In a small, hot room in a compound located in Tanzania’s lush southern highlands, one day in mid-December, were three white-clad technicians, a glass-and-metal chamber and a large brown rat named Charles.
After being gently dropped into the chamber, Charles aimed his long snout towards the first of a series of 10 sliding metal plates in the chamber’s base. A technician swiftly opened it, revealing a small hole. Charles sniffed at it … and moved on. The hole was closed, and there was a clink as the next plate was yanked back. This time, Charles was gripped. He sniffed hard, scratching at the metal, the five claws on each of his paws splayed with the pressure. The technician called out: “Two!”
Over by the window, her colleague held a chart, which he kept raised so the others could not see it. He inserted a tick. I glanced over. The chart was a grid of small boxes, 10 across by 10 down, each marked with a code. Two of the boxes in each line were shaded grey. The tick had been placed in a white box. It is highly possible that Charles had just saved a person’s life.
Charles is an African giant pouched rat, a species endemic to sub-Saharan Africa. He is also a pioneer, one of 30 of his species that live and work in Morogoro, a few hundred kilometres west of Tanzania’s largest city, Dar es Salaam. The rats are engaged in a programme to sniff out tuberculosis, a disease that can destroy the lungs. About nine million new cases of TB are diagnosed worldwide every year, a quarter of them in Africa. Africa also has the highest TB death rate per head of population. Antibiotics can cure the disease, but it is 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% of cases – and that figure drops as low as 20% for people also infected with HIV.
This is where Charles comes in. He and his rodent colleagues sniff cough-and-spit samples provided by suspected TB patients. The rats are not infallible, but they do detect about 70% of cases, whether or not a patient has HIV – which matters a great deal in Tanzania, where about four in every 10 people with TB are HIV-positive.
That particular morning Charles sniffed 100 samples, missing one that had been identified as positive by the public clinic – shaded grey on the chart – but identifying 12 new suspected cases, which would then go for secondary checking.
The next rat brought into the testing room, a sleeker, bigger-eared, three-and-a-half-year-old named Vladić (after a Bosnian Croat footballer; many of the rats are named after footballers), was even speedier than Charles. There was a rapid clatter of metal plates being pulled back and replaced. The two technicians manning the chamber called out numbers: “Three! … Nine!” Ticks rapidly accumulated on a fresh copy of the same chart. About 15 minutes later, Vladić had correctly identified eight out of 10 clinic-positives, and also 15 new suspected cases.
Fidelis John, the training supervisor, was looking on. The African giant pouched rat (Cricetomys gambianus), unlike the standard lab rat, Rattus norvegicus, is not a species that has been bred over many generations to cooperate well with people. It is very laborious to train them to perform. “It’s not easy …” John agreed, smiling. “But it’s possible. When a rat does not perform well, it is usually the trainer who is to blame.”
Around the world, other animals – mostly dogs – are being used experimentally to screen human samples for disease; the TB-sniffing rats of Tanzania are the only animals routinely used as disease detectives. When medics first hear about the programme, they are often sceptical about the idea of using rats rather than machines, said 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. Based on these figures, there are calls for dogs to be more widely used in disease diagnosis.
The first “Lancet letter” came in 1989. Writing in the prestigious medical journal, a pair of dermatologists reported the case of a patient whose dog constantly sniffed at a mole on her leg, and on one occasion even tried to bite it off. The woman sought medical advice. Tests showed it was a malignant melanoma, almost 2mm thick. It was removed, and she suffered no lasting effects.
The second Lancet letter (as they are known in the dog-cancer-detection community) was published in 2001. John Church, a British doctor, and his colleague reported the case of a 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, UK, 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 400BC, 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 people, including John Church, thinking: might animal noses be quicker, or more accurate, and cheaper – and so more widely accessible – than some high-tech cancer-screening techniques? If dogs really could sniff out cancer, what other diseases might they smell? And might the noses of other animals be useful too?
Over the past decade, there have been projects investigating the use of bees to sniff out cancer, for example, but that research has not advanced very far. The overwhelming focus in the field now is on dogs. Rats are a recent addition to the field.
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 just beginning, a former product designer from Belgium called Bart Weetjens was wondering about applying the particular skills of African giant pouched rats.
Weetjens already knew that TB had a distinctive smell. “In my native language, Dutch, the name for TB traditionally is tering, which etymologically refers to the smell of tar.” Weetjens also knew that African giant pouched rats are superlative sniffers. More than that, he understood how to breed them and how to train them. He already had a strong track record of using the species to save lives, albeit in a very different setting.
As a boy, growing up in Antwerp, Weetjens had kept pet rats. “Not only rats – I was very fond of all kinds of rodents. Hamsters and mice, and then rats. I tried gerbils and squirrels as well.” He bred them in his bedroom. “I learned that they smell very well, but I was not bothered with that. I was simply breeding these animals to sell 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. “I saw a documentary about Cambodia, and also Princess Diana in Angola visiting mine-extraction operations.” 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 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. This was for me an a-ha moment.”
Except that Weetjens did not think cockroaches. He thought rodents. In 1997, at a time when the local military academy in Antwerp was working on a landmine-detecting robot, he secured his first research grant, from the Belgian Development Cooperation, a government agency. “The secretary for the Development Cooperation had been a director of Doctors Without Borders. He knew the African realities much better than the army folks did, actually. He immediately said to one of the professors in our team: ‘This is a stupid idea, let’s do it!’”
First, Weetjens had to figure out which species to use. Ideally, he wanted an animal endemic to sub-Saharan Africa, which at the time was the region most affected by landmines: one that was not that susceptible to disease, that relied heavily on scent (because it would have to sniff TNT in tiny concentrations in the air), that was long-lived and that could be trained. 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, well, 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 did not breed well in captivity, and it took a while to work out how best to train them. But the landmine programme, which operates from a base on the campus of Sokoine University of Agriculture, 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 50 square metres per day for a person using a metal detector. They sniff for traces of TNT, and when they find them, they scrabble at the spot. Apopo, the organisation Weetjens founded, dispatches trained rats to areas of land known or suspected to be mined, that cannot be farmed or lived on because of the risk of explosions.
Areas that are not intensively mined can be disproportionately dangerous, because local people are more likely to take the risk of venturing into them. James Pursey, who manages communications for Apopo, tells a story: “I was just in Angola. There’s an area next to a school where a landmine once went off. I was talking to the headmaster and he said if the boys kicked a football into this area they would draw straws as to who would go and get it. None of the boys had been hurt. But when the rats searched the area, they found another landmine.”
The Apopo rats are trained on a practice field a short drive from the Morogoro headquarters. Early one morning, I caught the “rat bus” – a truck that transports the rats from their kennel – along a bumpy road to a kiosk at the end of a red dirt track. There, trainers were gathering to collect their blue coats with the Apopo logo, and water bottles, peanuts and bananas for the rats. When they had everything they needed, they headed down to the field.
On that site, 1,500 deactivated landmines are buried up to 30cm below grass and shrubs. The field is taped off into rectangles, varying in area from 5x3 metres up to 10x20 metres. The trainers work in pairs, each pair working a different rectangle. They start at one end. The trainee rat wears a harness with a spring attached to it. A cord runs from one trainer’s boot, through this spring to one of the other trainer’s boots. The rat runs freely along the cord, sniffing the ground as it goes. Tapes are also attached to each end of the spring, and the trainers hold the tapes. They use them to gently tug the rat back into position, or into action if it stops moving for too long.
Once the rat has sniffed the first half-metre’s width of the rectangle, the trainers take a half-metre step to the side, and the rat sets off again. The trainers know where the landmines are. When a rat stops and sniffs and scratches in the right location, one squeezes a clicker (the kind routinely used in training dogs and dolphins) and the animal darts over for a nibble of banana or a nut.
In a real (rather than practice) field, paths for the trainers are first cleared by metal detectors. If a rat sounds the alarm, a trainer puts down a marker, and when the zone has been fully checked, someone with a metal detector goes to the spot to confirm the rat alert.
To graduate as a landmine-sniffer, a rat has to find 100% of the landmines in a test field in a single sweep. Abdullah Mchomvu heads the landmine-training team. He was out there that morning, supervising the session. “You have to be patient,” he said. “Some learn quickly and others more slowly – but all in all they normally reach the goal.”
Apopo rat teams have now worked in Angola, Mozambique, Cambodia, Thailand, Vietnam and Laos – not just on landmines, but also on old ammunition, mortars and grenades. The Apopo team working in Mozambique, for example, has destroyed 13,294 landmines and returned more than 11m square metres of land to communities over seven years. This programme played a big role in the country’s ability to declare, in September 2015, that it was landmine-free.
Mchomvu started working with the rats in 2002. He has 24 trainers under his supervision. It is satisfying work, he said. “To train the rats to detect landmines means we save the lives of people. To work at serving other people – I like it.”
In another small, hot room at the Apopo TB centre, down the road from the landmine HQ on the Sokoine University campus, a skittish four-month-old rat dug his nose into one of three holes in a scaled-down version of the full TB testing chamber. He scraped so hard at the hole it looked as though he was trying to disappear down it. Then he heard a click, and quickly turned to gape his jaw at a small opening in the side of the chamber for his reward: a syringe-delivered slug of mashed banana, avocado and pellets.
The initial stage of training for rats, whether they’re destined to smell landmines or TB, is socialisation, Fidelis John explained. Baby rats are first taken from their mothers when they are about five weeks old. They are handled every day for gradually extended periods, building up to their being carried around for the day on a trainer’s person. The next stage is clicker training: they learn that the sound of the clicker means food. Rats in the landmine stream then learn to associate the scent of TNT with reward. The rats who will work on TB are given a TB-positive sample, explained John. “Once the rat sniffs the hole, I click. So the rat understands that if they smell this and the clicker comes, it means they get food. So then they understand: ‘If I smell TB, I get food’.”
It takes about nine months to train a rat. When an animal is thought to be ready, it is 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 mashed food. (The clinic’s positive results are generally confirmed as positive by the rats, Apopo says; it’s the large proportion of missed cases that constitutes the main problem with the standard microscopy technique.)
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. On the day of my visit in December, two technicians were at work. One showed me what the TB bacteria look like through his microscope: tiny, bright fluorescing stripes. It is 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 TB epidemic, said Helen McShane, a professor of vaccinology at the University of Oxford and a specialist on TB in Africa. “Anything that is quicker, or more sensitive – or both – at picking up TB than current methods is to be welcomed. Particularly something like this, which is not resource-intensive.”
Still, any new method for diagnosing TB needs to be both highly sensitive (to pick up all the cases) and highly specific (to avoid identifying too many samples as TB-positive when they’re not), said McShane.
GeneXpert, a highly accurate DNA-based technique, which is supported by the World Health Organisation, performs strongly on both variables. 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. It costs about $1 to screen a sample using a rat, compared with $10 for GeneXpert. GeneXpert requires a stable electricity supply and controlled temperatures; the rats require food and water and play cages.
It is not possible to get both very high sensitivity and accuracy with the rats, Christophe Cox told me. Sensitivity can be improved (by using more rats to sniff each sample), but then accuracy worsens, and vice versa. Still, he is convinced that the rats have a crucial role to play in diagnosis. For developing countries, he argued, the rats are a fast and affordable life-saving triage tool.
The use of dogs to sniff out cancer was initially met with scepticism, and continues, partly because no one has identified exactly which compounds the dogs are sniffing. However, there is work showing that metabolic changes brought about by cancer cause the pattern of so-called “volatile organic chemicals” produced by affected cells to alter – and dogs seem to be able to detect patterns characteristic of specific cancers. Dr Georgies Mgode, head of Apopo’s TB programme in Tanzania, explained that, unlike with cancer-sniffing dogs, it is known what the rats are detecting. He did the studies himself for his PhD. His series of careful studies revealed that they respond to a combination of six volatile organic compounds produced by the Mycobacterium tuberculosis pathogen. And the rats can detect this combination even at very low levels, which is why they do not have a problem identifying TB in someone with HIV.
Because of their weakened immune systems, people with HIV develop TB when infected with far fewer bacteria than are needed to make a healthy person sick. Relatively few bacteria in the cough-and-spit sample make it less likely that a technician using a microscope will spot them. But they still produce a smell that can be detected by the rats.
It may even be the case that the rats can sniff out the bacteria at levels so low as to be undetectable even by sophisticated laboratory techniques, Mgode suggested. “You will get a [clinic] sample that is indicated by 11 rats, but you can’t confirm it’s TB [with the LED microscopy]. To me …” he tapped his chest, “…to me, I know this is TB. But since we don’t have a conventional method which is approved, we don’t report this patient.”
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 other people. Mgode is planning to do more research to investigate this. But the biggest aims right now with the TB programme are more practical: getting results to patients faster and expanding the programme’s reach.
The programme started with four clinics in 2007. Now, 21 clinics in Dar es Salaam, about a third of the total, send samples via motorbikes and a bus to the rats. The rats also get samples from one clinic on the coast and three in Morogoro. A smaller sister programme, launched in Maputo, Mozambique, in 2013, using nine rats trained in Morogoro, receives all suspected TB samples gathered there.
In 2015, the TB rats screened over 40,000 samples. In total, since the programme began, they have screened 342,341 samples and identified 9,127 patients who had been told by the clinics that they did not have TB. Overall, the rats have hiked the TB case detection rate in the populations they are screening by around 40%. Apopo is now in talks to start a new rat TB programme in Addis Ababa, Ethiopia. If impressive detection data can be gathered from a third centre, this may help to convince remaining sceptics about the usefulness of the rats.
The other main goal right now is to switch the Tanzanian TB testing from Morogoro to Dar es Salaam. That should allow the rat results to be returned to the clinics in time for them to be given to patients at the same time as the standard microscopy results, instead of many days later – a delay that currently means that just less than a third of patients diagnosed thanks to the rats do not actually receive their positive results. It would mean, Mgode said, that the programme will save even more lives.
In Dar es Salaam I met Claudi, a boy whose TB was picked up by Apopo. He was waiting for me on the crumbling concrete porch of his home in Tandale, a slum suburb, in a yellow short-sleeved school shirt and grey shorts. It is in suburbs such as this, where many people often share a house and nutrition is poor, that TB can spread relatively easily, explained Scholastica Myemba, who works for Apopo and is completing a master’s in public health at the University of Dar es Salaam.
Myemba supervises Apopo’s team of outreach volunteers – people who track down patients identified by the rats and make sure they take their medication. She translated as Claudi’s grandmother explained what happened. Claudi is eight now. He was six when he got sick. “He was not in a good condition,” his grandmother said. “He was coughing and coughing and not feeling good.”
When she took him to the TB clinic at nearby Tandale Hospital, the standard microscope test for TB came back negative. Claudi’s coughing did not improve. But then, a little more than a week after the negative result, the family was contacted by an Apopo volunteer, who explained that Claudi’s sample had been checked again, this time by rats. The rats had flagged Claudi’s sample for further testing – and this test confirmed he had TB.
Claudi was prescribed antibiotics by the doctors to treat his TB. The volunteer came every day to make sure Claudi took his pills for the full six-month course of treatment. Now, he is healthy and able to work hard at school.
Still, Mgode explained, the benefits of a correct diagnosis go beyond access to life-saving drugs. For some patients, there is also the stigma of being suspected of having HIV.
Not long ago, with a group of Apopo donors, Mgode met a man in Morogoro whose TB had been detected by the rats. “Afterwards I asked him in Swahili: ‘When you went to hospital and were diagnosed negative, how did you feel?’ He said: ‘Ah, my colleagues were asking me: “Man, if not TB, what else?”’ That is the problem. He was feeling like even his friends were thinking he had HIV. So when he got the rats’ result showing TB, he was so happy.”
Weetjens and Mgode both talked about how difficult it is to get funding for the rat programme. Much of what Apopo does get consists of an assortment of relatively small donations from various governments and businesses, along with proceeds from an initiative that allows individuals to “adopt” a rat.
But whatever happens in the future in terms of expansion – and funding – “already the technique is saving a lot of people,” Mgode said. “Already, the impact is huge.”
Main illustration by Parkin Parkin