Roundworms are the cornerstone of scientific discoveries that have helped shape how we understand human disease and treatment. BioSpace takes a look at advances in C. elegans research.
To most, roundworms, or C. elegans, are just that: microscopic worms that live beneath our feet in the soil. But to scientists and researchers, roundworms are the cornerstone of scientific discoveries that have helped shape how we understand human disease and treatment.
Texas-based NemaLife is determined to take worms to the next level by using them for in vivo testing, or studies that take place in living organisms that typically precede testing in humans. The worms would be able to take the place of in vitro testing, or testing that is conducted “in the glass”, where researchers observe how cells in culture react to new therapeutics or other investigative compounds.
“In vitro testing is awkward,” Dhaval Patel, Ph.D., director of research and innovation at NemaLife told BioSpace. “It doesn’t give you whole organism data. So, for example, you could be looking at a neurodegenerative disease and testing only in neurons and what you might find out later is that the drug causes hepatic toxicity. You wouldn’t know that from the in vitro screen, so many false positives could move forward.”
The World’s Best-Characterized Animal
But why microscopic worms? Believe it or not, C. elegans is by far the best-characterized animal on the planet. It was the first multicellular organism to have its whole genome sequenced, which was published in 1998, and the developmental fate of every single somatic cell of the tiny worm has been mapped. C. elegans also touts orthologs or strong homologs in 30-60% of its genes, meaning that investigating the function of its genes can be applied to similar genes found in human development and disease.
Not only that, but studies using the roundworms are 10 to 20 times faster and 50 to 100 times cheaper than those using mice models according to NemaLife and could potentially allow researchers to bypass rodent studies depending on what system they are studying. The worms are transparent, have a fast reproductive cycle, a short lifespan and reduce the need for energy and water consumption.
The worms are amazing, but the technology supporting the use of worms in research has been lackluster in the past. Researchers typically use agar plates, which contain a gel that has a food source for the worms as well as a drug or compound stored in the agar. The researchers rely on passive diffusion to deliver the drug or compound through the agar to the worm, an inefficient process that often requires dosing the worms at high levels to observe a response. To bypass this issue, researchers turned to liquid-based assays, which did improve drug delivery to the worms, but it puts the worms at risk for hypoxia and they can run out of food.
Enabling the Use of Worms in Drug Development
Enter NemaLife’s microfluidic chip.
“Our technology is designed to overcome these challenges. It’s scalable because of the use of microfluidic chips. It’s covered in about 40,000 micropillars, enabling the worms to crawl, so the animals are not swimming in this device. The use of liquid media facilitates efficient drug delivery into the animal’s gut. It is also fully gas permeable, so you don’t get CO2 buildup, and you don’t get oxygen depletion,” Patel explained. “These chips are designed to hold up to 100 animals each and we can manufacture these at scale.”
Patel stated that the company is currently able to process 500 chips a day in the lab, with plans to add automation that would allow the company to scale 1,000 chips. NemaLife is also designing a new platform that could potentially allow its labs to process 10,000 chips within the next year, bringing down the cost of worm screening.
NemaLife’s worms are at the helm of several government-funded brain health studies.
Worms have Nervous Systems Too
“When you look at the behavior of animals, you can ask more interesting questions. Even though it’s a worm, it has a nervous system. It has the signaling systems we tend to think of as being involved in the behaviors we see in humans. For example, it has serotonin signaling and dopamine signaling. They also have wiring that is functionally the same in the sense that these circuits drive reward and other kinds of behavior,” Patel said. “So, it’s kind of surprising when you think about it that there are almost a billion years of evolutionary distance between a worm and a human, but the circuits that drive the worm to find food and eat it are the same as what drives our motivation.”
Enabling New Approaches to Cocaine Addiction, Alzheimer’s and Anxiety
The National Institute on Drug Abuse approached NemaLife’s chief business officer, Marton Toth, to see if the company was interested in using its AI platform to study worm behavior in the search for drugs against substance use disorders. NemaLife was awarded a grant to develop its AI technologies to perform high-throughput behavioral screens to identify new therapeutics for cocaine addiction.
“We can expose animals to cocaine and other substances and look at their behavior. Now, we can use our AI platform to do a screen to identify drugs that potentially block addictive behaviors,” Patel said.
NemaLife has also been awarded a grant by the National Institute of Environmental Health Sciences to produce a new screening approach capable of testing thousands of chemicals relevant to agriculture, nutraceutical and biotech markets utilizing its microfluidics, computer vision, laboratory automation and its genetically diverse nematode species. The company is also working with the National Institute on Aging to identify a subset of pharmacological longevity interventions that will exert neuroprotection against Alzheimer’s Disease-relevant stresses.
In April, NemaLife announced a research partnership with the University of California, Davis to test the therapeutic potential of several novel psychoplastogens, a class of fast-acting therapeutics that promote structural and functional neural plasticity, which could be used to treat anxiety.
“You can’t think about anxiety in worms the same way you would think about it in humans, but a lot of the circuitry is the same,” Patel said. “Instead, you can look at basic behavioral motifs, and if you see changes in the worms, that will always tell you whether the underlying circuitry is changing. So that’s what I think is critical with compounds that alter synaptic plasticity because we want to see if there is a change in the worm’s behavior. For example, we can take genetic mutants that might be associated with circuits that are involved in anxiety and see if these treatments restore a more ‘normal’ behavior.”
Worms in Space
Worms aren’t just for researching brain functioning, though. In February 2021, NemaLife’s microfluidics chip loaded with live worms was sent into outer space, so researchers could study how the muscle strength of the worms changed as multiple generations were born and raised on the International Space Station.
Where will the worms go next? At NemaLife, the possibilities are seemingly endless.
