Summary:
In this discovery science project, researchers in Dr. Christina Smolke's laboratory at Stanford University engineered yeast (Saccharomyces cerevisiae) metabolic pathways to convert glucose into thebaine, an opiate precursor to morphine (Galanie et al., 2015). In order to do this, the scientists added 21 new genes from a variety of species including poppies, goldthread, rats, and the Pseudomonas putida bacterium to the yeast genome. Many of these transgenes had to be optimized to the yeast system in order to successfully produce thebaine. By adding another two genes, the scientists were able to produce hydrocodone, another medically important opioid (Service, 2015).

This project built on the work of other groups, including Dr. Smolke's laboratory, that were attempting to optimize various parts of the opioid production pathway in yeast. Although this project succeeded in producing thebaine from glucose, the biochemical pathway that these scientists made would need to be 100,000 times more efficient in order to be used by drug companies. Dr. Smolke has founded her own company, Antheia, to help achieve this goal.

This article also draws attention to the fact that some bioethicists have expressed concerns about this yeast opiate synthesis pathway being used to produce large quantities of illegal drugs such as heroin, which is "a simple chemical conversion from morphine" (Service, 2015). They have called for the development of policies to limit the risks posed by these unintended applications of this kind of technology.

Genomic Technology Used:
Researchers in Dr. Smolke's lab used data from other studies as well as their own work to identify optimal target genes for each step of the biosynthetic pathway. As mentioned previously, these genes came from a wide variety of taxa, including plants, mammals, and bacteria. The scientists inserted these genes into yeast genome in regions that were actively transcribed but that, when disrupted, would not lead to growth defects (Galanie et al., 2015). They were able to easily insert the entire pathway into these regions at once using microhomology-based gene disruption (Hegemann et al., 2006) and a DNA assembler that allows for one-step in vivo homologous recombination in yeast (Shao et al., 2008). These methods both take advantage of the cell's natural DNA repair process to insert new pieces of DNA into the genome based on similarity of surrounding sequences.

Take Home Message:
This article gives a short timeline of how the yeast opiate synthesis pathway was developed. It emphasizes how quickly synthetic biology can move—the whole pathway, from glucose to thebaine, was optimized in about a year. Therefore, this article provides a glimpse into a future in which microbes could be optimized to produce medicine easily and cheaply. An additional benefit of microbe-based drug synthesis strategies would be the ability to produce "more effective, less addictive version[s]" of the drugs we have today (Service, 2015). It is much easier to improve the quality of drugs by modifying a biochemical pathway in yeast, a single-celled organism that can be grown in large quantities in a laboratory, than it is to modify a biochemical pathway in the poppies that naturally produce opiates. However, the fact that the amount of thebaine produced by Dr. Smolke's pathway was 100,000 times too low to be commercially useful shows that synthetic biology projects such as these need to be optimized and scaled up greatly in order to compete with traditional production methods.

My Evaluation:
This article reports on a very interesting and promising project. Dr. Smolke's work shows the potential of synthetic biology to improve lives by providing a consistent, easily modified source of painkilling drugs. In addition, if yeast production of opiates were optimized to be even cheaper than traditional poppy-based production, this synthetic opiate production method could even decrease drug costs. This is especially relevant in the context of widespread concerns about American drug costs and political discussions about changes to the health care system. However, this work also has serious implications in terms of illegal drug production. Therefore, the ethical and legal implications of microbial medicine production must be carefully analyzed before this type of technology is scaled up and used widely.

Sources:
Galanie S, Thodey K, Trenchard IJ, Interrante MF, Smolke CD. 2015. Complete biosynthesis of opioids in yeast. Science. 349(6252):1095-1100. Available from AAAS.

Hegemann JH, Güldener U, Köhler GJ. 2006. Gene disruption in the budding yeast Saccharomyces cerevisiae. Methods Mol Biol. 313:129-144. Available from Google Scholar.

Service, RF. 2015. Modified yeast produce opiates from sugar. Science. 349(6249):677. Available from AAAS.

Shao Z, Zhao H, Zhao H. 2008. DNA assembler, an in vivo genetic method for rapid construction of biochemical pathways. Nucleic Acids Res. 37(2):e16. Available from Oxford University Press.