Controlling Malaria - Are GM Mosquitoes the Answer?

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...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.

UPDATE:  (August 2020):  Florida has just announced trial of genetically modified mosquitoes. 750 million Aedes aegypti, they carry several diseases such as Zika, dengue, chikungunya, yellow fever, will be released.  The mosquito, named OX5034, has been altered to produce female offspring that die in the larval stage, well before hatching and growing large enough to bite and spread disease. Only the female mosquito bites for blood, which she needs to mature her eggs. Males feed only on nectar, and are thus not a carrier for disease.  It will be interesting to see how the trial goes.

No news of any vaccines yet!

 I would love to hear your views about this topic of great public interest.  

Please comment here or write to ektalks@yahoo.co.uk

Space Colonization - A Realistic Assessment of the Current Status - A community Outreach Talk

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Space Colonization (SC) refers to permanent self-sufficient human habitation of locations outside the Earth.

There is much confusion about Space Colonization.  SC will happen when proper technology is available - we are not there yet - just now only Exploration  of near Space (SE) is possible; the international space station (ISS) has been doing a good job for almost 20 years.

In my outreach talk at Dumfries, Scotland on 3rd May, 2016, I have looked at SC and put it through the test mill of What?, Why?, Where?, When? and How? from the perspective of an inquisitive layman.  I conclude that we do not yet have the technology and financial resources for SC. There are many poorly understood science and human anthropology questions - radiation protection, sub-gravity effects,  psychology of living in isolation, politics of individual colonies - their interaction with each other and the Earth, economic viability of individual colonies etc. 

In the following, I publish the slides of my talk with some comments added to help continuity of presentation:
Click on a slide to view bigger image: 

The only way to start is by considering suitable places where colonization might be successful.  These are locations nearest to the earth in our Solar System - either in orbit around the Earth or on a rocky planet 

Some of the fundamental unsolved problems associated with long-term habitation in space are highlighted by a statement from Scott Kelly who returned to the Earth in March 2016 after spending 340 days in ISS.  

ISS gets all its supplies from the Earth at great financial costs.  Kelly's problems are personal problems related to human physiology and psychology.  There are many many other issues that need to be addressed - we shall come to these later in the talk.

An object on earth is attracted by a force directed towards the centre of the earth and equal to mass times the gravitational acceleration at the earth's surface (g=9.81 m/s^2). We feel this force as our weight.  ISS is on average about 415 km above earth and its distance from earth's centre is not much different than the distance when you are on the earth (6375 km).  So, g in ISS should be very similar  to g on earth's surface.  Why, then in ISS objects are weightless - they feel no gravity:

 In an orbiting satellite, the force due to its motion in the orbit (centrifugal force) balances the gravitational force due to the earth's attraction creating a zero gravity environment.  At Moon, Earth's gravity force is very small due to its distance from the earth. But objects feel a gravitational force due to the Moon itself - the force is only a sixth of what it is on the earth's surface because Moon is a much smaller body than the earth is.

Private enterprise is never very far away when it comes to making money.  Zero-g excites people and a company actually offers zero-g experience (lasting only about 25 seconds - repeated 20 times or so) for a cost. I show some amazing acrobatics one can do in zero-g in ISS.

Building an orbital colony seems like a good start - problem of weightlessness can be solved - people live along the rim of the colony in 1g environment.  The gravity decreases as you move towards the axis of the colony; gravity being zero at the axis.  This allows all sorts of recreational possibilities.
Building obital colonies will be easier than similar structures on earth as construction materials are weightless in space - they are easy to move and do not need to support much weight.  Because of its smaller gravity, transporting  materials from the Moon will be much easier and cheaper to use.  A mining enterprise at Moon will do the trick.

Ionising radiation in space is damaging to human health - high energy particles in cosmic rays cause damage to the genetic material (DNA). On Earth, we have the atmosphere that attenuates a large part of the cosmic radiation and provides us a safer environment to live.  An orbital colony or colonies  on Moon or Mars will not have this protective layer and inhabitants will be exposed to dangerous levels of cosmic rays.
The Sun produces solar flares which mainly consist of high energy protons.  Besides their biological effects, solar flares can cause serious disruption to electronic equipment etc. The Earth's magnetic field deflects and hence protects us from the charged particles in solar flares. Orbital colonies will, in most part be protected but colonies on Moon and Mars will not have this protection. 

FOOD:  Space colonies must produce their own food.  The food will be mostly plant based with possible fish farming. This should not be a problem as a vegetarian diet can provide a wholesome and interesting range of food.  In fact, humans have descended from the apes who in most part eat plant based food.  As vegetarians, we shall only be going back to our evolutionary roots and eating what human bodies were designed to do.

Some final thoughts:    In this talk I have restricted myself to a discussion of space colonization using the technology as we have at present. This is obviously a gross simplification of the subject as technology is moving forward at an exponential rate and capabilities of what we can do are bound to change very rapidly.  Robotic exploration and colonization of space is an obvious extension to what I have discussed here.  Robots do not require food or radiation protection or 1g environment.  This will already make the design of the colonies much simpler.  3D-printing will allow a population of intelligent robots to be assembled in the colony and less material will need to be transported from the earth.

Humans present a big problem.  They are competitive and love power and wealth. How will this be consistent with space  colonies living in peace with each other is a question, I do not have an answer to.  If the idea of space colonies is to ensure the survival of human race then this might be an unrealistic aim. What seems possible is that we can exploit the resources of space for making life on Earth more fulfilling and enjoyable.  It will be best if we can start to care and cherish the wonderful planet that we have inherited.  It makes no sense to destroy what we have and try to rework hostile space as our new home. 
See also

Will love feedback from you- please write to  - ektalks@yahoo.co.uk