Virology is the Queen of the Biological Sciences

"On reading," by Simon Wain-Hobson, is a weekly discussion of scientific papers and news articles around gain of function research in virology.

Since January 2024, Dr. Wain-Hobson has written weekly essays discussing risky research in virology that were originally published on the Biosafety Now website.

We will republish these essays on our Substack every Friday, so the full archive will become available under the “On Reading” tab at the top of our Substack homepage.

Southern Italy, gouache on carton by Marius Avy (1871-1939)

On wondering about the last twenty essays.

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Some readers may have spotted the quip that virology is the Queen of the biological sciences. Which it is. Rather than leaving it as an opinion, On wondering hopes the few lines below make a good case. Enjoy.

• Estimates of the numbers of viruses in the biosphere are as high as 10³¹-10³². Up to 2.5 10⁸ viruses can be found in a milliliter of coastal sea water - essentially viruses that infect bacteria. Viruses exceed the number of cells by at least a factor of 10. One of the most recent publications showing this concerns snow viruses. This means that the vast majority of viruses go nowhere. Their genetic material, proteins etc. get degraded and recycled. But remember, the vast majority of acorns dropped by a majestic oak tree never get to do the same, so it is a common strategy in evolution.

• Given this, Stephen Jay Gould was incorrect to say we live in the age of bacteria. We live in the age of viruses.

• The human and mouse genomes contain around 9% and 10% of vestiges related to retroviruses. Agreed, mitochondrial DNA is of bacterial origin, so quits.

• Outside of virology, wherever you look, there are only DNA genomes. Virology has viruses with DNA genomes which are formidable success stories – variola or the smallpox virus now eradicated by vaccination. There are herpes and papillomaviruses if more examples are needed. Yet there are viruses with uniquely RNA genomes which are redoubtable too – Spanish flu, the COVID-19 virus, hepatitis C or yellow fever viruses. And then there are the schizophrenic retroviruses which ying and yang between RNA and DNA. Think HIV or hepatitis B virus.

Hereditary RNA is unique to virology. Students absorb RNA and DNA viruses as though its normal - it isn’t.

• Outside of virology, if a family tree is made using common gene sequences encompassing bacteria, slime molds, insects, plants, animals, Bond, James Bond, there is a common trunk. No matter the gene analyzed, there is always a single trunk. This means that all living organisms alive today, which show up as leaves on such trees, derive from a common ancestor – LUCA for the Last Universal Common Ancestor.

Another way of saying this is that between you, aka the reader, and a bacterium there is an uninterrupted line of DNA division. The funny retort is ‘it shows!’ Darwin used ‘descent with modification’.

There is a consensus that an ‘RNA world’ preceded the DNA dominated world of today. In short, DNA genomes emerged from RNA genomes. The corollary is that LUCA isn’t in fact the last ancestor, you have to go back further. It’s just that virology wasn’t factored in.

That would be a simple modification to adopt, except that there are multiple origins for viruses. Some are down-sized bacteria, some are escaped transposons (mobile genetic elements), escaped origins of DNA replication, escaped introns or packaged plasmids. In short there are multiple origins.

All this means is that there is no easy definition of a virus as some can spring forth from parts of the DNA world. So, virology is a collection of RNA and DNA genomes bandied together? You could have suggested a smörgåsbord. Tasty, can live with that.

• Genomes. Outside of virology there are circular double stranded (ds) DNA genomes (bacteria), linear dsDNA (a few bacteria like the Lyme disease agent) or those with multiple dsDNA chromosomes. Fine. Yet there are not only circular or linear dsDNA viral genomes but also those made of only single stranded DNA. While linear RNA viral genomes of all sorts abound, there are even a few circular RNA genomes. There are viruses with the equivalent of 2 to 11 RNA chromosomes - think of flu or rotaviruses. Virology covers more genome bases.

• Watson-Crick DNA is made of T, C, G and A. In some bacterial viruses modified building blocks like methylcytidine or diaminopurine are incorporated into the genome during multiplication. Only in virology.

• You’ll find viruses in the eukaryotic kingdom and phages in the bacterial kingdom. This linguistic distinction is merely historical, phage = virus. When archaebacteria finally emancipated themselves from the bacterial world, the burning question was would their ‘viruses’ be called phages? The painful separation ensured that the word virus was chosen for the archaebacterial kingdom. Lol.

• Language shows up again in the names of viruses: Above maiden virus, Alajuela virus, Carnation Italian ringspot virus, Gloriosa stripe mosaic virus, Honeysuckle yellow vein mosaic virus, Isla Vista virus, Meadow saffron breaking virus or Narcissus late season yellows virus. Glorious. The latter two could be from a poem by John Keats. By comparison there’s Borrelia burgdorferi, the Lyme disease bacterium. No contest.

• The visual arts? Do a web search with ‘ambrosius bosschaert tulips’ and you’ll find some wonderful paintings by this Dutch grand master (1609-1645). Striped tulips result from infection by a RNA virus, one being called Rembrandt tulip-breaking virus. Simply put, the virus causes depigmentation of parts of the petals breaking them into stripes. The color of the stripes is dictated by that of the underlying petal color which is generally white or yellow. Dutch bulb growers loved the stripes. Unfortunately, as they resulted from an RNA virus infection stripes were unstable. This was in part responsible for the collapse of the Dutch tulip bulb bubble.

Yet it's not finished. US tulip grower Scott Kunst said You can grow what are called modern Rembrandt’s. These modern hybrids totally lack the grace and beauty of the old tulips. Only in virology.

• Music? Like the rest of humanity, musicians, both composers and performers, have suffered from infection. That said, Beethoven’s genome sequence was recovered from authenticated hair, and in so doing recovered fragments of HBV DNA that probably contributed to his liver disease.

• Genomes are packaged, right? Everything in the DNA world is wrapped up into what is called a cell, that globular or spherical thing bounded by a membrane. Viruses too – think of flu (RNA genome) or herpesviruses (DNA). But not all. Polio- and papillomaviruses have their RNA and DNA genomes packaged by protein. Look Ma, no membranes! Only in virology.

• One essay (Going places) mentioned naked virus DNA and RNA being infectious in a lab setting. Can this happen in the real world? Yes. The smallest known genomes are called viroids that infect plants and are made of naked RNA – as few as 250 building blocks strung together. Viroids can cause havoc among coconut plantations to name but one example. Are these really viruses? With its fuzzy borders, virology welcomed them into the smörgåsbord, and they aren’t going to leave.

• Genomics? Everything from LUCA onwards have big genomes from bacteria with a little over a million building blocks to the rice genome – 50 billion blocks. That’s a range of 10,000. Note that bigger is not better – the human genome is smaller than that of the rice plant. The same is true for viruses where genome sizes span a 10,000 fold range. So quits.

• What was the first complete genome sequence published? That of a small phage (virus) with an RNA genome in 1976. The first human genome was that of hepatitis B virus in 1979, which is obviously a play on words. The first human genome ever sequenced was that of mitochondrial DNA back in 1981. Viral genomes were obvious targets of Fred Sanger’s lab because they were small. Sanger pioneered genome sequencing by the brilliantly simple dideoxy method that earned him a second Nobel Prize in Chemistry. Virology benefited and went genomics 20 years before bacteriology.

• Some viruses can piggyback on the genomes of other organisms. The best known example is HIV that splices its DNA intermediate into the human genome. Yet back in the late 1950s, it was realized that some phages/viruses could insert their DNA into bacterial genomes. There is a wonderful example where a bird retrovirus (same broad family as HIV) has integrated its DNA intermediate into that of Marek’s disease herpesvirus of chickens and is transmitted with the herpesvirus.

• Nobels? There are ten awarded for things virological. What is interesting is they highlight the breadth of virology’s contribution to biology. Peyton Rous was the first to show viruses could cause cancer. Years later using what was called Rous sarcoma virus, Bishop, Varmus and colleagues work gave rise to the oncogene. Richards and Sharp contributed gene splicing while Doherty and Zinkernagel worked out the raison d’être of T cell immunology using an RNA virus. The Nobel Prize in Chemistry for 1946 was awarded to Stanley who showed that tobacco mosaic virus could be crystalized. This meant that it had a regular shape which stunned everybody.

There is a neat story connecting the Chemistry Nobel with the first bullet point of this essay. Take a look at a paper from 1997. So much dog papillomavirus is made that they crystalize into hexagonal arrays within the infected cell!

• Has there even been a hiatus in Darwin’s descent with modification? Yes, the first example involved the chemical synthesis of the poliovirus genome which was mentioned in the essay Going places.

• Virology is tolerant. And while it scoops up infectious agents of all sorts, it can let go a few. Eons ago Chlamydia and Rickettsia were considered part of virology since they couldn’t divide independently. Today they belong to the bacterial world. Ironically, what are now referred to as giant viruses were originally thought to be some sort of Rickettsia.

• Time and Newsweek covers? Viruses overwhelm all other microbes.

• In the cyberworld you’ll find viruses galore and a handful of worms. No bacteria. Game over.

On wondering rests the case, your honor.

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Simon Wain-Hobson is an emeritus professor at the Institute Pasteur, Paris, from which he retired in 2021. He and his colleagues were the first to sequence the genome of HIV, and Wain-Hobson has published more than 230 papers on virology and cancer.