Photo caption: Kelly Drew works in her lab in the Murie Building at UAF in spring 2019. UAF photo by JR Ancheta.
Kelly Drew ’81 was studying hibernating arctic ground squirrels in UAF’s Irving Building about a decade ago when a revelation set her on the course to finding a new way to treat people with brain injuries — and perhaps a lot more.
“I remember I was in this little spot in the hallway, and I don’t know if I was looking at anything or what, but all of a sudden it came to me,” she said.
Her realization pointed her toward a unique combination of drugs that result in an artificial state of hibernation, offering a way to avoid the negative side effects often caused by low body temperatures. It shows promise particularly for brain-injured patients, for whom keeping cold is one of the best treatments.
Photo caption: An arctic ground squirrel checks out the scene in Denali National Park and Preserve in 2014. UAF photo by Todd Paris.
Drew, a faculty member who specializes in the effects of drugs on the brain, had studied the squirrels for years before her discovery. The animals are famous for their ability to drop below freezing without injury, a phenomenon revealed by another UAF researcher in 1989.
Drew and others always wondered: How might humans benefit if they could mimic even a few of hibernation’s features?
So, during the 1990s, she and other UAF researchers started looking at ground squirrels from every angle — ecological, physiological, even social.
This past fall, UAF patented Drew’s brain trauma treatment method. Now, she and the university are working to deliver it to the medical field.
A Japanese paper
In the mid-2000s, Drew hired a chemistry student, Ben Warlick ’06, as an undergraduate research assistant. His innovative method of searching for hibernation studies unearthed something interesting, Drew said.
“He came across a paper in Japanese, working on a database that I wasn’t even familiar with,” she said.
The paper showed that a type of drug, when injected into hamster brains, would induce a hibernation-like state.
But the details were a mystery.
“I don’t read Japanese,” Warlick explained, when contacted earlier this year for his recollection of the moment.
However, he remembered, “the abstract was in English and the figure was also in English.” He could tell the study might be relevant.
After receiving bachelor’s degrees in chemistry and philosophy at UAF, Warlick earned a doctorate from the University of Illinois at Urbana-Champaign and is now a senior production scientist at Millipore Sigma in St. Louis, Missouri. He was surprised to hear that his discovery had been a catalyst in Drew’s new patented method for brain injury treatment.
“It was very accidental,” Warlick recalled.
The details also took some time to tease out.
“We carried that paper around for like two years, and finally I found someone who spoke Japanese,” Drew said. “They interpreted it all for us.”
It turned out that the drug works on hamsters in the same way that a natural molecule in ground squirrels helps induce hibernation as winter approaches on the tundra.
“We wanted to try it in ground squirrels,” Drew recalled. What would happen if you exposed arctic ground squirrels to the synthetic molecule?
The results weren’t simple, and the exposure led to some unwanted complications.
But now, a dozen years later, Drew and her co-investigators have found a way to counteract the complications. They believe they are on the cusp of an innovative breakthrough in the way brain-injured patients can be cooled.
Cooling an injured brain helps stop inflammation and a cascade of other damaging effects. It also reduces the demand for oxygen and energy-supplying sugars in brain cells, which can die when low blood supply leaves those demands unmet.
Photo caption: Brian Barnes at Toolik Lake Field Station in 2013, one of the sites where he conducted arctic ground squirrel research. UAF photo by Todd Paris.
Brian Barnes, the UAF faculty member who first discovered arctic ground squirrels’ supercooling ability, said Drew’s work could transform the treatment of strokes and heart attacks.
“There’s no doubt in my mind that if we had a really effective and safe way to reduce metabolic demand quickly in patients, it would save lives, and fairly routinely, as it gets adopted by hospitals and first responders,” said Barnes, who is now the director of UAF’s Institute of Arctic Biology.
Smitten by squirrels
Fairbanks is an odd place to find a neuropharmacologist like Drew. Most people with doctorates in the field go to work for big drug companies or academia in major urban centers.
Family brought her here, Drew explained.
She came to Fairbanks in 1976 as a high school student when UAF hired her father, Jim, as director of the Agricultural Experiment Station. He had grown up on a New Jersey dairy farm before earning a doctorate in agronomy at Rutgers University. He spent a few summers studying soils on Alaska’s North Slope in the late 1950s and joined the faculty at the University of Nebraska-Lincoln.
When the family of five arrived in Fairbanks the town was packed with workers building the trans-Alaska pipeline, which began carrying oil in 1977. James Drew quickly became dean of the School of Agriculture and Land Resource Management. Since he was a persuasive advocate of not only agriculture but other industries, the Greater Fairbanks Chamber of Commerce elected him chairman.
Kelly Drew graduated from UAF with a bachelor’s degree in psychology in 1981, then earned a doctorate in pharmacology from Albany Medical College. After three years in Sweden as a post-doctoral fellow, she returned to Fairbanks in 1990 with her husband and a new baby.
“I came back because of my family. I came back for all the wrong reasons,” she said with a laugh. “I didn’t come back for job opportunities. It was touch-and-go there.”
At UAF, Professor Sven Ebbesson let her use lab space in the Irving I Building while she scrambled for grant money.
“We didn’t have a position but did have the ability to house researchers who can get their own money and buy support for their program,” Barnes recalled.
Photo caption: A researcher in Kelly Drew's lab holds an arctic ground squirrel in 2012 in the Irving Building lab. UAF photo by Todd Paris.
Barnes, whose office was also in Irving, introduced Drew to an arctic ground squirrel shortly after she started working there.
“At some point, Brian came down and handed me this hibernating ground squirrel,” Drew said. “Oh my gosh, you just can’t even imagine when you hold them. You know what they’re like when they’re awake, I mean they’re wild and they’re mean. And now here they’re this passive little deal — that’s cold. I mean they’re really cuddly, except they’re cold.”
“I was completely smitten, you know. It was so amazing,” she said. “I was interested in the brain, what’s the role of the brain in the process.”
The Army’s interest
Drew and Barnes found a specialized government entity with a keen interest in ground squirrel research about a decade after she joined the UAF faculty in 1993.
“I got funded first for hibernation from the Army research office for combat casualty care. I had always promised them that we would be able to induce this state in humans,” Drew said.
The Army wanted to know if hibernation would help stave off the effects of injuries as soldiers awaited removal from combat areas.
Barnes said Drew discovered early in her work with hibernating ground squirrels that their brains seemed to resist scar damage after surgeries better than the brains of non-hibernating rats.
“The damage was greatly attenuated, as if they were protected,” Barnes said. “That right away led to an interest in how that protection is provided. And, wow, wouldn’t that be useful in human applications?”
The National Institutes of Health provided the first five years of funding to study the idea through support for the Alaska Basic Neuroscience Program, led by UAF Professor Lawrence Duffy ’72, ’77.
The late Sen. Ted Stevens, R-Alaska, provided the second infusion of money. Barnes said the university’s Washington representative, Martha Stewart, arranged a 15-minute meeting with Stevens to discuss the research.
Barnes said he “put a suit on, went into Ted’s big office, showed him data and slides, and as a result of that they initially made a little earmark in the [Department of Defense] budget.” It provided about $2 million.
The department wanted more information, though.
“We had to expand the proposal. It had to be reviewed. We had to respond to criticisms,” Barnes said. Eventually, the Army awarded the earmarked money, with Barnes as principal investigator.
“It supported us for about 10 years, including faculty at UAA,” Barnes said. “It worked just as those kinds of appropriations should. From that, both Kelly and I were able to get [National Science Foundation] and [National Institutes of Health] money.”
A heart-stopping challenge
As the research progressed, Warlick turned up the Japanese paper on inducing hibernation in hamsters. Once translated, it seemed promising — up to a point.
The drug given to hamsters was a type of synthetic adenosine, which plays a well-known role in natural sleep cycles.
“When we are sleep deprived, adenosine accumulates and makes us tired, and, when we sleep, adenosine dissipates,” Drew said.
Adenosine also suppresses thermogenesis – the body’s heat-producing mechanisms such as shivering and the burning of brown fat.
As a result, “when we give it to an animal, it really looks like we’ve induced hibernation,” Drew said.
However, using an intravenous needle to inject an adenosine solution into a person’s arm would be a very bad idea.
That’s because, while adenosine affects the brain, it also disturbs receptors in the heart.
“If you give it, it’ll stop the heart,” Drew said.
To avoid that reaction, Drew started experimenting with adenosine injections directly into the brains of rodents.
“But that’s not very useful therapeutically because, in critical care [of humans] they might go that far, but generally they would prefer not to,” she said. “So I was looking for a way to give the drug intravenously, or what we call systemically, that would only target the brain.”
Photo caption: Senior biology major Colleen Bue ’13 assists Professor Kelly Drew with research involving hibernating ground squirrels in Drew's lab in the Irving Building in 2012. UAF photo by Todd Paris.
Using the blood-brain barrier
Today, Drew works out of a northeast corner office in UAF’s Murie Building, one of the newest facilities on the Fairbanks campus. Large windows give her a view over north campus and the hills beyond. Outside her door, graduate students occupy multiple cubbies.
Back when she was pondering how to keep adenosine from stopping the hearts of her rodent subjects, however, she was still working deep in the dark halls of Irving I. It was there that she experienced the long-awaited revelation.
What she needed, she realized, was a drug that, when administered simultaneously with adenosine, would block adenosine’s effect on the heart but not the brain. That way, the animals could enter simulated hibernation and be cooled, but their hearts would continue beating well.
“It was so obvious. So then I started thinking, ‘Well, what drug would do that?’” she said.
It took some searching, but she eventually found a candidate – a type of theophylline, which is one of the stimulants found in tea.
“The reason we drink coffee is because it blocks adenosine,” Drew said. “So caffeine, theophylline, those are both adenosine antagonists.”
The particular form of theophylline that Drew identified has a unique and very useful feature, though. It doesn’t cross from the bloodstream into the brain.
“Your blood vessels normally have holes in them – they’re kind of leaky membranes,” Drew explained. “In the vessels that provide blood to the brain, there’s no holes in those vessels. They’re really tightly packed. For any compound to go from the blood into the brain, it has to go through the membrane. It has to be membrane-soluble. Usually that has to do with being fat-like, having some lipid properties.”
The theophylline derivative that Drew found is not very fat-like, so it can’t pass easily into the brain from the blood vessels.
Drew guessed that the theophylline-like drug, when injected into the blood, would block adenosine’s effects on the heart but not the brain.
Drew set about testing the idea on lab rats and arctic ground squirrels.
After some method refinement, the results showed much of what she’d hoped. She and her fellow researchers gave rats and ground squirrels the theophylline-like drug first, then the adenosine. The rodents went into simulated hibernation and cooled, but their heartbeats remained high. The theophylline-like drug prevented the slow heartbeat and low blood pressure that adenosine would have caused alone. Regular injections from miniature pumps maintained the condition.
UAF illustration by Kari Halverson.
Not all went as expected, though. Curiously, the arctic ground squirrels, when exposed to adenosine at levels presumed to be similar to those that develop naturally in their brains, only go into hibernation if winter is already near. Apparently, they must be ready to hibernate before they will respond to this particular type of adenosine. Drew and her research team are still studying the phenomenon. Rats responded to a higher dose regardless of season.
That difference didn’t impede the research or the patent process, she said.
Drew noted that her use of the blood-brain barrier is actually familiar to many people.
Opiate drugs, prescribed as painkillers, have a well-known side effect: they cause severe constipation, she said. To prevent constipation, doctors administer an opiate antagonist that doesn’t cross the blood-brain barrier. So the opiate continues to block pain in the brain while the antagonist blocks receptors in the gut.
“It wasn’t where the idea came from, but it’s the only other application of this concept that I’m aware of,” Drew said.
The next question is whether a similar process could help cool humans with brain injuries. “So far, it is looking good,” she said.
Photo caption: Pages from the university's patent application describe some of the methods and results of Kelly Drew's experiments in inducing a hibernation-like state in rodents.
A better way to cool brains
Cooling patients with brain injuries is “really similar to putting ice on a sprained ankle,” Drew explained. “It blocks inflammation.” It also stops a condition called excitotoxicity.
“The neurotransmitter that creates this excitotoxicity, called glutamate, is usually released when the brain is injured,” Drew said. The release causes more excitation, which causes more glutamate to be released. Soon, the overstimulated neurons in the brain begin to die.
Cooling a patient to a hypothermic state shuts down these damaging processes. Studies from the early 2000s showed that brain-injured patients who were cooled for between 12 and 24 hours recovered much better, Drew said.
“In one study, it was almost double the survival — survival with good neurologic outcome,” she said.
Hospitals already have ways of cooling injured patients, but these techniques have some drawbacks that Drew believes her system could avoid.
When patients are cooled with standard methods, they shiver, sometimes violently. This is counterproductive because it warms the patient and uses oxygen needed by the brain. Doctors can stop the shivering by administering paralytic drugs, but those drugs cause myopathy, or muscle weakness, and extend hospital stays. So hospitals hesitate to use such measures, she said.
Doctors also have some drugs that will repress shivering. “But they don’t just wipe it out like our drug does,” Drew said.
Shutting down thermogenesis with a dose of adenosine entirely eliminates the shivering response.
It has two additional advantages.
Drew said adenosine lowers the risk of seizures, a common side effect of brain injuries and cardiac arrest. Seizures can kill nerve cells, worsening injuries.
Adenosine will also “shut down neural activity,” which “helps protect the neurons when they don’t have enough energy, when they don’t have enough blood flow,” she said.
“Those three features are why we think this drug is going to be more effective than what is used now,” she said.
Making something useful
Drew said her long-standing effort to find a practical application for hibernation research arose in part from her unusual background in pharmacology.
“I’ve got a lot of friends in the pharmaceutical industry,” she noted. “So I’m always thinking about that stuff, just from my colleagues and my interaction there.”
She also credited inspiration from her father, who died in 2008.
“I think I get it from my dad — this whole [idea of] economic stimulus and making something useful from basic research,” she said.
Bringing Drew’s method to hospitals will require a lot more work, however, and much of it won’t be scientific.
UAF applied for a patent on Drew’s process in 2014. The U.S. Patent Office approved it in October 2018.
Now, Drew is working on the next steps through a biotech company she founded, Be Cool Pharmaceutics LLC, and the UAF Office of Intellectual Property and Commercialization.
“There’s a lot of logistics and hoops to jump through to move it forward – [federal Food and Drug Administration] approval and all that stuff; it’s a field of its own,” she said. “But we don’t have any biotech companies in Alaska. There was nobody to partner with. So I started a company myself that will help us focus on what we need to do.”
Photo caption: Kelly Drew holds a drug she uses to simulate hibernation in rodents, part of her work to develop a new treatment for brain injuries. UAF photo by JR Ancheta.
More possibilities
While Drew’s focus has been on helping people with brain injuries, she can see how her method might help treat other afflictions involving the brain, such as epilepsy.
UAF’s patent, in fact, describes the range of possibilities.
In addition to treating epilepsy, the method might eventually help people who need “treatment for drug addiction, post-traumatic stress disorder, depression or other mental health conditions,” the patent states.
“To me that’s what has the greatest potential, not only for what we’re trying to do with brain injury but for all these other things,” Drew said. “If we can combine these agonists with antagonists to selectively target the brain, it opens up all kinds of possibilities.”
Barnes said the university’s research into the minutiae of hibernation sometimes provokes questions about its utility. So he has been talking for decades about the potential benefits beyond basic scientific knowledge.
“Everybody says, ‘Well, why are you doing this?’ And so you throw these things out as, well, someday,” he said. “The day seems to be getting closer.”