Woolly umbrella, a relative of sunflowers and lettuce, blooms in a Weizmann Institute greenhouse
(photo credit: Dr. Sagit Meir)
A South African plant called a “woolly umbrella” is completely
unrelated to the cannabis plant, but it produces dozens of the active
compounds found in cannabis – cannabinoids – including some that may have new medical uses.
In a study published today in the prestigious journal Nature Plants,
researchers at the Weizmann Institute of Science in Rehovot identified
more than 40 cannabinoids in the woolly umbrella. The team revealed the
series of biochemical steps the plant takes when it makes these
compounds and also showed how these steps can be reproduced in the lab
to synthesize or even engineer new cannabinoids.
Known to botanists, as Helichrysum umbraculigerum, the woolly
umbrella is a tufted perennial herb that can reach one meter in height
and is popular for making a garden border. The young parts are gray and
thinly woolly, velvety and leafy, and the golden yellow flowers grow in
clusters webbed together with “wool,” forming a parasol-like structure
between January and April.
The familiar cannabis plant
makes more than 100 different cannabinoids, and it remains their iconic
producer. But the woolly umbrella – which grows very fast – is a
respectable runner-up. “We have found a major new source of cannabinoids
and developed tools for their sustained production that can help
explore their enormous therapeutic potential,” said Dr. Shirley (Paula)
Berman, who led the study in Prof. Asaph Aharoni’s lab in Weizmann’s
plant and environmental sciences department.
Cannabinoids used for medical purposes
(l-r): Dr. Tali Scherf, Dr. Jelena Cveticanin, Dr. Adam Jozwiak, Dr.
Shirley (Paula) Berman, Prof. Asaph Aharoni, Dr. Luis Alejandro de Haro,
Zoe Pinkas-Pazi, Dr. Sagit Meir, Rotem Livne and Dr. Yonghui Dong
(credit: WEIZMANN INSTITUTE OF SCIENCE)
Cannabinoids are already widely applied to relieve pain,
nausea, anxiety and epileptic seizures, and the list of their possible
uses is quickly growing. Molecular receptors that respond to these
compounds are common in humans, not only in the brain but also
throughout the body; this suggests that the cannabinoids that bind to
them might be used to treat everything from cancer to neurodegenerative
diseases.
The promise that cannabinoids hold for medicine
is precisely why Aharoni’s lab launched a study of the woolly umbrella.
Its relatives include sunflowers, daisies and lettuce. But woolly
umbrella has long been known to be burned in folk rituals to release
intoxicating fumes, which hinted that it might contain chemicals
affecting the brain. In fact, German scientists who studied the plant
more than four decades ago found evidence that it contains cannabinoids,
but more modern studies failed to reproduce their findings.
Now Berman and colleagues, using a battery of state-of-the-art
technologies, confirmed that early report. They sequenced the entire
genome of the woolly umbrella and used advanced analytical chemistry,
including high-resolution mass spectroscopy, to identify the kinds of
cannabinoids it contains. Using nuclear magnetic resonance, the
researchers revealed the precise structure of more than a dozen of these
cannabinoids and other related metabolites. They traced the entire
biochemical pathway involved in the production of cannabinoids and
determined where in the plant they are made.
It
turns out that the woolly umbrella manufactures cannabinoids primarily
in its leaves, possibly giving it an economic advantage over cannabis,
which makes these compounds in the shorter-lived and harder-to-harvest
flower clusters (inflorescences categorized on the basis of the
arrangement of flowers on a main axis (and by the timing of its
flowering). Despite this difference, the Weizmann scientists found a
great deal in common between the woolly umbrella and cannabis. In
particular, the enzymes used in every step of their cannabinoid
production process belong to the same families throughout the first half
of the biochemical pathway.
Six
of the cannabinoids found in the woolly umbrella are identical to those
in cannabis. The six do not include the two most famous ones, THC and
CBD, but they do include cannabigerol (CBG), a rising star of
cannabinoid research: It has potential therapeutic applications but
lacks mood-altering effects. The acid form of CBG, which appears in a
relatively high concentration in the plant, serves as a precursor for
the production of all the classical cannabinoids. This supports the idea
that the woolly umbrella could become a valuable source of plant-based
cannabinoids.
What purpose cannabinoids
serve in plants is unknown, but they probably provide defenses against
animals or environmental hazards. “The fact that in the course of
evolution, two genetically unrelated plants independently developed the
ability to make cannabinoids suggests that these compounds perform
important ecological functions,” Aharoni suggested. “More research is
needed to determine what these functions are.”
His
team has already taken their latest insights into cannabinoid genetics a
step further, using them to generate the newly discovered
cannabinoid-making enzymes in tobacco plants. The researchers also
managed to use these enzymes to create finished cannabinoids in yeast,
pointing to a new way of manufacturing the compounds for research and
the biotech industry.
In
the future, the study’s findings might even lead to engineering
cannabinoids that don’t exist in nature. These could be designed to
better bind to the human forms of the cannabinoid receptors, for
example, or to achieve specific therapeutic benefits.
The
cannabinoids naturally occurring in the woolly umbrella might also open
up new possibilities. “The next exciting step would be to determine the
properties of the more than 30 new cannabinoids we’ve discovered, and
then to see what therapeutic uses they might have,” Berman concluded.
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