A History of the Search for Where We Came From

Alison Liou ’14, THURJ Staff

How life originated from Earth’s primordial soup remains one of the biggest unanswered questions in biology. Although humans have pondered the topic since antiquity through various means of inquiry, the answer remains elusive to this day.

Early ideas about the natural origin of life (as opposed to creationist ideas) were rather simple. Pre-Aristotelian thinkers suggested that life began through spontaneous regeneration, regularly emerging fully-formed from  inanimate material. Some of the later pre-Aristotelian thinkers, including Empedocles, began to express rudimentary ideas of evolution in their theories about the origin of life, such as the idea that only successful creatures survive.

The idea of spontaneous generation, however, began its descent in the 1600s when Francesco Redi showed that what people thought was “spontaneous generation” of maggots in rotting meat was actually maggots hatching from eggs deposited by flies on the meat. Later in the 1880s, Louis Pasteur put an end to this idea once and for all by showing that microorganisms only appear in a sterile meat broth after it has been contaminated by germs from the environment.

The most popular modern scientific theory regarding the origin of life involves evolution and self-assembly, which hypothesizes four basic steps that must have occurred on early Earth: 1) the prebiotic synthesis of small biological molecules, 2) the formation of higherorder structures such as biopolymers and vesicles through self-assembly, 3) the self-replication of these higher-order structures, and 4) the natural selection of more suitable “specimens” over others.

Within this framework lies the RNA world hypothesis, which claims that an RNA-dominated world preceded our current world of DNA, RNA, and proteins. Support for the hypothesis is founded on the discovery of RNA-based enzymes called ribozymes. An important example is the ribosome, which not only demonstrates that RNA has catalytic ability, but also indicates that RNA must have preceded protein enzymes. RNA would have been able to catalyze reactions necessary for life, carry genetic information in its base sequences to be passed down to subsequent generations, and eventually provide the blueprint for translation. RNA could have, alone, performed the tasks that DNA, RNA, and proteins carry out together.

The Origin of RNA

Until recently, there was no known plausible prebiotic synthetic pathway for RNA. This gap in the knowledge was, in fact, one of the biggest weaknesses of the RNA world hypothesis. The most intuitive synthetic pathway would be to find a prebiotic synthesis of the ribose sugar in RNA and the nucleobases, and then to join the two components together with phosphate to make ribonucleotides. While nucleobases, sugars, and phosphates can form spontaneously under prebiotic conditions, in experiments ribose could not be made at the necessary quantities that would explain its abundance on early Earth because it was highly unstable.

Such an observation led some scientists to believe that the RNA world was preceded by an even simpler “world” that was more chemically plausible, perhaps not involving ribose. Some scientists suggested molecular alternatives to RNA, such as peptide nucleic acid (PNA), which is formed out of a protein backbone. Other scientists speculated that RNA precursors may have come from outer space, or even that life emerged as “networks of catalysts processing energy.”

Ascertaining the origins of the phosphate portion of nucleic acids also presented a problem initially, as phosphorus is mostly trapped in minerals that, although abundant, do not easily form a solution in water, where life most likely originated. The high temperature of volcanic vents could have potentially dissolved these phosphoruscontaining minerals. However, based on examination of modern-day volcanoes, the amount released would have been small. Pasek and Lauretta (2005) resolved this problem with their discovery that schreibersite, a common mineral in meteors, could have also been a source of phosphorus in a much more soluble form.

Powner et al. (2009) recently developed an innovative idea for the prebiotic synthesis of ribonucleotides that side-steps the energetically unfavorable problem of joining together sugar, nucleobase, and phosphate, employing compounds abundant on early Earth to join them together simultaneously. The intermediate formed can then react with glyceraldehyde to yield precursors, which in the presence of phosphate, cyanoacetelene, and UV light, give rise to pyrimidine ribonucleotides. Elegantly, by-products from earlier steps of this reactive pathway help facilitate reactions at later stages. The groundbreaking discovery of this pathway for RNA synthesis breathed new life into the RNA world hypothesis. Prebiotically plausible synthetic schemes for purine ribonucleotides, however, have yet to be found.

Early RNA Replication

Once RNA nucleotides have been formed, the next step toward life would be their polymerization. In the watery environment where life most likely began on early Earth, however, the formation of the phosphodiester bonds  during the polymerization of RNA is not spontaneous and requires energy input. Experiments have shown that adding chemical catalysts can allow the formation of short RNA oligomers from 2 to 40 nucleotides long – this, however, does not adequately explain a prebiotic scenario.

Jim Ferris’s group, in the late 1990s, was able to tackle this problem by showing that clay minerals improve polymerization of RNA nucleotides by binding nucleotides to its surface, bringing molecules of RNA closer together which would allow them to more easily and likely to react. With the help of clay minerals, oligomers up to around 50 nucleotides long can be produced. Of course, 50-nucleotide oligomers are still a long way away from a modern gene that can consist of thousands and millions of nucleotides, but it does support a scenario where RNA nucleotides can elongate prebiotically. Some scientists surmise that life could have emerged in ponds with clay-based floors formed by hot springs.

The next step toward life would then involve reproduction. In this early stage, this would entail the replication of genetic info, or the nucleotide sequences of RNA polymers. There are currently two main models of early RNA replication. One is ribozyme-catalyzed, which means that a RNA enzyme catalyzes the addition of nucleotides on a template strand in the process of replication. The other model is non-enzymatic RNA replication. In this scenario, free activated nucleotides polymerize on a RNA template to form a complementary strand, driven by the departure of the leaving group that had activated each nucleotide. After the formation of a complementary  strand in either of the scenarios, the two strands could separate under heated conditions and would then serve as new templates for the formation of new complementary strands, one of which will be a replicate of the original template strand. In terms of research so far, these early RNA replication scenarios have not yet been fully simulated in laboratory settings.

The Need for Compartmentalization and the Formation of Early Membranes

At one point or another, ribozymes that catalyze RNA replication, or RNA replicases, would have come about according to modern biochemical thought regarding the origin of life. Compartmentalization, at this point, becomes crucial as it is the key to efficient RNA replication. By compartmentalizing replicases in membrane-bound structures like vesicles, replicases will only replicate what is in the compartment and avoid overwhelming itself with many different RNAs. Additionally, membranes would harbor controlled internal environments for important biochemical reactions. Thus, the evolution of membranes would have been adaptive.

Cell membranes nowadays are made of a lipid bilayer consisting of phospholipids and cholesterol, which encloses a cell’s working components to provide a barrier from the outside environment. Early cell membranes were likely to be much simpler, made up of fatty acids, a component of modernday phospholipids. These fatty acids could have formed near hydrothermal vents via catalysis by clay mineral surfaces, which allow the formation of hydrocarbon chains. In order to form primitive membranes in the form of micelles and vesicles especially, the fatty acids would have to be concentrated in a region. Lab work in the late 1970s has demonstrated that fatty
acids can, indeed, form fatty acid bilayer membranes spontaneously. Work in the Szostak lab has shown that membranes begin as spherical entities that grow thin filaments when new fatty acids are absorbed. The filaments can  easily break up into many smaller spheres, which could have been how the first protocells “divided”. In terms of a prebiotic scenario for such formation of primitive membranes, scientists have suggested that fatty acids could have accumulated in pools of water where primitive membranes spontaneously assembled. Once assembled, they are relatively stable but are very dynamic on the molecular level, with fatty acid molecules constantly leaving and joining the membrane and exchanging between the leaflets of the bilayer membrane. The flipping of the fatty acids between the layers may have, in fact, facilitated the entering of small molecules such as RNA nucleotides into the confines of the membrane.

It has been shown that nucleotides can, indeed, enter these primitive fatty acid membranes. In an experiment, fatty acid membrane vesicles, each with a short piece of single-stranded DNA inside, were exposed to an environment containing activated nucleotides. Results showed that the nucleotides were able to spontaneously cross through the membrane and complementarily base-pair to the single-stranded DNA inside the membrane.  Such an experiment confirms that the first protocells on Earth could have contained RNA, which could have replicated inside the protocells.

The Big Picture

It is easy to envision that with the ability for the self-assembly of membranes and the self-assembly of RNA, the two components eventually came together. It is possible, for example, that membranes enveloped pre-existing RNA oligomers during its formation and that the onset genetic replication was triggered by some external stimulus. Ricardo and Szostak (2009) present a scenario where the first protocells existed in a pond that was partially frozen and partially heated by a volcano. In such a scenario, nucleotides can enter the membrane of a protocell that has already formed around a polymerized single-stranded RNA sequence. A complementary strand can form and as the protocell nears the heated portion of the pond, the heat can separate the RNA strands. As fatty acid molecules are incorporated into the protocell membrane, the protocell can eventually divide into daughter cells each containing a copy of the genetic material. The start of such reproduction cycles likely opened the door for evolution, driven by mutation and natural selection, and the ability for protocells to reproduce by themselves—an event that would mark the origin of life.

Although we have come a long way from the idea of spontaneous generation in explaining the origin of life, there are still many gaps in our knowledge of how life could have emerged, providing an ongoing challenge for the labs continuing to delve into the past.

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