virology

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ebola

Recent accounts of Ebola in West Africa are terrify particularly since some cases have now spread to the US and other Western countries. At the end of the 3rd year university course in molecular virology I used to teach, the students were asked which viruses could be weaponised for bioterrorism. The usual three viruses that come up were influenza, small-pox and Ebola. All these viruses required a high degree of technological expertise and state-of-the-art laboratory containment facilities with personnel trained in molecular genetics and DNA technology. Influenza had the advantages of being an air-borne infection — the question was how easily could you reconstruct the Spanish flu of 1914 from published sequences of the virus into a current influenza virus. For small-pox, there are presumably deep freezers in the US and Russia that still have samples of the virus or one could use a close relative like camel-pox and reverse engineered it to contain the known published sequence of virulence genes of small-pox. Both of these viruses could be produced but were probably beyond the capability of your common variety terrorist.

Similarly Ebola would be difficult to produce in a laboratory due to its highly contagious nature. Ebola was initially thought to have a short incubation period of 2-3 days so the possibility of someone from a West African village boarding an airplane on an international flight seemed remote. With the incubation period now being as long as 21-days this changes everything. With the outbreak in West Africa the question of virus supply is no longer an issue — all you need is a bucket of vomit or vials of infected blood.  Also recent events have shown that a few cases of Ebola can be contained and quarantined but the health systems can not cope with hundreds or thousands of cases.

To put Ebola into perspective, it was thought to be a rarely occurring exotic virus disease in distant jungles in West Africa. Not something we in the West need concern ourselves with  — compare this to the response to SARS when it spread in Western countries. Now some 38 years later we are scrambling to understand more about Ebola. We live in a global world and need a massive global effort to get on top of this problem.

I don’t think anyone in my virology class was a potential jihadist terrorist but the world has just become more complicated.

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Tao-to-MS2There has been a lapse in recent posts to this blog due to deaths in the immediate family. They have served as a reminder of one’s own mortality and ‘resets’ one’s priorities.

This post is a concluding one on the topic: ‘the equation for intelligence’ — F = T ∇ Sτ. I have noticed that whenever I try to explain it at any social occasion there is either a glazed over look in the eyes of the listener or a furtive check of their smartphones for a nonexistent recent text message. Understandably most people read the news or browse the blogs to confirm their preconceptions of their world view (aided by being in a Google bubble). Rarely are they willing to undergo any questioning or change in their status quo. I think that by the age of about 25 you’ve formed a world view and you may make small changes as you go along but almost never make a paradigm shift.

It is in this context that ‘the equation for intelligence’ appeals to me. Having a Taoist predisposition to seeing the universe as self-organising and naturally flowing along intelligence lines, the universal law of intelligence proposed by Wissner-Gross  seemed imminently sensible. Having spent more than 40 years as a molecular virologist I have marvelled as to how fundamental life processes follow this knife-edge path between chaos (disorder) and stability (stagnation).  One of my favourite examples of this is the life cycle of a simple bacterial virus MS2. For the purposes of the story-telling I shall simplify some details but hopefully preserve the elegance of the life-cycle.

MS2 Phage Life-Cycle

The host of this virus is the common E.coli bacteria found in vast quantities in your gut (and faeces).  MS2 is one of simplest viruses consisting of 180 molecules of a coat protein, one copy of a maturation protein and an single-stranded RNA molecule consisting of 3569 nucleotides. The virus forms an icosahedral shell with the RNA inside, (see the right-handed side of the diagram above). This  RNA codes for four proteins — the maturation  (A-protein), the coat protein (CP), a lysis protein (which overlaps the coat protein) and the replicase protein (RdRp) for making RNA copies (see gene order and diagram below). The expression of these genes - their timing and the quantities produced is orchestrated in the most elegant way. The reading of genes on an RNA molecule by ribosomes and the protein translating system occurs from left to right (this true of all messenger RNA’s including our own).

Leviviridae_genome

When the viral RNA molecule enters the bacteria the first gene is the maturation gene (protein-A) which would normally be the first gene expressed by the ribosomes but its 5’-end is hidden within a RNA secondary structure so the first gene to be read is the coat protein which makes sense since the virus needs 180 copies. The start of the maturation protein gene is only accessible in RNA freshly replicated (before it can fold on itself) — only a few copies are made per RNA (only one copy is actually required). As the ribosomes travel along the RNA, the gene downstream to the coat protein is the replicase gene — this enzyme is necessary to make RNA copies but only a few copies are necessary since one replicase enzyme molecule can make hundreds of RNA copies. To shutdown this gene dimers of the coat protein bind to the start of the replicase gene and block further ribosomes from binding — shutting down the making of more copies of replicase.

Copies of the coat protein continue to be made — 180 are required per virus particle. Finally the lysis protein is expressed and this is controlled by ‘slip back’ by the ribosomes to the start of the lysis protein gene within the coat protein gene (the gene within a gene). Ribosomes as they travel along the RNA are ‘noisy’ and can fall off or slip —particularly at a slippery part of the RNA near the start of the lysis gene at about a 5% frequency.  This ensures that lysis expression occurs late in the life cycle (you don’t want cells bursting open before sufficient virus accumulates). The lysis protein forms pores in the cell wall of the host and the bacteria breaks open releasing hundreds of progeny virus particles that can infect more bacteria.

The key points of this story were to illustrate the elegant self-organising mechanisms that regulate the interplay between gene expression and RNA secondary structure and that the expression of the lysis gene depended on noisy ribosomes (entropic increase in the possible futures) to complete the life cycle of the virus. An example of “intelligence acting to maximise the future freedom of action — F = T ∇ Sτ ”. Or from a Taoist point of view the life-cycle follows the Tao "the path" or "the way” — the universal principle that underlies everything from the creation of galaxies to the interaction of human beings.

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Pithovirus

Although this made headlines around the world, it is probably only of concern to amoebae and evolutionary virologists. But the researchers suggested that as the Earth's ice melts, this could trigger the return of other ancient viruses, with potential risks to human health. The scientific virological community responded by pointing out that this "stretched scientific rationality to the breaking point" (Curtis Suttle - University of British Columbia, Vancouver)

This is not to say that this virus does not have some interesting properties -- it is the largest virus at 1.5 micrometers long (the size of a small bacterium) -- one end appears to sealed with a cork (photo) -- the French researchers named it from the Greek word 'pithos' for the large container used by the ancient Greeks to store wine and food. It is unrelated to other giant viruses such as Mimivrus or Pandoravirus that have been isolated from amoeba. Pandoravirus has a large viral genome at 2.8 million base pairs compared to Pithovirus at 0.6 base pairs. Only 32% of the predicted Pithovirus proteins have homologs in protein databases (this number is 61% for Minivirus and 16% for Pandoravirus).

Pithovirus hints at the vast unimagined viral diversity that awaits our discovery.

For more, see article by Professor Vincent Racaniello

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The short answer to the question: -- YES.

Following on from the previous posting about Pandoraviruses, the virological world has become much more complex than we could have imagined -- a network of diverse genetic elements with different reproduction strategies and lifestyles -- the transpovirons, polintons, and virophages.

Virophages
Comparison of the genome architectures of the virophages, polintons, some viruses, and transpovirons. Homologous genes are marked by the same colors. (CLICK TO ENLARGE)

The rapid advances of genomics and the growth of sequence databases has led to the discovery of fundamentally novel types of genetic elements. The giant viruses, Mimiviruses that infect amoeba, possess their own parasites and communities of associated mobile genetic elements. The first virus infecting a giant virus, the Sputnik virophage, was shown to replicate within the mimivirus factories and partially inhibit the reproduction of the host Mimivirus. A second isolated virophage was named Mavirus and the third virophage genome was isolated from the Antarctic Organic Lake (hence OLV, Organic Lake Virophage). The virophages possess small isocahedral virions and genomes of 20 to 25 kilobase encoding 21 to 26 proteins.

Analysis of the Mavirus genome resulted in the unexpected discovery that this virophage shared 5 homologous genes with the large, self-replicating eukaryotic transposable elements called Maverick/Polintons. In addition to the virophages, the giant viruses host several other groups of mobile elements. These include self-splicing introns, inteins, putative bacterial-type transposons and the most recently discovered novel linear plasmids named transpovirons. In a recent paper published in the Virology Journal, the authors sought to decipher the evolutionary relationships between the three known virophages, the Maverick/Polintons, transpovirons and bona fide viruses.

Their conclusion was that the virophages and related genetic elements formed a vast network of evolutionary relationships with multiple connections between bona fide viruses and other classes of non-virion mobile genetic entities -- a genetic soup.