War Goes Both Ways

That’s a question you are probably asking at this point. (If you haven’t asked that, I’ll pretend you did anyways.) There are two things you could be trying to say with this question.

1. Why was Chrono-Nautical lying dormant for a long time? I had quite a few other things that I wanted to work on, and for the past few weeks, I was spending most of my time on those things. That meant that I didn’t really have much time to write new articles. Luckily, I’ve found some time now.

2. What’s the point of this article? Isn’t COVID-19 over already?

   Unfortunately, no.

   I published my previous article on COVID-19 on June 7, when there were 6 799 713 confirmed cases worldwide1. As of October 23, there were more than 41 million confirmed cases2. That’s a roughly seven-fold increase. Needless to say, the pandemic is not dead yet.

   So how come it seems like it’s gone? How can it be that, in the US, people are so complacent that they’re voting to reopen schools when America is leading the global pack in terms of case counts2, 3? There are a bunch of answers to this question, but one is that people get bored. The human mind is hungry for novelty. This helps people learn, explore, and discover. But on the other hand, it means that in times like these, when it is crucial to stay updated on the status of an event that has been going on for a while, our mortal human minds just … can’t.

   But I digress. Unfortunately, COVID-19 is still a problem — however, there are ways to solve it. This is a tour of some of those solutions.

Generally, there are a few main approaches to stopping a virus:

• Stop the virus from getting into cells4. A virus’s entire survival strategy is to get inside living cells and use their existing machinery to make copies of itself. Understandably, a major approach to fighting viruses is to just stop them from getting into cells in the first place so that they can’t replicate. In the case of SARS-CoV-2, the straightforward approach is to obstruct the spike protein, which acts as the “key” that allows the virus to enter cells. In the previous article, I talked about how the spike protein needs to be “primed” before it can do its job — that is another point where a medicine might be able to intervene.

• Stop the virus from replicating once inside cells4. Even if a virus is able to get inside cells, it is possible to prevent it from reproducing. There are many ways to do this. You can prevent the cell from producing virus parts. You can prevent the virus from setting things up so that the cell doesn’t even get a chance to produce virus parts. You can even interfere with the machinery that assembles viruses out of freshly-produced parts.

• Stop the virus from leaving cells. Some viruses need special machinery to get themselves out of cells so that they can go on to infect more. The flu virus, for example, uses a protein called neuraminidase for that purpose5.

  SARS-CoV-2 has two similar proteins: ORF3a (open reading frame 3a), which helps the virus get out of cells, and ORF7a (open reading frame 7a), which prevents the cell from stopping the virus’s escape6.

  Some groups, such as one at Brookhaven National Laboratory, are investigating how to inhibit these proteins so that newborn viruses can’t go on to infect more cells7. However, this doesn’t seem to be a very mainstream approach.

• Inhibit the immune system4. In many cases, the worst symptoms of COVID-19 are caused by our very own immune systems. In its attempt to quell the virus, the immune system sometimes overreacts and triggers massive inflammation8. Sometimes, simply suppressing the inflammation signals can vastly improve a patient’s condition8.

• Help activate the immune system. Wait, what? Didn’t I just say that you need to inhibit the immune system? Well, yes and no.

  It is true that the immune system can sometimes overreact. But sometimes, it underreacts. This is the reason that a protein called interferon-α is sometimes used to treat hepatitis by reinvigorating the immune system9.

  However, it doesn’t seem that the immune system underreacts when faced with COVID-19, so this type of treatment might not be super effective.

Now that we have this background information, let’s talk about some of the major COVID-19 treatments from these categories. Then we’ll go into vaccines, which can prevent infections before they even begin.

APN01’s name appears to come from the company developing it, Apeiron Biologics. The medicine’s strategy is to stop the virus from getting into cells in the first place.

The SARS-CoV-2 virus enters cells by attaching to a protein called ACE2 (angiotensin converting enzyme 2), also known as hACE2 (human ACE2), found on the surface of cells10. The virus’s spike proteins bind tightly to any hACE2 they may stumble upon. APN01 takes advantage of this — it is essentially a slightly modified hACE2 protein that doesn’t have a cell attached to it11. SARS-CoV-2, unable to distinguish this fraudster from the hACE2 it’s actually looking for, attaches itself to the APN01 molecules.

This hurts the virus in two ways. First of all, some of the virus’s spike proteins will now be occupied. Since the virus needs spike proteins to enter cells, the “loss” of some will mean that the virus has less opportunities to enter cells11. Secondly, the virus now has a rather clunky molecule attached to it that inhibits its movement.

APN01 also has some completely unrelated effects that may improve patients’ outlook. hACE2 serves an actual purpose in the body — specifically, it is responsible for regulating inflammation, scarring, and blood vessel size12, 13, 14. These are all great things — in fact, those “immune system overreactions” we talked about earlier mostly involve excess inflammation and scarring8. The problem is that SARS-CoV-2 reduces the production of hACE2 — in biology parlance, it downregulates hACE215. That means that hACE2 never gets a chance to reduce inflammation much. However, since APN01 is hACE2, this medication can reduce inflammation in patients and improve their condition11.

Well, it’s sound in theory, but how did APN01 do in practice? In cells grown in the lab, APN01 can reduce the amount of virus particles by 99.9%11. Furthermore, the medicine has helped a patient who had severe COVID-19 — a 45-year-old woman with some pre-existing conditions11.

APN01 is currently undergoing clinical trials4.

One of the most famous potential medications for COVID-19 is remdesivir. Originally developed to help fight Ebola (although it wasn’t very useful for that purpose), it could be helpful in battling COVID-1916.

SARS-CoV-2 contains RNA that provides instructions for how to make and assemble its components16. Every virus needs to have a copy of this RNA genome, so SARS-CoV-2 has its own specialized protein — called RdRp (RNA-dependent RNA polymerase) — to copy the RNA. RNA’s information is carried by the sequence of chemical “letters,” or nucleotides, in it. In the case of RNA, the nucleotides are the chemicals adenine, uracil, guanine, and cytosine17.

Remdesivir is a prodrug, meaning that the body processes it to create the active ingredient18. In this case, that active ingredient is GS-441524, a chemical which RdRp thinks is an adenine18. Thus, when producing new copies of RNA, RdRp occasionally substitutes in a GS-441524 molecule where it should have placed an adenine18. Once this happens, the trap has been set — shortly afterwards, this impostor prevents additional nucleotides to be added on to the copy. In other words, it prevents viral RNA from being fully copied, which in turn means that it prevents the virus from reproducing16.

There seems to be conflicting evidence on remdesivir’s effectiveness. A study designed and funded by NIAID, whose results were published in the prestigious New England Journal of Medicine (NEJM) in October, found that remdesivir noticeably improved the time it took for patients to recover — but its effect on mortality rates was found to be not nearly as pronounced19.

However, a trial called “Solidarity,” run by none less than the WHO, found that remdesivir didn’t have any effect on mortality, hospital stays, or other important metrics20. It is important to note that, as of the time of this writing, the study has not yet passed a rigorous review process. This isn’t because of a flaw in the study, but rather because it’s so new that there hasn’t been time for anyone to review it. Which study is right? We don’t know yet.

Amidst the controversy over these conflicting results, the US FDA decided on October 22 that it would be a perfect time to approve remdesivir as a COVID-19 treatment21.

We’ll really just need to wait and find out what the deal is with remdesivir.

Another potential treatment which has gained traction more recently is dexamethasone, which works by calming down the immune system22. More specifically, dexamethasone can reduce inflammation22. It is able to do this in several ways. First of all, it belongs to a class of chemicals called corticosteroids, which can bind to a protein inside cells called the GR (glucocorticoid receptor)22. This activates the GR, setting off a complicated chain reaction that produces a variety of chemical “signals” which reduce inflammation22. Dexamethasone in particular has some extra tricks up its sleeves — for instance, it can mess with NF-κB (nuclear factor kappa B — “kappa,” by the way, is the greek letter “κ”), a protein involved in, among other things, inflammation22, 23. In fact, dexamethasone has a long and venerable career as an anti-inflammatory drug22.

Now, let’s address the elephant in the room: why is your room large enough to house an elephant? Wait, no, sorry, wrong question. What I meant to write is this — does dexamethasone actually help COVID-19 patients? Well, according to a paper published in the NEJM — yup, we’re dealing with yet another NEJM paper! — the answer appears to be yes, with a catch24. The paper examined data from a UK clinical trial called “RECOVERY” (Randomised Evaluation of COVID-19 Therapy), funded by the University of Oxford, which examined the effects of dexamethasone and other potential medications24, 25. According to that data, dexamethasone was effective in patients who were on ventilators or oxygen — in other words, patients who had severe COVID-1924. However, it didn’t have much of an effect in healthier patients24. So dexamethasone does something, but it isn’t the panacea we’ve been hoping for.

If you saw any COVID-19 news around March or so, chances are that you’ve heard of hydroxychloroquine. The story with hydroxychloroquine has been … let’s just say a confusing one.

Hydroxychloroquine, originally a malaria medication, was first thrust into the spotlight because of politics26. Certain prominent figures, including politicians, promoted it as a treatment for COVID-19 despite not having any convincing evidence that it worked, but the resulting popularity boost was enough to jumpstart several studies into its efficacy20, 26, 27.

Many other potential COVID-19 medications are controversial, but scientists seemed to have reached a consensus on hydroxychloroquine — it doesn’t work. Both the RECOVERY and Solidarity trials mentioned earlier agree on this point, so I won’t go into much more detail20, 27.

No matter how effective a medicine is, though, it can only treat people who already have COVID-19. It would be better if we could proactively prevent cases — and that is where vaccines come in.

The vaccine being developed by Moderna, which has the technical name of mRNA-1273, is one of the most well-known candidate vaccines28. It is unique in that it is an example of an RNA vaccine — a radical new type of preventative medication28. To understand it, we must first understand more traditional vaccines.

The great thing about the immune system is that it can adapt — when it encounters a pathogen, it can launch a specialized response against it, and if it later detects the same pathogen again, it can launch a faster, stronger response29. In other words, the immune system learns. Vaccines are designed to take advantage of this. The goal of a vaccine is to present the immune system with something that looks like a pathogen, but which actually won’t do any harm29. That way, if the immune system later encounters the real pathogen, it can produce the more rapid response29.

Traditionally, vaccines are composed of dead or weakened pathogens, or perhaps even just small parts of the germs29. The Moderna vaccine, however, doesn’t have any of that. Instead, it carries only RNA instructions that allow cells to make harmless parts of the SARS-CoV-2 virus — specifically, a piece of the spike protein28. In other words, it can turn any ordinary cell into a vaccine factory.

As for its effectiveness, we must turn to yet another article in the NEJM, reporting the results from early trials of the vaccine28. That trial didn’t find any unusual side effects, although one patient did have an infection for reasons that was deemed unrelated to the vaccine28. It also seems that the vaccine can provoke a strong immune response, although finding out whether or not this enhanced response will be of any help will require further study28.

The Moderna vaccine is currently undergoing Phase III trials — the last phase before the vaccines can be released to the public30.

Another vaccine candidate, called ChAdOx1 nCoV-19 because sensible names are apparently bad, is being developed by the University of Oxford and the pharmaceutical company AstraZeneca31. Like the Moderna vaccine, it carries spike protein RNA — but unlike the Moderna vaccine, ChAdOx1 nCoV-19 uses a virus’s “shell” to carry the RNA32.

You might be freaking out a bit right now. After all, isn’t virus RNA in a virus shell a whole virus? Well, in this case, no. The vaccine consists of a repurposed adenovirus — a virus which commonly causes colds — that infects chimps32, 33. However, all of the RNA that lets the virus replicate has been removed32. The only RNA inside the adenovirus is the spike protein RNA, which can’t do anything on its own. An adenovirus is used because it can quickly and easily enter cells and release its RNA payload. The downside of this approach is that it is possible that the immune system can attack the adenovirus before the RNA gets a chance to enter cells.

A study with results published in The Lancet found that the vaccine appeared to be safe and promoted a strong immune response, although, again, further research is needed to see if it actually helps prevent COVID-1931. There was one dramatic event related to trials of this vaccine — a patient in the trial was diagnosed with a condition called transverse myelitis, which is essentially a particular form of inflammation of the spinal cord34. As a result, the trials were paused worldwide while an analysis was done to see if the condition was a side effect of the vaccine34. In most parts of the world, the trial was quickly resumed, but US officials were a bit more cautious. Perhaps they were overly paranoid, because the US trials were paused for about a month34. At last, though, the trials were resumed on October 23 after it was decided that the ailment probably had nothing to do with the vaccine34.

In China, CanSinoBIO and the Beijing Institute of Biotechnology are trying a similar approach, except they’re using a different type of adenovirus35. Although early results show that the vaccine appears to work, the Chinese government skipped the necessary clinical trials and approved the vaccine as early as July, receiving condemnation from experts around the world35, 36.

There are still more candidates! We’re repurposing old medicines and inventing novel potential treatments that work in entirely new ways. And we’ve done so in record time. There were hiccups. There were occasions where we could have done better. But overall, we’ve done remarkably well. It looks like we are winning this war.

• Yes, the pandemic is still very much a thing.

• Viruses use cells’ molecular machinery to reproduce. They then go on to infect other cells. Thus, when making an antiviral medicine, you can prevent the virus from getting into cells, prevent it from using the machinery inside cells, or prevent it from leaving cells. You can also use medicines that stop the immune system from going into overdrive or medicines that stimulate the immune system, depending on the situation.

• APN01, a medicine candidate which isn’t especially famous yet, works by preventing the virus from entering cells and by reducing inflammation. It has progressed to clinical trials.

• Remdesivir interferes with some of the virus’s own machinery that helps it make copies of itself inside cells. (Technically, the body processes remdesivir into another molecule called GS-441524, and that does the interfering.) There’s conflicting evidence about how effective it is, but nonetheless, it has been approved in the US.

• Dexamethasone calms down the immune system. That means that it can be a big help in severe COVID-19 cases, but it’s not really helpful for patients who have milder cases.

• There was a lot of hype around hydroxychloroquine, but that was unjustified — it does absolutely nothing for COVID-19. In fact, taking it for a COVID-19 case can actually hurt you because of its side effects.

• Moderna is developing a vaccine called mRNA-1273. It is essentially a blueprint (in the form of RNA) that allows your own cells to make the active part of the vaccine. So far, it appears safe and effective, but there’s still one more round of trials left to go before it can get approved.

• AstraZeneca and the University of Oxford are co-developing a vaccine called ChAdOx1 nCoV19 that is conceptually similar to Moderna“s vaccine, but it differs in the way it delivers the RNA to cells. This different approach has both benefits and trade-offs. It also appears safe so far — there was an issue with a trial participant who was diagnosed with a serious condition, but it was later decided that this condition was unrelated to the vaccine.

• CanSinoBIO and the Beijing Institute of Biotechnology are developing a vaccine that uses the same basic idea as ChAdOx1 nCoV19. Concerningly, the Chinese government has approved the vaccine for use even though it has not completed large clinical trials.

• I’ve said this in the previous article, and I’ll now say it less subtly: SARS-CoV-2 was not made in a lab. There is absolutely zero evidence that it was, and there are so many opportunities it could have taken to evolve naturally that it would be surprising if it were man-made37.

  I had the full intent of thoroughly gutting and debunking some “evidence” that it was man-made, but now that I think about it, this section is called “Microfacts,” and this bullet point is already kind of long. If you are interested in seeing some professional-quality debunking, check out this excellent document made by people at the Johns Hopkins Center for Health Security.

• Some companies are investigating new approaches to COVID-19 tests that try to identify the virus’s unique proteins, called antigens38. These antigen tests are less accurate than the standard PCR (polymerase chain reaction) tests done in labs, which look for the virus’s DNA38. But the antigen tests are much more portable — you can even take them from the safety of your own home38. They won’t be able to replace PCR tests, but they can still be a useful tool.

• It’s been confirmed — reinfection with COVID-19 is possible39. Exactly how SARS-CoV-2 manages to reinfect people isn’t very clear, but this might entail long-term revaccination campaigns.

• The traditional picture of COVID-19 transmission was that it spread through droplets from coughing, sneezing, breathing, and the like. It is theoretically possible that SARS-CoV-2 can also go directly from various surfaces to people long after the droplets that carried them to those surfaces are gone40. However, there’s no concrete evidence of this yet40.

There are countless more medicines and vaccines being investigated. In time, we’ll be able to beat this pandemic. Just not yet. So stay safe, and unless you’re in a part of the world that’s doing exceedingly well, spread the word: the pandemic is still around.

This article is dedicated to Johann Friedrich Miescher (1844–1895), who first isolated nucleic acids (DNA and RNA)41. Meischer was born to a family of renowned scientists in Basel, Switzerland41. He was initially interested in practicing medicine, but later switched gears and decided to look at the factors that made cells do what they do41.

He began to study white blood cells painstakingly isolated from pus on used bandages from hospitals, at first focusing on proteins41. One day, he noticed that dissolving cells in acid produced some strange solid substance41. Meischer suspected — correctly — that this substance came from a prominent yet little-studied part of a cell called the nucleus41. His observations then revealed that this substance was unlike any other known biological material at the time41. He creatively called it “nuclein,” and, after facing skepticism from his superiors, managed to get his findings published41. Today, we know that he had found nucleic acids — but back then, nuclein was puzzling41. Meischer almost uncovered the secret of DNA when he theorized that nuclein might play a critical role in fertilization, but he thought that there must be multiple factors that lay out the plans for something as complex as life41. Even his incorrect theories turned out to be remarkably accurate — he once proposed that the information for life could be carried in the shapes of diverse molecules using a sort of “alphabet,” and we now know that nucleic acids are, indeed, based on an alphabet-like system41.

Finding nuclein wasn’t Meischer’s only accomplishment — he performed research on the early development of embryos, investigated the chemical composition of blood, and founded a cutting-edge research institute in his hometown of Basel41. He died when he was only 51 years old due to tuberculosis, which might have been worsened by the fact that he had grown a tendency to massively overwork himself41.

Even though few recognize his name today, his discovery is of immense importance — we were only able to make progress on COVID-19 so quickly because we sequenced the virus’s RNA, and many candidate vaccines use RNA.

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I am not a scientist, doctor, or a professional in any field. The content of this article is based on reliable sources, but it is not intended for use as professional advice on any matter.

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