Communities of practice
Malaria research: “a way to contribute”
21 Oct 2009
It was a combination of Albert Schweitzer and the Vietnam War that led Louis H. Miller to enter a career that has so far extended over four decades.
Schweitzer – the German physician, musician and philosopher who set up a hospital in what is now Gabon – was awarded the Nobel peace prize while Miller was still at Quaker school in the fifties. “He was in the limelight,” says Dr Miller. “I was very influenced by him and wanted to do something in Africa.”
Although a missionary leprologist eventually talked him out of clinical work in Africa, Miller’s medical training sparked an interest in research. The Vietnam War thwarted his first attempts to get into NIH (the US National Institutes of Health) but, ironically, the conflict ended up determining the career path he was to follow for the next four decades.
During the war, newly-qualified doctors were expected to choose between working in the military or public hospitals in the US. “They put off your draft until you finished your medical school. In fact they wouldn’t let me come to NIH because I was already committed to the military,” he says.
So Miller was sent to Thailand and Cambodia and here began malaria research. “That’s when I decided to do research in malaria as a way to contribute,” he says.
Protection against P. vivax
Miller is best known for solving a puzzle that had perplexed malaria researchers for over 50 years. No one had worked out why the parasite Plasmodium vivax, which is responsible for over two-thirds of cases in India, does not cause disease in parts of West Africa. Less deadly than Plasmodium falciparium, P. vivax causes serious recurring malaria throughout Asia, Latin America, and other parts of Africa.
In the mid-1970s, Miller’s group discovered that a specific molecule on red blood cells allows P. vivax malaria parasites to invade them and proliferate in the bloodstream . That molecule is a protein called the Duffy blood group antigen and is a receptor for P. vivax. Importantly, the group found that many West Africans do not have Duffy antigens. Being Duffy-negative means they do not suffer from this particular form of malaria.
The role of Duffy antigens, led Miller and colleagues to explore the concept of receptor mechanisms shared between the malaria parasite and its host cells and how the receptor might be exploited for use as a vaccine.
Indeed, his group, which included Chetan Chitnes (see TropIKA.net Profile), worked on cloning the part of the parasite responsible for binding to the red blood cell, called the Duffy binding protein, because it could be used in vaccines.
Chitnes is now in India, working on, amongst other things, a vaccine based on the Duffy binding protein.
Back to basics
More than 30 years after the Duffy discoveries, Miller is heading back to basic research. He is returning to the Malaria Cell Biology Section at the Laboratory of Malaria and Vector Research, based at the National Institute of Allergy and Infectious Diseases (NIAID).
Actually, the job is not completely new. He has worked here on a part-time basis while heading NIAID’s Malaria Vaccine Development Branch (MVDB) for the last decade.
MVDB is developing vaccines that target all stages in the life-cycle of the deadliest malaria-causing parasite, Plasmodium falciparum. The candidates include the AMA1-C1/Alhydrogel+CPG 7909-based vaccine that has been trialled in collaboration with the Malaria Research and Training Center in Mali, which features in a TropIKA.net Profile.
Now MVDB is being turned over to Patrick Duffy, the scientist credited with discovering how the malaria parasite causes disease in pregnant women.
For his part, Miller is returning full-time to basic research. He is tight-lipped about what he’ll be looking at. But the future holds many opportunities, he says and a chance to delve into areas that could dramatically affect the war against malaria.
When last focused on basic research, he and his team identified the molecules that malaria-infected red blood cells use to stick to blood vessel walls to avoid passing through the spleen where they would be destroyed. (These molecules are now being tested for possible development into a malaria vaccine.)
He soon began looking at mosquitoes, immunology and how the immune system sees parasites – especially when they enter the liver. This work led another important discovery, that CD8 is very important for blocking infection.
Much to be done
There are many interesting areas that need work Miller says. A more in-depth understanding of the parasite’s interaction with red blood cells is still vital. He is particularly interested in a technique called reverse genetics, which analyses the entire parasite genome as a means towards selecting the most effective potential antigens.
The genome could be used to identify proteins embedded in the surface of the pathogen’s cells, for instance, since these are more likely to be the first detected by the immune system of the infected host. Reverse genetics could reduce the time taken to find effective antigens. It is a technique that has been used already to create a meningitis vaccine by looking at the bacterium Neisseria meningitides. “It’s a bit more difficult to do in malaria,” says Miller. “But reverse genetics is an approach that could be used.”
Perhaps inspired by almost six years of work on the mosquitoes themselves earlier in his career, Miller says he would like to see more focus on vector control. That is because he believes without vector control, malaria eradication is not possible. The only way to eradicate malaria, says Miller is this: “We need to make the vector a pest, a way to be completely refractory to Plasmodium, so that the organism cannot be transmitted by the mosquito, because something in the mosquito is stopped.”
Controlling the mosquito is not a huge focus of research today, which has typically focused on vaccines, drugs and insecticides. Indeed vector control more often means developing new insecticides, ramping up indoor residual spraying and increasing the coverage of treated bed nets.
Of course, progress on vaccines, drugs, and bed nets is absolutely essential to controlling the disease, he says.
“I’m not saying not to do research on ways to control disease, new drugs, vaccines and insecticide. That must be done because it’s critical for people to survive, “he says. “But if you want to eradicate, you need a different approach. I personally think that you are going to need to attack the mosquito in Africa.”
The fact is the Anopheles gambiae mosquito is so highly efficient at spreading the disease in Africa. That’s why research must also focus two areas, says Miller. Firstly, researchers must precisely understand how mosquitoes deal with the parasite. Some types of mosquitoes – such as Aedes aegypti – have been feeding on humans for thousands of years, but never transmit malaria, for instance.
Some great work on precise mosquito mechanisms is already being done, says Miller. As featured in TropIKA.net News, groups in London and France have, for example, examined mosquito immune systems to determine how three proteins that occur in mosquitoes form an effective parasite killing machine . Together, two of the proteins circulate in mosquito blood and are able to detect malaria parasite intruders, activate a third protein which then kills the parasite by latching onto the surface of the parasite and penetrates it by punching holes in the cell membrane.
An understanding of these underlying mechanisms could be invaluable because researchers could use it to alter the mosquito and prevent transmission of the disease, says Miller. In other words, he proposes a rather controversial move, to genetically alter mosquitoes. “Yes, transgenic anything, including a crop like transgenic corn can drive people crazy,” he says. “The question is, will it work?”
A few projects are looking at ways to alter mosquitoes already. A Genetic Strategy to Deplete or Incapacitate a Disease-transmitting Insect Population is actually the seventh Grand Challenge, big scientific problems posed by the Bill & Melinda Gates Foundation, which funds projects that seek to solve them.
But far more basic research is needed to understand exactly how mosquitoes and parasites interact, says Miller to work out genetic methods that allay fears and ensure that there are no unintended consequences.
He also proposes  a 21st century version of a group called the Vector Biology Network (VBN) that was sponsored by the MacArthur Foundation over a 10-year period until 2000. The consortium of research laboratories collaborated in the development and application of new molecular and genetic vector biology and in training a new generation of scientists. New groups could look how to successfully introduce genetic mutations to the many different types – or populations – of mosquito that co-exist in the environment today, he suggests.
Whatever happens, however, such research will take time. “You’d have to do a lot of work to show that it is not going to be a problem. It won’t happen tomorrow,” he says.
But many believe transgenic strategies may be best left on the drawing board. For a start, they are likely to be far too controversial to ever win public approval, even if they worked. Dr George K Christophides, who heads up the research team at Imperial College, London told TropIKA.net News earlier this year: “Transgenic insects is an idea we think theoretically could work on paper. The problem will be whether society can accept it to release thousands or millions of transgenic insects in the world. It might not be a viable method”.
Existing methods might be enough to eradicate malaria, say others. Jo Lines, coordinator of vector control and prevention for the global malaria programme at WHO says insecticide-based methods are extremely effective.
Indeed, insecticide-treated bed-nets are a critical tool because they specifically target the most dangerous mosquitoes. These are the older female mosquitoes, which have lived long enough to gestate malaria parasites, and need to feed (most mosquitoes never reach this stage). Bednets, therefore, are a good way of killing these specific mosquitoes. In contrast genetically modification would have to target a far greater number of insects. “I’m not arguing against research in that area. We badly need new tools to control malaria,” adds Lines. “I wish I saw more immediate potential for this than I do. But I suspect that we will eradicate without [genetic modification].”
1. Miller LH, Mason SJ, Clyde DF, McGinniss MH (1976). The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. N Engl J Med; 295(6):302-304. Available from: http://www.ncbi.nlm.nih.gov/pubmed/778616
2. Povelones M, Waterhouse RM, Kafatos FC, Christophides GK (2009). Leucine-rich repeat protein complex activates mosquito complement in defense against Plasmodium parasites. Science; 324(5924):258-261. Available from : http://www.ncbi.nlm.nih.gov/pubmed/19264986
3. Beaty BJ, Prager DJ, James AA, Jacobs-Lorena M, Miller LH, et al. (2009). From Tucson to Genomics and Transgenics: The Vector Biology Network and the Emergence of Modern Vector Biology. PLoS Negl Trop Dis 3(3). Available from: http://www.ncbi.nlm.nih.gov/pubmed/19333394
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