A tiny swimming, crawling worm may not seem like an animal that can tell us much about humans. But appearances can be deceiving.
“We actually face quite a lot of similar challenges as other animals on this earth do. They have to figure out how to survive, how to reproduce, how to find their food. Those things are fundamental,” said Fred Hutchinson Cancer Research Center neuroscientist Dr. Jihong Bai.
Meeting these challenges requires animals to act on their perceptions of the world around them. To understand the essential processes that shape how all animals do this, and the possible implications for human disorders, Bai studies the nervous systems of minuscule worms called nematodes.
Our last known link to nematodes lies millions of years in the past, which means that if we share a biological process, it’s likely to be the answer to a challenge that all animals face. For example, many of the molecules that worm neurons use to communicate with each other are also used by human neurons.
The trick to using nematodes to understand humans is to pick a relevant question, Bai said.
“We think about, ‘How do we understand the world?’” Bai said.
This question can lead to answers that inspire other scientists to take Bai’s findings and make links to vertebrates, humans, or even, someday, the clinic.
Bai studies the neural circuits that connect sensation with behavior, examining how information flows between neurons that sense the environment, through intermediary neurons, to the neurons that control worm muscles.
Neurons and molecules that help worms sense odors and temperatures are well understood.
“But the neuromuscular junction where actions are produced, or how signals go from sensation to the motor system — these are less well developed,” Bai said.
These neural circuits are complex and interconnected — input through one sensory system can alter how information passes through another, and ultimately, how worms respond. As simple as they are, even nematodes must make complex decisions about how to respond to their world.
All these decisions come down to informational flow through interconnected neural circuits, like traffic through a city.
“I want to be able to engineer the nerve system to change the animal's perception, changing the animal's behavior by tuning the molecules,” Bai said.
He recently published work in which he was able to reroute worms’ broken neural circuits, revealing how these circuits work — the first step toward understanding how particular circuits underlie sensation and behavior.
Previously, scientists could only observe the neural map, but strategies like Bai’s have made it possible for them to better understand neural “traffic” flow by erecting barriers, widening “streets,” and connecting new routes.
“We can change the traffic flow now,” Bai said. “We can do infrastructure building, and understand the traffic flow of the ‘city’ better.”
The links between basic research and human health often come from unexpected connections. Most recently, an unexpected connection helped Bai shed light on why drugs used to treat Parkinson’s disease, or PD, often cause movement difficulties in patients.
The neurotransmitter dopamine is often produced at lower levels by people with PD. So, doctors give a synthetic precursor called levodopa to raise their dopamine levels.
“But over time, patients develop movement disorders,” Bai said. Initiating or sustaining a rhythmic movement like walking becomes difficult.
Worms also rely rhythmic motions, in their case swimming and crawling, to get around. Once they’ve found their groove, the tiny creatures can easily swim for hours.
Bai’s team had showed that dopamine plays a role nematodes’ rhythmic actions, but hadn’t considered their findings’ implications for human health. But in 2017, when he gave a scientific talk at the Hainan Medical University in Haikou, China, a few clinically minded researchers in attendance wondered if worms could help them better understand levodopa’s side effects.
A collaboration was quickly born. Ye Xu, a graduate student in the lab of Dr. Zhibin Chen, joined Bai’s lab for a year and half to further explore the link between dopamine and movement. She found that dopamine regulates both the initiation of rhythmic motions like swimming and the maintenance of them — and that these two phases are controlled by different dopamine-detecting molecules. The team published the work in the journal iScience.
“Basically, she figured out that if you change the dopamine signaling pathway, the motion defect results from the mismanagement of two different pathways,” Bai said.
The findings suggest that long-term treatment of Parkinson’s with drugs like levodopa might cause changes in dopamine signaling that lead to dopamine mismanagement and, ultimately, movement changes.
Moreover, Xu found that the dopamine pathway that works to sustain swimming is turned on in a neuron that had previously been linked to sleep. While patients with PD often experience disordered sleep, it’s too soon to know whether Xu and Bai’s findings help explain that, he said. And worms, in this case, may not be the right model to explore that connection: While they do sleep, after a fashion, it’s not tied to the day-night cycle the way human sleep is. (Instead, worms enter a quiescent state prior to entering each of their larval stages.)
“It will be for other scientists to see whether this mechanism relates to sleep disorders in Parkinson’s,” Bai said.
Ultimately, simple animals like worms give Bai the flexibility to ask and answer questions that can’t be addressed in more complex models, he said. Besides exploring questions about movement that may ultimately be relevant in disorders like Parkinson’s, Bai is also interested in investigating processes ranging from aging to memory.
Once researchers like Bai have sketched the outlines, other scientists can use different animal models to fill in nuances. His findings can also act as signposts to give direction to researchers seeking answers that are more pertinent to humans.
The beauty of basic research like Bai’s is that it isn’t hampered by preconceived notions of what findings are most likely to translate to the clinic. It may take years — even decades — after a fundamental discovery for the connections to human health to become clear.
By looking how worms live and act, “I’m generating possibilities,” Bai said.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at firstname.lastname@example.org.
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