For decades, Katalin Karikó’s work into mRNA therapeutics was overlooked by her colleagues. Now it’s at the heart of the two leading coronavirus vaccines
By the mid 1990s, Karikó’s bosses at UPenn had run out of patience. Frustrated with the lack of funding she was generating for her research, they offered the scientist a bleak choice: leave or be demoted. It was a demeaning prospect for someone who had once been on the path to a full professorship. For Karikó’s dreams of using mRNA to create new vaccines and drugs for many chronic illnesses, it seemed to be the end of the road… ”It was particularly horrible as that same week, I had just been diagnosed with cancer,” said Karikó. “I was facing two operations, and my husband, who had gone back to Hungary to pick up his green card, had got stranded there because of some visa issue, meaning he couldn’t come back for six months. I was really struggling, and then they told me this.”
Karikó has been at the helm of BioNTech’s Covid-19 vaccine development. In 2013, she accepted an offer to become Senior Vice President at BioNTech after UPenn refused to reinstate her to the faculty position she had been demoted from in 1995. “They told me that they’d had a meeting and concluded that I was not of faculty quality,” she said. ”When I told them I was leaving, they laughed at me and said, ‘BioNTech doesn’t even have a website.’”
Donald Knuth is a legend amongst computer scientists.
I have been a happy man ever since January 1, 1990, when I no longer had an email address. I’d used email since about 1975, and it seems to me that 15 years of email is plenty for one lifetime.Email is a wonderful thing for people whose role in life is to be on top of things. But not for me; my role is to be on the bottom of things. What I do takes long hours of studying and uninterruptible concentration. I try to learn certain areas of computer science exhaustively; then I try to digest that knowledge into a form that is accessible to people who don’t have time for such study. [emphasis added]
I retired early because I realized that I would need at least 20 years of full-time work to complete The Art of Computer Programming (TAOCP), which I have always viewed as the most important project of my life.
Being a retired professor is a lot like being an ordinary professor, except that you don’t have to write research proposals, administer grants, or sit in committee meetings. Also, you don’t get paid.
My full-time writing schedule means that I have to be pretty much a hermit. The only way to gain enough efficiency to complete The Art of Computer Programming is to operate in batch mode, concentrating intensively and uninterruptedly on one subject at a time, rather than swapping a number of topics in and out of my head. I’m unable to schedule appointments with visitors, travel to conferences or accept speaking engagements, or undertake any new responsibilities of any kind.
John Baez is indeed a relative of that other famous J(oan) Baez. I used to read his blog avidly
The great challenge at the beginning of ones career in academia is to get tenure at a decent university. Personally I got tenure before I started messing with quantum gravity, and this approach has some real advantages. Before you have tenure, you have to please people. After you have tenure, you can do whatever the hell you want — so long as it’s legal, and you teach well, your department doesn’t put a lot of pressure on you to get grants. (This is one reason I’m happier in a math department than I would be in a physics department. Mathematicians have more trouble getting grants, so there’s a bit less pressure to get them.)
The great thing about tenure is that it means your research can be driven by your actual interests instead of the ever-changing winds of fashion. The problem is, by the time many people get tenure, they’ve become such slaves of fashion that they no longer know what it means to follow their own interests. They’ve spent the best years of their life trying to keep up with the Joneses instead of developing their own personal style! So, bear in mind that getting tenure is only half the battle: getting tenure while keeping your soul is the really hard part. [emphasis added]
Scientists straying from their field of expertise in this way is an example of what Nathan Ballantyne, a philosopher at Fordham University in New York City, calls “epistemic trespassing”. Although scientists might romanticize the role and occasional genuine insight of an outsider — such as the writings of physicist Erwin Shrödinger on biology — in most cases, he says, such academic off-piste manoeuvrings dump non-experts head-first in deep snow. [emphasis added]
But I do love the language…
Susan Haack is a wonderfully independent English borne philosopher who loves to roam, casting light wherever her interest takes her.
Better ostracism than ostrichism
Moreover, I have learned over the years that I am temperamentally resistant to bandwagons, philosophical and otherwise; hopeless at “networking,” the tit-for-tat exchange of academic favors, “going along to get along,” and at self-promotion
That I have very low tolerance for meetings where nothing I say ever makes any difference to what happens; and that I am unmoved by the kind of institutional loyalty that apparently enables many to believe in the wonderfulness of “our” students or “our” department or “our” school or “our” university simply because they’re ours.
Nor do I feel what I think of as gender loyalty, a sense that I must ally myself with other women in my profession simply because they are women—any more than I feel I must ally myself with any and every British philosopher simply because he or she is British. And I am, frankly, repelled by the grubby scrambling after those wretched “rankings” that is now so common in philosophy departments. In short, I’ve never been any good at academic politicking, in any of its myriad forms.
And on top of all this, I have the deplorable habit of saying what I mean, with neither talent for nor inclination to fudge over disagreements or muffle criticism with flattering tact, and an infuriating way of seeing the funny side of philosophers’ egregiously absurd or outrageously pretentious claims — that there are no such things as beliefs, that it’s just superstitious to care whether your beliefs are true, that feminism obliges us to “reinvent science and theorizing,” and so forth.
From a wonderful article in the Economist
As Michael Massing shows vividly in “Fatal Discord: Erasmus, Luther and the Fight for the Western Mind” (2018), the growing religious battle destroyed Erasmianism as a movement. Princes had no choice but to choose sides in the 16th-century equivalent of the cold war. Some of Erasmus’s followers reinvented themselves as champions of orthodoxy. The “citizen of the world” could no longer roam across Europe, pouring honeyed words into the ears of kings. He spent his final years holed up in the free city of Basel. The champion of the Middle Way looked like a ditherer who was incapable of making up his mind, or a coward who was unwilling to stand up to Luther (if you were Catholic) or the pope (if you were Protestant).
The test of being a good Christian ceased to be decent behaviour. It became fanaticism: who could shout most loudly? Or persecute heresy most vigorously? Or apply fuel to the flames most enthusiastically?
And in case there is any doubt about what I am talking about.
In Britain, Brexiteers denounce “citizens of the world” as “citizens of nowhere” and cast out moderate politicians with more talent than they possess, while anti-Brexiteers are blind to the excesses of establishment liberalism. In America “woke” extremists try to get people sacked for slips of the tongue or campaign against the thought crimes of “unconscious bias”. Intellectuals who refuse to join one camp or another must stand by, as mediocrities are rewarded with university chairs and editorial thrones. [emphasis added]
As Erasmus might have said: ‘Amen’.
According to a helpful app on my phone that I like to think acts as a brake on my sloth, I retired 313 days ago. One of the reasons I retired was so that I could get some serious work done; I increasingly felt that professional academic life was incompatible with the sort of academic life I signed up for. If you read my previous post, you will see this was not the only reason, but since I have always been more of an academic than clinician, my argument still stands.
Over twenty years ago, my friend and former colleague, Bruce Charlton, observed wryly that academics felt embarrassed — as though they had been caught taking a sly drag round the back of the respiratory ward — if they were surprised in their office and found only to be reading. No grant applications open; no Gantt charts being followed; no QA assessments being written. Whatever next.
I thought about retirement from two frames of reference. The first, was about finding reasons to leave. After all, until I was about 50, I never imagined that I would want to retire. I should therefore be thrilled that I need not be forced out at the old mandatory age of 65. The second, was about finding reasons to stay, or better still, ‘why keep going to work?’. Imagine you had a modest private income (aka a pension), what would belonging to an institution as a paid employee offer beyond that achievable as a private scholar or an emeritus professor? Forget sunk cost, why bother to move from my study?
Many answers straddle both frames of reference, and will be familiar to those within the universities as well as to others outwith them. Indeed, there is a whole new genre of blogging about the problems of academia, and employment prospects within it (see alt-acor quit-lit for examples). Sadly, many posts are from those who are desperate to the point of infatuation to enter the academy, but where the love is not reciprocated. There are plenty more fish in the sea, as my late mother always advised. But looking back, I cannot help but feel some sadness at the changing wheels of fortune for those who seek the cloister. I think it is an honourable profession.
Many, if not most, universities are very different places to work in from those of the 1980s when I started work within the quad. They are much larger, they are more corporatised and hierarchical and, in a really profound sense, they are no longer communities of scholars or places that cherish scholarly reason. I began to feel much more like an employee than I ever used to, and yes, that bloody term, line manager, got ever more common. I began to find it harder and harder to characterise universities as academic institutions, although from my limited knowledge, in the UK at least, Oxbridge still manage better than most 1. Yes, universities deliver teaching (just as Amazon or DHL deliver content), and yes, some great research is undertaken in universities (easy KPIs, there), but their modus operandi is not that of a corpus of scholars and students, but rather increasingly bends to the ethos of many modern corporations that self-evidently are failing society. Succinctly put, universities have lost their faith in the primacy of reason and truth, and failed to wrestle sufficiently with the constraints such a faith places on action — and on the bottom line.
Derek Bok, one of Harvard’s most successful recent Presidents, wrote words to the effect that universities appear to always choose institutional survival over morality. There is an externality to this, which society ends up paying. Wissenschaft als Beruf is no longer in the job descriptions or the mission statements2.
A few years back via a circuitous friendship I attended a graduation ceremony at what is widely considered as one of the UK’s finest city universities3. This friend’s son was graduating with a Masters. All the pomp was rolled out and I, and the others present, were given an example of hawking worthy of an East End barrow boy (‘world-beating’ blah blah…). Pure selling, with the market being overseas students: please spread the word. I felt ashamed for the Pro Vice Chancellor who knew much of what he said was untrue. There is an adage that being an intellectual presupposes a certain attitude to the idea of truth, rather than a contract of employment; that intellectuals should aspire to be protectors of integrity. It is not possible to choose one belief system one day, and act on another, the next.
The charge sheet is long. Universities have fed off cheap money — tax subsidised student loans — with promises about social mobility that their own academics have shown to be untrue. The Russell group, in particular, traducing what Humboldt said about the relation between teaching and research, have sought to diminish teaching in order to subsidise research, or, alternatively, claimed a phoney relation between the two. As for the “student experience”, as one seller of bespoke essays argued4, his business model depended on the fact that in many universities no member of staff could recognise the essay style of a particular student. Compare that with tuition in the sixth form. Universities have grown more and more impersonal, and yet claimed a model of enlightenment that depends on personal tuition. Humboldt did indeed say something about this:
“[the] goals of science and scholarship are worked towards most effectively through the synthesis of the teacher’s and the students’ dispositions”.
As the years have passed by, it has seemed to me that universities are playing intellectual whack-a-mole, rather than re-examining their foundational beliefs in the light of what they offer and what others may offer better. In the age of Trump and mini-Trump, more than ever, we need that which universities once nurtured and protected. It’s just that they don’t need to do everything, nor are they for everybody, nor are they suited to solving all of humankind’s problems. As had been said before, ask any bloody question and the universal answer is ‘education, education, education’. It isn’t.
That is a longer (and more cathartic) answer to my questions than I had intended. I have chosen not to describe the awful position that most UK universities have found themselves in at the hands of hostile politicians, nor the general cultural assault by the media and others on learning, rigour and nuance. The stench of money is the accelerant of what seeks to destroy our once-modern world. And for the record, I have never had any interest in, or facility for, management beyond that required to run a small research group, and teaching in my own discipline. I don’t doubt that if I had been in charge the situation would have been far worse.
Sydney Brenner, one of the handful of scientists who made the revolution in biology of the second half of the 20th century once said words to the effect that scientists no longer read papers they just Xerox them. The problem he was alluding to, was the ever-increasing size of the scientific literature. I was fairly disciplined in the age of photocopying but with the world of online PDFs I too began to sink. Year after year, this reading debt has increased, and not just with ‘papers’ but with monographs and books too. Many years ago, in parallel with what occupied much of my time — skin cancer biology and the genetics of pigmentation, and computerised skin cancer diagnostic systems — I had started to write about topics related to science and medicine that gradually bugged me more and more. It was an itch I felt compelled to scratch. I wrote a paper in the Lancet on the nature of patents in clinical medicine and the effect intellectual property rights had on the patterns of clinical discovery; several papers on the nature of clinical discovery and the relations between biology and medicine in Science and elsewhere. I also wrote about why you cannot use “spreadsheets to measure suffering” and why there is no universal calculus of suffering or dis-ease for skin disease ( here and here ); and several papers on the misuse of statistics and evidence by the evidence-based-medicine cult (here and here). Finally, I ventured some thoughts on the industrialisation of medicine, and the relation between teaching and learning, industry, and clinical practice (here), as well as the nature of clinical medicine and clinical academia (here and here ). I got invited to the NIH and to a couple of AAAS meetings to talk about some of these topics. But there was no interest on this side of the pond. It is fair to say that the world was not overwhelmed with my efforts.
At one level, most academic careers end in failure, or at last they should if we are doing things right. Some colleagues thought I was losing my marbles, some viewed me as a closet philosopher who was now out, and partying wildly, and some, I suspect, expressed pity for my state. Closer to home — with one notable exception — the work was treated with what I call the Petit-mal phenomenon — there is a brief pause or ‘silence’ in the conversation, before normal life returns after this ‘absence’, with no apparent memory of the offending event. After all, nobody would enter such papers for the RAE/REF — they weren’t science with data and results, and since of course they weren’t supported by external funding, they were considered worthless. Pace Brenner, in terms of research assessment you don’t really need to read papers, just look at the impact factor and the amount and source of funding: sexy, or not?5
You have to continually check-in with your own personal lodestar; dead-reckoning over the course of a career is not wise. I thought there was some merit in what I had written, but I didn’t think I had gone deep enough into the problems I kept seeing all around me (an occupational hazard of a skin biologist, you might say). Lack of time was one issue, another was that I had little experience of the sorts of research methods I needed. The two problems are not totally unrelated; the day-job kept getting in the way.
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.
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.
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.
I won’t even mention COVID-19.
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.
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]
‘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.
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.
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.
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.
“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.”…
“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
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.
Image source and credits via WikiCommons
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.
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.
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.
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.
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.
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
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.
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.
Daniel S. Greenberg (1931–2020) has died. Nice obituary about him and why he mattered in this week’s 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.”
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).
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.
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)
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).
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:
A fair cop.
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.
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.
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.
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.
Two letters in Lancet Oncology. This bloody story never ends. We have not invented truth machines: judgement has never been exiled from discovery.
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”.
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)