Pharmaceutical drugs are an integral part of healthcare, but a treatment regimen that works for one individual may not produce the same benefit for another. Additionally, a given drug dose may be well-tolerated by some, but produce undesired (and sometimes severe) adverse effects in others. In the United States (with similar statistics in other parts of the world), serious drug adverse reactions account for over 6% of hospitalisations, with over 100,000 cases of fatal drug reactions. Understanding why individuals react to drug treatments differently is key for optimizing healthcare and avoiding potentially preventable harms associated with side effects.
Individual differences in diet, activity levels, and other lifestyle factors obviously contribute to this variation in drug response. However, this variation also has a genetic basis. This is evidenced by results of twin studies, and ethnicity-specific differences in response to drugs such as anti-cancer agents. By now, a number of genetic variants have been linked with variations in drug response. These can be classified into several major groups:
- Variants that alter the therapeutic target of the drug: These can affect how well a drug can exert its effect on the cell, and hence the patient. For instance, asthma patients with a mutation in the gene ALOX5 (which encodes 5-lipoxygenase, an enzyme needed for manifestation of asthma symptoms) fail to derive a clinical benefit from the anti-asthma drug ABT-761. The mutation in question reduces the expression of ALOX5; it could be that this reduces the effect of ABT-761 by reducing its path to affect the cell.
- Variants that affect how a drug is metabolised, either to produce its active form, or for excretion: An example of this is seen with tamoxifen, a drug used to treat estrogen receptor-positive breast cancer. Tamoxifen itself is inactive and needs to be metabolised by the P450 2D6 enzyme (encoded by the gene CYP2D6) to its active forms. However, a considerable portion of the population (up to 23% of Caucasians) carry a variation in CYP2D6 that reduces the activity of P450 2D6; this prevents the mutation carriers from gaining full therapeutic benefits from tamoxifen.
- Variants that affect drug transport: For example, the statins (a class of cholesterol-lowering drugs) are normally transported out of the bloodstream to the liver by a protein called OATP1B1, encoded by the gene SLCO1B1. However, a particular variant in SLCO1B1 leads to reduced function of the transporter, leading to increased levels of drug in the bloodstream. This variant has been linked to an increased risk of simvastatin-induced muscle toxicity, an unfavourable side effect associated with many statins.
The study of how genes affect drug response is known as pharmacogenetics. However, despite the fact that our understanding of why individuals react to drugs differently has greatly expanded since the term was first coined in 1959, more work remains to be done. A small but significant portion of adverse drug reactions are idiosyncratic, meaning they are difficult to predict based on previous knowledge of how a drug works, but can have grave health consequences. Furthermore, programs for developing new drugs are costly, and are typically plagued by high attrition rates, with inadequate efficacy or safety being leading causes. Thus, more study on what controls individual drug response can improve treatment for patients and help to develop new items for the pharmaceutical toolkit.
Help in addressing these issues can come from a surprising source—the single-celled baker’s yeast, Saccharomyces cerevisiae. While initially yeast and humans may not appear to have much in common, S. cerevisiae has been extensively used in biomedical research, producing findings that can be translated to humans. It has thus been established as a model organism (alongside higher systems, such as nematode worms, fruit flies, and mice, among others) for helping to understand biological processes that are not as easy to investigate in humans. About a third of yeast genes have homologous human disease-related genes and the basic internal structure and function of the cell is conserved between yeast and humans. Furthermore, different strains of yeast have been reported to contain similar levels of genetic variation to human individuals, and can thus be used as a proxy for human individuals in studies of drug response.
What makes yeast particularly attractive as a model organism is how extremely easy it is to work with. It is non-hazardous, does not require highly specialised growth conditions, and produces a new generation approximately every one and a half hours. An experiment that may take months to execute in mice can be performed in yeast in a matter of days. Furthermore, it’s very simple to work with very large yeast populations; studying millions to billions of individual organisms requires no more than a few test tubes and several millilitres of media. Such large populations are key in order to get sufficient power when looking for associations between particular genetic variants and drug response; human studies at only a fraction of the power would require a significant organisational effort, in terms of gathering volunteers, obtaining ethics approval and collecting and testing genetic samples. Finally, the small genome of yeast (only 0.4% the size of the human genome) makes it very cheap and straight-forward to carry out genome-wide sequencing, particularly with the advent of next-generation sequencing technologies.
We are still not at the point where a person can be given a medication that is assured to have a desired outcome and not give unwanted side effects. Genetic analysis can help to identify individuals that might be at risk of severe adverse reactions, or treatment failure, and having a comprehensive knowledge of genetic factors that can affect individual drug response is key for providing better treatment. This knowledge can be difficult to gather through human trials, but model organisms such as yeast are important for guiding this line of research. Findings from yeast can be tested in humans and can form the basis of improving healthcare and producing better and more effective pharmaceuticals for the future.
Featured article credit: Baker’s Yeast by Zappys Technology Solutions. CC BY 2.0 via Flickr.
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