Auditory Rangers

SIU scientists use teamwork, experience, creativity to improve hearing

Written by Steve Sandstrom • Photography by Jason Johnson
Aspects Magazine, 39-3 Summer 2016

Hearing loss is the third most common health problem in the U.S and more than 25 million citizens between the ages of 20 and 69 have high frequency hearing loss due to exposure to noise, according to the National Institutes of Health (NIH). In addition, roughly 50 million people in the U.S. experience chronic tinnitus ─ a persistent ringing in the ears.

SIU School of Medicine has a reputation for its world-class hearing research thanks to the efforts of a corps of scientists and auditory professionals, working sometimes separately, but more often in collaboration, to advance the understanding of hearing. These super scientists approach the problem of hearing loss from almost as many paths as sound enters the human brain.

 

THE ORIGINATOR

Every heroic chronicle should begin with an origin story.

As a young boy growing up in New York City in the late 1950s, Don Caspary tinkered with the family’s primitive television set to improve reception. His Belgian grandmother who lived with the family was deaf. He remembers one afternoon using alligator clips to hook up the bone conduction headpiece from her hearing aid directly to the speaker wires on the TV.

"She said ‘wow’ in French," Dr. Caspary says. "I’m lucky I didn’t electrocute her. But I’d be lying if I said that’s why I got into hearing research. I’ve just always loved sensory systems."

That affection ultimately brought Dr. Caspary to central Illinois in 1973, where a new medical school was being built. He was a post doc from SUNY-Albany "still wet behind the ears" when he was hired by SIU School of Medicine.

Don Caspary, PhD, is one of three original SIU faculty members still working at the School. (Former Dean J. Kevin Dorsey, MD, PhD, and Carl Faingold, PhD, chair of the Department of Pharmacology, are the other two.) He has been instrumental in the development of the auditory research program and its scientists and students for more than 40 years. An SIUC Distinguished Scholar and professor of pharmacology, Dr. Caspary’s research has focused on age-related hearing loss, central sensory plasticity, tinnitus, sensory pharmacology, anatomy, physiology and neurochemistry of the auditory pathway.

In the normal hearing process, sound waves received in the ear are converted into electrical impulses that travel through the auditory nerve to different stations in the brain. Areas within the brain read the impulses and reinterpret them as specific sounds. Dr. Caspary’s research has attempted to identify exactly how the brain does this, and how aging degrades hearing of speech-like sounds.

His present studies examine the impact of aging on certain neurotransmitters receptors, called nicotinic cholinergic receptors, in one specialized hearing area within the brain. Changes to this receptor may partially explain the difficulty older individuals experience when trying to attend to and understand speech, especially in a noisy environment. Dr. Caspary’s research has been continually funded by the National Institute of Deafness and Other Communicative Disorders within the NIH since 1979, most recently with a $2.6 million, five-year grant. He says that "success today, is only possible because of the commitment of a hard working group of scientists committed to this research." Drs. Tom Brozoski, Carol Bauer and Brandon Cox work with the Caspary Lab of Lynne Ling, Rui Cai, Ashley Lebshier and PhD student Sarah Sottile to make it happen.

Historically, Dr. Caspary credits two key factors for creating the successful environment he calls home. "In the beginning, we had all the money we needed to set up a really fine lab," he says. "The ability to have a high quality lab was huge."

The other catalyst was Ron Konrad, MD, the new medical school’s first chair of otolaryngology (Ears, Nose and Throat, or ENT), who was hired in 1978. According to Dr. Caspary, Dr. Konrad’s love for research was infectious, and he attracted bright, talented people who worked well together. When Konrad hired Leonard Rybak, MD, PhD, in March 1981 as the second full-time faculty member in otolaryngology, the auditory research program really took off.

THE TOXIN BLOCKER

If you could take a drug that would help cure your cancer, but as a side effect you’d go deaf, would you take the drug?

Cancer patients receiving the chemotherapy drug cisplatin face that difficult choice. Dr. Rybak, professor emeritus of surgery in the Division of Otolaryngology Head and Neck Surgery and SIUC Distinguished Scholar, doesn’t think that’s a fair choice.

For the past three decades, Dr. Rybak has studied how to reduce hearing loss in patients undergoing cancer treatment. His research has shown that cisplatin, an effective anti-tumor drug for certain types of cancer, triggers reactive oxygen species (ROS) that damage the inner ear, causing permanent hearing loss. The research has identified several different pathways that can be targeted to decrease cisplatin-induced hearing loss without compromising its tumor-killing capacity.

His initial studies in the ’80s included some collaborations with Dr. Caspary, who embraced the pioneering spirit of his colleague. "Dr. Rybak was doing antioxidant research before anyone knew what they were, and in the inner ear no less, easily 20 years ahead of its time," Dr. Caspary says.

While a practicing ENT surgeon in the ’90s, Rybak was a mentor to many students, post docs and new faculty, including Kathleen Campbell, PhD, who would go on to establish her own research lab and biotech firm.

Rybak’s current research team at SIU includes Vickram Ramkumar, PhD; Debashree Mukherjea, PhD, and Kelly Sheehan. The group is testing a potential co-therapy called capsaicin. It contains a component of red hot chili peppers and has shown promise in reducing hearing loss and kidney damage if given prior to or after a dose of cisplatin.

"We believe the capsaicin desensitizes an ion channel in the ear, blocking the detrimental effect of cisplatin," Dr. Rybak says. "Now we’re trying to determine the smallest doses of capsaicin possible that will prevent hearing loss yet still allow cisplatin to treat tumors." The results of the research could lead to cancer treatment with fewer negative side effects.

Dr. Rybak’s years of balancing the demands of a busy lab and the operating room created another quantifiable side effect. "Len got a lot of people interested in mechanisms of ototoxicity," Dr. Caspary says. "He did good, diverse research and it gave identity to the group, and it brought SIU School of Medicine credibility and a positive reputation in auditory research."      

THE PROTECTOR

Military service is inherently dangerous, but few outside the armed forces would guess that noise induced hearing loss (NIHL) is the most common reason troops cannot be redeployed. It’s the military’s most costly disability: The U.S. Department of Defense (DoD) and U.S. Veteran’s Administration estimates that treating NIHL and tinnitus costs between $2 - 4 billion annually.

Kathleen Campbell, PhD, has discovered and patented agents that can protect against noise- and drug-induced hearing loss and other side effects of cancer therapies. Dr. Campbell is a Distinguished Scholar and professor in the Department of Medical Microbiology, Immunology and Cell Biology. A new drug she has developed may be the magic bullet that solves the military’s persistent hearing problem.

Dr. Campbell’s grandmother worked at the South Dakota School for the Deaf and her father had noise induced hearing loss from military service and hunting. Her urge to take a proactive approach intensified in college. As a young clinician in Iowa, she grew frustrated watching cancer patients undergoing chemotherapy. "All you could do was sit by and watch their hearing deteriorate," she says. "I wanted to do something interventional."

She would get the opportunity after gaining successive clinical experience in South Dakota and British Columbia. In 1982, she was hired by the University of Iowa to head the auditory electrophysiology program and began doing research while also getting her PhD. In 1989, Dr. Campbell was recruited and started the SIU School of Medicine’s audiology program including the clinic, teaching and research. And with mentoring from Dr. Rybak, she started looking for an agent to prevent hearing loss.

Flash forward to today.

Dr. Campbell’s decades of research into protective agents have proven remarkably successful. She’s the sole inventor of five U.S. drug patents. With more than $10 million in research funding for noise- and drug-induced hearing loss, she is finalizing the FDA Phase 3 clinical studies that will move one of her drugs closer to becoming the first clinical therapy to treat and prevent NIHL. A specific amino acid called D-Methionine (or D-Met for short) has shown enormous potential and is currently used in a clinical trial with drill sergeants at Fort Jackson, South Carolina, who are exposed to the damaging noise of 500 rounds of M-16 weapon fire during training exercises.

D-Met is a component of fermented proteins. It is a powerful antioxidant present in many foods, including cheese and yogurt. In addition to the noise protection, D-Met is showing promise in three other areas: drug-induced hearing loss from platinum-based chemotherapy and aminoglycoside antibiotics used for moderate to severe infections and radiation-induced oral mucositis, a condition that occurs following radiation treatment for head and neck cancers. It also has been shown to reduce other side effects of chemotherapy and radiation cancer treatments, including weight loss, loss of sensitivity in hands and feet, oral soreness and swallowing disorders.

If noise exposure is predictable, as often is the case, D-Met has also been able to restore hearing if administered up to 24 hours after a noise exposure event – referred to as "rescue therapy." This could be beneficial after a loud concert, an explosion or when an airbag deploys during a car accident.

As her research has moved from bench to bedside, Dr. Campbell has relied on her co-workers’ assistance and expertise from the Office of Technology Transfer, directed by Robert Patino. Her lab’s co-investigators have included Bob Meech, Daniel Fox, PhD, and Shari Randall. Dr. Fox recently moved to New Jersey to become product manager for MetArmor, Dr. Campbell’s new biotech company, to prepare D-Met for its launch in the commercial marketplace.

If the drug is approved, it will be the first of its kind. And it could help improve the quality of life for individuals in professions with high noise exposure: the military, farming, law enforcement, airline employees, construction, mining and the music industry. If you work at the business end of a jackhammer, ride a tractor, or attend a loud concert, it will be cause for celebration.

THE REJUVENATOR

With D-Met still in clinical trials, no FDA-approved drugs are available to treat hearing loss or tinnitus. Today, the treatment strategy for these conditions is hearing aids or cochlear implants. They provide some benefit but do not restore normal hearing.

While doing post doc training at St. Jude Children’s Research Hospital, Brandon Cox, PhD, worked with an undergraduate student who had a cochlear implant. The device is surgically implanted into a person’s cochlea to collect sound impulses and then stimulate different regions of the auditory nerve to approximate hearing. Seeing some of the student’s struggles made an impact on the young researcher.

"Talking on the phone was nearly impossible for her," she says. "When we had conversations I had to make sure we maintained eye contact."

Hearing loss is primarily caused by the death of sound-sensing cells called hair cells, which are found in the inner ear. These cells can naturally regenerate in birds, frogs and fish, allowing recovery of hearing. However, hair cells were not thought to regenerate in humans or other mammals until very recently. At St. Jude, Dr. Cox discovered their ability to spontaneously regenerate in newborn mice.

Dr. Cox, an assistant professor in pharmacology, was hired by SIU in 2013, soon after her discovery. She was attracted by SIU’s strong core group of hearing researchers. "A concentration like this is extremely rare," says Dr. Cox. "It’s a lot easier to get things done, to share equipment, and be more efficient when you’re in the same space with your collaborators." She says Dr. Caspary quickly became her mentor. In addition they are natural collaborators because Caspary studies one of the brain’s neurotransmission systems within the auditory realm, and Dr. Cox did her PhD dissertation on the same neurotransmitter system in the visual realm.

Dr. Cox now has a three-year, $1.5 million grant from the U.S. Office of the Assistant Secretary of Defense for Health Affairs, a division of the DoD, to advance her investigation of the genes and proteins that make hair cell regeneration possible. The regeneration period in mammals appears to be time-sensitive, occurring within a very short window in the first week of life. Dr. Cox says, "We’re studying what pathways allow spontaneous regeneration to occur in the young cochlea that has not matured. This will direct studies in the adult cochlea where we hope to eventually design drugs to simulate hair cell regeneration in people."

Dr. Cox’s research team includes Michelle Randle, Kaley Ramsey, Melissa McGovern, Yuanzhao Lv, PhD, and otolaryngology residents Scott Montgomery, MD, and Nnenna Ezeilo, MD. In addition to her work on regeneration, Dr. Cox has recently received a five-year, $1.4 million grant from the NIH to investigate genetic factors that regulate hair cell survival during development, and within the contexts of noise or ototoxic drug exposure, cochlear maturation and spontaneous hair cell regeneration.

 THE DYNAMIC DUO

Sometimes a merging of the minds toward common research goals pays unexpected dividends in the heart. The husband and wife team of Vickram Ramkumar, PhD, professor of pharmacology, and Debbie Mukherjea, PhD, research assistant professor of otolaryngology, are proof of this. They have been making solid progress on otoprotection studies separately and with Dr. Rybak for 20-plus years. The couple first met in the SIU labs and now are parents to three children and another promising patent for a drug called transplatin.

Dr. Ramkumar’s initial work focused on the cardiovascular inputs of the brain. While helping one of Dr. Rybak’s grad students, he found adenosine receptors, a system previously known to be in the heart and brain, in the cochlea. The discovery ignited his interest in auditory research and prompted numerous experiments.

Dr. Mukherjea came to SIU as an international grad student in 1999 and earned a PhD in medical microbiology. She then began working on the Rybak and Ramkumar studies and expanded them to include molecular readings, adding gene microarrays and new techniques. "Our molecular studies have helped us narrow the time window available for treatment and prevention of hearing loss," says Dr. Ramkumar. "We now know that events occur as early as within two minutes of either acoustic or chemotherapeutic assault to the cochlea, and when treatments are given within two hours of injury, there is almost complete protection. Microarray studies have expanded our understanding of how different genes interact to mediate hearing loss or the recovery process."

During one of the experiments, Drs. Ramkumar and Mukherjea discovered that the inactive analog drug to the chemotherapy drug cisplatin, called transplatin, was blocking the uptake of cisplatin in the cochlear hair cells. Further study showed it provided hearing protection in rats when administered by multiple routes, and it didn’t affect the cancer-killing capacity of cisplatin.

The drug appears to help protect against hearing damage, kidney damage and neuropathy. "It works wonderfully and doesn’t seem to have any toxic effects," Dr. Ramkumar says. Because transplatin is a variation on cisplatin, which is already approved to treat cancer, the scientists believe it will move quickly through clinical trials.

 

They are presently looking at its role in NIHL and collaborating with Dr. Rybak on his capsaicin study. However, on the day of the interview, Dr. Mukherjea was celebrating a small – but important – engineering innovation. She and her grad students had devised a way to keep minute cochlea samples anchored in position for live imaging under a microscope using household items that would make MacGuyver proud: a 10 cent washer, superglue and a patch of panty hose stretched taut.

"We’ve been working on this for a year and a half, and I’ve never been happier in my life that we got this damn thing to work," she says with a chuckle. The accomplishment will enhance the lab’s efficiency at handling mouse models and allow more cohorts to be examined for each trial.

Dealing with the tiny structures within the inner ear has also become easier thanks to another technology upgrade. This spring Dr. Brandon Cox and members of the auditory research group obtained a new confocal microscope from a DoD grant. The Zeiss model LSM 800 with Airyscan uses light emitting diodes (LEDs) that are much more powerful and stable than gas lasers. The Airyscan components allows for super resolution imaging that nearly doubles the resolution of the group’s previous confocal microscope.

The OTO OVERSEER

Carol Bauer, MD, professor and chair of the Division of Otolaryngology, is a researcher and clinician with a background in surgery, psychology and neuroscience. Dr. Konrad recruited her to join the auditory research corps in 1995, which by then already contained renowned investigators Drs. Caspary and Rybak. She partnered and mentored with them while pursuing tinnitus research with fellow SIU researcher (and since 1991, husband) Tom Brozoski, PhD. The two wanted to understand the mechanisms for the perception of chronic tinnitus – where the "phantom sounds’ come from.

"Tom’s a genius – you can quote me on that," Bauer says, laughing. "He’s a neuroscientist and neurophysiologist and he’s the one who invented the animal model for tinnitus – a key to driving this whole research program forward." The tinnitus model allowed detailed examination of the brains of rats and chinchillas as they processed sounds.

And thanks to a collaboration with the Beckman Imaging Center at the University of Illinois in Urbana, the lab could obtain functional imaging studies to visualize where neural activity associated with tinnitus in the brain. This included a surprising area outside the auditory pathway, in the cerebellum. Dr. Bauer is proud that labs around the world are now exploring another novel finding that originated here.

She also appreciates the peer input. "You’re able to get different perspectives and knowledge on auditory systems and auditory pathology. When we work together, we tend to come up with more "aha’ moments and more interesting avenues to explore," she says. "No one person has all of the techniques to investigate a problem completely, but if you put a lot of brainpower together, you can really accomplish some interesting work."

She and Dr. Caspary are especially grateful for the addition of "young superstar" Dr. Cox. "We’re able to use her skillset to look at hair cell regeneration and see how that may apply to our study to prevent or reverse tinnitus. Having two groups together in one location makes that happen."

Another factor informs her work. Dr. Bauer has had tinnitus for more than 10 years, and a significant part of her clinical practice is taking care of patients with tinnitus. "It’s a positive experience in a lot of ways, because it allows me to speak from the heart when I’m talking to people who have the same problem," she says. "You can’t underestimate the importance of hearing a patient’s history and how they are affected by tinnitus, to direct your research."

THE FUTURE

For all these promising developments, Dr. Bauer believes the auditory research group is approaching a critical time, and it is due to one of the same factors that affects hearing loss: aging.

"You can look around the country and see institutions that once had famous research labs, and they’re now gone because they didn’t keep reinvesting in their group," she says. "Attracting outside researchers to come and build their careers at SIU is a lot easier when you have great people already in place. But even the best labs need to be replenished if they are going to stay that way and survive. I’m thankful that SIU has invested in auditory research."

And she remains optimistic about what’s ahead.

"Fifty years ago, we thought once you lost your hearing, that was it. About all you could do was withdraw from social interactions or learn sign language," says Dr. Bauer. "Now people who are hearing impaired can get cochlear implants and it’s a whole new world. They can hear again and be part of a community and socialize and work.

"I think within 20 years, we should be able to reverse hearing loss and prevent tinnitus. People now might say, "Well, that’s impossible.’ But it’s not. It will come about because of the work of scientists like Brandon, looking at the molecular mechanisms of damage to cells in the auditory system."

These potential solutions to hearing loss could originate from right here in central Illinois. Hear, hear.