Although viruses challenge the concept of "life" they are essential to sustaining the fabric of life
Luis P. Villarreal
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In one episode of the classic XNUMXs TV comedy The Honeymooners, the bus driver, Ralph Kramden of Brooklyn, shouts to his wife Alice, "You know I know how you catch a virus easily." Half a century ago, even simple people like the Karmden family knew that viruses are microscopic creatures that cause disease. But it is likely that they did not know exactly what a virus is. They weren't the only ones then, nor are they now.
It has been about 100 years that the scientific community has repeatedly changed its mind about the nature of viruses. At first they were considered as poisons, then as a kind of life forms, then they were considered biological chemicals and today they are considered to be in the gray area between the living and the inanimate: they cannot reproduce by themselves but they can reproduce inside a real living cell and they can have a decisive effect on the host cell their. Viewing viruses as inanimate matter during most of the modern period of biological science had an unintended effect: most researchers ignored viruses during the study of evolution. But now scientists are beginning to understand that viruses play a fundamental role in the history of life.
A matter of definition
It is easy to understand why it was difficult to classify the viruses. Their identity seems to depend on the eye of the beholder. The initial interest in viruses arose due to their connection to disease. Indeed, the origin of the word "virus" is in the Latin term "poison". At the end of the nineteenth century, researchers realized that certain diseases, such as rabies and foot-and-mouth disease, were caused by particles that behaved like bacteria but were much smaller than them. Since it was clear that these particles were biological particles and that they could be spread from victim to victim, viruses were considered the simplest gene-carrying life form.
In 1935, Wendell M. Stanley and his research partners at the institution now known as Rockefeller University in New York, synthesized for the first time a virus called the tobacco mosaic virus and subsequently the viruses were demoted and declared inert chemicals. The researchers saw that the virus does indeed consist of a package of complex biochemicals, but it lacks the essential systems for metabolism - the biochemical activity of life. For his work, Stanley received a Nobel Prize, in chemistry rather than in physiology or medicine.
Additional studies conducted by Stanley and others established the fact that a virus consists of nucleic acids (DNA or RNA) contained within a protein shell that can also contain viral proteins that participate in the infection process. According to this description, a virus looks like a chemical system rather than a living organism. However, when a virus enters a living cell (called a host after infection), it is far from tolerant. It sheds the protein shell, exposes its genes and causes the cell's replication system to produce the invader's DNA or RNA and produce more viral proteins according to the instructions written in the viral nucleic acid. The new viral pieces cluster together and create more and more viruses that can also infect more cells.
This behavior led many to think of viruses as creatures that exist on the border between the world of chemistry and the world of animals. Virologist Mark H. V. Van Regenmortel of the University of Strasbourg in France and Brian W. C. Mahy of the Centers for Disease Control and Prevention described it poetically when they recently said that due to their dependence on the host cell, viruses lead "a kind of borrowed life." Interestingly, although biologists have long adhered to the view that viruses are just boxes of chemicals, they have used the viral activity in surrogate cells to determine how nucleic acids are coded for proteins. Indeed, modern molecular biology rests on the foundations of information obtained with the help of viruses.
Molecular biologists have since formulated most of the essential components of the cell and today they are used to dividing the components of the cell, for example ribosomes, mitochondria, membranes, DNA and proteins into three groups: chemical machines, raw materials of chemical machines or their products. This extensive exposure to complex chemical structures is probably the reason why molecular biologists do not invest much thought into the question of whether viruses are living beings. For them it is a mental exercise identical to the question of whether the components of the cell are living beings that stand on their own. This myopia allows them to see only how viruses take over cells or cause disease. The more sweeping question of the contribution of viruses to the history of life on Earth, which I will now discuss, usually remains unanswered and often not even asked.
to be or not to be
The seemingly simple question, whether viruses are living beings, often asked by my students, remained without a simple answer for so many years, probably because it touches on a basic issue: "What exactly defines 'life'"? A precise scientific definition of life is quite elusive, but most scientists agree that life includes additional features besides the ability to reproduce. For example, a living entity exists in the state of being bounded by birth and death. Living things are also supposed to need some biochemical autonomy to carry out the metabolic operations that produce the molecules and energy needed to sustain the organism. This degree of autonomy is an essential element in most life settings.
In contrast, viruses are parasites in almost all biomolecular aspects of life. That is, they depend on the host cell for the raw materials and energy needed for the synthesis of nucleic acids and proteins, processing and transport and any other biochemical activity that allows viruses to reproduce and spread themselves. It can therefore be concluded that although these processes are controlled by the virus, viruses are simply non-living parasites that exist on living metabolic systems. But there may be intermediate shades between what is certainly living and inanimate matter.
A stone is not alive. A bag with metabolic activity that does not contain genetic material and is incapable of reproduction is also not alive. A bacterium, on the other hand, is alive. Although it is a single cell, it can produce energy and the molecules needed to sustain itself and it can reproduce. But what is the seed? It is possible not to see a seed as a living being, but it contains the potential for life and it can also be destroyed. In this sense, viruses are more like seeds than they are like living cells. Viruses have some potential that can be truncated, but they do not reach a more autonomous form of life.
Another way of looking at life is to see it as a feature emerging from a collection of inanimate details. Both life and consciousness are examples of such complex systems. For each of these two systems to emerge, a certain critical degree of complexity is required. A single neuron, or even a network of neurons, does not have consciousness, this requires the level of complexity of an entire brain. And yet, even an intact human brain can be biologically alive but unconscious, in a state of "coma". Similarly, single genes or proteins, both cellular and viral, do not live by themselves. A cell without a nucleus is in a coma-like state because it lacks its full critical degree of complexity. The virus does not reach a critical level of complexity either. That is, life is an emergent state, but it consists of the same basic physical building blocks that make up the virus. According to this point of view, viruses are not fully alive, but they can be seen as more than inanimate matter: they are on the verge of life.
In fact, in October 2004, French researchers announced findings that demonstrate once again how closely related viruses are to the animal world. Didia Raul and his collaborators at the University of the Mediterranean in Mercy reported that they have sequenced the genome of the largest virus known to us, Mimivirus, discovered in 1992. The virus, which is the size of a small bacterium, infects amoebas. Analysis of the virus sequence revealed many genes that until now were thought to be unique to cellular organisms. Some of these genes are involved in the production of the proteins encoded by the viral DNA and may make it easier for the Mimivirus to take over the replication systems of the host cell. As observed by the research group, which published its work in the scientific journal Science, the enormous complexity of the mimivirus genome "challenges the accepted boundary between viruses and parasites that are cellular organisms."
The effect on evolution
Debates about labeling viruses as living things naturally led to another question: Is the question of whether a virus is a living thing or not more than a philosophical exercise that serves as a basis for lively discussions but with almost no real impact? I think the issue is really important, because the way scientists see this question affects the way they think about the mechanism of evolution.
Viruses have an ancient evolutionary history of their own, beginning right with the formation of cellular life. For example, some of the viral repair enzymes, which are responsible for removing and resynthesizing damaged DNA and repairing damage caused by oxygen radicals and the like [see box below], are unique to certain viruses and have probably existed almost unchanged for billions of years.
However, most evolutionary biologists argue that since viruses are not living, they do not deserve serious attention when trying to understand evolution. They also believe that the origin of viruses is the host's shields that escaped in some way from the host and put on a protein coat. According to this approach, viruses are escaped surrogate genes that have degenerated into parasitic life. And since this eliminated the viruses from the fabric of life, it is easy to miss important contributions that they may have contributed to the origin of species and the existence of life. (Indeed, only four of the 1,205 pages of the 2002 Encyclopedia of Evolution are devoted to viruses.)
Of course, evolutionary biologists do not deny that viruses have played some role in evolution. But because they define viruses as dormant, they put them in the same category of externalities as, say, climate change. Because of such external influences, a process of natural selection is created between individuals with different genetically determined traits, and only those individuals who are able to survive in the best way and thrive when faced with such challenges, continue to breed optimally and pass their genes on to future generations.
But viruses directly exchange genetic material between themselves and living beings, that is, within the fabric of life itself. A fact that will surprise most doctors, and possibly most evolutionary biologists as well, is that most known viruses are harmless and have a constant presence in cells. They settle in cells, where they remain dormant for long periods or take advantage of the cell's replication machinery to reproduce at a slow, steady rate. These viruses have developed many sophisticated methods to prevent detection by the host's immune system, so that practically every step of the immune response can be changed or controlled by different genes found in any virus.
Moreover, a viral genome (the total DNA or RNA content of the virus) can settle permanently within the host, so that the viral genes are added to the lineage of the host and eventually become an essential part of the host's genome. That is why there is no doubt that viruses have a faster and more direct effect than external forces that only make a difference out of the slowly created genetic variation. The huge population of viruses, combined with their rapid rate of reproduction and generation of mutations, make viruses the world's leading source of genetic innovations, because they are constantly "inventing" new genes. And unique genes of viral origin can migrate, find their way to other creatures and contribute to evolutionary changes.
Information published by the Human Genome Sequencing Consortium suggests that approximately 113 to 223 genes found in both bacteria and the human genome are absent from well-known organisms such as the yeast Saccharomyces cerevisiae, the fruit fly Drosophila melanogaster, and the nematode (roundworm) Caenorhabditis elegans, which lie between these two evolutionary extremes. Some researchers believe that these organisms, which evolved after bacteria but before vertebrates, simply lost these genes at some point in their evolutionary history. Others claim that these genes were directly transferred to the human lineage by invading bacteria.
My research partner Victor DePhillips, from the Institute for Immunotherapy and Gene Therapy at Oregon Health and Science University, and I propose a third possibility, which is that viruses produced these genes and then colonized two different lineages, such as bacteria and vertebrates. It is possible that a gene apparently given to humanity by a bacterium was actually given to both by a virus.
In fact, Philip Bell of Macquarie University in Sydney, other researchers and I argue that the cell nucleus itself is of viral origin. It is impossible to explain in a reasonable way the appearance of the nucleus, which distinguishes eukaryotes (organisms containing a true cell nucleus), including humans, from prokaryotes, such as bacteria, only based on the gradual development of prokaryotic cells until they became eukaryotes. Instead, the nucleus may have evolved from a large DNA virus that resided permanently within prokaryotes. Some support for this idea can be found in data on DNA sequences showing that there is a close relationship between the gene for DNA polymerase (an enzyme that replicates DNA) of a virus called T4 that infects bacteria, and other DNA polymerase genes in both eukaryotes and viruses that infect them. Patrick Porter from the University of South Paris also analyzed data on enzymes that replicate DNA and concluded that the origin of the genes for these enzymes in eukaryotes is probably viral.
Viruses affect all forms of life on Earth, from single-celled organisms to human populations, and they often determine what will survive. But the viruses themselves also evolve. New viruses, such as the HIV virus that causes AIDS, may be the only biological entities that researchers actually witness being formed. These new viruses provide real-time examples of evolution in action.
Viruses are important to life. They are the ever-changing border between the world of biology and the world of biochemistry. The more we progress in deciphering the genomes of more and more organisms, the more we will understand the contribution of this ancient and dynamic gene pool. Already in 1959, the Nobel laureate Salvador Luria thought about the effect of viruses on evolution. "Should we not consider," he wrote, "that the viruses, capable of uniting with a cellular genome and then separating from it, are in fact the entities and the process that in the course of evolution created the successful genetic patterns underlying all living cells?" If we define viruses as living beings and if not, it is time to recognize them and study them in their natural environment - within the fabric of life.
Title for the image page 100
Viruses are found on the border between the animal world and the inanimate world
Credit on page 101
Brian Christy, design
Text box and image on page 102 above
What's in the word?
"'Life' and 'to live' are words that the scientist borrows from the common man. The question of the words was successful until recently, because the scientist usually did not care, and he certainly did not know, what exactly these words meant in his eyes or in the eyes of the common man. But today, systems are being discovered and studied that are neither clearly alive nor clearly dead, and it is necessary to define these words or give them up and replace them with new ones."
Norman Pearce, British virologist, circa 1934
"You think life is just not being still as a stone."
George Bernard Shaw, St. John, 1923
Label pictured on page 102
HIV
Credit on page 102
Russell Keightley, Scientific Photo Library (SPL)
Text box on page 102
Overview/ A bit of life
Viruses are parasites found on the border between living and non-living matter. They contain the same proteins and nucleic acids found in living cells, but they need the help of these cells to reproduce.
For decades, researchers have debated whether viruses are living things or not. This debate has distracted from a more important issue: viruses play a vital role in evolution.
A huge number of viruses multiply and change by mutations all the time. This process creates many new genes. A new gene with a beneficial function can occasionally enter the genome of a host cell and become a permanent component of that cell's genome.
Picture on page 103 - please turn right-left
Whether viruses are technically "living" or not, they certainly have a property that characterizes life, that is, they can reproduce, albeit with the help of a host cell. This figure shows one form of viral culture, that of a virus containing double-stranded DNA as its genetic material. The replication processes of phages (viruses that infect bacteria, which are creatures without a nucleus), of RNA viruses and of retroviruses differ in some details, but the general idea is the same.
Labels inside the image, in the direction of the numbering
1. A virus attaches to a cell and enters it
2. A virus releases its genetic material
Viral genes
cellular enzymes
3. Cell enzymes replicate the viral DNA and transcribe it into RNA
host cell
nucleus
Viral RNA
ribosome
A protein at the beginning of its construction
viral protein
4. Ribosomes in the cytoplasm translate the RNA into viral proteins
5. Viral proteins and DNA aggregate and form new virus particles
6. New virus particles leave to infect other cells
Viral DNA
A new viral particle
Credit on page 103
Brian Christy, design
Text box on page 103
About the author
Luis P. Villarreal (Villarreal) is the director of the Center for Virus Research at the University of California, Irvine. Born in East Los Angeles. He received his doctorate in biology at the University of California, San Diego, and he did his postdoctoral research in the field of virology at Stanford University with Nobel laureate Paul Berg. He is active in science education and won the Presidential Award of the American Science Foundation for individual instruction. In his current role, Villarreal established programs for the rapid development of defense against biological terrorism. He has two sons and is a fan of motorcycles and South American music.
Text box and image on page 104 above
Distracting cells
"For almost a full century, biologists have been distracted by arguments about whether viruses are organisms or not. The debate stems mainly from the generalization originating in the second half of the 19th century that claims that cells are the building blocks of life. Viruses are simpler than cells, so the logic says that viruses cannot be living organisms. It seems the most correct thing to do is to dismiss this widespread point of view as semantic handwaving.”
Paul Ewald, American evolutionary biologist, 2000
Label pictured on page 104 above
Bacteriophage T4
Text box and image on page 104 below
Resurrection and other antics
Because viruses reside in an intermediate world between the animal world and the inanimate world, they can perform some amazing tricks. For example, although viruses usually reproduce only in living cells, they can also multiply, or "grow" in dead cells, and even bring them back to life. Amazingly, some viruses can even return to their "borrowed lives" after being destroyed.
A cell whose DNA in its nucleus has been destroyed is a dead cell, because it lacks the genetic programs to create essential proteins and divide. But a virus can take advantage of the cellular production machinery in the remaining cytoplasm to reproduce. That is, it can cause the cellular machinery to use the viral genes to produce viral proteins and to replicate the viral genome. This ability of viruses to grow inside a dead host is particularly evident in unicellular hosts, many of which are found in the oceans. (Indeed, there are an almost imaginary number of viruses on Earth. It is estimated that in the oceans alone there are about 1030 viral particles, some inside cellular hosts and others floating in the water independently.)
Bacteria, such as blue photosynthetic bacteria (cyanobacteria) and algae, usually die when ultraviolet (UV) radiation from the sun destroys their DNA. Some viruses contain enzymes or genes for enzymes that know how to repair various molecules of the host, thus bringing the host back to life. For example, blue-green bacteria contain an enzyme that acts as a photosynthetic center, but this too can be destroyed by too much light. When this happens, the cell is unable to photosynthesize, its metabolism is impaired and it dies. But viruses called blue phages encode their own version of the bacterial photosynthesis enzyme, and the viral version is largely resistant to UV radiation. If such viruses infect a cell that has just died, the viral photosynthesis enzyme can take the place of the destroyed cellular enzyme. It can be thought of as life-saving gene therapy for the host cell.
Sufficient UV radiation can also destroy blue phages. In fact, destroying viruses with the help of UV radiation is a common method in the laboratory. But such viruses can sometimes be resurrected. This happens in a process known as multiplicity reactivation. If any cell has more than one damaged virus, the viral genome can reassemble from the pieces. (It is this reproducibility that allows us to create artificial recombinant viruses in the laboratory.) The different parts of the genome can also sometimes provide individual genes that work together (in a process called complementation, or complementation) to provide full activity without necessarily creating a complete or autonomous virus. Viruses are the only biological entity with the "phoenix trait", meaning the ability to rise from the ashes.
Caption for image on page 104 below
Tobacco mosaic virus
Credit on page 104
Department of Microbiology, SPL Biocentre [above]; Jeremy Burgess SPL [below]
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Life on the border
"The essence of the virus is its fundamental entanglement within the host's genetic material and metabolic mechanisms."
Joshua Lederberg, American Nobel laureate, 1993
"It's a matter of taste whether viruses should be thought of as organisms or not."
Andre Loew, French Nobel laureate, 1962
"A virus is a virus!"
Loof, 1959
And more on the subject
Viral Quasispecies. Manfred Eigen in Scientific American, Vol. 269, no. 1, pages 42–49; July 1993.
DNA Virus Contribution to Host Evolution. LP Villarreal in Origin and Evolution of Viruses. Edited by E. Domingo et al. Academic Press, 1999.
Lateral Gene Transfer or Viral Colonization? Victor DeFilippis and Louis Villarreal in Science, Vol. 293, page 1048; August 10, 2001.
Viruses and the Evolution of Life. Luis Villarreal. ASM Press (in press).
A site dealing with the theory of viruses
They knew evolution - bacteria and viruses
Scientific American website in Hebrew. where you can also purchase a subscription to the magazine
https://www.hayadan.org.il/BuildaGate4/general2/data_card.php?Cat=~~~191259823~~~244&SiteName=hayadan
