Are viruses even alive? 2-Viruses and the definition of life

CNV virus
Reconstruction of the Cucumber necrosis virus. Image from here

It is not clear whether viruses are alive or not.

All life in this planet follows a series of rules that separate them from non-living beings., but viruses do not seem to follow them, exactly. We reviewed how viruses works and what constitutes life in Are viruses even alive? 1- What is life? 

Here, we go through every life-rule and see how viruses follow them (or not). What we encounter, is that viruses are more complex than expected, and that the definition between life and death may not be as straightforward as we know.

1) Life uses metabolism

Without a host, a virus is as alive as a grain of sand. It does not perform any function and thus, does not require transforming energy to survive. In fact, many viruses cannot live without a host for too long, and changes in humidity or light intensity easily break their structure.

However, some viral processes need energy. Some bacteriophages, bacteria-infecting viruses, use a mechanism similar to a syringe that contracts and injects their DNA into the host, something that would require energy. But where does this energy come from?

Bacteriophages have a tail full of ATP, the main molecule used in energy transfer across the tree of life, and an ATPase, an enzyme that can extract energy from that molecule. There is an additional mystery, though. Normally, ATP is created by any living being through the so-called “electron chain”, a process that only occurs in cell membranes.  As we have seen, though, the membranes of a virus are not really “theirs”, and lack the capacity to perform “electron chains”. Both the ATPase and the ATP tail are in fact proteins coded by the virus DNA and produced by the host!

And this is not only the only action viruses can perform! In stage 6 (see Are viruses even alive? 1- What is life?), a procapsid, a protein structure that serves as the virus’ “body”, is built and latter filled with genetic material and other viral structures (built). Similar to the virus entry inside the cell, this process requires not only energy, but a complex machinery created by the host, but ultimately used by the virus (see below). 

Viruses, then, are not able to use external energy to transform it into their own energy, but still can use a very rudimentary form of metabolism that allows them to transfer energy through ATP, the energetic coin of life. 

procapsid
Genome packaging in some viruses may require a complex protein machinery and the use of energy (ATP). Image from here

2) Life is self replicating

If viruses had a ultimate goal it would be reproduction. As we have seen, though, viruses are unable to duplicate their genetic material by themselves and, with no exception, need to infect a cell to reproduce.

However, viruses are not passive entities waiting for their DNA to be read and duplicated, and can use some strategies to make sure their duplication and chances of infecting more hosts are maximized.

Many bacterial viruses can switch between a lytic and a lysogenic cycle. While the lytic cycle allows the virus to reproduce immediately and ultimately destroy its host cell, the lysogenic cycle is a dormant cycle, where the virus’ DNA remains in the host’s cell, but remains silent. As the host cell duplicates its DNA for reproduction, so will the virus’ DNA. This not only allows the virus to duplicate into other cells without the need to kill its host but also allows the virus to wait until the conditions are optimal to burst out. In that condition, the virus DNA can even code for proteins that repress other viruses’ DNA that have also entered in the host.

800px-Phage
Multiple bacteriophages anchored to a bacteria. Image from here.

The switch between lytic and lysogenic can be changed depending on exterior conditions. If the host cell is in danger, for example, the virus would change to a lytic cycle as a last chance to leave the cell before it dies. Similarly, the so-called “satellite viruses” , are minute viruses that are normally harmless. However, if the cell is infected by another virus, they activate and use the machinery of the other virus to replicate themselves.

Similar to the “satellite viruses” are virophages. Virophages are also minute, and do not code for the necessary machinery to duplicate themselves. For this reason they make use of a specific group of viruses to replicate: the Mimiviruses. Mimiviruses are not giants, but gargantuans in the virus world, bigger than some bacteria, and with more genetic material. Virophages wait for their host cell to be infected by a mimiviruses and similarly highjack their machinery. In this case, though, this results in the inactivation of the mimivirus, which can help the host cell to survive!

3) Life has an identity

Viruses, have a protein enveloping their contents minimum, the capsid. This is very different from any other organism, in which the main envelope is a lipid-based cell membrane. Different from prions and virions (see A race to be alive?, below), viruses are separated from their medium and have an identity, although different than usual.

However, viruses can also have membranes. Some viruses “burrow” a membrane from the host. Viruses can escape their host not by bursting out, but by recruiting the cell’s membrane. This membrane is not actually theirs, but can be matured by adding viral proteins, creating a hybrid between viral and cellular membrane. Other viruses, though, encode for a membrane in their DNA, which can be formed over or inside the capsid.

4) Life evolves

As any other biological structure, virus mutate. Errors while reading or duplicating the virus’ genetic material, recombination, mutations… all contribute to change a virus genetic material. With change, there is variation and with variation, there is selection. As only some viruses are able to trespass the immune system of an organism, only some viruses will have the adequate sequences to enter a host and reproduce, giving their successful genetic material to the next generation. Virus evolution is perhaps one of the fastest on Earth, and our continue struggle against fast evolving viruses, such as influenza, are proof of this evolution.

Furthermore: Not only are viruses subject to natural selection, but also have means to highly increase their genetic variability. One of this methods is recombination. We are not kidding. Recombination of DNA, in which pieces of DNA are interchanged to create new strands is mostly related to sexually reproducing organisms. Of course, viruses are not able to do that for themselves. When a cell is infected by several viruses that anchor their DNA to the host DNA, the recombination of the host’s DNA may result in recombinant viruses. Similarly, viruses can also obtain a host’s gene and develop some small property of their host. The most common example would be the ability to code for a protein of the host, a protein that can be later integrated into the virus’ structure and allow it to sneak through the host’s immune system.

A race to be alive?

So, are viruses alive or not?

Well, depends on first, how you define life, and second, on which parts of the definition are deemed most important. Although viruses clearly have living properties (they have a genetic code, they evolve…), they lack others (they do not transform energy to create their own…).

And how do viruses compare to other similar structures that bounce between life and death? In order to reach an answer regarding viruses’ “aliveness”, we should take a look at prions, viroids, plasmids and the AL. 

Prionsetal
The race to be alive: from left to right: a prion, a viroid, a plasmid and a robot. Images from Srivastava & Lapidus 2017, Hernández & Flores 1992,  Wikimedia and  here.

Prions are folded proteins that induce other proteins to fold in a similar way, thus being “able to duplicate” without a genetic code and causing multiple neurodegenerative diseases. Thus, prions are only able to self-replicate, although indirectly. This, then, represents an extremely rudimentary form of “life” that does not even use DNA, but still uses organic molecules.

More complex than prions are viroids. Viroids are single naked strands of RNA without membranes or any other structure that separates them from the medium. Viroids are commonly found in plants, and enter their cells through the small holes that connect plant cells or through the mouthparts of biting insects. Viroids don’t get integrated into the host’s DNA, but are instead duplicated using a RNA polymerase II, a common enzyme. Viroids represent a next step in the race to be alive: although they do not have an identity, they are based on genetic material (RNA) and are able to create copies of themselves. 

If viroids are made of RNA, plasmids and transposons are small pieces of DNA. Plasmids are bacterial DNA strands that can be shared between bacteria and result in an exchange of new genes. Transposons are sequences present in the DNA of an organism that when read, create a machinery that cuts, duplicates and transports them to other positions of the DNA strand. Plasmids and transposons, then, are part of the body of an organism (unlike a virus), but can work independently from the main genetic code. Plasmids and transposons, although fundamentally different, represent a next step in the race to be alive: they are based on DNA, they duplicate, they code for own proteins and they are able to “travel”, even outside of their own cells (in plasmids). These are starting to be more similar to a virus, but would still lack an envelope, for example. 

Other contestant for the race to become “alive” are extremely recent and interestingly originate from the hands of humanity; artificial life. Artificial life can encompass many things: from software (called soft AL), to hardware (hard AL), to molecular engineered (wet AL). So far, these are exploratory projects that try more to understand how life originated and developed than to create any new type of life. These, though, are included here because similar to viruses they explore some parts of the definition of life.

A very interesting initiative is Tierra. Tierra is a software environment inhabited by self-replicating computer programs. These programs reproduce, but not perfectly. As any program, sometimes there are informatic bugs which end up creating code differences.  The oldest copies get deleted, thus providing the two fundamental pieces for evolution: variation and selection. Therefore, the inhabitants of Tierra (let’s call them “terrestres”) have two qualities of life: self replication and evolution! Of course, these have no metabolism (their life is guaranteed as long as the computer has energy) and neither they have any type of cellular structure, but provide an interesting take on life, that could become increasingly closer to a full definition of life as technology advances. 

Parallel to soft AL, “wet” artificial life or synthetic biology is advancing every year. So far, scientists have managed to transplant DNA between bacteria, making the recipient bacteria behaving like its donor! Similarly a group of scientist has synthetized a complete genome for an artificial species of bacteria, named Caulobacter crescentus-2.0. C.crescentus exists in nature (is a harmless fresh water bacteria) but the 2.0 version has half its genome, and has been created entirely in the lab. So far, though, the 2.0 version is but DNA in a tube, and has not been implemented in a cellular structure.  It seems then, that there is still a long way to fully understand and create life. 

-A sharp boundary between the living and non-living is but an illusion- Koonin & Starokadomskyy, 2016

So, are viruses alive? The answer is… is complicated. We have seen that all depends on the definition of aliveness, but that even then, it is difficult to trace a strict line between both worlds. Prions, viroids and plasmids provide interesting intermediates across life and not-life. 

Viruses, in their simplicity, are more complex than non-living structures, and more complex than prions, viroids and plasmids. As time goes by, we encounter more and more surprising qualities of viruses, which tie them closer to living beings. Maybe viruses where once completely living organisms, but took a turn to become the simplest and most effective of parasites. This is not a crazy idea, but several questions would still need to be answered: why do some viruses have RNA as their only molecule, instead of DNA, which all living beings have? Why do they have a protein envelope, instead of a cell membrane? 

Or maybe viruses had a different origin from living beings, a different origin of life on Earth, one that is so different to everything else, that casts doubts about their aliveness. Maybe life in other planets does not follow the rules we know for living beings, either. Maybe neither DNA nor RNA is their coding structure, and their envelope is not a cell membrane. Artificial life provides us examples of structures that do not follow these rules either, implying that either our definition of life should be broadened or that the race to be alive is becoming increasingly competitive. 

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References

https://viralzone.expasy.org/

https://www.eurekalert.org/pub_releases/2019-04/ez-fbg032819.php

Bedau, M. A. (2003). Artificial life: organization, adaptation and complexity from the bottom up. Trends in cognitive sciences, 7(11), 505-512.

Carter, J., Saunders, V., & Saunders, V. A. (2007). Virology: principles and applications. John Wiley & Sons.

Kassanis, B. (1962). Properties and behaviour of a virus depending for its multiplication on another. Microbiology, 27(3), 477-488.

Koonin, E. V., & Starokadomskyy, P. (2016). Are viruses alive? The replicator paradigm sheds decisive light on an old but misguided question. Studies in history and philosophy of science part C: Studies in history and philosophy of biological and biomedical sciences, 59, 125-134.

Macklem, Peter T., and Andrew Seely. “Towards a definition of life.” Perspectives in Biology and Medicine 53, no. 3 (2010): 330-340.

Mougari, S., Bekliz, M., Abrahao, J., Di Pinto, F., Levasseur, A., & La Scola, B. (2019). Guarani virophage, a new sputnik-like isolate from a Brazilian Lake. Frontiers in Microbiology, 10, 1003.

Murant, A. F., & Mayo, M. A. (1982). Satellites of plant viruses. Annual Review of Phytopathology, 20(1), 49-68.

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