Have we got a pill for you

Warren Hochfeld


It was a most peculiar newspaper headline, on 8 December 2003 the British broadsheet newspaper the Independent announced: ‘Glaxo chief: ‘ Our drugs do not work on most patients’. The subsequent report covered a conference at which Allen Roses, vice-president of genetics at the pharmaceutical giant GlaxoSmithKline, admitted the ‘open secret within the drugs industry’, that fewer than half of the patients prescribed some of the most expensive drugs actually derived any benefit from them. This could be a quick way to a self-induced sacking, except that this isn't the revelation of a close-held industry secret, but rather, common knowledge among drug developers and doctors.

The one size fits all approach rarely does

The administration of a drug, given in ordinary doses, is usually accompanied by a gradual rise in drug concentration in the blood that reaches a peak or steady state and if the drug attains a concentration within the therapeutic range, the characteristic response is expected. The aim of drug therapy is to administer the appropriate drug in the correct dose to produce the desired effect with a minimum of toxicity. However it is a familiar fact of medical life that a medicine effective for one patient may not work for another, even though both suffer the same condition.

This is because drugs are approved and developed on the basis of their general performance in large clinical trials, and although they are essential in demonstrating the general efficacy of new medical products, they rarely if ever will tell us which treatments are best for which patients. The “One size fits all" approach rarely does, from clothes to shoes to hats, few people find that items carrying that label work with their individual bodies.

Prescribing is a tricky science

Physicians prescribe drugs on the basis of the characteristics of the medications and on the probability that reliable and reproducible clinical effects will result, but since some drugs are approved on efficacies of less than 30% and about 90% of today's drugs work for only 30% to 50% of patients, it makes the practice of prescribing a rather tricky science.

In fact there remains few, if any situations in medicine in which a clinician can predict with certainty an individual’s response to drug therapy. It is therefore not surprising that the United States lists adverse drug reactions (ADRs) as the fourth leading cause of death behind heart disease, cancer and stroke. The annual toll: 108000 deaths, more than 2 million hospitalisations and a US$136 billion bill for drug induced illness as a result of adverse drug reactions to doctor prescribed, FDA approved medicine.

It’s in your genes

The order of building blocks (nucleotides) along a strand of DNA encodes genetic information, somewhat like the way a sequence of letters creates a sentence. These particular sequences form genes and even though the majority of our 3 billion letters are lined up in the right order (99.9%), scattered throughout the human genome are millions of variations and a plethora of different sequences.

Each person's genetic makeup is a result of his/her own sequences of letters and forms a well-defined set of directions for hundreds of thousands of different molecules called proteins, which combine, break down and recombine into the same or a myriad of other forms of molecules. They control everything from our height, to the texture of our hair, the amount of oxygen one carries in our blood, our athleticism and our even our IQ. One of the less obvious ways our genes make us all different, less obvious than pretty green eyes or a knack for singing on key, is the way our bodies respond to medicines.

As medicines travel through the body they interact with many of these proteins and small variations in your genes can produce proteins that work differently from those of your friends or relatives.

Happy Hour Pharmacogenetics

Pharmacogenetics is the burgeoning field of investigation that aims to further elucidate the inherited nature of interindividual differences in drug disposition and effects, with the ultimate goal of providing a stronger scientific basis for selecting the optimal drug therapy and dosages for each patient. We all know someone who will laugh excessively at bad jokes after a small glass of champagne, and someone else who can down several pints of beer and yet still discuss celestial mechanics with intellectual clarity. This is happy-hour pharmacogenetics in action. This new field of research is trying to take out the prescribing guesswork and help doctors to identify people who don’t fit the standard prescribing mould.

Don’t find it and fix, predict and personalize

The maturation of the human genome initiative has provided a wealth of primary genetic information and functional genomic data to fuel the understanding of our genetic differences and its functional consequences. Dozens of companies have sprung up over the past few years, quantifying and cataloguing human genetic variation and using algorithms to tease out correlations among markers, genes and drug response. The prospect of examining a person's entire genome, or at least a large portion of it in order to make individualized risk predictions and treatment decisions is tantalizingly within reach.

Insert chip, cure disease?

Outstanding in this technical revolution are DNA microarrays which consists of a glass microscope slide supporting thousands of microscopic features (spots) arranged in a grid. Each feature comprises a DNA-based probe designed to detect the activity of a different gene of known identity; the identity of each probe is known from its location in the grid. Each spot has a unique DNA sequence, different from the DNA sequence of the other spots around it. Thus each spot will hybridize only to its complementary DNA strand. In this way each spot is acting as a probe to determine the levels of a specific gene expression in a collection of cells.

The right drug for the right patient in the right dose at the right time

Imagine visiting your doctor for an annual exam, only this time the checkup begins not with a physical but with a routine sequencing of your genome. With a handful of concrete examples to go on so far physicians have been able to use this information in conjunction with a full and accurate description of clinical symptoms and prescribe the right drug for the right person at the right dose at the right time. Although the image of a straightforward glide into perfect, personalized medicine is way off the mark, Pharmacogenetics in its infancy represents a structural model for efficient healthcare; preventive, coordinated, and evidence-based.

For more than 20 years the industry had been dominated by “one size fits all” blockbuster drugs, so it is likely the big pharmaceutical companies will remain sceptical, but economics aside the real winners will be patients. The stakes are high and the future uncertain but a tectonic shift is taking place and the pharmaceutical ground is certainly starting to shake.

* Warren Hochfeld has a BCom from Unisa, a BSc, Bsc Honours and an MSc from The University of Pretoria, and is currently engaged in PhD research at The Department of Medical Genetics, Cambridge University


February 2010