For uncovering how a cell population helps ensure food, liquid and acid reflux are kept out of our airway – and instead sent to our GI tract – Laura Seeholzer is the winner of the 2024 Eppendorf & Science Prize for Neurobiology. Her findings, detailed in April in Science, have motivated her to study what's happening with these cells in diseases where this critical protective reflex is compromised.
"These findings are crucial for understanding potentially life-saving reflexes that are activated in the airway, in response to noxious stimuli," said Peter Stern, Senior Editor at Science, who oversaw the prize.
For most every breath we take and most every morsel or sip we consume, the lungs are protected. Air enters the lungs, but food, liquid and stomach acid are sent to the GI tract.
In a flash, however, this process can go wrong – a foreign agent can get into our airway. This can cause discomfort, at minimum. And at worst it can lead to airway blockage, acid-induced lung damage, or aspiration pneumonia – outcomes that occur frequently in people with neurological or esophageal disorders and which are a leading cause of aspiration pneumonia and mortality in older people.
Scientists already know that sensory systems in the upper airway, namely the larynx and trachea, rapidly detect the things that we need to exclude from our lungs. Innervated with sensory nerve fibers, the larynx and trachea respond to foreign agents – and clear them.
But scientists don't know if the nerve fibers in the larynx and trachea act alone.
Seeholzer's work uncovered another entity – neuroendocrine cells – that operate in the larynx and trachea, to play a protective role. In her prize essay, "(Don't) take my breath away," Seeholzer – a postdoctoral fellow at the University of California San Francisco – writes, "you should thank your neuroendocrine cells the next time you clear water or acid reflux out of your airway."
Neuroendocrine (NE) cells are a rare group of epithelial cells throughout the larynx and trachea. They have been understood for their important role in repairing the airway epithelium after injury.
They had not been thought to be involved in airway protection.
However, because these cells are near sensory nerve fibers, Seeholzer and her colleagues speculated that they could be specialized sensory cells that play a role in protecting our lungs.
Seeholzer said she wasn't even sure there were NE cells in the trachea and larynx when she started her work. "I started from the ground up, learning how these cells operate. I then used that to generate a hypothesis about their importance in the airway."
Her efforts involved work in cells and in mice – and methods including calcium imaging, electrophysiology, and optogenetics.
The road wasn't always easy.
"I had been studying NE cells for a year or two to figure out what they detect, which could inform what they do," said Seeholzer. "I performed a sequencing experiment to see what the cells expressed. When I looked at the data, not many receptors were expressed that supported my hypothesis that these were sensory cells that could detect stimuli that could get into the airway. The sequencing led to all dead ends."
Seeholzer did not give up, however. She spoke with David Julius, her mentor, and professor and chair of physiology at UCSF. She explained her sequencing work was not revealing what NE cells detected. "He encouraged me to step back and think about what they could be detecting, and to use that to nominate substances the NE cells could be frequently exposed to."
That led to an "ah-hah!" moment she describes in her essay, where she changed how she set up her experiments. As a result, she discovered that water and strong acid solutions (like stomach acid) very consistently activated the NE cells.
She then sought to understand what the water and acid did to the cells. Using optogenetic techniques, she could specifically activate NE cells in mice. "When I did that, the mice started swallowing very quickly." Seeholzer attached a device to the mice to study related changes in breathing. "I very consistently saw that activating NE cells led to swallows and to cough-like reflexes." That supported her hypothesis that NE cells were detecting water and acid to elicit protective responses in the airway, to keep foreign substances out.
She says NE cells add another layer – on top of sensory neurons researchers have previously studied – giving full protection in the airway. This was further evidenced by experiments in mice in which the NE cells were knocked out; this led to the airway not being fully protected against foreign threats.
Now having done work in mice, Seeholzer wants to understand how these cells operate in healthy and diseased humans. Her findings suggest these cells are not functioning properly in people with dysphagia, which is the inability to swallow well – a major cause of mortality. "I'm really interested in looking at patients who aspirate frequently to see if there's something going on with cells there," she said. "And I'm interested in looking at what happens with these cells in people who smoke, where dysphagia is also more prevalent."
There are also implications for people with refractory chronic cough, where the NE cells may be hyperactivated.
"Eppendorf and the journal Science have been awarding this prestigious prize since 2002," said Axel Jahns, Vice President of Corporate Citizenship & Governmental Affairs at Eppendorf SE. "Since its initiation, the prize has acknowledged over 70 winners and finalists, who have gone on to become leading scientists in their field. Congratulations to Dr. Seeholzer on her amazing achievement in winning this year."
Seeholzer expressed how her supportive lab environment made it possible to achieve the findings she did, even after significant obstacles. "The lab I'm in really made all the work fun and enjoyable," she said.
Finalists
Rosemary J. Cater is a finalist for the prize, for her essay, "Food for thought." Cater received her undergraduate degree and PhD from The University of Sydney. After completing her postdoctoral fellowship at Columbia University, she started her laboratory at the University of Queensland's Institute for Molecular Bioscience in 2024. Her research uses an integrated structural biology approach to understand how nutrients obtained through the diet are transported across the blood-brain barrier.
Claudia Kathe is also a finalist for the prize, for her essay, "Rewiring movements." Kathe received an undergraduate degree and PhD from King's College London. After completing her postdoctoral fellowship at Swiss Federal Institute of Technology Lausanne (EPFL), she started her laboratory in the Department of Fundamental Neuroscience at the University of Lausanne in 2024. Her research investigates the reorganization of neuronal networks in the spinal cord in neurological disorders and its impact on sensorimotor function.
