29 December 2020

COVID Pandemic and the New Variant

29th December 2020

Exponential Growth of the Pandemic in Britain

     For the last 30 days (from the 28th November) there has been a steady 'monotonic' rise in the number of daily new cases of COVID reported on the Government site. On a semi-logarithmic plot this looks like a straight line, signifying exponential growth. Throughout December there has been a more-or-less steady doubling time of 17 days. If no change is made to the way we behave, or the virus behaves, this means that the predicted number of new cases in mid-January would be 82,000 per day. 

     In the Figure below, the horizontal axis shows the day (counting from 1st Jan 2020), the vertical axis show the Log(10) of the number of new cases on that day. The Blue points roughly correspond to October, Green to November and Red to December. The y parameter indicates the slope, and R(squared) indicates the extent to which the data follow the modelled line.


     Of course, as every viron has a chance of mutating, and of replicating, twice the viral load by mid-January will mean twice the mutation rate (for good or ill), and twice the growth rate.  (It is perhaps worth noting that the increased rate of propagation noticeable since 1st December is not reflected yet in an increase in the daily number of deaths. Though, of course, COVID deaths will always lag COVID infections by two or three weeks.)

     The Government has made clear their policy on schools: that scholars 'stagger' back and get tested by the 50% efficient 'flow-test'. I would advocate rethinking that, till we can bend the curve back into a falling trajectory. Or at least make non-attendance be an option.

     The Government has also made clear that the vaccine will go first to NHS staff and the over-eighties. I would think the over-eighties are not spreaders.  I would suggest that priority should go to (in order): 

  • NHS front-liners (nurses and doctors),
  • Other front-liners on whom we depend (shop staff, bus-drivers, postal and delivery staff)
  • Others forced by Government into harm's way (scholars, military)
  • Spreaders (compulsive talkers, and social drinkers, and thoughtless people generally)
  • The mobile vulnerable (a sheltered vulnerable is surely at less risk).

     I am aware that the general public have no clue as to who the spreaders are, nor how effective the light mask, and the 'full-kit'. I wonder who has compiled this information and whether it would not be worth publishing. (Please!!)







16 December 2020

Steve Baker & Mark Carney

Steve Baker & Mark Carney

After Mark Carney’s 3rd Reith lecture of 2020, Steve Baker  asked:  “So there is such a thing as a ‘free lunch’?”  Carney was not given space to answer, for Anita Anand spoke over him, asked Steve Baker to repeat his point and then moved on to another questioner. 


I am sure Steve Baker knows this perfectly well. But, no; there is no such thing as a ‘free lunch’, nor a ‘magic money tree’. Writing new money into the British money supply will cause inflation in the long run, unless it is written out again at some stage (ideally before the inflation is noticeable). 


It is better that the ability to turn credit into pounds sterling lies with the Central Bank rather than the government. Government operates in the short term and is highly sensitive to the public clamour. It is too tempting for the executive to buy an election and create problems for the future. 


The Bank of England moves in (deliberately?) mysterious ways. But it is answerable to Parliament and is given the task of maintaining inflation at 2%. If it fails, its governor can be reprimanded or removed, or the entire Bank liquidated. 


A crisis like the COVID-19 pandemic is exactly the sort of crisis that justifies Quantitative Easing. If each citizen spent 1% of their total cash in buying a government bond, Steve Baker would not object. The effect is the same as 1% inflation, except that there might be some who neglected to buy the bond, but furtively pocketed the money. QE is fairer, as it hits all equally. Surely no-one objects to having 1% of their cash wealth taken (albeit without their consent) to support furlough, buy masks, build hospitals, etc. If any object, they should consider living elsewhere. 


The unfairness of QE is that it taxes (fairly) only cash; while land, houses, jewels, old-masters, etc are exempt. That is why we still need Death Duties and a Wealth tax.  I do not think this is what Steve Baker is clamouring for. But perhaps I am wrong.


One of the greatest threats to democracy in Britain is that few people understand money. The ones that do understand it own property, grow rich, and smile. 



16 November 2020

Paying Taxes -- both a virtue and a necessity

 Why pay tax? 

    It is amazing how many people in Britain think taxes are wrong and should be avoided where possible. 
    Nevertheless, I was slightly surprised the other Sunday when the subject cropped up over a pre-prandial pint in the Greatworth Inn. My friend 'the accountant' said he thought that death duties were wrong; that they amounted to double taxation and little different from plain theft. 
    "Maybe", I said, "but still necessary", for I saw an opportunity to lay out my favourite recent aperçu.
    (Apparently it takes a certain sort of intelligence to realise that there are benefits that accrue from taxation: railways, roads, bridges, medicines, the disposal of waste, safety from violence, etc. Some rare citizens even wince at the sight of poverty in the streets. Many can be cajoled into paying taxes by ensuring that all people pay them in some sort of 'fair proportion'. But defining and ensuring fairness is far more easily said than done.  A few years back I crossed swords with a 5th Viscount over the existence of 'altruism' in human populations, which he pooh-poohed . 
    "What about in the paying of taxes?" I had said. 
    "But we do not pay taxes willingly" he objected. 
    "Of course we pay them willingly", I expostulated. "That is to say, a majority of MPs in the house of Commons voted through all the relevant legislation."  The Viscount turned then to other questions, and I was left with the distinct feeling I had routed him.)
    "Have you noticed," I said, returning to my accountant friend and my recent aperçu, "how money continuously flows from poor people to rich people, steadily and inevitably; taxes are needed to return money to the poor so the process can continue." 
    This is a novel idea, for even quite poor people think of  tax as a net loss rather than a net gain, which to them it clearly is. 
    "But, but, but !!! " he protested; "The large incomes of the rich are the result of market forces; it is earned income; the money belongs to the rich by right; they are paid well because they are worth it."
    "All that may be true", I replied; "but it still has to be returned to the poor. It is the accumulation in the hands of the rich that has to be prevented. If the rich spent their income properly, that is to say fully, the inequality might be better tolerated. But they hoard their wealth. And so it must be prised out of their clenched fists." 
    Silence fell.
    "Who is for another beer?"  I offered, for I realised my companions were not up for radically rethinking taxation, and I could see another aperçu coming towards me: "What is a fair tax regime?  It must clearly be a tax regime that prevents the rich from getting richer, and the poor from getting poorer."
    Rather neat, do n't you think, for a Sunday morning?  Death duties are obviously the best way of collecting what must be collected; for only then is it clear how much is involved. (See also: https://occidentis.blogspot.com/2016/09/estate-tax-and-limits-to-wealth.html)
==================

13 November 2020

RNA Vaccines

RNA Vaccines

Currently (12 Nov. 2020), the World Health Organisation (WHO) is aware of 

48 different teams around the world who are working on the production of vaccines against the SARS-Cov2 virus that have already got to the stage of clinical evaluation. The Pfizer/BioNTech/FosunPharma team, known to all since 9th November when it announced a degree of success, is one of these 48. (There are in addition 160 other vaccine-production teams that are in pre-clinical stages of development.)

A number of different vaccine technologies are being tried in the 48 different vaccine-teams that are already at the stage of clinical trials, listed by WHO [1].  I summarise these below. 


Type 1. Inactivated virus (in this case inactivated SARS-Cov2). This is the approach used in the Salk polio vaccine, which used formaldehyde to ‘kill’ the virus. Formaldehyde can modify the shape of proteins, and the antibodies produced may only react with formaldehyde-treated virus. The virus must be really, really, dead, and safety is a perpetual concern.


Type 2. Replicating viral vectors. Thus, the SARS-Cov2 spike protein gene can be inserted into the genome of a mild virus (e.g. the measles virus or adenovirus). These viruses have their own way of getting into cells and replicating, but introduces a SARS-Cov2 antigen, against which the host can raise antibodies. (See [2]


Type 3. Non-replicating viral vectors. Adenoviruses often used.These can get into cells but will not spread in the host. Higher doses are therefore needed. (This is the strategy used by the Oxford/Astra Zeneca team.) 


Type 4. DNA vaccines. The mRNA for a viral gene is copied (using reverse transcriptase) into a double-stranded DNA plasmid that grows happily in bacteria. Large quantities of the plasmid are grown up, purified on columns and used as vaccine. Once inside a cell they should direct the synthesis of e.g. Spike protein (amongst several others.)


Type 5. Protein subunit vaccines. These are a more recent development, and becoming popular, as no virus is involved in the manufacture. The gene for a viral protein can be used to produce large quantities of the protein in vitro. However, the isolated and purified protein may not have the right shape to trigger formation of antibodies effective against native virus. 


Type 6. Virus-like Particles (VLPs) can be prepared by growing cultured cells that produce only sufficient of the viral proteins to form a particle, but are not able to reproduce whole virus. If RNA is needed to form a particle, small bits of irrelevant RNA can be added. These particles, purified from cell cultures, can be used as vaccines, and are often more potent antigens than the isolated soluble protein or protein subunits of type 5. Again, no virus is involved in the process of manufacture.


Type 7. RNA vaccines. In this strategy single-stranded mRNA that codes only one viral protein (e.g. the Spike protein) is encapsulated in a Lipid Nano Particle (LNP) some 70-100 nm in diameter [3] (1million nm = 1 mm). Human cells have an inherent tendency to engulf particles of a particular size and attempt to digest them (a hangover, no doubt, from our amoeboid ancestry). The released mRNA directs the synthesis of spike protein (or its Receptor Binding Domain) in the cell. This technology has been developed over the last 20 years for experimentally silencing genes; and since 2012 for producing vaccines against single-strand RNA viruses such as influenza. It was first used in humans in 2017 [4]. The advantage is that an equipped factory can turn to producing a novel vaccine within a week. All it needs is to know the sequence of the mRNA. (This is the strategy use by the Pfizer/ BioNTech/ FosunPharma team, and a team at Imperial College, London.) RNA is far more susceptible to hydrolysis than either protein or DNA (because of the -OH, group missing in 2' desoxyribose). Vaccines are conventionally kept at 5-8ºC, but RNA vaccines must be kept at –78ºC or lower. That is not a problem. A 6 litre dry-ice or liquid nitrogen Dewar, twice the size of a pressure cooker, will hold its temperature for 200 days.


We see that the different vaccine strategies have their own advantages and disadvantages. The RNA technology has the advantage of speed; and relative safety. 

References

[1]    https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines

[2]    https://doi.org/10.1016/j.virol.2014.01.002 

[3]    https://www.liebertpub.com/doi/full/10.1089/nat.2018.0721

[4]    https://pubmed.ncbi.nlm.nih.gov/28457665/



04 November 2020

Open letter to the PM

Dear Boris Johnson,

I am by no means your greatest fan, but I thought you ought to know that the R0 number is now (3rd November 2020) below 1. That is to say, your 3-tier system has, to some extent, worked. Though it may well be best to stick with the 4 week lockdown-2, already announced. We still have much to learn about hygiene.

In the attached picture I have plotted the logarithms (base 10) of the daily new cases as reported on https://coronavirus.data.gov.uk. The horizontal axis shows the days of the year (day 279 is 5 Oct,, day 294 is 20 Oct., day 308 is 3 Nov.). 



It is clear that the rising line in blue (data from the first 3 weeks of October) cannot be extended through the most recent data (20 Oct - 3 Nov), shown in red.

The rising blue data show a doubling time of 24 days. The least-squares line of best fit is objective, but is not a close fit because of chance vagaries of the data (R-squared=0.62). The falling red data show a halving time of 200 days. (The line is again the least-squares line of best fit). That is to say, in late May 2021 we would still have 10,000 new cases a day (and c. 70 deaths a day) unless we improve our personal hygiene, (or we have a vaccine).  

So the 4 weeks of lockdown-2 should help. In June and July we had 40 times less virus buzzing around, but most people were foolishly unaware that the R0 number was already above 1. (See: https://occidentis.blogspot.com/2020/09/covid-19-case-data-uk.html ). Personal hygiene deteriorated further in early September. 

Yours sincerely, Ian West

---
Ian West
9 Thenford Road, Middleton Cheney,
BANBURY, OX17 2NB,
Tel: 01295 713 889; (Mobile: 07474 572 588)
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25 October 2020

Free school meals

     It is a mistake to see the provision of free school meals as costing M£20 for the 5 days of half term. The lunches in question will cost precisely the same with, as without, the vouchers. It is a question only of who pays. In one case those in jobs with enough spare money to pay taxes; in the other case the certified needy, the out-of-work, incapacitated, or single-parent. The only way to save money is if some children go hungry. 

    One of the main costs of means-tested assistance is the cost of testing the need. But that has been done. The needy are identified, and the particular need for food has been accepted. 

    I admit to slight surprise that it is as many as 15.9% of secondary school pupils that fall in this category (in the academic year 2019/20), [1,2]. But I note that Conservative and Labour parties have both accepted this call on the public purse. 

[1]. https://lginform.local.gov.uk/reports/lgastandard?mod-area=E92000001&mod-group=AllRegions_England&mod-metric=2174&mod-type=namedComparisonGroup

[2].  21% in NE England, 11% in SE England

16 October 2020

Put more trust in good sense and decency

 

Dear Guardian Letters Editor,
I get the impression that control of the COVID pandemic in the UK is slipping out of Government control. 
I notice that COVID is largely a disease of the elderly;  that the median age of COVID deaths is 82.4 years. And I conclude that the Cabinet is taking an old-persons-view of the epidemic. 
The decision whether to shelter or work depends to a large extent on age and circumstances. A man aged 30, in good health, with a mortgage and no savings might feel differently from a retired person on a pension. The important thing is that everyone has the information they need to make the decision that suits them.
      Some may think the Government's instructions are bossy and detrimental; that the Government is taking the wrong tone and missing the complete picture. Others are worried at the lack of parliamentary endorsement on constitutional grounds. 
My own unease concerns the blurring between advice and law. I believe that in Sweden the 'rules' were issued as guidance, but were followed to much the same extent as here.  
Should we not try a more consensual approach? It seems to work in Sweden.

Yours sincerely, Cawstein
cawstein@gmail.com
---


11 October 2020

The Root Problem

The Root Problem is World Population

     What is wrong with the world? The daily number of new cases of COVID-19 leap higher and higher. But the pandemic is not the only thing going wrong in the world this year.  There are forest fires in Australia, Brazil, and California, war and starvation in Yemen and Syria, melting ice-caps, strange weather patterns, and waves of migrants lapping at the shores of Europe. These coincidences make one wonder if there is perhaps a link? Does world population crops up among the contributory causes of all these problems? Let us explore this idea further.

Global Warming

     Twice as many humans, other things being equal, will burn twice as much fossil fuel, and generate twice as much CO2. The problem depends linearly on world population. So, even without industrialization, and concrete, there will be a population element to the increase in Global Warming. Of course there is industrialization and life-style on top of that. The discovery or fossil fuels gave rise to a way of life that freed mankind from toil and opened many possibilities for pleasure. It is hard to see us going back voluntarily to a low-energy way of life. We put our hope in renewable fuel sources. But each year there are more homes to heat, cars to drive, dinners to cook.

Famine

     There are food shortages in many parts of the world. It is estimated that famine leads directly or indirectly to 9 million deaths a year [1].  Famines can arise from drought or other natural disasters. They are often caused by war, preventing the getting and distribution of food. Nevertheless, whatever the cause of the shortage, twice as many mouths need twice as much food. Once again the problem depends linearly on world population.

War

      Murderous armed conflicts can have an ethnic, cultural, religious, or dynastic cause. (E.g. in Kashmir, Palestine, Nagorno-Karabakh.) But in some cases there is clearly an element of competition that triggers conflict, or exacerbates existing tensions. (E.g. the First World War.) 

Pandemic

      It is clear from the present pandemic that infectious disease spreads more rapidly in places of high population density. Of course, there were plagues since biblical times, in countries and civilizations that supported congested cities. It is congestion that spreads disease. But congestion is increasingly unavoidable as the world population grows.

Migration

     We are familiar with the categories of assylum seakers and economic migrants. Both can be seen as resulting from population pressure in parts of the world that offer very meagre resources of food and water.

World Population

     There is a website (https://www.worldometers.info), which purports to clock the current world-population; the numbers flicker up and down suggesting that each second some new deaths and some new births are recorded, but the trend is upwards. It may be a gimmick but the numbers agree with other sources. The net increase today was estimated as circa 194,000; this year it was 63 million. There was a period (1600–1950) of approximately exponential growth. Fortunately the curve is now bending towards slower growth but our numbers are still growing at a frightening rate; more than doubling in the last 50 years.

1960 - - - - 3,035,000,000
1970 - - - - 3,700,000,000
1980 - - - - 4,458,000,000
1990 - - - - 5,327,000,000
2000 - - - - 6,143,000,000
2010 - - - - 6,957,000,000
2020 - - - - 7,795,000,000

     We are already exhausting fish-stocks, water-resources, destroying habitats and extinguishing species by the hundreds in our increasingly desperate search for food, housing, and fuel.
     We must stop the population growing, and start the downward trend.

The Elephant in the Room

Yes, we must switch to renewable energy – and lower the population.
Yes, we must conserve species and habitats – and lower the population.
Yes, we must learn how to prevent pandemics – and lower the population.
We must continue to press for International Law – and lower the population.

References

[1] https://www.theworldcounts.com/challenges/people-and-poverty/hunger-and-obesity/how-many-people-die-from-hunger-each-year/story

09 September 2020

COVID-19 Case data (UK)

 COVID-19 Case data (UK): May - September.

    I seem to be among the very few commentators who present data in semi-logarithmic plots. My rationale is that the chance of catching the virus depends on the fraction of the population carrying active viruses. So the rate of increase of infection depends on the level of infection in the population. This is the characteristic of logarithmic growth; as in the growth of bacteria in fresh medium, and in the cooling of a jug of hot water, where the rate of loss of heat depends on the temperature difference between the jug and the room air. 

    The advantage of semi-logarithmic plots is that, in a steady situation, with the virus spreading at a steady rate and data points following a continuously steepening upward curve, it is hard to extrapolate -- i.e. to predict. But, when plotted as their logarithm (against time on the x-axis) the points will follow a straight line, and extrapolations (i.e. predictions) can be made, trends can be determined, and changes in regime detected.

    In the picture below, I present log(base10) of the daily increment of new cases (as reported by the government) on the vertical axis against the days since 30th April 2020 on the horizontal axis. (1,000 cases daily shows as 3.0; 10,000 would show as 4.0; 1st June shows as 32, etc.)


    The falling line of blue data points shows that during lockdown the virus was being steadily eliminated from the population, monotonically, and steadily. In epidemiological language R0 < 1.0. The R^2 value of 0.934 indicates that the data conform rather well to a straight line (with the slope of -0.0152 per day).

    The rising line of pink data points shows that after the relaxation of lockdown the virus has been gaining ground in the country with a rather consistent, quasi-monotonic, rate. I.e. between 9th July (day 70) and 4th September (day 127), the R0 value has been greater than 1.0. Not "between 0.9 and 1.1", nor "levelling off", as reported by the BBC on many occasions during that period; it was consistently greater than 1.0 all that time. How the BBC could continue through July and August saying the viral spreading rate was below 1.0 baffles me. 

    On 5th September there was a jump in the daily increment that was large enough for everyone to notice (See the last 3 data points in pink). It is impossible for me to fit a line to 3 points, so we shall have to wait a week to see if a new regime is in operation – a new slope on the semi-logarithmic plot. A 'back to work/school' regime.

(See also previous blog-posts.)

13 August 2020

The Direction of Evolution

The Direction of Evolution

It is often supposed that biological evolution tends toward ever 'higher' forms of life; more complex, more sophisticated, more worthy. And it is usually taken for granted that Man (Homo sapiens) is at the apex of this advance. 

However, in fact, as indeed in theory, life evolves towards ever better 'reproducers' and 'survivors'. At the apex of 'the tree of life' are not Homo sapiens, but viruses and insects.

The humble bed-bug (Cimex lectularius [1]) is a parasite almost perfectly adapted to preying on human blood. Its flat body can slide into tiny crevices where it can hide, survive for months without food, and escape the application of insecticidal sprays and powders. And it does essentially nothing to diminish its flock of potential hosts.

I say 'almost' perfect, for its bite can, on some hosts, raise itchy red lesions or even raised welts. However, on some 50% of hosts its bites cause no visible effect [1]. These are likely to be the bed-bugs of the future. 

Nor have we eliminated the SARS-CoV2 virus. Viruses and insects are the conquerers of the conquerers. 

Reference

[1]  https://en.wikipedia.org/wiki/Bed_bug


25 July 2020

SARS-CoV2 (Continued)

SARS-CoV2 (Continued)  

     One of the puzzling features of this virus is that some infected people, while carrying a considerable viral load, and shedding infectious virions, nevertheless develop such trivial symptoms that they never notice they are infected. While other, of course, develop virally driven hyper-inflammation,  respiratory failure, and sometimes also kidney and heart failure.
     This variability in response is especially striking when it affects a whole nation-state. Thus the official WHO figures record that Vietnam, with a population of 97 million, has confirmed only 416 cases of COVID-19, and that none have died. (c.f. UK, population 67 million, 297,914 cases, 45,677 deaths on 24th July. )

Possible explanations for variable responses.

     The hypothesis of genetic variability in the human host, which supposes that the Vietnamese lack e.g. the ACE2 receptor site (See my SARS-CoV2 post), is more-or-less ruled out by anecdotal observations such as that of an asymptomatic carrier infecting 5 family members [1]. As also is the hypothesis of genetic variability among the circulating SARS-CoV2 strains, for the carrier would obviously infect the household with the strain she was carrying. 
     Could there be competition between two co-infecting viral strains, where one causes trivial, often negligible, symptoms but occupies all the binding sites? 
     Or could there be, in some people, residual anti-bodies at a sufficient titre from a previous infection by the same (or sufficiently similar) coronavirus?  This last seems the best hypothesis, and in the last 10 days has received some support. 
    The group of Antonio Bertoletti at the Duke-NUS Medical School in Singapore has just published in Nature [2] an online report showing that previous infection with a virus of the beta-coronavirus family can leave long-lasting and multispecific T cell immunity to the nucleocapsid structural protein (N protein, or NP, See my Coronavirus post) that can cross-react with the N protein of SARS-CoV2). This previous infection could be a harmless "common cold" member of the corona virus family, but in Singapore it was possible also to study survivors of the 2003 SARS pandemic. 
     Back in 2013 a group in Taiwan explored the antigenicity of the N protein of the mild common cold virus HCoV-OC43, and had found that the middle section was highly antigenic [3]. Well over 90% of healthy young adults contained antibodies in their serum against the N protein of this common virus. These antibodies were even found in cord-blood samples showing that newborn babies acquire some immunity against coronaviruses from their mothers. 
     We have already learnt that it is foolish to infect yourself deliberately with SARS-CoV2; you could become very ill or die. But there may be a beta-coronavirus, prevalent in Vietnam, that does protect you against COVID-19. And it may be that here in Britain a sufficiently recent 'common cold' may leave you with enough circulating antibodies to prevent or greatly limit the effect of SARS-CoV2 infection

References

[1]  Susan Lee,  Paula Meyler,  et al. (2020) Can J Anaesth. : 1–7. "Asymptomatic carriage and transmission of SARS-CoV-2: What do we know?". 
[2]  Le Bert N, Tan AT, Kunasegaran K, et al. (2020)  "SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls." [published online ahead of print]. Nature. 2020;10.1038/s41586-020-2550-z. doi:10.1038/s41586-020-2550-z.  
See also  Ruairi J. Mackenzie, Science Writer for Technology Networks (2020) “'Common Cold' Coronaviruses Could Help Produce Anti-SARS-CoV-2 Immune Cells." 
[3]  Fang-Ying Liang, Leng-Chieh Lin, (2013  J Virol Methods;187(2):413-20. "Immunoreactivity characterisation of the three structural regions of the human coronavirus OC43 nucleocapsid protein by Western blot: implications for the diagnosis of coronavirus infection. "





COVID is not retreating

Easing the Lock-down-2

(COVID-19 is no longer retreating)

     Using governmental data  for the "new UK cases each day", the numbers have been declining markedly since I started logging them on the 1st of May.  Then we were getting 6000 new cases per day, now only 500 - 700. 
     Now, if there are fewer active cases in the community there should be fewer new cases; i.e. the decline should be exponential, or logarithmic, like a cooling curve.  So, in the Figure below I have plotted the logarithm of the daily increment in UK cases against days (since the 1st of May, so 85 is the 24th July). (A value of 3.0 would mean 1000 new cases per day (1000=10^3); a value of 2.0 means 100 new cases per day (100=10^2).) 
    The data from 1st May to the 24th June are coloured blue, and fit a logarithmic decline. However, the data from 30th June to the 24th July, coloured red, show that the disease is no longer on the decline. We are in steady-state. 
     At the worst there could be a "second-wave", as we have been warned; at the best we shall live like this indefinitely, or until there is an effective and safe vaccine.


Semi-log plot of new cases per day in UK
(See text for details)

20 July 2020

SARS-CoV2


SARS-CoV2

    After looking briefly into coronaviruses in general (see previous post), I have turned to SARS-CoV2, the virus responsible for the current pandemic of the respiratory infection called COVID-19.


Interesting aspect at this stage in the pandemic include:

  • Important biochemical and biological differences between SARS-CoV2 and SARS-CoV viruses.
  • Hight infectivity; 100 or 1000 times higher than SARS-CoV.
  • Why are 30-40% of infected  'carriers' symptom-free?


Difference between SARS-CoV2 and SARS-CoV(1) that might cause higher infectivity.

    SARS-CoV2 is said to be 1000 time more infectious than SARS-CoV1; a pretty loose statement, but there is some biochemistry to investigate. Is this high infectivity due to:  
a.    different, more accessible or numerous, targets on host;
b.    tighter binding to target; 
c.     epidemiological factors like shedding before or without symptoms, or more coughing and sneezing; 
d.    better evasion of host responses. 


[a] Target on host

    The host receptor for both SARS-CoV and SARS-CoV2  seems to be the dimeric membrane-bound protease called ACE2 (for Angiotensin Converting Enzyme 2). There is a small mystery here, as the first investigators found very little ACE2 protein, or mRNA, in human lung tissue, though lots in arteries, gut, kidney, testes and elsewhere [1]. Yet SARS-CoV2  seems to attack the lower respiratory tract (as well as gut, blood-cells, kidney, etc). This was so important that the question was re-examined and some ACE2 was found in lung tissue, particularly around arterioles [2].  (It is notable, however, that SARS-CoV2  can cause diarrhoea and kidney damage [3].) Other coronaviruses act primarily as gut pathogens (See previous blog). I worried that the polyclonal antibody used by Hamming to test the presence of ACE2 (which was reared against a stretch of 19 amino acids distinctive to ACE2) might cross-react and mislead. However, it seems to be universally accepted that the receptor for SARS-CoV2  is ACE2.


[b] Tighter binding of Spike to Target.

    The spike protein is not highly conserved; the opposite rather, and it seems likely that mutations, deletions and insertions in spike can affect host range; possibly infectivity as well. There are distinctive features in the spike protein of SARS-CoV2 not found in SARS-CoV spike.  Thus, there is an insert of 4 amino acids (PRRA) into the sequence, which generates a cleavage site absent from the spike protein of SARS-CoV and several other coronaviruses (but present in MERS!). 
                                                                                ↓            
            SARS-CoV2: CASYQTQTNSPRRARSVASQSI
            SARS-CoV  : CASYQTQTNS­­– – – –RSVASQSI
Cleavage is effected by a host protease present cytoplasmically throughout the body. It is a 'subtilisin-type' calcium-dependent protease (called furin), which cleaves after the marked serine residue, but the cleavage site is flagged by the paired basic amino acids (–R+R+–). The furin enzyme is obviously present to service host proteins. But SARS-CoV2 is not unique among viruses in using it for pathologicial purposes, for furin also operates in the activation of: HIV, influenza, dengue fever, Marburg virus, papillomavirus, and even anthrax toxin. It is suggested that processing of progeny virions before release may facilitate the spread of virus (c.f. SARS-CoV)[4]. 
    The spike protein of SARS-CoV2 operates as two peptides (S1 and S2) formed into a trimeric "clove-like" structure.  Tai et al. (2020) were able to compare the binding (to human ACE2) of SARS-CoV2 spike with that of SARS-CoV spike, and found it bound 9 time more tightly. (Interestingly, it bound even more tightly to bat ACE2). [5] 


[c] Epidemiological factors.

     It is important to distinguish pre-symptomatic from truly a-symptomatic carriers; both categories of infected subjects experience no symptoms, but in the former case they eventually develop symptoms, while in the latter they never do. When I use the term 'asymtomatic' in this post it will always mean that the subject did not develop sysmptoms, in at least 4 weeks. Both categories can spread the disease.
    Compared with SARS-CoV of 2003, SARS-CoV2 causes more cases with mild (or very mild) symptoms, and larger numbers stayed at home in the community. There was also twice as long incubation period before the appearance of symptoms (4–12 days). Similarly relevant for the spread of the disease, the new strain can shed infective particles as soon as symptoms appear; or even before (see above). And they can continue shedding for 3 weeks [6].   Susan Lee et al. [7] mentions a family in Anyang (China) where an asymptomatic carrier tested positive for the virus and infected 5 family members. 
    Other factors of obvious relevance to infectivity are propensity to cough or sneeze. 


[d] Evasion of host defences.

    Two recent well referenced summaries are by Indwiani Astuti and Ysrafil [8] and Swatantra Kumar et al. [9]


 References


[1] Donoghue, M., Hsieh, F. et al. (2000) Circulation Research. 87:e1–e9; "A Novel Angiotensin-Converting Enzyme–Related Carboxypeptidase (ACE2) Converts Angiotensin I to Angiotensin 1-9".
[2] Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H.  (2004)"Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis." J Pathol.; 203:631-637. doi:10.1002/path.1570
[3] Martinez-Rojas, M.A. et al. (2020) "Is the kidney a target of SARS-CoV-2?"; Am J Physiol Renal Physiol.; 318:F1454-F1462.
[4] Coutard, B., Valle, C. et al  (2020)
Antiviral Res.; 176: 104742. "The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade."
[5] Tai, W-B. He L.,  Zhang, X-J. et.al. (2020) Cellular & Molecular Immunology volume 17, 613–620. "Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine"
[6] Petersen, E., Koopmans, M. et al (2020).Lancet, Infectious Diseases, https://doi.org/10.1016/ S1473-3099(20)30484-9 "Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics.".
[7] Lee S, Meyler P, Mozel M, Tauh T, Merchant R. "Asymptomatic carriage and transmission of SARS-CoV-2: What do we know?"  Can J Anaesth. 2020;1-7. doi:10.1007/s12630-020-01729-x
[8]  Indwiani Astuti & Ysrafil, (2020) Diabetes Metab Syndr. 2020 July-August; 14(4): 407–412.
Published online 2020 Apr 18. doi: 10.1016/j.dsx.2020.04.020 "Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response"
[9]  Kumar S., Nyodu R., Maurya V.K., Saxena S.K. (2020) Host Immune Response and Immunobiology of Human SARS-CoV-2 Infection. In: Saxena S. (eds) Coronavirus Disease 2019 (COVID-19). Medical Virology: From Pathogenesis to Disease Control. Springer, Singapore. Published online 2020 Apr 30. doi: 10.1007/978-981-15-4814-7_5


09 July 2020

Corona Viruses

Corona Viruses

(Some notes on Coronaviridae to put SARS-CoV2 into context)

Coronaviridae – the Corona Virus family

     The name “corona virus”, and the biological family name Coronaviridae, were coined in 1975 by Tyrrell and co-workers. However the viruses had been discovered ten years earlier, in 1965 by Tyrrell et al., and independently (in 1966) by Hamre & Procknow, in tissue or organ cultures inoculated with material from volunteers with “common colds” [1]. The salient features at this stage were [a] RNA viruses, [b] ether-sensitive (so with a lipoid envelope), [c] cultivable in cultured human tissue or organ cultures but not in fertilised chicken’s eggs, [d] isolated from volunteers with mild upper-respiratory tract infections [1].
     With the electron microscope it was possible to visualise particles of 80 to 150 nm diameter (c. 10-4 mm), decorated with widely spaced club-shaped knobs, or ‘spikes’; this picture has become well-known the world over during the pandemic of SARS-CoV2 of 2019/2020 [1].  (It has been suggested that the name refers more to a solar corona than directly to a crown or coronet.)
    Considerable progress was made between 1965 and 2002 in understanding the biology of the these ubiquitous viruses that caused mild disease symptoms. Especially studied were two strains called OC43 and 229E. The continuous RNA strand is approximately 30,000 bases long, single-stranded and is in the ‘positive’ orientation (so it can be directly translated into protein, 5’-terminus of RNA corresponding to NH2-terminus of protein).  Like other RNA viruses, the genome is susceptible to frequent mutations. Immunity of the host tends to be transient, so an endemic strain of virus (like 229E in the USA) can cause wave after wave of epidemic disease in a population, recurring every 2-3 years [1].

Taxonomy and Evolution

     It is now believed that corona viruses are very ancient in evolutionary terms, having been around some 300 million years, i.e. as long as their bat and bird hosts [2]. Identification and taxonomy are both based on cloning up complimentary DNA using quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR), employing primers synthesised to match highly conserved parts of the genome; often in the RNA-dependent RNA polymerase (RdRP), coded at the overlap of the two large open reading frames (See Figure below). There are now held to be 4 genera of viruses in the family Coronaviridae (see Table). 

Table


Figure [See ref. 3]



    With the outbreak of Severe Acute Respiratory Syndrome (SARS) in China in 2003, interest in the Coronanviridae intensified. This was a dangerous disease with average fatality of those infected of around 10%, and much higher for the elderly. It spread readily from human to human by droplet infection, and indirectly by touching contaminated surfaces. It was found to be caused by a new coronavirus, named SARS-CoV. This strain is related to bat viruses, but seems to have jumped to a human from a palm civet [3]. Cases were eventually reported in 29 countries, mostly with links to east Asia. But the disease then died out. Apart from a small escape-infection from a Chinese laboratory in 2004 it has not been seen since, anywhere in the world. 
    In 2013 another novel coronavirus disease broke out in the Middle East with an even higher mortality rate of 35%. This Middle East Respiratory Syndrome (MERS) has remained confined to the Middle East, where it lingers still (some 14 cases were reported in the first 5 months of 2020). While SARS-CoV seems to have jumped from bat to man via civet cats, the MERS virus seems to have jumped via the dromedary camel, which may explain its restriction to Saudi Arabia and neighbouring countries.  It has been endemic in camels for at least 3 decades [3].
    Over the last 17 years, intense study of the SARS-CoV virus  (which for clarity I shall sometimes call SARS-CoV1) has laid the foundation of our knowledge of SARS CoV2, the closely related agent of our present COVID-19 pandemic. I shall therefore expand a bit on the biology of SARS-CoV1.

SARS CoV1 Molecular Biology

     This, like all coronaviruses, is an enveloped, RNA virus containing a single-stranded, positively orientated, RNA molecule of 29,751 nucleotides [4]. This RNA codes for 28 proteins: 4 Structural proteins (S=spike protein, E=envelope protein, M=membrane protein, N=nucleocapsid protein); 16 non-structural proteins, derived by cleavage from two large polyproteins; and 8 accessory proteins, so-called because they are non-essential in tissue culture, though presumably important in the wild. The 2 polyproteins are coded by Open Reading Frame 1a (pp1a) and Open Reading Frame 1b (pp1b). 
    The functions of S, M, and N are relatively straightforward; not so the multi-functional E protein:
 S, a glycoprotein expressed on the outer surface of the excreted virion, is the docking mechanism of the virus, and contains specificity for the host target site. In the case of SARS-CoV1 the target is human Angiotensin-Converting-Enzyme 2 (ACE2), which is primarily expressed in the lower respiratory tract. (The HCoV-229E S-protein is specific for the host protein CD13; the MERS-CoV spike binds to dipeptidyl piptidase, so target gut and kidney.) 
 M, the most abundant protein, and the one that defines the shape of the virion.
● N, a protein that binds the genomic RNA, (I suppose like the histones that wrap and protect our DNA). 
● E, the 'envelope' protein, contain a hydrophobic domain of 24-28 amino acids, so presumably spans the lipid membrane. It is the smallest of the structural proteins at 76 amino acids, binds to M in the virus membrane, where it may act as an ion-channel or 'viroporin' [5,6]. But a great fraction of the completed E peptides are not found in the membrane, and E seems to have several other functions. There is a PDZ-bininding-Motif (PBM) at the extreme carboxyl end of E, which suggests that it can bind to a PDZ motif on some host proteins. (Of the 320 such PDZ-containing proteins in the human, only 5 are known to bind the E protein of SARS-CoV1; (a) Na/K ATPase alpha-1 subunit, (b) stomatin, (c) syntenin, (d) PALS, and (e) BcL-xL. It is therefore easy to imagine that the virus can, by means of these protein-protein interactions, disrupt tight-junctions in the lung, and Na+ concentration in nerve and muscle, while (with syntenin) it could cause a 'cytokine storm'. [5] (See Pathology below.)
    Several of the non-structural proteins (nsp) are highly conserved. Thus, nsp1, coded at the extreme 5' end of the genome, is highly conserved between all coronaviruses, but has very little homology with anything else in protein and nucleotide data bases; it is unique to Coronaviridae. The protein, of about 20kD, may inhibit cell protein synthesis, perhaps by degrading messenger RNA.[7].  
    The RNA-dependent RNA polymerase (RdRP), coded at the junction betwee the two large open reading frames (see Figure) [8], is the enzyme that, with auxiliary proteins, replicates the genome, and creates smaller fragments of RNA that act as templates for protein synthesis [8]. RdRP is one of the most tightly conserved regions of the geneome and the primers used for diagnosis and taxonomy are usually based on sequence from this region. 

Pathology

A high proportions of cases of SARS-CoV1 (and especially of MERS) occurred among health care workers rather than close family members, from which it is can be inferred that shedding of infectious virions occurs well after the onset of symptoms and hospitalization. It was often found that, as symptoms of distress increase, viral load decreases. This suggested that part of the pathology is due to the immune response. (See also the 'cytokine storm' in Swine Flu.) A comparison between those that survive and those that succumb to severe infection points to a failure (in the latter) to switch from innate immunity to acquired immunity. [3] 

References

[1]  Kahn, Jeffrey S. &  McIntosh, K. (2005) The Pediatric Infectious Disease Journal: Vol 24, S223-S227, "History and Recent Advances in Coronavirus Discovery."
[2]  Wertheim J.O., Chu D.K.W., Peiris J.S.M., Pond S.L.K., Poon L.L.M. (2013) J Virol. 87, 7039–7045. "A case for the ancient origin of coronaviruses."
[3]  de Wit, E., van Doremalen, N., Falzarano, D., Vincent JM. (2016) Nat Rev Microbiol. ; 14: 523–534. 
[4]  Marco A., Marra, et al., (2003) Science, 300, 1399-1404
"The Genome Sequence of the SARS-Associated Coronavirus".
[5]  Wu, QingFa,  Zhang, YiLin, et al. (2003) Genomics, Proteomics & Bioinformatics, Volume 1, 131-144. "The E Protein Is a Multifunctional Membrane Protein of SARS-CoV".
[6]  Castaño-Rodriguez C, Honrubia JM, et al. (2018). mBio. 22;9(3):e02325-17.  "Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis."
[7]  Connor,  R.F. & Roper, R.L. (2007) Trends Microbiol; 15: 51–53. "Unique SARS-CoV protein nsp1: bioinformatics, biochemistry and potential effects on virulence."
[8]  Pasternak, A. O., Spaan, W.J.M., Snijder, E.J. (2006) J Gen Virol  87,1403–1421, "Nidovirus transcription: how to make sense…?"



27 June 2020

Adrenergic Angina Pectoris

Introduction

     Angina pectoris is a pain in the chest, usually attendant on exercise. It is widely thought that stable Angina pectoris is a result of Ischaemic heart disease [1]. For this there are said to be a number of 'risk' or pre-disposing factors [2]:

  • increasing age, 
  • smoking, 
  • high-fat diet, 
  • lack of exercise, 
  • overweight, 
  • excessive alcohol consumption, 
  • (other conditions, including high blood pressure, high cholesterol and diabetes, a family history of CVD, being of south Asian, African or African-Caribbean descent.)

     I shall assume that the rational man will neither smoke nor eat nor drink too much. Clearly, you cannot do anything about your increasing age, or your ethnic or familial inheritance. But I think it is highly interesting to know more about how all these factors impinge on the heart and its coronary blood supply (i.e. oxygen supply.)
    In my own case I was able to get my blood pressure and cholesterol values into the 'healthy' range by taking a low does of a statin for a few months (supplemented with CoQ to offset one of the deleterious effects of inhibiting HMGCoA synthase. [See my blog post]), and by eschewing completely the double-cream I liked to pour over my dessert. In addition I tweaked my consumption of alcohol down by 20%, and exercise up by 20% (aiming at ≧60 minutes walking per day, and running up and down stairs when a trip was required). As for 'long acting nitrates', after reading up the literature I never touched the packet of tablets I had been prescribed,  for it was clear that they cause desensitisation, and gratuitously mess with your glutathione (and all -SH groups in general). I used to carry a little vial of 'short acting' glyceryl trinitrate (GTN) tablets [see blog post 'Angina and GTN'] (as my father did, to his dying day aged 86); but I now find I can leave them behind without regret. The 'low dose aspirin' seemed counter-indicated in my case as there is no evidence of clotting [3]
     That I was prescribed a synthetic β1-blocker (Bisoprolol) interested me. What does adrenaline or noradrenaline have to do with blood flow?  They are the "fight or flight" hormones after all? As I am a minimalist when it comes to interventions, and because I had discontinued all the other pills, I first asked the doctor to halve the dose then quartered it by snapping the tiny pills in half, then stopped altogether my daily β-blocker. I was intent on lowering my adrenergic stimulation by more natural means, if at all possible.
      On the other hand, I had clear evidence that mental stress could cause me the ischaemic pain of angina in the absence of increased exercise-related oxygen demand. Resentment, aprehension, and fear all caused ischaemic chest pain even when I was physically at rest. Once, when playing the fiddle in a pub I realised that I had forgotten the second half of the tune. Suddenly, the familiar tightness in the chest; and I had to stop playing and sit down. Of course:  "the fight-or-flight response"! So, I have to look into mental stress as a cause (or even the cause) of my angina; for I can sometimes walk energetically without trouble from my heart.
     First, let us note that there are two rather similar adrenergic chemicals, adrenaline and noradrenaline; the former released into the bloodstream by the adrenal glands (and thus a 'hormone'), the latter released by nerves (and thus a 'neurotransmitter'). Both are catecholamines, both are referred to as 'adrenergic', and their activieties greatly overlap. 
    Next, let us note that there is an array of 9 (or more) closely related adrenergic receptors, all being 7-helix transmembrane proteins of the rhodopsin family, and GTP-binding-protein-linked receptors. They were divided into two basic types by Ahlquist in 1948 on the basis of affinity (alpha and beta). However, since then, a combination of gene sequencing and pharmacological analysis in transfected cells has led to the distinction of three main types: α1, α2, and β, with the identification  of  three  subtypes for each of them [4]. See table.


TABLE

Name Action Typical site

α1A       ↑Ca2+Ch artery
α1B        IP3/DAG heart
α1C        IP3/DAG (Not human)
α2A       ↓cAMP, ↑K+Ch,↓Ca2+Ch platlet, brain
α2B       ↓cAMP,↓Ca2+Ch
α2C       ↓cAMP, spleen
β1       ↑cAMP heart
β2       ↑cAMP lung
β3       ↑cAMP fat


Experiments using Endogenous Catecholamines and Pharmacological Agents.

     (1) Plunging the hand and wrist into icy water for 90 s (the 'cold pressor test') causes release of both adrenaline and noradrenaline. In healthy subjects, blood pressure rises markedly during immersion, but falls as steadily afterwards.   [5]
    (2)  In similar experiments, Monahan et al. found that, besides the increase in blood pressure, the catecholamines released by the icy-water caused pronounced vasodilatation in healthy young men (to supply the extra oxygen needed by the heart muscle), but that this effect was lost with age. Moreover, in young men, blocking α- and β-adrenergic responses mimics the effect of ageing, suggesting a critical role for an adrenergic mechanism in this ageing effect. [6] 
    (3) Nabel et al. (1988) applied the cold pressor test to healthy controls and patients with varying degrees of atherotic damage; group I healthy, group II mildly sclerotic with some smooth vessels and some damaged vessels, group III heavily sclerotic.  The catecholamine release produced vasodilation in group I. In group II the smooth segments dilated, while the damaged segments contracted. In group III only 2 smooth segments were found, but they dilated. The authors speculate that this constricting effect may represent 'altered catecholamine sensitivity' and/or a defect in 'endothelial vasodilator function'. [7]. 
    (4)  Heusch et al. (2000) review a number of indication that there is α-adrenergic coronary constriction whether evoked by cold water, exercise or emotional stress (a public speaking ordeal). Such α-adrenergic coronary constriction, augmented  by coronary endothelial dysfunction and atherosclerosis, is "powerful enough to induce myocardial ischaemia and limit myocardial function". [8]. 
    (5)  Recent studies indicate a genetic determination of α2-adrenergic coronary constriction. Apparently, a C to T polymorphism at nucleotide 825 in the gene coding for the Gβ3 subunit of G protein leads to shortening the protein by 41 amino acids and is associated with enhanced signal transduction, and hypertension, and also with pronounced sensitivity to α2-adrenergic coronary constriction.[9] Such individuals comprise 30% in caucasian populations [10].
   (6)  Experimentally, it is found that β-blockers blunt or ameliorate the pain of stable angina in 70% of cases. But not 100%.  [11]


Conclusions

     It is tempting to think that one's inherited genotype is at least partly to blame for one's angina, and that it is not entirely due to idleness and over-eating. My father had very similar angina at a similar age, and his mother also; both were lean and active people. 
     I am familiar with the autonomic nervous system going wonky in older people [12], such as sluggishness in the auto-regulation of cerebral blood pressure, and the the intense desire to urinate that leaves you as soon as you start walking. However, it seems possible that, when it comes to adrenergic effects on cardiovascular function, ageing might always mean 'sclerotic damage to endothelium', when you have the means to look for it. 
     Note [my post] that the endothelium seems to be the site of NO release from endogenous arginine, and that 'Heusch et al invoked an 'endothelial vasodilator function'. Is it the endogenous production of NO that is damaged in atherosclerosis?
     Note also [my postthat GTN seems to work by cGMP rather than cAMP, It is also the case that NO from GTN can (usually) relax coronaries even when catecholamines cease to cause coronary dilation and cause only contraction?  

References:

  1. https://www.heart.org/en/health-topics/heart-attack/angina-chest-pain/angina-pectoris-stable-angina 
  2. https://www.nhs.uk/conditions/atherosclerosis/
  3. https://www.nhs.uk/news/medication/aspirin-bleeding-risk-balances-out-lower-heart-attack-risk-worried-well/
  4. Strosberg, A.D. (1993) Protein Science, 2, 1198-1209.
  5. Silverthorn, DU, and J. Michael (2013) "Cold stress and the cold pressor test"; Advances in Physiology Education Vol. 37, 93-96.
  6. Monahan, KD., RP Feehan, et al. (2013) J Physiol. 2013; 591: 2937–2947.
  7. Nabel EG, Ganz P, et al. (1988) Circulation, 77, 43-52
  8. Heusch, G. et al. Circulation. 2000;101:689–694
  9. Circ Res..1999; 85:965–969.
  10. C. K. Naber, R. Erbel, W. Siffert.  Current Genomics (2003) Vol. 4, 337-342.
  11. Elliott, WC., JM. Stone, (1969) Progress in Cardiovascular Diseases Vol. 12, 83-98.
  12. Parashar, R., M. Amiret al. (2016) J Clin Diagn Res. 2016: CC11–CC15. "Age Related Changes in Autonomic Functions"
(Please comment direct to Cawstein@gmail.com)