Are Placebo’s Getting More Effective?

At least some people believe they are – particularly those drug companies whose pipeline champions are being sunk by the famous effect. This Wired article offers a great list of drugs recently entombed by the placebo effect. It also explains it’s history and the concern it is causing in drug development. But I disagree that the placebo effect is ‘increasing’ as they suggest.

The drop in drug approvals they cite and many of the specific examples they give are probably not due to an ‘increasing placebo effect’ but poor trial design, less effective new therapies and the lack of low hanging fruit. I would even suggest that the perceived change in the effectiveness of Prozac is actually the result of better experimental measurement leading to better data that demonstrates what clinicians have always known.

Trials are becoming harder to design as there is less money available – in part because potential profits from new drugs are not what they used to be. Studies are ‘powered’ at an absolute minimum, and resources sent offshore to clinics with high capacity but lower quality guarantees. This is of particular concern in studies where drug efficacy is highly dependant on patient or clinician reporting rather than hard measures such as well defined lab tests. They Merck scientist in fact demonstrates this when he says they saw different effects in Spain and France.

They author also fails to mention that many new drugs being trialled are in therapeutic areas fairly well served by existing drugs. there is less room for improvement and therefore it is harder to create more efficacious drugs. Early phase testing is easily misleading due to small sample size and other biases.

When the article delves into the cognitive neuroscience behind the placebo effect they indeed point to the fact that by definition, the placebo effect can’t ‘increase’ unless the human brain changed substantially in the last 40 years.

Despite this it is a great article and I look forward to hearing more about the Placebo Response Drug Trials Survey.

Maximising Evolution to Generate new Organisms

The idea of genetic engineering has until now focused on the process of separately modifying individual genes in organisms then selecting out these new organisms for use. A common example is transfecting a gene into a bacterial, yeast or mammalian cell to express a desired protein.

A team in Harvard has employed a technique they describe as Multiplex Automated Genome Engineering (MAGE) where they ‘retooled evolution’ to generate genetic diversity at an unprecedented rate, increasing the odds of finding cells with desirable properties.

They used E. coli bacterium, which we know contains approximately 4,500 genes. The team focused on 24 of these – honing a genetic pathway to increase production of the antioxidant lycopene, optimizing the sequences simultaneously. They took the 24 DNA sequences, divided them up into manageable 90-letter segments, and modified each, generating a suite of genetic variants. Next, armed with specific sequences, the team enlisted a company to manufacture thousands of unique constructs. The team was then able to insert these new genetic constructs back into the cells, allowing the natural cellular machinery to absorb this revised genetic material.

Some bacteria ended up with one construct, some ended up with multiple constructs. The resulting pool contained an assortment of cells, some better at producing lycopene than others. The team extracted the best producers from the pool and repeated the process over and over to further hone the manufacturing machinery. To make things easier, the researchers automated all of these steps.

“We accelerated evolution, generating as many as 15 billion genetic variants in three days and increasing the yield of lycopene by 500 percent,” Harris says. “Can you imagine how long it would take to generate 15 billion genetic variants with traditional cloning techniques? It would take years.”

A damn long time! Hopefully we begin to see this technology used in the creation of mammalian cells lines for used in medical-biotech production too.