All you ever wanted to know about viruses but were afraid to ask

(Well not really all you ever wanted to know, but a few basic facts that will help you make sense of some of what you might hear on your TV and wireless sets during the current coronavirus crisis.)

Complex cells

Let us start with ourselves. We are made of cells. Complex cells[i]. There are a few things to be aware of: Our cells are quite large. You can just about see a human egg cell with your naked eye if you have good eyesight. To see any detail, however, you need to view our cells under a light microscope. This (and some clever preparation and staining) reveals that our cells have outer-membranes (to keep good stuff in and bad stuff out); all sorts of other bits and pieces[ii]; and a nucleus. The nucleus is where our chromosomes live, and chromosomes are basically long strings of DNA[iii].

Simple cells

Most cells in the world are not complex cells, they are simple cells[iv] - such as bacteria. Bacterial cells are generally much smaller than ours; do not have a nucleus and the (usually) single chromosomes (i.e. long strings of DNA) just live directly inside the cell rather than their own little compartment. Like our cells, their cells have outer-membranes, but they also usually have much tougher cell walls around their membranes. As we shall see, these walls are both their Achilles elbow and their Achilles heel.

Figure 1: Some Human cheek cells with accompanying bacteria.[v]

Bacterial infections (and what we can do about them)

The bacteria in the above picture are not inside the cheek cells, they are on the surface of those cells. Cells do not usually get inside other cells and live to tell the tale. It was the two or three times they managed to do this during whole of the evolution that gave rise to complex cells[vi]. Bacteria generally live in and on our bodies in complete harmony with our cells. In fact, our continued well-being depends on their presence. But when “bad” bacteria infect us, they generally do so by getting “inside” our guts or our blood stream or our hair follicles or whatever. This means that you can try to zap them without ripping apart our own cells to get at them. But you still need something that will zap bacterial cells without harming the complex cells (our cells) just next to them.

Fortunately, nature (with a little help from science) has provided a way of doing this in the form of antibiotics. As I have hinted above, there are some key differences between our cells and bacterial cells and antibiotics can exploit those differences to selectively kill bacteria without killing us in the process. One way that antibiotics often work is by attacking the cell walls of bacteria. Since our cells do not have walls, they are normally immune to such assaults.

Antibiotics

Many antibiotics (including, famously, penicillin) come from (or originally came from) other living organisms (fungi or other bacteria) that evolved these substances as chemical weapons to fight other organisms competing for the same territory. Unfortunately, evolution never stops. The target organisms of specific antibiotics tend to evolve counter measures that render them resistant to those antibiotics and we then have to try and find new antibiotics that will still work. Even more unfortunately, we have been misusing antibiotics on an industrial scale since they were first discovered. By doing things like prescribing antibiotics for viral infections (where they usually have no effect whatsoever – see below) or feeding them in bulk to farm animals in order to increase yields (now banned in Europe), we have reached the stage were many no longer work, and where some bacteria are becoming resistant to all known antibiotics. Thanks to Brexit, we may soon be “free”, again, to purchase US-reared antibiotic fed meat in our local supermarkets.

So what about viruses?

Viruses – though often described as “micro-organisms” – are not really living things. They do not, for example, feed or excrete anything or grow or respire or react to things you do to them. One key life-like thing they can do is reproduce; but they can only do that by getting inside a cell and hijacking the cell’s internal machinery.

Viruses are basically bits of chromosome. They also have a kind of coat, and often an outer envelope, but all these outer garments are discarded as (or soon after) a virus enters a cell. The viral chromosome then “tells” the cell it has invaded to make squillions of copies of the virus (complete with a new set of outer garments) and then to release those copies by letting the new viruses escape from the cell – a process that typically involves the complete destruction of the host cell.

Viral chromosomes

Imagine if you will a building site where the person in charge keeps certified copies of the architectural drawings and plans safe in his/her briefcase but hands-out photocopies of key pages to the various workers on site so they can follow them in their work. The photocopies get amended, damaged, and re-photocopied but the originals stay safe in the briefcase – taken out only for making more photocopies to hand out. This is a very rough analogy to what goes on in cells. The master copy (in this analogy) is the DNA chromosome. The slightly dodgy photocopies in the hands of the site workers are RNA copies of the DNA. While all cells have double stranded DNA chromosomes, some viruses have DNA chromosomes, and some have RNA chromosomes – which may get to work in an infected cell directly (imagine a saboteur posing as a manager and surreptitiously handing out doctored photocopies to the workers in the above analogy) or may first reverse engineer a DNA copy (and slip it in the site manager’s briefcase I suppose). Viral chromosomes may also be double or single stranded. As the two strands of double stranded D or R NA are complimentary – mirror images if you like – some viruses have to reverse-engineer a “positive” DNA or RNA chromosome strand from their own “negative” single strand before they can get going. (Imagine the site worker handed a photocopy in mirror writing in the above analogy). Viruses with RNA chromosomes are much less stable than viruses with DNA chromosomes and tend to mutate rapidly. Their general weirdness makes RNA viruses easier to try and defeat using anti-viral drugs than DNA viruses (see also discussion below) but their propensity to mutate makes them harder to defeat because they present a moving target. Both HIV and the COVID-19 viruses are single-stranded positive-sense RNA viruses but HIV is also a “retrovirus” (it makes DNA from its RNA). One of the ways in which the successful cocktail of anti-HIV drugs work is by inhibiting this reverse process - our cells don’t normally make DNA from RNA. This line of attack is not available in the case of COVID-19.

Viruses are (typically) very small. Too small to be seen under a light microscope. The average COVID-19 coronavirus is about 100nm in diameter[vii]. For comparison, a typical bacterial cell is about 1000nm across and a human cheek cell about 50 000nm.

Figure 2 Scanning electron microscope image, in false colour, showing the COVID-19 virus (coloured yellow) as it emerges from the surface of a cell (coloured blue and pink).[viii]

Viruses may attack simple (eg bacterial) cells) or complex (eg human) cells – though different types of virus specialize in different types of cell.

Because some types of virus attack bacteria, they can be used as an alternative to antibiotics to treat people (or animals) infected by bacteria[ix]. For various reasons, this use of such viruses has never really taken off as a mass treatment option.

Viruses that infect us – or, more correctly, our cells – are almost always bad news. And eliminating them from our bodies, without thereby also eliminating our bodies, is rather tricky.

As has been noted, bacterial cells that infect our bodies nevertheless live outside our cells, and they have special features that allow us to set about them with chemical weapons that are unlikely to harm our cells. These weapons are almost entirely ineffective against viruses.

One obvious strategy would be to put something inside our cells that destroys bits of chromosome. That would work very against viruses. Unfortunately, this would have the equally obvious side effect of destroying the host cell chromosomes.

In view of these facts, we have to be a bit cleverer and try to design medicines that help stop specific viruses getting into our cells, or getting  out of our cells, or getting in or out of the cell nucleus, or reproducing within our cells. In order to do the last thing, we have to try and be really clever and figure out how a virus is misusing our cellular machinery (to reproduce) in ways that are not part of the normal repertoire of activities for that machinery.

We do have a few anti-viral compounds but, with the obvious exception of treatments for infections with the human immunodeficiency virus (which are now very effective), most anti-viral drugs do not work very well. Sadly, we certainly do not have much today in the way of anti-viral drugs that we can offer to those infected with COVID-19. (See also Viral chromosomes box above.)

What should I do during the current epidemic?

[NB the information below is now out of date and some of it is incorrect]

I do not pretend to be an epidemiologist and I am loath to predict how this might all pan out. My advice is to get up-to-date information from reputable sources like the NHS[x] rather than from the media or stuff you read on the internet.

I shall, however, reiterate the advice that they give:

•  cover your mouth and nose with a tissue or your sleeve (not your hands) when      you cough or sneeze
•  put used tissues in the bin immediately
•  wash your hands with soap and water often – use hand sanitiser gel if soap and water are not available
•  try to avoid close contact with people who are unwell
•  do not touch your eyes, nose or mouth if your hands are not clean

The COVID-19 virus’s outer envelope can be defeated by alcohol gels, but thorough washing with soap and water is even better[xi]. Face masks may help you stop touching your own face and might conceivably help catch droplets of snot in the air that contain the virus (especially if worn by the sneezer) but they will not catch tiny airborne viruses and for general wear, they are almost certainly “neither use nor ornament” [but see below] - as they say in these parts.

Stay well!

PS Just to clarify some of the terminology you might hear: The virus itself has been named "SARS-CoV-2"; the illness cause by the virus has been named "COVID-19"; and SARS-CoV-2 belongs to a group of different but related viruses called the "coronaviruses".

PPS Since I wrote this, the evidence in favour of mask-wearing has become much stronger. It is still not as clear cut as many would claim and, as I suggest above, the main benefit would seem to be that mask-wearer protects others rather than him or her self, but I have now taken to wearing a mask when shopping. If I were writing today I wouldn't write that masks are “neither use nor ornament”.

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[i] “Eukaryotic” cells in more technical language.

[ii] Such as mitochondria.

[iii] You may remember pictures of chromosomes that show them as fuzzy, roughly X-shaped beasties, but they only look like that – all scrunched up and double – when a cell is getting ready to divide; which is a good time to try an take a picture of them. Most of the time they are too thin to be visible under a light microscope. Confusingly, DNA is, itself, a double stringed molecule.

[iv] “Prokaryotic” cells in the jargon.

[v] From https://www.canadiannaturephotographer.com/guide_buying_microscope.html

[vi] Mitochondria (which help produce energy for our cells), chloroplasts (which make plants green and perform photosynthesis), and quite possibly – though we don’t know for certain - the nucleus of complex cells were all originally simple cells that took up residence inside other cells.

[vii] A Novel Coronavirus from Patients with Pneumonia in China, 2019 https://www.nejm.org/doi/full/10.1056/NEJMoa2001017

[viii] This Is What The COVID-19 Virus Looks Like https://www.sciencealert.com/this-is-what-the-covid-19-virus-looks-like-under-electron-microscopes  

[ix] Bacteriophages: potential treatment for bacterial infections. https://www.ncbi.nlm.nih.gov/pubmed/11909002

[x] Overview -Coronavirus (COVID-19) https://www.nhs.uk/conditions/coronavirus-covid-19/

[xi] How to wash your hands https://www.nhs.uk/live-well/healthy-body/best-way-to-wash-your-hands/

RNA, the True Secret of Life?

In THE DOUBLE HELIX A Personal Account of the Discovery of the Structure of DNA, James Watson narrates the famous story of Francis Crick bursting into the Eagle Pub to tell everyone within earshot that he had found the secret of life.

Certainly, DNA is one secret of life and (leaving aside a few viruses – which aren’t really alive) is a common (and rather vital) denominator of all terrestrial life. But life has many secrets. Since Crick and Watson (building on the often neglected contributions of Rosalind Franklin) elucidated the structure of DNA, life has revealed more and more of those secrets. But one important secret remains almost as well kept as ever: the secret of just how life emerged in the first place.

There are several rival theories as to how life may have originated on earth (or some other space-rock) but the question of just how we got from a non-living “Primordial Soup” to DNA-based life presents a particular puzzle.

What struck Crick and Watson immediately as they surveyed the model double helix they had constructed were the implications of that structure for DNA replication. Each strand of the DNA double helix comprises a series of nucleotides and (as was later found) these nucleotides constitute the individual “letters” of the DNA code. The two strands of the DNA helix are complementary and the sequence of one strand can be inferred from the sequence of the other. If two strands are separated and furnished with a supply of fresh nucleotides, each strand can serve as the template for the assembly of a new copy of the original double helix.

But if all DNA could do were to serve as a template for making more copies of itself, it would be pretty boring stuff. What makes DNA interesting is that it also serves as a template for making proteins.

It is important to realize here that while proteins are often structural molecules – like muscle proteins – they may also be enzymes – like the enzymes often included in modern detergents. Enzymes are tightly folded proteins that “catalyse” (ie speed-up without getting directly involved themselves) other reactions. Enzymes have specific shapes which allow them to bind to other molecules and thereby encourage those other molecules to react with one another. Enzymes are crucially important for regulating what goes on inside living things.

The way in which proteins (including enzymes) are produced from DNA is quite complex. The first stage involves the creation of multiple RNA copies of the “master” DNA template. RNA is a very similar molecule to DNA – consisting of long chains of nucleotides – but it is normally single-stranded. The second stage involves the creation (from the RNA templates) of long chains of amino acids (which is what proteins are).

But here’s the thing ....

In order to make proteins from DNA, and even to replicate DNA, you need to have proteins (enzymes) that make everything work properly. And where do these enzymes come from? They are coded for by the DNA.

While this system works perfectly well once it is all in place, it is difficult to imagine how the system ever got going in the first place. The solution to this conundrum is that the DNA/protein system is probably not what originally got going. It is almost certainly a refinement of a far simpler system.

It is a feature of the aforementioned single stranded RNA molecule that (as well as serving as a DNA analogue – at least for one strand of DNA) it can also adopt tightly folded configurations which double-stranded DNA could never imitate. This means that, in certain respects, RNA molecules are rather like protein molecules and, it was discovered, can act like primitive enzymes that catalyse other reactions.

Once you have RNA molecules (formed entirely randomly as the primordial soup dribbled down hot rocks) that just happen to be able to catalyse (however poorly) reactions that result in RNA copying, you’re away! The “chicken and egg” problem presented by the DNA/protein system is circumvented. A self-catalysing RNA system will, given a supply of nucleotides, keep on replicating until the cows come home – which, given that replicating systems constantly mutate and the best mutations are chosen by natural selection (and later on in the process by human breeders) is exactly what happened in the end.

Nobody knows for certain how terrestrial life began, but the RNA hypothesis is a strong contender. We may never know exactly what did happen but there is a plethora of exciting research going on with RNA (and similar nucleotide polymers) that is confirming the plausibility of some theories as to what might have happened.

So next time you are enjoying a pint in a university-town, watch out for someone bursting in and announcing that the real secret of life has just been found.