The Nature of Consciousness: Consciousness, Life and Meaning

The Origin of Replication

The mystery of the origin of genes is particularly challenging because a gene is such a complicated structure and is unlikely to evolve spontaneously.

The US biologist Walter Gilbert noted that most of a person's DNA does not code genes but what appears to be gibberish, and even the part that is code is distributed in fragments (or "exons") separated by useless pauses (or "introns"). In his opinion the first genetic material was made of exons, that symbiotically got together and formed new, more complex genetic material. Introns are not random leftovers, but sort of gluing elements from the original material. In a sense, his theory points to the possibility that the gene is not the ultimate unit, but exons are.

Attention has been focusing on RNA since RNA has been shown to be a self-replicating molecule that can act as its own catalyst. DNA cannot make copies of itself, and proteins cannot create themselves. They both depend on each other. But (some kind of) RNA can act as its own enzyme (i.e., its own catalyst). Therefore, RNA is capable of replicating itself without any need for proteins.

Stanley Miller proposed that the first living creatures may have been able to synthesize protein and reproduce without the help of the DNA, depending solely on RNA to catalyze their growth and reproduction. The US chemist Thomas Cech had already proven (in 1982) that RNA molecules alone can induce themselves to split up and splice themselves together in new arrangements. It is also chemically plausible that all four RNA nucleotide bases could have been created in nature by ordinary atmospheric, oceanic and geological processes. Miller's theory, though, requires that life be born in lukewarm water, not the very high temperatures of thermophiles.

The German physicist Manfred Eigen induced RNA molecules to replicate by themselves, thereby lending credibility to the hypothesis that RNA came before DNA and that the first forms of life employed only RNA. Eigen's experiments with "autocatalytic cycles" involving RNA showed that, under suitable conditions, a solution of nucleotides gives rise spontaneously to a molecule that replicates, mutates and competes with its progeny for survival. The replication of RNA could then be the fundamental event around which the rest of biology developed. Eigen speculates that the genetic code was created when lengths of RNA interacted with proteins in the "primordial soup". First genes were created, then proteins, then cells. Cells simply provide physical cohesion. Cells first learned to self-replicate and then to surround themselves with protective membranes.

The US physicist Freeman Dyson believes that one cannot consider life only as metabolism or only as replication. Both aspects must be present. Therefore, we must look not for the origin of life, but for the origin of replication and for the origin of metabolism. Since it is unlikely that both metabolism and replication occurred at the same time in one of the primitive organic molecules, Dyson thinks that life must have had a double origin. It is more reasonable to assume that life "began" twice, with organisms capable of reproduction but not of metabolism and with (separate) organisms capable of metabolism but not of reproduction, and only later there arose a mixture of the two by some kind of symbiosis: organisms capable of both reproduction and metabolism.

Dyson's idea is that organisms that could reproduce but not replicate came first. The most elementary form of reproduction is simply a cell division: two cells are created by dividing a cell into two. Replication implies that molecules are copied. Reproduction with replication implies that the new cells "inherit" the molecules of the mother cell. Replication became a parasite over metabolism, meaning that organisms capable of replication needed to use organisms capable of metabolism in order to replicate. First proteins were born and somehow began to metabolize. Then nucleic acids were born and somehow began to replicate using proteins as hosts.

The two organisms became one thanks to a form of symbiosis between host and parasite. Dyson borrows ideas taken from Manfred Eigen (who claims that RNA can appear spontaneously) and Lynn Margulis (who claims that cellular evolution was due to parasites). Basically, his theory is that RNA was the primeval parasite.

The French virologist Patrick Forterre (“A hypothesis for the origin of cellular domain”, 2006), instead, thinks that today’s living beings are descendants of three RNA viruses. These RNA viruses originally evolved the double-stranded DNA molecule to defend their RNA genes, and eventually this “shield” took on a life of its own and became the main mechanism for bacteria, archaea, and eukaryota. It is a fact, that the genes of viruses seem to date back in time to before the birth of cell-based life.

The genetic code is just a code that relates mRNA triples and protein's aminoacids. The genetic code is the same for every being. It is just a code. It translates the instructions in the genotype into a phenotype. But it is an extremely sophisticated code. Did the genetic code itself evolve from a more primitive code? It is unlikely that the first self-replicating organisms were already using today's genetic code. How did the genetic code arise? And why don't we have any evidence of a pre-existing system of replication? Why is it that today there is only one code, rather than a few competing codes (just like there are a few competing genomes)?

Viruses

The German virologist Karin Moelling believes that life originated with virus-like organism, a theory that she shares with biologists like Luis Villareal. Viruses need cells to become "alive" and therefore it has long been assumed that the cell came first. Viruses are supposed to be non-living matter but Moelling and Villareal placed them at the beginning of living matter. The first virus was discovered in 1892 by Dmitri Ivanovsky and named "virus" (recognized as something else than bacteria) in 1898 by his student Martinus Beijerinck. Viruses are ubiquitous in all environments. There are about 10 to the 32rd viruses on Earth, compared with only 10 to the 9th humans, and 98% of the total biomass on Earth is contained in viruses, and so she starts by emphasizing that we invaded the world of viruses, not viceversa. Humans, like all animals, have a genome. But humans also have a microbiome, which actually contains a lot more information than the genome: several million genes versus 20,000 genes of the genome. Genetically speaking, we are 99% bacteria (and incidentally our body contains bacteria from about 10,000 different species so that up to 90% of the cells of the human body might be made of bacterial material). Moelling proposes that we have a third genome, one made of viral information. The human genome is about 80% viral information, and in particular it is almost 50% retroviruses (or sequences related to retroviruses). A retrovirus is a virus whose primary genome is RNA and causes the infected cell to convert the retroviral RNA into DNA (from RNA to DNA, unlike the normal process of DNA producing RNA producing proteins). The human body consists of 10,000,000,000,000 cells but it houses ten times more microbes. The human body is a superorganism, or, better, an ecosystem of human cells, bacteria, viruses and much else. That third genome is already a clue that viruses were important for the evolution of life. Moelling thinks that life started in an RNA world. RNA evolved to catalytic ribozymes, able to replicate, mutate and evolve even though they had no genes. Ribozymes are tiny RNA molecules that have no genes. Since its discovery, RNA had been viewed as a carrier of genetic information, while enzymatic functions were viewed as the exclusive realm of proteins. The catalytic properties of RNA (that RNA itself also functions as an enzyme) were discovered indipendently in 1982 by Thomas Cech and in 1983 by Sidney Altman who then speculated that the first genetic material was probably RNA, not DNA. They had discovered the rybozyme. Ribozymes are "viroids" (today, widespread plant pathogens), which consist of non-coding single-stranded RNA without protein coats. Ribozymes store primitive genetic information and possess primitive catalytic functions. Viroids are the smallest known non-living entities that can replicate and evolve. Viroids were discovered in 1965 by William Raymer and named in 1971 by Theodor Diener, who was the first to hypothesize in 1989 that viroids may date from the early non-cellular RNA world. Several clues lead biologists to believe that viroids existed before the genetic code developed. Their RNA is non-coding, it has nothing to do with protein synthesis. Moelling emphasizes that RNA is both software and hardware: it carries information (today written in the genetic code) and it is an enzyme for its own replication. Freeman Dyson, a physicist who in 1984 gave a famous lecture "Origins of Life" (later a book), believed in two origins of life: the genetic code and metabolism. But if RNA was the original starting point, only one origin might well do. The opposite of viroids (RNA with no protein) are the proteins called prions, discovered in 1982 by Stanley Prusiner, which cause infections just like viruses but have no genetic material. Neither viroids nor prions are usually classified as viruses but Moelling see them as part of a continuum. Viruses are commonly depicted as parasites that depend on the energy of a host in order to operate (to "come alive"). Moelling speculates that early viroids simply used some energy available in the environment. After all, there is no living being that doesn't exploit the energy of the environment (e.g. hydrothermal vents). Moelling believes that non-coding RNA existed before DNA and before the genetic code itself. The first biomolecules of 3.9 billion years ago were composed of short RNA. Then ribozyme RNA, merging with some basic proteins, should have evolved into ribosomes (with their protein-synthesizing machinery). Then an entity known as "Reverse Transcriptase" (the enzyme which copies RNA into DNA, that "reverse-transcribes" RNA into DNA, typical of retroviruses but present in many organisms) should have fostered the transition from RNA to double-stranded DNA. "Reverse" because the "Central Dogma" of Biology assumes a flow of information from DNA to RNA to protein, not from RNA to DNA. (The reverse transcriptase was discovered in 1970 by Howard Temin the University of Wisconsin and by David Baltimore at MIT who both proved that retroviruses replicate through a DNA intermediate, the reverse of the central dogma. Originally it was found only in retroviruses but later it was found in many other organisms). Moelling also describes two close relatives of reverse transcriptase: the enzyme Ribonuclease H (RNase H), important today for antiviral defense, and the enzyme telomerase, which generates DNA from RNA in retroviruses and, alas, cancer cells: both contribute to this day to the "reverse" flow of genetic information. Moelling believes that the oldest flow of biological information was from RNA to DNA, the "reversed" one (which means that today's flow is actually, historically, the "reversed" one). She also emphasizes the intrinsic innovation ability of RNA which may have contributed to speed up evolution. The high mutation frequency of RNA molecules during replication yields the innovative potential of RNA viruses (HIV, covid, influenza), i.e. their proliferation of variants. RNA is error-prone. While we see this as simply a problem for developing vaccines, we can also see it as a "skill" capable of producing variation in great quantity at great speed, i.e. of fostering evolution. In contrast, DNA replication is more stable because of the double strand. The first giant viruses were discovered in 1981, the mimivirus in 1992, with a genome of 1,000 genes, and the pandoraviruses in 2013 (by Jean-Michel Claverie), with a genome of 2,500 genes. By comparison, the HIV, discovered in 1983, which causes AIDS, has ten genes, and SARS-CoV-2, which causes covid, probably has 16. Bacteria have 3,000 genes, so these giant viruses are closer (in genetic size) to bacteria than to the most popular viruses. Perhaps not surprisingly these giant viruses are hosted in amoebas, whose genomes are gigantic (up to 700 billion base pairs, 200 times more than the human 3.2 billion bases). Giant viruses encode several components of the translation apparatus, i.e. contains components of the apparatus for protein synthesis, something that viruses are not supposed to be able to do. These giant viruses can even be infected by other viruses. Moelling views giant viruses as the missing link between viruses and bacterial cells, i.e. between the virus and the living cell, between the RNA viruses and the last universal cellular ancestor (LUCA). Viruses are unable to replicate autonomously: they depend on the machinery of a host cell for synthesizing proteins. Giant viruses do not synthesize proteins (the requirement for "life") but otherwise contain all the necessary elements of a living cell. This blurs the border between viruses and bacteria, between dead matter and living matter, a border that is already blurred by viroids, which are required for protein synthesis ("ribosomes are ribozymes" as Cech famously stated). Moelling likes to think of a continuum from dead matter to living matter. She thinks that the first protein synthesis started with RNA. Protein synthesis does not need DNA. DNA could have been created later from RNA via a reverse transcriptase. Moelling thinks that, after jumpstarting life, viruses also influenced genetic evolution via a mechanism of horizontal gene transfer: virus infection of a cell is an effictive process for generating genetic diversity, more effective than mutation. At the same time, viral RNA genome became part of the cellular DNA genome as viral "reverse transcriptase" was making DNA copies: some viruses became "endogenous". Viruses can invade not only cells but also DNA. The evolutionary usefulness of endogenous viruses is that they protect against foreign viruses. A virus can be transmitted horizontally (by infection of cells that is transmitted to other cells), and it's therefore "exogenous", or vertically (by "infected" DNA that is transmitted from parent to child), and it becomes endogenous, inherited. Moelling estimates that the human genome codes for about 40,000 endogenous retroviruses, and speculates that the genome was once composed solely of retroviral elements. It is a fact that viruses populate both the human body and the human genome (ditto for any other mammal). Viruses became part of the human body just like bacteria became part of the cell as mitochondria (the cell's powerhouse) and just like cyanobacteria became the chloroplasts of plants, responsible for photosynthesis. Moelling speculates that a giant virus could be the source of the nucleus of the cell, the precursor of LUCA. DNA is supposed to code for proteins but in reality only about 2% of our DNA does that: the remaining 98% originates non-coding RNA, which is regulatory RNA. John Mattick showed that this kind of RNA is more prevalent in more complex animals, like humans: up to 98% of our RNA is non-coding, but regulatory. Moelling thinks that regulatory RNA has something to do with higher complexity.

The Origin of Proteins

Yet another theory is that perhaps the original living material was neither DNA nor RNA but proteins themselves. DNA and RNA carry the instructions for making proteins, and proteins make up bodies, and bodies make other bodies that carry new sets of instructions. This is a brief summary of how life works today. The question is who could have done it all by itself: which natural structure can be both a body and a program? RNA seems like the ideal candidate because it does both jobs: RNA transmits DNA's instructions on how to make proteins, but RNA can also fold up and catalyze reactions, i.e. the jobs of proteins. In 1985 the US physicist Ken Dill had developed a mathematical tool to solve the protein-folding problem ("Theory for the folding and stability of globular proteins", 1985). Later, using the same tool, Dill showed that foldable polymers ("foldamers") can originate an autocatalytic set, i.e. a loop in which they catalyze the formation of copies of themselves ("Foldamer hypothesis for the growth and sequence differentiation of prebiotic polymers", 2017).

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