From Whence Came SARS-C-V-2?

Some of you may have heard rumours that SARS-CoV-2 arrived for us via bats. Now I know that a lot of people think it came from a research lab in Wuhan, but my guess is bats, and recent research into bats gives food for thought. They have a weird immune system, and they can tolerate all sorts of viruses. Accordingly, there are a number of research centres sprouting up around the world. Both China and the US have announced specific funding pots into research into bats and viruses. However, according to Nature (vol 615, pp576 – 580) one of the better advanced such studies is housed in Singapore. There, they captured 19 specimens of cave nectar bats and from them have bred a small colony that now has 140 members. Apparently this is quite an achievement because in general bats are very difficult to breed in captivity. The bats enjoy freshly chopped melon, papaya and mango, powdered milk, and, er, nectar. Which I suppose they would, given their name. There are apparently 1,450 species of bat in the world, but very few have been bred. So far, the successes include these cave nectar bats, Jamaican fruit bats, Egyptian fruit bats, and “big brown bats”. Nobody so far has managed to breed a horseshoe bat. (How did it get that name?) Why is this important? Because horseshoe bats are known to host an exceptional diversity of coronaviruses.

Subsequent research into bats is difficult. Actually catching them is difficult and there are safety challenges, given that such bats may well give you a disease you do not want. Then, once you have bats, it appears bat cells are extremely difficult to propagate. All the genetic toolkits used for mice and human cells are not available. There are  very few monoclonal antibodies that are used to tag immune cells. For a long time there was no high-quality genome, which means researchers still do not have a clear picture of the basic architecture of the bat immune system.

It is not just coronaviruses that are of interest. Some species also host viruses as deadly as rabies, Ebola and Marburg. (Collecting such bats would be problematical.) The question then is, how come bats can host the viruses without showing signs of infection? It seems that one of their attributes is they maintain high levels of interferons, which raise the alarm and set off the means of quashing viral replication. They also have proteins that interfere with viral replication and prevent viruses from leaving cells  if they get in. Their cells are equipped with an efficient system of disposing of damaged cell components. Finally, when pathogens do intrude, they do not overreact with an outsized inflammatory response, which is often more dangerous to humans than the actual damage done by the virus. However, this has another effect. Instead of expending all the effort to get rid of all the virus, the bat tolerates a low level and creates an adaptive response that clicks into action if it encounters further pathogen.

Thus a couple of horseshoe bats were captured in a cave in Spain, and from the body parts (after bats died) pluripotent stem cells were obtained and sequenced RNA expressed from these and found an abundance of sections that were essentially viral fragments, many being from coronaviruses. The bat cells appeared to suck up viral information “like a sponge”. It is not clear what this means but it would seem to indicate that the bat is continuously polishing up its immune system, generating and maintaining the equivalent of a low level of multiple vaccines all the time. Thus, from the viral point of view, bats are the ideal propagating medium. Once infected, they can spread the infection for an indefinite time.

Where this will go is anyone’s guess. Apparently in the US a start-up has raised $100 million in venture capital funding, so some think there is a future in bats. On the other hand, a bat that can carry around Marburg without showing adverse signs is not a species I would want to get too close to.

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A Pox on Them

For those of us somewhat tired of Covid-19, there is more depressing news. An article in Nature (605, 419 – 422) noted that virtually every viral pandemic that has occurred since the beginning of the 20^th century was triggered by the virus jumping from animals to people. Now for more bad news: an analysis of outbreaks over the past four centuries indicates that the annual probability of pandemics could increase several-fold in the coming decades because of human-induced environmental changes. We are doing it to ourselves! But wait: there is a fix, and it only costs the world around $20 billion a year, provided everyone cooperates. (Do I hear the “Good luck with that” comment?) That is asking for about $3 from every person, but given the way incomes are distributed, probably somewhat ore for those in the West.

According to Nature, that is small compared with the millions of lives lost and the trillions of dollars spent as a consequence of SARS-C0V-2. It is also 1/20 of the statistical value of lives lost each year to viral diseases that have spilled over from animals since 1918. Yet interestingly the WHO set up a panel to consider what should be done in the future to prevent such pandemics, and in an 86-page report apparently wild-life got two mentions and deforestation one mention. Either the “experts” did not understand where these pandemics originate, or they did not care. The article suggests four actions are required.

Spillover is more likely to occur when the number of animal-human interactions increase, such as in farming, the trade in wild-life, or when forests are cleared and the animals no longer have their normal environment for living. The article suggests four actions:

1. Tropical and subtropical forests must be protected. Wildlife that survives such cutting of forests includes the wildlife that can live alongside people, and they also often host pathogens capable of killing people. As an example, bats in Bangla Desh carry Nipah virus, which can kill 40 – 77% of the people it infects. These now roost in areas of high human population because their forest habitat has been largely cleared. Loss of forest also increases climate change. Besides stopping such climate forcing, it also stops driving animals out of regions that have become too inhospitable for them to stay. Once upon a time, if the climate changed, animals could migrate. Now their environment tends to be in islands, and if they have to leave, that is into human living areas.
2. Commercial markets and trade of live wild animals must be banned or strictly regulated. Some progress is being made here. In China, the trade and consumption of exotic wildlife has been banned since Covid 19.
3. Biosecurity must be improved when dealing with farmed animals. We need improved veterinary care, better surveillance for animal disease, improved housing and feeding for animals, and quarantines to limit pathogen spread. Up to a point, we have made progress here, in controlling mad cow disease, but more is required. It is important to stop livestock pathogens since nearly 80% of such pathogens can infect multiple host species, including humans.
4. More attention needs to be made to contain early outbreaks, and that includes increasing people’s health and economic security. A big problem is that people in poor health, and particularly people with immunosuppression, can host pathogens long enough for the virus to mutate before being passed on.

If we could stop spillover, we eliminate the need to contain it. As most will recall, disease surveillance, contact tracing, lockdowns, vaccine development and therapeutic development are expensive, and unless done properly, ineffective. As most will realize now, the response to Covid 19 immediately ran into people who refused to have their rights infringed, in the belief they were young enough to get through it, or did not even care. “It won’t happen to me.” That caused 6.25 known million unnecessary deaths, but Nature estimates the deaths to be between 15 – 21 million who would not have died but for the pandemic. By 2025 we will have spent $157 billion on Covid-19 vaccines.

So, the question is, will we do something about it? My guess is, probably not much.

And no sooner did Nature publish that article and we suddenly found we have a new disease: monkeypox. Now guess where that is likely to have come from?

Nanotech Antivirals

Most by now will have heard of nanotechnology, although probably rather few actually understand its full implications. There are strict limits to what can be done, and the so-called nanotech that was to be put into vaccines to allow Bill Gates to know where you were is simply not on. (Why anyone would think Bill Gates would care where you are also eludes me.) However, nanotechnology has some interesting uses in the fight against viruses. The Pfizer and Moderna vaccines that use messenger RNA to develop cell resistance, but the RNA is delivered to the cells by being encased in lipid nanoparticles. Lipids are technically and substance from living organisms that are soluble in organic solvents and insoluble in water, but they are often just fats. The lipid breaks open the cell wall, allowing the messenger RNA to get in, and of course that is the method of the virus as well: it is RNA encased in lipid. This technique can be used in other ways, thus such nanoparticles are showing promise for acting as delivery vehicles for other drugs and vaccines.

However, there may be an even more interesting use, as outlined in Nature Biotech. 39: 1172 – 4. The idea is that such nanomaterials could engage with viruses directly, either disrupting them or binding them. A route to disruption may involve nothing more than breaking apart the virus’ outer membrane. The binding approach works because many viruses rely on glycoproteins on their surface to bind to host cells. Anything that can mimic these cellular attachment points can bind the virus, effectively “nanosponges” for mopping them up. One way to make such

 “sponges” something like red blood cells have their contents removed then the remaining membrane is broken into thousands of tiny vesicles about 100 nanometers wide. They then get these vesicles to encase a biocompatible and biodegradable polymer, with the result that each such piece of polymer is coated with genuine cell membrane. Viruses recognize the cell membrane, attach and try to enter the cell, but for them the contents are something of a disappointment and they can’t get back out.

Such membranes obtained from human lung epithelial type II cells, or from human macrophages have angiotensin-converting enzyme 2 (ACE 2)and CD147, both of which SARS-C0V-2 binds to. Potentially we have a treatment that will clean up a Covid-19 infection. According to a study with mice it “showed efficacy” against the virus and showed no evidence of toxicity. Of course, there remains a way to go.

A different approach that shows promise is to construct nano-sized particles that are coated with something that will bind the virus. One example was used in a nasal spray for mice that led to a 99% reduction in viral load when treated with SARS-CoV-2 laden air. It is claimed the particles are not absorbed by the body, although so far the clinical study has not been peer reviewed. The advantage of this approach is that it can in principle be applied to a reasonably wide range of viruses. A further approach was to make “shells” out of DNA, and coat the inner side of these with something that will bind viruses. With several attachment sites, the virus cannot get out, and because of the bulk of the shell cannot bind to a cell and hence cannot infect. In this context, it is not clear whether the other approaches that bind viruses can still infect if the bound virus can attack from its other side.

Many viruses have an outer membrane that is a phospholipid bilayer, and this is essential for the virus to be able to fuse with cell membranes. A further approach is to disrupt the viral membrane, thus stop the fusing. One example is to form a nano-sized spherical surfactant particle and coat it with entities such as peptides that bind to viral glycoproteins. The virus attaches, then the surfactant simply destroys the viral membrane. As can be seen, there are a wide range of possible approaches. Unfortunately, as yet they are still at the preliminary stages and while efficacy has been shown in vitro and in mice, it is unclear what the long-term effects will be. Of course, if the patient is dying of a viral attack, long-term problems are not on his/her mind. One of the side-effects of SARS-CoV-2 may be that it has stimulated genuine research into the topic. This the Biden administration is firing $3 billion at research. It is a pity it takes a pandemic to get us into action, though.

Microplastics

You may have heard that the ocean is full of plastics, and while full is an excessive word, there are huge amounts of plastics there, thanks to humans inability to look after some things when they have finished using them. Homo litterus is what we are. You may even have heard that these plastics degrade in light, and form microscopic particles that are having an adverse effect on the fish population. If that is it, as they say, “You aint heard nothin’ yet.”

According to an article in the Proceedings of the National Academy of Science, there is roughly 1100 tons of microplastics in the air over the Western US, and presumably there are corresponding amounts elsewhere. When you go for a walk in the wilderness to take in the fresh air, well, you also breathe in microplastics. 84% of that in the western US comes from roads outside the major cities, and 11% appear to be blowing in from the oceans. They stay airborne for about a week, and eventually settle somewhere. As to source, plastic bags and bottles photodegrade and break down into ever-smaller fragments. When you put clothes made from synthetic fibers into your washing machine, tiny microfibers get sloughed off and end up wherever the wastewater ends up. The microplastics end up in the sludge, and if that is sold off as fertilizer, it ends up in the soil. Otherwise, it ends up in the sea. The fragments of plastics get smaller, but they stay more or less as polymers, although nylons and polyesters will presumably hydrolyse eventually. However, at present there are so many plastics in the oceans that there may even be as much microplastics blowing out as plastics going in.

When waves crash and winds scour the seas, they launch seawater droplets into the air. If the water can evaporate before the drops fall, i.e. in the small drops, you are left with an aerosol that contains salts from the sea, organic matter, microalgae, and now microplastics.

Agricultural dust provided 5% of the microplastics, and these are effectively recycled, while cities only provided 0.4%. The rest mainly come from roads outside cities. When a car rolls down a road, tiny flecks come off the tyres, and tyre particles are included in the microplastics because at that size the difference between a plastic and an elastomer is trivial. Road traffic in cities does produce a huge amount of such microplastics, but these did not affect this study because in the city, buildings shield the wind and particles do not get lifted to the higher atmosphere. They will simply pollute the citizens’ air locally so city dwellers merely get theirs “fresher”.  Also, the argument goes, cars moving at 100 k/h impart a lot of energy but in cities cars drive much more slowly. I am not sure how they counted freeways/motorways/etc that go through cities. They are hardly rural, although around here at rush hour they can sometimes look like they think they ought to be parking lots.

Another reason for assigning tyre particles as microplastics is that apparently all sources are so thoroughly mixed up it is impossible to differentiate them. The situation may be worse in Europe because there they get rid of waste plastics by incorporating them in road-surface material, and hence as the surface wears, recycled waste particles get into the air.

Which raises the question, what to do? Option 1 is to do nothing and hope we can live with these microplastics. You can form your own ideas on this. The second is to ban them from certain uses. In New Zealand we have banned supermarket plastic bags and when I go shopping I have reusable bags that are made out of, er, plastics, but of course they don’t get thrown away or dumped in the rubbish. The third option is to destroy the used plastics.I happen to favour the third option, because it is the only way to get rid of the polymers. The first step in such a system would be to size reduce the objects and separate those that float on water from those that do not. Those that do can be pyrolysed to form hydrocarbon fuels that with a little hydrotreating can make good diesel or petrol, while those that sink can be broken down with hydrothermal pyrolysis to get much the same result. Hydrothermal treatment of wastewater sludge also makes fuel, and the residues, essentially carbonaceous solids, can be buried to return carbon to the ground. Such polymers will no longer exist as polymers. However, whatever we do, all that will happen is we limit the load. The question then is, how harmless are they? Given we have yet to notice effects, they cannot be too hazardous, but what is acceptable?

An Infestation of Bacteria

One of those things you probably don’t need to know (but I am going to tell you anyway) is that there are more bacterial cells in your gut than there are cells in your body. This may seem weird, but remember much of your body, like water, is not cellular. And, of course, there is more than just one type of bacteria, indeed according to a Naturearticle from last year, there more than one hundred times the number of genes in the gut than there are in the human host. That, of course, gives a lot of scope for studying, er, colonic material. And yes, some people apparently do that, and there are some “interesting outputs”.

With such a range of “starting material” to study, the first step was to break the bacteria into four enterotypes. One of those sets, labeled Bacteroides 2, is associated with inflammation. Thus 75% of those with inflammatory bowel disease have this enterotype, while fewer than 15% of those who do not have the disease harbor it. This enterotype has another problem: if you have this enterotype it suppresses the manufacture of butyric acid, which is argued to preserve the barrier function of the epithelial cells lining the gut. In short, too little butyric acid and you get more inflammation. This suggests a corrective measure: eat butter, various fats, milk, parmesan cheese, and some rather unpleasant sources. The problem is that such foods still do not give enough. As an aside, butyric acid is quite foul smelling, and is a significant component of vomit. This suggests that supplements are unlikely to be chosen.

Gut bacteria can make trimethylamine oxide, which is claimed to accelerate atherosclerosis and lead to adverse cardiovascular outcomes, and the article adds, “including death”. Yes, that could be described as an adverse effect. Apparently a research group made a study on 2000 individuals and sorted out something like 1400 variables. For me that is far too small a number of subjects for that number of variables, but nevertheless they came out with the claim that a higher prevalence of this Bact-2  enterotype led to a higher probability of cardiovascular disease, but also it correlated with a  higher body-mass index and with obesity.  Note that correlation does not imply causation, and excess weight has been correlated with cardiovascular difficulties before. 

But there was more. If we consider only the obese, it was found that those taking statins have a pronounced reduction in this Bact-2 enterophyte, in which case they presumably help build up butyric acid. Statins also inhibit an enzyme on the route for making cholesterol, leading to cells to boost low-density lipoprotein (LDL), which in turn captures more cholesterol, which is supposed to lower the risk of cardiovascular disease. Statins also have anti-inflammatory action.This leads to a problem that in my opinion confounds medical research. We have an observation from a study in which there were almost as many variables as subjects that in one very small subset statins reduced the level of a gut bacteria group that can be correlated with cardiovascular problems. It seemed particularly effective at doing this in obese patients. Do you notice some rather tenuous links? In this study there were a huge number of variables that were not separated. Could we argue that we have been on the wrong track and something else is the cause of this effect, assuming the effect is real and not an accidental outcome of a small subset? How can we be sure that those taking statins were not better treated or more health conscious? On the other hand, if the effect is real, should not statin consumption, under proper medical prescription, be encouraged? What I hope this shows is how easy it is to find correlations, with the risk you are misleading everybody, which is why there are so many articles on medical issues that seem to contradict other ones. It is not an easy subject to analyse data, but we all have an interest in delaying death and misery.

That Virus Still

By now it is probably apparent that SARS-CoV-2 is making a comeback in the Northern Hemisphere. Why now? There is no good answer to that, but in my opinion a mix of three aspects will be partly involved. The first is a bit of complacency. People who have avoided getting infected for a few months tend think they have dodged the bullet. They would have, but soldiers know that you cannot keep dodging bullets forever; either you do something about the source or get out of there. In the case of the virus, sooner or later someone with it will meet you. You can delay the inevitable by restricting your social life, but most people do not want to do that forever. 

The second may be temperature. Our Health Department has recommended that places where people congregate and have heating systems should raise the temperature to 18 degrees C from the 16 currently advocated. Apparently even that small change restricts the lifetime of the virus adhering to objects, and viruses exhaled have to settle somewhere. This won’t help from direct contact, but it may prevent some infections arising from touching some inert object. That can be overcome by good hygiene, but that can be a little difficult in some social environments. My answer to that is to have hands covered with a gel that has long-term antiviral activity. (Alcohol evaporates, and then has no effect.)

The third is the all-pervasive web. It seems to be unfortunate that the web is a great place for poorly analysed information. Thus you will see claims that the disease is very mild. For some it is, but you cannot cherry-pick and use that for a generalization. If you say, “Some, particularly the very young, often only show mild symptoms,” that is true, but it identifies the limits of the statement. For some others the disease is anything but mild. 

A more perfidious approach is the concept of “herd immunity”. The idea is that when a certain fraction of the population have been infected, the virus runs out of new people to infect, and once the infection rate falls below 1 it means the virus cannot replace itself and eventually it simply dies out. Where that value is depends on something called Ro, the number of people on average that the virus spreads itself to. This has to be guessed, but you see numbers tossed around like herd immunity comes when 60% of the people are infected. We then have to know how many have been infected, and lo and behold, you find on the web that a couple of months ago estimates said we were nearly there in many countries. The numbers of infections were guessed, and given the current situation, were obviously wrong. It is unfortunate that many people are insufficiently sceptical about web statements, especially those where there is a hidden agenda.

So, what is the truth about herd immunity? An article in Nature 587, 26-28 (2020) makes a somewhat depressing point: no other virus has ever been eliminated through herd immunity, and further, to get up to the minimum required infection rate in the US, say, will, according to the Nature paper, mean something like one to two million deaths. Is that a policy? Worse, herd immunity depends on the immunity of those infected to remain immune when the next round of viruses turn up, but corona viruses, such as those found in the common cold, do not give immunity lasting over a year. To quote the Nature paper, “Attempting to reach herd immunity via targeted infections is simply ludicrous.”

The usual way to gain herd immunity is with a vaccine. If sufficient people get the vaccine, and if the vaccine works, there are too few left to maintain the virus, although this assumes the virus cannot be carried by symptom-free vaccinated people. The big news recently is that Pfizer has a vaccine they claim is 90% effective in a clinical trial involving 43,538 participants, half of which were given a placebo. (Lucky them! They are the ones who have to get the infection to prove the vaccine works.) Moderna has a different vaccine that makes similar claims. Unfortunately, we still do not know whether long-term immunity is conveyed, and indeed the clinical trial still has to run for longer to ensure its overall effectiveness. If you know you have a 50% chance of getting the placebo, you may still carefully avoid the virus. Still, the sight of vaccines coming through at least parts of stage 3 trials successfully is encouraging.

We Need Facts, not Fake News

Some time ago I wrote a post entitled “Conspiracies and Fake News” (https://ianmillerblog.wordpress.com/2020/02/19/conspiracies-and-fake-news/) and needless to say, I have not succeeded in stopping it. However, it seems to me this is a real problem for changing public policy or getting people to comply with the new policy. To be effective, policy needs to be based on facts, not on what someone would like it to be or fears it might be, or worse, doesn’t even care but feels the need to be seen to say something. Recently, our TV news has had about four different quotes of President Trump saying New Zealand is in a crisis regarding COVID – 19. I don’t want to give the impression it is like Utopia here; it isn’t, and we have our problems but we have a population of five million and so far the total deaths come to 22. Take your own country and multiply that 22 by your population in millions and divide by five. I think you will find we are doing some things right, and our current problems are almost certainly because the quarantine restrictions for returning citizens were too kind. Most obeyed the rules, but there were a very small percentage who did not. Here, the policy did not recognize the fact that some people are totally irresponsible. A few days ago someone who knew he had the virus broke out and went to a local supermarket for something. You cannot run a quarantine like that, and that selfish oaf will have made things much worse for future entrants.

But for me, the worst things are those who spout what can only be termed “fake news”. One lot of people, particularly young people, argue the virus is just like a mild cold. Well, fact check. Mild colds do not kill 800,000 people in a little over half a year. It is true that for the young it seems to be not very hazardous, but for the older people it is serious. Why? Here, understanding of causes might be desirable. Part of the reason may lie in angiotensin-converting enzymes, of which for the present there are two important ones: ACE1 and ACE2. These modulate the effects of angiotensin II (ANG II) that increases blood pressure and inflammation, which in turn leads to various tissue injury. The elderly tend to have more ANG II, which leads to higher blood pressure, etc. ACE2 mitigates the pathological effects of ANG II by breaking it down. However, ANG II does have useful effects, and so the body has ACE1, which leads to an increase in ANG II. If you are wondering where this is going, I apologise, but now to the virus, SARS-Cov-2; it binds to the ACE2 receptors as a way of getting into the cells and stops its action. As a result, ACE1 is busy stimulating ANG II, and too much of that leads to cell scarring, etc. As partial good news, ACE inhibitors, used to treat high blood pressure, block the activity of ACE1, and so may help stop the bad effects of the SARS virus. As to why the young are less affected, they seem to have fewer ACE sites. (The very young also have lower levels of androgens, which stimulate viral reproduction.) The reason I have gone on a little on this is because as you learn the facts, it becomes a little easier to see how this virus might be defeated. You win by logically applying true facts.

Another objection I have heard is the flu is worse, and I heard one assertion that in the 2018 season it killed 1.5 million. The CDC website says the figures are not yet in, but the biggest earlier figure was a little under 800,000 infected sufficiently to be hospitalized. On request for where the 1.5 million came from, no reply. It appears some figures are made up. Another figure that gets bandied around is the infection fatality rate. This is cited as extremely low. How? Because the number of infected are estimated. You can estimate anything you like! However, if the number of harmless infections and hence those with immunity were true, the virus problem would be over. It isn’t.

Some other bad news. First, masks don’t make much difference, then suddenly, yes they do and everyone should wear one. How did this situation arise? In the absence of tests, and hence facts, various people have expressed opinions. Here, you have to ask what you are trying to defend from. If you are trying to defend against coarse droplets any mask will do, but if you want to defend against an aerosol you need something more sophisticated, and it has to fit properly. On the other hand, a mask will not make the situation worse, so from mathematics if you don’t know, wear one and hope.Perhaps the worst news: vaccines are bad. Apparently someone made up the claim that vaccines have mercury in them, or aluminium nanoparticles. There are even claims that vaccines will contain nanobots that allow the authorities to keep track of you. The fact that these do not exist (application of energy conservation laws will indicate a minor problem with them) and if they did, someone in the vaccine business would object is no problem for these near paranoid rumourmongers. If someone knows that such pollutants occur, why don’t they take the samples to the authorities so the perpetrators will get long jail sentences. Oh, didn’t you know the government is out to get you? They are encouraging this to kill off citizens. That is the most ridiculous balderdash out. OK, Putin appears to have ordered specific attacks on people like the Skripals, but besides being incompetent, that is not general, and Western governments would not do that, and if they tried they would be exposed. However, it leaves the question, how can society survive if this sort of nonsense and non-critical thinking continues?

Scientific Discoveries, How to Make Them, and COVID 19

An interesting problem for a scientist is how to discover something? The mediocre, of course, never even try to solve this while it is probably only a small percentage that gets there. Basically, it is done by observing clues then using logic to interpret them. The method is called induction, and it can lead to erroneous conclusions. Aristotle worked put how to do it, and then dropped the ball at least twice in his two biggest blunders when he forgot to follow his own advice. (In fairness, he probably made his blunders before he worked put his methodology, and lost interest in correcting them. The Physica was one of his earliest works.) 

The clues come from nature, and picking them up relies on keeping eyes open and more importantly, the mind open. The first step is to seek patterns in what you observe, and try to correlate your observations. The key here is Aristotle’s comment that the whole is more than the sum of the parts. That looks like New Age nonsense, but look at it from the mathematics of set theory. A set is simply a collection of data, usually expressed as numbers, but not anything should go into it. As an example, I could list all green things I can see, but that would be pointless. I could list all plants, and now I am making progress into botany. The point is, the set comprises all the elements inside it, together with the rule that conveys set membership. It is the rule that we seek if we wish to make a discovery and in effect we have to guess it by examining the data. This process is called induction, and if we get some true statements, we can move on to deduction. 

There are, of course, problems. Thus we could say:

All plants have chlorophyll

Chlorophyll is green

Therefore all plants are green.

That is untrue. The chlorophyll will be green, but the plant may have additional dyes/pigments. An obvious case is red seaweed. The problem here is the lazy “therefore”. Usually it is somewhat more difficult, especially in medicine.

Which, naturally in these times, it brings me to COVID-19. What we find is very young people, especially girls, are more or less untroubled. The old have a lot more trouble, and, it turns out more so old men. Now part of the trouble will be that the old have weaker immune systems, and often other weaknesses in their bodies. Unlike wine, age does not improve the body. That is probably a confusing observation, because it leads nowhere and is somewhat obvious.

Anyway, we have a new observation: if we restrict ourselves to severe cases in hospitals, there is a serious excess of bald men. Now, a correlation is not causative, and trying to work out the cause can be fraught with difficulty. In this case, we can immediately dismiss the idea that hair has anything to do with it. However, baldness is also correlated with higher levels of androgens, which are male sex hormones. It was also found that the severe cases in males also usually had high levels of androgens. By itself, we can show this is not a cause either.

So, this leads to a deeper investigation, and it is found that the virus uses an enzyme called TMPRSS2 to cleave the Sars-Cov-2 spike protein, and this permits the cleaved spike to attack the ACE2 receptors on the patient’s cells, and thus permit the viral RNA to enter the cell and begin replicating. What the androgens do is to activate a gene in the virus that expresses TMPRSS2, so what the androgens do is to increase the amount of enzyme necessary to attack a cell. This suggests as a treatment something that will inhibit the viral gene so no TMPRSS2 is expressed. We await developments. (Suppressing androgens in men is not a good idea – they start to grow breasts. However, it also suggests that ACE inhibitors, used to reduce hypertension, might offer some assistance.) Now, the value of a theory can be shown by whether it helps explains something else. In this case, it argues that since pre-puberty children should be more resistant, and girls keep this benefit longer. That is found. It does not prove we are correct, but it is comforting. That is an example of induced science. Induction does not necessarily produce the truth, and conclusions can be wrong. We find out by pursuing the consequences, and either finding we have discovered something, or go back to the drawing board.

The Virus, and How Science Works, or Doesn’t

It may come as no particular surprise to hear that COVID-19 has become a source of fake news, conspiracy theories, whatever. Bill Gates was one victim. In various assertions, he created the virus, patented it, and was going to develop a vaccine and in it he would monitor people using quantum-dot spy software. Various forms got more likes, shares or comments on Facebook than most news items. Leaving aside the stupidity on view, what about facts? Nobody seems to have asked if he patented it, what is the patent number? Mike Pompeo alleged without a shred of evidence the virus originated in a Chinese laboratory. Political gain and nationalism sure beats truth as an objective there. According to Nature (581, 371-4) an academic subdiscipline has sprung up, tracking the false information, and studying how it is spread. The interesting thing about this is the observation that social-media are run to maximise user engagement and evidence-based information is way back in priorities. 

Also missing was an answer to the question, how does science work? If you watch certain TV shows, someone carries out some weird mathematics on a blackboard, and hey, we have it. It isn’t like that. Apart from a few academics that like to generate papers to keep up their publications, and for people applying standard theory (for example, NASA sending a rocket to a site on Mars, and then it is not a trivial task for a genius on a blackboard) the usual problem is for a new problem where the answer is not known, we sift through the evidence, try to find relationships, use such a relationship to form a hypothesis, then design some method to test it on new situations.

COVID-19 became a problem because genuine information was scarce, in turn because nobody knew, but look what happened as shreds came to light. President Trump advocated an “unproven cure”. But who says? The general feeling seems to be to trust the experts with “good credentials” (the logic falacy ad verecundiam). Since about 1970 there have been hardly any debates, and the funding models of science have forced only too many to “get in behind”. As an example of where wheels fell off, think chloroquine and its hydroxy derivative. 

First, two quotes from Gao et al., Bioscience Trends, 14: 72-3. “results from more than 100 patients have demonstrated that chloroquine phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus- negative conversion, and shortening the disease course according to the news briefing. Severe adverse reactions to chloroquine phosphate were not noted.” and “The drug is recommended for inclusion in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People’s Republic of China.” The Chinese issued a handbook that indicates how and when to use it. 

Then, from Gautret et al. DOI : 10.1016/j.ijantimicag.2020.105949 Twenty cases were treated with hydroxychloroquine. Those who refused, and the cases at another centre were used as a control. Those treated “showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination.”  Yes, a small sample, and patients who were known to have an allergic reaction to the drug, or other strong contraindications were excluded from the study. There was a third French report of about 80 patients that showed similar good results. Those two papers cited are fairly clear. It does not mean that an iron-clad conclusion should be drawn, but it does suggest potential effectiveness. 

However, a paper was published in The Lancet, one of the most respected medical journals that used statistical analysis from data from 96,032 patients, some of whom were treated with these drugs, and concluded the drugs were not helpful and more likely to cause death. So that should settle it, right? When I read this, my initial reaction was, not so fast. Of those treated, approximately 15% had coronary heart disease, 6% other heart problems, about 14% diabetes, 30% hypertension, 31% hyperlipidaemia, 10% smoked, 17% formerly smoked. Thus 96% had something wrong with them before treatment and 27% smoked or had smoked. Of course, some would not have such problems; some would qualify in two or three categories. The control group had 81,144 patients, and overall, 11.1% died in hospital, with 9.3% in the control group. So treatment made things worse. Convinced?

Do you see a problem? First, the control group may well have had a large number of young people who had mild symptoms, which lowers the death rate, which, as an aside, is remarkably high. New Zealand had a death rate of 1.46%. Second, we have no data on how treatment was selected and carried out. But, you say, statistics do not lie. Actually, that is not true, at least if care is not taken. My first reaction was to think, Simpson’s paradox (https://en.wikipedia.org/wiki/Simpson%27s_paradox), which shows it is possible to get the opposite conclusion if there are confounding variables, and this is particularly troublesome in medical reports where such variables are all over the place. I had had discussions with friends previously where I expressed optimism for the hydroxychloroquine, based on the two papers cited above, then I expressed the “not so fast” view about The Lancet paper. Needless to say, friends thought I was simply refusing to accept the truth.

However, there have been further developments. The Editors of The Lancet published a brief comment stating that “Important scientific questions have been raised about data reported in the paper…” Shortly after a bombshell: (https://www.theguardian.com/world/202…) The data appeared to come from a small US company called Surgisphere, “whose handful of employees appear to include a science fiction writer and an adult-content model”. They refuse to explain their data or methodology. The Australian data came from hospitals that say they have never heard of Surgisphere, and worse, the casualties from the trials exceeded the total Australian casualties. It seems a case can be made that Surgisphere generated fake news, and it was published in two of the most respected medical journals (the other was New England Journal of Medicine).

Following these papers based on Surgisphere results, the WHO attempted to end the use of chloroquine and hydroxychloroquine for COVID-19, and a number of hospitals have complied and stopped using it. 

However, to add to the confusion the University of Oxford published this: “A total of 1542 patients were randomised to hydroxychloroquine and compared with 3132 patients randomised to usual care alone. There was no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs. 23.5% usual care” (http://www.ox.ac.uk/news/2020-06-05-no-clinical-benefit-use-hydroxychloroquine-hospitalised-patients-covid-19). Now the University of Oxford should be a reliable source, and it clearly shows no benefit in this set of patients but my question still is, how was this set selected? The trial will be randomized, but the overall death rate of 23.5% in “usual care” seems to signal this is a selected set. (Recall the NZ death rate of 1.46%; our doctors are good, but I would not expect them to be that superior to the University of Oxford, so is something else going on?)

So what is going on? I have no idea. My guess is that the chloroquine and hydroxy-derivative do convey benefit to some patients, but not all, and/or they convey benefit but only if some other variable is present. In this context, there is one proposal that chloroquine plus zinc has an effect (https://www.webmd.com/lung/news/20200… ) (although on checking this link before posting shows it has a problem. Who knows what is real?). That apparently came partly from Turkey, and Turkey claims to have been successful with HCQ (https://www.cbsnews.com/news/hydroxychloroquine-coronavirus-covid-19-treatment-turkey/)  If so, the effectiveness in other trials might depend on the diet. Why would zinc have any chance? The chloroquine structure has three nitrogen atoms more or less focused in one direction. Zinc has an affinity for nitrogen, and tries to form octahedral ligands. What that means is, if the chloroquine or derivative can take zinc up to the virus, it has a strong affinity for more amine functions, and could well bind to a nucleobase. If so, the RNA could not reproduce. This produces a hypothesis that has a causal basis and may comply with the data, but only if we had a zinc analysis for all nutrients taken by the patients. Further, it will not work once the virus takes a certain hold because it would be unsafe to put enough zinc into the patient to have a chance.

This example shows in part how difficult science can be, not helped by the likes of The Lancet item. The short answer, in my opinion, is we cannot be sure what works, and hydroxychloroquine probably is at best a means of reducing the virus load and letting the body recover if it can, but then is that not desirable? It would also be helpful if people would stop poresenting false of grossly incomplete information. Maybe one of these days we shall know what works and what doesn’t, but probably not very quickly.

Business Under Stress

In my last post, I outlined some of the problems as I see them on getting out of this virus problem. A clear example of the problems to be faced comes from what happened here within an hour of my posting. It turned out that the German conglomerate Bauer had bought up all the major magazines in New Zealand. It was one week into the lockdown when it said it was closing down the lot. Normally in tough economic times, weaker businesses can be expected to go under due to competition, but in this case, it was the strongest, the ones that had been going for up to eighty years, that go to the wall. Why? The stated reason was that due to lockdown, advertising revenue had dropped. Well, yes, but the lockdown will not last forever. It could have tried to last it out, and if everybody complies with the lockdown, the virus is supposed to die out in about four weeks. Bauer was seemingly buying up competition to its Australian magazines, and it needed the money. (Why it didn’t try to sell the NZ magazines is unclear.) It also probably thought the smaller New Zealand market would buy the Australian equivalent.

However, there were additional factors here that may apply more generally. The first is that in economic terms, if the owner is going to close down because that is inevitable, it is best to do it as soon as possible because all money spent in the intervening period between problem arising and submitting to it is money lost forever. A second factor is that the big conglomerate has no emotional link to its business; all it cares about is whether it is a sufficientlyprofitable business. Can it make more money by switching its resources elsewhere? In this case there is also a considerable cultural loss. Unfortunately, that is intangible, and only applies to the customers. The conglomerate seldom cares, and in this case since it is homed at the other side of the world, there is no benefit to it. Only dollars flowing in matter.

Looking at the consequences, a large number of journalists, proof-readers, etc. are unemployed, and at least for a limited amount of time, there is no further possible work for any of them. Nobody is likely to take over any of the magazines right now because of the lack of advertising revenue, although the lockdown period is likely to be over by the time all the legal complexities would be completed. There are downside consequences. The printer has just lost a very large amount of work, and maybe they cannot continue. Stores that sell magazines will not have any, and many of these stores would have magazines to attract people in who might not otherwise come, but when they do, they often buy other things. Also, a high fraction of the magazine sales would be on subscription. Subscribers have no comeback if the conglomerate does not refund unused money, but that would sour the field for anyone trying to resurrect such magazines.

Another problem for exports comes from the fact that many fruit such as kiwifruit and pip fruit are due to be harvested about now. With lockdown, pickers are in short supply, and the requirement for them to keep two meters apart can be a problem. If the fruit are not picked, the farmer loses valuable income, and that income only comes once a year. Owners of tourism ventures will be pulling out their hair because movement is forbidden, and when the lockdown is over, who will come?

The overall consequences of stories such as these is that only too many people are going to be short of money. That makes investment in new businesses very difficult to raise. There will be many rich people with lots of spare cash, and the ability to raise a lot more through banks, but that may not be available to start new businesses, as what that sort of money tends to do is to buy up existing assets that happen to be very cheap. The virus has brought a lot of problems, but such problems may also be opportunities. The difficulty is to see them, and act on them. Thus it is obvious that New Zealand has an opportunity for a new magazine, or maybe a continuation of the more successful of the old ones. Will that happen? Watch this space.Finally, in these testing times, Easter is upon us, and I wish you all a pleasant Easter.