Unravelling the magic — the history behind placebos in research

TODAY, we take the use of placebos in clinical trials for granted, often assuming that this is a relatively recent innovation. The truth, however, is more interesting and begins in pre-revolutionary France.

In 1778, Parisians who were sick and rich could try a novel treatment from a charismatic physician called Anton Mesmer who had recently arrived from Vienna. His clinic was in the exclusive Place Vendôme in Paris. There you would enter a dimly-lit room and join others seated in concentric circles. At the centre of the room was a wooden tub filled with ground glass, iron fillings and bottles of magnetised water along with metal rods. You would be invited to hold one of these rods on your affected body part. In the background there would be hushed silence punctuated by the ethereal sounds from the glass harmonica – a newly invented musical instrument sounding like a wet finger stroking the rim of a wine glass.

The scene set, Mesmer would appear in a lilac silk coat carrying a metal wand. He would sit en rapport with some patients – knees touching and gazing intently into their eyes. His assistants, reported to have been young and handsome, would also help the magnetic flux by massaging the knees, backs and breasts of patients. This combination of sensory stimuli caused many patients to become entranced or mesmerised and some to faint or convulse. And, of course, many claimed to be cured.

But what was really happening here? Lighting, music, costume, drama and sensuality – what was going on was more ritual than medicine, more suggestion than treatment, a little more Dumbledore than doctoring. Perhaps in a pre-enlightenment era, this would simply have been viewed as magic. But, this was the 1780s – the world had moved on. Now, this magic had to have a rational scientific basis and Mesmer provided it. He believed magnetic fluid flowed into us from the stars and that disease was the result of an obstruction to this flow. His treatment was designed to realign this animal magnetism.

Mesmer’s treatments soon became the height of fashion, but he was not without critics, and the establishment would have nothing to do with him. Indeed, the King himself stepped in and appointed a commission to investigate, asking the elderly American Ambassador to France to take the lead. This was none other than Benjamin Franklin. Today we remember Franklin as an elder statesman, but in his lifetime he was among the most celebrated scientists and it was in this capacity that the King sought his help.

Franklin and his colleagues devised a series of experiments using placebos for the first time. Subjects were presented with magnetised objects and with sham objects that looked the same but were untreated. The patients were unable to distinguish the two and variably reported the effects. As a result of these placebo-controlled experiments, the commission was able to conclude that there was no basis to Mesmer’s claims. Instead, they explained that animal magnetism “owed its apparent efficacy to the power of suggestion in susceptible or naïve individuals.”

Although the term placebo did not enter medical parlance until 1785, it is clear that for centuries before healers had used remedies they knew to be inactive, but which they also knew would appease their patients. Placebo indeed is Latin for “I shall please”. However, Franklin and the Commissioners are credited with being the first to use placebos in a clinical research setting.

Placebos are now an essential part of modern research, used to prevent confounding from the so-called placebo effect, i.e. the effects that an inactive substance, procedure or device may have when administered in a clinical context over and above the effects observed of no treatment. This effect is complex and still relatively poorly understood, but it is undoubtedly real and can significantly impact our evaluation of different treatments if not taken into account. Whatever the treatment, it may be possible to create a matched, but ineffective alternative to act as a control. Benefit may only be claimed if the active treatment produces significantly greater effect than the placebo.

Thus, without the ingenuity of a group of enlightened French scientists led by an aging American diplomat, perhaps today we would not have the placebo-controlled randomised clinical trial. Perhaps our clinical practice might still be based only on observation and anecdote rather than hard evidence. And perhaps physicians would still have wands.

© Allan Gaw 2018

Originally published in FYi on July 26, 2018

https://www.mddus.com/resources/publications-library/fyi/issue-20/unravelling-the-magic

 

If you are interested in reading more about the history of clinical research take a look at my books:

‘Trial by Fire’ and ‘On Moral Grounds’ — paperback copies of these are available from my website:

http://www.allangaw.com/sapress.htm

and e-copies are available from kindle on Amazon.

 

 

At rest but not forgotten

A year ago, a friend died.  We had known each other for over four years, but we had only met in person three times.  Most of our friendship had been virtual and what began as part of my research into the ethics of clinical trials was to end one evening in a deep and painful sense of loss.

I had been expecting the email from her husband for some time.  We all knew just how sick Joanna was, but, as is often pointed out by the bereaved, expectation does not forestall the shock when it actually comes.  Her death had at least been peaceful and pain-free, surrounded by family, and I suppose that is all most of us can hope for, but she was only 62.  Her cancer had been particularly exotic and pernicious and the end though slowed by everything modern medicine could muster was, I’m afraid, inevitable.  And, now I feel so deeply saddened that we will never meet again.  There was still so much to do and say and write, but a door was simply closed on our friendship. Slammed.

I had first tentatively contacted Joanna because of my professional interest in her father, Maurice Pappworth, who had in the 1960s been a firebrand in the world of research ethics.  I wanted to write about him and I felt I needed her permission and that of his surviving family.  After explaining what I wanted to do, I think she was quite naturally suspicious.  Her father had been a highly controversial figure who had polarised those he met, and I suspect Joanna was anticipating a hatchet-job that would do nothing to serve her father’s memory.  However, my intention was quite the opposite, feeling that history had been especially unkind to him and that his actions and their motives deserved a fairer analysis.  I felt it was time for his contributions to be brought before a wider public.

Joanna agreed to meet me in London, on the steps outside the V&A, so we could talk about my project in the museum tearoom.  I arrived early, which was a mistake, as the passing time only served to magnify my anxiety.  History is comfortable when it is confined to dusty pages, but here was I about to meet the flesh and blood end of it.  She was colourful when she arrived: red beret and bright purple coat and a lipstick that dazzled.  She was a tiny woman and I towered over her, but she was unfazed for Joanna was only small physically.  We spent a couple of hours in the V&A tearoom talking and eventually laughing about things.  As we parted, I confessed how nervous I had been to meet her and she simply dismissed my silliness but allowed me to kiss her hand in thanks before we went our separate ways.

I wrote my first paper about her father’s work and sent it to Joanna and she in turn shared it with her two sisters.  I honestly did not know what to expect.  It’s easy to write about history in the abstract, where the characters involved might be thought of as nothing more than fictions.  But here I was writing about a very real man, recently deceased, and his three children were reading my words.  I was overwhelmed by the positive responses I received from Joanna and her sisters and my confidence was buoyed to carry on the project. I wrote a further paper and a book chapter and gave a number of talks about his work and I hope in a small way I have brought his name and his contributions back into the ongoing discussion of the ethics of clinical research.

But, I had only written about her father’s role as a whistle-blower, exposing unethical clinical research.  As part of my research, I had also interviewed his former students who held him in nothing short of awe, and his secretary, a remarkable woman called Helen Bamber.  She attributed much of her own later success in the fields of international human rights as having their origins in her conversations with Pappworth. What was emerging was an even more interesting story, only fragments of which were widely known.

I was one of the people to encourage Joanna to write her own memoir of her father, realising that her perspective as his eldest daughter would be unique.  She completed the manuscript in the weeks before her death and kindly sent it to me to read.  My last email to her a couple of days before the end was to tell her just how well she had told the story.

It was a beautifully crafted piece of work,  successfully blending together her family’s personal history with a fiercely objective analysis of her father’s professional life.  As a result, she sculpted a three dimensional portrait of the man.  It might have been easy, as his daughter, to paint either a simple loving or an equally simple hateful portrait, but Joanna offered the reader an unsentimental narrative, that rang true.   His professional story was familiar to me, but most of the back story was not, and the way she wove that into her narrative provided much needed context for the man, his attitudes and his actions.  I found the moments when she offered her own personal reminiscences of her father especially poignant, and one of the biography’s greatest strengths.  No one else could have written such a memoir and I was delighted that she had.  However, it is part of my sadness that I’ll never know if she read my comments on it.

With a death, our thoughts must naturally turn to those left behind, to Joanna’s husband and her children and her sisters.  But, there is also the matter of legacy, especially if we have an eye on history.  Joanna was a daughter, a sister, a wife, a mother, an academic, a teacher, and, for me, a friend and through all those roles she was an inspiration, touching those she met and worked with in many ways and it is our collective memories of her that will abide.

People, of course, only die if they are forgotten, and no one, I expect, who ever met Joanna will forget her. I will never forget her warmth and encouragement, her impeccable manners and her hospitality even when she was gravely ill. And I will never forget the debt I owe to her and her family.

Rest peacefully, Joanna, but in your sleep do not expect to be forgotten.

Joanna Seldon (1954-2016)

 

 

Translational Shopping

The supermarket was small by any standard and tiny compared with what I was used to in Glasgow, but here in Kyle of Lochalsh on the Western edge of Scotland and in sight of the single span of the Skye Bridge, was a shop remarkably well-stocked. But, as well as the obvious, there was also fun to be had as I noticed with curiosity that the aisles and shelves were labelled in Gaelic as well as English.

I already knew that ‘aran’ meant bread, but to see my meagre knowledge of Gaelic validated by the green sign hanging over the bakery section gave me a small but palpable thrill. The feeling reminded me of the first time, as a child, that I overheard a native French speaker casually utter words I had only ever seen in my school books. At that moment, I realised that, after all, the French language was real. It wasn’t all just an academic exercise designed to torment. And now standing in the Co-op in Kyle I was reliving that moment and it felt warm.

I looked around eager for more and was not disappointed. ‘Làgar’ did not present too much of a challenge for the beer shelf; ‘gràn’ for cereals was likewise reasonably clear and of course ‘yogurt’ was self-explanatory. Just when I thought I was getting the hang of the lingo, the vocabulary moved up a notch, along with Gaelic’s delightfully floral approach to spelling. The sign said, ‘croispaichean’ and hung over the shelves of crisps. ‘Tràth ullamh’ signposted the ready meals, while ‘baidh eadar-nàiseanta’ proudly, if cryptically, pronounced international foods, and indeed there was a surprisingly rich selection from around the globe in this little supermarket on the edge.

I did know that the cheerful salutation of ‘Slàinthe’ that traditionally accompanied the clinking of whisky glasses meant health, so the sign ‘slàinthe is maise’ came as no surprise to be hanging over the paracetamol and cough mixtures as well as the cosmetics for this was health and beauty.

And then there was my favourite, ‘fuineadaireachd-dachaigh’ which was one of those Gaelic words that you struggled to get a handhold on, being elusively full of vowels and any obvious meaning. Despite its inaccessibility to my meagre language skills, all I found it meant was home baking. You’ve got to love a culture that can turn flour and sugar and bicarbonate of soda into that.

Translation might be a pleasant game but it is also talked about endlessly these days in science. We are expected to work on so-called translational research, and indeed the Medical Research Council states, ‘Translation is the principle of turning fundamental discoveries into improvements in human health and economic benefit.’ That seems laudable, but there is an underlying difficulty, or at least I think there is. The MRC and indeed many other such funding organisations are powerful advocates of such translational research stating that it drives innovation, speeds up the transfer of the best ideas into new interventions, and improves the return on investment in fundamental research. In other words, fundamental research seems only to have worth today if we can readily see the practical payback from it and in double-quick time at that. And that’s where I think the problem lies.

Fundamental research is by its nature not inherently practical. It’s about studying how fruit flies live and die; it’s about finding new ways to look at molecules down a microscope and it’s about detecting what were once thought only to be theoretical waves in gravity. None of these have obvious benefits; none are going to change our lives for the better in the short term; and of course none are going to make anyone any real money any time soon. But those forays into fundamental research have just earned the scientists who pioneered them the 2017 Nobel Prizes in Medicine, Chemistry and Physics.

Such discoveries may or may not change the world in your lifetime, but they may change your children’s or your grandchildren’s. The point is we don’t know, and our focus today on funding only what can be obviously translated into short term benefit is doing a disservice to the process of scientific discovery, and perhaps depriving us of the most important breakthroughs — the practicalities of which are the stuff of the future.

I like translation. I like the riches to be found when watching one language become another. And I love to learn and appreciate what cannot be readily translated and what might be uniquely expressed in one language and not another. In the same way, sometimes I wonder if a piece of beautiful science, a new understanding, a unique discovery, might be just as beautiful if it cannot be translated, or at least not yet.

© Allan Gaw 2017

 

Now available in paperback…

Testing the Waters: Lessons from the History of Drug Research

What can we learn from the past that may be relevant to modern drug research?

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“I cannot recommend it highly enough: even if you read nothing else about the origins of drug research and what it can (should?) teach us, read this….This is a ‘buy’.”  Madhu Davis review in Pharmaceutical Physician May 2016.

My other books currently available on kindle:

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The Last Words of a Fool

 

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Grammar can be contentious.  The conventions by which we write have been honed over centuries and have become rules of practice. Some would argue, however, that language is in a constant state of development, evolving to meet the needs of each succeeding generation.  This is undoubtedly true of the spoken word, but what of written language, especially formal, written English?

I have recently been assessing the written work of fourth year medical students.  Despite being at the very top end of the educational pyramid these young men and women often struggle to write coherently and correctly.

Common grammatical errors abound and rather than concentrating on the ideas and opinions of the writers I found myself going through the text with a red pen in hand, much as my elementary school teacher did.  Some grammar is complex and controversial.  Some conventions vary on different sides of the Atlantic.  However, some aspects of grammar are not open to debate and failure to apply them is not just distracting, it forces the reader to the uncomfortable conclusion that the writer is a fool.

Let me illustrate this with one example of the kind of thing I mean.  “Should have”, “could have” and “would have” may be contracted in informal English to “should’ve”, “could’ve” and “would’ve”.  Now, when we use these contractions in speech, as we all do, they sound as if they have the word “of” after each, instead of the contraction “ve” standing in for the “have”.  The problem comes when a writer mistakenly transliterates this speech form back into writing.  Who would do this? Well, one of these students did it 23 times in the course of a 12 page assignment.  “The patient could of…” and, “these results would of…” jarred my reading to the point that I couldn’t see anything else.  There were probably good parts to the work, but I didn’t get that far.  All I could see were the grammar crimes being perpetrated before my eyes.  Perhaps, unfairly, I was affected by this trauma and I concluded before I had reached the end that the person who had written this was undeserving of anything close to a pass mark.

Like it or not, your readers will judge you not only by what you write, but how you write it.  The rules of grammar are flouted when we speak and that’s not only fine, it is appropriate.  If we had to craft every sentence before we spoke not much would be said. Similarly, in our informal writing we are relaxed when it comes to grammar (although in the spirit of full disclosure, I must declare I do use commas when I text).  We use contractions liberally in our emails and blogs, and split infinitives even find their way in without too much difficulty.  But, the line is drawn when it comes to our formal writing.  Our scientific papers, our dissertations and our university essays should, I would argue, be written as well and as accurately as possible.

I know what I want when I read the work of my students and my peers, but obviously, as the case above illustrates, I don’t always get it.  This raises the question: “why?” Why did this student think that it was acceptable and correct to write “should of” when he meant “should have”?  Had he never been taught the basics of grammar?  Had he never been corrected when making this mistake in the past?  How could he possibly have made it through 13 years of schooling and 4 years of university without being brought to book over such a basic grammatical infringement?

I have read of other academics who bemoan the fact that their students cannot write grammatical English.  Declining standards and educational liberalism are blamed.  However, I am not so sure it is as simple as that.  To say we live in a changing world, where standards of written language are in flux, is so obvious to be trite.  But, things do seem to have speeded up in recent years.  The majority of students’ written practice will, over the last few years, have been in the drafting of sound bites for facebook and twitter.  Grammar is not a high priority there, nor should it be.  These are quick, and dirty, forms of communication.  Few of these students are called upon to write longer pieces of coherent prose in the medical curriculum and probably do not write much beyond their studies.  When was the last letter of several pages you received from anyone, let alone a student?

Formal writing practice is clearly at a low ebb, but grammar is acquired not just by writing, but, possibly even more importantly, from reading.  Do our students read?  Well they can read and some claim in their personal statements to be avid readers.  Actually, all claim to be avid readers, for they believe that this will make them appear intellectually suitable material for entry into medical school.  Whether they do in fact continue with this self-professed literary zeal is moot.

For current students the reasons may be unimportant at this stage of the game.  The damage is already done and the solution is simple.  They need to learn, or at least re-learn, basic English grammar.  And, they have to have an incentive for doing so.  They have to know they will fail if their work is deemed to be poorly presented and poorly written, as well as poorly researched. Fourth year medical students who cannot write are unlikely to turn into Consultants and academics who can.

Lest I appear curmudgeonly, I do not wish to tar all students with this particular brush.  Some students’ written work is not only good but better that I could ever hope to write.  What troubles me though is the number who submit written work that is ungrammatical in such a way that it reveals them to be ignorant of their own state of ignorance.

Beverley Knight sang, “And I wonder, wonder, wonder what I’m gonna do. Shoulda woulda coulda are the last words of a fool.”  I’m with Bev.

© Allan Gaw 2012

My books available on kindle:

SlideEasy and The Business of Discovery are now published and available on kindle and they’re free to download if you’re on Kindle Unlimited.

What can we learn from the past that may be relevant to modern drug research?

Screen Shot 2015-10-14 at 21.22.11

“I cannot recommend it highly enough: even if you read nothing else about the origins of drug research and what it can (should?) teach us, read this….This is a ‘buy’.”  Madhu Davis review in Pharmaceutical Physician

Also available on kindle:

Screen Shot 2015-01-18 at 17.18.54Screen Shot 2015-01-18 at 17.19.16Screen Shot 2015-01-18 at 17.19.58Screen Shot 2015-01-18 at 17.20.06Screen Shot 2015-01-18 at 17.19.43

Screen Shot 2015-01-18 at 17.19.00BIS Cover copyScreen Shot 2015-01-18 at 17.19.29