The August announcement that
Massachusetts-based company Medicinal Genomics had sequenced the entire genome
of Cannabis sativa L. received much
national attention, including coverage by media outlets from National Public
Radio (NPR) and CBS to recreational marijuana blog HailMaryJane.com.1,2,3
While the development makes for attention-grabbing headlines—“Marijuana Genome
Sequenced for Health, Not Highs,” “Science Cracks the Cannabis Genome”—how will
it impact research and public health?
Medicinal Genomics founder Kevin McKernan
became interested in decoding the cannabis genome when working with a clinical
oncologist to sequence the DNA of cancer tumors and patients.
“As a result of this,” said McKernan, “[I] had
a few friends with cancer ask about medical marijuana” (e-mail, September 29,
Then he read Spanish scientist Manuel Guzmán’s research documenting
that cannabinoids, some of the biologically active compounds in cannabis, have a
favorable therapeutic index in cancerous cell cultures and animal models.4
McKernan said this “really drove it home,” as that finding is rare with most
potential cancer drugs. Additionally, McKernan read Etienne de Meijer's work
emphasizing that the cannabis chemotype is strictly governed by genetics,5
“but we only knew CBD [cannabidiol]
and THC [tetrahydrocannabinol]
synthase sequences to date.”
“I naively figured we could sequence the whole
genome for under $50k and that this had to be a priority,” he said. “Turned out
to be far more complicated of genome than one could gather from the
Though other scientists and organizations have
been working on sequencing cannabis, Medicinal Genomics
is said to have produced the “largest known gene collection” at more than 131
billion bases of sequence.6 The sequence bases of C. sativa were made available on August
18th on Amazon EC2—a public cloud computing service—via Nimbus Informatics,
an open source data management website. A data assembly is also available for
of Genome Decoding
Before the sequencing of the cannabis genome,
about 12 cannabis genes were known, and now tens of thousands are known, said
McKernan. Additionally, the genome has provided a better understanding of THC synthase
genomics, as well as more than 2 million single nucleotide variants.
McKernan also noted that the genome has made
apparent that THC synthase is not one gene with 2 copies in a diploid genome,
“as all of the previous papers have postulated.” Instead, the recent sequencing
implies that the gene has been replicated 8 times—with the potential assistance
of a transposable element—and diverged.
In discussing the genome's importance with
NPR, McKernan said it will allow scientists to investigate the genes that
govern cannabis compounds other than THC and CBD, and to sequence other
cannabis strains to highlight different traits.1 Leading cannabinoid
researcher Ethan Russo, MD, finds these possibilities “very exciting.”
“The publication of the cannabis genome is a
welcome scientific development," said Dr. Russo, “but one whose potential
applications remain to be determined. The possibilities are enticing, and it
seems certain that many able minds will apply their imagination to the task. Every
phytocannabinoid that has been closely researched so far has demonstrated
unique therapeutic potential. There are hundreds of strains available on the
black market, but these are not necessarily stable and reproducible” (e-mail,
September 22-29, 2011).
Dr. Russo thinks the most promising new
investigations that might stem from the genome could be in the area of
epigenetics—the study of heritable gene function changes that occur with no
change in DNA—such as determining the factors regulating cannabinoid
production, biosynthetic pathways, and terpenoid regulation.
“One example,” he said, “might be the
production of high-CBD strains. Some researchers,
like myself, believe that terpenoids synergize phytocannabinoid effects. Thus,
it might be theoretically possible to produce plants that express one
cannabinoid and one terpenoid to therapeutic advantage, say in treating
The sequencing of the genome has resulted in a
discussion that it will enable researchers to study cannabis without actually
having to use real cannabis plants, which can be difficult to obtain within the
strict US regulatory environment surrounding cannabis. Researchers could study
cannabis’s genome through bioinformatics, said McKernan, noting that the human
genome project enabled the understanding of how to reprogram cells to be
capable of making several different cell types, such as adult stem cells.
The cannabis genome, he said, will enable people to potentially discover novel
genes related to terpenoid synthesis by comparing the sequence to grape (Vitis vinifera) and hops (Humulus lupulus).
“This isn’t to say no one will ever need the
plant again,” said McKernan. “But a much larger audience can now legally study
the plant than prior to August 18, 2011.”
But Donald Abrams, MD—professor of clinical medicine at the University of
California San Francisco, chief of hematology/oncology at San Francisco General
Hospital, and a researcher of cannabis's effect in humans—stressed the
importance of having access to actual cannabis material. “We know already a lot
about the plant and its components without knowing the genome,” said Dr. Abrams
(e-mail, September 19, 2011). “You don’t need the genome; you need the plant.”8
Cannabis Genetics Work
Though several media outlets reported McKernan
as saying that not much has been accomplished in cannabis genomics,6,9
he told the American Botanical Council (ABC), “One article took a comment out
of context and it went viral through the news.”
Instead, McKernan recognized that much
valuable work has been completed. “Many people intimate with the science of
cannabis have offered up their time to help guide us on good places to apply
this work in both the medical and hemp areas,” he said. “There is a lot of
previous groundwork on THC and CBD synthase so there is a lot to learn from the
road which has been paved to date.”
According to Dr. Russo, "Arguably, the
genes for the most pharmacologically versatile components in cannabis have
already been identified.”10 Dr. Russo, who is the senior medical
advisor to GW Pharmaceuticals—manufacturer of Sativex®, an oromucosal spray
containing cannabis extracts that is in late stage clinical trials in the
United States for treatment of cancer pain—further explained, "While this
development will, without doubt, spur further investigation, a tremendous
amount of genetic work on cannabis has been accomplished previously."
Among these genetic breakthroughs, Dr. Russo
listed the biochemical characterization and synthesis of THC; cloning and
crystallization of THCA synthase; purification and sequencing of cannabidiolic
acid; and the isolation of THCA synthase and identification of a unique single
nucleotide polymorphism from an ancient cannabis sample found in a Chinese
Additionally, Dr. Russo noted that high-THC,
-CBD, -CBG, and -CBC strains of cannabis plants have been produced already, as
have high-THCV, -CBDV, -CBGV, and -CBCV strains that are currently being
“A lot of great work has already been done on
CBD and THC synthase,” said McKernan, “and all of those cannabinoids mentioned
above are derivatives within those 2 isolated pathways. The next question is what
makes the other 77 cannabinoids reported to be in the plant?”
And though some news stories reported that the
genome will enable scientists to breed cannabis plants containing no
cannabinoids, McKernan said in his interview with ABC that this has already
been accomplished and clarified that he hopes the genome will give scientists a
better understanding of the cannabinoid pathways that can be regulated up or
McKernan noted the genome of mustard weed (Arabidopsis thaliana)—the first-ever
plant genome to be sequenced—that has been said to potentially enable “crops to
be grown without pesticides, or to be grown in poorer soil… help native plants
fight invasive species… and bring about new medicines for humans.”12
“Every plant genome which has been decoded has
resulted in a radical change of the field,” said McKernan. “I think I'd be
called myopic if I claimed cannabis genetics ends at cannabinoid RNA sequences
in terms of potential for the plant when one considers hemp and the many
unknowns about the genetics governing the terpenoid and cannabinoid pathways.
“Compared to other plant genomes like
Arabidopsis, where hundreds to thousands of genomes are now being sequenced,”
McKernan continued, “cannabis was a desert and our work has simply built an aqueduct,
but by no means makes it a rain forest. The reference we have to date is still
a draft. The important thing to note is that once you have a reference genome
you can then leverage these next gen sequencing tools to drive the whole genome
sequencing costs down tremendously.”
McKernan said he hopes the genome will open
investigation into the reason behind the low levels of expression of the other
cannabinoids, and if they could be regulated to be expressed more, and which
genes are responsible for these cannabinoids.
Medicinal Genomics, which also has offices in
the Netherlands, is currently working to sequence the genome of C. indica—which McKernan said has an
assembly that is 50% larger than the public Chemdawg strain assembly of
C. sativa sequenced—and will be
debuted as an iPad® app.
1. Barclay E. Buzz kill: marijuana genome
sequenced for health, not highs. National Public Radio. August 19, 2011: Shots
NPR Health Blog. Available at: www.npr.org/blogs/health/2011/08/19/139762352/cracking-the-marijuana-genome-in-search-of-therapeutic-highs.
Accessed September 28, 2011.
2. Genetic code of cannabis reported unlocked.
CBS News. August 18, 2011. Available at:
September 28, 2011.
3. Science cracks the cannabis genome. Hail
Mary Jane. August 29, 2011. Available at:
4. Blázquez C, Salazar M, Carracedo A, et al. Cannabinoids
inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2
expression. Cancer Res. 2008;68(6):1945-52.
5. de Meijer EP, Bagatta M,
Carboni A, et al. The inheritance of chemical phenotype in Cannabis sativa L. Genetics.
6. Medicinal Genomics sequences the cannabis
genome using roche's GS FLX+ System [press release]. Branford, CT: Roche.
August 18, 2011. Available at: www.roche.com/media/media_releases/med_dia_2011-08-18b.htm.
Accessed October 3, 2011.
7. Russo E. Taming THC: potential cannabis
synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology. 2011;163:1344-1364.
8. Tirrell M. Marijuana DNA sequenced by startup
in search for medicinal uses. Bloomberg. August 17, 2011. Available at:
Accessed September 28, 2011.
9. Johnson C. Marblehead startup seeks to
unlock secrets of cannabis. Boston Globe.
August 18, 2011. Available at: http://articles.boston.com/2011-08-18/news/29901462_1_sequencing-cannabis-genetic-blueprint.
Accessed October 3, 2011.
10. Russo E. Cannabis genome uncloaked:
commentary on the scientific implications. Article for the International
Cannabinoid Research Society. Unpublished. Sent to L. Stafford by E. Russo,
September 22, 2011.
11. Russo E, Jiang HE, Li X, et al. Phytochemical
and genetic analyses of ancient cannabis from Central Asia. Journal of Experimental Botany. 2008;59(15):4171–4182.
12. Hansen A. A small plant’s genome has huge
impact. National Science Foundation. July 23, 2004. Available at:
www.nsf.gov/discoveries/disc_summ.jsp?cntn_id=100162. Accessed October 2, 2011.