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A protocell (or protobiont) is a self-organized, ordered, spherical collection of lipids proposed as a rudimentary precursor to cells during the Abiogenesis. A central question in evolution is how simple protocells first arose and how their progeny could diversify, thus enabling the accumulation of novel biological emergences over time (i.e. biological evolution). Although a functional protocell has not yet been achieved In vitro, the goal to understand the process appears well within reach.
A protocell is a pre-cell in abiogenesis, and was a contained system consisting of simple biologically relevant molecules like , and encapsulated in a simple membrane structure – isolating the entity from the environment and other individuals – thought to consist of simple fatty acids, mineral structures, or rock-pore structures.
Another conceptual model of a protocell relates to the term "chemoton" (short for 'chemical automaton') which refers to the fundamental unit of life introduced by Hungarian people theoretical biologist Tibor Gánti. It is the oldest known computational abstract of a protocell. Gánti conceived the basic idea in 1952 and formulated the concept in 1971 in his book The Principles of Life (originally written in Hungarian, and translated to English only in 2003). He surmised the chemoton as the original ancestor of all organisms, or the last universal common ancestor.
The basic assumption of the chemoton model is that life should fundamentally and essentially have three properties: metabolism, self-replication, and a Cell membrane. The metabolic and replication functions together form an autocatalytic subsystem necessary for the basic functions of life, and a membrane encloses this subsystem to separate it from the surrounding environment. Therefore, any system having such properties may be regarded as alive, and will contain self-sustaining cellular information that is subject to natural selection. Some consider this model a significant contribution to origin of life as it provides a philosophy of evolutionary units.
In the aqueous environment in which all known cells function, a non-aqueous barrier is required to surround a cell and separate it from its surroundings.Morowitz HJ. (1992) Beginnings of Cellular Life. Yale University Press, New Haven and London This non-aqueous membrane establishes a barrier to free diffusion, allowing for regulation of the internal environment within the barrier. The necessity of thermodynamically isolating a subsystem is an irreducible condition of life. In modern biology, such isolation is ordinarily accomplished by Lipid bilayer of a thickness of around 10−8 meters.
Researchers including Irene A. Chen and Jack W. Szostak have demonstrated that simple physicochemical properties of elementary protocells can give rise to simpler conceptual analogues of essential cellular behaviors, including primitive forms of Darwinian competition and energy storage. Such cooperative interactions between the membrane and encapsulated contents could greatly simplify the transition from replicating molecules to true cells. Competition for membrane molecules would favor stabilized membranes, suggesting a selective advantage for the evolution of cross-linked fatty acids and even the of today. This micro-encapsulation allowed for metabolism within the membrane, exchange of small molecules and prevention of passage of large substances across it. The main advantages of encapsulation include increased solubility of the cargo and creating energy in the form of chemical gradients. Energy is thus often said to be stored by cells in molecular structures such as (including sugars), , and , which release energy when chemically combined with oxygen during cellular respiration.
Rather than being made up of phospholipids, early membranes may have formed from monolayers or bilayers of simple fatty acids, which may have formed more readily in a prebiotic environment. Fatty acids have been synthesized in laboratories under a variety of prebiotic conditions and have been found on meteorites, suggesting their natural synthesis in nature. Oleic acid vesicles represent good models of membrane protocells
Cohen et al. (2022) suggest that plausible prebiotic production of fatty acids — leading to the development of early protocell membranes — is enriched on metal-rich mineral surfaces, possibly from impact craters, increasing the prebiotic environmental mass of lipids by 102 times. They evaluate three different possible synthesis pathways of fatty acids in the Hadean, and found that these metal surfaces could produce 1011 - 1015 kg of 6-18 carbon fatty acids. Of these products, the 8-18C fatty acids are compatible with membrane formation. They also propose that alternative amphiphiles like alcohols are co-synthesized with fatty acid, and can help improve membrane stability. However, despite this production, the authors state that net fatty acid synthesis would not yield sufficient concentrations for spontaneous membrane formation without significant evaporation of Earth's aqueous environments.
Protocells composed of fatty acids would have been able to easily exchange small molecules and with their environment. Modern phospholipid bilayer cell membranes exhibit low permeability, but contain complex molecular assemblies which both actively and passively transport relevant molecules across the membrane in a highly specific manner. In the absence of these complex assemblies, simple fatty acid based protocell membranes would be more permeable and allow for greater non-specific transport across membranes. Molecules that would be highly permeable across protocell membranes include nucleoside monophosphate (NMP), nucleoside diphosphate (NDP), and nucleoside triphosphate (NTP), and may withstand millimolar concentrations of Mg2+. Osmotic pressure can also play a significant role regarding this passive membrane transport.
Environmental effects have been suggested to trigger conditions under which a transport of larger molecules, such as DNA and RNA, across the membranes of protocells is possible. For example, it has been proposed that electroporation resulting from lightning strikes could enable such transport. Electroporation is the rapid increase in bilayer permeability induced by the application of a large artificial electric field across the membrane. During electroporation, the lipid molecules in the membrane shift position, opening up a pore (hole) that acts as a conductive pathway through which hydrophobic molecules like can pass the lipid bilayer. A similar transfer of content across protocells and with the surrounding solution can be caused by freezing and subsequent thawing. This could, for instance, occur in an environment in which day and night cycles cause recurrent freezing. Laboratory experiments have shown that such conditions allow an exchange of genetic information between populations of protocells. This can be explained by the fact that membranes are highly permeable at temperatures slightly below their phase transition temperature. If this point is reached during the freeze-thaw cycle, even large and highly charged molecules can temporarily pass the protocell membrane.
Some molecules or particles are too large or too hydrophilic to pass through a lipid bilayer even under these conditions, but can be moved across the membrane through fusion or budding of Lipid vesicle, events which have also been observed for freeze-thaw cycles. This may eventually have led to mechanisms that facilitate movement of molecules to the inside of the protocell (endocytosis) or to release its contents into the extracellular space (exocytosis).
A study in the 1990s showed that montmorillonite clay can help create RNA chains of as many as 50 nucleotides joined together spontaneously into a single RNA molecule. Later, in 2002, it was discovered that by adding montmorillonite to a solution of fatty acid micelles (lipid spheres), the clay sped up the rate of vesicle formation 100-fold.
Some minerals can catalyze the stepwise formation of hydrocarbon tails of fatty acids from hydrogen and carbon monoxide gases—gases that may have been released from hydrothermal vents or . Fatty acids of various lengths are eventually released into the surrounding water, but vesicle formation requires a higher concentration of fatty acids, so it is suggested that protocell formation started at land-bound hydrothermal freshwater environments such as , mud pots, and other geothermal features where water evaporates and concentrates the solute.
In 2019, Nick Lane and colleagues show that vesicles form readily in seawater conditions at pH between 6.5 and >12 and temperatures 70 °C, meant to mimic the conditions of alkaline hydrothermal vents, with the presence of lipid mixtures, however a prebiotic source to such mixtures is unclear in those environments. Simple amphiphilic compounds in seawater do not assemble into vesicles because of the high concentration of ionic solutes. Research has shown that vesicles can be bound and stabilized by prebiotic amino acids even while in the presence of salt ions and magnesium ions.
In hot spring conditions, self-assembly of vesicles occurs, which have a lower concentration of ionic solutes. Scientists RNA in alkaline hydrothermal vent conditions in the laboratory. Although they were estimated to be 4 units in length, it implies RNA polymers possibly were synthesized at such environments. Experimental research at hot springs gave higher yields of RNA-like polymers than in the laboratory. The polymers were encapsulated in fatty acid vesicles when rehydrated, further supporting the hot spring hypothesis of abiogenesis. These wet-dry cycles also improved vesicle stability and binding. UV exposure has also been shown to promote the synthesis of stable biomolecules like nucleotides.
In the origin of chemiosmosis, if early cells originated at alkaline hydrothermal vents, proton gradients can be maintained by the acidic ocean and alkaline water from white smokers while an inorganic membranous structure is in a rock cavity. If early cells originated in terrestrial pools such as hot springs, quinones present in meteorites like the Murchison meteorite would promote the development of proton gradients by coupled redox reactions if the ferricyanide, the electron acceptor, was within the vesicle and an electron donor like a sulfur compound was outside of the lipid membrane. Because of the "water problem", a primitive ATP synthase and other biomolecules would go through hydrolysis due to the absence of wet-dry cycles at hydrothermal vents, unlike at terrestrial pools. Other researchers propose hydrothermal pore systems coated in mineral gels at deep sea hydrothermal vents to an alternative compartment of membranous structures, promote biochemical reactions of biopolymers, and could solve the "water problem". David Deamer and Bruce Damer argue that biomolecules would become trapped within these pore systems upon polymerization and would not undergo combinatorial selection. Catalytic FeS and NiS walls at alkaline hydrothermal vents has also been suggested to have promoted polymerization.
However, Jackson (2016) evaluates how the pH gradient between alkaline hydrothermal vents and acidic Hadean seawater might influence prebiotic synthesis. Three main criticisms emerge from this evaluation. Firstly, the maintenance and stability of membranes positioned suitably between turbulent pH gradients seemed implausible. They claim that the proposition of CaCO3 and Mg(OH)2 precipitates interacting with fluid mixing in subsurface pores do not produce satisfactory environments. Secondly, they suggest that the molecular assemblies required to utilize key energetic gradients available at hydrothermal systems were too complex to have been relevant at the origin of life. Lastly, they argue that even if a molecular assembly could have harvested available hydrothermal energy, those assemblies would have been too large to operate within the proposed membrane thicknesses accepted by proponents of the hydrothermal vent hypothesis. In 2017, Jackson takes a further stance, suggesting that even if an organism successfully originated in alkaline hydrothermal pores, exploiting natural pH gradients for energy, it would not be able to withstand the drastic change of environment after emergence from the vent environment in which it had solely evolved. This emergence, however, is essential to the niche differentiation of life, allowing for the diversification of habitats and energetic strategies. Counters to these arguments suggest that the close resemblance between biochemical pathways and geochemical systems at alkaline hydrothermal vents gives merit to the hypothesis, and that selection on these protocells would improve resilience to environmental change, allowing for emergence and distribution.
It has been considered by other researchers that life originating in hydrothermal volcanic ponds exposed to UV radiation, zinc sulfide photocatalysis, and occurrence of continuous wet-dry cycling would not resemble modern biochemistry. Maximal ATP synthesis is shown to occur at high water activity and low ion concentrations. Despite this, hydrothermal vents are still considered to be a feasible environment as some shallow hydrothermal vents emit freshwater and the concentration of divalent cations in Hadean oceans were likely lower than in modern oceans. Nick Lane and coauthors state that "alkaline hydrothermal systems tend to precipitate Ca2+ and Mg2+ ions as aragonite and brucite, so their concentrations are typically much lower than mean ocean values. Modelling work in relation to Hadean systems indicates that hydrothermal concentrations of Ca2+ and Mg2+ would likely have been <1 mM, which is in the range that enhanced phosphorylation here. Other conditions considered here, including salinity and high pressure, would have only limited effects on ATP synthesis in submarine hydrothermal systems (which typically have pressures in the range of 100 to 300 Bars). Alkaline hydrothermal systems might also have generated Fe3+ in situ for ADP phosphorylation. Thermodynamic modelling shows that the mixing of alkaline hydrothermal fluids with seawater in submarine systems can promote continuous cycling between ferrous and ferric iron, potentially forming soluble hydrous ferric chlorides, which our experiments show have the same effect as ferric sulphate".
Vulnerability to damage could be reduced by maintaining two or more copies of each RNA segment in each protocell, i.e. by maintaining diploidy or polyploidy. Genome redundancy would allow a damaged RNA segment to be replaced by an additional replication of its homolog. For such a simple organism, the proportion of available resources tied up in the genetic material would be a large fraction of the total resource budget. Under limited resource conditions, the protocell reproductive rate would likely be inversely related to ploidy number, and the protocell's fitness would be reduced by the costs of redundancy. Consequently, coping with damaged RNA genes while minimizing the costs of redundancy would likely have been a fundamental problem for early protocells.
A cost-benefit analysis was carried out in which the costs of maintaining redundancy were balanced against the costs of genome damage. This analysis led to the conclusion that, under a wide range of circumstances, the selected strategy would be for each protocell to be haploid, but to periodically fuse with another haploid protocell to form a transient diploid. The retention of the haploid state maximizes the growth rate. The periodic fusions permit mutual reactivation of otherwise lethally damaged protocells. If at least one damage-free copy of each RNA gene is present in the transient diploid, viable progeny can be formed. For two, rather than one, viable daughter cells to be produced would require an extra replication of the intact RNA gene homologous to any RNA gene that had been damaged prior to the division of the fused protocell. The cycle of haploid reproduction, with occasional fusion to a transient diploid state, followed by splitting to the haploid state, can be considered to be the sexual cycle in its most primitive form. (1991). 9780120928606, Academic Press. ISBN 9780120928606 see pgs. 293-297 In the absence of this sexual cycle, haploid protocells with damage in an essential RNA gene would simply die.
This model for the early sexual cycle is hypothetical, but it is very similar to the known sexual behavior of the segmented RNA viruses, which are among the simplest organisms known. The Orthomyxoviridae, whose genome consists of 8 physically separated single-stranded RNA segments, is an example of this type of virus. In segmented RNA viruses, "mating" can occur when a host cell is infected by at least two virus particles. If these viruses each contain an RNA segment with a lethal damage, multiple infection can lead to reactivation providing that at least one undamaged copy of each virus gene is present in the infected cell. This phenomenon is known as "multiplicity reactivation". Multiplicity reactivation has been reported to occur in influenza virus infections after induction of RNA damage by UV-irradiation, and ionizing radiation.
In a similar synthesis experiment a frozen mixture of water, methanol, ammonia and carbon monoxide was exposed to ultraviolet (UV) radiation. This combination yielded large amounts of organic material that self-organised to form globules or vesicles when immersed in water. The investigating scientist considered these globules to resemble cell membranes that enclose and concentrate the chemistry of life, separating their interior from the outside world. The globules were between , or about the size of red blood cells. Remarkably, the globules fluoresced, or glowed, when exposed to UV light. Absorbing UV and converting it into visible light in this way was considered one possible way of providing energy to a primitive cell. If such globules played a role in the origin of life, the fluorescence could have been a precursor to primitive photosynthesis. Such fluorescence also provides the benefit of acting as a sunscreen, diffusing any damage that otherwise would be inflicted by UV radiation. Such a protective function would have been vital for life on the early Earth, since the ozone layer, which blocks out the sun's most destructive UV rays, did not form until after photosynthetic life began to produce oxygen.
Additionally, postulation into the conditions for protocellular origins of life on Earth remain debated. Scientists in the field emphasize the importance of further hypothesis based experimentation over theoretical conjecture to more concretely constrain the prebiotic plausibility of different protocell morphologies, geologic conditions, and synthetic schemes.
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