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The cell. 1. Introduction.

The ORIGIN of the CELL

The theory of the origin of life is the theory of the origin of the cell. It is not known how the first cell appeared on Earth, but it is widely accepted that it was by physicochemical processes. Towards the twenties of the last century, A.I. Oparin and J.B.S. Haldane proposed the first physicochemical theories on the origin of life (also suggested by C. Darwin in one of his personal letters). The development of theories about the emergence of the first cells is based on suggestions and laboratory experiments that simulate the conditions thought to be present during the origin of life on Earth.

The origin of life as a physicochemical process has consequences in the field of biology. a) We can create life. A cell could be made from scratch by using molecules that exist in today's cells and placing them together into a membranous compartment. Currently, synthetic biology, a branch of biology, is undertaking the first serious attempts to make a new cell from just molecules. The whole DNA of a prokaryotic cell has already been synthesized in the laboratory, introduced into a protoplasm, and a new functional new cell was obtained. A complete eukaryotic chromosome has also been synthesized. b) Existence of extra-terrestrial life. Physicochemical conditions, similar to those present on Earth during the origin of life, may have occurred elsewhere in the Universe. So, life forms could have appeared in the past and may exist today in other parts of the Universe. Extraterrestrial life may have emerged in many planets and many times, perhaps it is happening right now.

1. What is a living organism?

When searching for the origin of life, it is first needed to know what a living organism is. We are all able to recognize a living organism, but it is more complicate to write a definition of what a living being is. It could be said that life is one of the properties that a living organism must have. However, there is a new problem: what is life? There is no one definition of life that is widely accepted by the scientific community. It is a paradox that Biology, part of the science dealing with living organisms, is studying something that is not yet precisely defined. Everybody can identify a living organism, but not because we have a precise definition. The perception of life is just a feeling. Nowadays, scientists often define life not with a single statement, but as a set of properties that an organism should fulfill to be considered as a living organism. Again, there is no general agreement on how many and what these properties are, but some of the most popular are the following:

a) Reproduction and transmission of information encoded by deoxyribonucleic acid (DNA).
b) Maintaining homeostasis by using external energy (metabolism).
c) Ability to respond to external and internal stimuli.
d) Ability to evolve by Darwinian evolution (variation and natural selection).
e) Some others.

2. Where did the first cells appear?

The drawbacks of not having a precise definition of life undermine the search for life in other planets. We can recognize what we are looking for, but only because it may be similar to living organisms that we have on Earth, and not by a good definition. So, if there are organisms in very unusual forms in other planets, we may overlook them or we may not be able to classify them as living beings. Some of the organic molecules that make up living organisms on Earth are known to be also present in other planets, as well as in the outer space. This is one of the reasons why the existence of life in other planets similar to Earth may be plausible, i.e. there are bricks for the building. Another reason is the discovery of water in other planets. Water was neccessary for the origin of life on Earth and it is essential for nowadays living beings.

The theory of panspermia (literally seeds everywhere) proposes an extraterrestrial origin of life or at least an extraterrestrial origin of the "seeds" that triggered the origin of cells on Earth. These seeds are supposed to be more or less complex organic molecules. A number of observations support this theory. For example, asteroids, some of them coming from Mars, contain complex organic molecules and it is known that in the outer space there is a huge amount of organic molecules. Although there is no evidence that cells reached Earth from another planet, it is thought there was a heavy “rain” of organic molecules during the first ages of the Earth, being a great source of organic material to be used during the origin of cells. In any case, the origin of the cell is still a physicochemical process.

3. When did the first cells appear?

The Earth is about 4500 x 106 years old. The fossils indicate that the first cells were already on Earth between 3500 x 106 and 3800 x 106 years ago (Figure 1). During the first 500 x 106 years, the environmental conditions were not suitable for living forms due to high temperature, lack of protective atmosphere, intense “rain” of meteorites, etcetera. However, 1000 or 1200 x 106 years later the first cells could have left sedimentary deposits and organic molecules as a consequence of their metabolism. It means that the physicochemical processes leading to the first living organisms should have started earlier, in a period callled the prebiotic era.

History clock
Figure 1. Temporal sequence of some relevant events since the beginning of life on Earth.

4. How did the first cell appear?

We can imagine the steps, starting from simple molecules until the appearance of the first cells, and therefore the emergence of life. There is no agreement on how many steps there were, what the order was, or how these steps occurred, but the main stages during the origin of cells may have been as follows:

Organic molecules

Miller-Urey experiment
Figure 2. Drawing of the device of Miller and Urey. This device were used to demonstrate the formation of complex organic molecules from simple organic ones. The chemical reactions were developed in an environment that was supposed to be similar to that present in the early Earth. Experiments were done in the fifties of the twentieth century.

Organic molecules, plus water and some ions, are the building blocks of living organisms. The most relevant are proteins, nucleic acids, sugars and fat. How were they synthesized in early Earth? There are several plausible scenarios. a) Extreme environmental conditions. If a flask containing CO2, ammonia, methane and hydrogen, is heated to high temperature and subjected to electric discharges, some complex organic molecules are obtained, such as hydrogen cyanide, formaldehyde, some amino acids, some sugars, purines and pyrimidines (neecessary for nucleotide synthesis). This was the experiment carried out by Miller and Urey when they were trying to replicate the earliest environment on Earth (Figure 2). It does not prove that the origin of life was like this. However, it shows that complex organic molecules can be formed by physicochemical reactions. Furthermore, different places on early Earth could have had distinct environmental features that yielded different sets of complex organic molecules. Plausible sites for prebiotic synthesis are hot sea vents, fumaroles and hot springs, where strong temperature gradients and high water pressure can be found, in addition to minerals. Minerals may have been key players because they could function as catalyzers facilitating chemical reactions. b) Extraterrestrial origin. It has been shown that more or less complex organic molecules can be synthesized in the outer space, and they can be found in comets and meteorites. It is possible that a huge amount of extraterrestrial organic compounds reached the surface of the Earth, which could have then started the chemical reactions for the origin of life.

Polymers

So, we already have organic molecules. However, the most relevant molecules for the cell are present as organic polymers: amino acids as protein units, nucleotides as DNA and RNA units, and some sugars as starch and glycogen. Nowadays, cells synthesize these polymers, but on early Earth it was a problem because joining molecules to make long chains is not an easy task. A good polymerization system that could have been worked properly at the origin of life has not yet been found. However, several hypothesis have been proposed. a) Heating and drying. In the laboratory, heating semi-dry compounds have been shown to produce chains of organic molecules. b) Minerals. Catalysis by minerals, such as polyphosphates and other catalytic minerals, produces polymers having randomly ordered units. The minerals could have been sheltered places in an adverse atmosphere and the surface of some minerals, such as clay, can act as catalytic centers for chemical reactions, which together with heat and water can produce polymers. In laboratory experiments, this process has been demonstrated for RNA and fatty acids, which are neecessary for cell membranes. c) Fumaroles. Again, sea vents, fumaroles and hot springs provide strong gradients of temperature and water pressure that facilitate chemical reactions. Currently, organic molecules are produced in fumaroles. d) Hydrothermal vents in fresh terrestrial water. They are places near volcanoes where hydration and drying cycles can concentrate organic compounds and facilitate chemical reactions at high temperatures. Furthermore, these environments are more suitable for spontaneous membrane assembly than the sea, and there are low concentrations of calcium and magnesium, ions that inhibit the formation and integrity of membranes. Rather than in the sea, many studies point to terrestrial hydrothermal vents as the places where the origin of the cells took place. e) Lipid membranes. In several laboratory experiments has been demonstrated that the surface of lipid membranes, such as cell membranes, can attract, select and concentrate simple organic molecules. In membranes, organic molecules are in close proximity and the lipid environment can facilitate chemical reactions such as those involving nucleotides and aminoacids. This scenario is interesting because it solves two questions: why only a few specific types of organic molecules were included in membrane bags or vesicles, and how the protocells were first formed.

Cell membrane

One of the major steps towards the birth of the first cells was the development of a barrier to separate the intracellular and extracellular environments. Membranes provide many advantages: a) molecules for metabolic reactions are held together and are not lost by diffusion; therefore, the probability of chemical reactions is higher and hence more efficient; b) internal molecules are not shared with neighbors, so new advantageous molecules for new chemical pathways are not used by competitors; c) a proper internal environment can be set to enhance chemical reactions and to counteract or buffer external environmental changes as well. This is known as homeostasis. Lipid membranes can be easily made from amphipathic lipids, which have hydrophilic and hydrophobic parts. All cell membranes contain amphipathic lipids: glycerophospholipids and sphingolipids. However, the ancient membrane lipids could have been different because the current membrane lipids require a complex metabolic pathway to be synthesized. Whatever they were, when added to aqueous solutions, and after applying mechanical forces to the solution, amphipathic lipids spontaneously form thin sheets, which are similar to cell membranes. Current membrane lipids have two fatty acid chains. This feature allows the formation of membranes at a micromolar concentration of lipids. Single-chain fatty acid pids require milimolar concentrations to spontaneously form a membrane. Furthermore, 10 to 14 carbons in fatty acid chains make the membrane structure more stable. It is possible to regulate membrane fluidity by changing the number of double bonds between the carbons and the concentration of sterols. It is unknown what type of lipids were components of the first membranes, but the current membranes are all made up of glycerophospholipids and sphingolipids, as well as sterols.

Protocell
Protocells

Two ways for the association between organic molecules, such as nucleotides or amino acids, and membranes have been suggested. a) It is plausible that water shaking could have led membranes sheets to form vesicles or small bags that enclosed groups of molecules. By chemical reactions, these molecules increased in number and the vesicle became larger. At one point, the vesicles gained the ability to divide by strangulation, giving rise to two new vesicles with the same types of molecules inside as the mother vesicle. The grow of the vesicles could have happened thanks to the properties of the membrane: allowing the extracellular supply of small molecules that could freely cross the membrane, but hampering the exit of larger molecules (sucha as polymers). b) Another scenario suggests that there was an association between simple organic molecules and lipid membranes. The membranes attracted and increased the concentration of organic molecules on their surfaces and facilitated chemical reactions. Thus, polymers (oligopeptides and oligonucleotides) originated in close association with membranes and gained complexity over time. At one point, these macromolecules became trapped into vesicles or, if synthesized on vesicles membranes, they acquired the ability to cross the membrane and remain within the vesicle. If this mechanism is the real one, it is convenient to reconsider the order of events because the membranes were then the most important elements during the formation of the first protocells.

Autoreplication

Another major step during the origin of life was the increase in the number of some polymers that could maintain a similar sequence of monomers, i.e., it was possible to produce copies of some polymers. It has been suggested that it could have happened by self-replication. Some molecules were capable of making copies of themselves. It led to a main property of life: the transmission of information. There are two types of information that can be transmitted by the self-replication of polymers: the particular sequence of monomers and the spatial organization of the newly synthesized molecule (the 3D structure depends on the sequence of monomers). Do we have already a genotype and a phenotype? The monomers and energy to synthetize these polymers were taken from the environment because they could cross membranes. Within the vesicles, more or less accurate copies of some polymers were made. However, the self-replication process could make mistakes leading to variations of the monomer sequences. Some polymers with slightly different sequences could have performed better during their own replication and yield more copies. Then, membrane vesicles with more productive molecules could grow faster, get more external resources and leave more offspring. Thus, we have a competition for external resources by populations of vesicles having different sets of polymers. They had discovered another property of life: variability and natural selection, i.e., Darwinian evolution. Some authors think that one type of molecule could not accomplished all these steps on its own. Instead, the groups of molecules connected by chemical reactions could have grown by increasing the number of every molecular type in the network. During the division of the vesicles, complete sets of molecules were distributed in the two new generated vesicles. Thus, we have the self-replication of the entire molecular network. This should have been flexible enough to change the weights of the chemical connections, as well as to incorporate new elements.

Mundo ARN
RNA world
tRNA
Figure 3. 3D form of a transfer RNA molecule present in the current cells. Complementary nucleotides from different parts of the molecule stablish electrical interactions (green lines), and fold the polymer into a particular 3D conformation.

If a single type of molecule is assumed to be the first self-replicator, what one was it? DNA is not a very reactive molecule and must be “manipulated” by proteins, which are the true workers of cells. In the current cells, proteins are synthesized from DNA-based information and DNA needs proteins. Then, which came first, proteins or DNA? The eyes turn to the RNA (Figure 3). Some RNA molecules have the ability to carry out enzymatic reactions (that is why they are known as ribozymes). For example, ribonucleoproteins can cut RNA molecules and join them (RNA splicing), and protein synthesis on ribosomes is accomplished by ribosomal RNA. Furthermore, it is plausible, although unlikely, that RNA molecules could make copies of themselves by synthesizing a sequence complementary to their own nucleotide sequence. The nucleotide sequence is known to determine the 3D form of RNA, influencing stability and activity. Thus, sequence and spatial conformations may have worked together to make molecules more competitive by increasing their stability and yielding more copies. In this scenario, some errors may have occureed during the copying process ("mutations") that gave more or less stable molecules. Darwinian competition and selection could have started. Over time, the vesicles were enriched for those RNAs that make copies more efficiently. Thus, sequence (genotype?) and spatial conformation (phenotype?) could provide profitable features. All these steps have been proposed that occurred during the prebiotic period on Earth, and are included in a theory known as the RNA world.

However, a “metabolic world” based on networks of chemical reactions also has some experimental support. In this model, replication was not carried out by a single type of molecule, but by a group of molecules connected by chemical reactions. At some point, a membrane was also needed, as was the growth and division of the system, and the ability to change (for example, increasing the complexity of the system). Authors supporting the “metabolic world” do not discard a major role for RNA during the origin of life. However, RNA could have participated during later steps in the evolution of these molecular systems. In fact, some authors suggest that RNA would initially be a parasite of the chemical systems. Eventually, the RNA took control of the system.

Molecular interactions

Independently of self-replication and competition, interactions should have occured between different types of molecules (polypeptides, DNA, RNA, lipids, sugars), leading to complex chemical systems. It can be imagined that the association of two types of molecules, let's say RNA and some polypeptides, would have ended up being beneficial for both. Later, the complexity increased and new molecules came into the net of chemical interactions like DNA. Over the time, the entire molecular mix evolves and faces environmental selection by changing interactions between each other. This introduces a new concept: coevolution of molecular forms. This could have happened 3500-4000 x 106 years ago.

Genetic code

At some point in this story, RNA must have been involved in the synthesis of proteins (polypeptides). This was a critical step because a code was invented, with 3 particular nucleotides in a particular order meaning a particular amino acid. This code is known as the genetic code, which is present in all living organisms. Every cell studied so far shows the same nucleotide triplets for the same amino acids (with some minor exceptions). The universality of the genetic code indicates that it was invented only once and was inherited by all living organisms. Then, all living forms are connected by lineages of descendants, creating generation after generation a tree of life. Organisms at its root invented the genetic code. These first organisms are known as LUCA (last universal common ancestor).

DNA

In current cells, the information inherited by a generation of cells from a previous one is encoded in DNA, not in RNA, neither in proteins. Compared to RNA, DNA is a more stable molecule because it is double strand, it is easier to replicate and repair. There is a type of enzymes known as reverse transcriptases with the ability to translate RNA sequences into DNA sequences. Many viruses, such as the AIDS virus, contain this enzyme to convert information of from RNA (present in the infectious phase: virion) into DNA to enable replication within the host cell. At some point before LUCA, information passed from RNA to DNA, which became the container for storing, transcribing and transmitting the information neccesary to form a new protocell.

There are many uncertainties and controversies about each one of these steps, and others not mentioned above. How did the events happen?, what were the most important molecules?, what was the real environment in every step?, and many more questions are still under heated debate. There is no doubt that knowing how was the origin of life, i.e., the origin of the first cells, is one of the main scientific challenges.

Bibliography

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