randombio.com | commentary
Tuesday, March 17, 2020

Don't Panic About the Wuhan Coronavirus

A possible cure has been sitting on the shelf since 2015


A s I write this, the US stock market has dropped by a third. Airlines across the world are facing bankruptcy. Much of the population has been told to stay home. Universities and restaurants are shut down, and government officials are salivating at what might be their best chance to nationalize the oil, transportation, and healthcare industries.

But some patterns are emerging that tell us that COVID-19 is not the virus that leads to the apocalypse. (Oh, but just you wait, you poor humans!). Everyone seems to be afraid, and they're admiring the ability of authoritarian states that can control the population. They're looking at the curve and it looks exponential, but in fact it's not.

What does ACE2 do?

ACE is an enzyme that creates the peptide angiotensin II, which raises blood pressure. ACE2 breaks down angiotensin II, producing a new peptide that binds to a specific receptor (known as Mas) and thereby counteracts the effect of angio­tensin II, lowering the blood pressure. So ACE and ACE2 work in opposition to each other. ACE inhibitors such as captopril are commonly prescribed as antihypertensive drugs; however, they also upregulate ACE2, perhaps increasing the chance of SARS or COVID-19 infection.

Was a cure sitting on a shelf for five years?

In 2015, researchers in California found that camostat (aka NI-03), an inhibitor of a protein called TMPRSS2, prevents SARS coronaviruses from infecting cells.[7] The inhibitor is also said to work against influenza[8] and SARS-CoV-2, the virus that causes COVID-19[9].

TMPRSS2 is a cellular protease that activates the SARS spike protein. It's essential for viral spread and pathogenesis in the infected host. The original 2015 paper was badly written; perhaps in recog­nition of that fact, their 2020 Cell paper is a bit overenthusiastic. But their experiments appear to have been carried out correctly.

I can find no records of any clinical trials on this drug other than an old Phase 1/2 trial of its safety in treating pancreatitis.

Yes, you read that right: an apparently effective treatment for this virus has been out there for five years. The world is plunged into chaos, Schumer wants to call out the National Guard, the US government is getting ready to hand out a trillion dollars, the S&P just lost $6 trillion, and nobody seems to know there's a possible cure sitting on a shelf. Just something to think about while you're being intubated.

Don't take my word for it. Read the papers and decide for yourself if Stefan Pöhlman and his colleagues are right.

First the risk factors:

  1. Hypertension, diabetes, coronary heart disease[1]
  2. High levels of ACE2 (angiotensin-converting enzyme 2), which is the receptor for the virus.[3] ACE2 is higher among Asians who smoke, but there are no other differences among ethnicities, sexes, or age groups. The virus recognizes and binds to ACE2 from a number of species, but not mice or rats. Binding to the human enzyme is inefficient, disproving any claims that this virus was engineered. One physician noted that SARS patients often had other diseases that were treated with ACE2 inhibitors and angiotensin II type I receptor blockers. These drugs upregulate ACE2, as do thiazol­idine­diones (such as pioglitazone, a drug used to treat type 2 diabetes) and ibuprofen, an over-the-counter NSAID[6].
  3. Smoking and nicotine vaping. Nicotine interacts harmfully with the renin-angiotensin system[4] and smoking is implicated in cardiovascular and pulmonary diseases. Patients who smoke have worse outcomes than non-smokers[5].
  4. Male sex[2] (possibly related to smoking rates)
  5. Existing lung disease
  6. Poor immunity, as in malnutrition or old age. As many have pointed out, Italy has the oldest population in Europe. As anyone who has worked with Italians knows, they are also have more interpersonal touching than other nationalities.
  7. Close contact with others during the early stages of virus propagation
  8. Non-steroidal anti-inflammatory drugs like aspirin and ibuprofen may aggravate the symptoms in an infected person, and that victims should take acetaminophen (which is not an NSAID) instead.
    Update: New research disputes this.

If the connection with smoking is true, we would expect the countries with greatest risk to be those with highest rates of heart disease or smoking.

Countries with highest rates of smoking (ranked by male %)

 Country        Male % Smoking        Female % Smoking        Total % Smoking      
Indonesia 76.2 3.6 39.9
Jordan 70.2 10.7 40.5
Russia 59.0 22.8 40.9
Georgia 57.7 5.7 31.7
Cuba 52.7 17.8 35.3
Greece 52.6 32.7 42.7
Armenia 52.3 1.5 26.9
Albania 51.2 7.6 29.4
Egypt 49.9 0.3 25.1
South Korea 49.8 4.2 27.0

Countries with highest rates of smoking (ranked by total %)

 Country        Male % Smoking        Female % Smoking        Total % Smoking      
Greece 52.6 32.7 42.7
Serbia 43.6 39.7 41.7
Russia 59.0 22.8 40.9
Jordan 70.2 10.7 40.5
Indonesia 76.2 3.6 39.9
Bosnia/Herz. 47.2 30.0 38.6
Lebanon 45.4 31.0 38.2
Chile 40.0 36.0 38.0
Latvia 48.9 24.3 36.6
Croatia 39.4 33.5 36.5


Smoking rates in other countries

 Country        Male % Smoking        Female % Smoking        Total % Smoking      
China 47.6 1.8 24.7
Italy 28.3 19.7 24.0
Iran 21.5 0.7 11.1
UK 19.9 18.4 19.2
USA 19.5 15.0 17.3
 

It's too early to say if this is really true—nicotine actually downregulates ACE2 expression but smoking worsens CV disease—but one thing is certain: the fatality rate will decrease over time. it's not necessary to catch the disease to develop immunity to it: all that's necessary is exposure. This gives your immune cells a chance to do their thing.

A crash course in immunology

To understand why, we need to know a bit of immunology. if you're an immunologist look away now. Below is an oversimplified crash course on the adaptive immune system.

Your adaptive immune system consists mainly of three types of cells:

  1. B cells, which produce antibodies and cytokines. The antibodies bind to pathogens that are floating around in the bloodstream or accessible on the surface of other cells. B cells can't detect pathogens that are inside infected cells.
  2. Dendritic cells, which float around checking for infected cells. Like tiny rat finks, the dendritic cells report what they've found to the T cells.
  3. T cells, which attack the body's cells that are infected, which is to say cells in which the pathogen is hidden inside. The T cells can find these cells thanks to the MHC/HLA system, which takes bits and pieces of whatever proteins are inside the cell and puts them on the surface, ‘presenting’ them to the immune cells. If the T cells find something they don't like, they kill the cell. This is obviously risky, so it's tightly regulated. When it goes wrong we get an autoimmune disorder.

When the T and B cells discover a new antigen, the cells do an almost magical thing: they evolve. Nature uses a form of deliberately accelerated evolution by shuffling their DNA by a process called V(D)J recombination and then randomly mutating the antibody DNA by a process called somatic hypermutation. A process of selection, similar to the Darwinian natural selection among animal species, then selects for those cells that produce the best antibody. Those that are most effective survive; the rest get a second chance to evolve. If they fail a second time, as almost all of them do, they die. This is a time-consuming process and our other immune system, called the innate immune system, tries to attack the virus first. But it is not nearly as powerful.

Here's the punchline: within a few weeks, you'll be exposed to this virus, if you haven't been already, and your immune system will be ready for it. You do not need to be infected for this to happen. A week or two after exposure, you'll be able to fight the infection. (This doesn't mean you should deliberately expose yourself. Licking things you should not lick is not an effective strategy!)

It's easy for scientists to create a vaccine nowadays—it's a simple matter of protein and cell engineering. The time-consuming steps are to have it clinically tested to make sure it doesn't cause any side-effects, and to wait for the FDA to approve it.

But long before any vaccine is approved by the bureaucrats at the FDA, your own immune system will have already done the exact same thing, and the pandemic will be over. By the time a vaccine is approved, the Wuhan Chinese Coronavirus will have become just another strain of flu. A few weeks from now the stock market will recover and people will go back to work. The Democrats will go back to trying to impeach President Trump, and everything will be back to normal.

Nine months after that, we may well have the biggest baby boom since the end of World War II.


1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet Mar 11. doi: 10.1016/S0140-6736(20)30566-3.

2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15, 395(10223):497–506. doi: 10.1016/S0140-6736(20)30183-5.

3. Wan Y, Shang J, Graham R, Baric RS, Li F. (2020). Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. J Virol. Jan 29. doi: 10.1128/JVI.00127-20.

4. Oakes JM, Fuchs RM, Gardner JD, Lazartigues E, Yue X. (2018). Nicotine and the renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol. Nov 1;315(5):R895–R906. doi: 10.1152/ajpregu.00099.2018.

5. Liu W, Tao ZW, Lei W, Ming-Li Y, Kui L, Ling Z, Shuang W, Yan D, Jing L, Liu HG, Ming Y, Yi H. (2020). Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease. Chin Med J (Engl). Feb 28. doi: 10.1097/CM9.0000000000000775. PMID: 32118640

6. Fang L, Karakiulakis G, Roth M. (2020). Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. Mar 11. doi: 10.1016/S2213-2600(20)30116-8. Link

7. Zhou Y, Vedantham P, Lu K, Agudelo J, Carrion R Jr, Nunneley JW, Barnard D, Pöhlmann S, McKerrow JH, Renslo AR, Simmons G (2015). Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. Apr; 116,76–84. doi: 10.1016/j.antiviral.2015.01.011. PMCID: PMC4774534

8. Yamaya M, Shimotai Y, Hatachi Y, Lusamba Kalonji N, Tando Y, Kitajima Y, Matsuo K, Kubo H, Nagatomi R, Hongo S, Homma M, Nishimura H. (2015). The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells. Pulm Pharmacol Ther. Aug; 33, 66–74. doi: 10.1016/j.pupt.2015.07.001. Link PMID: 26166259

9. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. (2020). SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, Mar 4. doi: 10.1016/j.cell.2020.02.052. PMID: 32142651


mar 17 2020, 6:59 am. last edited 5:11 pm


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