Some history: double-blind trials are a hundred years old (give or take a year)

Sorry, no bad science trashing this week – a bit of scientific historical rambling instead, reflecting another of my part-time interests. Probably too serious, too. I blame the clocks going back – pesky SAD.

The recent plethora of (often rather good) TV and radio programmes commemorating the 90^th anniversary of the end of World War One set me to thinking this week.

What is the link between the WW1 trenches, a best-selling modern novel and a pretty good film, and the history of double-blind trials?

The answer is a man – William Halse Rivers FRS (1864-1922), Gold Medallist and Croonian Lecturer of the Royal Society, scientist, ethnographer, founding father of British anthropology, psychology and psychotherapy, Cambridge don, physician, wartime Royal Army Medical Corps doctor and author of a key early account [1] of treating ”war neurosis” – shell shock as they might have said then, post-traumatic stress disorder (PTSD) as we would say now.

Rivers died comparatively young (58), from an acutely ischaemic bowel. He fell ill while alone, and by the time he was discovered it was too late to operate. He was much mourned by his scientific colleagues – for instance, the then President of the Royal Society, the Nobel Laureate Charles Sherrington, referred to Rivers’ death as “cutting short in the fullness of his activity and powers a psychologist and ethnologist of exceptional significance”. Rivers was also mourned by the many young officers with “war neurosis” who he had helped at the Craiglockhart War Hospital near Edinburgh, notable among them the writer and poet Siegfried Sassoon. It is this episode in Rivers’ and Sassoon’s lives that has made Rivers famous again. Their relationship as doctor and patient features centrally in Pat Barker’s novel Regeneration.(1991) and the 1997 film of the same name, aired again recently on the BBC digital channels, in which Jonathan Pryce portrays Rivers.

[The book and film also portray Sassoon’s friendship with another Craiglockhart patient, the war poet Wilfred_Owen. There is a good interview with Pat Barker which discusses her work here]

Caffeine, alcohol, and double-blind trials

As already noted above, Rivers’ career took in an amazing range of disciplines. His role in the instigation of double-blind trials comes from one of the less well-known bits, his researches into the effects of caffeine and alcohol on muscle fatigue. This work was carried out around 1906-7 in Cambridge, and is described in a 1907 paper in the Journal of Physiology [2] and in Rivers’ 1908 Croonian Lectures to the Royal Society [3]. Rivers had been appointed to a Cambridge University lectureship in ‘physiological and experimental psychology’ in 1897, and worked in Cambridge for the rest of his career, barring anthropological expeditions and his wartime work. As the job title suggests, Rivers’ interest was in the interplay of the physiological and the psychological. This can be seen in his interest in the effects of alcohol, where the measured “physiological” changes in a subject’s exercise performance were clearly heavily influenced by his psychological state and reactions. In addition, there was a possible psychological effect on the experimenter, who might bias the results by, for instance, being more encouraging and enthusiastic if he knew the experiment was using the drug rather than the control.

The placebo and blinding techniques Rivers and Webber used were an attempt to minimize these psychological influences. In the 1907 paper they describe the method for the caffeine experiments:

“Each experiment was prolonged over a number of days, on some of which a dose of caffeine was taken, and on others a dose of the control. Both the caffeine and control mixtures were in most cases prepared for us by Dr W. E. Dixon for whose kind help in this respect we are very greatly indebted.

We took the caffeine in the form of the citrate, and the control consisted of a mixture of gentian and citric acid … it was not till the end of the whole experiment that we acquainted ourselves with the nature of the dose on any given day.’

Walter.E. Dixon FRS (1871-1931) was a famous early British pharmacologist who you can read about here. Dixon shared River’s interest in disentangling the psychological and physiological aspects of the effects of things like alcohol. Gentian was presumably used because it has a strong bitter taste, mimicking the bitterness of caffeine; Gentian is one of the main flavours in Angostura Bitters, a fairly loathsome herbal concoction used to this day in making cocktails. For enthusiasts of British Imperial Tradition, Angostura is one of the ingredients in the British Naval officer’s traditional Pink Gin.

Rivers and Webber’s experiments with alcohol used a similar double-blind placebo design, with the alcohol, or (placebo) control, again prepared by a third person and with the experimenter and subject (Rivers and Webber alternated in these roles) not knowing which was which. Disguising the taste of alcohol required a more complex concoction containing capsicum, (hot chilli pepper extract), cardamoms, chloroform and peppermint. What this would have tasted like I cannot imagine, but it must have been quite something.

“Ancient wisdom”, belief, and medicine

Rivers was clearly regarded in his time as a significant scientific figure. Though many of his ideas have inevitably been superseded or disproved, his place as a key founder of British psychology and anthropology, is secure. Indeed, in the age of vanishing habitats, languages, tribal customs and indeed entire ways of life, many of his remarks about primitive peoples, and their endangerment by the actions of Western society, seem prophetic. Rivers studied the social structures of the tribal people of Melanesia – he is said to have felt that his History of Melanesian Society, published in 1914, was his finest work – as well as their traditional healing practises [4]:

“… I hope that the facts brought forward in these lectures are sufficient to show that in the department of his activity by which he endeavours to cope with disease, ”savage” man is no illogical or prelogical creature, but that his actions are guided by reasoning as definite as that which we can claim for our own medical practices.”

– Rivers, second Fitzpatrick lecture, 1915

So does this mean Rivers would have been a fan of modern alternative medicine, with its enthusiasm for “Ancient Healing Wisdom”? Personally I think not. Rivers was clear that in all his many activities he tried to apply the best of the scientific method as it stood at the time. In the passage above he is saying that “ancient healing wisdom” is based on a clear and structured set of beliefs. He is not saying that these beliefs are true, or that the practises work. Indeed, I suspect Rivers would have believed that any effectiveness of these methods depended on suggestibility, and particularly the patient’s and healer’s shared belief. This shared belief is culturally specific; a traditional healing practise would have a psychological effect dependent on its setting and culture, not due to any “intrinsic power” of the actual healing method.  So what Rivers is saying here is nothing like the “it is traditional and therefore it is just as good as the modern scientific stuff” view popular with modern Alternative Reality types.

Rivers’ treatments of the shell-shocked officers were psychotherapeutic in nature – “talking therapy” – and Rivers was clearly aware of, and fascinated by, the interplay between the physiological and psychological side of medicine and treatment. In this his thinking somewhat puts me in mind of modern medical social scientists who emphasise ”Health_Beliefs” as part of understanding the process of treatment, and the perception of how well it is working.

“As medicine has progressed and has been differentiated from magic and religion, [the] play of psychological factors has not ceased.

Few can now be found who will deny that the success which attended [many remedies and treatment regimes] of the last generation was due mainly, if not entirely, to the play of faith and suggestion. The salient feature of the medicine of today is that these psychical factors are no longer allowed to play their part unwittingly, but are themselves becoming the subject of study, so that the present age is seeing the growth of a rational system of psychotherapeutics.”

– Rivers, final Fitzpatrick lecture, 1917.

Rivers would doubtless have found modern psychological therapies, like Cognitive behavioral therapy (CBT), fascinating. A bit fancifully, I would guess that a Rivers re-born in the modern age would also be fascinated by contemporary research into the placebo effect, in all its different manifestations. I like to think that, faced by modern Alternative Therapy, Rivers would want to insist on a clear-headed scientific discussion of the role played by beliefs and suggestion. He would certainly have insisted on the need to design experiments and trials rigorously to take account of, and where necessary exclude, such effects. After all, before one can study where physiology and psychology interact, one needs to make the effort to be able, as far as possible, to tell them apart. This is as true now as it was when Rivers was doing his caffeine and alcohol experiments a century ago.

Memorials

Rivers is not much remembered these days for his pioneering use of the double-blind experimental design, though he does get an honourable mention for it over at the James Lind Library site. And while Rivers’ role as a founder of modern British psychology and ethnology is well-known in academic circles, it probably does not go far beyond that.

Perhaps fittingly, given the affection in which Rivers was held by so many of those he came into contact with, the aspect of his life that has given him his most lasting memorial was the wise and concerned doctor and therapist, helping his Craiglockhart patients cope with their war nightmares and flashbacks. Apart from Pat Barker’s fictionalized account, Sassoon and his friend Robert Graves both wrote about Rivers in their respective memoirs [5], and Sassoon made clear that he felt Rivers had saved his life –as the poem below, written many years after the war, attests. It is not a terribly good poem, but the last couple of lines of each stanza give a sense of the debt Sassoon felt he owed Rivers. Finally, in a discussion a few years back in the British Medical Journal about “portrayals of doctors in fiction that would be good role models”, the Rivers character portrayed in Regeneration was mentioned several times. Which strikes me as a pretty good way to be remembered.

Revisitation 1934 – Dr W H R Rivers – Siegfried Sassoon

What voice revisits me this night? What face

To my heart’s room returns?

From that perpetual silence where the grace

Of human sainthood burns

Hastes he once more to harmonise and heal?

I know not. Only I feel

His influence undiminished.

And his life’s work, in me and many unfinished.

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O fathering friend and scientist of good

Who in solitude, one bygone summer’s day,

And in throes of bodily anguish, passed away

From dream and conflict and research-lit lands

Of ethnological learning, – even as you stood

Selfless and ardent, resolute and gay,

So in this hour, in strange survival stands

Your ghost, whom I am powerless to repay.

1. Rivers WHR “The Repression of War Experience” Lancet, XCVI., pp. 513-33, 1918. The article can be found on the net here.

2. Rivers WHR and Webber HN. “The action of caffeine on the capacity for muscular work” Journal of Physiology 36: 33-47: 1907 (August).

3. Rivers WHR. “The influence of alcohol and other drugs on fatigue”: Croonian lectures 1906” London: Arnold, 1908 Some pages from the lectures can be read.here.

4. Rivers WHR. “Medicine, Magic and Religion” Fitzpatrick Lectures 1915, 1917.. Lancet 1916; i: 59-65, 117-123; 1917;2: 919-23, 959-64.

5 Sassoon writes about Craiglockhart and Rivers in Sherstons Progress, the third and final part of his memoirs of WW1; Graves mentions Rivers in his famous memoir Goodbye To All That

[BPSDB]

The Multi-Coloured Golf Umbrella

This week saw the death of arguably the 20^th century’s greatest novelist, and certainly one of its moral consciences, with the passing of Aleksandr Solzhenitsyn [1]. Solzhenitsyn was also a mathematician and physicist, teacher, and most famously a political prisoner in the Soviet Gulag.

Although the first Solzhenitsyn I read was One Day in the Life of Ivan Denisovich (required reading for school kids studying Russian back in the days when we still had a Cold War), the book that I have re-read the most over the years is The First Circle. The Ukranian Professor down the corridor from me insists this is actually a lazy translation of the Russian title, “V krugye pyervom”, which means “In the First Circle”. The title is a literary allusion to the First Circle of Dante’s Hell in The Divine Comedy. As Wikipedia puts it:

“[In] Dante‘s first circle of Hell in The Divine Comedy … the philosophers of Greece live in a walled green garden. They are unable to enter Heaven, but enjoy a small space of relative freedom in the heart of Hell.”

The small space of Solzhenitsyn’s First Circle is a special prison, or sharashka, where an assortment of engineers, scientists, mathematicians and philologists – all prisoners of the Soviet state – work on special technical projects for the Soviet Interior Ministry or MVD. So – a slave labour camp for scientists. Perhaps it is this which has me re-reading the book every so often. Many of the characters in The First Circle are recognisable scientist types, trying to find some escape, and some reason to carry on, in the technical problems that they are set by their work, and in the fellowship of scientific colleagues. Solzhenitsyn’s early training as a mathematician and physicist explains how he ended up in the sharashka (the character of Gleb Vikentich Nerzhin in The First Circle is autobiographical) some time after his original arrest for writing a letter criticizing Stalin.

Solzhenitsyn is not what you would call a humorous writer, but there is a black humour in his work. He, and his characters, are ever alive to (usually bitter) irony.

So after the preamble, here, as a small personal tribute to Solzhenitsyn, is a short piece written by a friend of mine who uses the pseudonym “Mark Cain”. It was originally written as a Christmas Story for the magazine Physiology News. The story is set in a modern British University, but is a kind of homage to Chapter 54 of The First Circle, “The Smile of the Buddha”. Read the book (which you should anyway) to see why.

Anyway, without further ado:

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The Multi-coloured golf umbrella

By Mark Cain

Once upon a time, a few years ago, and somewhere in the UK, there was a medical school – a fairly typical one. The medical school building was showing its age. The drains and sinks stank, especially after the ventilation was turned off at 5.30 pm. The smell of phenol-chloroform mixture would often waft down from the molecular biology labs upstairs. The cleaners came every couple of weeks to re-arrange the dust on the floor, but avoided the really nasty bits under the benches, and also most of the labs (too hazardous). The tops of the 1970s wooden benches were thick in accumulated sticky grime, because there were no technicians left to clean them (cut-backs and voluntary redundancies). And it was always dark. The windowless corridors were gloomy. Even the light fittings that worked had only half the number of fluorescent tubes they were made for, since every second tube had been removed in an early 80s ‘electricity economy drive’. So half the proper number of flickering, bare, fluorescent tubes shed a sickly light as the workers scurried along.

Then, one day, strange things started to happen.

First, extra cleaners started to appear – or at least, the same cleaners appeared more often. Rubbish was removed every day. Corridor floors were scrubbed and polished every week – even the dark corners that were usually ignored. Posters and notices stuck on the doors and walls were pulled down, and the lab staff sternly admonished not to put them up again. The next week painters came and repainted several corridors in sunny yellow-white tones, rather than the usual institutional pale green.

The staff was surprised, and asked each other what it could all mean.

Next, something truly astonishing happened. A man in brown overalls appeared, and began to put fluorescent tubes back in the light fittings. Not all of them, to be sure, but all the light fittings in the main corridors. And then he started re-fitting the diffuser panels to the light fittings.

The staff was amazed. The light fittings had had no diffuser panels since half the tubes had been removed all those years ago. Where had these diffuser panels come from? Had they been hidden away somewhere for the intervening nigh-on two decades? Had they been specially cleaned? Were they new? And what did it all mean?

And then – the rumours began to circulate. An Important Visitor was expected, people whispered. More than merely Important – a VERY Important Personage altogether. Though no-one knew when, the unusual events gathered pace. The grass in the building quadrangle was cut, and all rubbish bins were emptied twice daily. Extra cleaning patrols scoured the building picking up stray food wrappers and crisp packets. The windows and glass doors at the medical school entrance were cleaned and all the signs renewed. The battered chairs by the reception area were replaced by ones newly re-covered in bright floral fabric, and fresh flowers in a vase appeared on the reception desk.

Finally, it was whispered that the senior secretary had been seen coming into the building with two brand-new, especially-large, multi-coloured golf umbrellas.

The great day came at last. A convoy of chauffeur-driven government Jaguars arrived, disgorging the Very Important Visitor, his assistants and his security men. A thin rain was falling, but the Very Important Visitor reached the front door without a single raindrop touching him, thanks to the resourceful chief secretary and an assistant wielding the multi-coloured golf umbrellas. The Important Visitor and his entourage passed rapidly down a pre-planned route through the medical school’s well-lit and re-painted corridors. They stopped briefly to look at the newest refitted laboratory, where they were greeted by several senior professors wearing white coats. (When photographs of this historic occasion later appeared, everyone agreed it was the only time they had ever seen the professors wearing white coats.) After ten minutes of photographs in the lab, the Important Personage, his retinue, and the professors proceeded to the site of the new medical school annexe. Here the Important Visitor donned a hard-hat and posed for more photographs with a ceremonial pickaxe and several important university administrators, including the University Vice Chancellor. Pausing only to tell everyone how immensely impressed he was, the Important Visitor and his entourage returned to their cars and left.

The next day, staff entering the medical school building saw that the flowers were gone from the reception desk. On their way to the labs they passed a man in brown overalls, who was removing every second fluorescent tube from the light fittings in the main corridors. Soon life returned to normal. The floors went back to a fortnightly clean. The piles of undisturbed dust returned to the corners, barely visible in the half-light. The drains smelled as bad as they ever had. The pictures of the Very Important Person with the University Vice Chancellor and the senior Professors appeared in the university newsletter a week after the visit, but they were soon forgotten too.

Before long, people began to wonder if it had all been a dream. Some even said it had been. Apart from the new annexe building going up next door, everything in the medical school was exactly as it always had been.

Except for one thing.

In the corner of the chief secretary’s office, leaning against the wall, stood an extra-large, multi-coloured, golf umbrella.

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[1] Alexsandr Isayevich Solzhenitsyn, decorated soldier, political prisoner, teacher writer and Nobel Laureate, born December 11 1918; died August 3 2008. His Guardian obituary is here, and one from The Times here.

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