Kenneth Poss, Morgridge’s newest investigator, studies how zebrafish can restore what is irreparable in humans — including damaged heart tissue.
Because Kenneth Poss is a true Badger, born and raised in Green Bay, it’s only natural that his scientific journey begins with a fish story.
The tale unfolds in the late 1990s at the Massachusetts Institute of Technology, where Poss is in the grind of thesis research for a Ph.D. in biology. He’s part of a team studying mice, trying to tease out the genes involved in learning and memory. But he has friends working in the lab next door, and they’re doing something Poss finds strange and wonderful.
The lab, led by MIT biologist Nancy Hopkins, was studying zebrafish as a model for understanding embryonic development. To do this, graduate students would sometimes cut tissue from the fins of adult zebrafish to analyze gene mutations. But whenever they lopped off a fin from one of the inch-long fish, within a few days, the missing parts would start coming back.
“They were kind of frustrated, because the fins would grow back, and they couldn’t really identify the fish [they had previously worked on],” says Poss, who is joining the University of Wisconsin–Madison and the Morgridge Institute for Research this fall to lead research on regenerative biology. “But I was just really fascinated by the fact that they could regrow these fins.”
Biologists had long known that many fish and amphibians could regenerate lost body parts, but at the time, they still knew very little about why or how. To Poss, who grew up combing the creeks and fields around his Green Bay home in search of interesting creatures, those seemed like questions worth studying.
“I’ve always been most interested in exploring something that we really don’t know a lot about,” he says. “Regeneration and zebrafish just seemed like this really open space, where there were so many questions to answer.”
And so soon after completing his doctorate, Poss convinced his postdoctoral mentor, University of Utah cardiologist Mark Keating, to let him buy a few zebrafish from a pet store and start working out the techniques he’d need to uncover their secrets. He quickly learned that the fish’s extraordinary remodeling skills extend far beyond fin replacement. They can regenerate complex tissue in a host of organs and systems, allowing them to survive injuries that would be fatal for any human. It’s known now that an adult zebrafish can endure having its spinal cord severed or even the obliteration of two-thirds of the tissue in its heart, and it will do … well, swimmingly. Like a sci-fi supervillain, it gathers its cellular tools and patiently rebuilds.
Poss has observed many thousands of these stunning recoveries in his lab at Duke University, where he has spent the past 20 years studying the fish’s remarkable genetic toolkit. And each one brings him closer to a tantalizing possibility — that those same regenerative abilities are lying dormant in our own DNA, and that we may soon figure out how to turn them back on. Such a breakthrough could lead to revolutionary new therapies, allowing doctors to fix damaged cardiac tissue following a heart attack or restore healthy neurons in a brain ravaged by Alzheimer’s disease.
But let’s not get ahead of ourselves. First, we need to do some more fishing.
Poss’ lab at Duke feels a bit like a very narrowly focused fish store, one with an uncommon enthusiasm for a single species of zebrafish. At any given time, 60,000 or more of the distinctively striped fish live in the lab’s large aquatics facility, darting chaotically around several thousand small tanks. But what the display lacks in visual variety, it makes up for in a less apparent diversity. Most of the fish have been engineered with mutations or transgenic DNA to help researchers see which genes and cellular mechanisms play a part in regenerating different types of fish tissue.
More than 25 years after meeting his first zebrafish, Poss is still a huge fan of the versatile species, which are native to river basins in India and common in home aquariums. They began to take favor in the 1990s as a model organism for studying embryonic development, mostly because they are easy to care for and make lots of little zebrafish, as well as the scientifically useful quirk that their embryos are initially transparent. But Poss was among the first to start hunting the genes that adult fish deploy in regeneration.
“I was fortunate just to be there early, to make some of the foundational findings in the field,” says Poss, who even after 30 years away from Wisconsin still talks with a characteristic Midwestern soft-spoken amiability. “It was just a great opportunity to be part of those early explorations and make an impact.”
In the early 2000s, Poss published the first research showing that zebrafish regenerate heart muscle after injury, findings that helped establish the fish as a central model for the emerging field. His lab, which at Duke comprised more than 20 staff, postdoctoral researchers and students, has made significant discoveries on regeneration in several of the fish’s organs and systems, including regrowth of fins, scales, skin and nerves in the spinal column. They have also studied tissue repair in pigs and mice. But the heart of the team’s work remains in the zebrafish’s tiny, miraculous heart.
“I think that’s what makes science the most exciting job there is — the opportunity to have a new path very quickly, and to follow it. I think that’s what we are supposed to do.” Ken Poss
Barely a microliter in volume, the adult zebrafish heart has an extraordinary talent humans lack: the ability to order up new muscle cells to restore heart function after an injury. When they sense damage, specialized genes orchestrate a strikingly ordered response, instructing waves of cells to proliferate and migrate around the site of the injury to produce the tissue types needed for repair. The process plays out over several weeks, but once it’s complete, there’s almost no sign anything was wrong.
Using advanced imaging and florescent molecules that light up specific gene activity and cell types, Poss’ team has figured out how to spy on this cellular dance in real time, documenting every genetic signal and cell movement. Their goal, Poss says, is to make a “full-length movie” of the key events involved in fixing a broken heart (and other tissues) — something that could essentially become a how-to video for researchers attempting to do the same for humans.
“More than anyone else, Ken has beautifully documented, in fine detail, the way that cells migrate, interact and ultimately give rise to the complex functions of the heart,” says Eric Olson, a molecular biologist who directs the Hamon Center for Regenerative Science and Medicine at the University of Texas Southwestern Medical Center. “And he’s been able to convey that excitement to the broader community of biologists.”
Olson, who is studying how neonatal mice produce new heart cells after an injury, notes that many mammals have the ability to regenerate heart muscle in early stages of life, only to lose it as adults. Understanding the levers that zebrafish use to launch regenerative responses can help scientists develop interventions that could reawaken those tools in humans, he says.
Poss agrees. “These animals that regenerate really well, they don’t have magic genes that we don’t have. It’s more how they control the genes,” he says.
But control isn’t just about turning the genes involved in regeneration on; it’s equally important to know how to turn them back off again, which is essential to prevent unwanted cell division that could lead to cancer. Poss’ team has identified the switches that appear to do that naturally in zebrafish — DNA sequences that he calls “tissue regeneration enhancer elements,” or TREEs. Even more encouragingly, the group reported in 2023 that those same elements are also able to control genes in pigs and mice, suggesting they could be adapted to direct a targeted regenerative response in mammals.
“You’re not going to be able to just take a pill that floods the system,” Poss says. “What you really want is to deliver something to the right place, just in the injured tissue, keep it there for the right amount of time, and then shut it off.”
Poss, whose academic home at UW–Madison will be in the School of Medicine and Public Health’s Department of Cell and Regenerative Biology, expects UW–Madison’s strengths in molecular biology and clinical research will help accelerate the study of these gene regulators in larger mammals, a key step toward developing therapies that could help reduce scarring and restore function following a heart attack.
“It’s a big goal but we are hopeful that we can leverage discoveries from zebrafish to help make heart muscle cells divide under control in humans,” he says.
Regenerative biology is no longer the uncharted frontier it was when Poss started collecting fish. Many dozens of labs now study regeneration in zebrafish, including some led by Poss’ former trainees, and many others are focusing on salamanders, flatworms, fruit flies and mice. He currently leads the Duke Regeneration Center, an interdisciplinary group of scientists from across biology and medicine who are studying the topic. In 2021, he co-founded the field’s first professional organization, the International Society for Regenerative Biology, as a forum for the growing community.
But even with the influx of new talent and energy into the field, many aspects of regeneration remain mysterious. Scientists don’t have a good handle yet, for example, on the specific mechanisms a zebrafish uses to rebuild its spinal cord, a complex rewiring job that allows a fish to go from complete paralysis to full movement in less than two months. And so, while Poss says it’s critically important for regenerative biology to start delivering clinical applications, “it’s also critically important to continue to learn how these things work.”
One advantage of joining UW–Madison, he says, is that it gives him the chance to do both. While he expects the team’s more advanced work on heart regeneration to move toward clinical applications, his affiliation with the Morgridge Institute affords him the flexibility to entertain more open-ended explorations.
“A place like Morgridge very clearly supports the idea of not necessarily doing what you wrote on a grant application four years earlier, but going after what you think is the most important thing to do that day,” he says. “I think that’s what makes science the most exciting job there is — the opportunity to have a new path very quickly, and to follow it. I think that’s what we are supposed to do.”
That’s an ethos that permeates Poss’ team, several of whom will join him in Wisconsin. He encourages students and junior researchers to chase down whatever makes them curious and to embrace the inherent uncertainty in their work. “He’s always telling us, don’t worry if you are getting positive or negative results. Whatever you find, you can learn something,” says Fei Sun, a postdoctoral researcher who began working with Poss as a graduate student in 2015.
Sun, who has also accepted a position at Morgridge, says it’s a standard Poss equally applies to himself. “I always see him exploring new areas and seeking out new collaborations,” she says. At Duke, for example, Poss’ team includes a nephrologist studying how zebrafish regenerate kidney tissue and a plastic surgeon interested in applications for skin and soft-tissue reconstruction.
“He’s very supportive of [people on his team] exploring new things, even if they aren’t the things he is known for,” Sun says.
It’s no surprise, then, that Poss is approaching his move to UW–Madison with the same sense of open-minded possibility. While he is enthusiastic about the opportunity to come home and to further establish the Midwest as a destination for cutting-edge biological research, he is cautious about laying out too proscriptive an agenda for his lab. He’d rather see what paths suggest themselves in a new environment.
“Any move like this is an experiment,” he says. “I can’t really predict what direction our research goes, but that’s part of the excitement.”
But Poss has given thought to one new direction his return to Wisconsin may take him. Still an outdoor enthusiast who loves hiking and exploring nature, he’s considering taking up ice fishing. “I’ve only been once, and I loved it,” he laughs. And as he says this, it’s easy to see him out there on a frozen lake, enjoying the contemplative quiet. Like science, it’s a pursuit that tends to reward the patient, the ones who are content to wait for the fish to reveal themselves.
Fearless Science Magazine
This story was featured in Fearless Science Magazine. The inaugural issue focuses on regenerative biology. How do some of the world’s most clever and fascinating organisms redevelop critical body parts after injury? And what might it mean for future advances in human health, from heart repair to infectious disease?