Have you ever wondered what is the most primitive form of life on Earth? If cells are the smallest single units of life, then what came before it?
To tackle these questions, we must dive into the biochemistry of biological molecules to unveil some answers.
The fundamentals of molecular biology
Life forms on Earth are composed of four main elements - carbon, hydrogen, oxygen and nitrogen. Together, these elements can be arranged stoichiometrically (with different chemical formula) or spatially (how atoms are positioned in space relative to an organic molecule, namely the carbon chain) into different organic compounds. Organic compounds are any molecules that contain carbon. Different groups of organic compounds include carbohydrates, lipids, proteins and nucleic acids - these are the essential building blocks of cells across all kingdoms of life. DNAs and RNAs carry genetic codes made from sugar phosphate backbones; lipids bilayers make up biological membranes on cells; proteins have a critical role in a vast range of functions such as metabolism; and carbohydrates can act as fuel source to generate energy.
To further study this, we will revisit the key biomolecular components present in cells.
Lipids
Lipids are made from long chains of hydrocarbons, some kinkier (e.g. saturated hydrocarbon chains) than others. They are generally hydrophobic macromolecules that are soluble in non-polar solvents such as benzene. Both lipids and benzene are classified as non-polar substances as they do not have a dipole. In other words, the electrons are equally shared between atoms with no overall charge (as the polar bonds in a large molecule cancel each other out).
The basic subunits for fats and lipids are fatty acid molecules. Meanwhile, a common type of lipid found in blood is triglycerides, it is composed of three fatty acid chains bound to a glycerol head. Fatty acids consist of an oxygen head group and a long, non-polar aliphatic tail. The hydrophobic nature in fatty acid tails make them suitable for forming selectively permeable membranes in cells by preventing the random passage of charged hydrophilic molecules across the cell, which can potentially disrupt the osmotic pressure maintained across the membrane. Additionally, lipids can act as an energy reserve, helping in insulation and shock absorption. As a result, lipids can reduce the magnitude of vibrating motion in the body.
Figure 1: An illustration of the chemical structure of fatty acids. On the left-hand side, the top structure shows the formula for unsaturated fatty acid tails (the kinky tails contain double bonds, which produces the kink); whereas the bottom structure represents saturated fatty acid tails, made of only single bonds in hydrocarbon chain. On the right-hand side, the peach-coloured circles symbolise the polar phospholipid head that is water soluble, with non-polar fatty acid tails highlighted as black lines. Phospholipids are the main constituents of cell membranes. Saturated fats tend to be solid at room temperature, but unsaturated fats tend to be liquids.
Carbohydrates are organic compounds consisting of carbon, hydrogen and oxygen. They are usually expressed by the general formula Cx(H2O)y. It is the most profuse organic compound and has a vast range of functions in the biochemistry of the body.
For instance, humans consume carbohydrates as fuels to generate energy for the body. It is the main source of energy and its consumption is a prerequisite for all living organisms on Earth. Interestingly, the human brain is the most energy-demanding organ, but it can only metabolize glucose. Hence, having breakfast is a highly important ritual as our glucose levels are closely linked to work efficiency.
Nucleic acids are believed by many to be the starting point of life. It is a biopolymer and an essential component for all known life forms, even viruses (although it is still controversial whether they are alive or not).
There are two general classes of nucleic acids, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), composed of a sugar deoxyribose and ribose respectively. Both are made of nucleotide monomers, which are each constructed with a 5’ carbon sugar, phosphate group, and a nitrogen-containing base.
DNA is a double-stranded helix, whereas RNA is a single stranded molecule that is often folded into stable structures such as the hairpin loop. In our cells, DNA code for different proteins, and they sit in the nucleus of a cell. During the expression (i.e. transcription) of a gene, particular sequences of DNA are transcribed into complementary RNA strands. These are delivered into the cytoplasm via nuclear pores to undergo translation.
Proteins are large polymers that are made of repeating units of amino acid subunits, whereby each of them is linked via amide bonds. There are 20 different amino acid building blocks in our body, with each of them having different physical and chemical properties. But all are primarily made of nitrogen, carbon, hydrogen and oxygen.
Protein synthesis occurs primarily inside the rough endoplasmic reticulum compartment, where ribosomes reside. Afterwards, post-translational modifications (PTM) of the protein can occur through numerous chemical or enzymatic processes such as biotinylation, whereby vitamin H (a.k.a. biotin) is covalently attached to a specific position on a protein. One major purpose of PTM includes increasing protein diversity and hence functions.
Check out the diagram below to get an idea of another type of common protein modifications:
Figure 2: This diagram showcases the one of the important posttranslational modifications (PTMs) that can occur to change the function or specificity of a newly made protein. Protein glycosylation is an enzyme-driven process that takes place both in the Golgi body as well as the endoplasmic reticulum. This reaction is essential in modulating the mechanism of proteins, as it affects the activity and reactivity of the protein made. The structure in the far left contains a high mannose sugar structure where individual shapes represent different sugar types. Here, the green circles represent mannose, the blue squares are N-acetylglucosamine (GlcNAc), and the black diamonds are sialic acid. As we progress from left to right, the sugar chain is modified with different sugar molecules, whereby some are added whilst others are removed. This image is adapted from https://www.uab.edu/BiomedFTICR/research/proteinglycosylation.php.
A contemporary theory on the origin of origins?
One of the most popular theories on the origin of life is the chemical evolution, where primitive molecules such as amino acids and lipids are theorized to have assembled under the abiotic geochemical atmosphere 3.5 to 4 billion years ago.
This idea was proposed by the Soviet biochemist, Aleksandr Ivanovich Oparin (1894-1980), in his book “The Origin of Life on Earth.” This sparked the pursuit of understanding how elements and small molecules can transform, self-assemble and evolve into more complex structured systems before emerging as the first form of life on Earth.
To test this hypothesis, scientists across various disciplines of sciences began tackling this concept by recreating life in a test tube.
What is evolution?
The word ‘evolution’ means change over time.
Biological evolution, which was first discovered by Darwin, describes the change in inherited traits over consecutive generations in the lineages of populations of organisms. Desired heritable characteristics or alleles are naturally selected by environmental pressures that are imposed on specific ecological habitats, favouring the reproduction of organisms with fitness advantage. Adaptive changes are made, and populations become better able to survive. As a result, biological evolution can drive the acquisition of new traits and abilities. For instance, when bacteria develop antibiotic resistance to penicillin, it will survive even if it is grown in a medium with penicillin.
Three key steps are required for this to occur - reproduction, variation and selection. The discovery of biological evolution was a breakthrough as it can explain the possession of complex traits (a trait that does not follow the Mendelian Inheritance laws such as a person’s height). Nevertheless, reproduction is indispensable for biological evolution.
But how did it all begin?
What is chemical evolution?
To tackle this problem, the concept of chemical evolution is explored.
Chemical evolution refers to the formation of complex organic molecules or entire chemical systems through chemical reactions in the early days of the young planet. In a chemical system, where molecules are free to collide and interact with one another, the direction of evolution is often towards simplicity; proteins denature when excess heat is applied, whereas oxidation occurs when metal reacts with oxygen to cause corrosion.
Therefore, there must be a way in which molecules can evolve to form diverse structures and increase in sophistication. Similar to biological evolution, chemical evolution requires a form of reproduction - repetitive production. This is a much simpler process and can be triggered by natural phenomena including lightning, wave propagation, erosion, tidal flow, and natural disasters like electromagnetic pulses and volcanic eruptions. These events are repetitive and create the primordial earth into a reaction vessel that produces new molecules and chemical systems. Over time, more molecules are generated, and they often obtain new characteristics.
An example to exemplify this is via the formation of fatty acids. Through experiments, scientists are able to build an entire chain of fatty acid in a lab by heating simple gases: carbon monoxide (CO) and hydrogen (H2) along with minerals found in Earth’s crust. This was done by re-creating the scenario where the Earth’s magma heats up underground chambers and assembles various simple molecules, like fatty acids. As pressure builds, these molecules rise to pools of water. When they encounter water, a simpler version of natural selection occurs as molecules will have different densities, dictating whether they will float or sink. Individual fatty acid chains will remain buoyant in warm water, rising in numbers as the cycle continues.
Once enough fatty acids have accumulated, a ball-like structure called micelle will form through the self-assembly of lipid molecules in a spherical form as a response to the polar nature of water. The oxygen head groups on fatty acids would then interact with water molecules to form hydrogen bonds, whereas the hydrophobic tails repel water but can form van der Waals interactions with other fatty acid tails. Over time, the concentration of micelles increases as they begin to merge into a large sheet. The dynamics in the sheet allows for edges to fuse, and the sheet eventually gets moulded into a round hollow ball, effectively resembling the membrane structure of a cell.
The formation of this new structure enables it to adopt a new function - separating material in its core from the outside, whilst creating a new chemical environment in the inside for evolution. It is believed that other molecules and systems are developed simultaneously, which interplay between systems that are involved in the birth of the first cell on Earth.
To help you understand this better, do check out this YouTube video: https://www.youtube.com/watch?v=mRzxTzKIsp8.
Figure 3: Diagrams demonstrating the cross-sectional, 3D differences between micelle. A micelle is a single layer of phospholipids sheet that is folded into a circle, creating a hydrophobic centre composed of fatty acid tails with hydrophilic phosphate heads facing outwards, thereby making the structure water soluble. In contrast, the phospholipid bilayer membrane is stretched out, the top and bottom hydrophilic layers enclose a non-polar core. Similarly, both of the two structures are soluble in water. This image is adapted from https://en.wikipedia.org/wiki/Micelle.
Any other popular theories on how life began?
Another prevailing theory on the origin of life is the RNA world hypothesis. It describes the prebiotic world as the primordial soup containing self-replicating RNA molecules, which are the ancestors of all life forms during the early history of planet Earth.
In principle, proteins require DNA as they contain the hereditary material coding sequence, as well as RNA to deliver genetic codes into cytoplasm for translation and protein synthesis. However, DNA requires specific protein enzymes to catalyze its replication.
Just like the chicken and egg problem, no one knows which one comes first. However, RNAs have a variety of functions. For example, some viruses can use RNA as their hereditary material, whereby a ribozyme is an RNA enzyme that is capable of catalyzing a chemical reaction in a similar manner to protein enzymes. With these two working in combination, RNA would be able to store both genetic information as well as possess auto-catalytic activity, satisfying the basis for chemical evolution.
Although self-propagating RNA molecules have not been found in nature, it has been an ongoing investigation for scientists.
Figure 4: Schematic diagram outlining the hypothetical evolution steps in which RNA are first formed to obtain its various functions. RNA nucleotides are first assembled from inorganic sources under repetitive yet stochastic natural events like volcanic eruption, weather and earthquakes (Step 1). Ribonucleotides are then built from these sugar scaffolds. When enough ribonucleotides accumulate, they begin to self-assemble and thread into longer chains of RNA via ribozymes (Step 2). RNAs are also capable of catalysing protein synthesis leading to production of linked amino acid chains (Step 3). Driven by evolutionary pressure, only ‘fit’ RNA systems with auto-catalytic activities will be able to replicate at higher rates in order to outcompete other RNA systems for inorganic resources. Not only are they capable of self-propagation, they can also catalyse the synthesis of protein molecules (Step 4). Lipid membrane formation of a hollow core allows for more interactions between molecules whilst changing the internal chemistry of the bilayer. Inside the membrane, various RNA began to code for both DNA and proteins. Over time, DNA, proteins and other components inside the membranes will evolve and adopt new functions and structures (Step 5). This image is adapted from: https://ib.bioninja.com.au/standard-level/topic-1-cell-biology/15-the-origin-of-cells/rna-world-hypothesis.html
Can RNA undergo natural selection?
Long stretches of polynucleotides can fold into numerous different three-dimensional (3D) structures, all with a different stability, reactivity and ability to duplicate. Sequences with higher number of successful replications will be in larger quantities and possibly outcompete other sequences for resources.
Since replication is an error-prone process, more variants will be produced constantly, thereby generating bigger pools of polynucleotides for selection. Other RNA molecules with catalytic activities are of equal relevance in the ‘mutually supportive RNA’ model, where a catalytic RNA assists the templated polymerization of any RNA molecule in vicinity. This has been demonstrated in vitro suggesting the possibility of a self-synthesizing RNA. Henceforth, an orchestra of different types of RNA molecules can cooperate and drive the replication of the entire group.
Is life possible outside of Earth?
There are also questions about the possibility of extraterrestrial life elsewhere in the universe.
Phosphine, a colourless, flammable, toxic gas compound with the chemical formula PH₃ was recently discovered in the atmosphere of Venus, whereby the only natural source of phosphine on Earth is microbes. This suggests the possibility of indigenous life form being present in the clouds of Venus “if minerals are also stirred up into the clouds from the surface”.
When the notion of life on Venus was proposed by Harold Morowitz, a Yale biochemist in 1967, their idea was not popularised at the time and encountered resistance. More than 40 years later, scientists had once again brought the idea back in sight with the new observations of atmosphere on planet Venus.
Perhaps you will be the one to design experiments and inform us where life came from and whether creating new life forms is possible through technological advancement.
Final note
There are still many unanswered questions surrounding the early evolution history on Earth or even the universe.
From all the published work from scientists, evidence supporting the formation of auto-catalytic and self-assembling systems are required during the chemical evolution. Nonetheless, through the findings of some answers, comes more questions - when was the point in time that turned these self-propagating molecules into life forms, and how did it happen? Suppose humans managed to find answers to all these questions, will we be able to recreate life? Or even another planet, Earth 2.0?
Looks like we still have a long journey ahead.
Author: Janet Zhong, BSc Biochemistry
Disclaimer: All figures used in this article are for educational purposes only.