Two plants that cause neurotoxicity and paralysis in the tiniest doses are also known to counter pain, malaria, cancer and pests. For the first time, researchers discovered a way to recreate these powerful compounds in the lab, helping lead the way to improved, naturally-sourced therapeutics.
Centered on the plants wolfsbane and larkspur, the discovery comes about through a collaboration between scientists at Michigan State University and the Czech Academy of Sciences, and is published in the journal Molecular Plant.
"These plants have been used in different forms of medicine throughout the world for thousands of years," said MSU alum Garret Miller, co-first author of the paper and now an assistant professor of biotechnology at University of Michigan-Flint.
"We know they interreact with our bodies in so many ways, and understanding how to create them can help provide totally new routes of testing."
Two plants, both alike in chemistry
For all the headway made in modern science, one adage holds true: nothing beats nature.
"Plants are the best chemists around, upgrading their arsenal of natural compounds over millions of years to help them survive," said Björn Hamberger, study author and the James K. Billman Endowed Professor in MSU's Department of Biochemistry and Molecular Biology.
"Humans have found countless uses for these molecules in everyday life," added Lana Mutabdžija, a graduate student at the Czech Academy of Sciences and co-first author of the latest paper.
"These include caffeine, capsaicin, menthol and vanillin, not to mention the fact many of the medicines we use today either come directly from plants or are inspired by plant chemistry."
At MSU, the Hamberger Lab explores these diverse compounds, better known as specialized metabolites, and how they can be leveraged for the greater good.
In recent years his team had set their sights on larkspur — also called delphinium for its dolphin-shaped flowers — wanting to know exactly how the plant produced a mix of toxic-yet-promising chemicals known as diterpenoid alkaloids.
This, of course, was easier said than done.
Diterpenoid alkaloids are the intersection of the two oldest and largest classes of plant chemicals on the planet, and researchers have faced an uphill battle to determine their mind-bendingly complex structures.
Despite being isolated nearly 200 years ago, one of the best-known compounds, aconitine, still hasn't been successfully synthesized in a lab.
Luckily, the new project benefited early on from some serendipitous collaboration.
While attending a research conference in Barcelona, Hamberger crossed paths with scientists from the lab of Tomáš Pluskal at the Czech Academy of Sciences.
The Pluskal Group, including Mutabdžija, were pursuing the same tricky diterpenoid alkaloids in a notoriously poisonous larkspur relative, wolfsbane, otherwise known as monkshood.
"When this happens, we can either go our own ways, or come together, and it's joining up that always leads to the best science," said Hamberger.
Blueprints and biofactories
With an international team assembled, the researchers began the task of identifying the exact chemical pathway the two plants took to produce their diterpenoid alkaloids.
Like a molecular scavenger hunt, this meant searching through multiple species of larkspur and wolfsbane, tracking thousands of individual genes to see which were "switched on" in certain plant tissues at the right time.
"You can imagine a biosynthetic pathway almost as an assembly line," said Miller, who earned his Ph.D. in the Hamberger Lab. "If you have ten steps in a row needed to build a finished product, and suddenly one quits, the next steps can't happen."
Because plants naturally produce specialized metabolites slowly and in tiny amounts, discovering these pathways is a vital step toward engineering plant chemistries that can tackle real-world, large-scale challenges.
After solving a pathway, the unique genetic blueprints for a compound can be inserted into a specially engineered host organism, such as yeast.
Through this bit of biohacking, the organism will begin producing the compound on its own in larger quantities, paving the way for expanded testing and development.
"In an ideal scenario, this could eventually help create new drugs inspired by these natural products," said Mutabdžija.
Once the team narrowed down a promising set of genes in wolfsbane and larkspur, those genetic codes were inserted into tobacco plants, which acted as ready-made biofactories.
When these tobacco plants were analyzed for the chemicals they'd been producing after being given new genes, the team finally had their "assembly line": six unique enzymes that successfully created a diterpenoid alkaloid called atisinium.
These enzymes helped the compound fold into its complex final shape, and they facilitated the addition of a crucial and unexpected nitrogen source.
Knowing the initial biochemical steps needed to produce atisinium gives researchers a new foothold on the path to unlocking the potent, medicinal qualities found across the larger diterpenoid alkaloid family.
"Our vision is to provide green, sustainable tools that will allow us harness these plants' natural power," Hamberger said.
