Monthly Archives: March 2013

Personalized placebo effect

A new article in Nature explores the placebo effect–therapeutic benefit from taking medicine without active ingredients. On the one hand, minimizing the placebo effect is a principle of ethical medical practice, a bulwark against hype, oversell, and charlatanism. Without controlling for therapeutic effects not caused by the drug, one may overestimate the drug’s potency. On the other hand, if the goal is to make the patient well, one might consider it ethical to use every option available—including whatever mysterious mechanisms the body can muster to augment the pharmaceutical therapy. The oldest tradition in medicine is that of helping the body heal itself.

Most interestingly, the placebo effect is highly individualized. This is not surprising, given the complex psycho-somatic interactions involved. Yet in an age in which personalized medicine is the idea of the moment, it seems essential to open the black box of the placebo effect. The authors summarize not only psychosocial variables known to influence patients’ responses to drugs—expectations, anxiety states, hypnosis, and so forth—but also a range of genetic and anatomical correlates of placebo responses. The strongest data are in the area of drugs for anxiety disorders and depression. Documented examples include polymorphisms in serotonin loci and in modulators of monoaminergic tone, plasma noradrenaline levels in interleukin-2 release, and brain anatomy in placebo analgesia.

Such data are exciting in historical as well as therapeutic context. In 1902, at the dawn of Mendelism, Archibald Garrod suggested that humans were as variable and individualized at the biochemical level as they are at the phenotypic level. If this were true, he continued, the phenomena of obesity, the various tints of hair, skin, and eyes, and “idiosyncrasies as regards drugs and the various degrees of natural immunity against infections” could be amenable to biochemical-genetic analysis.

Rufus of Ephesus

Rufus of Ephesus

Going further back, the Hippocratic physician Rufus of Ephesus noted that drugs act differently on different people, and that to prescribe appropriately the physician must ask the patients about their habits, their diet, preferences, sleep patterns, familial diseases, degrees of pain, and numerous other facets of the patient’s history and context. For the Hippocratic physician the body’s own powers of healing, mysterious though they be, were a crucial component of therapeutics. The Nature article’s abstract concludes with a nice statement of individuality that sounds like updated Hippocratism:

Personalizing placebo responses — which involves considering an individual’s genetic predisposition, personality, past medical history and treatment experience — could also maximize therapeutic outcomes.

Personalized medicine is often portrayed as a return to ancient Hippocratic ideals. It is and it isn’t. Despite the hype, “one-size-fits-all” medicine is too cost-effective to abandon. Personalized medicine has always been reserved for those who can pay for it, and little in the age of high-tech genomic medicine seems likely to change that. And yet, this attention to the unique constellation of essential and historical factors that combine in a given patient’s “irrational” drug response does bode well to be anodyne against some of the dehumanizing forces in the recent history of medicine.

 

Sexuagenerian Double Helix

It’s not “DNA day.” That’s in April–fittingly, the date of publication. Today is double helix day.
On this date in 1953, Watson and Crick solved the structure of DNA. What better day to lay to rest a few myths about it?

Watson and Crick

Another, more candid shot from Barrington Brown’s roll.

1) It sparked a scientific revolution.
The double helix caused a stir in the scientific fields closest to Watson and Crick’s work: X-ray crystallography and bacteriophage genetics. But it took several years for the structure and it’s most important implication–the copying of the genetic material–to be confirmed. True, Time Magazine sent a photographer to Cambridge to shoot for a possible feature. From it came Barrington Brown’s famous photo of the duo before a mock-up of the structure, with Crick brandishing of all things a slide rule at it and smirking at the silliness, and Watson gazing, baffled, up at his hero. But they pulled the story. The double helix didn’t become world-famous until after the Nobel Prize, in 1962. the revolution did come, then, but it reverberated from the fusillade of discoveries from molecular biology of the fifties and early sixties: the double helix, the Meselson-Stahl experiment, the operon, and, perhaps most importantly, the genetic code.

Photograph 512. Watson stole Photograph 51.
The beautiful photograph of the diffraction pattern of b-form DNA taken by Rosalind Franklin and Raymond Gosling famously provided crucial evidence that enabled Watson and Crick to solve the structure. Watson obtained the image without Franklin’s knowledge. But the image was given by Gosling to Maurice Wilkins, who gave it to Watson. As correspondence recently published in The Annotated and Illustrated Double Helix makes clear, the administrative relationship between Wilkins and Franklin was murky. Franklin reasonably assumed she was independent of Wilkins; yet he apparently was technically if not in practice her supervisor. Watson may well have exploited these ambiguities; he was intensely competitive for that time. But theft is such an ugly word.

3. Watson and Crick were racing against Linus Pauling.
Pauling seems to have been genuinely surprised to learn that he was racing for the double helix against the oddball duo from Cambridge. Watson probably felt a sense of competition with the great pioneer of structural chemistry, but it takes two to race. Watson thought he was racing against everyone, with the possible exception of Crick. The real competition was with the group at King’s College London–Wilkins and Franklin.

4. The Double Helix is a history of the double helix.
Watson’s best-selling book is a literary-historical memoir. It is an important source for historians, but it must be read with care. The book was shaped by personal goals, politics, and literary strategies as much as by historical events. It is naive to treat it as a literal account of what “really happened.”

In the past sixty years, DNA has become the foundation of biomedicine, an emblem of innateness, the most famous molecule in history. It promises more revolutions to come, in healthcare and in our sense of identity. Let us celebrate it by demystifying it. History, too, can be salutary.

Read On

Comfort, Nathaniel. “‘Novel Features of Considerable Interest’.” Science 339, no. 6120 (2013): 648-48. doi:10.1126/science.1233356.

Gingras, Yves. “Revisiting the “Quiet Debut” of the Double Helix: A Bibliometric and Methodological Note on the “Impact” of Scientific Publications.” J Hist Biol 43, no. 1 (2010 2010): 159-81.

Creager, Angela N. H., and G. J. Morgan. “After the Double Helix: Rosalind Franklin’s Research on Tobacco Mosaic Virus.” Isis 99, no. 2 (2008 2008): 239-72.

de Chadarevian, Soraya. “Portrait of a Discovery : Watson, Crick, and the Double Helix.” Isis 94 (2003 2003): 90-105.