How to make a virus

There was a pretty good seminar I saw on the subject of virology, which is not my area of expertise nor necessarily of interest. However, the presentation and work done was explained well and was done in an engaging way, such that even though this is an area I am not particularly concerned with, I enjoyed immensely.

(Aside: These leads to a particular rant I have. I see that many lab heads avoid departmental seminars unless said seminar is directly related to their particular field. I understand this mindset, because we are all extremely busy, we have many seminars, meetings, and duties beyond research and teaching that vie for our time. However, this mindset is being passed down to the post-docs and, more importantly, the students in these labs. Over the course of several years of this, the end result is a batch of students with little breadth beyond their specific research area, students who are unaware of technical or intellectual advances in other fields that may in fact aid their research, and students who may not have the skills to succeed on their own. /Aside)

The specific seminar I attended was on Hantavirus. Like all organisms, even pseudo-organisms like viruses, there are interesting biological problems and questions associated with them. One thing of interest with the Hantavirus, and other viruses of the Bunyaviridae family, is that it has a segmented genome. This is similar to us, our genome is comprised of 23 individual chromosomes (2 copies of each). Thus, our genome is segmented. This can be contrasted to many, but not all, bacterial species, which have their genomes comprised on a singular circular chromosome. So, the Hantavirus genome is comprised of 3 segments. If you click on the picture, which is from the CDC, you can actually see some of the strands in the viruses that are the RNA segments that comprise the genome. In answer to your question, yes RNA! These viruses maintain their genome as RNA, not DNA. So the discovery of the virus, seeing it inside of cells, analysis of its genomic structure is all basic biology that was worked out over the last few decades.

So what is the profoundly interesting thing here? Well, its a question I do not know the answer to, nor am I sure anyone does in this particular case. However, it does represent an interesting biological problem. A bit more background, when a virus infects a cell, the genome regardless of RNA or DNA is uncoated, in other words freed from the protein shell it travels around in. This allows the virus to replicate, make messages, and make all the proteins necessary to make more viruses. Now once all these new viral genomes are made, they have to be packaged into new shells before leaving the host cell. (Free nucleic acid in the environment usually gets eaten.) For a virus with a single bit of RNA or DNA that gets packaged, you can simply have a protein that grabs one end of the genome and nucleates shell formation or you simply make a bazillion protein shells along with a bazillion genomes and simply play the odds: some shells will be empty but many will not be.

However, our organism of interest, Hantavirus, has a segmented genome. The virus requires all 3 pieces of its genome to be in a shell to have a productive virus. Our previous 2 approaches no longer work so well. In the first approach we need 3 proteins, one for each genomic segment. We could use the same protein 3 times, but how can you ensure all three segments are in each shell and not simply segment 1 and its associated protein 3 times. We could have 3 different proteins, 1 for each segment. The problem here is that Hantavirus only encodes for 3 different proteins total: the shell protein, the RNA polymerase, and an RNA binding protein that does several different things. So we don't appear to have the information necessary to take this approach.

The second approach tends to fail as well. If we make a bazillion shells and a bazillion of each segment. If there is an 80% chance a given segment randomly ends up in a shell then we have a 0.8 x 0.8 x 0.8 = 51% chance of a shell getting all 3 segments, so 0.5 bazillion. That doesnt sound so bad, but I did just make up the 80% number, what if its 50%? then ~12.5% of the shells will have all 3 segments. Is that enough to maintain a viable infection? I don't know, but its knowable and interesting to think about. This issue is more complicated, because we have assumed that once a given segment gets in, the same segment won't get in again. If we abandon this assumption, then our 80% chance of a given segment to get in isn't 51% but 11% (.8 x (.8 x 2/3) x (.8 x 1/3)) We could help our scenario out by making the shells large enough to hold more than 3 segments worth of material. If a shell can hold 5 segments worth of material, then we dramatically increase our chance of getting all 3 segments in.

So what does Hantavirus do? Well based on the seminar, that is still a question that needs answering. Maybe one of the above approaches is right or maybe the 3 segments are not truly separate but tethered together with 1 or more of their proteins or host proteins that the virus coopts for its own devices or maybe its something else even more interesting! Regardless, this is why biology and science in general is cool. We have an obvious problem an organism (Im using the term loosely) needs to solve, how does it do it? By the way, his isn't simply fun for the sake of fun, in the case of Hantavirus, if we know how packages its genome maybe we can develop ways to stop it and effectively combat Hantavirus it or similar viruses.

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