Synthetic
Biologists Engineer Yeast to Produce Opiates from Sugar
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).
The chemical structure
of thebaine. Image courtesy of Wikimedia
Commons.
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.
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