Like many cardiologists, Manuela Thienel spends most days in the chlorinated, temperature-controlled halls of a large hospital. But one week in February 2019, her work brought her to a snowy Swedish forest, where she stood shuddering in a winter coat, looking on as veterinarians and rangers walked into a bear den to drug a hibernating bear and retrieve its blood.
Thienel believed hibernating bears may hold an answer to an ailment that kills up to 100,000 Americans every year. When humans are rendered immobile for weeks or months, laid low by infection or paralyzed by a traumatic injury, they are at high risk for a potentially fatal blood clot called venous thromboembolism.
Yet every year brown bears curl up for four to seven months and suffer no blood-congealing consequences.
“It’s a strange thing,” said Thienel, a physician and researcher at Ludwig-Maximilians-University of Munich, in Germany. “A deep paradox.”
Four years later, Thienel and her 39 collaborators — it takes a village to study a bear — think they’ve cracked it. In a sprawling study that spanned pigs, mice, spinal cord patients, and blood from 10 otherwise healthy people who volunteered to help the European Space Agency simulate the physiologic effects of spaceflight, the researchers zeroed in on a single protein that all but vanishes from bears’ blood when they lie down for winter.
The protein, known as HSP47, is found on platelets, the sticky cellular nurses that rush to patch wounds when they occur and stop the bleeding. Thienel’s study, published Thursday in Science, showed that the same gene appears to serve a similar function in humans. When HSP47 levels decline in humans, so too, some early evidence suggests, does bleeding risk.
The finding raises hope that researchers can develop drugs that block HSP47, giving doctors a new tool to treat or even prevent clots in immobile patients.
“Whenever we find new mechanisms, it gives us a potential new therapeutic target and we are in need of new therapeutic targets,” said Marc Rodger, who studies venous thrombosis at McGill University and was not involved in the work.
He cautioned that the research was still “30 steps away” from medicine. Researchers have to cement the link between this protein and venous thrombosis, design drug candidates, and test them in animal studies and clinical trials. They will have to see if such a drug comes with the same potentially fatal downside that accompanies virtually all blood-thinners: putting patients at high risk of dangerous bleeds.
Nevertheless, Rodger and other coagulation researchers were surprised and impressed by the group’s decision to look beyond humans or the usual lab animals for answers to one of the biggest problems in medicine.
“I found it really amazing,” said Mirta Schattner, director of the Instituto de Medicina Experimental del CONICET in Buenos Aires, who also wrote a perspective accompanying the paper. The idea “was completely new.”
Completely new to coagulation perhaps, but over the last few years, the study of so-called non-model organisms — virtually any organisms on earth besides the roughly eight (mice, yeast, fruit flies, frogs, nematode, zebrafish, a type of weed, and E. coli) used in the vast majority of lab experiments — have gotten increased attention, spawning a couple of well-heeled companies and at least one National Institutes of Health project.
These researchers have been inspired by the memory that some of medicine’s greatest breakthroughs, including aspirin and ACE inhibitors, have come from the most unlikely organisms. And they’ve been enabled by technologies that have made it far cheaper and easier to both sequence an animal’s genome and take molecular polaroids of the proteins, RNA, and metabolites active at a given moment.
“It’s becoming a little renaissance,” said Ashley Zehnder, co-founder and CEO of Fauna Bio, a startup that develops therapies by studying how animals adapt for hibernation.
Thienel’s blood clot study was spurred by Ole Frobert, a Swedish cardiologist, who, in the 2000s, wondered why hibernating animals don’t suffer the same consequences of stasis that humans, like some of his patients, do. He started a collaboration with the Scandinavian Brown Bear Research Project to investigate. “The bear,” he wrote in a 2015 review, “has solved most of the health challenges faced by humans.”
“They barely lose muscle or bone mass, they don’t develop bed sores, kidney failure and what have you,” Frobert added in an email. “Bears avoid all the conditions that our present sedentary lifestyle is associated with.”
Hibernation can be a particularly enticing process for researchers, in part because hibernating mammals largely rely on the same genes humans do. By looking at how bears or squirrels use these genes in active versus hibernating times, scientists can zero in on precisely how they survive such harsh conditions. In theory, other groups can then try to manipulate the same genes in humans.
Frobert, whose previous studies tackled obesity and arrhythmia, approached Thienel at a conference a few years ago, proposing that bears might help the group in its clotting research.
Thienel would ultimately join the Swedish expedition five times, first returning in June 2019 to collect blood from the same brown bears when active.
Initially, they found little. The coagulation cascade is notorious for keeping med students up at night, a complex yin-and-yang network of proteins that coordinate to congeal blood around wounds and pathogens, while still keeping the circulatory system flowing. Yet none of those major proteins appeared to be responsible for the bears’ stunning clot resistance.
Instead, they found an early signal that platelets might be involved. They decided to peer closer. There are established methods to do so in mice, but bears are less charted territory.
So Petzold and Thienel called Johannes Müller-Reif, a researcher then at the Max Planck Institute. In 2020, he had used a method of serially cutting and weighing proteins to take a snapshot of the specific proteins present in 100 different organisms. He did the same to the bear’s platelets, looking for anything that was dialed up or dialed down during hibernation.
One protein stood out. Levels of HSP47, or heat-shock protein 47, plummeted 55-fold.
“It was black and white,” Müller-Reif said.
This was an unlikely candidate — “completely striking,” said Thienel. Heat-shock proteins, which activate in response to stressors, weren’t generally thought to play a role in coagulation.
Thienel, though, eventually showed it fits well into an emerging theory of venous thromboembolism.
Clots in immobile patients are partially a biophysical question. “Blood that pools, clots,” said Rodgers.
Yet clotting is also influenced by inflammation. Platelets swarm to wounds and infections, but they don’t swarm alone. They activate neutrophils, an immune foot soldier, that then form neutrophil extracellular traps, or NETs, a thickly woven mesh of DNA and protein that can snare bacteria and provide a scaffold for platelets and red blood cells to congeal together.
These NETs can be essential for healing, but in the wrong context — such as amid poor blood flow — they can also clog veins.
Over a series of lab and mice experiments, the researchers showed the protein is essential for allowing platelets and neutrophils to coordinate. It appeared the bears were reducing their HSP47 levels to prevent NETs from clogging their veins when they hibernate.
And it appeared that other mammals, including humans, do the same. A patient’s risk of blood clots is only high directly after they are rendered immobile, Thienel said. Then it slowly drops back to baseline.
No one knew why this was, but the researchers linked it to HSP47 in two ways. First, they took blood samples from chronically paralyzed spinal cord patients and showed they had dramatically lowered levels.
Then they turned to some of the only healthy people in the world who sit still like hibernating animals: Volunteers who agreed to lie in bed for 27 days to help the European Space Agency understand what would happen to astronauts in zero gravity. Researchers on that project agreed to share blood samples they had taken before and after. Sure enough, HSP47 levels dropped sharply over the 27 days.
They also found reduced levels in pigs immobilized after giving birth. These follow-on studies quelled common questions about how relevant findings in far-flung animals are, and suggested that lowering HSP47 could treat clots or lower the risk in newly immobilized patients, as they wait for their bodies to adapt.
“The question we always get is translatability,” said Zehnder, the Fauna Bio CEO. “They addressed that head-on.”
Thienel will be back in the Swedish woods come June. She hopes to do follow-up studies to better understand the exact mechanism at play, as well as whether inhibiting HSP47 can help other people, such as cancer patients, at high risk of venous thrombosis. Frobert hopes the findings will help convince funders, who have generally been skeptical of his pitch. He had to cobble grants from different sources for this and other projects.
“There will [be] thousands of other solutions lying there if we look,” he said.
If he does get more funding, the bears don’t sound as if they’ll mind too much. A bit after the blood draw, they tend to stir and, like anyone who’s woken up in a strange place, groggily rise, glance around and slouch off to find a new place to curl up.
https://www.statnews.com/2023/04/13/blood-clots-bears-hibernate-potential-cure/
