In a small, hot room within a compound in Tanzania's southern highlands are three white-clad technicians, a glass-and-metal chamber and a rat named Charles. After being gently dropped into the chamber, Charles aims his snout at the first of a series of 10 sliding metal plates in the base. A technician swiftly opens it, revealing a small hole. Charles sniffs… and moves on. The hole is closed, and the next one opened. This time, he sniffs hard, scratching at the metal. The technician calls out: "Two!" Over by the window, a colleague holding a chart inserts a tick. It's highly possible that Charles has just saved someone's life.
Charles is an African giant pouched rat, a species endemic to sub-Saharan Africa. He's also a pioneer, one of 30 of his species that live and work in Morogoro, a few hundred miles west of Tanzania's largest city, Dar es Salaam, on a programme to sniff out tuberculosis (TB).
TB is a disease that can destroy the lungs. About nine million new cases are diagnosed worldwide every year, one-quarter of them in Africa. Antibiotics can cure TB, but it's fatal if untreated, and many patients are never diagnosed. This is partly because the 125-year-old microscope-based test used across Tanzania (and in many other cash-strapped countries) picks up only about 60 per cent of cases, a figure that drops as low as 20 per cent for people also infected with HIV.
This is where Charles comes in. He and his fellow rats sniff cough-and-spit samples provided by suspected TB patients. The rats aren't infallible, but they do detect about 70 per cent of cases, and it doesn't matter to them if a patient has HIV – which matters a great deal in Tanzania, where about four in every 10 people with TB are HIV positive. This particular morning Charles has sniffed 100 samples, missing one that has been identified as positive by the public clinic but identifying 12 new suspected cases, which will now go for secondary checking.
Fidelis John, the training supervisor, is looking on. Unlike the standard lab rat, Rattus norvegicus, the African giant pouched rat (Cricetomys gambianus) is not a species that has been bred over many generations to cooperate well with humans. Is it hard to train them to perform like this? "It's not easy…" he says, smiling. "But it's possible."
Around the world, other animals – mostly dogs – are being used experimentally to screen human samples for disease; but the TB-sniffing rats of Tanzania are the only animal disease-detectives in routine use. When medics first hear about the programme, they are often sceptical about the idea of using rats rather than machines, says Christophe Cox, CEO of Apopo, the Belgian-based organisation behind the project. But then they are shown the case detection data. The rats are saving lives every day and, argue some advocates, the time has now come for dogs to do the same.
The first "Lancet letter" (as they're known in the dog-cancer-detection community) came in 1989. Writing, as the name suggests, in the medical journal, a pair of dermatologists reported how a patient's dog had constantly sniffed at a mole on her leg, once even trying to bite it off. The woman sought medical advice. Tests showed it was a malignant melanoma. It was removed, and she remained well.
The second Lancet letter was published in 2001. John Church, a British doctor, and his colleague reported the case of 66-year-old man whose pet labrador, Parker, kept pushing his nose against the man's leg, sniffing at a rough patch of skin that had been diagnosed as eczema. The man went back to his doctor. The eczema was found to be a basal cell carcinoma, which was swiftly removed. "This is how it started," Church told the inaugural international conference on medical biodetection, held in Cambridge in September 2015. "It was all anecdotal."
At least, that was how interest in using dogs to sniff out cancer began. But the idea of smelling breath, urine and stools to diagnose disease goes back millennia. In the time of Hippocrates, around 400BCE, it was reportedly common for patients to cough and spit on hot coals to generate a smell that the physician would sniff to aid diagnosis.
Methods for disease diagnosis have clearly come a long way. But the Lancet letters got some, including John Church, thinking: might animal noses be quicker, or more accurate, and/or cheaper – and so able to be used more widely – than some high-tech cancer-screening techniques? If dogs really could sniff out cancer, what other diseases might they smell?
When someone with TB coughs, he or she exhales compounds produced by the bacterial pathogen Mycobacterium tuberculosis. If the TB is advanced enough, the smell of these compounds can even be detected by people. In 2002, when research into the potential of using dogs in cancer diagnosis was in its embryonic stage, a former product designer from Belgium called Bart Weetjens began wondering about African giant pouched rats and TB.
Weetjens already knew that TB has a distinctive smell. "There is a lyric of a Van Morrison song: 'I can smell your TB sheets'." Also: "In my native language, Dutch, the name for TB traditionally is tering, which etymologically refers to the smell of tar." Weetjens also knew that these rats are superlative sniffers. More than that, he understood how to breed them and how to train them.
As a boy growing up in Antwerp, Weetjens had kept pet rats. He bred them in his bedroom. "I learnt that they smell very well, but I was not occupied with that. I was simply breeding these animals to give offspring to the pet shops. It was a way to get pocket money. I gave up all rat breeding in my bedroom when I was 14."
After graduating and starting work as a product designer, Weetjens found himself increasingly preoccupied with the problem of landmines. He began to consider landmine-detection systems: in theory, what kind of engineering solution would work best? Then he met a Dutch researcher who had come across stalled plans to try to use cockroaches to detect TNT exuding from buried landmines. "I thought, yes – this was the way forward: using local resources, a solution based on what was available in the context."
Except that Weetjens didn't think cockroaches. He thought rodents. In 1997, at a time when the local military academy was working on a landmine-detecting robot, he secured his first research grant, from the Belgian Development Cooperation, a government agency. There were all kinds of questions to address, not least: which species to use? Professor Ron Verhagen, head of evolutionary biology at the University of Antwerp, who had worked in Morogoro for many years, had a suggestion. "He said, 'I might have a suitable animal for you': the African giant pouched rat, which he had seen at some point in a village on a leash." There were some early setbacks. At first, the rats didn't breed well in captivity, and it took a while to work out how best to train them. But the landmine programme, which operates from the Sokoine University of Agriculture campus in Morogoro, has become hugely successful.
At an average weight of about 1kg, the rats are too light to set off mines. They can scurry across and search 200 square metres of ground in 20 minutes, compared with 50sq m per day for a person using a metal detector. Apopo, the organisation Weetjens founded, dispatches trained rats to areas of land known or suspected to be mined and which cannot be farmed or lived upon because of the risk.
The Apopo rats are trained on a practice field a short drive from the headquarters. Here, 1,500 deactivated landmines are buried up to 30 centimetres below grass and shrubs. The trainers know where the landmines are. When a rat stops and sniffs and scratches in the right location, the trainer squeezes a clicker (the kind routinely used in training dogs) and the animal darts over for a nibble of banana or a nut. The initial stage of training for rats, whether they're destined to smell landmines or TB, is socialisation, Fidelis John explains. Baby rats are first taken from their mothers when they're about five weeks old. They're handled every day for gradually extended periods. The next stage is clicker training: they learn that the sound of the clicker means food.
It takes about nine months to train a rat. When an animal is thought to be ready, it's presented with 30 samples, eight of which are TB positive. To graduate, it has to detect seven out of eight positive samples with no false indications or eight out of eight with up to one false indication. Training then continues on the job. The public clinics taking part in the programme send in half of all the cough-and-spit samples given by suspected patients, along with the results of their microscopy tests, which look for the presence of Mycobacterium tuberculosis. The testing rats sniff at least 10 sets of 10 samples every weekday. Two clinic-positive samples in each set of 10 act as training reinforcers: when a rat correctly identifies one of these, it hears a click and receives a slug of food.
At least two (if not more) rats sniff all the clinic-negative samples sent in. Any sample indicated as positive by any of the rats then goes for checking with a more sophisticated, more accurate – and more expensive – microscope technique than the one used in the clinics. In another lab in the complex are the five LED microscopes generally used for this final diagnosis. It's only if the LED microscope check confirms the rat indication that a positive result is sent back to the clinic.
Better ways of detecting TB are badly needed in southern Africa, the epicentre of the epidemic, says Helen McShane, a professor of vaccinology at the University of Oxford. "Anything that is quicker, or more sensitive – or both – at picking up TB than current methods is to be welcomed." The thing is, GeneXpert, a highly accurate DNA-based technique, which is supported by the World Health Organization, performs strongly – and in an ideal world, most clinics would use LED microscopy or GeneXpert – but these techniques are expensive and slow. A rat, which costs $6,500 to train, can rattle through 100 samples in 20 minutes. A GeneXpert device, which costs $17,000, takes around two hours to analyse a single sample.
But what about the dogs? Well, the walls of Dr Claire Guest's office are covered with framed pictures of them. And behind her head is a portrait of a golden Labrador called Daisy, who has a special place in Guest's heart. In 2009, when she was researching whether a group of dogs, including her pet Daisy, could reliably sniff breast cancer in human samples, the dog started "acting weird".
"One day, I opened the boot of my car to get her out and she kept jumping at me. It was strange, because she's a very gentle dog. She bashed at me a few times, and I pushed her off. I felt where she'd bashed me" – Guest touches her chest – "and I thought: there's a bit of a lump there..." She ended up in hospital, had a core biopsy – and discovered she had a deep-rooted malignant tumour.
At that time, Guest was about a year into her role as chief executive of Medical Detection Dogs (MDD), a charity that she set up with support from John Church, co-author of the second Lancet letter. MDD, which operates out of buildings not far from Milton Keynes, has two aims. Just before her cancer diagnosis, Guest, who originally worked as a psychologist and dog trainer, was pursuing medical assistance training – teaching dogs to sniff, say, a low blood sugar level in someone with diabetes – as well as work on cancer detection. The assistance dog training was going well. "But then Daisy did what she did, and I thought: this is something we have to get to the bottom of."
Guest is now regarded as one of the world's leading dog-cancer-detection researchers and she and her team have published a series of papers demonstrating that, yes, dogs can sniff cancer, and that more sophisticated training protocols dramatically improve their accuracy. Other teams have published work reaching the same conclusion. Dogs can smell bladder cancer, colorectal cancer, ovarian cancer and prostate cancer. One Italian study, for example, found that the dogs could accurately identify urine samples from men with prostate cancer about 98 per cent of the time.
Guest's team is now working on two major studies, one on breast cancer, in conjunction with the Buckinghamshire Healthcare NHS Trust, and another, with Milton Keynes University Hospital, which will try to replicate the Italian prostate cancer study. Ten years ago, Guest says, there was "massive scepticism" among medics. To some extent, she says, it continues, partly because no one has identified exactly which compounds the dogs are sniffing, but the research taking the concept beyond anecdote does seem to be changing minds
When she first embarked on the dog research, to engage sceptics, she said it was purely proof-of-principle work, aimed at investigating whether human cancers really do have distinctive odours. The ultimate aim, she told anyone who asked, was to use the results to develop electronic-nose cancer detectors – to take dogs out of the equation. She does still believe that, one day, life-saving e-noses should result from all this research. But, she says, "What about the people who are dying now?"
Dr Georgies Mgode, head of Apopo's TB programme in Tanzania, explains that, unlike with the cancer-sniffing dogs, it is known what the rats are detecting. He did the studies himself for his PhD – and they revealed that the rats respond to a combination of six volatile organic compounds produced by the Mycobacterium tuberculosis pathogen. It may even be that the rats can sniff out the bacteria at levels so low as to be undetectable even by sophisticated laboratory techniques, Mgode suggests.
If the rats can detect TB at an earlier stage of infection than any other method, this could be a huge benefit, since a patient who is treated earlier is less likely to transmit his or her infection to others. In 2015, the TB rats screened more than 40,000 samples. In total, since the programme began, they have screened 342,341 and identified 9,127 patients who'd been told by the clinics that they didn't have TB. Overall, the rats have increased the TB case detection rate in the populations they're screening by around 40 per cent.
For Guest, the success of the Apopo rat programme is "inspirational". When it comes to the dogs, the next three years will be critical, she says. If the prostate cancer and breast cancer studies go well, then she hopes dogs will join the rats as fully fledged disease detectors.
As for the rats, no matter what happens in the future in terms of expansion – and funding – "already they are saving a lot of people," Mgode says. "Already, the impact is huge."
This is an edited version of an article that first appeared on Mosaicscience.com and is republished here under a Creative Commons licence
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