Pharmacogenomics: Tailored Drugs, Bespoke Medicine

A DNA laboratory [Image: University of Michigan School of Natural Resources and Environment]

The Worldly’s Samuel Horsfield takes a deeper look into one of the most hotly debated topics of modern science: Pharmacogenomics.

What is Pharmacogenomics?

Genetic factors are known to play into the effectiveness of a drug treatment

The topic of pharmacogenomics is one that hasn’t yet found its place in the public spotlight. The word itself is alien to most people, let alone the exciting, yet somewhat controversial concept behind it. In fact, it promises to revolutionise modern medicine. Pharmacogenomics is concerned with how the variation within an individual’s genome affects their response to a drug. Putting it another way, anyone who has ever had a prescription, or any other kind of drug therapy (presumably a large proportion of the readership), will most likely remember a long list of possible side effects made explicit by their doctor, ‘possible’ being the word to take note of here. There is a possibility (quite large in most healthy individuals) that none of the side effects will show themselves over the course of the treatment. An unlucky few will, however, produce these adverse effects to the drug due to a number of factors. Chiefly however, the adverse reactions are down to the way in which their bodies take up, utilise and eventually eliminate the drug from their system. You could say they were predisposed to react this way to the treatment, a predisposition written in their genetic code.

Pharmacogenomics is the tailoring of drugs to treat the wide genetic variation seen within a population. The ‘one size fits all’ mentality has been gradually fading out of medicine, with age recently becoming a key determinant in prescription dosage. Genetic factors are known to play into the effectiveness of a drug treatment, however are not currently implemented in a huge majority. Take common bacterial infections for example. A number of antibiotics are known to be ototoxic (damaging to the ear) in around 33% of cases, 3% of which lead to irreversible damage. By implementing pharmacogenomics into medical practice alternatives could be used to avoid such debilitating adverse drug reactions (ADRs).

 

What does this mean for medicine?

‘One size fits all’ is no longer a viable approach to drug therapy

It is not the genes themselves that directly affect drug response. Genes are sections of long double stranded molecules of deoxyribonucleic acid (DNA), which act as a code for functional biomolecules, known as proteins. Proteins have a vast array of structures, which relate to their function, and make up every structural and active component within the body. This ranges from the keratin in your hair and fingernails, to the digestive enzymes in your stomach acid. It is the functional proteins, those that control metabolic reactions (reactions in which various molecules are built and degraded), being targets for both the drugs themselves and the logistical machines, allowing the uptake and eventual elimination of the substance from the body.

Being encoded for by genes, proteins are naturally as malleable as the DNA themselves. The DNA sequence shared by every cell in an individual’s body can vary slightly from person to person and because of this, so can the various proteins for which the genes encode. A group of proteins responsible for the onset of ADRs is the cytochrome P450 family found predominantly in the bodies detoxification centre, aka the liver. 6 of the 50 cytochrome P450 enzymes are known to metabolise 90% of all available drugs including antidepressant and antipsychotic medications. If one or both copies of the gene are variants from the healthy version (see article on genetic counselling to find out more about genetic inheritance) the ability of the individual to expel potentially toxic substances from the body can be critically hindered. 7% of Caucasians, and even higher proportions in individuals of Asian/ African descent, are so called ‘slow metabolisers’. This can lead to high and potentially lethal levels of drugs remaining in the body for prolonged periods of time. Amazingly, there are even instances in which individuals are ‘ultrafast metabolisers’, inheriting genes encoding for super efficient versions of cytochrome P450 enzymes. In these cases drug levels in the body are never high enough to elicit any kind of therapeutic effect at a normal prescription dosage. It is clear ‘one size fits all’ is no longer a viable approach to drug therapy, and so both the type of drug and the size of the prescription must be addressed in order to provide effective treatment for all members of the public.

 

At what cost?

Mammoth sum of $640 billion to sequence the entire population of the USA

The incentive to provide a personalised service of drug therapy naturally has both ethical and economic implications. According to the FDA, in the US alone ADRs occur in over 2.2 million hospitalised patients annually, accounting for over 100,000 deaths. This places ADRs as the 4th highest cause of death amongst American citizens, ahead of both AIDS and diabetes. The costs involved in the care of ADR patients in US hospitals amounts to a staggering $136 billion each year.

To achieve such an enormous reinvention of modern day drug therapy requires a revolutionary movement in the sequencing and storage of genetic information. To save a huge amount of both time and money, only genes that are known to be linked with drug response are investigated. More specifically, sections within said genes prone to variation are sequenced, containing single nucleotide polymorphisms. These are areas in the genome that can vary by a single DNA base (aka nucleotide) between individuals, but have a profound effect on the protein for which they encode (to put this into perspective, the average human gene is made up of between 10,000 and 15,000 bases!). According to the Journal of Pharmacogenomics, the cost of sequencing one single nucleotide polymorphism varies between 1-10 cents. A range of over 200,000 genes known to have polymorphisms implemented in ADRs can be therefore be sequenced in their entirety for around $200 per patient, in which case the records can be stored for future eventualities.

Crunching the numbers produces a seemingly mammoth sum of $640 billion to sequence the entire population of the USA. The question now is, would it be worth it?

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