Scents and Sense Ability

and Sense Ability Scents

By Paul Brockwell Jr.

Two researchers’ novel application of technology passes the smell test for restoring olfactory function.

Imagine, for a moment, never enjoying your favorite smells again — gone are the aromas of fresh-baked cookies, clean sheets or a favorite scented candle. Gone too is the ability to enjoy the flavor of favorite foods and drinks. And the ability to recall cherished memories so closely linked to smell vanishes without a trace.

This condition — the complete loss of a person’s sense of smell — is called anosmia. Researchers have found it challenging to know how many people are affected by it. Grant funding for more thorough assessment and study of the condition has been scarce, but the most current studies estimate around 3.4 million people, or 3.2% of the general U.S. adult population, suffer from complete or severe loss of smell. 1 The problem’s scope receives less attention than vision and hearing disorders, but anosmia has an unseen cost. Losing olfactory system function can dramatically affect a person’s quality of life. People report an inability to enjoy food and flavors. Anosmia patients also face significant lifelong safety risks when they can no longer detect threats, such as gas leaks or spoiled food.

No treatment currently exists to restore the loss of smell caused by severing of the olfactory nerves. That’s been a nagging problem for Richard M. Costanzo, Ph.D., professor emeritus and director of the Smell and Taste Disorders Center in the VCU Health Department of Otolaryngology — Head and Neck Surgery. The clinic is one of the few of its kind in the country, and rarely a week goes by that Dr. Costanzo doesn’t hear from another person seeking help. Dr. Costanzo’s lab investigates methods to promote regeneration and repair of the olfactory system, and his research focuses on the unique ability of the olfactory system for neurogenesis and replacement of degenerating neurons. That singular ability, however, is unable to compensate for the loss of smell that results from severing nerves from the olfactory bulb.

EXISTING TECHNOLOGY MEETS AN UNSOLVED PROBLEM Since Dr. Costanzo arrived at VCU in 1979, he’s been trying to develop a clinical solution for patients experiencing the complete, neuronal-based loss of smell. The condition is common in people who have experienced head trauma, when temporary displacement of the brain can sever connections between neurons in the nose and the olfactory bulb. Recent advances in understanding how the olfactory system functions and can be mapped provided him with the inspiration to continue searching for a solution.

Dr. Costanzo says he was envious of what could be done for hearing loss by colleagues like Daniel M. Coelho, M.D., Douglas Hayden Professor of Otology, Neurotology and Skull Base Surgery and director of the Cochlear Implant Center at VCU Health. Dr. Coelho has expertise in cochlear implants, the complex devices that bypass damage to the normal hearing process in order to directly stimulate the auditory nerve with electrical signals that provide a sense of hearing to individuals with severe hearing loss. “I’ve been searching my whole career for a way to help people with loss of smell, and not so far away in the human head is another sense with a wild success story,” Dr. Costanzo said. “I thought, it’s too bad we can’t do that. Dan and I were talking one day, and he told me, ‘You know with hearing we use a strategy where we can bypass the damage and stimulate the nervous system and restore hearing, so why can’t we do that for a sense of smell?’”

Their idea sent the two doctors on a promising path and led to a research partnership both describe as fortuitous, given their respective expertise. They received funding from the MEDARVA Foundation that was critical for their early stage research. The grant helped keep the research project alive, enabling Drs. Coelho and Costanzo to establish proof of concept on a high-risk venture. “If that hadn’t happened, the idea would likely be buried like so many others,” Dr. Costanzo said. The progress made possible by the MEDARVA grant inspired private giving from Scott Moorehead (see page 35), an Indiana-based entrepreneur who suffers from anosmia. This type of support for basic science research was crucial because federal funding is increasingly more challenging to secure for untested ideas related to olfaction.

ESTABLISHING PROOF OF CONCEPT The team conducted two studies that tested their theories about creating smell perceptions using electrical stimulation of the olfactory bulb. Their first experiment confirmed that different odors produced different neural activity within the olfactory bulb. They recorded the neural response patterns to various odor stimulants with a 32-electrode array connected to a monitoring system. Data from their study

Olfactory System

This illustration shows how an intact olfactory system would function. In patients with anosmia, or the complete loss of smell, the nerve connections to the olfactory bulb (inset) are severed when injuries shift the brain and shear the nerve connections to the olfactory bulb, which run through delicate, spongy bone known as the cribriform plate. Illustration: Jacopin / BSIP / Science Photo Library

indicated that different odors result in localized response patterns within the olfactory bulb. In 2016, they published findings from these efforts to spatially map the olfactory bulb through both odor presentation and direct electrical stimulation of olfactory systems. 2 A second study, published in 2018, confirmed that direct stimulation of the olfactory bulb created spatial patterns of neural activity similar to those observed during normal, functioning olfaction. 3 Both studies supported the theory behind using electrical stimulation for treatment of anosmia.

Their basic research has produced important discoveries. While the idea of restoring a sense of smell through electrical stimulation poses technical hurdles, the studies suggest that unique perceptions can be achieved by using the same principles of highly focused patterns of electrical stimulation to the olfactory bulb. Additionally, the use of different current and time intervals may, similar to the development of cochlear implants for hearing loss, be critical for refining the perception.

Eric Holbrook, M.D., an associate professor of otolaryngology at Harvard Medical School, completed an NIH fellowship in Dr. Costanzo’s lab prior to his residency at VCU Health. In 2018, he and his team published a report on their success in using electrical stimulation to create a smell sensation in a small study of five human subjects.

In this study, the subjects were screened to confirm their ability to smell. Each participant was already undergoing a nasal endoscopy, which enabled Dr. Holbrook to insert electrodes at three areas along the thinnest part of the cribriform plate and to induce anosmia with topical anesthesia. The study participants were then exposed to electrical stimulation of the olfactory bulb to see if they could perceive smell while current was stimulating the olfactory bulb. Three people reported the sensation of an odor with the electrical stimulus. None could specify what kind of smell they experienced, but one participant described it as an “onion-like smell.” All participants tolerated the study with minimal discomfort. 4 “That’s really important — to be able to confirm and really drive Dan and Rich’s research forward and even get more interest in this concept of artificially stimulating the olfactory bulb through the use of electricity and preparing for the use of implants to have some chance for restoring sense of smell,” Dr. Holbrook said.

Dr. Holbrook hopes that other scientists and industry leaders will see this line of inquiry as a viable future treatment option for anosmia. “We’ve been many years without breakthroughs in restoring smell,” he said. “It’s going to take a lot of work still, but we need to search this avenue of potential therapies for people with smell loss.”

MAKING FUTURE SENSE After establishing proof of concept, Drs. Coelho and Costanzo are continuing their research on smell restoration and have partnered with the university’s office of research and innovation to navigate the path from invention disclosure to a patent-protected technology. “Over the past several years, VCU Innovation Gateway has helped transform the treatment of anosmia from the theoretical to the possible,” Dr. Coelho says.

The prototypes they developed use the same technology behind cochlear implants, with both external sensors and internal processors, and Drs. Coelho and Costanzo are cautiously optimistic about the direction of their project. Now they are refining sensors on prototypes and thinking through the design of surgical protocols that will ensure patient safety and effectiveness with the device. They are heartened by the response of one survey of anosmia patients. Of those surveyed, nearly 30% of respondents expressed willingness to undergo head surgery to correct their smell disorder. 5 That sentiment is encouraging as they

work to create a device and surgical method that could be either minimally or significantly invasive.

The patent contains novel methods for gas sensing technology that would aid in detection of different odors. “That technology still needs some further development,” Dr. Costanzo said. “But we can start with some basic detections and simple discriminations. And Dan was explaining to me that when they first started cochlear implants it was a similar path.”

It is true that early cochlear implant developments provided not the perfect fidelity of sound, but the ability to detect sound. Similarly, they are realistic about what to expect as their research continues. The olfactory system is more sensitive and more complicated than hearing and even vision. The human nose can distinguish around 1 trillion different odors according to research in the journal Science. 6 However, the ability to fine-tune a device to that level of discrimination may not be necessary. For example, the scent of a rose can include up to 275 unique odorants, but only a small fraction of them may be required for a person without congenital anosmia to identify what they’re smelling.

The initial aim for Drs. Coehlo and Costanzo is not to achieve perfect detection of certain scents, but they are not shy to say they hope that ultimately may be possible. “Our first goal is to achieve some sort of smell perception,” Dr. Coelho says. “We’re currently planning human pilot studies that will further our proof of concept.” Dr. Coelho and Dr. Costanzo have built partnerships with collaborators at medical device manufacturing companies who provided some of their cochlear implant components for modification. They are working with other Harvard-based surgeons, including Dr. Holbrook, to develop and refine surgical protocols for the first in-human applications.

What remains most exciting to them is how this effort to develop smell restoration technology has been a collaborative, grassroots initiative originating here at VCU Health. Through their partnership, both Dr. Coelho

A sensational partnership was forged when Richard M. Costanzo, Ph.D., professor emeritus and director of the Smell and Taste Disorders Center in the VCU Health Department of Otolaryngology, began working with Daniel Coelho, M.D., professor of otolaryngology and director of the VCU Health Cochlear Implant Center, to develop proof of concept for their theories on how to restore complete neuronal smell loss through electrical stimulation. Photo: Karl Steinbrenner

The Early Prototype:

This illustration models how the smell restoration device designed by Richard Costanzo, Ph.D., and Daniel Coelho, M.D., would function. The device includes sensors to detect odor particles and processors that would send electrical current to directly stimulate the brain’s olfactory bulb and create a sensation of smell.

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How It Works:

1. The external sensors detect odors.

2. Signals from the sensor transmit to the external processor to be coded.

3. The external processor sends a unique code (based on the odorants) to the transmitter.

4. The transmitter sends the signal wirelessly across the scalp to the internal receiver-stimulator.

5. The internal receiver-stimulator sends the signal through a wire to the electrode array on the olfactory bulb.

6. The olfactory bulb is stimulated with a unique pattern based on the original odor.

7. Brain perceives a sense of smell.

and Dr. Costanzo have made real progress toward a solution for this problem that effects millions.

“We’ve invented something that can help people in the next 5–10 years,” Dr. Coelho said. “Our challenge now is more practical. Our idea applies existing technology, but what’s novel about what we’re doing is modifying it for this particular application.” The two wrote in one recently published article that “Although there is much to be done before an ‘olfactory implant’ is available, the present

1. Howard J. Hoffman, Shristi Rawal, Chuang-Ming Li, and Valerie B. Duffy. New chemosensory component in the U.S. National Health and Nutrition Examination Survey (NHANES): First year results for measured olfactory dysfunction. Reviews in Endocrine and Metabolic Disorders. 17(2): 221-240. (2016).

2. Daniel Coelho and Richard Costanzo. Spatial Mapping in the Rat Olfactory Bulb by Odor and Direct Electrical Stimulation. Otolaryngology – Head and Neck Surgery. DOI: 10.1177/0194599816646358 (2016).

3. Daniel Coelho and Richard Costanzo. Activation of the rat olfactory bulb by direct ventral stimulation after nerve transection. International Forum of Allergy and Rhinology. DOI: 10.1002/alr.22133 (2018).

Illustration: Tom Edwards

findings lay the foundation for a novel method for treating anosmia, and in doing so, offer hope to those who suffer from the condition.” 2

If you would like to contribute to Coelho’s and Dr. Costanzo’s research to develop smell restoration technology, please contact Brian Thomas, vice president and chief development officer at the MCV Foundation, at 804-828-0067 or brian.thomas@vcuhealth.org.

4. Eric Holbrook, Sidharth V. Puram, et al. Induction of smell through transethmoid electrical stimulation of the olfactory bulb. International Forum of Allergy and Rhinology. DOI: 10.1002/alr.22237 (2018).

5. Gerold Besser, David T. Liu et al. Olfactory implant: Demand for a future treatment option in patients with olfactory dysfunction. Laryngoscope. Epub 2018/08/27. doi: 10.1002/lary.27476. (2018).

6. Caroline Bushdid, Marcelo Magnasco, Leslie B. Vosshall, and A. Keller. Humans can discriminate more than 1 trillion olfactory stimuli. Science. 343,1370–1372. DOI: 10.1126/science.1249168 (2014).

This illustration of their prototype shows how smell restoration sensors would detect, process, and stimulate the olfactory bulb in order to restore a sense of smell. Sensors attached to glasses detect odor particles and relay information to a processor, which would signal an implanted device to deliver electrical current to the olfactory bulb. The next stage of research involves refining surgery protocols and implant prototypes developed by Richard M. Costanzo, Ph.D., professor emeritus and director of the Smell and Taste Disorders Center in the VCU Health Department of Otolaryngology and Daniel Coelho, M.D., professor of otolaryngology and director of the VCU Cochlear Implant Program. Illustration by Tom Edwards Scott Moorehead was teaching his 6-year-old son how to skateboard in their driveway when his feet slipped, and he went hurtling down toward the pavement.

Within an instant, a touching father-son moment turned into an emergency. The back of Scott’s head absorbed the brunt of the impact when he hit the driveway, and his injuries were severe — he sustained four contiguous fractures on his skull, two subdural hematomas and a massive concussion. The rural hospital near his house had to airlift him to Fort Wayne, Indiana, for advanced trauma care.

Scott remembers feeling loopy, annoyed and confused by a frequent question in the days following his accident. The staff were often checking on him and asking if he could smell. At the time, he insisted that he could, but at some point he realized he had, in fact, lost his ability to smell. Anosmia and other smell-related disorders are common in patients who suffer traumatic brain injuries. Some patients may recover the ability to smell over time as neurons regenerate and reconnect to the olfactory bulb. Unfortunately for Scott, his accident had severed the neural pathways and robbed him of this ability.

The next few years were challenging for him, he says. Without any treatment options to restore his sense of olfaction, Scott had to adjust to life with an invisible injury that had ended his ability to enjoy the things he loved most. The first thing Scott noticed was how losing his sense of smell affected his quality of life, particularly enjoying food and flavor. The experience of taste comes from two different sources — the tongue, which can distinguish between temperature and four basic areas: sweet, sour, spicy or salty; and the olfactory system. What people often describe as flavor originates primarily from aromas detected by the olfactory nerves and the nearly 1 trillion unique odors that can be detected and sent to the brain. 1

Dad and entrepreneur Scott Moorehead lost his sense of smell following a traumatic brain injury. His support of research by Drs. Costanzo and Coelho at VCU Health has helped move forward promising inquiries that aim to develop a device that can restore a sense of smell in patients like Scott who suffer from anosmia, or the complete loss of olfactory ability. Photo: Courtesy of Culture of Good

“If you blindfolded me and put six different ice cream flavors in front of me, I probably wouldn’t be able to tell the difference,” Scott says. “They’d all be cold and somewhat sweet. It’s super frustrating — how it impacts your taste — and that’s difficult to explain to a lot of people.”

Safety is also a huge concern for people with anosmia. Without the ability to smell, individuals are unable to detect when there may be a gas leak or spoiled food. Scott recalls one terrifying moment when he was home alone and watching TV. His wife arrived home with their kids in tow, and she immediately rushed them out into the yard. When she found Scott inside the house, she quickly yelled at him to get outside because the house reeked of gas. Scott, without a sense of smell, had no way of knowing the tank for their propane fireplace had been steadily leaking gas

“If you blindfolded me and put six different ice

cream flavors in front of me, I probably wouldn’t

be able to tell the difference. They’d all be cold and

somewhat sweet.”

Scott Moorehead

into the house. The situation was a dangerous one that could have ended in tragedy.

“That scared the crap out of me,” Scott remembered. “There was propane gas all over my house, and I had zero idea I was sitting in the middle of it.”

Scott also struggled with the emotional weight of losing the sense of smell. In addition to worrying about personal hygiene, he remembers sleepless nights thinking about how his ability to recall major life moments and loved ones had been impaired and limited by his inability to smell. “It definitely had me in a funk,” Scott recalled. “I dealt with a lot of anxiety and stress. If I’m being honest with myself, I was probably borderline depressed.”

Scott searched endlessly for a solution online and came up empty-handed. After encountering many similar stories, he eventually found peace with his condition, but never fully gave up his interest in the problem.

“You just reconcile and say this wasn’t my choice. I’m going to move on,” Scott said.

Several friends and colleagues pledged to alert Scott if they ever encountered anything that might lead to treatment for his anosmia. Years later, a colleague and friend discovered the work of Dr. Costanzo and Dr. Coelho at VCU Health and shared it with Scott. They were far enough along with patents and testing to intrigue him. “I’m an entrepreneur,” Scott explains. “I’m used to being my own boss and believe almost any problem can be solved with enough time, effort and money.”

After touring their labs and meeting with the team investigating the restoration of smell through electrical stimulation at VCU Health, Scott found himself in a position to financially support their research at a crucial time to continue the lab’s work.

“All of these things came into a collision — this miniature explosion happened in my brain in a good way this time,” Scott said.

In part because of Scott’s support, the team at VCU Health was able to build off their research establishing proof of concept for a device to restore smell. And their work to develop technology that can restore a sense of smell in humans remains ongoing.

“The scars that I have are pretty permanent,” Scott said. “If I could help somebody else not have to go through the same type of mental and physical anguish that I did, then that’s a huge win.”

1. Caroline Bushdid, Marcelo Magnasco, Leslie B. Vosshall, and A. Keller. Humans can discriminate more than 1 trillion olfactory stimuli. Science. 343,1370–1372. DOI: 10.1126/science.1249168 (2014).

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