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. The first genome to be sequenced was that of an RNA phage in 1976: it has four genes.

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 (although positive-stranded RNA viruses such as SARS-CoV and MERS-CoV have relatively low mutation rates). 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 viruses of measles, yellow fever, polio and ebola have fewer than ten genes. The HIV, discovered in 1983, which causes AIDS, has ten genes, and SARS-CoV-2, which causes covid, probably has 16. (See also Oldstone's "Viruses, Plagues & History"). 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.

Moelling mentions only in passing another interesting theory. It is commonly assumed that evolution leads to more complex beings (from the primordial cell to you) but it is also possible that it moved in the opposite direction, towards ever increasing simplicity, in which case a virus (that doesn't need the cumbersome machinery of replication) would be the temporary peak of evolution: a being so lean and efficient that can replicate simply by hijacking living cells. Moelling doesn't explore this possibility because the book is truly about how a viroid became trees and elephants, not how dinosaurs became viruses.

At the beginning of the book Moelling mentions the influence that viruses had on human history: they killed millions of people (37 million by AIDS alone, which originated in Congo and brought to North America by Haitian refugees, and possibly 100 million by the "Spanish Flu", whose virus H1N1 was "revived" at Mount Sinai laboratory in 2005) and destroyed entire civilizations. There are some interesting books written about this, like William McNeill's "Plague and Peoples" and Michael Oldstone's "Viruses, Plagues, and History".

Moelling doesn't tell us much about how to fight the viruses that are indeed pathogens, the ones that kill millions of humans. She mentions in passing that antibiotics can kill bacteria but nothing can kill viruses, but doesn't elaborate on why. When we are infected by a virus, our strategy is to boost the immune system (with a "vaccine") so the immune system will neutralize the virus, a strategy invented in 1796 by Edward Jenner, but "killing" a virus makes no sense because the virus is not alive in the first place. We have two immune systems, an innate one, sculpted by evolution, and an adaptive or acquired one, which learns from experience. Bacteria are living beings and antibiotics (first discovered in 1928 by Alexander Fleming) attack their "lives" (i.e. typically stop bacteria from reproducing). But viruses are inert matter. It is only when they break into a cell that they come alive and start multiplying (using the invaded cell as their self-replication factory). Only the immune system can prevent this takeover from happening and only the immune system can do something if the takeover succeeds. Antiviral drugs can't kill cells the way antibiotics do because the cells that are involved in viral infections are the very cells that we want to save. Viruses basically take hostages. Antiviral drugs aim at suppressing virus replication, not to eradicate it (hepatitis C might the the only exception so far).

The book doesn't discuss at all zoonosis, the process by which viruses are transmitted from animals to humans, by far the most frequent cause of epidemics. Other books, like David Quammen's "Spillover", cover that territory.

The book is also lacking a description of the co-evolution of viruses and immune systems (in general, antiviral defense), which is probably a big story in itself.

Moelling's book also doesn't tell us much about the environmental impact of viruses, and the impact of the environment on viruses. Curtis Suttle studies the role of viruses in the environment, particularly in oceans, where viruses probably infect all living things, from bacteria to whales (See my conversation with Curtis Suttle).

Viruses are not the only microorganisms that kill us. Tuberculosis, the world's biggest infectious killer (it killed 1.3 million people in 2022, down from two million in 2018), is caused by a bacterium, just like pneumonia, salmonella, sepsis (which isn't contagious but kills 10-20 million people each year), meningitis, diarrhoea, gonorrhea, etc. Bacterial infections can be highly contagious because they can spread, just like viral ones, through coughing, sneezing, sex, etc. Diseases caused by bacteria can be treated with antibiotics, which kill bacteria. Malaria (600,000 deaths in 2022) is caused by a single-celled parasite called Plasmodium, which is neither a virus nor a bacteria. The parasite enter the blood stream via mosquito bites. Mosquitoes are also carriers of viral diseases like Zika virus, West Nile virus, dengue, encephalitis, etc. There was no malaria vaccine until 2021 and to this day the only certain way to avoid malaria is really to prevent mosquito bites (antimalarial drugs are not very effective and the first vaccine is only 50% protective). Both bacterial diseases and malaria are caused by living organisms. That's the big difference with viral diseases.

There are many mysteries discussed in this book. For example, the dominance of DNA phages (RNA phages are rare) and the dominance of RNA plant viruses. Humans are infected by a wide range of both RNA and DNA viruses. The largest group of viruses are the viruses of bacteria: the phages (discovered in 1917 by the French microbiologist Felix d'Herelle). Moelling calls them "the most abundant and diverse entities on our planet and most successful in replication." But almost all phages have double-stranded DNA genomes. On the other hand, plant viruses almost always have single-stranded RNA. She thinks it's clue to how life evolved at the beginning, but her explanation leaves a lot of question marks.

For more details on the history of the most famous viruses and epidemics, see Oldstone's "Viruses, Plagues & History".

TM, ®, Copyright © 2024 Piero Scaruffi