A Biology Lesson on this Pandemic

What is this thing?

Rewind all the way to biology 101 and recall what a virus is. Viruses are not quite alive. Why? They don’t fit all the criteria to be considered living. For instance, they can’t reproduce on their own and they have no way to regulate their internal environments (maintaining homeostasis). They’re still biological things, but what exactly? The simplest description you can get of a virus is a bundle of genetic material that hijacks living cells to reproduce.

When you hear the word virus, you may think of something that looks like this:

Or with the COVID-19 outbreak, you may be familiar with this viral (ha) image:

The truth is that there are many, many different types and species of viruses. The one that looks like a lollipop on spider legs is a bacteriophage. It only infects bacteria, hence the name. The second one is a coronavirus, specifically SARS-CoV-2, which is what causes the COVID-19 disease.

Classifying viruses is tricky and very inexact. They evolve just like us living beings, but at hyperspeed, which is why new strains and species are always popping up. Additionally, it’s extremely rare to find fossils of things as small as viruses, so all we have to trace their evolutionary history are the patterns in their genes. It’s also known that unlike animals, fungi, or plants, which have an evolutionary tree with a common ancestor at the trunk, viruses have evolved independently on many different occasions, so they have more of an evolutionary forest.

Let’s classify SARS-CoV-2 the best we can though. Recall that SARS-CoV-2 is the name of the virus that causes the COVID-19 disease. We’ll get into why it’s called that later, but for now, remember this diagram from your first biology class:

It’s actually slightly different for viruses, so let’s make some small changes:

Coronaviruses contain genomes made of RNA rather than DNA. This puts them in the one and only realm of Riboviruses. DNA viruses sadly don’t get their own realm because of how convoluted virus taxonomy is.

Up next, coronaviruses fall into the phylum of Incertae Sedis. In fact, incertae sedis means “uncertain placement” and most viruses fall into this category because there are no phyla that fit them. There is one phylum under the ribovirus realm called negarnaviricota. It’s distinguishing factor has to do with the structure of the viral RNA, but coronaviruses don’t fall into this category.

Even with the phylum gap, we can still go further. Coronaviruses, along with Arteriviruses, Meson Viruses, and Roni Viruses belong to the order Nidovirales. The distinguishing factor for Nidovirales is a bit complicated to explain here, but it has to do with the messenger RNA sequences produced when the virus infects its host. Go deeper and you’ll reach the Cornidovirineae suborder, where the distinguishing factor, again, has to do with the structure of the viral RNA.

Anyway, we now reach Coronaviridae, the family of viruses containing the infamous COVID-19 virus. A bit further and we enter the similarly named subfamily: Coronavirinae. Where does the “corona” part come from though? It has to do with the structure of the virus. Here is a picture of SARS-CoV-2 under an electron microscope:

Notice the blue outlines around the individual viruses? Those blue outlines correspond to the red things sticking out of the virus in this image:

Remember how the outer layer of the sun, the part you can see during a total eclipse, is called the corona? Coronaviruses have their name because the “things” that stick out create what looks like a corona under an electron microscope. These “things” are called spike proteins, and they’re very important as we’ll see later.

But we’re not done classifying yet. The subfamily Coronavirinae contains four genera: Alphacoronaviruses, Betacoronaviruses, Gammacoronaviruses, and Deltacoronaviruses. Alphacoronaviruses and Betacoronaviruses can only infect mammals (which includes us). Gammacoronaviruses and Deltacoronaviruses mainly infect birds and occasionally mammals. SARS-CoV-2 belongs to the genus of Betacoronaviruses.

Betacoronaviruses are really a whole slew of human misery. Along with SARS-CoV-2, which is responsible for the COVID-19 outbreak, the genus also contains SARS-CoV, which was responsible for the SARS outbreak in 2003, and MERS-CoV, which was responsible for the MERS outbreak in 2012.

SARS and MERS are respiratory tract infections. The acronyms stand for Severe Acute Respiratory Syndrome and Middle Eastern Respiratory Syndrome, respectively. This is why people with asthma and other pre-existing respiratory conditions are at high risk, because the combined effects of such conditions and a respiratory virus can make it impossible to breathe. It’s also why ventilators are currently more valuable than gold.

SARS-CoV-2 stands for Severe Acute Respiratory Syndrome related CoronaVirus 2, which tells us about the type of disease it causes (hence “SARS”), what kind of virus it is (hence “CoronaVirus”), and that it is essentially a sequel to the original SARS virus (hence “2”).

So how does this thing work?

As you may recall, viruses cannot reproduce on their own. They need to hijack the biological machinery of host cells to replicate their genomes and produce the proteins that build more viruses. To do so, the virus will need to get itself (or at least its genome) inside a host cell.

Cells are very complex, organized, and especially secure sacs of goo—they’re not going to let just anything get inside them. A virus has to bypass a set of security measures enforced by both its target cell and the host organism’s immune system. You may have heard of this microbiological brawl referred to as the evolutionary arms race. Viruses and living beings are constantly evolving new strategies to best each other, and this is all due to the central process driving evolution: natural selection.

One example of how a virus can trick cells is how it’s physically covered. Some viruses pack their genomes into a protein shell called a capsid. Other viruses, like coronaviruses, have a lipid bilayer membrane just like cells do. Some viruses use both. Finally, others, which are too small to be called viruses and are called viroids instead, have no covering whatsoever. They’re just pieces of floating DNA or RNA. The viruses that use lipid membranes have an advantage. Why? Where do they get their lipid membranes? They steal them from their host cells! This means they’re also taking everything on the membranes that give the host cells their identity. The virus can use the membrane to sneak as a wolf in sheep’s clothing past immune system defenses. Such a strategy isn’t foolproof though. The evolutionary arms race has been raging for billions of years and living things have many countermeasures such as attacking the viral messenger RNAs after the virus enters the cell.

You shouldn’t put all your faith in your body’s natural defenses though—you need to supplement it—with hygiene. You’re told to always wash your hands with soap and water as a preventative measure, but how does soap work and why is it so crucial that we use it?

Soap is an emulsifier. This means it takes things that don’t mix (like oil and water) and forces them to mix. The lipid membrane that covers some viruses (as well as all living cells ever) is made of lipids. Lipids are hydrophobic; they don’t mix with water. If you introduce a lipid membrane to soap, the soap will break it apart in order to let it mix with water, destroying it. Bacteria have hard cell walls that provide an extra layer of protection to ward off soap most of the time, but membrane-covered viruses like SARS-CoV-2 are absolutely defenseless.

Now, let’s get onto how SARS-CoV-2 actually infects people. Remember the spike protein mentioned earlier? That spike protein is the virus' key to enter the cell. Here’s a closeup model of it (the black line represents the membrane of the virus):

On the surface of some of our human cells in the respiratory system, you can find a protein called Angiotensin Converting Enzyme 2, ACE2 for short. ACE2 is but a humble enzyme involved in regulating our blood vessels. The viral spike protein hijacks it. Using the green bit pointing up on the above picture, the spike protein attaches itself to ACE2, which causes the viral membrane to fuse with the cell and release the viral genome inside, where the cell will unknowingly produce more of the virus. You can see the process in the cartoon below (dark orange = spike protein, light orange = ACE2, and turquoise = cell membrane):

SARS-CoV-2 (of COVID-19) and SARS-CoV (of the 2003 outbreak) are nearly identical viruses. They have the same structure and they both use ACE2 as a gateway into the cell, but their spike proteins are where their differences matter. Remember that proteins are made of amino acids. The spike protein of SARS-CoV-2 differs from that of SARS-CoV by mutations in only a few amino acids, but those few changes cause SARS-CoV-2 to attach itself to ACE2 about fifteen times more efficiently than SARS-CoV. This is also part of the reason COVID-19 is much more infectious than SARS of 2003.

How will we fight this?

Since this spike protein is essential for the virus to function, it’s the main target for medical researchers looking to produce a vaccine or antiviral drugs. In fact, Regeneron Pharmaceuticals Inc. is on top of the challenge. They are already developing a drug—though not quite a vaccine yet—to treat COVID-19. The drug is set to start clinical testing by the beginning of summer. With the help of specially engineered mice with human immune systems to produce it, the drug will be a cocktail of two different antibodies that target and neutralize the spike protein, thus preventing the virus from infecting new cells. Hopes for this drug look high as Regeneron used the same antibody method to create an effective Ebola treatment years ago.

But that all doesn’t mean much if you don’t quite recall what an antibody is or how it works, so let’s go over it.

Our immune systems have special cells called B cells and T cells. These B and T cells are what allow our bodies to “remember” diseases so that we can fight them much quicker after the first time we get infected. How do they work?

It’s said that the DNA in all of your cells is identical. This is almost true. B and T cells produce antibodies. Antibodies are proteins, and if you recall the central dogma of biology (DNA to RNA to protein), antibodies need genes to code for them. Whenever a new B or T cell is made, a genetic reshuffling process purposefully introduces random mutations to the genes that code for antibodies. Consequently the cell’s genomes do not match the rest of the body. This, in turn, changes the actual antibody produced.

Antibodies need to be able to attach to disease-causing things to fight them. If you’re infected with COVID-19, there will be countless numbers of B and T cells in your body producing many different antibodies. Eventually, one of these antibodies will be able to successfully attach itself to the virus and take it down. When this happens, the specific B and T cells that “matched” the virus reproduce (like a lot, Like A LOT A LOT), conserving the luckily randomized gene.

Most of the reproduced B and T cells become effectors, which pump out insane amounts of antibodies to combat the virus. Some of the reproduced cells become immortal memory cells, so that if you get infected with COVID-19 again in the future, they can start producing the right antibodies immediately. In fact, you probably wouldn’t even notice you got infected. This whole immune cascade is highly energy-intensive, by the way, which is why rest is one of the best ways to help your body fight infection.

Unfortunately, the biggest drawback of our body’s amazing immune system is time. It could take a while for your body to find an antibody match to the virus. If the matching doesn’t happen fast enough, the virus could kill you. This is where Regeneron’s anti-coronavirus drug comes in handy: the drug contains antibodies that are already effective against SARS-CoV-2, and can serve as a short-term pseudo-vaccine or symptom-mitigation medicine.

Why a pseudo-vaccine and not an actual vaccine? Vaccines contain bits of dead or weakened disease-causing things (like viruses) that essentially serve as target practice for your B and T cells to develop “memories” against so that they’re ready if an actual infection hits. This anti-coronavirus drug only contains a shot of antibodies. If the proper antibodies are present in your body, the virus is going to have a harder time getting through. The drug will either slow the infection to the point where your body can take care of it without taking as hard a hit, or make it harder to get infected in the first place if you’re exposed to the virus.

This isn’t all to say a vaccine isn’t or won’t be developed. Vaccine development is just much more laborious and time-consuming in terms of clinical testing and mass production. As a matter of fact, it can take years to develop and deploy a vaccine. In the heat of a pandemic like COVID-19, vaccines fall behind on the priority list compared to simple, effective, short-term drugs.

Featured Image by Sinan Ates

References

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Graham, R. L., Donaldson, E. F., & Baric, R. S. (2013, November 11). A decade after SARS: strategies for controlling emerging coronaviruses. Retrieved March 13, 2020, from https://www.nature.com/articles/nrmicro3143

Jiang, S., & Road, D. A. (n.d.). Receptor-binding domain as a target for developing SARS vaccines. Retrieved March 31, 2020, from http://jtd.amegroups.com/article/view/1209/html

Regeneron Pharmaceuticals, Inc. (2020, March 17). Regeneron Announces Important Advances in Novel COVID-19 Antibody Program. Retrieved March 30, 2020, from https://www.prnewswire.com/news-releases/regeneron-announces-important-advances-in-novel-covid-19-antibody-program-301025247.html

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Wrapp, D., Wang, N., Corbett, K. S., Jory A. Goldsmith, C.-L. H., Abiona, O., Graham, B. S., & McLellan, J. S. (2020, March 13). Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Retrieved March 13, 2020, from https://science.sciencemag.org/content/early/2020/02/19/science.abb2507

Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y., & Zhou, Q. (2020, March 4). Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Retrieved March 13, 2020, from https://science.sciencemag.org/content/early/2020/03/03/science.abb2762?intcmp=trendmd-sci