Out of Africa: Livingstone's Legacy
First as a missionary doctor and later as an intrepid explorer, Glasgow alumnus Dr David Livingstone gained as many medical insights as he made geographical discoveries on his expeditions into the African interior. Two centuries after his birth, the University of Glasgow continues to play a leading role in combatting tropical diseases.
Regarded as the father of Scottish parasitology in his day, Livingstone influenced a generation of young Scottish scientists: many of them also Glasgow alumni; who set off for Africa in the hope of building a healthier world.
This commitment to furthering science and alleviating human and animal suffering lives on at Glasgow today, where current research focuses on parasites that continue to cause devastating tropical diseases such as malaria, sleeping sickness and leishmaniasis.
Much of the University’s expertise exists within the Wellcome Centre for Molecular Parasitology, which has one of the largest groupings of parasitologists in the world. There, scientists use genetic and molecular technology to study the biology of parasites, their lifecycle, how they interact with humans and what they can teach us about our own immune systems.
Professor Andy Waters is director of the centre. His research focuses on a form of the plasmodium parasite responsible for malaria. ‘We need to know as much as possible about the biology of the parasite, the nature and mechanisms of its interactions with us as its host and the mosquito as vector. If we can take that knowledge further forward we might then be able to design new drugs or vaccines or completely novel approaches that we have yet to formulate.’
Menace of malaria
Livingstone was the first to make the connection between mosquitoes and malaria. On his 30,000-mile walk into Africa’s interior, Livingstone is believed to have contracted malaria 27 times, and he was one of the first to administer quinine in a dosage that is now considered effective.
Although the world has moved on in many ways from the time of Livingstone, the menace of malaria is by no means diminished. Just under half of the world’s population is at risk from the disease. Globally, it is responsible for 9% of deaths of children under five.
An evolving threat
Combination drug therapy is key to dealing with the constant threat that the malaria parasite will evolve resistance to a particular drug, but this requires a fast-flowing pipeline of drugs available for rotation. By applying molecular and genetic technology, Professor Waters is currently exploring a specific stage in the developmental biology of the parasite in a bid to advance new cures. ‘To move from its mammalian host into the mosquito, the parasite makes male and female gametocytes that can freely circulate in the blood and potentially become part of the mosquito’s next blood meal. How the parasite commits to producing these gametocytes, which are essential for transmission, is particularly interesting. If we can control that, we can either reduce transmission or interrupt it altogether.’
Much of the tropical diseases research at Glasgow is laboratory-based, but time in the field can be invaluable. A belief in getting to ‘know the enemy’ has led Dr Heather Ferguson to Tanzania to study the ecology of malaria-carrying mosquitoes. She thinks it’s possible that mosquitoes are adapting their behaviour to circumvent barrier controls like bed nets, by biting earlier in the evening or outdoors. Dr Ferguson has trained African postgraduate students in effective vector control, and will contribute to a substantial EU project by developing innovative tools to detect mosquitoes displaying ‘unconventional’ behaviours.
Championing collaboration over competition is essential in beating tropical disease. As a centre of excellence for malaria research, Glasgow is host to EVIMalaR: the European Virtual Institute for Malaria Research; a network that connects 50 European research groups and partners in Africa, India and Australia to achieve more rapid progress in controlling malaria. ‘If we can work more collaboratively,’ says Professor Waters, ‘I am confident that we will eventually succeed in at least controlling the spread of malaria and ideally eradicating it.’
Always fatal
The latest estimates suggest that 70 million sub-Saharan Africans are at risk from sleeping sickness, also known as human African trypanosomiasis. Trypanosome parasites are transmitted by the bite of a tsetse fly, entering first the peripheral system: blood, lymph nodes and organs; and after a number of weeks, crossing the blood-brain barrier to reach the central nervous system. Here the parasite produces all sorts of neurological problems, including the characteristic sleep disorder.
‘Sleeping sickness is one of the few diseases that is virtually always fatal,’ says Professor Peter Kennedy, Burton Chair of Neurology. ‘Leave it untreated, you die. Malaria kills far more people, but not everyone infected with malaria dies.’
Livingstone was the first to introduce the use of arsenic to treat animal trypanosomiasis in a horse: a treatment that is used to this day for sleeping sickness.
But treatment of sleeping sickness is far from safe or effective and it is in this area that most scientific endeavour is concentrated.
Two strains of trypanosome parasite affect humans: Tb gambiense, which is more prevalent and causes chronic sleeping sickness, and Tb rhodesiense, which results in more acute cases. Rhodesiense accounts for only 3–5% of total cases, but 18% of the risk.
Until a few years ago the only cure for both was melarsoprol: an arsenic compound so dangerous it kills over one in 20 patients treated. A safer intravenous drug has been developed for the gambiense disease and in 2011 a major development at Glasgow led to hopes of safer treatment for rhodesiense cases.
The hope comes from a new technique, where researchers combined the melarsoprol with cyclodextrins: molecules that surrounded the drug allowing it to be administered orally, increasing its solubility and releasing the drug more slowly in the gut. ‘Melarsoprol is very effective at killing the parasites,’ explains Professor Kennedy, ‘but when given intravenously it probably does this too quickly, which is in part why we think it so dangerous. By controlling the rate of release of the drug with this new oral formulation, we believe we make it safer.’
In laboratory tests in a highly reliable mouse model of sleeping sickness, the altered drug was shown to clear parasites from the brain and in response to this world-leading research, the European Medicines Agency officially designated complex melarsoprol an orphan drug for the treatment of sleeping sickness. Professor Kennedy’s next challenge is to secure funding for a clinical trial of complex melarsoprol in Uganda, where most rhodesiense cases are found, planned for 2014.
Making progress faster
It currently takes more than six months to determine whether new chemicals are effective in killing trypanosomes once they have crossed from the blood into the brain. In 2009, Professor of Biochemical Parasitology Mike Barrett and colleagues secured a grant of $3m from the Bill & Melinda Gates Foundation to develop a test to speed up the rate at which scientists could test the effectiveness of drugs in killing the trypanosome parasite once it had reached the brain. The grant was used to develop trypanosomes with bioluminescent capability.
‘A new generation of microscopes can detect photons of light particles emitted from trypanosomes deep within the tissues, including the brain,’ explains Professor Barrett. ‘Any drug that reaches the brain and kills parasites can then be identified, as the light emitted from living trypanosomes is diminished as drugs kill them.
‘We’ve actually got the test that previously took six months down to two months or even better. We’re currently talking to both GSK and Novartis, both of whom have drug campaigns against trypanosomiasis.’
It was Livingstone who first identified the tsetse fly as the vector responsible for transmitting trypanosomes, having seen livestock decimated by disease. Today, the parasite continues to impede development across Africa: wherever the tsetse fly is present, cattle are conspicuous by their absence.
The University’s Vet School has played a vital role in researching animal trypanosomiasis. For example, Emeritus Professor Max Murray and his earlier colleagues investigated the mechanisms of trypanotolerance: where some breeds of cattle have superior immune systems that render them tolerant to trypanosomes.
Today, genetic variations such as increased susceptibility or tolerance interest Dr Annette MacLeod. She has just been awarded £2.7m by the Wellcome Trust to set up a network of African scientists to look at human susceptibility to trypanosomiasis through a large-scale genome study. ‘It will be interesting and important to find out what genes are involved in susceptibility. We will be sequencing around 150 people and our study will also feed into other genetic diversity studies in Africa, because the African population is so diverse and not really represented in other studies that are generally focused on Europeans.’
A neglected disease
A disease that doesn’t get a lot of media attention but threatens around 350 million people in 88 countries is leishmaniasis, a disease caused by the parasite leishmania, which is spread by sandflies. Named after its discoverer, Glasgow alumnus William Boog Leishman, it is classified by the World Health Organization as a neglected tropical disease, with 12 million people currently infected and
1-2 million new cases occurring every year.
Treatment is still frequently based on very old drugs developed in the 1940s that are highly toxic. And according to Glasgow Professor of Molecular & Cellular Parasitology Jeremy Mottram, drug resistance is also an issue.
His team is developing a programme of collaboration with scientists in India, Brazil and Sudan to sequence the genomes of the parasite that causes visceral leishmaniasis, a clinical form of the disease which is fatal if left untreated. The team have identified variations in the genetics of the parasite in different areas of the world.
‘We have a theory that the genetics impact on the way that the parasites cause different clinical manifestations of the disease,’ says Professor Mottram. ‘If we sequence the genomes of a number of leishmania parasites from different parts of the world which show differences in their gene content, we should be able to identify factors that are involved in the virulence and pathogenicity of the parasite and also the potential mechanisms behind drug resistance. That’s going to be a major focus of our studies over the next five years.’
Though the landscape of tropical disease research is constantly changing, it’s clear that Glasgow is covering new ground all of the time.
‘I am prepared to go anywhere, provided it be forward,’ the father of Scottish parasitology once famously said. Dr Livingstone would find himself in good company were he to return to the University today.
Elimination through vaccination
Contrary to popular belief, very few dogs in Africa are strays and while wildlife populations are affected by rabies, they don’t sustain the disease. Professor of Comparative Epidemiology Sarah Cleaveland has been collating evidence to instil confidence in policymakers that rabies elimination is entirely feasible via dog vaccination. Moreover, this can result in substantial savings, by reducing demand for the more costly human vaccine. Momentum is building in Kenya, and Professor Cleaveland has been invited to rewrite the national control policy programme, which is scheduled for ratification in November 2013.
Find out more
To mark the bicentenary of his birth, the University has created a video that explores the life, travels and discoveries of Dr David Livingstone. Watch the video to gain insight into the explorer's connections with Glasgow and the ways in which his medical legacy are still being felt at the University today.
Funded by the European Commission, the European Virtual Institute of Malaria Research, which is hosted by the University of Glasgow, has designed an interactive comic book that is the latest educational toll in the global fight against malaria. To learn more, view a PDF of the comic book, which is being used to teach school and college pupils about the disease and the scientific community's battle against it.
- Prof Andy Waters
- Dr Heather M Ferguson
- Prof Peter G Kennedy
- Prof Michael P Barrett
- Dr Annette MacLeod
- Prof Jeremy C Mottram
- Prof Sarah Cleaveland