Thursday, January 10, 2013

I shall please

Saint Jerome—one of the four traditional Great Doctors of the Western Church—was born around 347 in the Roman province of Dalmatia, at a place located in present-day Slovenia. He is celebrated for his translation of the Bible into a Latin version referred to as the Vulgate.

Saint Jerome in his study by Antonio da Fabriano II (Italian, 15th century)
In my modern copy of the Bible, which is not based upon Jerome's work, Psalm 116 verse 9 reads as follows:
I shall walk in the presence of the Lord
in the land of the living.
This statement evokes the curious image of the psalmist going for a stroll with God. While it's a fact that the original Hebrew and the Greek version known as the Septuagint does indeed refer literally to walking, Jerome realized that it should be interpreted as a metaphor meaning "I shall be in step with the Lord" or simply "I shall please the Lord in the land of the living".  So, in Latin, he produced a line that starts with the first-person singular form of the future tense of the verb "to please":
Placebo Domino in regione vivorum.
And, many centuries later, Jerome's verb—I shall please—became celebrated in the domain of medicine. There, it was no longer a question of pleasing God, but rather a down-to-earth affair of pleasing a sick person by giving him something—anything at all, if need be—that makes him feel better. The mysterious phenomenon of placebos was born. A placebo is a would-be medicament that contains no proven therapeutic agent whatsoever. So, when an improvement in the patient's health appears to have taken place after his ingestion of the placebo, we are obliged to conclude that the causes of that improvement (if indeed they might be determined objectively) are not of a purely pharmaceutical nature.

The Christian invention of so-called "holy water" remains one of the most ancient kinds of placebo... although most believers would be offended if this substance were to be designated as a product designed to be used in a medical sense. Placebos of a more explicitly therapeutic kind are provided by the everyday pseudo-pharmacological wizardry known as homeopathy, which I evoked in my article of 11 February 2012 entitled Herbal and homeopathic products [display].

At this level, the patient is entitled to declare "I shall please", neither to God nor to himself, but to shareholders of the prosperous companies that make a fortune through the sale of such stuff.

Up until quite recently, I was inclined to assert personally that substances such as holy water, homeopathic preparations and herbal concoctions cannot possibly have any authentic therapeutic effects, for the simple reason that they incorporate no genuine chemical agents capable of influencing objectively the physiology of patients. This was a mistake. Mea culpa. Today, in the purest of homeopathic traditions, I wish to water down my formerly negative remarks. My current opinion is that products such as holy water, homeopathic preparations and herbal concoctions can indeed lead to significant improvements in the health of many patients. But they do so, not because of molecules within the products themselves, but because of a curious set of circumstances, which we are only starting to understand, that can be designated globally (for the moment) as the placebo effect.

The starting point for an understanding of this effect is the famous organic chemical called dopamine, which is synthesized by the human body. As recently as 2000, the Swedish scientist Arvid Carlsson was awarded the Nobel Prize in Physiology or Medicine for his discovery that dopamine acted as a neurotransmitter. That's to say, whenever this substance happens to be synthesized in one region of the human body, it can flow to a neighboring region and act, as it were, as a messenger. Above all, the messages conveyed by dopamine are perceived invariably by their recipients as "good news". In simple terms, when your cerebral factory happens to be churning out a high volume of dopamine, the chances are that certain parts of your brain are going to start convincing you that you're on top of the world. You'll be on a genuine dopamine high! And you'll forget about pain!

In the special case of a patient who has been given a miraculous pill or a drop of a magic elixir, and told that it will make him feel better, the outcome will depend upon whether or not this simple set of events succeeds in turning on the patient's dopamine factory. In the case of some lucky patients, it's as if they start to feel better (thanks to a surge in their dopamine production) as soon as they detect on the horizon the silhouette of a friendly nurse (or exorcist, or maybe Prince Charles). Less fortunate patients might ingurgitate countless spoonfuls of aromatized snake oil without the least change in the level of their dopamine production. Consequently, they'll remain in a dismal state of mind, and will fail to understand why their high-dopamine companions are dancing around on the table tops of the homeopathy ward.

Up until recently, nobody knew why it was that many patients reacted favorably to placebos (even when they were told that their "medication" was nothing more than sweet water), whereas the state of other patients didn't budge until they received their dose of genuine high-powered (maybe expensive) pharmaceutical molecules. A couple of months ago, a fascinating breakthrough was announced in a journal of the US Public Library of Science.

The researchers belonged to two celebrated medical centers: Harvard Medical School and the Beth Israel Deaconess Medical Center in Boston.

Now, if researchers at these centers have been intrigued for ages by suspected differences in the reactions of patients to placebos, it's not because they're interested in promoting quackery, but for a quite down-to-earth reason that concerns the everyday testing of new medication. In all clinical trials, researchers are always obliged to create a control group of patients whose members receive placebos. Obviously, it's important to realize that findings at the level of such a control group would be biased if some of its members belonged to the category of prolific dopamine producers. So, they were seeking some kind of criterion that would enable them to detect such individuals, and exclude them from clinical trials. And it would appear that they have found a perfect criterion.

All humans possess a gene known as COMT (for catechol-O-methyltransferase) that is associated directly with the phenomenon of dopamine release. As often happens, the exact composition of this COMT gene can vary from one individual to another. And these variations concern particularly two short sections of the DNA double-helix string, which can be coded in three different fashions:

1. In some individuals, their COMT gene contains a pair of molecules of the amino acid called methionine. Such people are designated as met/met.

2. In other individuals, their COMT gene contains a pair of molecules of the amino acid called valine. Such people are designated as val/val.

3. Finally, there are individuals whose COMT gene incorporates both a molecule of methionine and a molecule of valine.

The Boston researchers were somewhat amazed but delighted to observe that all their met/met patients turned out to be big dopamine producers, who reacted strongly to placebos. All their val/val patients, on the other hand, turned out to be low-level dopamine producers, who shunned the placebo effect. And patients with both a med and a val molecule were in a lukewarm middle zone, with no clearcut reaction to placebos.

This is a truly amazing discovery. What it suggests is that people are predetermined genetically to either react positively, or fail to react, to placebos.

Although the research in Boston was limited to a particular medical problem and clinical situation, it is tempting to extrapolate their findings to all kinds of settings in which individuals are expected to either "believe" (in a general sense) or "fail to believe". Kathryn Hall, the study's lead author, put it as follows:
"It's really interesting to now think that there's this potentially fundamental difference between people. And it involves not just the placebo or the physical pill, but also involves this interaction that you have with your caregiver. It's really important to think about the ways in which we're similar and different, and design or develop medicines that are going to help us all heal."
Needless to say, I'm most curious to learn whether I'm personally met/met, val/val or met/val. In fact, in spite of my intellectual aversion to quackery of all kinds, I have every reason to believe that I'm met/met. I have recollections of painful times, back in Paris, when I was suffering from acute otitis. The arrival on the scene of a caregiver, particularly if she was a charming female, would cause my suffering to cease miraculously. And I didn't even need to swallow mysterious pills or pray to the Lord. My personal placebo was the nurse. It was she who pleased me.

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