To catch a killer on the wing

October 7, 2005

Malaria plagues The Gambia, especially in the rainy season. Becky McCall visits scientists at the front line of immunological and genetic efforts to halt the disease and the misery it causes

It is mid-morning in late June and local women are standing in a field in the Gambian bush. The heat is stifling, and the clouds gather as they eagerly await the start of the annual rains. Jainaba Ceesay, a 38-year-old farm labourer, is preparing the soil for this year's crop of peppers. She is heavily pregnant with her ninth child.

But giving birth is the least of her worries; indeed, women here typically work right until onset of labour. Ceesay is more concerned about the imminent threat of malaria. Pregnant mothers and young children are at greatest risk. The women will celebrate the arrival of the rain that feeds this parched soil, but as stagnant water collects it will provide the ideal breeding ground for Anopheles gambiae, the mosquito that carries malaria.

Malaria and other infectious diseases have engaged the research efforts of Medical Research Council staff in The Gambia since local peanut farmers were stricken by the illness in the mid-20th century. This former British colony is the smallest country in Africa, with a river that runs 300 miles from one end of the country to the other. The flood plains of the River Gambia harbour the mosquitoes that attract the scientists.

David Conway is one of them. He is head of the malaria programme at MRC Laboratories in The Gambia. He did his PhD on malaria parasitology in the 1980s, then worked on other tropical diseases in Bangladesh and Jamaica before focusing on malaria at the London School of Hygiene and Tropical Medicine. A year ago, he uprooted his family and moved to The Gambia.

"Before we went, I was mostly based in the UK but made several trips to endemic countries each year," Conway says. "London is a great environment for any scientist, but I think it is important to study a disease where it happens."

Although Conway regards working in Africa as a privilege, it has also come as a culture shock. "In London, it is easy to become absorbed in the microscopes and molecules. It is a world apart from The Gambia," he says.

"Out there, you cannot escape the reality of children dying of malaria. The first time you see that, it makes a big impression. Death from malaria is common, but each one is a tragedy."

The parasite, which kills upwards of 2 million people worldwide every year, is relentless in the challenges it presents medical research. Fifty years of investigation in The Gambia has delivered a range of interventions. Bed nets, insecticides, combination-drug trials, educational initiatives and even the first African clinical trial of the malaria vaccine, known as RTS,S, have made a considerable impact. But a lasting remedy is yet to be found.

As soon as researchers feel they are getting a grip on the disease, it evades their grasp. It is like trying to hit a moving target, they say. But Conway is determined. "With better research efforts and more substantial investment in delivering available interventions, this disease can be controlled much better than it is now," he says firmly.

There is cause for optimism. Increased understanding of the human genome over the past few years has sent research shooting off in a new direction.

Three thousand miles north of The Gambia, in his laboratory at Oxford University, MRC research professor Dominic Kwiatkowski and his team are using the latest genomic tools to discover the molecular mechanisms at play during the disease process.

Research hopes lie in marrying genetic information derived from the malarial parasite with our growing understanding of the human genome. Both genomes have been deciphered, which allows researchers to follow two lines of attack on a genomic level. Conway is leading research at MRC Gambia on the parasite, while Kwiatkowski is looking at human genetic and immunological responses.

Kwiatkowski's team compares the genetic code of people who survive malaria with those who die in the hope of finding vital clues about the molecular mechanisms of the immune system that protect some individuals but render others susceptible.

Our genome has numerous variations. In addition to the 25,000 genes common to all humans, there are roughly 10 million points that vary and account for our individuality. In the case of malaria, a variety of genes that determine the fine structure of the red blood-cell surface may affect whether the parasite can invade these cells and cause disease.

This is just one example of many different genetic mechanisms that are suspected of conferring malarial resistance, but the process of identifying individual changes is long, arduous and requires reams of data.

Africans have unrivalled genetic diversity compared with Europeans and Asians. "Modern human beings came out of Africa and have lived there for thousands of years," Conway explains. "So the gene pool is hugely diverse in contrast to the rest of the world. It is the best place to look for an immunological response to malaria."

Research has found that the Fulani people - a pastoral tribe distributed across West Africa, from northern Nigeria and Chad to the Atlantic coast - show remarkable resistance to malaria, with higher antibody levels than other groups in the same region. Kwiatkowski and his team are examining the genes that control the antibody response to the pathogen.

Humans serve as vehicles in which the malaria parasites can reproduce. They enter the blood through a mosquito bite and then invade the liver, where they multiply until their numbers can no longer be contained and they burst back into the host's bloodstream.

This is the point at which the infection can turn lethal. Infected red blood cells can lodge in the brain, causing cerebral malaria. The infection can also degrade red blood cells so rapidly that severe anaemia results, which is another cause of death if left untreated.

The quest to understand malaria is not dissimilar to a detective story.

Conway is gathering clinical evidence from patients, which he then matches to activity at blood cellular level. Thousands of cases of severe malaria are admitted to his hospital annually, so he sees the full clinical range of disease.

"It is remarkable that different malaria parasites invade red cells in quite different ways at molecular level," he says. "Now that we know the genetic code for these molecules, we would like to create a vaccine based on an engineered combination of their structures that would elicit a protective response from the immune system."

As Conway talks in the cool comfort of an Oxford college in late August, the rains are reaching their peak in The Gambia - and so, too, is this year's malaria epidemic. The fields flood and mosquitoes fill the warm night air. The wards in the capital's Royal Victoria Teaching Hospital are squeezing four children into each bed.

The malaria parasite is a formidable opponent, but its tenacity is matched by that of the researchers. Conway gathers his things and gets into a cab.

The next flight to The Gambia leaves early in the morning.


CV: DAVID CONWAY

Age: 40

Education 1987-91: PhD at Edinburgh University

1983-86: Degree in zoology at Nottingham University

Research work

Currently senior lecturer in the pathogen molecular biology unit, department of infectious and tropical diseases, London School of Hygiene and Tropical Medicine. Also head of malaria, Medical Research Council, The Gambia

1993-95: Research fellow in department of clinical sciences, London School of Hygiene and Tropical Medicine

1991-93: Postdoctoral research associate, department of biology, Imperial College London

Teaching

Includes Medical Research Council Laboratories, The Gambia; University of Ibadan, Nigeria; department of zoology, University of the West Indies, Jamaica; International Centre for Diarrhoeal Disease Research, Bangladesh
Focus: Malaria

Malaria defeats the best drugs, insecticides and medical researchers. From basic research into vaccines to eliminating the mosquito vector itself, scientists are attacking this disease from every angle.

At the MRC Unit in Farafenni, The Gambia, Steven Lindsay is trialling a natural acceptable method of killing the mosquitoes that carry the malaria parasite. He intends to spray mosquito breeding grounds with a mixture of bacteria that will induce a cholera-like death.

This method of controlling the disease was started in the 1960s but abandoned with the arrival of drugs such as chloroquine. Lindsay hopes it will offer an alternative to the use of environmentally harmful insecticides.

Net effects

One practical and simple approach to preventing malaria is to use insecticide-treated bed nets. MRC researchers in The Gambia are seeking ways to improve the uptake and correct use of nets.

In the 1980s, a trial carried out at MRC Laboratories in The Gambia showed that bed nets reduced child deaths by about 63 per cent. This success led to the World Health Organisation introducing the use of bed nets across the continent. These have become a cornerstone of the WHO's Roll Back Malaria campaign.

But use has fallen dramatically. Many communities fail to use nets regularly and where they do, nets with holes go unrepaired or they are used for other purposes, such as fishing.

Vaccine hopes

An effective malaria vaccine for wide-scale use is a long way off, but the most promising potential vaccine has reached large-scale trials. The RTS,S vaccine, developed by scientists at Oxford University and at GlaxoSmith-Kline Biologicals, has induced a protective immune response in trials at the MRC Gambia Unit.

A study is now being carried out on about 2,000 children in Mozambique. The vaccine is effective in preventing cerebral malaria in babies, but there remains much room for improvement, and protection needs to be sustained for more than a few months.

Adrian Hill, professor of human genetics at Oxford, has developed the "prime-boost" vaccine that induces an immune-cell response against the malaria antigen.

Hill found that when a volunteer was given a fragment of virus DNA followed by a virus vaccine containing the same malaria antigen, the T-cell response was ten times greater. The second vaccine acts as a boost to the T-cell memory formed after administering the first.

Encouraging clinical trials in Oxford have led to trials being conducted in The Gambia.

Becky McCall

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