The malaria revolution: from mosquitoes to molecules
This essay was written by Tony Holder and was first published in the 2002 Mill Hill Essays. An updated version was published in the Mill Hill Essays anthology.
At the end of the nineteenth century a revolution occurred in the study of malaria that laid the foundations for efforts to control the disease. Within just twenty years the disease was shown to be caused by a unicellular parasite that lives in the blood and is transmitted by mosquitoes. Previously the cause of the disease was wrongly ascribed to the noxious air of the swamps (mal’aria) or to drinking foul water. The twenty-first century has begun with another revolution in understanding malaria now that the structure of the genomes of the parasite and its mosquito vector have been completely described. Together with the complete description of the human genome a year earlier, these latest findings may have an even more dramatic impact on controlling the disease than those exciting observations made just over one hundred years ago.
The parasite that causes malaria was first observed in the bloodstream of malaria sufferers by the French army surgeon Laveran whilst working in Algeria in 1880. Seventeen years later, in India, Ronald Ross identified the parasite in the blood meal of a mosquito. Very soon both the entire life cycle of the parasite and the crucial role that the mosquito plays in the parasite’s transmission of the disease from one individual to another were well established, especially through the work of the Italian school of malariology. The single-celled parasite that causes malaria is called Plasmodium and there are four species of Plasmodium that infect humans. Plasmodium falciparum is the most important because of the severity of the disease and the high frequency of human mortality associated with P. falciparum infection. Plasmodium vivax is also widely spread geographically and transmission of this parasite can occur in cooler climates. Only one group of mosquitoes – the Anopheles – can transmit malaria parasites from an infected individual to another human.
When an infected female Anopheles feeds on its host it injects its saliva into the wound to prevent the blood from coagulating. It may also inject some parasites with the saliva. These parasites then travel to the host’s liver and invade liver cells. They then multiply by the thousand before bursting out from the cells into the bloodstream. In the blood each parasite invades a red blood cell where it multiplies again to produce further parasites that invade more red blood cells. If not controlled by the host’s immune system or by treatment with anti-malarial drugs, this cycle will continue with severe consequences. For example, P. falciparum can multiply up to twenty times every two days leading to severe anaemia, and the infected red blood cells can become lodged in organs such as the brain, which results in cerebral malaria. Some parasites will develop into different forms that are necessary to complete the life cycle. When a mosquito takes up some parasites in these forms in its blood meal it becomes infected itself. The parasite eventually migrates to the mosquito’s salivary glands to continue its life-cycle.
Several factors combine to affect the severity of malaria: the parasite, the human host, the mosquito vector, and the environment. Malaria has shaped humanity, for example it has imposed strong selective forces on the human genome. The best known instance is a genetic trait responsible for sickle cell disease, which causes defects in the function of human red blood cells and also provides some protection against malaria. Human activity and behaviour have shaped the distribution of the disease today, whether through their impact on the environment, through wars and migrations, or through the application of political will and economic means to reduce poverty and apply control measures. Today malaria is largely confined to the tropics, but even so about forty percent of the world’s population is at risk. There are several hundred million clinical cases each year and at least one million children die from malaria each year in sub-Saharan Africa alone. The impact of the disease on health and economic well-being is tremendous. The interplay between the factors and forces that drive it are still as important today as when the disease was first defined. The new knowledge that is flooding from the scientific revolution must lead to the application of new control methods that complement or improve the current approaches. We still do not know what determines the level of malaria in a community and what determines how many in it will die from malaria.
Following the identification of the parasite, early researchers investigated whether using drug treatments to kill the parasite would protect individuals from death and disease. This required accurate medical diagnosis and proper treatment in hospital. Quinine had already been purified and had been shown to be the active ingredient in Jesuit’s or Peruvian bark from the Cinchona tree that was introduced into Europe in the seventeenth century for the treatment of malaria fever. Throughout the first part of the twentieth century many new antimalarial compounds were synthesised and tested. This culminated in the discovery and application of drugs such as chloroquine and pyrimethamine, which were safe, cheap and effective. Unfortunately P. falciparum quite quickly became resistant to these drugs and few new drugs have been developed. Current drugs include mefloquine (Larium®), Malarone®, and artemisinin derivatives. Artemisinin is a drug originally identified as the active ingredient in a traditional Chinese herbal remedy derived from plants in the Artemisia family. There is still an urgent need for new drugs but only a handful are currently in the pipe-line.
The knowledge that malaria is transmitted by mosquitoes had immediate practical value for public health. By targeting the mosquito and preventing its contact with humans malaria transmission could be controlled. Strategies for reducing the numbers of mosquitoes have included environmental control, for example by reducing their breeding, spraying campaigns using insecticides such as DDT, and the use of bed nets as a barrier between the mosquito vector and the human host. Some of these approaches were very successful, such as the introduction in the late 1940s of DDT as a residual house spray. However it proved difficult to eradicate malaria completely and the use of DDT has become contentious because of its environmental impact. Furthermore, mosquitoes are developing resistance to DDT and to other insecticides that are used to impregnate bed nets. The focus now is on controlling the disease.
Following extensive exposure to malaria infected individuals develop an immunity which protects them against death and disease. In an area where malaria transmission is very high, therefore, those who have not acquired immunity will be most at risk, particularly young children and visitors. Vaccination is an approach to controlling malaria that has gained in popularity in the last half of the twentieth century. It is based on the ideas that immunity can be stimulated artificially and that an effective vaccine would protect both the individual and the community and would prevent transmission.
The end of the twentieth and the beginning of the twenty-first centuries have witnessed an explosion in biological sciences, fuelled by the integration of chemical, physical and mathematical approaches. Biologists have begun to analyse the molecular basis of life, using the entire genetic information of individual organisms as the starting point. In 2001 a draft of the human genome of 40,000 genes was published. This year has seen another major advance in knowledge that might lead to the control of the devastating disease of malaria. It has been an historic year in malaria research: two series of articles were published in October about the parasite and mosquito genomes, together with detailed analyses of some of the proteins that they encode and a mass of additional information and analyses. The information contained in the genomes of Plasmodium falciparum and Anopheles gambiae, the principal mosquito vector in Africa, is now available to all.
The malaria parasite’s genome contains about 5,300 genes which code for the proteins that make up the organism. For example, the enzymes that carry out the biochemical transformations essential for parasite life, the molecules that define how the parasite recognises and invades host cells, and the substances that help it to evade the immune defences of both its human and insect hosts. Understanding the parasite’s processes for getting energy, for growth, multiplication and division enables potential targets for drug therapy to be defined. Knowing which genes are essential for parasite survival and how similar or different they are to the equivalent genes in humans is essential for planning new strategies for drug development. Enzymes that digest the haemoglobin in the host’s red blood cells or that make fatty acids within the parasite are promising areas for further study. Some of the proteins are made in the mosquito vector and some are made in the human host. Many proteins have characteristics that suggest they might be important components of future malaria vaccines, and the available information for the human genome will facilitate studies to identify which components of the immune system are switched on or switched off during infection. However, for about sixty percent of the genes there is not much to go on since they have little similarity with any known genes in other organisms and the big challenge will be to discover what they do.
The mosquito’s genome is much larger than that of the parasite, containing approximately 14,000 genes. Fortunately the genome of another insect, the fruit fly, has already been studied and the two insects share about half of their genes. This makes the analysis of the mosquito genome easier since the functions of many of the fruit fly genes are already known. Interestingly, the mosquito seems to have many more genes involved in its immune defence against pathogens, perhaps because its diet makes it much more susceptible to invaders. The new molecular information on the mosquito can help in three areas where it is important to understand more. How can the numbers and life expectancy of infectious mosquitoes be reduced?; what attracts some mosquitoes to humans rather than animals; can the ability of the parasite to develop within the mosquito be reduced? It can also help scientists to deduce how mosquitoes develop resistance to insecticides, and how such resistance can be overcome. This will facilitate the development of new insecticides. The molecular basis of the mosquito’s attraction to a variety of odours that may determine who they bite is currently being investigated, and this may lead to the development of more effective mosquito repellents. The basis of mosquito resistance to infection is currently being examined, and there are many who believe it will be possible to introduce genes for resistance into wild mosquito populations such that they will no longer be able to transmit malaria. For this to work researchers will have to identify suitable genes, find ways to drive them into the population, and ensure that there are no deleterious effects associated with the genetically manipulated mosquitoes. There are also many ethical and other issues that would need to be addressed before modified mosquitoes can be released into the wild. The availability of the genome will also facilitate a range of population genetic and biological studies, for example on biting and resting patterns, which will be useful to determine when and where to apply mosquito controls.
In addition to parasite, host and vector the fourth factor in the interaction is the environment. Until recently Plasmodium vivax malaria was endemic in parts of England and even now the Anopheles mosquitoes that can transmit malaria are still present. It has been suggested that environmental changes, particularly global warming could have an impact on the incidence of malaria. The climate affects the survival of mosquitoes during the winter and the availability of breeding sites in the summer, thereby controlling mosquito breeding and feeding habits. Temperature also affects the ability of the parasite to develop completely in the mosquito vector. Plasmodium vivax requires a temperature of at least 16o C for sixteen days before its cycle can be completed and it becomes infective again to humans. In contrast, P. falciparum requires a temperature of at least 20o C to develop fully in the mosquito. In Britain there are five species of Anopheles that are capable of transmitting malaria. The most efficient of these is probably Anopheles atroparvus because of its preference for feeding on humans rather than on animals. Plasmodium vivax was probably transmitted in Britain by A. atroparvus which breeds in slightly salty water and is therefore a coastal species extending along estuaries and areas prone to marine flooding. Its greatest density extends from the Norfolk fens to the marshes of Essex and Kent, and in former times may have extended up the Thames and into London. There is overwhelming evidence, summarised by Mary Dobson in her book “Contours of Death and Disease in Early Modern England”, that “marsh fever” or “ague” which afflicted people living in the low-lying, unhealthy areas, was malaria. In the seventeenth and eighteenth centuries the poor did not have access to Jesuit’s bark to treat the disease and they relied more often on charms, herbal treatments and various concoctions containing opium and alcohol. The hottest decades of the seventeenth century were accompanied by the highest mortality in the marshland areas, probably because hot and dry summers would have increased the numbers of stagnant pools suitable for mosquitoes to breed. In the nineteenth century mild winters and springs, allowing greater mosquito survival over the winter, were associated with a higher prevalence of malaria. During the Great War of 1914-1918 some troops who had previously been posted to the Mediterranean area and to India were stationed in the marshlands back in the UK and soldiers carrying the parasite caused the mosquitoes to become infected. As a consequence there were over five hundred cases of malaria in individuals who had not left the country. In some villages in the marshes of northern Kent up to one fifth of the local population became infected with malaria.
There is a constant need for vigilance because mosquitoes are such efficient vectors. With global warming the return of malaria transmission to Southern Europe and even to Britain is a strong possibility. Currently there are around two thousand clinical cases of malaria imported each year into Britain by travellers from areas where malaria is endemic who become infected and return to Britain. October 2001 was the warmest in Britain since records began in 1659. According to Meteorological Office figures, the first six months of 2002 have also been the warmest on record, with a warm winter, and spring arriving earlier than ever before. In the same period the average temperature in the Northern Hemisphere was the highest in the last 143 years. Not only is global warming a reality, but the weather is likely to become increasingly extreme and unpredictable with the return of El Nino and a new “Asian brown cloud” of man-made pollutants spreading across this continent and beyond. Just three years ago the West Nile Virus was reported in New York, and this year it has spread west across half the United States. Although causing relatively few fatalities the rapid spread of this virus that is transmitted by a common house mosquito, Culex pipiens, and has an alternate reservoir – in wild birds – is alarming.
The world currently spends about two hundred million dollars each year on research into malaria and its control, a tiny amount of money relative to the size of the problem. In the last few years there have been several much-needed initiatives to promote research and control, such as the Multilateral Initiative for Malaria, the Medicines for Malaria Venture, the Malaria Vaccine Initiative and WHO’s Roll Back Malaria programme. There is an increasing recognition that malaria and other diseases are strongly linked to poverty and must be dealt with to facilitate economic viability as well as health benefits. The history of malaria research is littered with stories of tensions between entomologists and parasitologists, vaccine and drug developers, and promoters of low-tech or high-tech approaches. In reality there is a need for a much more integrated approach in the application of existing knowledge and the acquisition of new. Perhaps malaria will only be taken really seriously when it threatens the rich and powerful.