By Ashley Stender | May 27, 2025

Harsh environmental conditions such as heat and drought significantly compromise crop yields. In the face of a rapidly growing world population and shrinking agricultural land, strengthening agricultural resilience has become both a scientific and global priority. But what if nature’s mechanisms to improve crop response to environmental stresses already exist, just waiting to be discovered? Funded by the U.S. National Science Foundation as a Global Center, the Center for Sustainable Plant Innovation and Resilience through International Teamwork (C-SPIRIT) was created to address the challenges that unstable environmental conditions pose to global food security. C-SPIRIT unites researchers from the United States, Canada, Japan, South Korea, and the United Kingdom to develop biology- and use-inspired strategies for improving crop performance under stress.

C-SPIRIT’s six research aims form a tightly connected pipeline designed to identify, test, and eventually deploy plant- and microbe-derived solutions that can help boost plant resilience. At the start of that pipeline is Aim 1: Metabolite Discovery, which focuses on identifying previously unknown or underexplored small molecules (called metabolites) that influence how plants respond to environmental stressors. These bioactive compounds could hold the key to developing crops that are better equipped to survive drought, heat, salinity, and more. Aim 1’s discoveries lay the foundation for everything that follows in the C-SPIRIT research pipeline.

From Molecules to Meaning

Leading this foundational work is Dr. Ola Skirycz, a plant biologist and plant biochemist at Michigan State University. Her lab investigates metabolites that act as biochemical signals, studying how they bind to protein targets to influence processes like development, metabolism, and responses to environmental stress.

“My group is especially interested in finding new small molecule regulators of central processes such as growth and resilience,” Skirycz explains. “Like drugs, small molecules need to interact with something—most often a protein—to cause a change in the system.” Her lab’s goal is to identify these molecular interactions and understand the biological effects they trigger.

While the work is rooted in fundamental science, C-SPIRIT adds a new dimension: bringing discoveries to farmers and their fields. 

Aim 1 serves as the starting point of the broader C-SPIRIT pipeline, generating candidate metabolites that feed into the center’s coordinated research process. Once promising compounds are identified, they are passed along for chemical characterization, biosynthetic mapping, production engineering, field testing, and safety assessment. Each step corresponds to a different C-SPIRIT aim. This collaborative structure ensures that discoveries are thoroughly evaluated from lab bench to real-world application.

“What I’ve always done is very basic research,” Skirycz says. “So this process of how you move a compound from the lab toward application is new to me. It’s exciting, but also a learning experience.”

Two Paths to Discovery

To uncover promising bioactive compounds, Skirycz and her colleagues are pursuing two complementary strategies. The first is untargeted metabolomics, which involves measuring and analyzing chemical signatures in plant tissues—especially under stress—to detect potentially important metabolites. The goal is to find compounds that are produced when a plant is under pressure, and that may play a role in how it adapts. But detection is only part of the challenge. “Measurement is one thing,” Skirycz says. “But what’s really hard is chemical identification.”

With current tools, only a small fraction of detected signals can be matched to known molecules. “We can maybe identify five percent of everything we measure,” Skirycz explains. “But we know there is this vast unknown dark matter. People ignore it not because they want to, but because they have no means to tap into it.” This challenge will be addressed by leveraging the expertise and technology of the MSU Mass Spectrometry and Metabolomics Core, along with a novel computational pipeline developed in Aim 2. The team is also developing tools and datasets to accelerate functional characterization of metabolites.

The second approach is screening existing compound libraries for activity. These libraries include synthetic molecules developed for drug discovery, as well as complex microbial extracts—some of which come from communities that naturally associate with plants. Collaborators at the Michigan State University Drug Discovery Core and the University of Michigan are providing access to large, curated collections of compounds. Moreover, research partners from South Korea will source extracts and compounds from the microbial communities extracted from the polar environments. 

“It’s a bit like what drug companies do,” Skirycz says. “They test hundreds or thousands of compounds in specific assays. We’re doing something similar, but looking for effects on plant resilience.”

This dual strategy of exploring both unknown and known compounds gives Aim 1 a flexible framework for identifying leads. It also feeds directly into early-stage fieldwork: in collaboration with Michigan State University Extension scientists Chris Long and David Douches, two potato varieties have been planted in Michigan for heat stress testing. Additional crop trials involving rice, soybean, and cassava are in development, with support from research partners in Canada, South Korea, and Japan. 

A Promising Peptide and the Pipeline Ahead

While much of Aim 1’s work is still in the early stages, one compound has emerged as particularly promising: a peptide known as cycloHisPro, first discovered in the human nervous system. Known for its neuroprotective activity in humans, the compound has also shown the ability to improve plant tolerance to salt stress in lab settings. 

“In our hands, it helps plants grow better under stress,” Skirycz says. “But we still need to see if that holds up outside of controlled lab conditions.”

Once a promising compound like cycloHisPro is identified, Aim 2 works to determine its chemical structure and function, while Aim 3 investigates the genetic pathways responsible for its biosynthesis. From there, Aim 4 explores how the compound can be sustainably produced using microbial or plant systems. The compound’s effectiveness is then evaluated by Aim 5, which tests its impact on crops in both lab and field settings. Finally, Aim 6 assesses environmental and animal safety to ensure the compound is viable for real-world use. Each step builds on the last, transforming molecular leads into applied tools for agricultural resilience.

Challenges

As with any scientific endeavor, discovery is only the beginning. A compound may work well in the lab but fail in the field, or even prove too costly or complex to manufacture at scale. Regulatory hurdles may arise depending on how a compound is delivered (for example, as a spray versus through genetic engineering), and some promising candidates may stall due to gaps in biosynthetic knowledge. 

Still, Skirycz knows what she wants to accomplish: she sees success not as a single breakthrough compound, but as a functioning pipeline capable of generating many strong candidates over time. 

“Experimental science can be slow, especially at the beginning,” Skirycz explains. “We’re in the process of hiring two postdocs who will really be able to push the experiments forward full-time. That will make a big difference.” 

In addition to these new postdoctoral researchers, Skirycz is also preparing to host visiting scholars from Japan to support both experimentation and metabolite screening across environments.

Looking to the Future

Aim 1 plays a pivotal role in C-SPIRIT’s broader mission: developing biologically driven tools that can make agriculture more resilient in a rapidly changing world. By uncovering and characterizing the molecules plants use to survive stress, Skirycz and her collaborators are laying the scientific groundwork for future technologies that could help farmers mitigate yield losses .

“The dream is that by the end of the five years, we’ll already have a number of compounds robustly tested in the lab and working in the field.” Even if that timeline proves optimistic, Aim 1 is doing what it was designed to do: advancing a deeper understanding of plant resilience, starting at the molecular level.