by MERLIN CROSSLEY

As the poem goes – Great fleas have little fleas on their back to bite them, and little fleas have lesser fleas, and so on ad infinitum.

To live you need food. Plants can make sugar via photosynthesis by trapping carbon dioxide from the air and combining it with water, but other organisms feed on one another. Viruses are near the end of the road when it comes to little fleas. Some viruses infect animals, others plants, and there are viruses that infect single celled bacteria. The CRISPR gene editing system is based on a DNA cutting machinery that bacteria use to destroy invading viral DNA.

In the living world – and I regard viruses as living (you only have to look at one under a microscope to know they are living!) – the key thing is to replicate. If you replicate, you will persist in the environment. If you don’t replicate, even if you work out how to be immortal, you will be overgrown. So all living things that we observe on our planet replicate.

You will be familiar with how humans replicate. You will also probably know that different life forms have different strategies. Cane toads lay thousands of eggs, which are then fertilised. Single celled bacteria and fungi replicate by growing and then dividing, by splitting in two, binary fission.

Bacteria are among the simplest lifeforms (simple in the sense of having the fewest component parts, they are actually highly evolved and sophisticated in many ways, but they are honed down so they can reproduce quickly). Bacteria basically consist of a bag – made of a fatty membrane, a cell wall to provide some solidity, and inside the bag is a genome, made out of one circle of DNA. The DNA encodes proteins that allow the bacteria to carry in food particles (chemicals like sugars etc) and the energy and substance from these particles allows the bacterium to increase its size. The cell wall and membrane must grow, the bacterium must replicate its DNA, and then it can divide. (There’s a cool saying, “in microbiology division and multiplication are the same thing!”).

Bacteria live pretty much everywhere. Some of them live on us without us noticing it. Others, like those that cause TB, leprosy, cholera, whooping cough, and puss filled abscesses on our skin, can also live on us and when they do, they cause symptoms. Some of the first antibiotics, like penicillin, mimic the building blocks that make up the bacterial cell wall. Importantly, penicillins are imperfect mimics that prevent growth of the wall,  and thus prevent bacterial replication. They do not affect our cells because our cells don’t have cell walls. Antibiotics were among the earliest wonder drugs. Vaccinations against bacteria were another great breakthrough. They cause the body to produce anti-bodies in the blood that stick to the bacteria and prevent them taking over our bodies.

Viruses take minimalisation down to the next level. They too have a genome – DNA or the related molecule RNA – inside a bag. But the smallest viruses don’t bother encoding genes for all the things they require in order to replicate. They will rely on their host to do most of the work for them. They will even get their fatty bubble by helping themselves to the host cell membrane. All they need is enough DNA or RNA to encode a protein key that will dock on a protein door on the surface of their target cell to let them in.

More complicated viruses do have other genes that encode proteins that counter the host immune response or manage the viral genome replication, and some have “cell walls” or as they are called “capsid proteins”. Viruses vary a lot. But the smallest ones are pretty much just a tiny genome inside a bubble that can replicate and go out to re-infect new hosts. They don’t have hearts or brains, they just replicate inside our cells.

This makes viral infections hard to treat. Viruses that infect humans use the human machinery to replicate, so you can’t poison viruses without poisoning the host. Once out of the host they are dormant, so they just sit there until sunlight or high temperatures eventually shrivel them up. UV light will eventually destroy the DNA or RNA and soap will dissolve the fatty bubble that envelopes them. Boiling will kill them but obviously you can’t boil someone who has a cold to cure them.

Given viruses are so small it is sort of surprising that they are so deadly. And, many, like the viruses that cause common colds, aren’t. Over time the viruses that kill their hosts too quickly have fewer opportunities to spread, and at the same time the hosts that survive tend to have more offspring too. So over time evolution ensures that most viruses (and indeed many bacteria) don’t cause severe disease. When myxomatosis was first introduced into Australia to kill rabbits, it was impressively lethal. But after a few years milder viral strains evolved and more resistant rabbits.

So most of the viruses that humans get every year cause mild or no significant disease. But the viruses that jump from another species – ebola, various avian influenza viruses, and of course the new corona viruses, SARS-CoV, MERS, and now SARS-CoV2, sometimes produce severe disease. It is not that individual humans have not seen the virus before and thus have no immunity – because, of course, all of us get the flu or a cold for the very first time at some stage in our life. It is the fact that the new virus and humans have not co-evolved that makes species jumping viruses so deadly sometimes. Others are not deadly at all – and find it difficult to survive in humans – but we never see those viruses and they don’t make the news!

New viruses do kill people, but how?

There are probably several mechanisms. First, the virus does just one thing, it replicates using our own cellular machinery. Like a computer virus this uses up our capacity to carry out our own functions. If virus loads are high, then infected cells may become non-functional. If the virus replicates in cells on the surface of our lungs that could cause breathing problems.

But the main problem is probably something else. Given that viruses use our own cells and cannot be poisoned, one approach our body uses to arrest viral replication is cell suicide. Infected cells detect unusual activity, things like double stranded RNA that does not usually exist in our cells, and the cells kill themselves. This is not a problem if it is just one or two cells – the cell next door or below will just double in size, divide, and fill the gap. But if many cells are infected, organs can be damaged.

And there is more. Infected cells carry bits of the virus out to their surfaces and display them on a special scaffold. Surveillance cells, called Killer T Cells, then execute infected cells. Again, if the infection is severe a lot of cell may die. The gooey debris from all the dead cells and the long chains of DNA that are released from our cells are what makes sputum and “snot” as slimy as it is.

And it gets worse. The Killer T Cells and other similar cells call the cavalry and the immune system comes to life. Signalling molecules called “cytokines” are released to attract more immune cells. This response can cause a fever. Viruses seem more sensitive to heat. They will have evolved either to be dormant – outside the body – or to replicate inside it. I guess they do not have any buffering systems to withstand higher temperatures, so they die, whereas humans can survive slight fevers. But only slight fevers. If the immune response is too strong – a cytokine storm – then people die of the response rather than the infection.

So how do we treat viruses?

Everyone is currently hoping for the development of anti-viral agents and/or vaccines. In the case of other viruses, like HIV, some great anti-virals were developed. HIV is an RNA virus that has a special gene that makes a protein that copies the RNA into DNA, called ‘reverse transcriptase’. This protein does not exist in humans, so inhibitors of reverse transcriptase that slot into it and block its function, serve as anti-viral agents. Other inhibitors block a protease that HIV requires. Researchers are trying to find agents that block the spike protein of the new corona virus, the protein that allows it to dock onto its target cells. Another drug, developed for ebola, Remdesivir, may inhibit the replication of the corona virus genome and thus reduce the viral load.

Vaccines are intended to do two things, cause our bodies to produce anti-bodies, neutralising molecules that will cover the virus and prevent it docking with our cells, and vaccines can also stimulate the replication of Killer T Cells that will specifically recognise virally infected cells and swiftly dispatch them. Different labs are trying different approaches as it is difficult to predict which strategies will work best. In the case of HIV it has not been possible to develop an effective vaccine and the new influenza vaccines are needed each year as the virus keeps changing via natural genetic mechanisms.

Humanity has defeated many viruses – small pox, polio, measles, mumps, rubella and the Australian researcher Ian Fraser developed the vaccine against the human papilloma virus. The anti-flu drug Tamiflu was also developed here. Across the world science has delivered and people continue to work together to explore new drugs and vaccine candidates. It won’t be fast but via careful public health measures and focussed research efforts lives will be saved.

Prof. Merlin Crossley

Deputy Vice-Chancellor Academic

UNSW