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Virology discoveries could change biology
Virology discoveries could change biology
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Viruses are tiny but “incredibly powerful creatures” without which we would not survive. Their influence on our planet is undeniable. It is easy to find them, scientists continue to identify previously unknown types of viruses. But how much do we know about them? How do we know which one should investigate first?

The SARS-CoV-2 coronavirus is just one of several million viruses that live on our planet. Scientists are rapidly identifying many new types.

Maya Breitbart has looked for new viruses in African termite mounds, Antarctic seals and the Red Sea. But, as it turned out, to really find anything, she just had to look into her home garden in Florida. There, around the pool, you can find orb-web spiders of the species Gasteracantha cancriformis.

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They have a bright color and rounded white bodies, on which black specks and six scarlet thorns are noticeable, similar to an outlandish weapon from the Middle Ages. But inside the bodies of these spiders, Maya Brightbart was in for a surprise: when Brightbart, an expert in viral ecology at the University of South Florida in St. unknown to science.

As you know, since 2020, we, ordinary people, have been preoccupied with only one particularly dangerous virus known to all now, but there are many other viruses that have not yet been detected. According to scientists, about 1031different viral particles, which is ten billion times the approximate number of stars in the observable universe.

It is now clear that ecosystems and individual organisms depend on viruses. Viruses are tiny, but incredibly powerful creatures, they accelerated evolutionary development over millions of years, with their help, the transfer of genes between host organisms was carried out. Living in the world's oceans, viruses dissected microorganisms, throwing their contents into the aquatic environment and enriching the food web with nutrients. "We would not have survived without viruses," says virologist Curtis Suttle of the University of British Columbia in Vancouver, Canada.

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The International Committee on Taxonomy of Viruses (ICTV) found that at the moment there are 9,110 separate types of viruses in the world, but this is obviously a tiny fraction of their total. This is partly due to the fact that the official classification of viruses in the past required scientists to cultivate the virus in the host organism or its cells; this process is time-consuming and sometimes seems unrealistically complicated.

The second reason is that in the course of scientific research, the emphasis was on finding those viruses that cause diseases in humans or in other living organisms that are of certain value to humans, for example, it concerns farm animals and crops.

Nevertheless, as the covid-19 pandemic reminded us, it is important to study viruses that can be transmitted from one host organism to another, and this is precisely the threat to humans, as well as to domestic animals or crops.

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The number of known viruses has skyrocketed over the past decade due to improved detection technologies and a recent change in the rules for identifying new types of viruses, which made it possible to detect viruses without the need to cultivate them with a host organism.

One of the most common methods is metagenomics. It allows scientists to collect samples of genomes from the environment without the need to cultivate them. New technologies such as virus sequencing have added more virus names to the list, including some that are surprisingly widespread but still largely hidden from scientists.

“Now is a great time to do this kind of research,” says Maya Brightbart. - I think that in many ways now is the time for the virome [virome - the collection of all viruses that are characteristic of an individual organism - approx. Transl.] ".

In 2020 alone, ICTV added 1,044 new species to its official virus list, with thousands more viruses awaiting description and so far unnamed. The emergence of such a great variety of genomes prompted virologists to rethink the way viruses are classified and helped to clarify the process of their evolution. There is strong evidence that viruses did not originate from a single source, but occurred multiple times.

Yet the true size of the global viral community is largely unknown, according to virologist Jens Kuhn of the US National Institute of Allergy and Infectious Diseases (NIAID) in Fort Detrick, Maryland: “We really have no idea that there is going on."

Everywhere and everywhere

Any virus has two properties: firstly, the genome of each virus is enclosed in a protein envelope, and, secondly, each virus uses a foreign host organism - be it a man, a spider or a plant - for the purpose of its reproduction. But there are countless variations in this general scheme.

For example, tiny circoviruses have only two or three genes, while massive mimiviruses, which are larger than some bacteria, have hundreds of genes.

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For example, there are bacteriophages that are somewhat similar to the apparatus for landing on the moon - these bacteriophages infect bacteria. And, of course, nowadays everyone knows about the killer balls studded with thorns, the images of which are now painfully familiar, perhaps, to every person in any country of the world. And viruses also have this feature: one group of viruses stores their genome in the form of DNA, while the other - in the form of RNA.

There is even a bacteriophage using an alternative genetic alphabet, in which the nitrogenous base A in the canonical ACGT system is replaced by another molecule designated by the letter Z [the letter A denotes the nitrogenous base "adenine", which is part of nucleic acids (DNA and RNA); ACGT- nitrogenous bases that make up DNA, namely: A - adenine, C - cytosine, G - guanine, T - thymine, - approx. transl.].

Viruses are so ubiquitous and nosy that they can appear even if scientists are not looking for them. So, for example, Frederik Schulz did not intend to study viruses at all, his area of ​​scientific research is the sequence of genomes from wastewater. As a graduate student at the University of Vienna, Schultz used metagenomics to find bacteria in 2015. With this approach, scientists isolate DNA from a range of organisms, grind them into small pieces, and sequence them. Then a computer program assembles individual genomes from these pieces. This procedure is reminiscent of assembling several hundred puzzles at once from separate fragments mixed with each other.

Among the bacterial genomes, Schultz could not help but notice a huge chunk of the viral genome (apparently because this chunk had viral envelope genes), which included 1.57 million base pairs. This viral genome turned out to be a giant, it was part of a group of viruses, whose members are giant viruses both in genome size and in absolute dimensions (usually 200 nanometers or more in diameter).This virus infects amoebas, algae and other protozoa, thereby affecting aquatic ecosystems, as well as ecosystems on land.

Frederick Schultz, now a microbiologist at the US Department of Energy's Joint Genome Institute in Berkeley, California, decided to look for related viruses in metagenomic databases. In 2020, in their article, Schultz and his colleagues described more than two thousand genomes from the group that contains giant viruses. Recall that previously, only 205 such genomes were included in the publicly available databases.

In addition, virologists also had to look inside the human body in search of new species. Virus bioinformatics specialist Luis Camarillo-Guerrero, together with colleagues from the Senger Institute in Hinkston (UK), analyzed human intestinal metagenomes and created a database containing more than 140,000 bacteriophage species. More than half of them were unknown to science.

The scientists 'joint study, published in February, coincided with other scientists' findings that one of the most common groups of viruses that infect human gut bacteria is a group known as crAssphage (named after the cross-assembler program that discovered it in 2014). Despite the abundance of viruses represented in this group, scientists know little about how viruses of this group participate in the human microbiome, says Camarillo-Guerrero, who now works for DNA sequencing company Illumina (Illumina is located in Cambridge, UK).

Metagenomics has discovered many viruses, but at the same time, metagenomics ignores many viruses. In typical metagenomes, RNA viruses are not sequenced, so microbiologist Colin Hill of the Irish National University in Cork, Ireland, and his colleagues searched for them in RNA databases called metatranscripts.

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Scientists usually refer to this data when studying genes in a population, i.e. those genes that are actively converted into messenger RNA [messenger RNA (or mRNA) is also called messenger RNA (mRNA) - approx. transl.] involved in the production of proteins; but the genomes of RNA viruses can also be found there. Using computational techniques to extract sequences from data, the team found 1,015 viral genomes in metatrancryptomes from silt and water samples. Thanks to the work of scientists, information on known viruses has increased significantly after only one article appeared.

Thanks to these methods, it is possible to accidentally collect genomes that do not exist in nature, but to prevent this, scientists have learned to use control methods. But there are other weaknesses as well. For example, it is extremely difficult to isolate certain types of viruses with great genetic diversity, since it is difficult for computer programs to piece together disparate gene sequences.

An alternative approach is to sequenced each viral genome separately, as is done by microbiologist Manuel Martinez-Garcia of the University of Alicante in Spain. After passing seawater through filters, he isolated some specific viruses, amplified their DNA and proceeded to sequencing.

After the first try, he found 44 genomes. It turned out that one of them is a type of one of the most common viruses living in the ocean. This virus has such a great genetic diversity (i.e., the genetic fragments of its viral particles are so different in different viral particles) that its genome has never appeared in metagenomics research. Scientists named it "37-F6" because of its location on a laboratory dish.However, Martinez-Garcia joked, given the genome's ability to hide in plain sight, it should have been named 007 after super-agent James Bond.

Family trees of viruses

Such ocean viruses, as secretive as James Bond, do not have an official Latin name, as do most of the several thousand viral genomes discovered over the past decade using metagenomics. These genomic sequences posed a difficult question for ICTV: Is one genome enough to name the virus? Until 2016, the following order existed: if scientists proposed for ICTV any new type of virus or taxonomic group, then, with rare exceptions, it was necessary to provide in culture not only this virus, but also the host organism. But in 2016, after intense debate, virologists agreed that one genome would be enough.

Applications for new viruses and groups of viruses began to arrive. But the evolutionary relationships between these viruses have sometimes remained unclear. Virologists usually classify viruses based on their shape (for example, "long", "thin", "head and tail") or based on their genomes (DNA or RNA, single or double stranded), but these properties tell us surprisingly little. about their common origin. For example, viruses with double-stranded DNA genomes appear to have originated in at least four different situations.

The initial classification of ICTV viruses (which implies that the tree of viruses and the tree of cellular life forms exist separately from each other) included only the lower steps of the evolutionary hierarchy, ranging from species and genera to the level that, according to the classification of multicellular life, is equivalent to primates or conifers. There were no higher levels of the evolutionary hierarchy of viruses. And many virus families existed in isolation, without any links with other types of viruses. So, in 2018, ICTV added higher order levels to classify viruses: classes, types and realms.

At the very top of the classification of viruses, ICTV put groups called "realms" (realms), which are analogs of "domains" for cellular life forms (bacteria, archaea and eukaryotes), i.e. ICTV used a different word to distinguish between the two trees. (A few years ago, some scientists suggested that some viruses could probably fit into the tree of cellular life forms; but this idea has not received widespread approval.)

ICTV delineated the branches of the virus tree and assigned RNA viruses to a region called Riboviria; by the way, part of this area is the SARS-CoV-2 virus and other coronaviruses, whose genomes are single-stranded RNAs. But then the vast community of virologists had to propose additional taxonomic groups. It just so happens that evolutionary biologist Eugene Koonin of the National Center for Biotechnology Information in Bethesda, Maryland, gathered a team of scientists to come up with a first way to categorize viruses. To this end, Kunin decided to analyze all viral genomes, as well as the results of studies on viral proteins.

They reorganized the Riboviria region and proposed three more realms. There has been controversy over some of the details, Kunin said, but in 2020 the systematization was approved by ICTV members without much difficulty. Two more realms were given the green light in 2021, according to Kunin, but the original four are likely to remain the largest. In the end, Kunin suggests, the number of realms could be as high as 25.

This number confirms the suspicion of many scientists: viruses do not have a common ancestor. “There is no single progenitor for all viruses,” says Kunin. "It just doesn't exist." This means that viruses have likely appeared several times throughout the history of life on Earth.Thus, we have no reason to say that viruses cannot appear again. “New viruses are constantly appearing in nature,” says virologist Mart Krupovic of the Institut Pasteur in Paris, who has been involved in both ICTV's decision-making and the research work of the Kunin group on systematization.

Virologists have several hypotheses about the causes of realms. Perhaps the realms originated from independent genetic elements at the dawn of life on planet Earth, even before cells were formed. Or maybe they left whole cells, "escaped" from them, abandoning most of the cellular mechanisms to maintain their existence at a minimum level. Kunin and Krupovich are in favor of the hybrid hypothesis, according to which these primary genetic elements "stole" the genetic material from the cell in order to build viral particles. Since there are many hypotheses about the origin of viruses, it is quite possible that there are many ways of their appearance, says virologist Jens Kuhn, who worked on the ICTV committee on a proposal for a new systematization of viruses.

Despite the fact that the viral and cellular trees are different, their branches not only touch, but also exchange genes. So where should viruses be classified - animate or inanimate? The answer depends on how you define "alive". Many scientists do not consider the virus to be a living being, while others disagree. "I tend to believe they are alive," says bioinformatics scientist Hiroyuki Ogata, who is researching viruses at Kyoto University in Japan. “They evolve, they have genetic material made of DNA and RNA. And they are a very important factor in the evolution of all living things."

The current classification is widely accepted and represents the first attempt to generalize the variety of viruses, although some virologists believe that it is somewhat imprecise. A dozen of virus families still have no connection with any realm. “The good news is that we're trying to put at least some order in this mess,” adds microbiologist Manuel Martinez-Garcia.

They changed the world

The total mass of viruses living on Earth is equivalent to 75 million blue whales. Scientists are confident that viruses affect food webs, ecosystems and even the atmosphere of our planet. According to environmental virology specialist Matthew Sullivan of Ohio State University at Columbus, scientists are increasingly discovering new types of viruses, with researchers "discovering previously unknown ways in which viruses have a direct impact on ecosystems." Scientists are trying to quantify this viral exposure.

“At the moment we do not have any simple explanation for the phenomena taking place,” says Hiroyuki Ogata.

In the world's oceans, viruses can leave their host microbes, releasing carbon, which will be recycled by other creatures that eat the insides of these host microbes and then release carbon dioxide. But more recently, scientists have also come to the conclusion that bursting cells often clump and sink to the bottom of the world's oceans, binding carbon from the atmosphere.

Melting permafrost on land is the main source of carbon generation, and viruses appear to be helping to release carbon from microorganisms in this environment, according to Matthew Sullivan. In 2018, Sullivan and his colleagues described 1,907 viral genomes and their fragments collected during the thawing of permafrost in Sweden, including genes for proteins that can somehow influence the process of decay of carbon compounds and, possibly, the process of their transformation into greenhouse gases.

Viruses can influence other organisms as well (for example, shuffle their genomes).For example, viruses carry genes for antibiotic resistance from one bacterium to another, and drug-resistant strains may eventually prevail. According to Luis Camarillo-Guerrero, over time, such gene transfer can cause serious evolutionary shifts in a particular population - and not only in bacteria. Thus, according to some estimates, 8% of human DNA is of viral origin. So, for example, it was from the virus that our mammalian ancestors received the gene necessary for the development of the placenta.

Scientists will need more than just their genomes to solve many of the questions about the behavior of viruses. It is also necessary to find the hosts of the virus. In this case, the clue can be stored in the virus itself: the virus, for example, can contain a recognizable fragment of the host's genetic material in its own genome.

Microbiologist Manuel Martinez-Garcia and colleagues have used single-cell genomics to identify microbes containing the recently discovered 37-F6 virus. The host organism of this virus is the bacterium Pelagibacter, which is one of the most widespread and diverse marine organisms. In some regions of the world's oceans, Pelagibacter accounts for almost half of all the cells that live in its waters. If the 37-F6 virus suddenly disappeared, Martinez-Garcia continues, the life of aquatic organisms would be severely disrupted.

Scientists need to figure out how it changes its host to get a complete picture of the impact of a particular virus, explains evolutionary ecologist Alexandra Worden of the Ocean Science Center. Helmholtz (GEOMAR) in Kiel, Germany. Warden is studying giant viruses that carry genes for a fluorescent protein called rhodopsin.

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In principle, these genes can also be useful for host organisms, for example, for such purposes as transferring energy or transmitting signals, but this fact has not yet been confirmed. In order to find out what happens to the rhodopsin genes, Alexandra Vorden plans to cultivate the host organism (host) together with the virus in order to study the mechanism of the functioning of this pair (host-virus), united into a single complex - "virocell".

"It is only through cell biology that you can tell what the true role of this phenomenon is and exactly how it affects the carbon cycle," adds Warden.

At her home in Florida, Maya Brightbart did not cultivate viruses isolated from the spiders Gasteracantha cancriformis, but she did manage to learn a thing or two about them. The two previously unknown viruses found in these spiders belong to the group that Brightbart has described as "amazing" - and all because of their tiny genomes: the first encodes the gene for the protein coat, the second - the gene for the replication protein.

Since one of these viruses is present only in the spider's body, but not in its legs, Brightbart believes that in fact its function is to infect prey, which is subsequently eaten by the spider. The second virus can be found in various areas of the spider's body - in the clutch of eggs and offspring - so Brightbart believes that this virus is transmitted from parent to offspring. According to Brightbart, this virus is harmless to the spider.

So viruses are "actually the easiest to find," says Maya Brightbart. It is much more difficult to determine the mechanism by which viruses affect the life cycle and ecology of the host organism. But first, virologists must answer one of the most difficult questions, Brightbart reminds us: "How do we know which one to investigate at the outset?"

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