Cannabis tyres

PlantI started my post-graduate scientific career as a plant biochemist (phytochemist to be more precise). Once talking to a geologist about how fascinating plants are, he replied, “plants just get in the way of the rocks,” and so I guess your interests very much depend on your viewpoint. I moved up the career evolutionary  tree from plants to clinical pharmacology, and clinical pharmacologists had one prospect in common with geologists, they also thought plants were boring. Clinical pharmacologists and geologists are both wrong.

The Flemish chemist and physiologist Jan Baptist van Helmont (1580-1644) showed his dedication to phytochemistry when he weighed a growing tree and the soil in its pot every day for five years. The tree gained weight, but the soil remained unchanged and so he concluded the increase in weight must have come from water perculating up through the roots. We know today Van Helmont was only half right. Imagine a lonely carbon atom in a molecule of carbon dioxide, minding its own business, just quietly causing climate change, when it wanders into a leaf. There photosynthesis, powered by the energy of sunlight, captures carbon from atmospheric carbon dioxide, splits water drawn up through the roots, and joins the molecular fragments together to make a substance called 3-phosphoglycerate. And from this molecule, it makes all the stuff of plants. This is itself amazing, because those vegetables you had with your dinner, that tea or coffee you just drank and the cotton vest you’re wearing, contains carbon that, a short time ago, was floating around in the air.

Proving my interests reflect my viewpoint, my early efforts with phytochemistry focused on substances called terpenes, and these still hold a fascination for me to this day. Carbon in terpenes, like all carbon in plants, ultimately came from carbon dioxide, but it’s their journey forward that interests me most. As its name implies, turpentine (or turps) used as a solvent and paint-thinner comes from plant terpenes, but that same phytochemical pathway branches out in many directions. From the same terpene origins, comes the fragrance of plants from lavender (linalool) to oranges and lemons (limonene) and pine disinfectant (pinene). Condense a few more terpenes together and you get plant sterols. Some margarines, for example, are rich in β-sitosterol, a plant sterol with cholesterol-lowering properties. Keep going, joining up more terpenes and you end up with rubber, which oozes out of tapped rubber trees as latex. Take a side branch of terpene phytochemistry starting with geraniol, which gives geraniums their aroma, and you finish up following a more notorious route to cannabidiol. All these substances are towns and villages along the same photochemical road, where you can stop and sample, or carry on to the next destination.

So next time you watch that TV traffic cop show, where boy racers have burned rubber and provided a positive test for cannabis, remember as they put the cuffs on the miscreants, the rubber in the tyres and the weed they smoked have an unseen phytochemical connection. Now tell me that’s boring – I dare you.

Ammonium nitrate: a Jekyll and Hyde chemical

Please donate to the appeal if you can, as hospitals are reporting they are unable to treat further casualties as hundreds of beds immediately filled up following the blast.

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Beirut explosionThe explosion which rocked Beirut’s Port was almost certainly caused by inappropriate storage of 2,750 tons of ammonium nitrate. But what is ammonium nitrate and why is it dangerous and yet used so widely?

Often called the elements of life, carbon, hydrogen, oxygen, sulphur and nitrogen, combine in the most stupendously complex ways, to make proteins, and with the absence of sulphur, DNA, which controls the biochemistry of all species on Earth. Photosynthesis captures elemental carbon, hydrogen and oxygen to make the stuff of plants, which then journey through the animal kingdom from insects to elephants, and even you and me. Nitrogen is a little different because some plants draw it up through their roots and others fix the element from out of the atmosphere. Either way, nitrogen is essential to plant growth, which is why the nitrogen fertiliser market is worth around $55 billion per year. Plant nitrogen sources come in two types, ammonia and nitrate. Ammonia (NH4) is the chemically reduced form of nitrogen, and nitrate is the oxidised form, NO3. Ammonium nitrate NH4NO3, therefore, has both the oxidised and reduced forms of nitrogen in the same molecule, which is why it’s so popular as a fertiliser. But containing both the oxidised and reduced forms also makes it a very odd compound, one which according to some interpretations of its chemistry, should not exist. Put this ghost-like chemical existence together with the fact that nitrogen is omnipresent in explosives and you get some idea of why I’ve called it a Jekyll and Hyde chemical.

Chemical bonds within certain nitrogen based compounds can release large amounts of energy with explosive capacity. Take, nitroglycerine, trinitrotoluene (TNT) and nitroamine in C4 as just three well-known examples. Ammonium nitrate is not in the same explosive category, but those high energy nitrogen bonds are nevertheless present. Sitting on a pivot between its reduced and oxidised forms, ammonium nitrate decomposes to nitrous oxide gas (NO2) and water when it gets hot, then as the temperature increases in turns to nitrogen, oxygen and water. These reactions are exothermic, in that they release heat and under right (or wrong) conditions, a chain reaction runs away releasing the gases with explosive power. The principle gas, nitrogen dioxide, is what caused the brown plume after the Beirut explosion, a characteristic telling chemists ammonium nitrate was involved even before it was announced.

Providing ammonium nitrate is stored and handled correctly, it presents little risk, evidenced by the fact farmers all over the world safely hold stocks as fertiliser. Do it wrong however, and you can get into big trouble. In 1921 in Oppau, Germany, a store of around 4.5 kilotons of ammonium nitrate set hard after it became wet. Workman, tired of using pickaxes to break it up, turned to dynamite. The resulting explosion killed an estimated 700 people and obliterated the town. Other ammonium nitrate explosions across the world have killed several thousand people over the years and in every case, the ultimate cause was poor handling or storage of the chemical.

Chemists can make ammonium nitrate intentionally explosive by mixing it with diesel fuel. It’s used as an industrial explosive known as ANFO (Ammonium Nitrate Fuel Oil) in mining and quarrying, but it also became a readily accessible favourite of the IRA in the 1970s and 1990s. Timothy McVeigh and Terry Nichols used the same mixture in the Oklahoma bombing of 1995.

If you’ve eaten any bread recently, it’s a good bet the nitrogen in the wheat came from ammonium nitrate. But if food production is the Dr Jekyll side of that chemical, its explosive potential is the Mr Hyde, be it deliberate terrorism, or chemical incompetence.

What is interferon and is it effective against Covid-19?

A blog post for the non-expert

Our best hope against Covid-19 is an effective vaccine, and efforts in that direction are galloping along like no other time in history. There are so many vaccines being investigated, it’s hard to keep up with the numbers, but at the time of writing there appear to be well over 100, with around 40 in active clinical trials. Despite a lot of dangerous nonsense circulating the internet that Bill Gates wants to control our DNA through microchips implanted via vaccines, in reality they are without doubt the most successful weapon in humankind’s fight against infectious disease. The adage that vaccines “prime the immune system against infection” hides an incredible biochemical complexity, that’s truly mind-blowing. If you want a simplistic, but more accurate description of what a vaccine does, I’d describe them as “interjecting into the body’s biochemistry to up-regulate the immune system against an infecting organism”. More accurate perhaps, but, I’ll grant, less catchy.

It’s undoubtedly true, Covid-19 is likely to remain as disruptive and destructive as ever, until one, or more, of those vaccines comes through. In the meantime however, scientists are also investigating drug-based approaches to alleviate symptoms and save the lives of those infected. Now and again one of these drugs, such as dexamethasone hits the headlines but there’s one reported recently, albeit behind the headlines, which, like a vaccine, interjects into the complexity of the immune system to exert its therapeutic effect – and that’s interferon.

As ever, we have to be cautious of the claims because so far we only have a press release (I blogged on science by press release previously) but interferon is currently used to treat, for example, viral infections in asthma patients and so does have an established track record. There are two sides to understanding the effectiveness of any drug, the mechanism by which it works, and to what extent it improves patient recovery. Let’s look at the mechanism first. 

Interferon is a protein, and since I’ve blogged on the complexity of proteins before, I’ll not repeat it here. There are three types of interferon, alpha (α), beta (β) and gamma (ɣ), but the one of interest here is β-interferon. It comprises 166 amino acids along with attached sugars (see image). In the immune army, interferon belongs to the signal corps. As virusesInterferon attack, cells release interferon sounding a warning bell to other cells that a virus is on the rampage. Cells receiving the message switch on genes to up-regulate antigen presentation, which essentially means they present the immune system with something to attack. Antibodies are then made against the antigen, which place flags on the viral particles for an army of white cells to attack and destroy. All well and good, but some viruses have evolved ways to block interferons, like jamming the signal corp’s radios so they can’t communicate. The virus causing dengue fever, for example, is well known for this assault on interferon and there’s evidence SARS-CoV-2 can do something similar. Introducing additional β-interferon directly into the lungs through a nebuliser, so the hypothesis goes, restores the balance and the signals can get through once more.

The theory appears sound, but how effective is β-interferon against Covid-19 in practice? Evidence to date comes from a single study of 101 patients randomised between those receiving β-interferon (code named SNG001) and those receiving a placebo. The study was conducted by Synairgen plc who reported patients receiving β-interferon were, on average, released from hospital 3-days earlier than those on a placebo. Recovery over 28-days was almost four-times higher with β-interferon although it had little effect on the death-rate. The key findings are in the company’s press release.

Media emphasis has been on Covid-19 death rates but the virus also causes much suffering and leaves some survivors with significant medical problems. Until an effective vaccine does come along, drugs such as β-interferon and aforementioned dexamethasone, which at first sight may seem to have limited efficacy, nevertheless have a potentially important role in the fight against the most severe symptoms. There are also other drug regimens emerging, such as administration of multiple therapies. One recent study looked at combining β-interferon with ritonavir and ribavirin, for example. 

As cells receive interferon’s viral distress call, it can induce flu-like symptoms, which on top of those of Covid-19 is certainly problematic. But small steps are welcome during a pandemic and it nevertheless gives reason for optimism.

Covid-19 was genetically-engineered

A Covid-19 blog post for the non-expert

Germ warfareThe story that Covid-19 is a genetically-engineered virus from a Wuhan laboratory has gone viral across the internet (dated pun intended). President Trump implied it, and the Daily Express ran a 10th March headline, “Coronavirus may have been genetically engineered for the efficient spreading in the human population, a bombshell new study has claimed.” The article was withdrawn soon after.

The title of this post is deliberately provocative, and it may attract conspiracy theorists, so I’ll say up front, there is no evidence whatsoever SARS-CoV-2, the causative virus for Covid-19, was genetically engineered in China, or anywhere else. Instead, everything points towards completely natural origins which Charles Darwin would recognise (and probably say, “I told you so”). If you’re not a conspiracy theorist and you want to know why I’m confident this is the case, read on.

Everyone has heard of Covid-19 (caused by SARS-CoV-2),  Middle East Acute Respiratory Syndrome (caused by MERS-CoV) and Severe Respirator Syndrome (caused by SARS-CoV). These are well known because the infection spread across multiple countries but there have been four other, less infective and therefore less well known outbreaks, HKU1, NL63, OC43 and 229E. In all seven cases, the coronavirus jumped from an animal species into human. How do we know this? It goes back to the genetic code and Darwinian evolution.

The molecular structure of DNA comprises bases called purines and pyrimidines pointingDNA inwards from a double helical backbone of phosphate and deoxyribose sugar. There are two purines called adenine and guanine and two pyrimidines called thymine and cytosine. The DNA molecule is constructed somewhat like a child’s magnetic building kit, where north and south poles of magnets stick together to make a cube or a pyramid, or other similar shape. The child soon discovers that although north and south poles stick together, north-north or south-south poles repel. They can’t build their pyramid from magnets joined with like-poles, no matter how hard they try. Like north and south poles of magnets, bases of DNA can only join pyrimidine to purine, never pyrimidine to pyrimidine or purine to purine. In fact, they are more specific than that, because adenine (A) always bonds to thymine (T) and guanine (G) always bonds to cytosine (C). The sequence of A-T and G-C in DNA forms the genetic code, and is collectively known as the genome. It encodes for all the processes of life that makes everything from viruses to you and me. (There are some great animations on DNA and its function here).

How does a sequence of A-T and G-C go to make the complexity of all life? The DNA helix unwinds and makes ribonucleic acid (RNA) from the A, T, G, C template. RNA is like DNA except it has ribose instead of deoxyribose, and instead of thymine it has another base called uracil. Putting aside the complexities of the three types of RNA (messenger – mRNA, transfer – tRNA and ribosomal – rRNA) the molecule translates the A,T, G,C code into a series of amino acids. Each amino acid is coded by a sequence of 3 bases, GGT, for example, codes for the amino acid, glycine. By joining together long strings of amino acids, we make proteins and proteins control all the biochemistry of life. To quote from a previous blog post:

“Proteins are hugely complex molecules made from strings of up to 20 distinct types of amino acids. Some proteins contain hundreds or even thousands of individual amino acids; the muscular protein, titin has 30,000 of them. The long strings of amino acids fold like tangled pieces of string but unlike string, the tangles are very precise. Proteins have molecular grooves and pockets where specific biochemical reactions take place. The grooves and pockets are analogous to spanners and wrenches in a biochemical tool kit, each fitting a particular sized nut or bolt in building the machinery of life.”

Coronaviruses take a shortcut that leaves out DNA, and goes directly to RNA, but it’s still the sequence of bases which codes for viral existence. It takes over the genetic machinery of mammalian cells, mostly human lung cells in the case of SARS-CoV-2, to make viral proteins, which builds lots of new viruses. The human cells are destroyed in the process, giving us the symptoms of Covid-19. If you wanted to engineer a coronavirus pandemic, then you would have to start with its RNA and it’s the same genetic sequence that tells us SARS-CoV-2 was made by mother nature herself.

Coronaviruses jump from one species to another, making them so called zoonotic viruses, but this isn’t that uncommon. In fact perhaps three quarters of all viruses are zoonotic, or at least transmitted through a vector, such as mosquitoes. SARS-CoV-2 most probably started out in horseshoe bats, based on a 96% identical RNA sequence to the RaTG13 virus endemic in that species. There is also a related RNA sequence in SARS-CoV-2 implicating the scaly anteater, called a pangolin, as an intermediary species before infecting humans. The origins of SARS-CoV-2 are written right there in its genetic code but we have to be careful because there’s much we don’t know about viruses carried by the thousands of mammalian species across the world. We do know that the vast majority of species-hops, result in a cul-de-sac for the virus and it’s only extremely rarely that a virus jumps into humans and then is able to transmit human to human. It seems however, a mutation in RaTG13 to SARS-CoV-2 is one of those rare cases.

But what about the 4% difference in RNA between RaTG13 and SARS-CoV-2, where did that come from? The genome of RaTG13 changed for the same reason the genome alters in any organism. Random changes as imperfections in the RNA→protein process arise as mutations. Some mutations are fatal and the organism dies, and some give it a small advantage so it perpetuates through the generations. Once a chance mutation in RaTG13 RNA gave it the advantage of human to human transmission – it then thrived giving us Covid-19. This random mutation, followed by biological selection is what defines Darwinian evolution. It’s happening all the time, it’s just we don’t see it until there’s a pandemic.

Not all parts of any genome are equally susceptible to mutation and one notable region of the SARS-CoV-2 RNA is particularly prone to variation. This is the region which codes for the so-called spike protein that recognises a receptor on the mammalian cell enabling it to enter that cell and infect it. It’s this variable region of RNA in coronaviruses generally that gives them their nasty species-hopping talent. From analysis of the RNA sequence, all seven coronavirus outbreaks likely originated from other mammalian species through variations in RNA coding for spike proteins. By looking at the RNA sequence in this variable region we know, both MERS-CoV and SARS-CoV, like SARS-CoV-2, most likely originated in bats, while the milder HKU1 coronavirus originated in mice and OC43 likely came from cattle. Scientists have identified precise changes in RaTG13 RNA and the corresponding amino acid sequence alterations in the spike protein which transformed it to SARS-CoV-2, enabling it to latch onto a human cell-surface protein called ACE leading to infection (I blogged about ACE previously). From the rate of coronavirus mutation, we can estimate this mutation probably occurred sometime in the last 40 to 70-years. There’s nothing unusual in the way RaTG13 mutated to SARS-CoV-2 and, indeed, it’s exactly what you would expect it to do, given the right opportunity as humankind expands into previously uninhabited ecosystems.

Worryingly, the mutation which gave us SARS-CoV-2 does not optimise the spike protein’s infectivity and so Covid-19 is actually a milder disease than nature might have given us. Even more worryingly, a variant was recently identified where another change in the variable spike protein region has increased SARS-CoV-2’s potency. The trouble is, a single error in copying the virus’s 30,000 base pairs in the RNA code can result in replacement of one amino acid in the protein for another, thereby changing the protein’s functionality. Where GGT codes for glycine, for example, just one changed base to GCT now codes for the amino acid alanine.

The problem with all conspiracy theories, be it genetically engineered SARS-CoV-2, or fake moon landings, they use a simple lie to hide the complex truth. As soon as you get below the surface, conspiracy theories lack detail and rely instead on the idea of vast networks of people, all somehow holding on to the dastardly secret. Like all the world’s virologists and molecular geneticists conspiring to keep genetically engineered SARS-CoV-2 from the unknowing public. And the fact I’ve just explained the natural process by which SARS-CoV-2 arose, just makes me part of the conspiracy. I’d like to explain more, but I’m scheduled to attend an illuminati meeting in Atlantis, so I’ll see you next time.

Murder and Atoms

Richard Hill and fellow hikers were walking in the Yorkshire Dales, about an hour’s drive from where I live, when they stopped to take a photograph. He stood by a stream near to the Sell Gill Holes caves in Pen-y-ghent but didn’t notice, just behind him, was the face-down body of a half-naked woman. They were two kilometres from the nearest road and the body had likely been dumped on higher ground one to two weeks earlier, before being washed down by torrential rain over the previous 24-hours.  It was the decomposing body of a 25-35 year old woman wearing green Marks and Spencer jeans, socks and a wedding ring. This was back in 2002 and an E-fit picture and police enquiries made at that time turned up nothing. Oddly, no one meeting her description had been reported missing anywhere in the country.

Locals affectionately called her the Lady of the Hills, they gave her a funeral and buried her in the village cemetery. The case went cold, until the new forensic technique of stable isotope analysis arrived on the scene. 

The chemical elements listed in the periodic table are defined by the number of protons in their nucleus, one for hydrogen, two for helium, and so on until the 92 protons of uranium. Although atoms of any given element always have the same number of protons, they can have different numbers of another sub-atomic particle, the neutron. All hydrogen atoms for example, have one proton but one in 6,250 also has a single neutron and about one hydrogen atom in a quintillion has two neutrons. This subclass of elements, defined by the number of neutrons, are called isotopes. Those hydrogen atoms with one proton are an isotope of hydrogen called protium. Those atoms with one proton and one neutron are an isotope of hydrogen called deuterium. Those atoms with one proton and two neutrons are an isotope of hydrogen called tritium. And as the atom packs in more neutrons, so its mass increases, protium with a mass of one, deuterium with a mass of two and tritium with a mass of three. Chemists identify which isotope is which from its atomic mass, including it as a superscripted prefix to the elemental symbol, such as, 1H for protium, 2H for deuterium and 3H for tritium. The periodic table, that we are all familiar with, lists only the elements themselves but behind each of the elemental boxes is a plethora of isotopes.

The chemistry and reactivity of isotopes of the same element are almost identical, prompting their discoverer, Frederick Soddy, to say “put colloquially, their atoms have identical outsides but different insides.” The neutron does have some effect on the behaviour of the isotope and they separate out slightly under the right conditions. Take a spoonful of water from the Arctic or Mid-Pacific ocean and the isotopes of oxygen and hydrogen will be slightly different. Water with lighter isotopes is the first to evaporate, leaving behind seas enriched with heavier isotopes in warmer climes. Pour a glass of water from your tap and the blend of 1H216O, 1H217O, 1H218O, 2H216O, 2H217O and 2H218O depends upon where on planet Earth your tap resides. Similar effects can be seen with all the isotopes to differing degrees, and as those isotopes are taken up into the body, they leave an atomic trail of breadcrumbs as to where you’ve been. Isotopes incorporated in tooth enamel is locked in for life and so reveal where you were raised as a child. Isotopes in hair reflect more recent travels.

The forensic scientist and author of a 2010 book on forensic isotope analysis, Wolfram Meir-Augenstein of Robert Gordon University in Aberdeen, arranged to have hair, teeth and bone from the Lady of the Hills analysed for isotopes of carbon (13C), oxygen (18O), hydrogen (2H) and nitrogen (15N). Those in her hair matched proportions found in North Lancashire or South Cumbria and given the rate of hair growth she must have lived close to those areas in the time immediately leading up to her death. Isotopes in teeth and bone however, indicated she was from Thailand. Was she a so called Thai bride? 

Enquiries in Thailand eventually identified her as Lamduan Armitage new Seekanya, who had married in Thailand and then moved to Portsmouth, Rugby and then to Preston in Lancashire consistent with isotope analysis of her hair. DNA comparisons with family members in Thailand confirmed her identity last year.

As with so many other cold cases, her killer has not been identified. Police have said her husband, who lives in Western Kanchanabur, Thailand, is not a suspect but the Thai Examiner expressed frustration with the investigation. The British Newspaper The Sun, is campaigning to bring the culprit, whoever that may be, to justice. 

Isotopes can only go so far but without them it’s unlikely the women buried in the Yorkshire Dales would have ever been identified. And that has to count for a lot. I hope this blog post becomes out of date quickly, and this cold case can indeed be closed.

Education through adversity

A different sort of pandemic blog post, and a rather personal one.

There are problems reopening schools, universities are going virtual and post-graduates are struggling to complete. Education is having a hard time, and many students are rightly concerned about the impact this will have on their careers. If I was in this situation, I’d be worried as well – but I want to tell my personal story because it might offer a glimmer of encouragement, at least I sincerely hope so.

I come from a very working class background. Although not so uncommon for the time, I was raised in a house without a bathroom and with an outside toilet. The bath, as it was, was in the kitchen and filled from the sole hot water tap in the house only on a Sunday night. This might sound like the start of a “Four Yorkshireman Sketch” but I tell you this because it wasn’t just the material things of life that were in short supply but an attitude to life more generally. Seen as something for other people, education was “not for the likes of us” and the only book in my home was a Bible. I failed my eleven-plus and went to a terrible secondary modern school in South East London where the highlight of the curriculum was football. My family made me leave school at sixteen with a few CSEs,* whereupon I became an apprentice plumber at the now long-gone gasworks on the Old Kent Road. It was on the number-53 bus journey to and from work, where I read my first book, the Kraken Wakes, by John Wyndham. Something inside me made me curious and, determined to get an education, I took every opportunity I could. Oddly, my lucky break was being made redundant and I ended up getting a job at the gas-appliance testing laboratory, also on the Old Kent Road. Scientist there were all too happy to show me how to calculate the efficiency of gas-appliances, which I could soon do for myself, giving me a step up in the world. One of my unofficial teachers wore leg braces because of childhood polio. That puts the times into perspective.

I went to night school to get qualifications for University but it’s a tough route and since that time I have nothing but admiration for those who choose a part-time education. I was doing well until one Saturday morning the motorbike I was riding collided with a delivery van. Smashed up very badly, I was lucky to survive. In and out of hospital for nearly three-years, somehow I kept the education going and eventually found myself an undergraduate at the ripe old age of twenty six. When I graduated, then married with one child, I managed to ignore my mother who constantly berating me to “get a proper job”, and I embarked on a PhD. This opened doors completely invisible to me in those early days. The journey took me to three adjunct professorships, some amazing experiences and, sadly, osteoarthritis from the motorcycle accident. Even so, my journey hasn’t ended and I’m still learning new things. Having been bitten by the bug of curiosity, I can never be cured of an insatiable desire for knowledge. It will stay with me until I am no more.

I’m recounting this mini-autobiography because although I’m sure there will be many students despairing for their future, if you are determined, if you have a drive for education, if that curiosity is overwhelming, you will make it in the end. It might take longer, it might be harder, but you’ll look back and be proud of an achievement through adversity. Take it from someone who’s been there, and if I can do it, believe me anyone can. Stick with it and it’ll be worth it, I promise.

* A top-grade Certificate of Secondary Education (CSE) was equivalent to a mid-grade O-level. They were replaced in 1987 with the GCSE (General Certificate of Secondary Education).

A sober look at dexamethasone

A Covid-19 blog post for the non-expert

It stared with a 16th June 2020 press release  from the University of Oxford “Low-cost dexamethasone reduce death by up to one third in hospitalised patients with severe respiratory complications of COVID-19” – which triggered the equivalent of a media cytokine storm (pun explained shortly).

I do not want, for one moment, to dowse good news when it comes to Covid-19, but medical science is progressing during the crisis by press release and so I think it worth taking a step back to understand at the time of writing, the clinical trial is unpublished and not peer reviewed. Trawl through the media, newspapers and websites, and you’ll find pretty much a rejigging of what’s in the Oxford press release. A few newspapers, such as the Guardian, took the trouble to add some interviews but overall there was no explanation of what dexamethasone is, or what it does. So I thought I’d try to address that question in this blog post.

I once attended a lecture by Sir Martin Rees, the Astronomer Royal here in the UK, who said Astronomy was a simple subject. Many in the audience expressed surprise by this but he explained he thought real complexity was in biochemistry where there were so many interactions between molecules, membranes, cells and different tissues of the body. We might one day be able to understand the Universe’s beginnings and perhaps even how it will end, but he doubted if we would ever fully understand the multifariousness nature of biochemistry. Looking at the action of dexamethasone, I think, Martin Rees is right.

The immune system is complicated – beyond Martin Rees’s astronomy complicated. There’s probably more that scientists don’t understand about the immune system than they do. It’s evolved because there’s a whole world out there intent on killing you, one way or another, and the immune system is the ultimate defending army. A key part of the immune defence is inflammation, which is difficult to precisely define in immunological terms but in a nutshell, it’s a response against an irritant, anything from a splinter to a deadly virus, or indeed in some people, nutshells. Symptoms are erythema (redness), raised temperature, swelling and pain, which in the case of a splinter are external. Inflammation can also occur internally, such as with nut allergy for example, in which case it might become life-threatening.

Inflammation results in an increase in blood flow and an influx of a wide range immune system cells, commonly called white cells. Many of these cells were identified before their action was understood and so were named after their reaction to different stains under the microscope. And so you get, for example, basophils, neutrophils and eosinophils (eosin is a pink-red dye) as well as cells types, not named after microscopic dyes, such as mast cells, monocytes and macrophages. These cells come piling into the affray, like the proverbial Fifth Cavalry in a western movie to the sound of a bugle. Infected cells, of course, don’t have a bugle, instead they communicate with the immune system through small proteins called cytokines. There are around 80 known cytokines, including interferons, interleukins and TNF. TNF stands for tumour necrosis factor (although disregard the tumour part in the current context) and it’s one of the first cytokines produced to open surrounding capillaries to increase blood flow to allow more white cells in.

This plethora of cells and cytokines, together with other factors of the immune response such as a cascade of proteins called complement and, of course, antibodies, all react with each other making the complexity of the universe look trivial. Usually this biochemical and cellular mêlée is pretty good at seeing off infection and the inflammatory response plays an important role in that process. Don’t get the idea it’s all completely chaotic because the entire operation is controlled – or regulated in biochemistry-speak, chiefly through a structure in the cytoplasm called the “inflammasome”. Sometimes however, it all gets out of control, like a scrap between two schoolboys turning into a full scale riot. The communication proteins, the cytokines, go mad, attracting more immune cells, releasing more cytokine. It’s like the schoolboy fight going viral on social media, inviting anyone who wants a scrap from miles around. This has attained the name, cytokine storm and although it doesn’t have a precise definition, it became notorious in the 2006 clinal trial with TGN1412, which went horribly wrong. The term cytokine storm (or cytokine storm syndrome) actually originated earlier from a 1993 paper concerning adverse effects of organ transplants (1).

Now enter dexamethasone. In some cases, infection with SARS-CoV-2, the causative virus of Covid-19, sends the inflammatory response into overdrive, and that is the ultimate cause of fatality. Dexamethasone is a synthetic steroid of the type produced in the cortex (outer layer) of the adrenal gland, located just above the kidneys, and hence is called a corticosteroid. Corticosteroids find receptors in cells which initiate a chain of events involving RNA and DNA, down-regulating protein synthesis, damping down production of cytokinins and calming the inflammatory response like switching off social media in the middle of our metaphorical riot. Dexamethasone comprises a molecular skeleton common to all steroids, but with a fluorine atom added. It is a very potent anti-inflammatory drug, being around 25-times more potent than cortisol, for example. (Cortisol is more associated with the “fight-or-flight” response but it also has a role in moderating inflammation and is used as a hydrocortisone cream to treat eczema and dermatitis).

Dexamethasone is a well-establish drug used to treat a wide range of inflammatory disease including allergic responses, arthritis, lupus and some breathing disorders. In many ways it’s not surprising it helps in cases of severe SARS-CoV-2-induced inflammation and so unlike hydroxychloroquine, promoted so heavily at one point, it does seem to hold a lot of promise.

It is not however, an anti-viral, it does not inhibit infection, it is not a prophylactic, but it may save lives and for that some celebration is justified.

(1) Ferrara, J. L., Abhyankar, S. and Gilliland, D. G. (1993) Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1. Transplant. Proc. 25 1216–1217

Has the scientific method been suspended?

There’s a scene in the Netflix series Space Force when Chief Scientist Dr. Adrian Mallory asks, “why do you distrust scientists?” To which General Naird angrily replies, “you scientists say don’t eat carbs one day and only eat carbs the next”. One of the scientists in the room interjects, saying, “because of the sample sizes and long time period, day-to-day science is by nature an imprecise…” Naird cuts in with a frustrated, “shut up, shut up…”

I’ve heard the criticism that science is fickle all too often and you’d certainly get that impression if your sole source of science news was from the daily press. The two philosophies, that of the press and that of science are diametrically opposite. The general press want the sensational, here and now, while science is considered and unhurried. That’s not to say science isn’t competitive and there’s often a rush to publish, but one paper very rarely initiates a scientific consensus. Science works from accumulated information over time and a consensus will only form once there’s a body of consilient evidence all pointing in the same direction. The general press however, are all too happy to pick out a single publication and present it as an uncritical headline.

One of the best examples of science through press release remains how Stanley Pons and Martin Fleischmann announced cold fusion in 1989. Amidst a media storm, scientists across the globe tried to reproduce their results based on scant information and even committed the same sin of announcing positive data through their own press releases. It all ended badly, when those claiming to confirm cold fusion found artefacts in their measurements and there was a rush, not to publish, but to retract. 

Publishing a single peer reviewed paper will not convince scientists of its truth, as evidenced by Andrew Wakefield’s 1998 press briefing and subsequent paper in the Lancet, that there’s a link between the MMR vaccine and autism. This incident did unquestionable harm to medical science’s reputation and the slow retraction and enquiry did nothing to help. Nevertheless, science moved along in the meantime, albeit with its own snail-like pace, with many studies finding no evidence of any MMR and autism link. The Daily Mail however, was still publishing MMR anecdote in 2003 while ignoring the growing body of scientific studies. Wakefield was eventually struck off by the General Medical Council in 2010.

The cold fusion and MMR cases illustrates all too well the difference between scientists, who are human, fallible and sometimes dishonest, and the objective scientific method. I’ve heard the Wakefield case, and other similar instances, given as reasons why we should distrust scientific opinion. I’ve even heard the argument they are reasons to distrust scientific opinion on anthropogenic climate change.  This is a false equivalence, of course, because unlike Wakefield, consilient evidence for climate change has been building since the first paper linking carbon dioxide to temperature back in 1896 (1) and it’s no longer an opinion but as close to scientific fact as you can get. 

Having said all that, we are living in unusual times, with a viral pandemic taking many thousands of lives. We have suspended the process of scientific consensus at times, with announcements as pre-prints or press releases ahead of peer-reviewed publications, and even retractions after the event. Although our government mantra has been, “we’re following the science,” what they really mean is they are following scientific advice and although the advice comes from of the best in their field, it’s not the same thing as following the science. This might seem pedantic, and a moot point of philosophy, but it really isn’t.  Complaints from the scientific community are numerous that the advice, and basis for that advice, is not transparent and unavailable for wider review. The extreme urgency of the situation undoubtedly pushes aside the usual scientific conservatism, which is of course understandable and sometimes on the spot decisions are necessary, without time to weigh up all expert feedback. But they do this at peril, “because of the sample sizes and long time period, day to day science is by nature an imprecise…” and the public interrupts, “shut up, shut up..” 

(1) Svante, A. 1886. “On the influence of carbonic acid in the air upon the temperature on the ground.” Philosophical Magazine and Journal of Science.

Broken Clock Fallacy

I had a terrible bout of flu in November. In fact, my wife said she’d never known me so ill. I had a fever that went up and down, aching joints, a prolonged dry cough and found it hard to breath when laying down at night. I have an oxometer which occasionally dipped below 90% accompanied by light-headedness bordering on delirium. Do the symptoms sound familiar?

I’ve spoken to a number of people who had a similar illness around the same time and there are now suggestions Covid-19 reached the UK earlier than first reported. I understand why some think this, and the possibility that my November illness was Covid-19 had crossed my mind. Furthermore, if I was a betting man, I’d put money on several people reading this blog thinking the same thing. There is however, a major problem with this assertion because there’s no evidence for it. It’s more likely November and December experienced another flu-like outbreak, certainly unpleasant but not on the scale of Covid-19.

I shouldn’t be too certain however, because if there’s one thing we know about this virus, it’s there’s a lot we don’t know about this virus. As time goes by, and our knowledge grows, the arrival of Covid-19 to the UK at the end of 2019 cannot be ruled out entirely. If this happens, there will be those shouting, “I knew it all along,” and “I told you so.”  And then we get into another problem, that of the logical fallacy.

Logical fallacies have some great names such as, there’s no such thing as a Scotsman, Texas sharpshooter and the nirvana fallacy to name just three. If you’re interested, then you’ll find a lot of them here. The fallacy covering the, “I told you so,” if Covid-19 did arrive early, is called the broken clock. Those making the claim had no basis or evidence for it at all, but can claim they were right after the event on the basis even a broken clock is right twice a day. Fallacy spotting can be fun, but also very frustrating at times. 

A scientific tightrope

The two most senior scientific advisors to the UK, Sir Patrick Vallance (Chief Scientific Advisor) and Professor Chris Whitty (Chief Medical Officer) have come into a lot of criticism recently for failing to say what they really believe regarding the Government’s response to the Covid-19 outbreak. As Civil Servants they are meant to be impartial and have steadfastly refused to be drawn into the politics. Some think this is a good thing, others not so much 

I thought I would recount an episode of my own career, which was not as pivotal to national safety by any means but tells a story of how a scientists can become conflicted between honesty and loyalty.

I ended my commercial days as the Chief Scientific Officer of a blue-chip company based in York, UK and Maryland USA. It was my job to give scientific advice on the commercial direction of the company and I helped Business Development present scientific options to potential clients. I needed diplomacy in that job and walking the tightrope between intellectual honesty and the company’s commercial goals was a tricky balancing act. I did it as best I could, although one person in Business Development (who I now consider a good friend) once said I suffered from “wise guy Tourettes”.

There was an occasion however, where the company started to sell a particular option which I believed was not viable. In fact I emailed the CEO explaining my concerns, and received the curt response, “solutions not problems.” It was a tough time because I was expected – indeed instructed – to sell this option even though I knew it wasn’t possible to deliver. I refused to do so, but dodged the inevitable bullet until one day I was on the podium at a conference in the USA, where the CEO presented this non-viable option to the audience. The participants, all experienced scientists, were skeptical and one asked me directly if I agreed. I decided the time had come and said, “no I don’t”. As you can imagine there were repercussions and I was prepared to lose my job. As it happened, other events interceded and I got away with it and this particular option was never actually sold.

This experience makes me empathise with Vallance and Whitty because their tightrope is a lot tighter than mine ever was. I recognise their careful responses to certain questions as the sort of bullet dodging answers I gave. The impact of one of them breaking ranks and defying the government however, would be much more far-reaching than me losing my job and so I understand how they continue to walk that tightrope.  There might come a time however, where scientific integrity overbalances and they have to take a stand. Perhaps the government going against SAGE’s advice to open schools might be one of those times, who knows?