Researchers at the California Institute of Technology have developed a
novel way to churn out large quantities of drugs, including antiplaque
toothpaste additives, antibiotics, nicotine, and even morphine, using
mini biofactories–in yeast.
A paper describing the research, now available online, will be featured as the cover article of the September issue of Nature Chemical Biology.
Christina D. Smolke, an assistant professor of chemical engineering
at Caltech, along with graduate student Kristy Hawkins, genetically
modified common baker’s yeast (Saccharomyces cerevisiae) so that it
contained the genes for several plant enzymes. The enzymes allow the
yeast to produce a chemical called reticuline, which is a precursor for
many different classes of benzylisoquinoline alkaloid (BIA) molecules.
The BIA molecules are a large group of chemically intricate compounds,
such as morphine, nicotine, and codeine, which are naturally produced
BIA molecules exhibit a wide variety of pharmacological activities,
including antispasmodic effects, pain relief, and hair growth
acceleration. Other BIAs have shown anticancer, antioxidant,
antimalarial, and anti-HIV potential.
"There are estimated to be thousands of members in the BIA family,
and having a source for obtaining large quantities of specific BIA
molecules is critical to gaining access to the diverse functional
activities provided by these molecules," says Smolke, whose lab focuses
on using biology as a technology for the synthesis of new chemicals,
materials, and products. However, the natural plant sources of BIAs
accumulate only a small number of the molecules, usually "end products"
like morphine and codeine that, while valuable, can’t be turned into
other compounds, thus limiting the availability of useful new products.
To their reticuline-producing yeast, Smolke and Hawkins added the
genes for other enzymes, from both plants and humans, which allowed the
yeast to efficiently generate large quantities of the precursors for
sanguinarine, a toothpaste additive with antiplaque properties;
berberine, an antibiotic; and morphine.
The researchers are now in the process of engineering their yeast so
that they will turn these precursor molecules into the final,
pharmacologically useful molecules. "But even the intermediate
molecules that we are producing can exhibit important and valuable
activities, and a related area of research will be to examine more
closely the pharmacological activities of these metabolites and
derivatives now that pure sources can be obtained," says Smolke, who
estimates that her system could be used for the large-scale manufacture
of BIA compounds in one to three years.
Smolke and Hawkins also plan to extend their research to the production of BIAs that don’t normally exist in nature.
"If one thinks of these molecules as encoding functions that are of
interest to us, the ability to produce nonnatural alkaloids will
provide access to more diverse functions and activities. By expanding
to nonnatural alkaloids, we can search for molecules that provide
enhanced activities, new activities, and not be limited by the
activities that have been selected for in nature," says Smolke.
"Our work has the potential to result in new therapeutic drugs for a
broad range of diseases. This work also provides an exciting example of
the increased complexity with which we are engineering biological
systems to address global societal challenges," she says.
Source : California Institute of Technology. August 2008.