Research

On rejection by editors and society

by reestheskin on 16/11/2020

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The history of science is the history of rejected ideas (and manuscripts). One example I always come back to is the original work of John Wennberg and colleagues on spatial differences in ‘medical procedures’ and the idea that it is not so much medical need that dictates the number of procedures, but that it is the supply of medical services. Simply put: the more surgeons there are, the more procedures that are carried out1. The deeper implication is that many of these procedures are not medically required — it is just the billing that is needed: surgeons have mortgages and tuition loans to pay off. Wennberg and colleagues at Dartmouth have subsequently shown that a large proportion of the medical procedures or treatments that doctors undertake are unnecessary2.

Wennberg’s original manuscript was rejected by the New England Journal of Medicine (NEJM) but subsequently published in Science. Many of us would rate Science above the NEJM, but there is a lesson here about signal and noise, and how many medical journals in particular obsess over procedure and status at the expense of nurturing originality.

Angus Deaton and Anne Case, two economists, the former with a Nobel Prize to his name, tell a similar story. Their recent work has been on the so-called Deaths of Despair — where mortality rates for subgroups of the US population have increased3. They relate this to educational levels (the effects are largely on those without a college degree) and other social factors. The observation is striking for an advanced economy (although Russia had historically seen increased mortality rates after the collapse of communism).

Coming back to my opening statement, Deaton is quoted in the THE

The work on “deaths of despair” was so important to them that they [Deaton and Case] joined forces again as research collaborators. However, despite their huge excitement about it, their initial paper, sent to medical journals because of its health focus, met with rejections — a tale to warm the heart of any academic whose most cherished research has been knocked back.

When the paper was first submitted it was rejected so quickly that “I thought I had put the wrong email address. You get this ping right back…‘Your paper has been rejected’.” The paper was eventually published in Proceedings of the National Academy of Sciences, to a glowing reception. The editor of the first journal to reject the paper subsequently “took us for a very nice lunch”, adds Deaton.

Another medical journal rejected it within three days with the following justification

The editor, he says, told them: “You’re clearly intrigued by this finding. But you have no causal story for it. And without a causal story this journal has no interest whatsoever.”

(‘no interest whatsoever’ — the arrogance of some editors).

Deaton points out that this is a problem not just for medical journals but in economics journals, too; he thinks the top five economics journals would have rejected the work for the same reason.

“That’s the sort of thing you get in economics all the time,” Deaton goes on, “this sort of causal fetish… I’ve compared that to calling out the fire brigade and saying ‘Our house is on fire, send an engine.’ And they say, ‘Well, what caused the fire? We’re not sending an engine unless you know what caused the fire.’

It is not difficult to see the reasons for the fetish on causality. Science is not just a loose-leaf book of facts about the natural or unnatural world, nor is it just about A/B testing or theory-free RCTs, or even just ‘estimation of effect sizes’. Science is about constructing models of how things work. But sometimes the facts are indeed so bizarre in the light of previous knowledge that you cannot ignore them because without these ‘new facts’ you can’t build subsequent theories. Darwin and much of natural history stands as an example, here, but my personal favourite is that provided by the great biochemist Erwin Chargaff in the late 1940s. Wikipedia describes the first of his ‘rules’.

The first parity rule was that in DNA the number of guanine units is equal to the number of cytosine units, and the number of adenine units is equal to the number of thymine units.

Now, in one sense a simple observation (C=G and A=T), with no causal theory. But run the clock on to Watson and Crick (and others), and see how this ‘fact’ gestated an idea that changed the world.

  1. The original work was on surgical procedures undertaken by surgeons. Medicine has changed, and now physicians undertake many invasive procedures, and I suspect the same trends would be evident.
  2. Yes, you can go a lot deeper on this topic and add in more nuance.
  3. Their book on this topic is Deaths of Despair and the Future of Capitalism published by Princeton Universty Press.

A carry-on of professors

by reestheskin on 11/11/2020

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There was a touching obituary of Peter Sleight in the Lancet. Sleight was a Professor of Cardiovascular Medicine at Oxford and the obituary highlighted both his academic prowess and his clinical skills. Hard modalities of knowledge to combine in one person.

Throughout all this, at Oxford’s Radcliffe Infirmary and John Radcliffe Hospital, Sleight remained an expert bedside clinician, who revelled in distinguishing the subtleties of cardiac murmurs and timing the delays of opening snaps.

And then we learn

An avid traveller, Sleight was a visiting professor in several universities; the Oxford medical students’ Christmas pantomime portrayed him as the British Airways Professor of Cardiology. [emphasis added]

This theme must run and run, and student humour is often insightful (and on occasion, much worse). I worked somewhere where the nickname for the local airport was that of a fellow Gold Card professor. We often wondered what his tax status was.

Breaking bad

by reestheskin on 02/11/2020

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From this week’s Economist | Breaking through

Yet nowhere too little capital is being channelled into innovation. Spending on R&D has three main sources: venture capital, governments and energy companies. Their combined annual investment into technology and innovative companies focused on the climate is over $80bn. For comparison, that is a bit more than twice the R&D spending of a single tech firm, Amazon.

Market and state failure may go together. Which brings me back to Stewart Brand’s idea of Pace Layering

Education is intellectual infrastructure. So is science. They have very high yield, but delayed payback. Hasty societies that can’t span those delays will lose out over time to societies that can. On the other hand, cultures too hidebound to allow education to advance at infrastructural pace also lose out.

Pace Layering: How Complex Systems Learn and Keep Learning

I won’t even mention COVID-19.

Fail. Fail again. Fail better.

by reestheskin on 28/10/2020

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I came across a note in my diary from around fifteen years ago. It was (I assume) after receiving a grant rejection. For once, I sort of agreed with the funder’s decision1. I wrote:

My grant was trivial, at least in one sense. Neils Bohr always said (or words to the effect) that the job of science was to reduce the profound to the trivial. The ‘magical’ would be made the ordinary of the everyday. My problem was that I started with the trivial.

As for the merits of review: It’s the exception that proves the rule.

  1. Bert Vogelstein, who I collaborated with briefly in the 1990s, after seeing our paper initially rejected by the glossy of the day , informed me that the only sensible personal strategy was to believe that reviewers are always wrong.

Where there is muck, there is…science

by reestheskin on 20/10/2020

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The background is the observation that babies born by Caesarian have different gut flora than those born vaginally. The interest in gut flora is because many believe it relates causally to some diseases. How do you go about investigating such a problem?

Collectively, these seven women gave birth to five girls and two boys, all healthy. Each of the newborns was syringe-fed a dose of breast milk immediately after birth—a dose that had been inoculated with a few grams of faeces collected three weeks earlier from its mother. None of the babies showed any adverse reactions to this procedure. All then had their faeces analysed regularly during the following weeks. For comparison, the researchers collected faecal samples from 47 other infants, 29 of which had been born normally and 18 by Caesarean section. [emphasis added]

Healthy childbirth — How to arm Caesarean babies with the gut bacteria they need | Science & technology | The Economist

Statisticians and the Colorado beetle

by reestheskin on 19/10/2020

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‘Statisticians have already overrun every branch of science with a rapidity of conquest rivalled only by Attila, Mohammed, and the Colorado beetle’

Maurice Kendall (1942): On the future of statistics. JRSA 105; 69-80.

Yes, that Maurice Kendall.

It seems to me that when it comes to statistics — and the powerful role of statistics in understanding both the natural and the unnatural world — that the old guys thought harder and deeper, understanding the world better than many of their more vocal successors. And that is without mentioning the barking of the medic-would-be-statistician brigade.

Freckles and angel kisses

by reestheskin on 14/10/2020

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I had forgotten this piece I wrote a few years back for Reto Caduff’s amazing book onFreckles. Here it is:

Imagine at some future time, two young adults meet on an otherwise deserted planet. They are both heavily freckled. What would this tell us about them, their ancestors and how they had have spent their time? First, all of us learn early in life that skin colour and marks like freckles are unequally distributed across the people of this earth. They are most common in people with pale skin, especially so if they have red hair, and we all know that we get our skin colour from our parents. Second, freckles are most common in those who have spent a lot of time in the sun. So freckles betray both something about our ancestors, and how we ourselves have lived our life.

Skin colour varies across the earth, and the chief determinant of this variation has been the interaction between sunshine (more particularly ultraviolet radiation) and our skin over the last 5 to 50 thousand years. Dark skin is adapted so as to protect against excessive sunshine, whereas we think light skin is better adapted to areas where the sun shines less. As some humans migrated out of Africa, say 50,000 years ago, a series of changes or mutations occurred in many genes to make their skin lighter. Their skin became more sensitive to both the good and the harmful effects of ultraviolet radiation. One way this change was accomplished was the development of changes in a gene called the melanocortin 1 receptor (MC1R), a gene we could also call a gene for freckles.

Skin and hair colour arises from a mixture of two types of the pigment melanin: brown or eumelanin, and red, or pheomelanin. If the MC1R works effectively, eumelanin is favoured; if the MC1R  works less well, pheomelanin is favoured. We know that the change to pheomelanin is associated with skin that is more sensitive to sunshine. When people who harbour changes in MC1R are exposed to sun they are much more likely to develop freckles, than those who contain no changes in their MC1R.

And what about the freckles themselves? They are just tiny areas of melanin production. Ironically, to the best of our knowledge the freckles themselves seem to protect against the sun quite effectively. It is the non-freckled areas that are most sensitive to the sun. If in a bid to protect skin against the harmful effects of excessive sun, we were to join all the freckles up, the sensitivity might disappear. Of course, on a planet located far away in time and place, our two young adults might already possess the technology to join all their freckles together. It is just that they chose not to.

The biomass of parasitism approaches unity.

by reestheskin on 09/10/2020

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Many years ago I was expressing exasperation at what I took to be the layers and layers of foolishness that meant that others couldn’t see the obvious — as defined by yours truly, of course. Did all those wise people in the year 2000 think that gene therapy for cancer was just around the corner, or that advance in genetics was synonymous with advance in medicine, or that the study of complex genetics would, by the force of some inchoate logic, lead to cures for psoriasis and eczema. How could any society function when so many of its parts were just free-riding on error, I asked? Worse still, these intellectual zombies starved the new young shoots of the necessary light of reason. How indeed!

William Bains, he of what I still think of as one of the most beautiful papers I have ever read1, put me right. William understood the world much better than me — or at least he understood the world I was blindly walking into, much better. He explained to me that it was quite possible to make money (both ‘real’ or in terms of ‘professional wealth’) out of ideas that you believed to be wrong as long as two linked conditions were met. First, do not tell other people you believe them to be wrong. On the contrary, talk about them as the next new thing. Second, find others who are behind the curve, and who were willing to buy from you at a price greater than you paid (technical term: fools). At the time, I did not even understand how pensions worked. Finally, William chided me for my sketchy knowledge of biology: he reminded me that in many ecosystems parasites account for much, if not most, of the biomass. He was right; and although my intellectual tastes have changed, the sermon still echoes.

The reason is that corporate tax burdens vary widely depending on where those profits are officially earned. These variations have been exploited by creative problem-solvers at accountancy firms and within large corporations. People who in previous eras might have written symphonies or designed cathedrals have instead saved companies hundreds of billions of dollars in taxes by shifting trillions of dollars of intangible assets across the world over the past two decades. One consequence is that many companies avoid paying any tax on their foreign sales. Another is that many countries’ trade figures are now unusable. [emphasis added].

Trade Wars Are Class Wars: How Rising Inequality Distorts the Global Economy and Threatens International by Matthew C. Klein, & Michael Pettis.

  1. William Bains. Should you Hire an Epistemologist. Nature Biotechnology, 1997.

Following the science

by reestheskin on 03/10/2020

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That “scientific management” bungled the algorithm for children’s exam results, verifies a maxim attributed to J.R. Searle, an American philosopher: if you have to add “scientific” to a field, it probably ain’t.

AD.Pellegrini in a letter to the Economist.

I have written elsewhere about this in medicine and science. We used to have physiology, but now some say physiological sciences; we used to have pharmacology, but now often see pharmacological sciences1. And as for medicine, neurology and neurosurgery used to be just fine, but then the PR and money grabbing started so we now have ‘clinical neuroscience’ — except it isn’t. As Herb Simon pointed out many years ago, the professions and professional practice always lose out in the academy.

  1. Sadly, my old department in Newcastle became Dermatological Sciences, and my most recent work address is Deanery of Clinical Sciences — which means both nouns are misplaced.

Alas poor Copernicus: when consultancy masquerades as expertise

by reestheskin on 01/10/2020

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“We’re going through a Copernican revolution of healthcare, where the patient is going to be at the centre. The gateway to healthcare is not going to be the physician. It’s going to be the smartphone.”…

and

“Christofer Toumazou, chief scientist at the Institute of Biomedical Engineering at Imperial College London, says there are “megabucks” to be saved by using technology and data to shift the focus of healthcare towards prevention.”

Ahem. I have been reading Seamus O’Mahony’s excellent Can Medicine be Cured in which he does a great job of following up on the crazy hype of big genetics from 20 year ago (and many other areas of sales masquerading as science). The above quotes are from only seven years ago. Still crazy after all these years, sings Paul Simon. Health care excels at adding tech as a new layer of complexity rather than replacing existing actors. And when will people start realising that prevention — which may indeed reduce suffering — will often increase costs. Life is a race against an army of exponential functions.

 In the FT

The way Brenner sees the world

by reestheskin on 29/09/2020

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Alas, there will no more new ones of these, as arguably the greatest of modern biology’s experimentalists, Sydney Brenner, passed away last year. One of his earlier quotes — the source I cannot find at hand — was that it is important in science to be out of phase. You can be ahead of the curve of fashion or possibly, better still, be behind it. But stay out of phase. So, no apologies for being behind the curve on these ones which I have just come across.

Sydney Brenner remarked in 2008, “We don’t have to look for a model organism anymore. Because we are the model organisms.”

Sydney Brenner has said that systems biology is “low input, high throughput, no output” biology.

Quoted in The science and medicine of human immunology | Science

Image source and credits via WikiCommons

Late night thoughts of a clinical scientist.

by reestheskin on 30/07/2020

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More accurately, late night thoughts from 26 years ago. I have no written record of my Edinburgh inaugural, but my Newcastle inaugural given in 1994 was edited and published by Bruce Charlton in the Northern Review. As I continue to sift through the detritus of a lifetime of work, I have just come across it. I haven’t looked at it for over 20 years, and it is interesting to reread it and muse over some of the (for me) familiar themes. There is plenty to criticise. I am not certain all the metaphors should survive, and I fear some examples I quote from out with my field may not be as sound as I imply. But it is a product of its time, a time when there was some unity of purpose in being a clinical academic, when teaching, research and praxis were of a piece. No more. Feinstein was right. It is probably for the best, but I couldn’t see this at the time.

 

Late night thoughts of a clinical scientist

The practice of medicine is made up of two elements. The first is an ability to identify with the patient: a sense of a common humanity, of compassion. The second is intellectual, and is based on an ethic that states you must make a clear judgement of what is at stake before acting. That, without a trace of deception, you must know the result of your actions. In Leo Szilard’s words, you must “recognise the connections of things and the laws and conduct of men so that you may know what you are doing”.

This is the ethic of science. William Gifford, the 19th century mathematician, described scientific thought as “the guide of action”: “that the truth at which it arrives is not that which we can ideally contemplate without error, but that which we may act upon without fear”.

Late last year when I was starting to think what I wanted to say in my inaugural lecture, the BBC Late Show devoted a few programmes to science. One of these concerned itself with medical practice and the opportunities offered by advances in medical science. On the one side. Professor Lewis Wolpert, a developmental biologist, and Dr Markus Pembrey, a clinical geneticist, described how they went about their work. How, they asked, can you decide whether novel treatments are appropriate for a patient except by a judgement based on your assessment of the patient’s wishes, and imperfect knowledge. Science always comes with confidence limits attached.

On the opposing side were two academic ethicists, including the barrister and former Reith Lecturer Professor Ian Kennedy. You may remember it was Kennedy in his Reith lectures who quoting Ivan Illicit described medicine itself as the biggest threat to people’s health. The debate, or at least the lack of it. clearly showed that we haven’t moved on very far from when C P Snow (in the year I was born) gave his Two cultures lecture. What do I mean by two cultures? Is it that people are not aware of the facts of science or new techniques?… It was recently reported in the journal Science that over half the graduates of Harvard University were unable to explain why it is warmer in summer than winter. A third of the British population still believe that the sun goes round the earth.

But, in a really crucial way, this absence of cultural knowledge is not nearly so depressing as the failure to understand the activity rather the artefacts of science. Kennedy in a memorable phrase described knowledge as a ‘tyranny’1. It is as though he wanted us back with Galen and Aristotle, safe in our dogma, our knowledge fossilised and therefore ethically safe and neutered. There is, however, with any practical knowledge always a sense of uncertainly. When you lift your foot off the ground you never quite know where it is going to come down. And, as in Alice in Wonderland, “it takes all the running you can do to stay in the same place”.

It is this relationship, between practice and knowledge and how if affects my subject that I want to talk about. And in turn, I shall talk about clinical teaching and diagnosis, research and the treatment of skin disease.

 
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The search space is always bigger…

by reestheskin on 02/07/2020

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Defining the appropriate probability space is often a non-trivial bit of statistics. It is often where you have to end up leaving statistics and formal reasoning behind. The following quote puts this in a more bracing manner.

There are no lobby groups for companies that do not exist.

The same goes for research and so much of what makes the future captivating.

On being an eternal student.

by reestheskin on 22/06/2020

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Freeman Dyson died February 28th this year. There are many obituaries of this great mind and eternal rebel. His book, Disturbing the Universe, is for me one of a handful that gets the fundamental nature of discovery in science and how science interacts with other modes of being human. His intellectual bravery and honesty shine through most of his writings. John Naughton had a nice quote from him a short while back.

Some mathematicians are birds, others are frogs. Birds fly high in the air and survey broad vistas of mathematics out to the far horizon. They delight in concepts that unify our thinking and bring together diverse problems from different parts of the landscape. Frogs live in the mud below and see only the flowers that grow nearby. They delight in the details of particular objects, and they solve problems one at a time. I happen to be a frog, but many of my best friends are birds. The main theme of my talk tonight is this. Mathematics needs both birds and frogs.

In truth he was both frog and an albatross. Here are some words from his obituary in PNAS.

During the Second World War, Dyson worked as a civilian scientist for the Royal Air Force’s Bomber Command, an experience that made him a life-long pacifist. In 1941, as an undergraduate at Trinity College, Cambridge, United Kingdom, he found an intellectual role model in the famed mathematician G. H. Hardy, who shared two ideas that came to define Dyson’s trajectory: “A mathematician, like a painter or a poet, is a maker of patterns,” and “Young men should prove theorems; old men should write books.”

Heeding the advice of his undergraduate mentor, Dyson returned to his first love of writing. He became well-known to a wide audience by his books Disturbing the Universe (1979) (1) and Infinite in All Directions (1988) (2), and his many beautiful essays for The New Yorker and The New York Review of Books. In 2018, he published his autobiography, Maker of Patterns (3), largely composed of letters that he sent to his parents from an early age on.

And as for us eternal students, at least I have one thing in common.

…Dyson never obtained an official doctorate of philosophy. As an eternal graduate student, a “rebel” in his own words, Dyson was unafraid to question everything and everybody. It is not surprising that his young colleagues inspired him the most.

Freeman J. Dyson 1923–2020: Legendary physicist, writer, and fearless intellectual explorer | PNAS

The beginning is where its at.

by reestheskin on 12/06/2020

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The best way to foster mediocrity is to found a Center for Excellence.

This is a quote from a comment by DrOFnothing on a good article by Rich DeMillo a few years back. It reminds me of my observation than shiny new research buildings often mean that the quality (but maybe not the volume) of reseach will deteriorate. This is just intellectual regression to the mean. You get the funding for the new building based on the trajectory of those who were in the old building — but with a delay. Scale, consistency  and originality have a troubled relationship. Just compare the early flowerings of jazz-rock fusion (below)  with the technically masterful but ultimately sterile stuff that came later.

Prose

by reestheskin on 09/06/2020

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The Nobel laureate David Hubel commented somewhere that reading most modern scientific papers was like chewing sawdust. Certainly it is rare nowadays to see the naked honesty of Watson and Crick’s classic opening paragraphs, or the melody not being drowned out by the the metrical percussion.

WE wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest [emphasis added].

A structure for nucleic acid has already been proposed by Pauling and Corey1. They kindly made their manuscript available to us in advance of publication. Their model consists of three intertwined chains, with the phosphates near the fibre axis, and the bases on the outside. In our opinion, this structure is unsatisfactory for two reasons : (1) We believe that the material which gives the X-ray diagrams is the salt, not the free acid. Without the acidic hydrogen atoms it is not clear what forces would hold the structure together, especially as the negatively charged phosphates near the axis will repel each other. (2) Some of the van der Waals distances appear to be too small.

And then there is that immortal understated penultimate paragraph.

It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.

Well here is another one that impresses me even if I can claim no expertise in this domain. It is from the prestigious journal Physical Review, is 27 words in length, with one number, one equation and one reference.  Via Fermat’s Library @fermatslibrary

 

 

 

 

 

Via Fermat’s Library @fermatslibrary

The slow now

by reestheskin on 18/05/2020

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Education is intellectual infrastructure.  So is science.  They have very high yield, but delayed payback.  Hasty societies that can’t span those delays will lose out over time to societies that can.  On the other hand, cultures too hidebound to allow education to advance at infrastructural pace also lose out.

Stewart Brand.

Would a medal do?

by reestheskin on 22/04/2020

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Interesting article from a final-year PhD student in Bristol. She writes:

Around one week before lockdown, Public Health England sent a message to UK universities; it needed their help to find PhD students, postdocs and other researchers to carry out diagnostic testing in London.

Despite the urgency of the call, the email didn’t mention pay or whether researchers should have permission from their grant funders to up and leave lab projects. It also omitted any details on accommodation or travel support for those of us living outside the capital…Then, on 2 April, we received another email, apparently from Public Health England (PHE), which was circulated to everyone in our faculty calling on us to join a “scientific reserve to support regional Covid-19 testing operations”.

The email cautioned that the work would be hard, and would require ‘five or seven day on/off shift patterns with long shifts’. No mention again of whether funders approved. Are the companies that provide testing or the reagents for testing getting paid, I wonder? She speculates as to  whether the government will be generous to her and others like her in the coming economic crisis.

My assumption is probably not: it will ask us to get ourselves in debt to the tune of tens of thousands of pounds to get the skills the country needs, but not pay us to work once we have them.

Well said.

Dan Greenberg RIP

by reestheskin on 17/04/2020

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Daniel S. Greenberg (1931–2020) has died. Nice obituary about him and why he mattered in this week’s Science.

Daniel S. Greenberg (1931–2020) | Science

At the time, the idea of a journalist-written section in a publication devoted to publishing research papers was highly unusual, and so was the approach that Dan and his team took. They covered basic research policy in much the same way a business reporter would cover development of economic policy: as a set of competing interests…[emphasis added].

However, it was not greeted with universal enthusiasm. In a preface to the second edition, Dan noted that it sparked “reactions that flowed from the belief that the scientific community should be exempt from the types of journalistic inquiries that are commonplace to other segments of our society.” He called that attitude “nonsense.”

Following your interest ‘du jour’

by reestheskin on 10/04/2020

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Many years ago I acted as the host of a visiting US dermatologist. He was due to give lectures in Edinburgh and elsewhere in the UK. I knew of him and, as I remember things, had spoken with him previously on a few occasions at US meetings. However, I did know of his research and, although it was in an area of skin research that was a long way from my professional interests, I admired it. He has taken a group of skin diseases (blistering aka bullous diseases) and explained at the molecular level what they all had in common. He had pulled back the veil, and shown the underlying unity of things that up until then had appeared different. I consider his work a beautiful example of clinical science.

I spent the day with him showing him around Edinburgh. We talked science and, as is often the case, the ‘meta’ of science: how is it done, how is it funded, what is good, and of course how the proposed work has been turned down for funding (’no track’ record’) etc.

At that time he was at NIH in the US. He stated that the great advantage of NIH — as he saw it then — was that if something bugged you at 9am you could spend the rest of the day (or week) thinking and reading about it. He wasn’t seeing patients, he wasn’t doing any formal teaching and admin was minimal. But he was insistent that blisters were ‘his problem’. If nobody would fund his interest in blisters he would do something else. Move to a university or a full time clinical role, but he wasn’t going to work on any other problem.

I know he did move several years later (to become Chair at an Ivy Laguen school) although I do not know the exact reasons why. I wouldn’t be surprised if kids going to college made him review his finances.

But the idea of spending you day in ‘your thoughts’ reading and asking questions appeals to some lifelong academics. Retirement has its pleasures (it is just the pay cheque that is missing).

Five year plans

by reestheskin on 02/04/2020

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Bruce Charlton pointed me to this entry in Wikipedia on Seymour Cray

“One story has it that when Cray was asked by management to provide detailed one-year and five-year plans for his next machine, he simply wrote, “Five-year goal: Build the biggest computer in the world. One year goal: One-fifth of the above.” And another time, when expected to write a multi-page detailed status report for the company executives, Cray’s two sentence report read: “Activity is progressing satisfactorily as outlined under the June plan. There have been no significant changes or deviations from the June plan.”

Which brings to mind Sydney Brenner’s comments that eventually requests for research grant funding will eventually resemble flow diagrams recording who reports to who.

All (insert name) careers end in failure

by reestheskin on 27/03/2020

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We are living in dark times, and since I have been sifting through the ashes of a career, it is no surprise that failures signal through like radioactive tracers. Below is one.

Through most of my career I have been interested in the relation between science and medicine. In truth, if what matters is what you think about in the shower, I have been more interested in the relation between science and medicine than I have been interested in either activity in isolation. If I were to use a phrase to describe my focus, although it is a term that I would not have used then, I am interested in the epistemological foundations of medical practice. Pompous, I agree. I could use another phrase: what makes medicine and doctors useful? Thinking about statistical inference is a part of this topic, but there is much more to explore.

These issues became closer to my consciousness soon after I moved to Edinburgh. My ideas about what was going on were not shared by many locally, and I was nervous about going public in person rather than in print at a Symposium hosted by the Royal College of Physicians of Edinburgh. My nervousness was well founded: whilst I liked my abstract, my talk went down badly. Not least because it was truly dreadful (and the evident failure still rankles). Jan Vandenbroucke, one of the other speakers and somebody whose work I greatly admire (his paper in the Lancet, Homoeopathy trials: Going nowhere. [Lancet.1997;350:824], was to me the most important paper published in the Lancet in the 1990s), said some kind words to me afterwards, muttering that I had tried to say far too much to an audience that was ill prepared for my speculations. All true, but he was just being kind. It was worse than that.

Anyway, some  tidying up deep in my hard drive surfaced the abstract. I still like it, but it is  a shame that at the appropriate time I was unable to explain why. 

JAMES LIND SYMPOSIUM: From scurvy to systematic reviews and clinical guidelines: how can clinical research lead to better patient care? (31-10-2003, RCPE Edinburgh)

Guidelines, Automata, Science and Algorithms

There are three great branches of science: theory, experiment, and computation. (Nick Trefethen)

Advance in the mid-third of the twentieth century, the golden age of medical research, was predicated on earlier discoveries in the nineteenth century in both physiology and medicinal chemistry (1). Genetics dominated biology in the latter third of the twentieth century and many believe changes in medical practice will owe much to genetics over the next third-century (1). I disagree, and I will give an alternative view more credence: in 30 years’ time we will look back more to Neumann and Morgenstern than we will to Watson and Crick. What the Nobel laureate Herbert Simon referred to as The Sciences of the Artificial (2), subjects which have largely been peripheral to medicine, will become central.

Over the last 20 years we have seen the first (largely inadequate, I would add) attempts to explicitly demarcate methods of obtaining and promulgating knowledge about clinical practice (3,4). This has usually taken the form of proselytising a particular set of terms – systematic reviews, evidence-based practice, guidelines and the like, terms that have little to commend them or rigour. What is interesting, however, is that they reflect a long overdue renaissance of interest with the practice of medicine and medical epistemology.

The change of emphasis from the natural to the artificial is being driven by a number of forces, mostly extraneous to biomedicine: the increasing instrumental role of science in medicine and society; the increase in corporatisation of knowledge, whether by private corporations or monopsonistic institutions like the NHS (5); the rising costs of healthcare; and a remaining inability to frame questions with broad support about how to chose between alternative disease states at the level of society (6,7).

I will try to illustrate some of these issues by the use of three examples. First, the widespread use of a mode of statistical inference largely ill-suited to medicine, namely Neyman-Pearson hypothesis testing (decision-making), and the way in which this paradigm has been used to undermine expert opinion (8). Second, I will argue that we need to think much harder about clinical practice and fashion a more appropriate theoretical underpinning for clinical behaviour. Third, I will suggest how UK medical schools, in so far as they remain interested in clinical practice, should look to alternative models, perhaps business and law schools, for ideas of how they should operate (2).

  1. Rees J. Complex disease and the new clinical sciences. Science 2002; 296:698-700.
  2. Simon HA. The sciences of the artificial. Cambridge, Mass. MIT Press; 1969
  3. Rees J. Evidence-based medicine: the epistemology that isn’t. J Am Acad Dermatol 2000; 43:727-9.
  4. Rees J. Two cultures? J Am Acad Dermatol 2002; 46:313-16.
  5. Hacking I. The emergence of probability: a philosophical study of early ideas about probability, induction and statistical inference. Cambridge: Cambridge University Press; 1975.
  6. Ziman J. Real science. Cambridge: Cambridge University
  7. Ziman J. Non-instrumental roles of science. Sci Eng Ethics
    2003;9:17-27.
  8.  Gigerenzer G, Swijtink Z, Porter T et al. The empire of chance: how probability changed science and everyday life. Cambridge: CUP; 1989.

Afterword. The symposium used structured abstracts, a habit that might have a place somewhere in this galaxy, but out of choice I would prefer to live in another one. Anyway, in the published version, it reads:

  • Methods: Not submitted
  • Results: Not submitted
  • Conclusions: Not submitted

A fair cop.

On the hazards of a good methodology

by reestheskin on 24/03/2020

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Alfred North Whitehead: “Some of the major disasters of mankind have been produced by the narrowness of men with a good methodology” (The Function of Reason).

Comments that seem germane to some of our current day covid-19 debates.

’Scuse Me while I Kiss the Sky

by reestheskin on 23/03/2020

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’Scuse Me While I Kiss the Sky | by A.J. Lees | The New York Review of Books

People are always demanding that medical students must learn this or that (obesity, psychiatry, dermatology, ID, eating disorders). The result is curriculum overload, a default in favour of rote learning by many students, and the inhibition of curiosity. It was not meant to be like this, but amongst others, the GMC, the NHS, and others have pushed a vision of university medical education that shortchanges both the students and medical practice over the long term. Short-termism rules. Instead of producing graduates who are ready to learn clinical medicine is an area of their choice, we expect them to somehow come out oven-ready at graduation. I do not believe it is possible to do this to a level of safety that many other professions demand, nor is this the primary job of a university. Sadly, universities have given up on arguing, intimidated by the government and their regulatory commissars, and nervous of losing their monopoly on producing doctors.

But I will make a plea that one area really does deserve more attention within a university : the history of how medical advance occurs. No, I do not mean MCQs asking for the date of birth of Robert Koch or Lord Lister, but a feel for the historical interplay of convention and novelty. Without this our students and our graduates are almost confined to living in the present, unaware of the past, and unable to doubt how different the future will be. Below is one example.

”In 1938 Albert Hofmann, a chemist at the Sandoz Laboratories in Basel, created a series of new compounds from lysergic acid. One of them, later marketed as Hydergine, showed great potential for the treatment of cerebral arteriosclerosis. Another salt, the diethylamide (LSD), he put to one side, but he had “a peculiar presentiment,” as he put it in his memoir LSD: My Problem Child (1980), “that this substance could possess properties other than those established in the first investigations.

In 1943 he prepared a fresh batch of LSD. In the final process of its crystallization, he started to experience strange sensations. He described his first inadvertent “trip” in a letter to his supervisor:

At home I lay down and sank into a not unpleasant, intoxicated-like condition, characterized by extremely stimulated imagination. In a dream-like state, with eyes closed (I found the daylight to be unpleasantly glaring), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors.

After eliminating chloroform fumes as a possible cause, he concluded that a tiny quantity of LSD absorbed through the skin of his fingertips must have been responsible. Three days later he began a program of unsanctioned research and deliberately ingested 250 micrograms of LSD at 4:20 PM. Forty minutes later, he wrote in his lab journal, “Beginning dizziness, feeling of anxiety, visual distortions, symptoms of paralysis, desire to laugh.” He set off home on his bicycle, accompanied by his laboratory assistant. This formal trial of what Hofmann considered a minute dose of LSD had more distressing effects than his first chance exposure:

Every exertion of my will, every attempt to put an end to the disintegration of the outer world and the dissolution of my ego, seemed to be wasted effort. A demon had invaded me, had taken possession of my body, mind, and soul. I jumped up and screamed, trying to free myself from him, but then sank down again and lay helpless on the sofa…. I was taken to another world, another place, another time.

A doctor was summoned but found nothing amiss apart from a marked dilation of his pupils. A fear of impending death gradually faded as the drug’s effect lessened, and after some hours Hofmann was seeing surreal colors and enjoying the play of shapes before his eyes.

Lees writes:

Many editors of learned medical journals now automatically turn down publications describing the sort of scientific investigation that Albert Hofmann carried out on himself. Institutional review boards are often scathing in their criticism of self-experimentation, despite its hallowed tradition in medicine, because they consider it subjective and biased. But the human desire to alter consciousness and enrich self-awareness shows no sign of receding, and someone must always go first. As long as care and diligence accompany the sort of personal research conducted by Pollan and Lin, it has the potential to be as revealing and informative as any work on psychedelic drugs conducted within the rigid confines of universities.

No old (nor broken) records here

by reestheskin on 21/03/2020

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Richard Horton in the Lancet writes:

Imagine if the entire edifice of knowledge in medicine was built upon a falsehood. Systematic reviews are said to be the highest standard of evidence-based health care. Regularly updated to ensure that treatment decisions are built on the most up-to-date and reliable science, systematic reviews and meta-analyses are widely used to inform clinical guidelines and decision making. Powerful organisations have emerged to construct a knowledge base in medicine underpinned by the results of systematic reviews. One such organisation is Cochrane, with 11 000 members in over 130 countries. This extraordinary movement of people is justifiably passionate about the idea that it is contributing to better health outcomes for everyone, everywhere. The industry that drives the production of systematic reviews today is financed by some of the most influential agencies in medical research. Cochrane, for example, points to three funders providing over £1 million each—the UK’s National Institute for Health Research (NIHR), the US National Institutes of Health (NIH), and Australia’s National Health and Medical Research Council (NHMRC).

Well, it really is a bit late for all this soul searching. See my earlier post here ‘Mega-silliness’ (commenting on what others had already pointed out); or my Evidence Based Medicine: the Epistemology That Isn’t, written over 20 years ago;  and my contribution to the wake (even if I didn’t put my hand in my pocket), Why we should let “evidence-based medicine” rest in peace. The genesis of EBM was as a cult whose foundational myth was that P values could act as a true machine. Those followers who had originally hoped for a place in the promised afterlife, soon settled for paying the bills, and EBM morphed into a career opportunity for those who found accountancy too daring. So, pace John Mayall on Jazz Blues Fusion, don’t come here to listen to an old record. I promise.

Offline: The gravy train of systematic reviews – The Lancet

Statistical significance and clinical evidence

Two letters in Lancet Oncology. This bloody story never ends. We have not invented truth machines: judgement has never been exiled from discovery.

Zombies.

Mining gold in them teeth

by reestheskin on 18/03/2020

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Stanley Cohen has died. A special place for those of us hooked on the ectoderm. Some nice comments about him in the Lancet from Geoff Watts.

A May, 1962, issue of the Journal of Biological Chemistry included a deceptively arcane study on the isolation of a protein that could accelerate incisor eruption and eyelid opening in newborn mice. The author, Stanley Cohen, later to become Professor Emeritus of Biochemistry at Vanderbilt University School of Medicine (VUSM) in Nashville, TN, USA, had named his protein “tooth-lid factor”. Cohen’s subsequent studies would not only lead him to rename the protein epidermal growth factor (EGF), but also mark him out as one of the founders of a new area of biology and eventually win him a Nobel Prize.

[says Lawrence Marnett], “When he came here he began studying some growth factors in animal cell extracts. One was of mouse submaxillary gland…It had peptides in it, and when he injected them into newborn mice their teeth broke though earlier than normal, and their eyelids opened sooner.” Cohen’s subsequent studies revealed that his extract worked by stimulating the growth of epidermal cells. Having consequently renamed the material EGF, he devoted the rest of his career to studying it. “He went on to identify the EGF receptor and define target cells that would respond to EGF”, recalls Graham Carpenter, Emeritus Professor of Biochemistry at VUSM, who joined Cohen’s lab in 1973 and worked with him on EGF as a postdoctoral fellow. The EGF receptor proved to be a useful target for drugs, and Cohen’s discoveries opened the door to research on diseases ranging from dementia to cancer. “He understood EGF’s biological importance”, says Carpenter. “But we did not have any idea that this would extend to cancer biology in a major way.”

And as for that most successful of all biology labs, the style of exploration  is familiar.

[Graham Carpenter] “In contrast to today, his research group was very small, seldom more than four people—himself, two technicians, and a postdoc…He was central to whatever was going on in the lab.” [Lawrence] Marnett also recalls that determination: “He was one of those guys that was just driven by his desire to understand how things work…It was a classic example of making an observation and then drilling down to try to understand it, not knowing what you’re going to find.” And at that time there was plenty to be found. Cohen, as Marnett puts it, was basically “mining gold”.

We too needed cash (then)

by reestheskin on 11/03/2020

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Terrific article on Covid-19 (Sars-CoV-2). in the LRB by Rupert Beale. He says written in haste but it doesn’t read that way. It contains some memorable lines.

As the US health secretary Michael Leavitt put it in 2006, ‘anything we say in advance of a pandemic happening is alarmist; anything we say afterwards is inadequate.’

And how do you think hard about research funding for the long term (I am old enough to remember when stroke and dementia were virtually non-subjects as far as ‘good research funding’ was concerned).

Virologists need more than clever tricks: we also need cash. Twenty years ago, funding wasn’t available to study coronaviruses. In 1999, avian infectious bronchitis virus was the one known truly nasty coronavirus pathogen. Only poultry farmers really cared about it, as it kills chickens but doesn’t infect people. In humans there are a number of fairly innocuous coronaviruses, such as OC43 and HKU1, which cause the ‘common cold’. Doctors don’t usually bother testing for them – you have a runny nose, so what?

And note the conditional tense:

The global case fatality rate is above 3 per cent at the moment, and if – reasonable worst case scenario – 30-70 per cent of the 7.8 billion people on earth are infected, that means between 70 and 165 million deaths. It would be the worst disaster in human history in terms of total lives lost. Nobody expects this, because everyone expects that people will comply with efficient public health measures put in place by responsible governments.

And to repeat my own mantra (stolen from elsewhere): the opposite of science is not art, but politics:

The situation isn’t helped by a president [Trump] who keeps suggesting that the virus isn’t that bad, it’s a bit like flu, we will have a vaccine soon: stopping flights from China was enough. Tony Fauci, the director of the National Institute of Allergy and Infectious Disease, deftly cut across Trump at a White House press briefing. No, it isn’t only as bad as flu, it’s far more dangerous. Yes, public health measures will have to be put in place and maintained for many months. No, a vaccine isn’t just around the corner, it will take at least 18 months. Fauci was then ordered to clear all his press briefings on Covid-19 with Mike Pence in advance: the vice president’s office is leading the US response to the virus. ‘You don’t want to go to war with a president,’ Fauci remarked.

And Beale ends by quoting an ID colleague.

This is not business as usual. This will be different from what anyone living has ever experienced. The closest comparator is 1918 influenza.

Caution: pace the author, ‘This is a fast-moving situation, and the numbers are constantly changing – certainly the ones I have given here will be out of date by the time you read this.’

Link. (London Review of Books: Vol. 42 No. 5,  5 March 2020: “Wash your Hands”: Rupert Beale)

Tidying up

by reestheskin on 04/03/2020

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I have spend a lot of time recently sifting through the detritus of a career. Finally — well, I hope, finally — I have managed to sort out my books. All neatly indexed in Delicious Library, and now for once the virtual location mirrors the physical location. For how long I do not know. Since I often buy books based on reviews, I used to put a copy of the review in with the book (a habit I have dropped but need to restart). I rediscovered this one by David Colquhoun (DC) reviewing ‘The Diet Delusion’ by Gary Taubes in the BMJ (with the unexpurgated text on his own web site).

I am a big fan of DC as he has lived though the rise and decline of much higher education in the UK. And he remains fearless and honest, qualities that are not always at the forefront of the modern university. Quoting the great Robert Merton he writes:

“The organization of science operates as a system of institutionalized vigilance, involving competitive cooperation. In such a system, scientists are at the ready to pick apart and assess each new claim to knowledge. This unending exchange of critical appraisal, of praise and punishment, is developed in science to a degree that makes the monitoring of children’s behavior by their parents seem little more than child’s play”.

He adds:

“The institutionalized vigilance, “this unending exchange of critical judgment”, is nowhere to be found in the study of nutrition, chronic disease, and obesity, and it hasn’t been for decades.”

On Taubes and his (excellent book):

It took Taubes five years to write this book, and he has nothing to sell apart from his ideas. No wonder it is so much better than a scientist can produce. Such is the corruption of science by the cult of managerialism that no university would allow you to spend five years on a book

(as would be expected the BMJ omitted the punch line — they would, wouldn’t they?)

There is also a neat quote from Taubes in one of the comments on DC’s page from Beth@IDblog, one that I will try hard not to forget:

Taubes makes a point at the end of the Dartmouth medical grand rounds video that I think is important: “I’m not trying to convince you that it’s true, I’m trying to convince you that it should be taken seriously.”

The thrill is gone

by reestheskin on 31/01/2020

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Today is my last day of (paid) work, and of course a day that will be infamous for many more people for other more important reasons. Europe and my professional life have been intertwined for near on 40 years. In the mid 1980s I went to start my dermatological career in Vienna. I had been a student at Newcastle and done junior jobs there, as well as some research on skin physiology with Sam Shuster as an undergraduate student. Sam rightly thought I should now move somewhere else — see how others did things before returning — and he suggested Paris, or Vienna under Klaus Wolff. Vienna was, and perhaps still is, the centre of the dermatological universe, and has been since the mid 19th century. Now, even if I haven’t got very far into this post — it is a day for nostalgia — so allow me an aside: The German literature Problem.

The German Literature

As I have hinted at above, in many ways there have only been two schools of dermatology: the French school, and the German school. The latter has been dominant. Throughout the second half of the 19th century dermatology was a ‘German speaking’ subject. To follow it you would be wise to know German, and better still to have visited the big centres in Germany, Switzerland or Austria. And like most of the modern research university, German medicine and science was the blueprint for the US and then belatedly — and with typos— for England (Scotland, reasonably, had taken a slightly different path).

All of the above I knew, but when I returned to Newcastle after my first sojourn away (a later one was to Strasbourg), I naturally picked up on all these allusions to the German literature, but they were accompanied by sniggering by those who had been around longer than me. Indeed there seemed to be a ‘German Literature Problem’. Unbeknown to me, Sam had written “das problem ” up in ‘World Medicine’, but World Medicine had been killed off by those from Mordor, so here is a synopsis.

The German literature seemed so vast that whenever somebody described a patient with what they were convinced must be a ‘new syndrome’, some bright spark would say that it had already been described, and that it was to be found in the German literature. Now the synoptic Handbuch der Hautkrankheiten on our shelves in the library in Newcastle ran to over 10 weighty volumes. And that was just the start. But of course only German speaking dermatologists (and we had one) could meaningfully engage in this conversation. Dermatology is enough of a a nightmare even in your own mother tongue. Up to the middle of the 20th century however, there were indeed separate literatures in German, French and English (in the 1960’s the newly formed ESDR had to sort out what language was going to be used for its presentations).

Sam’s sense of play now took over (with apologies to Shaw: nothing succeeds like excess). It appeared that all of dermatology had already been previously described, but more worryingly for the researchers, the same might be true of skin science. In his article in World Medicine he set out to describe his meta-science investigation into this strange phenomenon. Sam has an unrivalled ability to take simple abstract objects — a few straight lines, a circle, a square — and meld them into an argument in the form of an Escher print. A print that you know is both real, unreal and illegal. Imagine a dastardly difficult 5 x 5 Rubik’s cube (such as the one my colleagues recently bought me for my retirement). You move and move and move the individual facets, then check each whole face in turn. All aligned, problem solved. But then you look in the mirror: whilst the faces are all perfect in your own hands, that is not what is apparent in the mirror. This is my metaphor for Sam’s explanation. Make it anymore explicit, and the German literature problem rears its head. It’s real — of a sort. Anyway, this was all in the future (which didn’t exist at that time), so lets get back to Vienna.

Night train to Wien

Having left general medical jobs behind in Newcastle, armed with my BBC language tapes and guides, I spent a month travelling through Germany from north to south. I stayed with a handful of German medical students who I had taught in Newcastle when I was a medical registrar (a small number of such students used to spend a year with us in Newcastle). Our roles were now reversed: they were now my teachers. At the end of the month I caught the night train in Ulm, arriving in Vienna early one morning.

Vienna was majestic — stiff collared, yes — but you felt in the heart of Europe. A bit of Paris, some of Berlin and the feel of what lay further east: “Wien ist die erste Balkanstadt”.  For me, it was unmistakably and wonderfully foreign.

It was of course great for music, too. No, I couldn’t afford the New Year’s Day Concerts, but there were cheap seats at the Staatsoper, more modest prices at the Volksoper, and more to my taste, some European jazz and rock music. I saw Ultravox sing — yes, what else— “Vienna” in Vienna. I saw some people from the ECM label (eg Eberhard Weber), a style of European jazz music that has stayed with me since my mid teens. And then there was the man (for me) behind ‘The Thrill is Gone’.

The Thrill

I saw BB King on a double bill with Miles Davies at the Stadthalle. Two very different styles of musician. I was more into Miles Davies then, but he was not then at his best (as medics in Vienna found out). I was, however, very familiar with the ‘Kings’ (BB, Freddie, Albert etc) after being introduced to them via their English interpreters. Clapton’s blue’s tone on ‘All Your Love’ with John Mayall’s Bluesbreakers still makes the hairs on my neck stand up (fraternal thanks to ‘Big Al’ for the introduction).

The YouTube video at the top of the page is wonderful (Montreux 1993), but there is a later one below, taken from Crossroads in 2010 which moves me even more. He is older, playing with a bunch of craftsmen, but all still pupils before the master.

But — I am getting there — germane to my melancholia on this day is a video featuring BB King and John Mayer. Now there is a trope that there are two groups of people who like John Mayer: girlfriends; and guitarists who understand just how bloody good he is. As EC pointed out, the problem with John Mayer is that he realises just how good he is. True.

But the banter at the beginning of the video speaks some eternal truths about craft, expertise, and the onward march of all culture — including science. Mayer plays a few BB King licks, teasing King that he is ‘stealing’ them. He continues, it was as though he was ‘stealing silverware from somebody’s house right in front of them’. King replies: ”You keep that up and I’m going to get up and go”. Both know it doesn’t work that way. Whatever the provenance of the phrase ‘great artists steal, not copy’, except in the most trivial way you cannot steal or copy culture: people discover it in themselves by stealing what masters show them might be there in their pupils. Teachers just help people find what they suspect or hope is there. The baton gets handed on. The thrill goes on. And on.