As far as working conditions go, Midas is probably one of the happiest laboratory employees there is. She works a five-day week, with no requirement to go in on weekends. She works for about 20 minutes at a time, with a maximum of an hour a day spent on the job. She’s home by 3.30 pm every day. And, best of all, she gets praise, treats and rewards every time she does her job – namely, detecting cancer in urine samples. So how did Midas negotiate such a great deal for herself? It probably helps that Midas, a Hungarian wirehaired viszla, is cute. It probably also helps that no laboratory instrument yet developed is capable of the sophisticated detection Midas is trained to do. The idea that dogs can smell cancer has been around for quite a long time, although until recently, the claims were all unsubstantiated. Claire Guest, co-founder of the charity Medical Detection Dogs, shared an anecdote about a Dalmatian whose repeated licking alerted its owner to the presence of a mole on her calf that turned out to be malignant melanoma – a cancer that was unlikely to have been caught so soon by any other means. This was the story that caught Guest’s attention and started her thinking about the potential implications. A psychologist working at Hearing Dogs for Deaf People, she was fascinated by canine behavior. Did cancer really have a smell? And if so, could dogs really detect – and possibly even diagnose – the disease?
Getting started
It was years later that Guest first heard John Church, the “maggot man,” interviewed on the radio. Church’s claim to fame is the introduction of maggot treatment to the UK National Health Service, using medical maggots to remove infected or necrotic tissue from wounds. In his interview, though, he also mentioned that he’d heard a plethora of stories like the one Guest encountered, and that he was intrigued by the possibilities. Did anyone out there have the interest and expertise to train a “cancer dog,” he wondered? The answer was yes – and by the end of the day, Church and Guest were sitting together, making plans for the first-ever proof-of-principle study to see whether or not dogs could be trained to detect human cancers by odor. But how could they begin training an ordinary dog to sniff out cancer? They needed a sample – something that would contain the odor of cancer, but not the cancer itself. After all, to a dog, a tissue sample is essentially a piece of meat. After weeks of deliberation, Guest and Church settled on testing urine samples from patients with bladder cancer; they knew that tumor cells are often shed into urine and can be detected via microscope, so they suspected it was possible that a volatile odor might also be present. The big question: could they teach a dog to detect it? As it turned out, the six dogs they trained were able to identify the urine of bladder cancer patients in 22 out of 54 cases – a mean success rate 14 percent higher than would have been expected by chance alone (1). One of the dogs was Guest’s own pet and cancer-sniffing pioneer, Tangle, who was able to detect cancer with 56 percent accuracy. In comparison with modern hospital tests, that success rate doesn’t necessarily inspire confidence – but the dogs had been exposed to only about 50 samples in total, half of which were positive. With a larger training set, the researchers were convinced the rate of detection would improve. And they weren’t the only ones. Suddenly, attention was drawn to the fact that cancer apparently had unique volatiles that could be identified through odor. For Guest, it was the beginning of an era – one in which she envisioned that well-funded training programs would produce teams of biodetection dogs to save countless lives. Although in practice, engagement has been somewhat slower, significant steps have been made since that day: electronics scientists have begun to analyze urine components in search of detectable volatiles, there have been breakthroughs in “electronic nose” diagnostics, and researchers have continued to build a strong evidence base supporting dogs’ noses as biosensors. Perhaps most significantly in Guest’s case, she and her first trustees set up Medical Detection Dogs and began a serious exploration of the possibilities of this off-the-wall, yet promising idea.
The nose knows
How good is a dog’s nose really? Humans have approximately five million sense receptors in their noses. Dogs, in comparison, have about 300 million – 60 times the sensitivity. “Some humans think they can smell a teaspoon of sugar in a cup of tea,” says Guest. “A dog with Midas’ nose would be able to smell a teaspoon of sugar in the equivalent of two Olympic swimming pools of tea.” And it’s not just the nose that does the job; dogs also have a vomeronasal organ, the organ of Jacobson, near the backs of their palates. When sniffing, they draw air into their throats so that it passes over this organ – which actually sends information to a different part of the brain. Sensory information from both the nose and the organ of Jacobson is consolidated in the brain before, ultimately, the dog makes a decision based on the scents it can detect. Guest knew she needed to determine exactly how well the dogs could smell – but the available literature varied widely. So rather than use “head space” (blowing air with volatiles into the dogs’ faces), she and her colleagues mimicked the technique they wanted to use by providing samples and asking the dogs to investigate them. “We wanted to find out how low the dogs could go,” she says, “and then I wanted to do some manipulation, by varying the temperature or how long the sample had been out, to see if I could improve their abilities.”“At one point, we had two very experienced dogs working on some samples that had come in from the hospital. The samples come with extensive patient notes, so we can see the Gleason scores, the PSA test results, and the clinician’s observations of the prostate. We gave one sample to the dogs three times, and every time, they said no – there’s no cancer. But we knew the patient had a Gleason score of seven and the biopsy showed cancer. So we scratched our heads, tried again – and again, they all agreed no. Even after a third trial, the dogs just completely ignored the sample. So the clinicians went back to the notes – and they found that there had been a mistake and, by the time the urine sample had been taken, the patient’s prostate had been removed. There was definitely no prostate cancer in that sample! And then we said, my God, the dogs are good.”
“My dog, Daisy, was in a study screening prostate samples when she started to behave strangely around me. This lasted for a couple of weeks, and then one day I took all of the dogs for a walk. But Daisy kept jumping into my face and staring at me with these massive eyes. I kept pushing her off saying, ‘What’s the matter?’ And as she ran off I thought, ‘Oh she’s bumped into me; I can feel something’,” says Guest. “I kept an eye on it for a few days, and eventually it started to feel like there was a lump under there – so I went to my doctor and was immediately referred. At first, I was told that it was a cyst, but eventually I was diagnosed with breast cancer. I went through surgery and radiotherapy, but luckily didn’t need chemotherapy because my lymph nodes were clear. And I was told by my clinician, my oncologist and my surgeon that had my attention not been drawn to it, I wouldn’t have had a mammogram for a further five years and by the time I’d felt the tumor, it would have been very large and very advanced. My story would have been completely different without Daisy. And it’s possible to apply this to people everywhere; every day of the week, we hear of people that have been diagnosed with or died of cancer. Early diagnosis saves suffering and lives, and that’s something our dogs can help give people.”
The dogs began by detecting amyl acetate diluted in mineral oil. The initial goal was to get them to “threshold,” the point at which they were experiencing a 50 percent success rate, before beginning manipulations – but the longer they worked, the better they got. No literature reflected that discovery, but experienced handlers had long suspected that, much like marathon training, the dogs needed to build up their abilities over time. Sure enough, the threshold point continued to decrease week after week, until after six months of training, the dogs were detecting at a threshold dilution of 1:5,000,000,000 – one part amyl acetate per half billion of mineral oil. But the real uniqueness of Medical Detection Dogs’ work came with their training system. Most systems are based on positive finds – dogs earn rewards for detecting something, but not if there’s nothing to detect. With cancer, though, the trainers didn’t know what the dogs were looking for, and they didn’t want to encourage a positive bias by rewarding the dogs only when they alerted. So they rewarded blank runs equally – resulting in a false positive rate of under 5 percent. That’s better than many medical tests, and at a fraction of the cost! At the moment, the charity is training a team of dogs to find prostate cancer; their accuracy using a 1 mL urine sample is over 90 percent, with a false positive rate below 5 percent. That means the biodetection dogs are actually performing better than prostate specific antigen (PSA) testing in the clinic (2)! The demand for the dogs reflects their performance. “We’re already in a position where medics are asking us – can we send samples to your center?” says Guest. Medical Detection Dogs has a partnership with nearby Milton Keynes Hospital, which sends hundreds of samples to the charity for screening. Each sample is screened by a minimum of two dogs – usually three – to ensure accuracy and then the outcome is sent back to the hospital. Clinicians use those results in concert with symptoms, scans and PSA tests to decide whether or not to send patients for biopsy.
Bringing up biodetectors
What’s it like to train as a biodetection dog? “We have to teach the dogs when they’re young that this urine is basically a soup – it’s got volatiles, it’s got protein, it’s got everything – and the dog has to ignore about 98 percent of it completely.” Guest likens the process to training humans to pick up visual cues. “Imagine if I show you Monet paintings, and you get £100 for each Monet painting you spot with a small red flower in the left-hand corner. But I’m not going to tell you that; you’ve got to work out what it is in that painting that earns you the reward. Of course, the more Monet paintings I show you, the better you get at it. To start with you’re just guessing!” But what makes the dogs better than electronic noses or other detection devices? “A dog can recognize a ‘red flower’ even if it changes slightly – even if the wind is blowing it slightly to the left or there’s a yellow flower in front of it,” Guest explains. “The electronic machines aren’t quite so good at that. Mass spectrometers are very good at finding specific things, but if you don’t know exactly what you’re looking for, it becomes much more complicated. Dogs are intuitive biosensors; they can tell you that they see a red flower even though it may not look exactly like the red flowers they’ve seen before. And that’s what makes them particularly good atthis work.”
Branching out
In 2011, the group published a second study (3). By that time, the highest-performing dogs showed sensitivities of over 70 percent, and the average dog could spot cancer in a sample two-thirds of the time. What’s more, the results weren’t specific to a type of cancer; dogs trained on bladder cancer samples and then presented with prostate cancer reacted in very similar ways. “When they went up to the prostate cancer samples, they went, ‘Oh, yes, I think that’s it, but not quite.’ You have to reward them a couple of times before they’re certain. So I think there's a big part of the odor that’s the same, but not all of it.” At the moment, Medical Detection Dogs has three separate sets of biodetection animals in training for bladder, prostate and kidney cancers – so that if a dog alerts, consultants will know to look for that dog’s particular specialty.“Just before they went to double-blind testing for our first study, the hospital urologist came to see the dogs working. All of the samples were new ones that the dogs had never seen, and one dog – Tangle – kept on indicating a particular sample. I couldn’t train him not to respond to it. I tried everything – giving him massive rewards, putting a positive cancer sample next to it to get him to pass over the normal one and indicate the cancer; he just kept going to this sample. Eventually, he started to get quite fed up about it. The consultant was ready to move to double-blind, but we had a major problem with our best dog. So we took the sample out and showed it to the clinician, and he pointed out that the response was the same as the one for bladder cancer. I said, ‘I know, but you’ve told me this man’s bladder is completely clear.’ He went back, looked at the notes, realized that the patient hadn’t had an ultrasound, and found that he had cancer of the kidney. About three weeks later, we got a letter from him saying, ‘Thank you, dear Tangle; you saved my life.’ His cancer was in the epithelial lining of the kidney, so it was part of the same system as the bladder. To Tangle, without any training, it was exactly the same,” explains Guest.
As engagement increases, Medical Detection Dogs is expanding the animals’ repertoire even further. Their sights are now set on breast, ovarian, colorectal and even lung cancer. The latter two are particularly exciting. Lung cancer, responsible for almost one in five cancer deaths, is the most common cause of cancer death worldwide (4). Over three-quarters of lung cancers are diagnosed at an advanced stage (5), and the charity is optimistic that, with a new breath test in development, the dogs will be able to improve early diagnosis of lung cancer in the same way that they’ve shown an ability to detect early bladder and prostate cancers. Colorectal cancer detection is equally useful – the disease is the second-most common cause of cancer death in Europe and the fourth-most common worldwide (6), and over half of patients are diagnosed at an advanced stage (7). “I asked the colorectal surgeon, ‘Do we really need better testing for this cancer? You have stool screening – don’t they know if you’ve got blood in your stool?’” says Guest. “He said that most people die of colorectal cancer because they won’t do the stool sample. There’s much higher resistance to doing a stool sample than a urine sample. And people are dying because of it. So if we could detect colorectal cancer in a urine sample, a lot more people would be screened.” Biodetection dogs clearly have potential. Although there’s always a need for more funding, more studies and more evidence, these hardworking animals have already carved out a niche in the world of early cancer diagnosis – and the results keep on coming. As Medical Detection Dogs expands its remit to include more diseases both within and outside the cancer sphere, it looks like the dogs are here to stay. Could pathologists one day share their laboratory space with furry, four-legged disease detectors? It seems unlikely, but you never know...
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References
- CM Willis et al., “Olfactory detection of human bladder cancer by dogs: proof of principle study”, BMJ, 329, 712 (2004). PMID: 15388612.
- MJ Barry, “Clinical practice. Prostate-specific-antigen testing for early diagnosis of prostate cancer”, N Engl J Med, 344, 1373–1377 (2001). PMID: 11333995.
- CM Willis et al., “Volatile organic compounds as biomarkers of bladder cancer: Sensitivity and specificity using trained sniffer dogs”, Cancer Biomark, 8, 145–153 (2010–2011). PMID: 22012770.
- Cancer Research UK, “Lung cancer mortality in Europe and worldwide”, (2014). Available at: http://bit.ly/1qdLRjv. Accessed May 11, 2016.
- Cancer Research UK, “Lung cancer incidence by stage at diagnosis”, (2015). Available at: http://bit.ly/1WpalEp. Accessed May 11, 2016.
- Cancer Research UK, “Bowel cancer mortality in Europe and worldwide”, (2014). Available at: http://bit.ly/1ZFdIVU. Accessed May 11, 2016.
- Cancer Research UK, “Bowel cancer incidence by stage at diagnosis”, (2015). Available at: http://bit.ly/1JZSvQN. Accessed May 11, 2016.