The red road

This essay was written by Tony Holder and was first published in the 2000 Mill Hill Essays.

It’s the dry season and the dirt road from Ibadan to Igbo-Ora is in good condition. Red African road dust settles heavy on clothes and skin, clogs every pore, and fills the nostrils and lungs. Small beads of sweat form in the heat and carve colourless tracks through the dust on the skin. At the end of the road the health centre, modest in design of cement and in content. On the shady veranda women in colourful print cotton ‘Iro, buba ati gele’ wait patiently for the small team of doctors and scientists, babies held close to their bodies. They and their families are a crucial link in a project that stretches across three continents. Even now, before the rains start and the mosquitoes multiply, some of these children carry in their bloodstream the deadly malaria parasite. Without effective treatment for malaria the next months will bring misery as the mosquitoes return. A couple of thousand miles away in London in an air conditioned room, malaria parasites proliferate ceaselessly in plastic flasks, nurtured by white-coated laboratory workers. Elsewhere, in Bethesda, Hinxton, and Palo Alto stand silent regiments of machines, their lasers scanning genes that reveal the parasite’s secrets of life. And in Oxford an apprehensive student waits for the tell tale signs; will the experimental malaria vaccine protect him from the injection delivered just a few days ago by infected mosquitoes? Different experiences of a world linked by a common thread.

Although most people have heard of the disease malaria and know that it is carried by mosquitoes, until recently the disease has not been headline news. One could have been forgiven for thinking that it was a disease of the past, and few realise how devastating it is in many parts of the world. Once prevalent in Europe it is now largely restricted to tropical and subtropical parts of the world where it causes widespread debilitation and death. Currently ninety percent of acute disease and deaths are in Africa. At least one million African children under five die each year from malaria. The social and economic costs to the people of this continent are enormous. Now, after years of neglect the international community is recognizing the size and consequences of the problem and a mass of new initiatives and new funds are being deployed. G8 politicians talk of HIV, TB, malaria and poverty.

The disease malaria is caused by infection with a parasite, a small single-cell organism, that is both bigger and more complex than either bacteria or viruses. Of the four types that infect humans, Plasmodium falciparum is the species that kills. After a brief phase in the liver multiplying many thousand times, the parasite invades, lives and multiplies again within red blood cells, establishing a remorseless cycle. If this multiplication is allowed to continue the infection may rapidly lead to coma and death. To attack the parasite in the body we need to understand how the parasite gets into red blood cells, and how it survives there. We need to know how it causes disease. By understanding how it lives we should be able to identify how to kill it, either by developing drugs that are poisonous to the parasite but not to humans or by developing a vaccine that will stimulate the body’s immune system to protect itself.

Since the discovery at the end of the nineteenth century that mosquitoes transmit malaria most attempts to control malaria have focussed on the insect. They culminated in the failed global eradication campaign between 1955 and 1969 with the extensive use of DDT, a residual insecticide. Global eradication was in any case a misnomer, eradication was not even attempted in Africa. Enthusiasm was dissipated and funding at all levels haemorrhaged. By 1993 the funding for malaria research worldwide was only about fifty million pounds sterling a year, less than a tenth of that spent on HIV. But in the last decade of the twentieth century things have changed: governments, international agencies and national funders have dramatically increased their support, particularly to implement malaria control strategies. The World Health Organisation has established the Roll Back Malaria campaign: the aim to halve malaria-associated deaths by 2010. The Bill and Melinda Gates Foundation has given one hundred and fifteen million dollars for vaccines, drugs and education, and the pharmaceutical company Glaxo Wellcome implements a donation programme for Malarone, one of the few new drugs against malaria to have been developed in recent decades.

DDT was not effective in eradicating malaria but it was effective at inhibiting research. This “solution” for malaria led many to believe that no further research was necessary because the problem was solved. The current campaigns must not stifle the on-going research that is the foundation for the future. The Roll Back Malaria campaign must provide not only tools at every level such as insecticide treated bed nets, or rapid access to effective treatment, but it must also build political will and provide success to maintain momentum. Whether or not the ambitious goal will be achieved, none of the research being carried out in laboratories today is likely to have a major impact in the process. This is because of the long time delay in translating fundamental knowledge into products. Recognizing that this process of translation is a bottleneck, the discovery and development of new drugs and vaccines, based on existing knowledge, is considered to be a major priority.

Effective drugs will need to kill the parasite and be harmless to humans, as well as being very cheap. They will also need to be deployed in a way that prevents a rapid development of resistance to the drug by the parasite. The cheap and once very effective anti-malarial drug chloroquine is now almost useless in large parts of the world due to the development of resistance. Many people believe that for a long term solution to malaria, a vaccine is the key. Vaccines are designed to stimulate the body’s immune system and prepare it to defend against attack. There is currently much research on malaria vaccines, and although no effective vaccine has yet been developed, there has been some encouraging progress.

Laboratory-based research provides the knowledge upon which future attacks against the parasite will depend. It received a considerable boost in the 1970s when for the first time Plasmodium falciparum was grown in suspensions of red blood cells in the laboratory. Now molecular and cell biology lead the way, fuelled by the development of tools to analyze the genetic material of the parasite which is leading to a new revolution in parasite studies. An international consortium is set to reveal the genetic blueprint for the malaria parasite – the genome is small compared to that of humans but the work is a major accomplishment. Approximately 30 million ‘bits’ of information to be identified, and soon the complete map of all six thousand or so genes that define the malaria parasite will be available. But building and stocking the library with the books of genes is just the first step; being able to read the books and use the information that they contain, as well as understanding the complex relationships between the genes and the proteins they code, is just beginning. Although parasites are very small they are also very complex and therefore it is not a simple task to develop suitable drugs, or an effective vaccine. To exploit the molecular information for the benefit of the children of the future is the challenge to be faced.

Parasitology has been an interest at the Institute since its inception and most recently our research efforts have focussed on malaria. When the Institute moved to Mill Hill fifty years ago, drug development studies blossomed and even in those early days the importance of understanding mechanisms of action was recognised, for example an early discovery was how the antimalarial compound proguanil, which is still in widespread use today, works.

By their very nature, parasites live within the body of other host organisms. We have chosen to study how the malaria parasite gets into the red blood cell in which it lives and how it modifies that cell to make it a home. One of the main reasons for this interest is that the growth of the parasite within the blood stream is the part of the life cycle that is responsible for the disease. When the malaria parasite, in the form known as a merozoite, enters a red blood cell it can develop and multiply such that every forty-eight hours up to thirty new parasites are formed and released to invade new red blood cells, leading to an explosive increase in numbers. How does a merozoite get into a red blood cell? First the merozoite sticks to the red blood cell, turns around and then “kisses” the red blood cell surface, at the same time injecting the contents of syringe-like structures that facilitate its entry into the cell. When the parasite is inside the red blood cell the transformation of the cell begins. Haemoglobin, the red protein that carries oxygen around the body and which fills the red blood cell is digested by the parasite to provide it with nourishment. This also creates space for the parasite to grow and multiply. The surface of the red blood cell is made “sticky” so that the infected red blood cells bind to the walls of blood vessels. This is particularly important because if they bind to the walls of blood vessels in the brain this can lead to cerebral malaria, a severe and often fatal disease, or if they bind to the vessels in the placenta there are dangerous consequences for both mother and child.

Understanding the balance between parasite, host, and the host immune system is fundamental to developing vaccines and other immune therapies. The immune system is the body’s defence to protect it from attack by a whole range of agents including viruses and bacteria as well as parasites. Different parts of the immune system have different functions but antibodies are of particular importance in stopping merozoites getting into red blood cells. Antibodies can bind tightly to the surface of the merozoite and interfere with invasion, and if the merozoite cannot get into a red blood cell then it dies. We are trying to identify the important parasite targets – our studies on antibodies that bind to a protein on the merozoite surface have identified how they act to prevent invasion and this knowledge has allowed us to identify a very promising candidate for vaccine development. Immunisation with this protein will help prepare the body to kill merozoites. The changes to the red blood cell surface, which were first discovered at the Institute, and the importance of the resulting binding for several aspects of malaria disease, have prompted researchers to focus on how this occurs and to investigate whether or not the immune system can be stimulated to stop the binding from occurring.

A few years ago scientists at the Institute identified a number of genes in the malaria parasite, which were to lead to some very surprising discoveries. We are all familiar with the fact that plants are green, even the simplest of plants use light as a source of energy. The light energy is collected by the green pigment chlorophyll and used to make glucose within a small factory-like unit within the cell called a plastid. Surprisingly malaria parasites and related organisms also have plastids! They are not green and do not use light but nevertheless this vestige of a former life is retained. The plastid is not just a signature of times gone by, it would surely have been lost millions of years ago unless it was essential for parasite survival. If it is essential for survival then not only is it of interest to know why it is essential, but also since human cells do not have plastids, then it is a potential target for a drug that will specifically kill the parasite by stopping the plastid doing its job without being toxic to the human host. In fact the structure of the plastid’s DNA suggests that there are several targets for antibiotics already developed to kill bacteria, which could be developed as antimalarial drugs. The parasite uses the plastid to make certain essential chemicals, in a way that is quite different from the ways used by human cells. Understanding the importance of the plastid promises to yield many potential targets for drug development.

Malaria is very much but not exclusively a disease of the poor, and is made much worse by war and unrest. To control malaria a range of economic, social, political and scientific hurdles will need to be overcome. Although part of the solution may be the development of new drugs and vaccines, the use of insecticide-impregnated bednets or new ways to control mosquitoes, and the effective delivery and use of pre-existing methods are essential. The solution to the problem of malaria cannot be imposed from outside. In the first part of the last century malaria control was an integral part of the pursuit of economic and commercial interests of the colonial powers. Now, there is a need for local solutions that require skilled and well-funded researchers, and an informed public in Africa. Control of the problem must be led by the countries and the communities that malaria affects. In ten years time the best research will be carried out globally, not just in the labs of North America, Europe, or Australia. As one of the first steps in this direction to create, restore and build the necessary infrastructure and to train the next generation of researchers, the Multilateral Initiative on Malaria, established after a landmark meeting in Dakar in 1997, is attempting to fulfil these needs.

In Nigeria a new democracy is a new beginning. Optimism for change abounds but fault lines in society are revealed by the new freedoms and threaten progress. Malaria is very much a problem of poverty, environmental destruction and abuse of natural resources. Only by respect of the individuals and the chance to engage and develop their full potential will it be possible to control the problem of malaria, and improve their quality of life. The children of Igbo-Ora deserve the chance.

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