Viruses: More Friends Than Foes (Revised Edition). Karin Moelling

      Knot-free splicing (cleaving and joining) of RNA allows combinations of exons to build new genes with high complexity, intron is deleted.

      Our genes are split, consisting of exons — regions that can be translated into proteins — and introns — regions in between, which are removed by cutting and splicing (rejoining) of the RNA ends. Human genes have on average approximately seven to nine exons, interspaced by introns. Think of a garden fence, with its planks and the spaces between them: these would correspond to the exons and introns respectively, although exons and introns are less regularly spaced. Furthermore, some introns can be very large (imagine a gate in the fence).

      One can combine the various possible connections between introns and exons, whereby the introns are normally the parts deleted. The introns are not really “empty”, as gaps in the fence are. What information do they contain? They do not code for proteins, but direct and regulate the production of the proteins; they harbor regulatory information, determining where and when the proteins are to be produced. Thus the introns control the exons. Scientists used to think that the exons are more important, but today it is recognized that they are even the dependents. According to the scientific definition, exons “code” for proteins, whereas introns are “noncoding” (nc). The catalogue of known ncRNAs is a rapidly growing family of very important regulatory RNAs — almost a dozen of them were discovered recently. Therefore, dear reader, please remember “ncRNA”. The corresponding DNA is called ncDNA, which is transcribed to give the ncRNA. I find it particularly interesting that humans and the viruses are the joint world champions in splicing! Why the viruses? Because they make so much out of so little! (Our ancestors!) The sailor did not know how complex the background was behind the spliced rope that he gave me as a present.

      As an example of generating many “messages” from a single all-embracing “message”, think of how many words you can generate from combined exons after splicing across any gaps: supercalifragilisticexpialidocious — not the longest English word, but the best-known for its length — just by deleting (but not rearranging) letters and thus created: super, supercilious, perfidious, precious, serious, superficial, fragile, pallid, series, focus; there are many more, and you may care to try for yourself. Viruses splice only within a word, as their minimalistic equipment comprises exons and no introns. In these different ways, we and the viruses have learnt to make the best possible use of our genetic material. This complexity lies at the heart of the complexity of the human organism, and that of the viruses, which is why I was doubly grateful for the sailor’s present.

Viruses — dead or alive?

      Viruses are not lifeless — at least not as lifeless as a stone or a crystal. One can over-simplify the issue and say that anything smaller than a virus is lifeless, and what is larger is alive. So viruses are at the borderline: dead or alive or both. I do not see a singularity, no point, no sharp borderline, but rather a continuous transition from individual biomolecules all the way up to the cell. At the origin of life RNA viruses were around as the largest biomolecules, and from then on they have always been present.

      “What is life?” This question was asked in 1944, in the title of the famous book by the physicist Erwin Schrödinger, a thesis that mobilized a whole generation of physicists into doing biological research. Life follows the laws of thermodynamics and energy conservation. Living cells are characterized by negative entropy based on organized structures, whereby entropy is often simply described as a “measure of disorder”. For example, left to itself my desk becomes more and more untidy; however, if I can muster enough energy to clear up, then it becomes ordered and tidy. Life and the second law of thermodynamics follow this rule: nutrition and energy allow an orderly life. Admittedly, Schrödinger was asking about the laws of life, not the origin of life.

      I think that NASA must have a good definition of life, because NASA is trying to find life outside our planet. They surely know what they are looking for. Jerry Joyce, then at the Salk Institute in California, may have contributed to their definition when he succeeded in producing self-replicating RNA in a test-tube, RNA that was also capable of mutating and evolving. This was his approach to “repeating the origin of life”. He may have inspired the US space agency NASA, which formulated a definition of life as a self-replicating system containing genetic information and able to evolve. (I would even omit the word “genetic”, because structural information able to evolve would also be possible. I am thinking of viroids.)

      Viruses can be compared to apples. An apple on a table cannot duplicate itself and turn into two apples — and a virus cannot do that either. An apple needs earth to become an apple tree and thereby to produce new apples. Are apples alive? What then of viruses? Can Charles Darwin help? He pictured a “warm little pond” as the place where life possibly originated, and imagined that the beginning was simple — but he predicted no more than that. A virus needs a pond, or at least a test-tube — an environment with nutrients for replication and for the production of progeny. And viruses are simple. So viruses are more alive than stones and only stones are really dead. Surprisingly, some viruses can aggregate and form symmetrical quasi-crystalline structures, which are extremely stable and heat-resistant, and in that respect they do indeed resemble stones. Crystals with malformations can even perpetuate their misfolding in a manner that looks almost like replication. Some protein aggregates in the brain can behave like this — prions for example; so are they then also something like viruses? I suggest that, as we shall see!

      Bacteria are generally accepted as living microorganisms: they can divide and thus replicate themselves, and — most importantly — they can synthesize proteins. Protein synthesis is accepted as an important borderline marker distinguishing living from non-living matter. Bacteria also need food from the outside; yet they are not completely independent entities either. And bacteria are not simple! There is no such thing as a biological “perpetual-motion machine”, something that can get away without an energy supply. Yet energy does not necessarily have to come from a cell. Energy can be chemical energy, without any sunshine around, as in the case of the black smokers in the depths of the ocean.

      Most surprisingly, the recently discovered giant viruses contain components for protein synthesis. So they are very close to the living bacteria, they are “quasi-bacteria”. Accordingly, the giant viruses are also called “mimiviruses”, because they seem to mimic bacteria. Just like bacteria, these giant viruses are hosts for smaller viruses, which replicate inside the bigger ones. All this was extremely irritating for classical virologists, because no previous convention or definition of viruses fitted for these giant viruses. Their discovery in 2013 was commented upon in the journal Nature to the effect that viruses now qualify to take a seat at the table where life is being debated, and that they should be placed at the bottom of the tree of life, this is what the discoverers of mimiviruses hoped! At the bottom there were no cells yet, and there are no mimiviruses — both are huge in comparison with viruses, therefore both cannot represent the origin of the tree of life. Probably, the early viruses did not need cells. This is a risky idea, and the only complication in my speculation that “viruses came first”. Today’s viruses need cells, but that could have been the result of long evolution. Indeed, there are the viroids, naked RNAs, which can replicate and evolve and may initially not have depended on cells as they do today. They are able to do all this in Joyce’s test-tube — no cell. They could be termed “naked viruses”.

      Viruses are inventors and suppliers of genetic innovation. They built up our genomes. This is what I believe, and I shall mention it more than once, my credo, my ceterum censeo.

      Viruses have certainly contributed to building cells. This is indeed a hard fact and no speculation. Today they are parasites and depend on cells. A parasite can delegate functions