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Innovators 2014 part one – Luke Alphey and Oxitec

Innovators 2014 part one – Luke Alphey and Oxitec - 14 April 2014. CDC/James Gathany

BBSRC Innovator of the Year 2014 winners reveal the secrets behind their innovations in the first of three articles.

In this, the first, Overall Innovator winner Professor Luke Alphey of The Pirbright Institute recalls the ups and downs of his journey to combat dengue fever using genetically modified mosquitoes. In the second, Commercial winner Dr Curtis Dobson from the University of Manchester explains how work on infections and Alzheimer's disease led to a new class of anti-infective compounds. And in the third, Most Promising winners Professor Cathie Martin and Dr Eugenio Butelli of the John Innes Centre provide the lowdown on the world of purple tomatoes.

How does it feel to win?

I'm very excited to win. You could see from the other finalists the wide range of outcomes from BBSRC-supported work, which is fantastic for UK bioscience. It would be interesting to be a judge and look at such different things. And anyone listening to my speech would realise I had not anticipated winning!

Professor Luke Alphey wins the Innovator of the Year Overall prize, netting £15,000 and a further £15,000 for his department. Image: Tim Gander
Professor Luke Alphey wins the Innovator of the Year Overall prize, netting £15,000 and a further £15,000 for his department. Image: Tim Gander

Describe your innovation in your own words…

I've been working on genetics-based methods to control pest insects. Insects do a huge amount of harm: mosquitoes transmit malaria and dengue fever, pests attack agricultural crops and livestock, and insects transmit disease-causing bacteria and viruses between all sorts of plants and animals.

On the other hand many insects are beneficial to humans, such as bees pollinating crops, and many more are harmlessly making their own way in the world and being part of an ecosystem. So we want ways to control pest insects while not harming neutral or beneficial insects; controlling what you want to control using the lightest possible touch without harming the rest of the ecosystem.

What are the benefits of your system?

An advantage of genetic systems is that they are based on releasing modified males of a specific species, Aedes aegypti, that will not mate with anything else. So the nature of the method makes it more targeted, because the males seek out the biting and disease-carrying females for you. Compare that with chemical control – you can't get a chemical to seek out the target insect and you can't make it as specific.

Where did the idea come from?

There are a number of people working in this area, and we wanted to improve upon the irradiation sterile release technique [when males are sterilised by radiation before release] which has been around for 50 years. You want the insects to be successful in competing for mates. We don't know what makes a sexy mosquito, but a sterilising dose of radiation is unlikely to help – it tends to reduce their fitness and survival and for many pest insects it's hard to find a level of radiation that doesn't weaken the mating fitness of the insects too much. So essentially we wanted to achieve the same outcome using genetics and not radiation.

Only females of the Aedes aegypti mosquito species carry disease. Image CDC/James Gathany
Only females of the Aedes aegypti mosquito species carry disease.
Image CDC/James Gathany

What stage is the technology at for your Aedes mosquito?

We've had success in field trials in the Cayman Islands, Brazil, and each time seen a 90%-plus reduction in mosquito numbers – 96% in a major trial in Brazil which models suggest should be enough to prevent epidemic dengue anywhere in the world.

If you have someone with virus and just one mosquito then theoretically there is a chance of getting a secondary case [the disease reappear], but from public health point of view you want to stop epidemics, and with this degree of suppression there would not be enough mosquitoes to sustain an epidemic density.

We now have a larger operation pilot study in Brazil which is going well. In a town of 50,000 people our Brazilian collaborators are releasing half a million males a week. Every time we've done this it's always with local partners, in Brazil it's a university and social company, and always with oversight from the national regulatory authorities.

How important has BBSRC funding been?

Well, really every step of the way. The original research came from the University of Oxford and was supported by BBSRC grants and CASE Studentships, which we found very useful for getting very good PhD students in to work on certain problems and link us to university academics. We also had SBRI grants when that was a BBSRC scheme, as well as more recently from TSB [Technology Strategy Board], and several BBSRC stand-alone LINK grants, which bring expertise from universities to apply to the problem.

For example that's been a fantastic route to get academic experts to use mathematical modelling to analyse what effect release of our RIDL males would have on the effect of the insect populations, and what effect that would have on disease transmission. Modelling lets you explore a whole range of possibilities faster and more efficiently than you can do experimentally. So we've had LINK grants for that. As a small company Oxitec is absolutely the best in the world at its core activity and core science, but we don't have such expertise in these other areas, we can't do everything.

We also received a BBSRC-TSB joint award on synthetic biology. Overall the variety of grants and schemes make a flexible portfolio.

What other funding have you pursued?

Another good thing about BBSRC involvement is that it's very helpful when we go to venture capitalists for investment funding. They want to know if the technology is good, so to have support from the likes of BBSRC, the Wellcome Trust and the Bill and Melinda Gates Foundation is really helpful validation – everyone knows those agencies look very carefully at the science before they support it. And it helps the venture capitalists too they are very good at understanding the business model but might struggle to weigh up the merits of the science.

Are you the first to have used GM insects in this way?

Yes, we're the first people let alone the first company. There are others working in the area, but none have got to the field trial level.

Dengue patients receive treatment in Thailand hospital. Image: Sanofi Pasteur on Flickr
Dengue patients receive treatment in Thailand hospital.
Image: Sanofi Pasteur on Flickr

What kinds of problems have you encountered along the way?

You have to talk to the different stakeholders all the time to try and explain what you're doing. When you go to a dengue endemic country people know it's a huge problem and that current control methods are inadequate. Governments know that and the people know that and that provides a shared ground for discussing a potential new control tool.

I think one of the problems for GM crops, in the past in Western Europe, is that back when they appeared it wasn't that obvious to the individual consumer what the point was. We were used to a supply of clean, cheap and safe food, so for a few pennies off… what's the benefit? Of course there are wider benefits but they are rather invisible. But for dengue I think it's a completely different situation.

What kind of criticisms do you get?

People get to the ecological questions very quickly. For example, does the mosquito do something good that we don't realise? Would we miss it if it were gone? Which is a sensible ecological question for regulators to ask and people will too. And the answer is very case specific to where you are, the insect and where it is… a different insect in a different place might yield a different answer.

In many areas in South America and Asia the dengue mosquito, Aedes aegypti, which we aim to control is actually an alien species. It's from Africa and was inadvertently spread around recently by humans. It now infests town and cities with human populations, but this is a relatively new phenomenon. And the alternative controls, such as spraying and fogging huge quantities of insecticide that will definitely kill beneficial insects, these can cause huge problems for biodiversity and conservation. So even for an ecologically sensitive area needing minimal off-target impact I can't think of a better method.

What do you say to opponents of GM that criticise your technology?

Come and talk to us! There are a number of different objections and I spend a lot of time engaging with people about why it's an appropriate and sensitive approach in the specific situations we use it. Some common concerns regarding GM crops don't really apply to us – in plant GM some are concerned that the field is dominated by very large multinational companies, but that doesn't describe Oxitec! Others are concerned because they don't want private companies involved in human health, but when vaccines are used someone is paying for it: the needles, the gloves, the vaccines themselves are all made by the private sector on a for-profit basis.

Warning poster for Dengue fever which is endemic in many developing countries. Image: Ming Xia on Flickr
Warning poster for Dengue fever which is endemic in many developing countries. Image: Ming Xia on Flickr

Did you have a 'Eureka!' moment when you thought of this approach?

This came out of a chance conversation with a teaching colleague at university who had been involved with the radiation-based method. I realised I could apply the genetic and molecular tools of my fundamental research to this problem. And I knew what I wanted to do, in terms of the genetics very quickly, although it took a lot more work to do it.

In our first small experiment in the Cayman Islands, I did wonder if our lab-reared mosquitoes would be able to successfully find and mate wild females in the real wide world; after all they had been bred in captivity for 100 generations, thousands of miles away in the UK, never having encountered predators or needing to fly more than 30cm to reach a mate or food source. As well as the lethal gene our males carry a fluorescent marker gene so we can see where they go – and we can detect this in the eggs from females they mate. So when we found some eggs carrying this fluorescent gene after we first released our males that was really exciting – it showed that those released males had indeed been able to find and mate wild females. That was crucial – if they couldn't have mated we would really have had to go back to the drawing board – but it worked and showed the technology worked in the field.

Being in the Caribbean did you celebrate with a few rums?

Ah… I couldn't possibly comment! Yes it was a big day.

What made you want to get into science?

I always wanted to be a scientist, from as long ago as I can remember. I had an outstanding biology teacher at 'A' level, so that is probably why biology rather than maths or physics. Science is about "how does the world work?" and I've always been interested in that.