At a time when many parts of the world are disproportionately fearful of emergent diseases and biological or chemical attack, malaria is a mundane but devastating killer that puts other causes of death in perspective. The lack of interest in malaria may partly be because it is endemic in Africa and India, some of the poorest places in the world. Every year, 1.5 - 2.7 million people (mostly children) die from malaria. It affects tropical countries across the globe, and has plagued humanity for all recorded history. It is also believed to have major economic consequences for African nations in particular.
Malaria mosquitos - Anopheles
An obvious, yet important, point is that not all mosquitos are malaria mosquitos. The malaria mosquitos are classified as members of the genus Anopheles. Anopheles is distributed throughout the world. It is the subject of much interest in the genetic community. The genes for one African species, A. gambiae, has recently been sequenced.
Mosquitos are any members of the family Culicidae. To wipe out Anopheles would still leave other Culicidae species to fill any empty ecological niches. This is important, as fish, frogs, turtles, birds and bats eat mosquitoes. Mosquitos are also pollinators (many live off nectar rather than blood). There may also be unknown roles played by mosquitos in the ecology.
Homing Endonuclease Genes
HEGs are special genetic sequences found in the DNA of many species. They are one of a number of [PDF] selfish genetic elements which exploit various genetic processes to replicate themselves. HEGs exploit cells' damage repair system to perpetuate themselves in the DNA.
A HEG, like many genes, codes for the production of an enzyme. In this case the enzyme is a homing endonuclease. Homing endonucleases catalyse the movement of their own DNA sequence, which is the HEG, inside a chromosome.
A homing endonuclease will search for a particular sequence of DNA. What DNA sequence it searches for is specified by the HEG. Once the homing endonuclease enzyme has found this sequence, it will slice through the DNA at that point, severing the chromosome in two.
This leaves a "hole" in the genetic code that must be filled. In a diploid cell with paired chromosomes, this problem can be fixed. The nucleus will attempt to repair the chromosome by copying the corresponding gene at the same point on the other chromosome in the pair - clearly a sensible solution to the problem. But this is playing straight into the HEG's hand - the HEG is this gene and is used as the template to repair the break.
Using HEGs to kill
HEGs, like most selfish genetic elements, are not harmful to the host. Their survival relies upon the survival and reproductive success of their host. This is because, unlike viruses, HEGs can only be transferred by being passed down from one generation to the next - they are not otherwise contagious. They never leave the DNA or produce carriers such as viruses. If the host dies without reproducing, the HEG will die with it.
However, this does not mean that HEGs cannot be modified to be harmful to their hosts by genetic engineering. The plan is to make the HEG target a gene crucial for development in mosquitos, so that the enzyme will destroy this gene when the HEG is activated. The HEG will only activate within newly divided eggs or sperm cells, so that both kinds of cells have 2 copies of the HEG and no copy of the normal gene. Because the HEG copies itself in the sperm and egg cells, even though a carrier may only have 1 copy of the HEG, their children must have at least 1 copy. This is in apparent defiance of Mendelian genetics, and is why HEGs are different from recessive traits.
When the HEG carriers reproduce with a non-HEG carrier, their children will develop normally, but carry the HEG on one of the chromosomes. They will live because they can use the gene on the other chromosome. But if a HEG carrier reproduces with another HEG carrier, the children will die, as they will not have a copy of the crucial gene, just two copies of the HEG. This delayed effect will mean that the HEG will be able to spread throughout the mosquito population without the carriers being negatively affected. This will be the case until carriers become predominant and start mating with each other. At such time, however, if enough carriers are in the population, a population crash could result as non-carrier reproduction becomes rarer and rarer.
Burt's article predicts that after 12 generations, 80 per cent of a population's offspring may be killed. This is if 1 per cent of the mosquito population are given the HEG and it copies itself to the sperm and egg cells in 95 per cent of cases. If the HEG can replicate in 99.9 per cent of cases or if more than one HEG is used, after 12 generations 99.8 per cent of a population's offspring will be killed. A mosquito generation may be as short as 3 weeks in tropical areas, which means that it may take only 36 weeks for near-extinction.
There would be a simple way for mosquitos to evolve resistance. Because the HEG will only home in on a specific DNA sequence, the mosquitos could simply evolve a gene that has a different, non-matching, sequence but performs essentially the same task. This could be avoided by using a number of HEGs, each targeting a different part of the same gene or targeting a number of different, but equally crucial, genes.
Resistance would only be an issue if the mosquitos were given enough time to develop it. A large enough release of HEG carriers would lead to such a swift population fall, this would hardly be an issue. It is worth pointing out that using HEG to control a population is fundamentally different from using a pesticide - it would not require repeated exposures over many years, just a single release of a batch of carriers. Given a large enough release, the chances of resistance forming can be minimised by making sure the population crash is swift.
The same development which could allow mosquitos to be resistant to HEG could be used to reverse the process once it has started. It could also be used protect other species in case the HEG somehow jumped species. By introducing a replacement gene, which is "immune" to the HEG, it would be possible to reverse any damage which had been done. The carriers of the new gene would have such a large reproductive advantage that the new gene should spread quickly throughout the population.
This proposal raises some difficult questions. Why would we want to stop with the malaria mosquito and not use the same techniques to remove other deadly pests? There are many other diseases carried by insects (Tsetse fly, West Nile virus). As we remove species after species would it may become a more acceptable option, until removing mere annoyances such as normal mosquitos or ticks would be a possibility.
Once we start wiping species out can we stop powerful interests groups from using the same technology and rationale to make extinct other species? Crop pests, for example, cause millions of dollars of damage (in lost crops and cost of control) every year. Many farming interests would see the HEG technique as a possible way to save money. There may be environmental benefits from avoiding the use of pesticides, but the risk of making species extinct should not be taken lightly. When there are such powerful economic interests in favour of such action, would it be possible to stop them?
The HEG is just one possible technique of many for controlling malarial mosquito populations. It should be considerably more effective and powerful than other techniques, such as the release of sterile males. It is also unproven, untested and entirely speculative. Additionally, the release of genetically modified animals is hardly a popular technique. However, the problem of malaria is so prevalent and widespread across the globe that the most powerful techniques in the scientific arsenal may need to be used.
There are more mundane solutions to the malaria problem: bed-netting can save lives. Removing and banning stagnant water in which mosquitos breed is another important public health measure. It is easy to forget the simple but effective techniques when technological "silver bullets" present themselves.
Malaria is a problem that we seem to have been inured to or have forgotten about. It doesn't have the novelty of murder, war or disaster even though it kills many millions of people every year. Yet it is an important and significant issue, both in humanitarian and economic terms. If malaria were to be wiped out, it would be a milestone in medicine and genetic technology.
The answer to this entire question may seem obvious to many: Of course we should use HEGs to eradicate malaria. But caution must be the rule when making such monumental decisions as the future of an entire species. At a time when many people are desperately trying to save species, to contemplate the destruction of even the most harmful species seems somewhat contradictory.
In any case, it would be the first ever animal species destroyed by people who had full knowledge of the possible consequences of such an action. Humans have made hundreds species on the planet extinct but in every case it was accidental, not a planned eradication. If we have it within our power to make species extinct, we bear an awesome responsibility. We must be sure not to misuse it for economic, rather than humanitarian, advantage.
New Scientist, 22 March 2003: Splat!, Oliver Morton