By Kathy Svitil

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 by plants.

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.

The research was supported by the Center for Biological Circuit Design at
Caltech and the National Institutes of Health.

Visit the Caltech Media Relations website at: [pr.caltech.edu].