Sarah O'Connor - Chemists engineer plants to produce new compounds
Periwinkle plant cells could synthesize potential drugs
Anne Trafton, News Office
January 18, 2009
In work that could expand the frontiers of genetic engineering, MIT
chemists have, for the first time, genetically altered a plant to produce
entirely new compounds, some of which could be used as drugs against
cancer and other diseases.
The researchers, led by Sarah O'Connor of the Department of Chemistry,
produced the new compounds by manipulating the complex biosynthetic
pathways of the periwinkle plant. This sort of manipulation, which O'Connor
and her graduate student, Weerawat Runguphan, report in the Jan. 18
issue of Nature Chemical Biology, offers a new way to tweak potential
drugs to make them less toxic (and/or more effective).
Genetic engineering is not new: Scientists have known for years how to get
plants to resist pests and herbicides or to produce substances such as
insecticides by inserting genes from other plants or animals. What is new,
however, is the ability to induce plants to create new products by tinkering
with the plants' own synthetic pathways.
O'Connor's laboratory has studied periwinkle for several years because it
produces a variety of alkaloid compounds of pharmacological interest,
including vinblastine, a drug commonly used to treat cancers such as
Periwinkle also produces serpentines, which have shown promise as
anti-cancer agents, and ajmalicine, which is used to treat hypertension.
Other plant-produced compounds have shown pharmacological activity but
are too toxic for use in humans.
The current work builds on research O'Connor and grad student Elizabeth
McCoy reported two years ago. They found that periwinkle cell cultures
could produce novel compounds if fed starting materials slightly different
from their normal substrates.
"That inspired us to think about metabolic engineering in a much more
sophisticated way," said O'Connor, the Latham Family Career Development
Associate Professor of Chemistry. "We can virtually re-engineer the
O'Connor and Runguphan focused on an enzyme involved in an early step
of the alkaloid synthesis pathway. The enzyme normally accepts a
terpenoid called secologanin and tryptamine, an alkaloid, as substrates.
Another graduate student, Peter Bernhardt, engineered a mutant form of
the enzyme that can accept tryptamine with a halogen (such as chlorine or
bromine) attached. Runguphan grew genetically engineered plant cell
cultures that produce the mutant enzyme and got them to synthesize
several compounds that periwinkle plants would normally never produce.
The halogens could serve as points of attachment to add other novel
chemical groups to the compounds, modifying their effectiveness and/or
toxicity as drugs, said O'Connor.
So far all of the genetic engineering has been done in plant cell cultures,
but Runguphan has started growing a tiny whole periwinkle plant with the
In the future, the researchers plan to use the same approach to produce
additional compounds, in hopes of creating new and more effective drug
The research was funded by the National Science Foundation, the National
Institutes of Health and the American Cancer Society.
A version of this article appeared in MIT Tech Talk on February 4, 2009. MIT News article.