work.
Three influential models exemplify the metabolism game at its best: the “Protenoid World” of Sidney Fox, the “Thioester World” of Christian de Duve, and a group of related hypotheses based on the reverse citric acid cycle, including the elaborate “Iron–Sulfur World” hypothesis of Günter Wächtershäuser.
THE PROTENOID WORLD
The granddaddy of all metabolism-first models emerged as the brain-child of protein chemist Sidney Fox, who began thinking about origin-of-life chemistry shortly after the publication of Stanley Miller's 1953 paper. Fox's career was strongly influenced by Thomas Hunt Morgan, a famed geneticist and a member of Fox's Caltech thesis committee. “Fox,” Morgan would often remark, “all the important problems of life are problems of proteins.” Fox took this lesson to heart and began studying proteins' role in life's origin as a faculty member at Florida State University in the mid-1950s.
He imagined a hot primordial Earth where amino acids from the soup dried and baked on cooling volcanic rocks. He mimicked these conditions in his lab, drying amino acids on a hot surface at 170°C, and found that his chemicals quickly polymerized into a lumpy substance he called “protenoid.” This discovery, announced in 1958, would shape his checkered three-decade career in origins research.
Fox's protenoids displayed fascinating behavior. They acted as catalysts, though to a rather modest degree compared to the modern protein catalysts that promote chemical reactions in every cell. When placed in hot water, they spontaneously turned into microbe-sized spheres, and sometimes these divided. He claimed that these spheres, though not as orderly as biological proteins, possessed a nonrandom structure with a permeable bilayer membrane. Increasingly, Fox suggested that the protenoids were “lifelike” and represented the key to life's origins.
Fox and a small army of students carried out experiments to bolster his origin model. Solutions of protenoids were heated and cooled in a cycle that produced structures he called “microspheres”—cell-like entities that could absorb more protenoids, grow, and divide, thus forming a secon
d generation of microspheres. These self-replicating objects, growing from nutrients in solution and lacking any genetic mechanism, formed the basis of a true metabolism-first model.
At first blush, the Protenoid World might seem to score well in the game of metabolism. Rule 1: The cycle is formed from widely available amino acids, which readily form protenoids that grow and divide. Rule 2: The environment, a volcanic setting near a tidal zone, is realistic for the early Earth. Rule 3: Protenoids seemed to conform to the principle of biological continuity, because closely related proteins are fundamental to modern life. What's more, experiments seemed to support each step of the hypothesis.
For a time, Fox's career thrived. Starting in 1960, he received generous grants from NASA's Exobiology program, which supported a variety of research projects on the origin and evolution of life. Fox's funds soon exceeded $1.5 million and allowed him to establish his own Institute of Molecular Evolution at the University of Miami in 1964. A steady stream of graduate students investigated protenoid properties.
As Sidney Fox increasingly fell in love with his Protenoid World model, his claims became more and more extreme. The origin-of-life problem had been solved, he said, and protenoids are “alive in some primitive way.” In his 1988 book, The Emergence of Life, he even made the bizarre and unsubstantiated claim that his protenoid microspheres possessed a kind of “rudimentary consciousness.”
As early as 1959, the mainstream origin-of-life community, led principally by Stanley Miller and Harold Urey, had begun distancing themselves from Fox's claims. They resented what they regarded as the sensationalistic use of terms such as “protenoid” and “lifelike.” They scoffed at the idea that amino acids might have baked into anything useful on a bed of lava. They questioned whether the protenoid structures were truly nonrandom in structure. The purported lifelike behaviors of microspheres were also challenged, especially the idea that they “replicated” in the biological sense. Equally strong was their objection that the Protenoid World scenario ignored the knotty problem of genetics. How would DNA and RNA have arisen in such a world?
Despite myriad objections to the theory, and the increasing scientific isolation of Fox, the Protenoid World was influential for at least two reasons. Not only did Fox develop the first comprehensive metabolism-first model, but he also championed the important philosophical position that origin processes might be nonrandom and deterministic—a view later embraced by numerous other origins workers. Nevertheless, by the late 1970s, Sidney Fox's efforts had been marginalized, and they remained the target of jokes and derision until his death in 1998.
THE THIOESTER WORLD
The Belgian chemist Christian de Duve made his scientific name studying the structural and functional organization of cells—work that won him the Nobel Prize in physiology or medicine in 1974. In an oft-repeated pattern, he then turned his attention to the origin of life, tackling the classic question from his perspective as a cell biologist. Not surprisingly, that background influences his origins theory.
De Duve takes a rather ambiguous stand in the metabolism- versus genetics-first controversy. For him, the simplest imaginable living thing is a cell-like entity that has a full complement of genetic material to control cellular functions. But he also recognizes the futility of jump-starting genetics without a well-established, elaborate arsenal of chemical reactions—what he calls “protometabolism” (as opposed to the more complex metabolism of modern cells). It's really a question of where you place the boundary between nonliving and living systems. I've argued that the complex sequence of emergent events leading from geochemistry to life requires a rich taxonomy of intermediate states. De Duve appears to agree: His “Age of Chemistry” (protometabolism) precedes the “Age of Information” (genetics), which in turn precedes the “Age of the Protocell” (genetics and metabolism combined). Only then, with the merger of metabolism and genetics, does modern life truly emerge.
Let's assume, de Duve says, that some early Earth environment (rather vaguely specified as a “volcanic setting” in his writings) was rich in hydrogen sulfide gas and iron sulfide minerals, along with the usual cast of carbon-based molecules. One chemical consequence of this sketchy scenario might be the production of sulfur-containing molecules called thioesters, which incorporate a strong bond between one sulfur atom and one carbon atom—a bond that can release a lot of energy if broken. De Duve's hypothesis rests on the assumption that a steady supply of these energy-rich thioester molecules was available on the ancient Earth—hence the Thioester World.
Why focus on thioesters? For one thing, they are essential in the metabolism of modern cells. By breaking the strong carbon–sulfur bond, they can transfer energy to promote metabolic reactions, thus building larger molecules from smaller ones. In the Thioester World, a steady supply of thioesters provides the chemical energy required to drive protometabolism.
Of particular import, thioesters have a propensity to bond with amino acids, which would have been readily available in the prebiotic soup. Remarkably, when placed in solution, these amino acid–thioester groups spontaneously assemble into peptidelike chains (de Duve calls them “multimers,” because they differ in some chemical details from true peptides). At first, the multimers thus formed would have had little effect on the chemical mix. But, he speculates, eventually some of these big molecules by chance acquired catalytic properties (reminiscent of Fox's protenoids). Gradually, as the environment became enriched in chemically active multimers, an autocatalytic cycle might have emerged, producing, he says, “protoenzymes required for protometabolism.”
The Thioester World hypothesis fits nicely with the primordial-soup paradigm favored by Miller and his allies. De Duve's scenario relies on the environment to provide a steady input of various molecular building blocks, including amino acids, carbohydrates, and of course the essential energy-rich thioesters themselves. Such a model metabolism, in which the first cells eat and assemble components from their surroundings, is said to be heterotrophic (from the Greek, “other nourishment”). Heterotrophs must scavenge their molecules from the environment.
So how does de Duve's Thioester World score in the game of metabolism? He certainly gets high marks for identifying a viable prebiotic environment rich in plausible simple molecules. Using thioesters as a reliable, renewable energy source is especially attractive, because it echoes the action of thioesters in modern biology. But he never specifies the molecules that comprise his metabolic cycle; the chemistry is vague. For de Duve, protometabolism is an awkward, transient, ill-defined phase that is necessary to set the stage for genetics. Thioesters promote the synthesis of catalytic multimers, which in turn promote the manufacture of a genetic molecule such as RNA. Only then does a well-defined biochemistry take root.
The bottom line: de Duve's scenario is appealing in its broad outlines, but lacking in specific chemical details. And so, if you like details, there's no better place to turn than Günter Wächtershäuser's Iron–Sulfur World.
15
The Iron–Sulfur World
You don't mind if I brag a little, but something like this has never been done in the entire field.
Günter Wächtershäuser, 1998
In bold concept, epic sweep, and sheer mass of detailed predictions, Günter Wächtershäuser's Iron–Sulfur World hypothesis for the origin of life stands alone. Since its first presentation in 1988, this theory has changed the landscape of origins research by calling into question many of the most deeply rooted assumptions about life's beginnings.
Wächtershäuser (whom we first met in Chapter 8 because of his pleasing reliance on minerals) argues for a strikingly original metabolism-first model, based on an autotrophic (self-nourishment) model. Autotrophic metabolism begins with chemical simplicity. All of life's essential biomolecules are manufactured in place, as needed, from the smallest of building blocks: carbon dioxide (CO2), water (H2O), ammonia (NH3), hydrogen sulfide (H2S), and so forth. All chemical synthesis is accomplished stepwise, just a few atoms at a
time. [Plate 8]
The contrast between heterotrophic and autotrophic existence is profound and represents a fundamental point of disagreement among origin-of-life researchers. Supporters of a heterotrophic origin argue that it's much easier for a primitive cell to use the diverse molecular products available in the prebiotic soup rather than to make them from scratch. Why go to the trouble of synthesizing lots of amino acids if they're already available in the environment? Modern heterotrophic cells are much simpler than autotrophic cells, because they don't need all the complex chemical machinery to manufacture amino acids, carbohydrates, lipids, and so forth. It makes sense to assume that the simpler mechanism—heterotrophy—came first.
Autotrophic advocates are equally insistent that true simplicity lies in building molecules a few atoms at a time, with just a few basic kinds of chemical reactions. Furthermore, such a mechanism is philosophically attractive: Autotrophism is deterministic. Rather than depending on the idiosyncrasies of a local environment for biomolecular components, autotrophic organisms make them from scratch the same way every time, on any viable planet or moon, in a predictable chemical path. For hardcore advocates of autotrophy, the random, hodgepodge, hopelessly dilute prebiotic soup is irrelevant to the origin of life. With autotrophy, biochemistry is hardwired into the universe. The self-made cell emerges from geochemistry as inevitably as basalt or granite.
Genesis: The Scientific Quest for Life's Origin Page 23