Scientists hunt for new drugs in plant ‘ammo’

(Credit: Getty Images)

A new method for identifying the gene networks plants use to create anti-predator chemicals could lead to more effective drugs, a new study suggests.

Plants create hundreds of thousands of small molecules (also called specialized or secondary metabolites)—including chemicals like cocaine, nicotine, and capsaicin—to use as “chemical ammunition” to protect themselves from predation.

Unfortunately, the difficulty of identifying the networks of genes that plants use to make these biologically active compounds, which are the source of many of the drugs that people use and abuse daily, has hindered efforts to tap this vast pharmacopeia to produce new and improved therapeutics.

Now, geneticists think they have come up with an effective and powerful new way for identifying these elusive gene networks, which typically consist of a handful to dozens of different genes.

“Plants synthesize massive numbers of bioproducts that are of benefit to society. This team has revolutionized the potential to uncover these natural bioproducts and understand how they are synthesized,” says Anne Sylvester, program director in the National Science Foundation’s Biological Sciences Directorate, which funded the research.

The revolutionary new approach is based on the well-established observation that plants produce these compounds in response to specific environmental conditions.

“We hypothesized that the genes within a network that work together to make a specific compound would all respond similarly to the same environmental conditions,” explains Jennifer Wisecaver, a postdoctoral fellow at Vanderbilt University who conducted the study.

To test this hypothesis, Wisecaver—working with professor of biological sciences Antonis Rokas and undergraduate researcher Alexander Borowsky—turned to Vanderbilt’s in-house supercomputer at the Advanced Computing Center for Research & Education in order to crunch data from more than 22,000 gene expression studies performed on eight different model plant species.

“These studies use advanced genomic technologies that can detect all the genes that plants turn on or off under specific conditions, such as high salinity, drought, or the presence of a specific predator or pathogen,” says Wisecaver.

But identifying the networks of genes responsible for producing these small molecules from thousands of experiments measuring the activity of thousands of genes is no trivial matter. That’s where the scientists stepped in; they devised a powerful algorithm capable of identifying the networks of genes that show the same behavior (for example, all turning on) across these expression studies.

How AI algorithms could help design new drugs

The result of all this number crunching—described in a paper in The Plant Cell—was the identification of dozens, possibly even hundreds, of gene pathways that produce small metabolites, including several that previous experiments had identified.

Vered Tzin from Ben-Gurion University’s Jacoob Blaustein Institutes for Desert Research in Israel and Georg Jander from Cornell University’s Boyce Thompson Institute for Plant Research in Ithaca, New York, helped verify the predictions the analysis made in corn, and Daniel Kliebenstein from the plant sciences department at the University of California, Davis helped verify the predictions in the model plant system Arabidopsis.

The results of their analysis go against the prevailing theory that the genes that make up these pathways are clustered together on the plant genome.

“This idea comes from the observation in fungi and bacteria that the genes that make up these specialized metabolite pathways are clustered together,” says Rokas. “In plants, however, these genes appear to be mostly scattered across the genome. Consequently, the strategies for discovering plant gene pathways will need to be different from those developed in the other organisms.”

Locust brains suggest new way to deliver drugs

The researchers argue that the results of their study show that this approach “is a novel, rich, and largely untapped means for high-throughput discovery of the genetic basis and architecture of plant natural products.”

If that proves to be true, then it could help open the tap on new plant-based therapeutics for treating a broad range of conditions and diseases.

Funding came from a National Science Foundation National Plant Genome Initiative Postdoctoral Research Fellowship to Wisecaver, as well as by National Science Foundation grants to Rokas and Jander.

Source: Vanderbilt University