Modified yeast produce opiates from sugar
Move
over, poppies. In one of the most elaborate feats of synthetic bio logy
to date, a research team has engineered yeast
with a medley of plant, bacterial, and rodent genes
to turn sugar into thebaine, the key opiate precursor to morphine and
other powerful painkilling drugs that have been
harvested for thousands of years from poppy plants. The team also showed
that
with further tweaks, the yeast could make
hydrocodone, a widely used painkiller that is now made chemically from
thebaine.
“This is a major milestone,” says Jens
Nielsen, a synthetic biologist at Chalmers University of Technology in
Göteborg, Sweden.
The work, he adds, demonstrates synthetic biology's
increasing sophistication at transferring complex metabolic pathways
into
microbes.
ILLUSTRATION: A. CUADRA/SCIENCE
By tweaking the yeast pathways, medicinal
chemists may be able to produce more effective, less addictive versions
of opiate
painkillers. But some biopolicy experts worry that
morphinemaking yeast strains could also allow illicit drugmakers to brew
heroin as easily as beer enthusiasts home brew
today—the drug is a simple chemical conversion from morphine. That
concern
is one reason the research team, led by Christina
Smolke, a synthetic biologist at Stanford University in Palo Alto,
California,
stopped short of making a yeast strain with the
complete morphine pathway; medicinal drug makers also primarily use
thebaine
to make new compounds.
Synthetic biologists had previously
engineered yeast to produce artemisinin, an antimalarial compound, but
that required inserting
just a handful of plant genes. To get yeast to make
thebaine, Smolke's team coaxed the cells to express 21 genes in total,
including many added from a diverse set of species
(see graphic); making hydrocodone took 23 genes.
Their success, reported online this week in Science,
caps a race to install the complex opioid pathway in yeast. Last year,
Smolke's team reported engineering yeast to carry
out the tail end of the process, going from
thebaine to morphine. In April, Vincent Martin, a microbiologist at
Concordia
University in Montreal, Canada, and his colleagues
said they had created yeast that could go from an earlier intermediate
compound called R-reticuline to morphine. A few
weeks later, John Dueber, a synthetic biologist at the University of
California,
Berkeley, and colleagues announced yeast that
carries out most of the first half of the pathway, going from glucose to
another
intermediate compound, S-reticuline. Finally, two
groups reported in late June that they had identified the long-sought
enzyme
needed to carry out the chemical transformation in
the middle, S-reticuline to R-reticuline.
Even so, many predicted it would take
years to put all the pieces together. As it turns out, back in May,
Smolke and her colleagues
had already largely finished the task. “It shows
this field is really moving fast,” says Kenneth Oye, a biotechnology
policy
expert at the Massachusetts Institute of Technology
in Cambridge.
The most important challenge, Smolke says,
was increasing the efficiency of each step so losses wouldn't build up.
In one
step, for example, a plant enzyme called SalSyn was
doing a poor job of converting R-reticuline to another compound called
salutaridine. Eventually, Smolke's team discovered
that the yeast made the enzyme incorrectly, attaching the wrong sugars
to it. The researchers fixed the problem by
reengineering the inserted plant gene.
Smolke plans to go on tinkering. The
microbes need to increase output of thebaine by a factor of 100,000 for
drug companies
to be interested in using them to make medicines.
That won't be easy. But Martin notes that researchers boosted the output
of the artemisininmaking yeast by a similar amount.
“It will happen,” he says. “The only question is how fast.” Smolke
recently
formed a company called Antheia, based in Palo
Alto, that aims to push that pace.
To keep up with the yeast engineers, Oye
says policy experts need to develop rules to limit the risk of
unintended uses of
engineered microbes. In the case of opiatemaking
yeast, such rules might forbid developing strains to produce illicit
drugs,
such as heroin, and require scientists to build in
genes that prevent the microbes from living outside of a controlled
laboratory
environment.
Not everyone is worried about home-brewed
opiates. Andrew Ellington, a synthetic biologist at the University of
Texas, Austin,
calls such fears “overblown.” The idea that
producing vanishingly small quantities of opiates through fermentation
is somehow
going dwarf the problem of illegal drugs made from
poppies is “laughable,” he says. But Martin disagrees. “Poppy fields are
not readily available to someone in Chicago,
whereas yeast can be made available to anyone.”