Modern solution for ancient disease
Interview: Dr Francisca Mutapi (University of Strathclyde)…
Modern solution for ancient disease
Dr Francisca Mutapi is a Reader in the School of Biological Sciences at the University of Edinburgh. She focuses on global health and tropical diseases, specialising in the study of bilharzia. She gained her first degree in Biological Sciences at the University of Zimbabwe, then studied for her DPhil in Biological Sciences at the University of Oxford, as a Beit Scholar. She then worked at the Institute of Tropical Medicine in Antwerp and went on to lecture at Oxford (Department of Zoology), Birkbeck College (Department of Microbiology) and the University of Glasgow (Department of Clinical Veterinary Studies), before she moved to Edinburgh on an MRC Training Fellowship.
When she was growing up in Zimbabwe, Francisca Mutapi was warned to be careful of snails – they could make you fall sick. Nowadays, Dr Mutapi knows better than most that one of Africa’s most troublesome diseases, bilharzia, is caused by a worm which develops in freshwater snails, but she also knows that humans are responsible – the parasite is spread when people with bilharzia urinate and defecate in freshwater rivers and lakes, where the excreted eggs hatch and multiply inside the snails. And not only does she have a scientific understanding of how the disease affects hundreds of millions of people worldwide, she has also done something about it, to improve treatment and reduce the numbers who contract it in the first place.
Bilharzia (also known as schistosomiasis or snail fever) is the second most prevalent tropical disease in Africa after malaria, but even though malaria is one of the world’s greatest killers, bilharzia can lead to complications such as chronic fatigue and anaemia, as well as poor growth and cognitive functions, and even potentially fatal conditions such as bladder cancer and increased susceptibility to HIV/Aids. Another problem is that it often eludes diagnosis for years; e.g., professional cyclist Chris Froome, who wasn't diagnosed for several years until a blood test in 2010. Froome's team believed the treatment of his illness may explain his “rapid transformation” from 84th place in the Tour de France to winner in 2013. Another celebrity victim, Prince William, contracted the disease on safari in Africa in 2003 and went for treatment in Dundee at Ninewells Hospital.
The disease was also documented in the Dead Sea Scrolls and ancient Egypt, where 5,000-year-old mummies have been diagnosed with the infection. It has also been suggested that bilharzia was the cause of the biblical “curse of Jericho”. Worldwide, says Mutapi, bilharzia affects about 250 million people, with 700 million more at risk of infection. One of the problems is that clinical signs are diverse, including blood in urine, which can lead to misdiagnosis; and if untreated, further complications such as fibrosis and calcified bladder, or enlargement of the liver, spleen and kidneys. In some regions, when young men pass blood in their urine, it is seen as a sign of maturity and can often go unchecked for years. That’s why education is a key part of the global solution, says Mutapi. You not only have to avoid risks, but also recognise symptoms in order to treat it correctly.
The progress of bilharzia is very unpleasant – the larvae of the parasites enter the bloodstream and when they mature and mate, the eggs laid by the females cut their way out of the blood vessels into the intestine or the uro-genitary tract, causing wounds which can become infected or expose sufferers to sexually transmitted diseases including HIV/Aids. When they’re at the stage infective to humans, the parasites are also quite “clever,” Mutapi explains, because they seem to know the time and adapt their behaviour by coming out of the snails into the water to fit in with their hosts. Experimental studies show that when snails are moved from areas where the hosts come to the water in the morning to areas where the hosts come to the water in the evening, the snails change their ‘infective parasite-shedding patterns’ from morning to evening.
The disease is also found in other regions of the world apart from Africa, including South America and China, and has also been recently detected in Corsica.
The learning curve
Mutapi’s knowledge of bilharzia has developed over other years of study. And today she is also a determined scientist, advocating evidence-based control strategies, who has played a significant role in persuading governments in Africa, as well as the World Health Organisation (WHO) and leading pharmaceutical company Merck KgaA, to make bilharzia control a public health priority.
The story starts when Mutapi was at university in Zimbabwe, studying biology under her mentor, Vic Clarke, who introduced her to the study of bilharzia and other parasitic diseases. After graduating in 1991, Mutapi spent the next two years at veterinary college, then won a Beit Scholarship which enabled her to go to the University of Oxford to gain her doctorate, studying under Professor Mark Woolhouse, now the Professor of Infectious Disease Epidemiology at the University of Edinburgh.
For Mutapi, going to Oxford was a major decision. At her interview before she went, she was “interrogated” by a roomful of academics and leading professionals who revealed that her mentor (who also gave his protégée an excellent reference) had told them that her plans to go to Oxford were “completely against his advice” – and nobody dared contradict him, Mutapi explains, with a smile.
When she got to Oxford in 1993, bilharzia became the major focus of Mutapi's research, and gradually the evidence began to point in several clear directions. In places where there was high transmission, there was also high resistance to infection, and this suggested people could acquire protective immunity to the disease. The big question was how – and what were the immunological mechanisms which lead to this immune resistance?
To answer these questions, Mutapi did extensive field work, asking boys and girls in Zimbabwe to allow her to study their urine, faeces and blood. And the “biggest compliment” Mutapi received at the time was from a colleague working on a laboratory model of the disease who said her results were as good as the data you'd normally gather from mice in the lab – a world apart from field work in rural Zimbabwe.
Mutapi was most interested in analysing differences in acquired immunity and tracking the progress of young people given a drug called praziquantel, developed by Bayer in the 1970s, which seemed to make the younger people’s immune systems mimic those of older people with resistance to bilharzia. Her hypothesis was that the drug was acting in the same way as a vaccine, presenting parasite proteins to the host immune system which led to a protective immune response. “We knew it worked in killing the worms,” says Mutapi, “but it seemed there were also additional longer-term benefits beyond killing the worms. It seemed the drug could also be used as a vaccine and thus prevent the clinical symptoms, as well as reduce re-infection.”
After publishing her Thesis, Mutapi went to Antwerp to continue her research, and got involved in solving an interesting puzzle. After the authorities in Senegal had built a dam in order to improve the production of sugar cane, there had been an epidemic of bilharzia among local people. The studies in Senegal confirmed Mutapi’s original results that treatment of bilharzia-infected people in this epidemic environment also resulted in a change in their immune system, promoting responses associated with reduced re-infection. And she continued these studies when she returned to Oxford to take up a departmental Lectureship in the Zoology Department.
Around this time, Mutapi applied for a number of posts and was faced with a difficult choice when all the applications were successful at once. In the end, she took on two of the jobs – lecturing at Birkbeck College (where one of the interview panel was Professor Tim O'Shea, now Principal at Edinburgh) and the University of Glasgow, before she moved to Edinburgh in 2001. “Some people said I was mad to leave Glasgow, because I had a tenured position,” Mutapi reveals, “but I wanted to learn more about the immune system and the mechanisms involved in disease, including proteomics.” Mutapi also realised she needed to develop her “molecular and immunology techniques,” to address the questions she was asking, and this drove her decision to go to Edinburgh to work with Professor Rick Maizels at the Institute of Immunology and Infection Research, “and focus on the immunology and molecular biology of the host–parasite relationship.”
This new research enabled Mutapi to identify more candidate proteins for bilharzia vaccines in one single year than the collective effort in the field had produced in the preceding decade. But despite this progress, the question remained: “Why does it take so long to develop protective immunity naturally in humans? And how does treatment speed it up?”
To attain protective immunity, Mutapi explains, the body needs a certain amount of the relevant proteins, and because the worms live for a long time, it can take decades to attain this protective “critical protein mass” naturally. “It’s no good waiting several years for all the worms to die,” she says. And this led to the realisation that treatment provides this critical mass by killing all the worms at once. It also followed that if treatment works so well, why not treat the whole population to prevent the disease from getting a foothold to start with?
The road to effective treatments still faced a lot of scientific obstacles, however, including the hygiene hypothesis – the suggestion that if you get rid of the worms, people will get sicker by exacerbating other conditions such as asthma. To counter this, Mutapi and colleagues got funding from the Wellcome Trust (2006 – 2010) to conduct research on “immune modulation,” proving that the treatment would not induce harmful responses to other conditions. Thus, in addition to giving more detail on how drug-induced resistance developed in treated people relative to naturally acquired resistance, this study also proved that treatment of bilharzia did not result in worse health for the people receiving the treatment.
Get them young
The next challenge faced by Mutapi was back in Zimbabwe in 2010, when she played a key role in persuading the Ministry of Health to conduct a national bilharzia survey. Health officials recognised the scale of the problem, but getting a national control programme underway was another matter entirely. Learning from colleagues in Zimbabwe who had run very similar programmes for HIV/Aids, Mutapi and collaborators from Zimbabwe got support from UNESCO, WHO, the Ministry of Health and other stakeholders to develop a control policy, draw up a plan of action and budget for a five-year National Bilharzia Control Programme. The control programme was launched in 2012 to annually treat all school-age children in primary and secondary schools in rural areas throughout Zimbabwe. The control programme in Zimbabwe has so far been such a success that it is being used as a model example by WHO, and Mutapi’s colleagues in Zimbabwe are now involved in helping roll out bilharzia control programmes in several African countries – targeting a total of 100 million young people.
But even that was not enough for Mutapi, because the control programmes were targeting only school-age children and neglecting preschool children and infants: “We proved that the drug is effective,” she continues, “but why only give it to children aged six and above? Why not infants and pre-school children as well? After all, small children are exposed to the infective water just the same as everyone else.”
There were several reasons for neglecting these younger children. The first problem was that there had not been clinical trials for the safety and efficacy of the drug in children less than four years old; so that was the next step, followed by the need to develop a form of the drug that would be easy to administer to infants – the tablets are too big and have a bitter taste and WHO no longer recommends liquid formulations for children. Mutapi and colleagues communicated the need for a soluble, better-tasting tablet for young children to WHO, which then presented their case at the London Declaration of Neglected Tropical Diseases in 2012 (supported by WHO, the World Bank, the Bill & Melinda Gates Foundation and the world’s leading pharmaceutical companies), which set out a roadmap for a new approach to tropical diseases, including the development of new drugs for bilharzia. And late in 2015, Merck KGaA announced a new paediatric formulation for bilharzia – the latest advance in the battle against the disease. This drug is now awaiting clinical trials to which Mutapi will contribute.
For Mutapi, the fight never ends. She has focused lots of energy on trying to understand bilharzia and how best to control it. She has also played a major part in launching health initiatives which promise to reduce the worst effects of the disease; not just fatigue and cognitive problems but low productivity and sometimes fatal conditions. And after her success in Africa and global health, Scotland is next on the list. Her expertise is being funnelled into the Health and Well Being working group set up by the YAS to address equality and poverty issues in public health, starting with communication and education.