Osa, an athletic yet stubborn 62-pound German shepherd with a long, fluffy tail and a fondness for red bandanas, seems an unlikely superhero. But this six-year-old dog has mastered the art of sniffing out cancerous tumors and plays a crucial role in a research project with the potential to revolutionize oncology.

Despite the significant success of immunotherapy, CRISPR gene editing, and other recent breakthrough treatments, oncologists still struggle to detect some cancers in their early stages, a persistent and fatal issue. For instance, an average of 75 Canadian women are diagnosed with breast cancer each day, a disease treatable when found early, yet 14 Canadians die from it daily.

Osa might soon help improve these odds. She is part of an ambitious effort started five years ago at the University of Pennsylvania, aiming to reverse-engineer one of the world's most powerful scent-detection machines: the canine nose. Osa can distinguish between blood samples from cancer patients and healthy individuals just by sniffing them.

She is one of five cancer-detection dogs trained by Annemarie DeAngelo and her colleagues at the university's Penn Vet Working Dog Center, a non-profit academy that breeds and trains detection dogs. The ultimate goal is to develop an "electronic sniffer" that can mimic the cancer-sniffing abilities of Osa and her peers. Such a device could then be deployed to doctors' offices and medical diagnostic facilities across the US.

Cancer is just one potential target. This type of system could lead to devices for detecting other major health issues, such as bacterial infections, diabetes, and epilepsy. Some dog trainers and university researchers are also working on developing a method to detect COVID-19 infections based on skin odor.

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It all starts with the canine nose. Our human sense of smell doesn't even come close. The average human has 6 million olfactory receptors, tiny proteins that detect individual odor molecules. These receptors are clustered in a small area at the back of the nasal cavity, meaning a scent must waft in and up the nostrils. In dogs, the internal surface area devoted to smell extends from the nostrils to the back of the throat, comprising an estimated 300 million olfactory receptors—50 times more than humans.

Dogs also allocate significantly more brainpower to processing and interpreting these signals than humans—the part of a dog's brain devoted to smelling is 40 times greater than ours. Overall, a dog's nose is about 10,000 to 100,000 times more sensitive than a human's.

"Sniffing is how dogs see the world," explains Marc Bekoff, professor emeritus of ecology and evolutionary biology at the University of Colorado Boulder. "That's how they pick up information about who has been there, whether they are happy, sad, if the female is in heat, or if they are feeling well or not. Their nose leads the way—dogs sniff first and ask questions later." Humans have always valued the potential of the canine snout. In the Middle Ages, authorities in France and Scotland used dogs' sniffing abilities to track down outlaws.

Search-and-rescue dogs emerged in the 18th century when the monks of the Great St Bernard Hospice in the Swiss Alps discovered that their dogs could lead them to victims buried beneath the snow from avalanches and snowstorms. 

Despite this history, scientists did not explore the possibility of dogs detecting cancer until the late 1980s. This changed when Hywel Williams, a 30-year-old medical resident at King's College Hospital in London, made a remarkable discovery. 

Upon starting his training as a dermatologist at King's, Williams was assigned to review every melanoma case seen at the hospital over the past 20 years. This was a monotonous task, Williams recalls. One afternoon, however, he noticed a four-word note in a file: "Dog sniffed at lesion." This intrigued him. Could the dog have actually smelled cancer?

"So I rang up the lady in the file," Williams recalls, leading to a fascinating conversation. The patient, a 44-year-old woman, explained that her dog, Baby Boo, a border collie-Doberman mix, had become obsessed with a mole on her left thigh, sniffing it repeatedly. This continued daily for months, with Baby Boo even nuzzling the mole through the woman's pants. Eventually, Baby Boo tried to bite the lesion off, prompting her to visit her doctor. When the mole was removed, it was found to be a malignant melanoma.

"Something about that lesion fascinated the dog," Williams remembers. "And it literally saved this woman's life." Williams and a colleague published their findings in The Lancet, one of the world's most respected medical journals. This publication led dog lovers worldwide to contact Williams, sharing similar stories. For example, a 66-year-old man's Labrador retriever became obsessed with a patch of eczema on his thigh, which turned out to be basal cell carcinoma. In another case, George the schnauzer, trained by a Florida dermatologist, reacted strongly to a suspicious mole on a patient’s leg, which was found to be malignant.

Over the years, evidence has accumulated suggesting that dogs can detect various conditions, including bladder cancer, prostate cancer, diabetes, and even malaria. However, not just any dog can perform these tasks. 

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Osa, for example, arrived at the Penn Vet Working Dog Centre from a breeder at two months old. "We look at their genetics," says DeAngelo. "We look at their work ability. They have to come from working lines, not show or pet lines, but ones with a hunt-prey drive." Osa quickly advanced through obedience, agility training, and basic odor detection skills. 

nobody is allowed to approach DeAngelo's house unannounced (to do so results in loud barking and pandemonium). Upon entering the home, visitor, host and dog must all proceed immediately outside to play ball to set Osa at ease before any business can be conducted. But with these neurotic traits also comes an uncommon focus.

"I often refer to our medical-detection dogs as the CPAs," Otto says.

"They would love to just look at the spreadsheets and find the one number that's out of place. They really like having things very neat and controlled. They're the detail dogs." While Osa had all the qualities that make up a great sniffer dog, that didn't guarantee that she'd be able to master the most essential task of all. To find out if she could, DeAngelo and her team put Osa in front of a scent wheel, a stationary metal contraption with multiple arms, each one large enough to hold two separate containers-one containing plasma from a woman with metastatic ovarian cancer and the other with plasma from a healthy volunteer. When Osa stopped in front of the correct sample, pointed her nose at it and froze, DeAngelo and her colleagues hugged and cried.

"You don't know if it's going to work, so you train it, and you train it," she says. "You're actually now going to put the real cancer in the wheel, in the plasma, and see if the dogs can identify it and ignore the other samples. And it worked! The very first time!

During these sessions, the dogs are introduced to a universal detector calibrant, a potent and distinct odor developed by a veterinary scientist for training purposes. The trainer places the calibrant, a powder contained in a Mylar bag with a tiny hole to release the scent, on the floor, on a wall, or holds it in hand. When the dog sniffs the odor, the trainer marks this behavior by using a clicker or saying "Yes" and then rewards the dog with a treat. This process is repeated until the dog associates the odor with receiving a reward.

Next, the trainer offers the dog choices, such as placing two distinct odors in identical containers, only one of which results in a click and a treat when sniffed. Once the dog masters this, the trainer withholds the treat until the dog freezes and stares at the correct container. During this foundational training, trainers assess the dogs' skills and temperaments to determine their area of specialization. Dogs that excel at running on rubble enter search-and-rescue training, while those with strong noses but a dislike for rubble might become narcotics or bomb detection dogs. 

Penn's medical-detection dogs are those with quirky personalities and a focused demeanor. Cynthia Otto, the founding director of the center, calls them the center's "sensitive souls." These dogs dislike noisy and crowded environments like airports or disaster recovery sites. For example, Osa is very suspicious of strangers, leading to loud barking and chaos if someone approaches DeAngelo's house unannounced. Upon entering the home, everyone must go outside to play ball to put Osa at ease before any business can be conducted. These neurotic traits come with an uncommon focus.

"I often refer to our medical-detection dogs as the CPAs," Otto says. "They love to find the one number that's out of place on a spreadsheet. They like having things very neat and controlled. They're the detail dogs." 

Despite Osa having all the qualities of a great sniffer dog, it wasn't guaranteed she could master the most essential task. To test this, DeAngelo and her team placed Osa in front of a scent wheel, a stationary metal contraption with multiple arms, each holding two containers—one with plasma from a woman with metastatic ovarian cancer and the other with plasma from a healthy volunteer. When Osa stopped in front of the correct sample, pointed her nose at it, and froze, DeAngelo and her colleagues hugged and cried. "You don't know if it's going to work, so you train it, and you train it," she says. "You're actually putting the real cancer in the wheel, in the plasma, and seeing if the dogs can identify it and ignore the other samples. And it worked! The very first time! It was very emotional.” 

However, that's only half the challenge. To transform Osa's remarkable abilities into a replicable electronic nose, researchers need to determine precisely what Osa and her fellow dogs are detecting. DeAngelo explains that the blood samples used to train the dogs contain hundreds of different organic compounds, any one of which could capture the dogs' attention. This is why the Penn team includes not only physicists and engineers designing the electronic nose but also chemists to identify what the device needs to detect. The team has been breaking down the cancer samples into smaller components and presenting them to the dogs to pinpoint which specific compounds (odorants) attract their attention. A similar method is used to train the device: starting with samples containing many odorants and ensuring the machine can distinguish between them. They then remove individual odorants, training the machine to detect increasingly subtle differences. The goal is to eventually place a vial of plasma inside a microwave-sized electronic sniffer, which might handle up to ten samples at a time.

Most people would prefer a sympathetic nose over a machine, but Bruce Kimball, a chemist at the Monell Chemical Senses Center in Philadelphia, explains that deploying enough dogs and handlers across the US is impractical. An electronic nose prototype has already been built and successfully detects cancer 90 to 95 percent of the time. This team has also accurately detected different types of cancer and is developing a cancer-detecting device for the National Institutes of Health. They have a good understanding of the compounds or chemicals that create the odor but aim for more specificity, such as distinguishing between early- and late-stage cancer. "It would be incredible to identify people at an early stage and really have an impact on saving lives," says Otto. With this capability, a blood test could be sent to a central lab or ideally performed in a doctor's office, becoming part of an annual checkup and potentially making hidden cancers a thing of the past.

If all goes as DeAngelo and Otto hope, commercial prototypes for the cancer-sniffing device are expected to be complete within nine months, marking a significant victory in the fight against cancer. Of course, the dogs are unaware of the importance of their work. "To them, it's just a game," says DeAngelo. "Osa knows that 'I was trained, and when I find this odor and indicate it, I get rewarded.'" Osa prefers her reward to be a piece of cheese—a small price to pay, considering Osa's nose could one day save thousands of lives.