Thursday, 26 May 2016

Controlling Malaria - Are GM Mosquitoes the Answer?


Blog Contents - Who Am I?

...there is serious concern that malaria parasites are once again developing widespread resistance to antimalarial drugs...

Malaria has been with us since prehistoric times and has killed more people than any other disease.  Some even claim that malaria has been responsible for the death of half of the people who ever lived - I find it difficult to justify. It is more likely that half of the people who ever lived contracted malaria.

Last year, 200-300 million people contracted malaria with 500,000 deaths. Controlling malaria must be our number one priority. Major efforts have been made in the past with some success - malaria cases have fallen significantly (500 million people used to contract malaria annually) in the past 100 years but it seems that they are rising again.  Figure from http://targetmalaria.org/why-malaria-matters/
(Click on a slide to view its full page image; press escape to return to the main text)



Malaria is common in Africa, Asia, South America and the South Pacific - home for over three billion people.  With increase in tourism and global warming, it is likely that malaria will also become more common in Europe and North America where cases of malaria are already happening.

Malaria is caused by a parasite.  Human to human transmission of the malaria parasite can only happen through mosquitoes.  The difficulty in controlling malaria stems from the tenacity of the parasite which can develop resistance to drugs rather efficiently; and of course mosquitoes fight their way through any measures used in the past to control their populations. 
To understand this better, we need to look at how the disease progresses in humans (and for that matter in other animals). Both the humans and mosquitoes are essential for malaria to spread.




Malaria may be controlled either by eliminating the vector mosquito or by killing/disabling the parasite.  Both methods have been tried in the past.  

Parasite Control:  The parasite may be made ineffective by using drugs. The slide lists the four main parasites that infect humans.
Unfortunately, all these parasites have developed resistance to antimalarial drugs and in some areas none of the known drugs are effective any more.  The situation is very serious. I refer to some detailed analysis in the Wiki.

Mosquito Control:  This is the subject that this blog is about.  As malaria spreads through mosquito bites, it can help if we can reduce the mosquito population by eliminating their breeding sites, their access to humans by using mosquito nets, repellents etc. or by killing them with insecticides.  All these methods are currently used and have helped in substantially reducing the cases of malaria infections. 
Mosquitoes have developed resistance to insecticides.  In the next slide, I reproduce the conclusions of a recent review 

Besides the traditional approaches mentioned above, there are other methods of controlling mosquitoes numbers. These methods depend on somehow affecting the mosquito reproduction cycle - either by using radiation or by genetic manipulation.  We look at these in the following: 

Sterile Insect Technique (SIT):  Sterile male mosquitoes are released in large numbers and compete with wild male mosquitoes to mate with the females.  Females that mate with sterile males either produce no offsprings or weakened ones which die prematurely.  This results in a reduction of total mosquito population.  Sterile mosquitoes are released repeatedly to control or even eliminate mosquitoes in the area.  
Sterile insects may be produced by nuclear or X-ray radiation. The problem with this method is that irradiation generally weakens the male insects and they are not  able to compete effectively with their wild counterparts in finding females to mate. Nevertheless, this method have had some notable successes:  For example, in the eradication of 
the screw-worm fly from USA, Mexico & Libya; the Mexican fruit fly; the tsetse fly from Zanzibar; the Mediterranean fruit fly from Chile, Peru & Mexico and the melon fly from Okinawa.
SIT may be summarized by the following slide.  In the slide R1, R2, R3 are three releases of sterile mosquitoes.



An alternate strategy might be to use genetically modified (GM) mosquitoes.  The beauty of a GM approach is that it is target specific and only affects the malaria transmitting Anopheles mosquitoes without harming other types of mosquitoes and insects.
There are two approaches that appear promising.  
1.  RIDL (Release of Insects with Dominant Lethality)
In RIDL, pioneered by Oxitec Ltd., male mosquitoes are genetically modified so that their offsprings die before they mature. There is a series of slides that explains the RIDL in detail.  I shall go over the method RIDL briefly but refer to the slides for details.  
To start with, it will be useful  to understand the mosquito life-cycle -- a mosquito has four stages in its development and takes about two weeks to develop from an egg to a functioning adult.
In RIDL, male mosquito is given a dominant lethal gene. On mating with a female in the wild the gene is transferred to the egg and prevents development of the adult mosquito.
So far, most work on RIDL has been done not on mosquitoes which spread malaria, but on the mosquito Aedes aegypti which is the vector for dengue fever. In spreading dengue only one mosquito species is involved and is a better candidate for field trials.
There have been several field trials of RIDL - in Great Cayman Island and Brazil where 80-95% suppression of wild mosquitoes populations were achieved over limited size areas.  




There is a well presented TED Talk by Hadyn Parry that introduces the background to dengue epidemic and comments on results of Oxitec trials.

2. Target Malaria Approach:  Target Malaria Group operates in sub-Sahara countries and has been developing genetically modification techniques for controlling the mosquito species Anopheles gambaie which is the active vector in the region. 

The method works along the following lines:   
Some single celled organisms produce enzymes, called nucleases, that can cut specific sequences of DNA.  
When introduced in the malaria mosquito, these nucleases identify and cut through essential genes, such as fertility genes targeted or genes key to pathogen transmission.  The interrupted genes will no longer function.
Two of the main areas the researchers are currently focusing on are biasing the sex ratio of mosquito populations and reducing female fertility with the aim of controlling the female mosquito population and hence the incidence of malaria infection.  
Biasing the sex ratio:  The idea is to decrease the number of female mosquitoes relative to males.  The sex determining chromosomes are XY for males and XX for females.  In order to produce female offspring, two functional X chromosomes - one from each parent - are required.
Nuclease enzymes (image 1) identify (image 2) and cut through several key sites on the X chromosome in the sperm of male Anopheles gambiae which leads to a fragmentation of this chromosome (image 3). When these males reproduce, they can still pass on a functional Y chromosome to their offspring, but they cannot pass on a functional X chromosome due to its fragmentation (image 4). This results in a bias toward male (XY) offspring.
The team at Imperial College, London in June 2014 successfully distorted the sex ratio of a laboratory population, as over 95% of the offspring produced by modified Anopheles gambiae were male, with only 5% being female (see the following two slides). By comparison, under normal circumstances, a 50:50 split between male and females would be expected, meaning that the GM modification reduces the number of females produced by 10-fold.


Reduce Female Mosquito Fertility:  This strategy focuses on using nucleases to knock out genes that are key to fertility in female Anopheles gambiae mosquitoes. The approach could significantly reduce the prevalence of malaria because the number and productivity of females in a population determines future population size. 
In order to knock out female fertility genes, the nucleases are designed to identify the specified genes and cut through them. When this stretch of DNA is repaired, the nuclease gene is copied and inserted into the cut site, interrupting the original gene and preventing it from working properly.
A female that has one copy of this fertility gene disrupted will be able to reproduce normally, but when both copies within her chromosomes are disrupted, the female cannot produce viable offspring.
The team at Imperial College has designed these nucleases so that they are only active in the cells of the mosquito that make the sperm and the eggs. Due to the preferential copying mechanism of these nuclease genes in the sperm and eggs, an individual initially containing only one copy of the gene will transmit it to many more offspring than normal.
As fertility genes are fully disrupted in females that inherit two copies of the nuclease gene, this should lead to an overall reduction in the population.
Looking Forward:  GM mosquitoes, as described above, hold great promise for controlling malaria.  GM is species specific and targets only the vector population leaving other mosquito species totally unaffected. There is disquiet about releasing GM species in the wild as one can not predict with absolute certainty how it will affect the rest of the biosphere. In the case of RIDL GM mosquitoes, they die after a few weeks and the GM genes die with them.    
It appears that the GM methods are relatively safe.
One also needs to weigh the situation when millions of people are infected by malaria every year which results in great loss of economic activity and loss to the communities. This level of tragedy must be addressed and it seems to me that the negative arguments against GM are weak in this case.
Another alternative that I have not discussed here is the development of a malaria vaccine. In January 2016, WHO published the status report  and it is not clear that a malaria vaccine would be available for wider use in the near future.
What seems a sensible strategy at present is to develop the GM technology which appears to hold excellent promise at least for limited area eradication of malaria.  The traditional method for mosquito population control like spraying, and avoiding exposure to mosquitoes like medicated mosquito nets along with traditional parasite control medication must be used in conjunction with control of mosquito populations using GM technologies.

I acknowledge some very willing support from Dr Luke Alphey, formerly of Oxitec Ltd. and Dr Tony Nolan of the Target Malaria Team at Imperial College, London.  This has helped me to understand the subject better, make it more accurate and improve this blog feature.

I would love to hear your views about this topic of great public interest.  Please write to ektalks@yahoo.co.uk
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