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.

6 thoughts on “The Virus, and How Science Works, or Doesn’t

  1. The present situation is probably abnormal when it comes to the scientific process as well. With pressure to produce a treatment or vaccine, corners are being cut and papers rushed into publication without sufficient testing?

    • It is definitely abnormal, Audrey. I think the problem is the sheer numbers of people rushing out to publish something that proper review just isn’t being done. The journals think that if something is going to save someone’s life, it is better to get it out early, and they trust that the people providing the information are honest and doing it in good faith. Unfortunately, that is not necessarily the case and seemingly the rush to get into print and claim “brownie points” is putting rigour to one side. The fact that some things might give small benefit to a few also makes things difficult when you don’t understand what is going on because you don’t want to prevent so many getting the benefit while the is and ts are dotted and crossed

  2. All politics. The two largest anti-quinine papers (one is the Lancet) were grotesque, and withdrawn. France, US used them as pretext to forbid HCQ. HCQ + AZT is known to reduce viral loads (and not just for Covid). However, mass HCQ (as in Turkey) would reduce the motivation for developing extremely expensive more advanced treatments. Biotechs trade as 1/HCQ… Quinine has been used by billions, including me.

      • Yes Oxford conducted its “studies” of quinine on desperate cases, ~ 25% lethal outcomes (where it’s known not to work)… and at 2,400mg a day… Instead of 600 mg/day. 2.4 gram of HCQ is a lethal dose, or close to it… Crafty greedy foxes know how to kill the hens… Now it seems Oxford is tied to wealthy Astrazeneca, itself tied to Gilead… Oh, and I know extremely wealthy (houses everywhere around the world) young PhDs from the area… The fact that HCQ was FORBIDDEN in countries such as France… In January 2020, as soon as the French wealth doctors learned that China was using HCQ massively (first thing it used). HCQ was over the counter, no prescription, for years. Remdesivir is known to cause severe renal problems… Whereas, at regular doses, HCQ is safe. When tied in to macrolide antibiotic (AZT) and at correct potassium dosage, with minimal cardiac surveillance, it’s OK (very few patients have to be excluded). I had HCQ for years, while among mosquitoes, in Africa, as a child. It was standard, it can make slightly nauseous…

  3. Yes, foxes guarding the henhouse is not exactly likely to lead to great success. Big Pharma has real sweet deals with Academia – they get huge amounts of work for virtually nothing.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s