Science in Society Archive

Two Takes on Malaria

Potentially hazardous transgenic mosquitoes are being promoted as a means for controlling malaria at a time when safe effective measures are already available.

Transgenic Mosquitoes Coming

Desperate measures are being considered to control malaria, a global scourge, including genetic engineered mosquitoes. Prof. Joe Cummins explains why this strategy is far from safe.

The most highly publicized strategy to dealing with malaria is to develop a vaccine to prevent spread of the infection. That strategy encountered difficulty related to the genetic virtuosity of the malaria parasites [1]. The parasites have about 14 chromosomes with both variable and conserved regions [2]. The main defence against the human immune system are Var genes coding for cell surface antigens, which create diversity by frequent recombination [3]. Another strategy being considered is to eradicate the vector mosquito that spreads the disease.

The causative agents in humans are four species of Plasmodium protozoa (single-celled animals) - P. falciparum, P. vivax, P. ovale and P. malariae. Of these, P. falciparum accounts for the majority of infections and is the most lethal. Malaria is a curable disease if promptly diagnosed and adequately treated (see next report).

When a mosquito bites an infected person, it ingests the microscopic malaria parasites found in the person’s blood. The malaria parasite must grow in the mosquito for a week or more before infection can be passed to another person. If the mosquito then bites another person, the parasites go from the mosquito’s mouth into the person’s blood. From there, the parasites travel to the liver and get inside the liver cells to grow and multiply.

During the time that the parasites are in the liver, the person does not feel sick. The parasites eventually leave the liver and enter red blood cells, which may take as little as 8 days or as long as several months. Once inside the red blood cells, the parasites grow and multiply. The red blood cells burst, freeing the parasites to attack other red blood cells. Toxins from the parasite are also released into the blood, making the person feel sick.

Recent discoveries have allowed genetic modification (GM) of Anopheline mosquitoes. The emphasis of current research has been first to create Anopheline mosquitoes that inhibit the establishment of the plasmodium parasite in the gut of the mosquito. Once strains of such transgenic mosquitoes are established, the next step is the devise means of replacing the native mosquitoes with the transgenic strain that cannot spread the plasmodium parasite to humans and animals.

Anopholine mosquitoes are modified using DNA transposons. Transposons are mobile genetic elements found in animals as well as plants, and many families and superfamilies of transposons exist. The transposons used to genetic engineer arthropods (including insects) are replicated as DNA, and integrated into chromosomes by transposase enzyme coded in the transposon. Other transposons replicate by reverse transcriptase, like retroviruses, but those elements are not used in current modifications of transgenic mosquitoes.

The specific transposons employed are called mariner and hermes. They were originally isolated from insects, but are closely related to transposons found since in vertebrates and higher plants. In the current design, the transgenes carried by the transposon are activated by an insect gut-specific promoter [4], because plasmodium is propagated in the insect gut; or else by a salivary gland-specific promoter to affect the salivary gland phase of the parasite’s replication [5].

A number of transgenes have been considered to prevent propagation of plasmodium. Two mammalian genes have come to the forefront of research, the first of these is a gene for a mouse monoclonal antibody that targets the salivary gland phase of the parasite [5]. The second gene (SM1) produces a peptide that prevents the plasmodium from adhering to the mosquito gut cells and replicating there [6]. The SM1 gene was identified in humans relatively resistant to malaria [7].

Even though these genes appear promising, plasmodium is highly variable, and has exceptional versatility in evading control. Once the mosquito proves resistant to plasmodium, the resistant strains may replace the deadly native strains. Although it seems intuitive that mosquitoes that maintain healthy blood-producing hosts should do better than mosquitoes that kill their hosts or make them ill, deadly mosquitoes dominate the ecology of tropical regions.

Another organism, the bacterium Wallbachia, which lives symbiotically in the cells of certain insects, may help improve the chance of survival of transgenic mosquitoes.

It appears that female insects infected with Wollbachia can mate and produce progeny with both infected and uninfected males, but an uninfected female insect can produce progeny only if she mates with an uninfected male. The result is that Wolbachia-infected females have a reproductive advantage. For this reason, genetically modified Wollbachia could be used for gradual introgression of any transgene into the wild population by mating [8]. (The bacteria have to be genetically modified so that their establishment in the mosquito can be controlled.) Wollbachia infected female mosquitoes have a reproductive advantage, allowing them to rapidly replace the malaria spreading moisquitoes. A population of mosquitoes may also be altered by methods analogous to those used to eradicate insect pests such as the pink bollworm [9].

The impact of introduced transgenes on humans and the ecosystems must be carefully evaluated before the genes are widely spread around the globe.

For example, the mariner and hermes transposons used in insect modification may spread and recombine with related transposons in vertebrates, invertebrates and higher plants. The hermes transposons, for example, are found human chromosomes and they have been associated with fragile chromosome sites associated with mental retardation and with cancer [10].

Wollbachia may also spread among a vast array of arthropods and extend its influence by genetic recombination.

The impact of transgenic insects must be carefully evaluated, especially in the light of safer methods for controlling malaria already available (see next report). We must now allow misplaced enthusiasm for new technology and worse, greed, to spread dangerous gene-constructs around.

  1. Kwiatkowski D and Marsh K. Development of a malaria vaccine Lancet 1997, 350, 1691-701.
  2. Carlton J, Galinsky M, Barnwell J and Dame J. Karyotype and synteny among the chromosomes of all four species of human malarial parasites. Molecular and Biochemical Parasitology, 1999, 101, 23-32.
  3. Taylor H, Kyes S and Newbold C. Var gene diversity in Plasmodium faliciparum is generated by frequent recombination events. Molecular and Biochemical Parasitology, 2000, 110, 391-7.
  4. Moreino L, Edwards M, Adhami F, Jasinkiene N, James A and Jacobs-Lorena M. Robust gut specific gene expression in transgenic Aedes aegypti mosquitoes. Proc. Natnl. Acad Sci USA 2000,97,10895-8.
  5. James A, Beerntsen A, de Lara Capurro M, Coates C, Coleman J, Jasinskiene N, and Krettli A. Controlling malaria transmission with genetically-engineered, Plasmodium-resistant mosquitoes: milestones in a model system. Paristologia 1999, 41,461-71.
  6. Enserink M. Two steps to a better mosquito. Science 2001, 293, 2370-1.
  7. Garcia A, Marquet S, Bucheton B, Hillaire D, Cot M, Fievet N, Dessein AJ and Abel L Linkage analysis of blood Plasmodium falciparum levels: Interest of the 5q31-q33 chromosome region. Am.J.Trop.Med.Hyg. 1998, 58,705-709
  8. Marshall A. The insects are coming. Nature Biotechnology 1998,16, 530-533
  9. Ho MW and Cummins J. Terminator Insects - The Killing of Females. ISIS news No 9/10 July 2001 http://www.i-sis.org.uk/isisnews/i-sisnews9-24.php
  10. Liehr T, Reiter L, Lupinski J, Murkami T, Clausen U and Rautenstrauss B. Regional localization of 10 mariner transposon-like ESTs by means of FISH-evidence for a correlation with fragile sites. Mammalian Genome 2001, 12, 326-8.

Rolling Back Malaria

Safe, effective measures for rolling back malaria are already available. All that is needed is political will to implement them widely. Sam Burcher reports.

Every year brings an estimated 3000-5000 million cases of clinical malaria. Malaria is one of the worlds’ most infectious diseases, killing 1.5-2 million annually. Ninety percent of fatalities are infants in Africa. Malaria is endemic in tropical and subtropical regions of sub-Saharan Africa, Central and South America, Middle East, Indian subcontinent, South East Asia and Oceania [1].

More than 50 African heads of states united under the world’s largest mosquito net in Nigeria in March 2000 and pledged to halve the continent’s malarial deaths by 2010 [2]. The meeting coincided with the third annual ‘Roll Back Malaria’ summit to highlight that malaria is preventable, treatable and curable [3].

There are four crucial areas of development that could help halt the spread [4]:

Insecticide-treated bed-nets, prompt diagnoses and treatment, multiple and cost effective means of prevention and early identification and effective responses to epidemics.

A recent review found that children who slept beneath treated bed-nets were half as likely to develop malaria. The World Health Organisation is calling for a 30 times increase in the availability of bed nets over the next 4 years.

New methods for malaria diagnosis are in development as an existing overlap between symptoms of malaria and other frequent diseases make misdiagnosis and mistreatment common. The most promising is an antigen detection test, the rapid ‘dipstick test’, that requires no special skills or facilities and is commercially available [5].

With some families in Africa still paying a ‘malaria tax’ (see below), it is important that access to cheap and effective anti-malarial combination therapies are available. ‘Malaria tax’ includes tax and tariff charged on mosquito nets, insecticides, anti-malarial drugs and tools used in malaria control all over Africa. Uganda has completely scrapped these taxes, following Tanzania’s lead of combining all tax and tariff to a rate of 5%, bringing the price of a bed-net down to an affordable US$3.50. It is estimated that only 3% of families in malaria endemic countries using bed-nets. With the price of a net reaching $45.00 in Swaziland and $30.00 in Sudan where tariffs are at 42% or more, it is hardly surprising. The problem is that most authorities view treated bed-nets as textiles instead of pharmaceutical materials with life-saving potential [6]. Pharmaceutical companies must continue to lower the price of drugs. An intentional liberalization of access to drugs must be encouraged where public sector health care is limited [7]. Current annual donations for malaria control from industrialized countries stand at £0.6bn or $1.6bn. But Professor Jeffrey Sachs, Director of the Centre of International Development in Harvard believes that donations alone are insufficient unless there is immediate debt cancellation. He cites Nigeria, a country that has to repay the International Monetary Fund $1.6bn this year. "This is five times more than Nigeria’s health budget, these funds are needed to save lives" [2].

An anonymous donation of US$100 million to John Hopkins University will support their Malaria Institute for the next ten years.

Complete cures and prevention of malaria have been possible since the homeopath Dr Samuel Hannehman discovered the source of quinine in 1791 from the bark of the Cinchona Tree [8]. Quinine concentrates in the digestive vacuole of the malarial parasite and inhibits the availability of iron by forming a complex compound of iron-porphyrin, which is toxic to the malarial parasite, Plasmodium. Resistance to quinine developed, however, and the search for other drugs uncovered chloroquine, pryrimethamine and mefloquine. Chloroquine has been available since 1934 and is still considered the "drug of choice" in treating non life-threatening malaria. Other quinine-based compounds are primaquine, used for treatment of P. vivax and P. ovale. [9]

Since 1992, research has focussed on Artemisian, an alkaloid shown to reduce the availability of iron to the malarial parasite, with even greater efficacy than quinine [10]. There are 25 different plant sub-species of the shrub Artemisia and all have similar properties to Chinona officinalis (quinine). Some sesquiterpine lactone compounds have been synthesized from the plant Artemisia annua, and are being used to treat severe malaria. They clear the parasite rapidly and resolve fever faster than other drugs. Artemisinins combined with longer acting antimalarials minimize the chances of parasites surviving initial treatment and reduces risk of resistance developing. In some areas of South East Asia a combination of mefloquine and artemisinins is the only cure for malaria due to multi-drug resistant P. falciparum [11]. The distribution of drug resistant P. falciparum malaria worldwide is well documented, with only Central America and some Caribbean Islands remaining resistance free. Border areas of Thailand, Cambodia and Myanmar report the highest risk for multiple drug resistant infections.

Other types of treatments are antifolate combination drugs. Their synergistic effect on the parasite can be efficacious even when resistance to individual components is present. A new antifolate combination is Lap-Dap, a mixture of chlorprogranil and dapsone; which has a greatly enhanced synergistic effect on malaria than existing drugs. Lap-Dap shows a greater cure rate and a decreased chance of resistance developing. It is also low-cost, at less than US$1.00 per adult treatment [12]. However, antifolates such as dapsone has been found to be carcinogenic [13], and should be used with caution.

Antibiotics such as tetracycline are potent anti-malarials, and are often used in combination with quinine.

An exciting discovery has surfaced in India. A substance found in mouthwashes and deodorants called Triclosan may hold the key to a new anti-malarial treatment. Researchers at the Jawaharlal Nehru Centre for Advanced Scientific Research in Bangalore have found that this antimicrobial agent completely clears the plasmodia parasite in mice. Dr Namita Suriola and her team have also identified the metabolic pathway by which Triclosan works [14]. Their results showed that Triclosan inhibits the growth of P. falciparum in red blood cells in vitro. Mice infected with the model for human malaria Plasmodium bergei were cleared of the parasite and regained health. An important enzyme essential to the synthesis of fatty acids in plants and many bacteria is Fabi. Triclosan inhibits Fabi in bacterial systems. Dr Suriola has identified and purified a protein in P. falciparum that has a similar sequence to Fabi, suggesting that Triclosan may be affecting the synthesis of essential fatty acids in the parasite.

As far as vaccine development is concerned, there is little interest because there is the countries needing it cannot afford it. But measures to use prevention as a safeguard in infants are underway. A study carried out in Tanzania on 701 infants administered treatment of malaria and anaemia at the same time as routine vaccinations at 2, 3, and 9 months of age. This was used as a preventative measure in an area where high P. faciparum infection occurs. Results collected this year indicated less hospital admissions for children who received doses of suphadoxine pyrimethamine, an antifolate combination. Treatment doses were well tolerated, and reduced clinical malaria by 55% and anemia by 50%. The study concluded that this preventative treatment in infancy is significant to public health in areas where malaria is endemic [15].

Article first published 01/11/01



References:

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  2. Yamey G. African Heads of State Promise Action Against Malaria. BMJ 2000, 320:1228.
  3. RBMNEWS@WHO.INT.
  4. Editorial. Donor Responsibilities in Rolling Back Malaria. The Lancet 2001, 356, 521.
  5. Craig MH, Sharp BL. Comparative evaluation of four techniques for the diagnosis of Plasmodium falciparum. Transactions of the Royal Society of Tropical Medicine and Hygiene 1997, 91, 279-82.
  6. African Nations urged to end Malaria Taxes. Press Release WHO/48 5 July 2000.
  7. Salako LA. An African perspective. World Health 1998, 3, 24-25.
  8. Cook T. Malaria, homeopathic prophylaxis and treatment. Homeopathy International 1999, 12, 12-13.
  9. Foley M. Tilley L. Quinoline antimalarials: mechanisms of action and resistance. International Journal of Parasitology 1997; 27:231-240.
  10. Price RN et al. Effects of Artemisinin derivatives on malaria transmissibility. The Lancet 1996, 347,1654-8.
  11. White NJ et al. Averting a malarial disaster. The Lancet 1999, 353:1965-7.
  12. Watkins WM et al. The efficacy of antifolate antimalarial combinations in Africa; a predictive model based on pharmocodynamic and pharmacokinetic analyses. Parasitology Today 1997,13, 459-64.
  13. NCI/NTP Carcinogenesis Technical Report Series, National Cancer Institute/ National Toxicology Program, US Department of Health and Human Services, http://toxnet.nlm.nih.gov/cgi-bin/sis/search Dapsone.
  14. Berger A. Mouthwash may treat malaria. BMJ 2001, 322, 316.
  15. Schellenberg D. et al. Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomized, placebo-controlled trial. The Lancet. 2001. 357, 1471.

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