Masks and COVID-19

Unfortunately, most people seem to think that science is about “knowing stuff”. In my opinion, that is plain wrong. Science is about the methodology needed to find out about nature. Of course, once we find out we record our findings so others do not have to waste their time rediscovering, and it is this ability to “stand on the shoulders of others” that gets us to where we are. We can deduce things from what we know, but as Aristotle noted in his Prior Analytics, if we come across a problem for which there are no means to deduce, we have to induce the premises necessary to make progress. That means examining the observed data and making guesses. The better spread the data, the more likely the guesses will be good, but the nature of induction is that it can be wrong. That is the basis of Popper’s concern that the aim should be falsifiability, to get rid of what is wrong. In happen to agree that is a good objective, but it is not the only one, if for no other reason than if we do not induce new hypotheses, eventually there is nothing to falsify, but equally we may remain quite ignorant of certain aspects of nature.

So, how does this apply to COVID-19? When we started this, we knew very little, although in a very short time we had found the structure of this virus. Also, while it was a new virus, we do know quite a bit about viruses in general. If you look around the web, we see that there have been a huge number of hypotheses, usually asserted as fact. In New Zealand the hypothesis applied was, if you stop transmission for two transmissibility cycles, the virus, unable to reproduce, will be eliminated. Interestingly, some assert that isn’t science – it is brute force, nevertheless it follows logic and better still, it worked. 

Some asserted that we should aim for herd immunity. The estimated number of cases needed to get this vary, but let us put this at the dead minimum of 60%. I believe that is too few because the SARS virus is transmitted for an unusally long time from a patient, nevertheless the planetary population is, say, 7.7 billion. That gives us 4.62 billion cases minimum. The death rate seems to be about 5% across a broad population age group, so that gives 231 million  deaths as the minimum price to pay for herd immunity. If you don’t like the 5%, put in your own figure. Places with few cases and good medical care lower that, but to get herd immunity you need that 4.6 billion cases and do we have that many good hospitals? Sweden is sometimes cited as an ideal example. However, they have had 74,333 cases and 5550 deaths at the time of writing this from a population of a little over 10 million. The death rate is 7.47% and the infection total is about 0.44% of the population, which is a long way from herd immunity. Maybe the Swedes are very careful, but the virus is still reproducing and such care eventually fails for each person. 

If you check the web now, you will see all sorts of assertions, and some people seem to make up figures. The figures I use are those posted by authorities as confirmed cases. It is true there will be many more cases where the virus did not create symptoms, especially in the young, but unfortunately, these are merely incubators for the virus. Spain has had 300,136 case and 28,401 deaths, a death rate of alost 9.5%, so are there a huge number of unrecordered cases? Spain has a population of about 46.75 million, so the confirmed cases reflect about 0.65% of the population, however a random sample of 61,000 Spaniards were given blood tests and apparently 5% of them had antibodies. It is still unclear from that report what the antibodies are to, because they may be to coronaviruses as a group, and who has not had a cold?

As for more misinformation, originally the WHO stated there was no reason to wear masks, but now they are saying yes, masks are good. Then we see that masks are good because the virus is spread in droplets, hence the two meter distancing. Then we see statements that the virus is small and will be lurking as an aerosol, hence the masks won’t offer protection. What do you make of that? 

In my opinion, the scientific response is obvious. First measure the air around such patients and see if the virus is airborne. There are various ways this could be done. The second is to measure the efficiency of masks by pumping air exhaled from patients that are known to have the virus (by testing) through the masks and see if the virus is removed. If we did that, we would know whether masks worked, and more to the point we would know whether certain masks were better than others.The logic of masks is that they cannot do any harm, and they should stop some of the viruses. That seems logical, but surely we can do better.

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.

Lockdown! Now What?

By now, everyone should be aware there is a virus out there, and it has been generally agreed that action was needed to protect citizens. So far there is no vaccine, and in some cases the treatment required to preserve life is restricted. In New Zealand, thanks to various travellers bringing it here, we are starting to feel the effects. It is easy to flash around figures but with a population of about 5 million, one estimate is that if nothing were done, about 70% of the population would get it, and about 80,000 would die. The reason is, if all those got it about the same time, say over a two-month period, there are insufficient ventilators, etc. for them. If they got it one at a time, most of those 80,000 would not die.  Our hospitals did not have 20,000 ventilators sitting around waiting for this event. So what we have done (as have many other countries) is we have initiated a lockdown, the idea being that by breaking the possible chains of transmission the virus will die out. The associated problem is, so will many businesses that cannot earn during this period. So the question is, what will emerge from this, or perhaps a more reasonable question is, what is more probable to arise from this?

The average estimate here is that unemployment will rise to about 9%, and many small businesses will go under. Life will be particularly difficult for restaurants, etc. because many of them tend to operate on slim margins, and they are more designed to offer the owners a life-style rather than direct them to be a developing business owner. Our airline will shrink down to 10% of what it was because international travel will almost disappear. One slight bright sign for them lies in the domestic market: their major competitor has already decided to call it quits here. Such competitors restricted themselves to the major intercity services and left the minor spots alone. The price for those tickets will now rise, but with the far lower ticket sales there would have been blood on the floor had such cheaper flights continued for that many aircraft. There will be a great reduction in the number of tourists for some time, because even if our lockdown works, what happens if other countries have not gone as hard? Do we want to succeed, at great cost, then let in fresh infection?

One of the other things that has happened is we have discovered the “just in time” purchasing ethic has a cost. One slightly ironic fact is there was a claim we were running low on hospital gowns, and the biggest manufacturer anywhere of hospital gowns is in Wuhan, except it closed because of the virus. Apparently, a couple of small manufacturers are switching to make some of this necessary equipment, including ventilators, but that will not continue because they cannot compete on price with China, and in any case, the hospitals will not need more when this dies down.

On the issue of more general manufacturing, I heard one small manufacturer say that in response to the difficulties some are having in getting certain things, he has ordered a major robotic machine. The capital cost is higher, but the wage bill is much lower, and if the equipment is sufficiently flexible, the major expenditure, apart from raw materials and capital cost, will be in paying designers. This suggests this pandemic may well be the straw that broke the back of the current way of making goods. Strategic niche manufacturing, manufacturing close to raw materials, and the use of brains may be the key factors in future prosperity.That raises the question of what happens to current workers. If half the small businesses go to the wall, there will be a lot of workers who have few resources and only limited skills. There will also be a number of highly skilled people who are unemployed. Think of the airlines. Where do pilots and cabin crew of the big jets find jobs? Nobody else will want them because all the other airlines are in the same boat, and it has nothing to do with management or mistakes. It is going to require a lot of imagination and investment to get out of this, and both may be in rather short supply. Also, new businesses need customers, and who is going to have spare money when this wrings out?

The Virus Strikes

By now it is impossible to be unaware of the presence of a certain coronavirus (SARS-Cov-2, causing COVID-19) that is sweeping around the world. (Wouldn’t it be better if some nit-pickers could stop changing the name and do something more constructive to deal with it?) Unfortunately, the time for containment has passed. It may have been that the only chance was early on in Wuhan because China can do things to stop the personal lack of consideration of others; the possibility of 5 years in a Chinese jail would inhibit most from personal stupidity, but the authorities did not get started quickly enough. This, in turn, may have been because the officials in Wuhan did no alert Beijing until it was impossible for Beijing not to notice. That golden opportunity was missed.

In New Zealand, we started with a law passed by which all people coming into the country had to self-isolate for two weeks. Within about two days a small number had been arrested for breaking that rule. In Wellington here we had someone fly in from Brisbane. He had been tested in Brisbane, but would he wait for the test results? No, he felt he wasn’t sick (so why was he tested?) Did he stay isolated until the test results? Of course not. When you are that self-centred, you do not suddenly become responsible. Wellington now has the second most cases in the country.

There was one woman who arrived in Auckland from overseas and was feeling ill.  At this stage she was advised to self-isolate but the law requiring her to had yet to come into play. So what did she do? She convinced herself she wasn’t so ill after all, so she flew to Palmerston North, where she discovered that maybe she really was sick so she flew back to Auckland. The net result of this is we shall get some idea of how easily this virus really does spread. So far, Palmerston North has three cases, but if there is an inexplicable surge over the next few days, we shall find out something. If, on the other hand, there are no such cases, we may be able to breathe a little easier. (It is not just the people sitting close on the aircraft; recall how people behave prior to boarding, during boarding, collecting luggage, and if using public transport, getting to and from the airport.)

While we were relying on voluntary compliance, the virus was actively spreading. The government has now required a complete lockdown, going out only for essential services. Will that work? In principle, if everyone on the entire planet stayed home for a month, all would be well. Those who had it would have to recover, but the virus would run out of people to transmit to. Simple? The problem there lies in everyone doing it at the same time. In the West, people want freedom of movement. Asking them to give this up seems to be beyond them. In New Zealand this might work. The police and if necessary the military are there to enforce it, and China appears to have shown this can work. We shall see.

As for me, I am self-isolating, only going out for groceries, but in my case, because I am retired it is no big deal. My day-time job used to be to do chemical research on contract for companies wanting to develop new products. That work has dried up completely. When potential clients are having problems staying open and paying their wages, research is the first to be stopped. As it happens, I was approached to write a chapter for an academic book on hydroliquefaction of algae, so writing that will keep me occupied. Searching the scientific literature can be done on-line these days.

The main tactic is not to get close to people. However, there is also the problem that the virus may land on something and you touch it. Staying at home is fine, but you still have to get groceries, and some people have to work.  Hand washing is important, but if you touch something after washing hands, that wash does nothing for what follows. The virus on the hand does no damage, but how often do you touch your face? What I intend to do is make a blocking gel to smear on my hands when visiting the supermarket. Two functions are desirable. One is to kill viruses. The second is to make the virus immobilized on the gel, like flies on flypaper. The coronavirus has a “crown” of protein so something that binds protein is called for. I won’t know for sure it works, but one advantage is that while I cannot get it tested for efficiency, I can back my own theoretical ability for myself.So, keep well, everyone. If all goes will and we all cooperate, this will pass. Finally, good luck all.

A New Coronavirus

2019-nCoV is having an effect that most will have heard of. It is apparently milder than some related viruses, such as SARS, which had a mortality rate of 10%, but that might be premature because the new virus has caused a very large number of seriously ill people, and nobody knows what will happen to them. So far, the probability of death appears to be around 3%, although a number of those are through people who had poor health anyway. Unfortunately, it appears to spread at a dizzying rate, and so far the number of patients appears to double every six days. It appears to have a period of about 12 days when it is asymptomatic, but it remains contagious. Most people will know about the effects of mild contagious coronaviruses. The common cold is caused by over 90 different viruses, the majority of which belong to the rhinovirus family, but coronaviruses participate in a good percentage.

This virus almost certainly came from animals, probably a bat, but when and how are uncertain. The genomic sequence of 2019-nCoV is 96.2% that of a bat coronavirus, and 79.5% is identical to sequences found in SARS. The Huanan Seafood Wholesale Market in Wuhan, which also sells animals as well as fish, may be the origin of the outbreak as the earliest patients had visited it, and 33 environmental samples from the Western end of the market, which is where the animals were sold, contained the coronavirus. However, the first patient apparently had no contact with this market, so it is possible it started elsewhere and infected the market. Genomic sequencing, which involves counting mutations since entering the human population, suggests the virus began spreading in mid November, 2019.

So, what can be done? At present, the best approach is containment, but whether this is possible when it takes two weeks for symptoms to appear is another matter. If it works, in a few months everybody will wonder what the fuss was all about. If containment fails, it appears to be as contagious as the common cold, and who hasn’t had one of those? One calculation has suggested there could be up to fifty million dead through it. Most would say that is unduly pessimistic, but is it? If there is any good news, it is that the number of reported cases in Wuhan have had about three days of falling. We hope the decline is real and not a consequence of poor reporting.

For current patients and those over the next year, we need something ready to go, and fully approved for use. That suggests trying drugs with antiviral properties. At this point we do not know whether any will work, but if used on patients with the virus, the argument is it is preferable to attempt to do good. In Wuhan, they are already trying a randomized controlled trial of two drugs that target the protease enzyme used by HIV to copy itself. These drugs apparently gave beneficial results against SARS, which is promising. The drug remdesivir, made by Gilead Pharmaceuticals, is a possibility. It interferes with the viral polymerase enzyme, and it has shown activity against every coronavirus tested so far. When combined with interferon it slowed viral replication in MERS-infected mice. (MERS is another coronavirus.) Another US biotech Regeneron is trying to develop monoclonal antibodies; it has previously managed to develop them that were effective against ebola and MERS. 

The next most obvious approach is to develop a vaccine, but historically there has never been a vaccine developed fast enough to have a significant impact on an emerging virus. Historically, vaccines were based on the concept of injecting dead virus into the body to stimulate the immune system, but this is not the current approach. The Chinese got proceedings started by publishing the genetic code of the virus, which was truly impressive work given how quickly they did it. One approach is to convert viral sequences into messenger RNA, which causes the body to produce a viral protein that triggers immune responses. Another approach, at the University of Queensland, is to try to develop a vaccine made of viral proteins grown in cell cultures. Another approach is to make a string of RNA that corresponds to a section of the coronavirus. Thus there are a variety of approaches, and the question then is, will they work?There is also the question, will they work fast enough? Suppose we developed one? It is inconceivable this could be done in less than three months, at which time there would need to be clinical trials. These would take several weeks, and that would have to be followed by a period of six months where it was determined whether there were any adverse effects. That would have to be followed by an extended period where it was examined whether the vaccine actually works, and the net result of this is that it would take over a year at the very least to decide whether we had a working vaccine. Then it has to be manufactured. A vaccine is our only defence if we cannot contain it and it becomes endemic. In the meantime, the scientific community is working; apparently there are at least 77 scientific papers made public on it since the outbreak became declared.

Cancer: the problem.

I read an interesting blog recently entitled “The War on Cancer” (http://sten.astronomycafe.net/the-war-on-cancer/). Apparently, in the US a little under 600,000 people die of it each year. The author, Dr Sten Odenwald, then set out to illustrate that funding for cancer research is far too low. I think it was President Nixon who coined the phrase, “war on cancer”, and set it as an objective, in the same way Kennedy had set the Moon landing as an objective, but this was doomed to fail, at least in the spectacular way. The reason is the nature of cancer, which, as an aside, is not one disease. We have been trying to cure this for a very long time, but with mixed results. Gaius Plinius Secundus recommended a poultice of broccoli for breast cancer, and asserted it works. There are indeed agents in broccoli that will deal with some breast cancers, but by no means all, and even then, the cancer would need to be near the surface. There are at least twenty different types of breast cancer. Drugs like tamoxifen stop the growth of at least one type, monoclonal antibodies help in some others. So we have made some progress, but there are still severe problems, especially if the tumour metastasizes (dislodges cells to other parts of the body).

It is the nature of cancer that is the problem. Cells grow around nucleic acid, and nucleic acids reproduce by base pairing, then splitting, each strand now being the frame for the production of more nucleic acid. Thus after splitting, when a new double helix is finished being assembled, the amount of nucleic acid has doubled, so a new pair of cells is possible, the old cell having been destroyed. So what can go wrong? You will usually read that copying is not correct, or something is added to the double helix, but I don’t believe that. It is the peculiar nature of the hydrogen bonding that either the correct nucleic acid goes onto the growing strand or nothing does. That is why reproduction is so accurate. In the double helix, the reactive sites are protected, as they are in the interior of the helix, and the outside is the phosphate. A further substitution on the phosphate to make a tri-ester would be a nuisance, but it would not be very stable, and it would repair itself. Further, it would require a highly reactive reagent to do this, as it is exceedingly difficult to make phosphate esters in cold water other than through enzymatic catalysis. No, I think the problem probably arises during the splitting stage when the reactive sites become exposed. If something happens to the nitrogen functions, then that will block the formation of the next double helix at that point.

At that stage, the body will attack the nucleic acid at that point, and the next usual outcome will be that the various parts of the strand will be degraded, and the bits reused or excreted. But if the problem occurred in certain places, it may be that what is left can start reproducing. If that happens you have something growing that has no function for you, BUT it looks like it is part of your body, because up to a point it is. The growth just keeps growing, and reproducing itself. The reason there are so many different cancers is there are so many places where a nucleic acid could go wrong, and each different place that can reproduce will lead to a growth that is slightly different from any others. Because it looks like part of your body, your natural defences ignore it.

So far, we have largely relied on surgery, radiation or drugs. So, how is progress? In some cases, such as leukemia, progress is good, and it is often curable. In other cases, life can be extended, but according to Wikipedia, since Nixon declared war on cancer, the US alone has spent $200 billion on research. Between 1950 and 2005, the death rate, adjusted for population size and age has declined by five per cent. On the other hand, while in remission many patients have had life extended.

However, we should ask, are we doing anything wrong? I think we are, and one problem relates to intellectual property rights. Here is an example of what I mean. In the 1980s I was involved in a project to extract an active material from a marine sponge. My company developed some scale-up technology and made a few grams of this material, which, from reports I received, if the odd microgram was introduced to a solid tumour, the tumour blistered and died, leaving a well-repaired skin outside wherever the organ was. This property was limited to studies on rats, probably with external carcinoma. Anyway, the company that hired us ran into difficulty with its source of funds and went bankrupt, however, somehow ownership of the intellectual property lived on. At the time, there was no known technique of introducing a material as reactive as this to internal tumours, nor did we know whether that would even be beneficial. Essentially, the project was in an early stage, and maybe the material would not be beneficial. Who knows? The problem is, now we don’t know and nobody is likely to work further because the patents have expired. Any company working on that will have all the expense, and then somebody else can come in and take the benefits. In my opinion, this is not a desirable outcome. We should not have a situation where promising knowledge simply gets lost because of formal procedure.

Equally, we should not have the situation where drugs become ridiculously expensive. Why should the unfortunates who get a rather rare cancer have to pay the huge prices of drug companies? I am not saying drug companies should not get a fair return, but I think society should pay for this. Think of it as compulsory insurance. The alternative is a family might have to decide whether to bankrupt themselves, kill the grandchildren’s education prospects to buy a year or so for grandmother, or whether to just let her die. What sort of society is it that allows this?

Cancer is one of those diseases that everybody comes into contact with one way or another. In my case, my father died of pancreatic cancer, and I am a widower because of cancer. Yes, these things happen, but isn’t it in everybody’s interest to try and do what we can to at least minimize the harsh effects?

Happenings!

Since my last post, things have been happening and there has been material for several posts. I have been in hospital getting a hip replacement, but that is of little importance, other than to me. The United States elected a new President, after what I thought was one of the most bizarre campaigns, and then there was . . . But more of that below.

The surgery and the follow-up care were carried out with professionalism, skill and commitment, and I can assure anyone wondering that New Zealand does have good skilled medical care. One can argue about the politicians’ involvement with health care (and many of us Kiwis do), but I could not have asked for more. While recovering, the election results were coming in, and I had nurses pausing and discussing. Many Americans probably do not appreciate the importance many ordinary people in other countries attribute to their political scene. Of course there is no personal involvement, so we could make our comments in a detached sort of way. I am sure all who are following my blog, or other writings, will have seen enough comments on the actual result, so I shall leave it at that, other than to add that only too many of such comments show some ugly aspects of the writer that probably should not have been shown.

Then it was time to come home. My daughter thought I was being silly coming home because I have some fairly steep steps to climb, but no problem. The hospital had the rule, if you cannot climb up and down steps, you cannot come home, and I had practised. A lot of people commented on how well I was doing, bearing in mind . . . I put that down to three things. First, for weeks before going in I had been doing exercises to strengthen hip muscles. You cannot do anything about what is to be cut, but with bad hips, the muscles around them tend to atrophy through lack of use. You can do something about that. The second, I was determined to do what had to be done, and I think attitude helps. Finally, I had some long-term goals. Simple goals, like being able to walk down the beach in our up-coming summer. Be that as it may, I mention it just in case anybody else is to face such surgery. One can imagine all sorts of things, but it helps if you can focus on the desirable.

So, the day I came home we had, in a 24 hr period, the total average rainfall for November, and here was me hobbling up towards the house. Any moss on concrete, when wet, tends to get slippery, and you need slipperiness under crutches like you need the plague. So, the end of the bad luck?

Nope. I came home on a Saturday, and had a quiet Sunday, but then shortly after midnight, the house started shaking: a 7.8 earthquake. (Equivalent, I have been told, to 5.35 Mt of tnt.) This was centred at Waiau, which is about 40 % of the way between Christchurch and Wellington. This has apparently got international attention, especially “cow island” – three cows stranded on a pillar where the rest of the land had subsided. In one sense it was good this happened at Sunday/Monday midnight because many of the high-rise buildings in the Wellington commercial district lost sheets of glass, and there would have been serious casualties had there been people wandering about down below. Meanwhile, the electricity to the house went out. For me, there was worse to come – just as I was getting back to sleep, the sirens for a tsunami warning started up. No real likelihood of a tsunami where I live, because I am about 70 meters up a hill. But these sirens went on and on.

Then on Tuesday I had to go back and get dressings changed. No problems, except there was a serious storm going on, a number of roads were closed, and I had to hobble both down and up my path to my house. Of course my inconvenience is nothing compared to others’. Apparently, the whole town of Kaikoura has to be evacuated by sea because all land routes to and from it are blocked by huge rock slips. These road closures are all over the country. Earthquake/storms have closed at least 7 roads in the Lower Hutt area where I live, and a good number of houses have had to be evacuated. Then, of course, the aftershocks; 2000 of them. These have ranged as far north as Taupo, (half-way up the north Island) and a number directly under Wellington. A number of high-rise buildings there are under suspicion.

Yes, this has been a period where things have been happening. I just wish they would slow down, or happen somewhere else. I know that is hardly fair to someone else, but I have felt that a quiet spell for recovery would be good.

A disastrous example of free market economics

Do we see crises coming, and if so, are we in the habit of preventing their arrival? Is our free market system of economics capable of preventing their arrival? In answer to the first question, I think some of us do. As the second, no, especially if it means we do not make so much money so fast. Climate change is an example. The scientific community has made it fairly clear that our addition of infrared absorbing molecules into the atmosphere is causing the planet to warm. The politicians, or at least some of them, wave their arms and say we have to burn less carbon, but who says we have to stop using spray cans? A device that led to air creating the spray would be fine, but hydrocarbons, fluorocarbons, etc are not. How about stopping the manufacture of sulphur hexafluoride? Or reducing the level of application of nitrates to the soil?

So, we are at best a quarter hearted about climate change, but what about other impending problems? It is here I think the answer to my third question is no, and in fact the free market is more than just a part of the problem. One such problem that I think needs more thought is the question of antibiotic resistance. How does this come about? Basically because when antibiotics are used, the surviving bacteria are more likely to be resistant, after all, how else did they survive? This is evolution at work; the survival of the adequate, and being adequate to survive in the presence of antibiotics is to develop resistance to the antibiotic. And the problem is, the resistance can be transferred to further bacteria.

So, how does that come about? The most obvious example comes from agriculture, where antibiotics at low levels are used to promote growth. This helps the farmer’s and the drug company’s profits. The object is not to kill off all the bacteria, but rather to reduce their number, hence the low levels. (If you kill off the lot, digestion is impeded.) So, we have a little fermentation pot where resistant strains can develop, and then be transferred to the general environment. Why is this permitted? Because there is more money to be made by the companies, and a bit more by the farmers. Up to 80% of the antibiotic usage in the US has apparently gone into agriculture, and the big pharmaceutical companies are not going to give away that market. The chances of the farming sector turning down the quicker bringing of stock to the market are somewhat slight. Some do not use them, but only because they can then sell meat that can be advertised as “grown antibiotic-free”. So, maybe the consumer is at fault. Are we prepared to pay a bit more to prevent antibiotics being used this way?

Does it matter? I think so. If antibiotics no longer work, or if there is a reasonable risk they will not work, then medicine goes back a hundred years. The more advanced surgery developed during that period may well have to be abandoned. Surgery in the late 19th century was not something many would want to see their family undertake, let alone themselves. Additionally, many cancer treatments seriously suppress the immune system, and antibiotics are needed to deal with adventitious infection.

Now, for the moment we still have a slate of antibiotics, and while resistance is growing, it is rare to get superbugs resistant to just about all of them. Accordingly, our society is responding to this problem in its usual way: we ignore it, and assume we can find a way around it. The way around it is to have a “last resort” antibiotic, or preferably, more than one. The problem is, what used to be the antibiotics reserved for the most serious problems are now being used loosely and widely. But we can discover more, can’t we? Well, probably not. The first problem is, who is going to do the discovering?

The usual answer would be, big pharma. Nevertheless, success there is somewhat unlikely because by and large big pharma is not looking. The problem is, drug discovery has become hideously expensive, and suppose one was discovered and put away as a drug of last resort, usage would be incredibly small compared with the costs of getting it. The reason, of course, is that to prevent getting resistance to this, it too would be used very rarely. The company would never get its money back. Big pharma wants drugs to treat chromic conditions.

There is another problem. One drug that has had a dramatic increase of sales to the agricultural sector is tylosin, and it, by and large has little use in human medicine, but it is in the class known as macrolides, and if resistance is developed to tylosin, it is quite plausible that resistance will be developed to all those in the macrolide class. The use of third and fourth generation cephalosporins in animals has jumped seriously, and these are essential to human medicine. Why are they used? Almost certainly because of direct marketing. These drugs are convenient to use, but they are by no means the most suitable. There have been large increases in the use of tetracyclines and aminoglycosides in the agricultural sector, the latter class includes streptomycin. This report shocks me because of direct experience. When she was about 40, my wife got severe brucellosis, and the only cure then was serious doses of both tetracyclines and streptomycin. At the time it was a close call what would die first: Claire or the bacteria. Fortunately the bacteria did, but brucella live in animals, and I would hate to see that become resistant.

Will the worst-case scenario actually happen? I don’t know, and hopefully it won’t. Nevertheless, from a strategic point of view, don’t we want to optimize our chances of avoiding disaster? And it is here that the problem is most apparent, because the sufferers of the disaster scenario are not the current beneficiaries. We have an economic model that is almost designed to maximize the chances of disaster. It is not time to panic, but equally, it is also not the time to continue being stupid. If we want to insure our medicine does not descend into the state where serious surgery is to be avoided, should we not be cautious and defend what we have? Or do we say, let the corporations make what they can now, and not worry, and hope we never need the antibiotics?

The day after first posting this, the Huffington Post reported: ‘THE END OF THE ROAD FOR ANTIBIOTICS’

Are drug prices fair?

Recently in the Huffington Post, Allen Frances wrote a blog asking, “Why are most cancer drugs so expensive and so ineffective?” The link is below for those interested.
(http://www.huffingtonpost.com/allen-frances/why-are-most-cancer-drugs_b_8294392.html?utm_hp_ref=science&ir=Science )
That is most certainly a good question. A summary of his points includes that the pharmaceutical industry is essentially a monopoly, in that only one company will make any given patented product. In the US, it exerts far too much political pressure, and as an example, he claimed Congress denied the Medicare program the right to negotiate drug prices. He claims there is a price monopoly, for even when generic drugs can be made, the pharmaceutical companies buy up the companies. He claims patent lives are extended with phoney variations. But in my mind, even worse, drug companies test their own products, but do not have to release the data for analysis by neutral observers. The companies hype the benefits and minimize disclosure of any risks.

He then cites some data from a Dr Prasad. Some of his findings include, the price of Gleevac rose from $30,000 in 2001 to $70,000 today, despite the fact the cost to make it is $200 (for a year’s course). However, at least Gleevac actually works. According to Dr Prasad, the median improvement in survival for 71 drugs for solid tumours produced in the last decade is 2.1 months. That may well be an overestimate because only 36% of those over 65 yrs old were in the trial, but that age group represents 60% of the patients in the wider community. Another interesting question is, given that many of these drugs have very severe consequences to the patient, is that 2.1 months worth it?

So, how do the companies do? Seemingly, remarkably well, with returns of between 10 – 42%. I saw a recent article that stated one product that had been sold for $20 per prescription had it raised to $1,000. When asked why, a spokesman said they wanted to make more money. Well, yes, I suppose they do. Don’t we all? The products are grossly overpriced, and only too often it appears they don’t really work all that well. There is the argument that research costs a lot. Yes, it does, but despite this, these companies are hugely profitable. In my view, this is simply price gouging, and it shows the ugly side of capitalism. A further interesting question would be, how much tax do they pay on these profits? Given that some large companies pay very little, one suspects the answer is, not much.

Usually, economic theory works on the basis that if there is a bad product, people will not buy it. However, with cancer drugs, that theory goes out the window. The average person has no hope whatsoever of deciding whether the product is any good, and you find out it is not when you die, or come close to it. Earlier this year, my wife died of cancer, so I know the pressure on the relations. Who can tell someone dying that product B is a waste of money, and it will bring penury to the remaining family members? And no, this situation did not arise for me. Claire was diagnosed in November, some simple treatment was provided as a holding measure while various things were done, and proper treatment was to start after Christmas. As it happened, her funeral was on the day scheduled for the start of treatment. Nevertheless, when someone you love is dying, you cannot really think rationally. There is a temptation to grasp at straws, but think what the grasping is like if you hear promising things from the drug companies? The very least we could ask for is a fair and open discussion of the prospects, and the basis for saying that. And we should expect that where there is little to substantiate the claims, at the very least the straw to be grasped should involve only reasonable expenses. Price gouging for performance is, in my view, not justifiable, but price gouging for what may be little better than snake oil is in my view criminal.