Artemisinin, a potent antimalarial drug derived from the wormwood plant
(left), is too costly for widespread use in poor countries. Researchers hope
to provide an affordable source of artemisinin by turning Escherichia coli (right) into microbial factories that pump out the
Collaboration Hopes Microbe Factories Can Supply Key Antimalaria Drug. JAMA. 2005;293(7):783-789. doi:10.1001/jama.293.7.785
Curing a disease in developing countries takes more than designing an
effective medicine because pharmaceutical companies have little incentive
to produce a drug that will not turn a large profit. But a recent collaboration
of three California organizations—a nonprofit institute, a biotech company,
and a university—could help change that paradigm.
A $42.6 million grant from the Bill and Melinda Gates Foundation will
help the Institute for OneWorld Health, in San Francisco; Amyris Biotechnologies
Inc, in Albany, Calif; and the University of California at Berkeley apply a breakthrough
technology to the production of the antimalarial drug artemisinin for developing
countries. Scientists at the University of California at Berkeley will conduct
the necessary research and development, OneWorld Health will work to clear
regulatory hurdles, and Amyris will scale up production of the drug. And all
three organizations will come out ahead.
Artemisinin is not a new wonder drug. The chemical has been around for
more than a 1000 years, extracted from the wormwood plant Artemisia annua and used as an ancient Chinese herbal medicine. It
destroys the malaria parasite by releasing free radicals that attack the cell
membrane of the parasite in the presence of high iron concentration, as found
in the blood.
But there are several problems with it. First, it costs about $2.40
per cure, which is twice the amount infectious disease officials deem a reasonable
cost for developing countries. In addition, cultivating the plant and stockpiling
artemisinin are not easy tasks, particularly because A annua grows only in certain regions of China and Southeast Asia.
“Growing of the crop and extraction are really subject to all
of the caveats of crop harvest,” said Jack Newman, PhD, founding scientist
of Amyris. “So, for example, if you get a hurricane through an area
that decimates your crop . . . that’s the end of
your drug for that year,” he explained.
Growing crops for drug production can also be difficult in countries
that may withhold resources to drive up prices. Such was the case recently
when the World Health Organization deemed a combination drug therapy including
an artemisinin derivative as the preferred treatment for malaria in countries
where the disease is resistant to conventional treatments. As a result, the
price of the wormwood plant in Asia increased dramatically. A better option
is needed if artemisinin is going to have a significant effect on malaria,
a disease that causes more than 300 million acute illnesses and at least 1
million deaths each year, most in Africa.
The pioneering technology that could solve these problems involves inserting
plant genes into Escherichia coli to fashion microbial
factories that pump out the lifesaving drug. About a dozen enzymatic steps
are involved in the production of artemisinin, and Jay Keasling, PhD, at the
University of California at Berkeley has unveiled these and is in the process
of expressing the relevant genes in E coli. “The
intermediates haven’t been completely mapped out yet, but we know where
we are and we know where we need to be,” said Keasling. “The chemistry
is fairly straightforward.”
Once all of the genes involved have been inserted into E coli, production of artemisinin can go full speed ahead. “In
the past, if you were to just take a gene out of a plant and put it into a
microbe, you would get sort of a trickle of products coming out. But with
this whole new pathway, it’s really more like a fire hose,” said
Newman. He added that Amyris will speed up production even more “by
tinkering inside the microbe genetically to get it to produce more per cell
and by using your standard tricks of the trade in scale-up of fermentation.”
Many other complicated molecules could be made in this way as well.
Artemisinin is a terpenoid, a class of the isoprenoid family of chemicals.
Isoprenoids are used to make a wide variety of products, including medicines
and additives. Inserting genes from the isoprenoid biosynthetic pathway into E coli enables scientists to synthesize various precursors,
which can be converted to any isoprenoid product. These include anticancer
drugs such as taxol, nutraceuticals such as carotenoids, as well as vitamins
In addition, using microbial factories to make products is a more efficient
and environmentally friendly technique than traditional synthetic chemistry
procedures. “You’re doing things inside the cell rather than using
solvents and things like that,” said Keasling. “And you can do
in one step in biology what would take you maybe five steps in chemistry.”
Replacing plants with microbes is not enough to make artemisinin affordable
for developing companies, but in this latest collaboration, all of the organizations
involved have vowed to not take a profit from artemisinin. And that promise
could be just what is necessary to make affordability a reality.
There are plenty of benefits to go around for the University of California
at Berkeley, OneWorld Health, and Amyris, though. Berkeley obtains funding
to use for academic research, OneWorld Health is able to do work that fulfills
its humanitarian mission, and Amyris receives support to perfect a technology
that it can use for the development of other products.
“My partners and I are very much committed to taking no profit
on the antimalarial, but there’s also quite a few other drugs and products
that can be made with this process,” said Newman.
OneWorld Health is on board because it is interested in finding a way
to decrease costs of medicines for developing countries. “There are
new biotechnology processes that could make medicines that are already in
the market be produced much more efficiently and much more affordably,”
said Katherine Woo, PhD, director of scientific affairs. “Artemisinin
is not new, but there really have been barriers to its widespread application
because of cost. So we looked into ways to help in that regard, and this technology
just kind of popped out from ones that we looked at,” she said.
Woo hopes other collaborations will arise due to this project. “This
is really an example that we want to use to entice other biotech companies,
or other entrepreneurs with new technologies, to think to develop the technology
both for the developed world and the developing world
at the same time,” she said.
For Keasling, the collaboration is a perfect opportunity to move his
research forward. “It made sense to be working with a small biotech
company to translate what we discover in the lab into something that might
be usable, and then to work with a nonprofit pharmaceutical that really specializes
in getting drugs to these people who need them,” said Keasling.
Despite excitement over the potential of this technology and the collaborative
effort to fight malaria, it will take years before any potential applications
“The timeline for my lab is to get everything out of the lab within
a 3-year period,” said Keasling. “We’re going to try to
shorten this timeline as much as we can, but there’s some really basic
research that has to be done.”
And although artemisinin is the most common herbal product used for
malaria treatment outside of the United States, it has not been approved by
the Food and Drug Administration or the European Medical Agency. OneWorld
Health will conduct a series of toxicology studies and perform the regulatory
work required by United States and other agencies that will allow the microbe-derived
drug to be substituted for the plant-derived product. The organization will
also conduct toxicology studies to determine the safest artemisinin derivatives,
adhering to Food and Drug Administration standards.
Keasling sees great promise for the broader field of synthetic biology,
in which scientists design biologically inspired products to address problems
that cannot be solved using naturally occurring entities. He foresees a time
when synthetic biology will be used to produce novel enzymes and materials
for a wide variety of applications, from treating patients, to cleaning up
toxic sites, to neutralizing chemical and biological poisons.