Unrevised

Members present

Earl of Selborne, Chairman

Lord Cameron of Dillington

Lord Fox

Lord Hennessy of Nympsfield

Lord Kakkar

Lord Krebs (co-opted)

Baroness Manningham-Buller

Lord Maxton

Duke of Montrose

Baroness Morgan of Huyton

Baroness Neville-Jones

Lord Patel (co-opted)

Lord Peston

Viscount Ridley

_______________________

Lord Taverne

Examination of Witnesses

Professor Luke Alphey, Head of Arthropod Genetics Group, The Pirbright Institute; Professor Paul Eggleston, Professor of Molecular Entomology, Keele University; and Professor Austin Burt, Professor of Evolutionary Genetics, Imperial College London

Q48 The Chairman: Welcome to our three professors who have kindly joined us today. We are most grateful to you. I am sure you are aware of the inquiry we are conducting on GM insects. Today we hope to hear particularly from you about the science behind GM insect technologies. You need to be aware that we are being broadcast on the web camera. Would you like to introduce yourselves and if anyone would like to make an introductory statement, please feel free to do so?

Professor Luke Alphey: Thank you for inviting me to your inquiry. I am Luke Alphey. I lead the arthropod genetics group at The Pirbright Institute. I know from previous hearings that you are aware of Oxitec. I co-founded that company in 2002. I was the research director there until early last year, and then a board member until the recent acquisition by Intrexon. Also, I have been involved in regulatory affairs and public engagement in various countries, including in the recent EFSA and WHO deliberations.

Professor Paul Eggleston: Good morning and thank you for inviting me as well. My name is Professor Paul Eggleston; I am professor of molecular entomology at Keele University and currently faculty research director. My background is very much in genetic engineering technologies for insects, predominantly mosquitoes.

Professor Austin Burt: Good morning. I am Austin Burt, professor of evolutionary genetics at Imperial College. I am also the principal investigator for Target Malaria, which is a not-for-profit research consortium trying to develop novel approaches for malaria control.

Q49 The Chairman: Thank you for that. If none of you wishes to make an introductory statement, I will start with a very general question. I am sure you will have noted from earlier evidence sessions that we have been informed of some of the underpinning science. Could each of you give us your understanding of the underpinning science behind population suppression? We will come to population replacement later, but if you could give us your version, in as clear a way as you can, as to how population suppression GM insect strategies might be underpinned by science?

Professor Luke Alphey: In the underpinning science there is a great deal of overlap between suppression and replacement. In each case you need to be able to make modified insects using transformation technology. Associated with that is the ability to rear the insects, sometimes in quite large numbers, and handle them in the lab, which is not the case for all insect species.

Of course, for population suppression you are trying to impose some sort of fitness load. You are trying to put some sort of lethal, sterile or perhaps sex ratio-distorting factor into the target population.

On the underpinning science for using these sorts of systems, what I have talked about there is more on the molecular biology/synthetic biology side—what sort of modification you want, what trait and how you are going to construct that. You could turn that around and look at it more from the field point of view, and say it is applied ecology, population genetics and population dynamics and how you are going to interfere with the target population, and that the synthetic biology aspect is merely the nuts and bolts, or cogs for the machine that is going to do that. So there are a number of ways of looking at it, and the underpinning science for all of that is pretty general. Most of it was developed not for these particular applied purposes but drawn from fundamental science carried out for other reasons.

The Chairman: Could you give us an indication as to how long ago this might have been implemented originally?

Professor Luke Alphey: Radiation-based sterile insects have been used for at least 50 years. There is a paper on population replacement from 1968, long before molecular biology, so these ideas have been around for a long time. It is one of the areas perhaps where theory is somewhat ahead of practice in synthetic biology, which is not that common.

Lord Fox: Turning to the other side, population replacement, what is there in addition, or that is different, and how will the effect of gene-editing techniques change the game for you?

Professor Paul Eggleston: On population replacement, as Luke has already mentioned, a lot of the basic underpinning science is the same. The intention with population replacement is to make a change to the insect and then try to force that altered insect into the natural environment to replace what was there before. The idea would perhaps be that you change a population of mosquitoes that was capable of transmitting disease for one that was not. A key difference here is that the insects would remain within the environment.

A key difference in the underpinning science here is that when you make the sorts of changes that we are talking about in a genetically modified insect, the end product is likely to be less fit, in a Darwinian sense, than what was there before. There is an argument that we may well need to alter the strategy for the release of these modified insects by using something that has become known as a gene drive system. Put very simply, that means, instead of having normal genetic inheritance, you bias the inheritance in favour of retaining the modified insects as opposed to the natural ones. By doing that you can change the nature of the population and, in theory, cause the modified insects to spread.

There are fundamental differences in the genetics and the ecology, but one key difference is that you would not end up with an empty ecological niche. You will have insects there at the beginning and at the end, and therefore food supplies for organisms that eat those insects.

Lord Fox: Do gene-editing techniques change what you can do and give you more things you can change?

Professor Paul Eggleston: It provides another set of tools we can use. There will be applications in which it might be particularly useful and there may be other applications where, I hesitate to say, more traditional genetic engineering techniques might still be preferable.

Lord Fox: It opens up more opportunities?

Professor Paul Eggleston: It opens up more opportunities, yes.

Professor Austin Burt: I want to clarify, this distinction between suppression and replacement is orthogonal to the issue of whether you drive something through or you inundate a population. You can do inundation with either replacement or suppression, and you can do inoculative drive with either replacement or suppression.

Lord Fox: In one case you flood the population.

Professor Austin Burt: Yes, inundate.

Lord Fox: In the other, you weigh the balance in favour of the genetics and the trait you want.

Professor Austin Burt: In the other one, you release a relatively small number and then over a period of generations that triggers a response.

Lord Fox: Because you bias the survival rate or whatever.

Professor Austin Burt: Each of those implementation modes—inoculation versus inundation—can be used for suppression or replacement, although I think a better term would be modification.

Professor Luke Alphey: To expand on what Austin was saying, you think of the outcome you are trying to achieve, whether you are trying to reduce or eliminate the number of the target population—that is suppression—or you are trying to modify them in some way, such as spreading a trait through the population that makes them less likely to bite humans and less able to transmit malaria or insecticide resistance; any trait that you may want to spread, short of killing them. The one we talk about most is to make the mosquitoes less able to transmit a pathogen, for example dengue virus.

Replacement looks similar: you still have mosquitoes out there filling their ecological niche, biting people, but less able to transmit disease. In suppression, the outcome is there are far fewer mosquitoes, perhaps none, and that is how you control the disease. How do you go about doing that? As Austin said, in either one you could have a so-called self-limiting genetic system that only stays out for a relatively short period of time, unless you supplement it by releasing more, or you could have a more invasive, or self-sustaining genetic system that will persist for a long time, perhaps increase in frequency locally and spread geographically of its own accord.

Lord Krebs: Following up on Professor Burt’s comment, as we look over the next decade or so, do you feel that the two approaches you describe—inundation and inoculation—are going to be pursued in parallel or do you think that eventually, one will come to be shown to be more effective than the other?

Professor Austin Burt: I imagine there will be different purposes for each one. For malaria in rural Africa, an inoculative approach would be very powerful. In other more confined settings that you want to target, an inundative approach would be fine too. It depends on the goal, the disease, the setting and the target.

Baroness Neville-Jones: I want to be clear, in these various techniques you have been talking about—inundation and inoculation—are we talking about actual use already or field trials or laboratory experiments? I want to know exactly what is happening and how far these things have been taken in practice.

Professor Austin Burt: Oxitec has carried out field trials of inundative releases of mosquitoes. No inoculative release has been done. There have been proof-of-principle experiments in the lab but no field release.

Viscount Ridley: Are there some insects for which population suppression will not work? As I understand it, it is based on the Sterile Insect Technique, whereby once an insect has mated it cannot reproduce, as it were, or the female would not go back and try again to reproduce. Are there some for which that technique will not work?

Professor Paul Eggleston: There are some for which it would be more difficult. It highlights something we have touched on a little bit. All of these strategies depend on insects breeding. If you are planning any release of this kind, you need a pretty good understanding of what the breeding structure of those populations might be. For example, mosquitoes that are transmitting malaria in Africa exist in nature in ways which might make population suppression quite a difficult route to take and may favour the choice of a population replacement strategy. It depends very much on the biology, the breeding patterns and the population structure of the insects you are working with.

Viscount Ridley: Can you give us an idea how much more effective at suppressing populations GM insects could be than the conventional irradiated Sterile Insect Technique?

Professor Luke Alphey: Compared with conventional approaches as well—it is hard to make a direct comparison with radiation. The radiation Sterile Insect Technique worked very well in some particular species—New World screwworm, Mediterranean fruit fly—and these are ones where it has been possible to find a sterilising dose of radiation that does not weaken or incapacitate the insects too much. That has proven difficult with mosquitoes. With some insects it would be very difficult to run an effective, or at least economic radiation-based sterile insect programme at all. Compared with other conventional methods, an expert mosquito control district estimated that, with the best of current methods, they could suppress Aedes aegypti by 30%; if they hit it with absolutely everything, maybe 50%.

Viscount Ridley: This is using pesticides?

Professor Luke Alphey: Yes, using pesticides, chemicals, breeding site restriction and that sort of thing. All of Oxitec’s field trials, even on a relatively small scale, have shown more than 90% suppression of the target mosquito populations.

Lord Maxton: Is it very largely mosquitoes you are talking about, or have you done trials with other insects as well?

Professor Luke Alphey: It is certainly not only mosquitoes, although they get most of the attention. A range of agricultural pests is certainly in development and either in or approaching trials. In fact, the first Oxitec collaborative field trial of GM insect release anywhere in the world was in Arizona, of a pink bollworm, which is a moth that attacks cotton, so it is not just mosquitoes.

Of course, that also comes back to which approach is more useful. As I said, for population replacement the most commonly talked about modification is something which will make a mosquito less able to transmit disease, and clearly that is appropriate for plant disease vectors, and animal as well as human ones. You can imagine doing that. If you think about the caterpillars which eat your cabbages, the damage they are doing is from direct feeding and it is not obvious what trait you would try to spread which would reduce that harm. Population suppression seems a more obvious approach to take in that case than for something that is transmitting a disease. Again, the nature of the insect and the harm it does might point you more to one strategy than another.

This comes back to what Austin said earlier. There are some cases where you want to treat a particular population and not another one, perhaps even nearby, and there a spreading system would be less appropriate. There are others where you have a very diffuse population and the economics point towards something that will spread itself. So all of these approaches will likely co-exist going forwards.

Q50 Lord Krebs: If I could change tack slightly, I want to ask the witnesses about the evolution of resistance and whether they think that is a significant concern with any of the techniques that we have been discussing and, if so, what consequences it might have for efficacy or the environmental risks.

Professor Paul Eggleston: Can I just clarify what you mean by resistance in this context?

Lord Krebs: I will give you an example. The Wellcome Trust says: “Resistance would be expected to evolve both to the drive mechanism (eg mutations in the genomic region you were targeting making the drive mechanism ineffective) and towards any genetic trait you were modifying (eg the ability to resist a particular pathogen).”.

The Chairman: Target malaria, too, identified that resistance to the gene drive mechanism might arise.

Professor Luke Alphey: Resistance is an issue for any technique—and you can finish the sentence there—not just the ones we are discussing here.

Lord Krebs: Yes, but obviously we are particularly interested in the ones we are discussing.

Professor Luke Alphey: My point is, yes, certainly it is an issue for these methods but in no way uniquely to these methods. Clearly, it is also an issue for chemicals or whatever. Aedes aegypti breeds in a particular type of container and you could fill it with concrete and it would evolve resistance to that, not by breeding in concrete but by changing its breeding sites and so on. It is a very wide issue. If you think about engineered sterile insects, you could imagine a situation where you are putting some sort of fitness-reducing gene—lethal, sterile or whatever—into the population, and that is generally the case for population suppression. You could imagine ways in which an emerging genetic factor in the wild population could make that sterilising or fitness-reducing effect less effective. You could also imagine more of a behavioural response. If the wild females, let us say, can differentiate between modified and unmodified males, there would be strong selection for ones that preferred to mate with the unmodified ones.

Lord Krebs: Certainly, I recognise your comment that the evolution of resistance applies to any technique that is used to control pests in the natural environment or elsewhere. Do you have any insight as to whether evolution of resistance is more or less likely to occur in, let us say, RIDL technology or in the kind of technology that Austin Burt has been developing using genetic drive, or can one not say at this stage?

Professor Luke Alphey: The fewer moving parts of a sterile insect method, the less prospect of resistance. Because you are releasing new batches repeatedly, you can monitor and also change things relatively easily.

With population replacement, where you have a drive and then separately a beneficial trait that you are trying to spread through the population, you have more separate parts that could become detached or stop working. One of the really elegant things about what Austin has been doing is using the drive directly so there is no additional beneficial trait to it, which reduces the number of working parts and reduces the possibilities for resistance, but Austin can talk about that better than me.

Professor Austin Burt: Overall, I would say it is too early to say whether resistance is more or less likely to evolve compared to a chemical. What I would say is that when you get resistance to a chemical, often it is a whole class of chemicals that they become resistant to, so that takes them off the table. There is a possibility that the genetic approaches will lead to resistance to a specific construct, and by tweaking the construct it would be able to get around the resistance. However, that is a hunch, not something we have proved.

Professor Paul Eggleston: In some ways we have talked about two different kinds of resistance there. The first is the breakdown of genetic technology, which could happen in a variety of ways. If you think instead, for example, of engineering an insect with a molecule that is designed to kill a parasite or a virus, then the parasite or the virus can evolve through natural selection and develop resistance to that particular intervention. The way that we might need to get around that problem is thinking of slightly more complex strategies. I usually think of them as multi-hit approaches so that you do not have all of your eggs in one basket. It would be more difficult for an insect to evolve a resistance mechanism to. It is analogous to using combination drug therapy for pathogens.

Lord Krebs: Could you unpack that a little bit further and tell us what the complementary approaches might be?

Professor Paul Eggleston: I will use my own work as an example. If you are trying to engineer an insect to introduce a molecule that will kill malaria parasites, for example, there are a variety of ways you could do that, but if you chose just a single way and built your engineered insect with a single trick that killed parasites, then those parasites are really quite adept at evolving ways around blockages in their transmission. A single intervention such as that may be something that parasites could work their way around. If you engineered your insect with two or three independent approaches that tackled the parasite or the pathogen from a number of different angles, it would be more difficult for those parasites or pathogens to evolve resistance. It is similar to combination drug therapy.

Lord Peston: Could you clarify one thing? The fact that resistance develops, it does not follow logically, or for that matter ethically, that you should not do it, does it?

Professor Paul Eggleston: No, as scientists we would all agree.

Lord Peston: It simply makes the problem more difficult and there may be different ways of dealing with it. I understand from the drugs that most of us take—a drug such as penicillin was the greatest boon, and if it had only come earlier it would have saved George Orwell’s life. But it is the bacteria that develops the resistance, so the pharmaceuticals have to go on spending tons of money inventing new antibacterials, but that is what they are supposed to do. Does the same logic apply to your field?

Professor Paul Eggleston: Absolutely.

Lord Peston: You would not like to leave the message, “Let all these people die because resistance develops”?

Professor Austin Burt: Quite the contrary, resistance evolves because you are having an effect.

Lord Peston: I just wanted you to say it.

Lord Fox: Professor Eggleston, you were touching on what I wanted to speak about. It seems that inoculation gives you more and different tools. If you are going to have a multiple set of things within your organism, rather than inundation, it is inoculation where you have multiple choice, in a sense; is that wrong?

Professor Paul Eggleston: I do not think that is necessarily true. The strategy you adopt is worked up in the laboratory. You develop an insect with a range of attributes that you think might be useful for controlling that disease, for example. Part of that strategy has to be to make a decision on how you intend to deploy it. If you intend to deploy it as an inundative release, you would not need to couple it necessarily with a drive mechanism, although that might help, but I do not think it makes a difference in the way you have suggested.

Lord Patel: While it is interesting to go into this debate, we are now indulging in pretty speculative science. The science of resistance on population reduction is understandable because we know where the science is, but when we talk about trying to change the genome of an insect in several different ways to increase its resistance or ability to be an effective vector, let us say for malaria, the amount of genome you are changing is so great that you are creating a completely new organism. Can you give us some examples that will work?

Professor Paul Eggleston: If you wanted to, you could build a piece of DNA in the laboratory that was designed to do two things. It could express a protein in the mid gut that damaged parasites or you could have a different protein that was expressed in the salivary glands. These are key regions where malaria parasites, particularly, are moved around. This could all be engineered as part of a single construct. It might be a relatively large construct.

Lord Patel: Exactly.

Professor Paul Eggleston: Then it could be introduced at one particular place in the genome of the insect, so that it does not change the rest of the biology of the insect.

Viscount Ridley: What do you mean by relatively large—1% of the genome?

Professor Paul Eggleston: No, tiny—tens of kilobases of DNA. Small in relation to a genome.

Professor Luke Alphey: You are talking about 10,000 or 20,000 bases for an organism such as Aedes aegypti, which has 1.4 billion bases, something like that.

Professor Paul Eggleston: A tiny fraction.

Professor Luke Alphey: Another way of looking at it would be, two or three functional genes in organisms that have tens of thousands of functional genes.

Professor Paul Eggleston: We already introduce multipart cassettes, and so you could have an effector gene designed to kill malaria parasites, for example, and a different part of that construct would be a marker gene designed to produce fluorescence so you could identify the modified insects. It is a relatively straightforward path.

Lord Patel: Can you explain to me about a vector, let us say, for carrying malaria? You are altering its gene to kill the bacteria or virus, for any disease but let us say malaria. An insect is just a vector and it is not affected by the disease itself, so you modify the insect to be not just a carrier or a vector but to deal with the disease-carrying parasite.

Professor Austin Burt: There are two approaches that have been taken here. One is to put in an effector gene, so an antiparasitic peptide that will put a hole in the membrane or a single-chain antibody that will coat the parasite in a particular way and which will impede its progress through the mosquito. That is to put something additional into the mosquito which disrupts the parasite. Alternatively, you can remove or try to knock out a gene in the mosquito that is useful but not essential for the mosquito but is essential for the parasite to get through the mosquito. For example, there could be a receptor in the mid gut that is recognised by the parasite and is needed to get through the mid gut, or a receptor in the salivary glands that is recognised by the parasite to get through into the salivary glands. You could add something to the mosquito and work on that and see what can be found, or you can try and knock out a gene in the mosquito which then renders it unable to transmit the malaria.

Professor Paul Eggleston: Either way the insect would cease to be a vector. In the case of malaria, if you have an intervention that stops sporozoites getting into the salivary glands, when that mosquito bites someone they will not get malaria. You are tackling what is a very complex parasitic disease with stages in insects and in humans by tackling it in the insect, which is possibly a better way of doing it than by tackling it in people, where you have billions of circulating parasites. There are much smaller numbers inside a mosquito and it is perhaps easier to kill them off there.

Q51 The Chairman: There is public concern about resistance. Everyone is familiar with the concept of chemical insecticides becoming ineffective and whole classes of compounds no longer being effective. What you are proposing is recoded, modified interventions, whereas perhaps a vector develops resistance so you remodify, as I understand it. Is this not yet another version of the arms war? Should we not be as concerned?

Professor Paul Eggleston: It is absolutely a version of the arms war but any kind of intervention against vector-borne disease is an arms war. None of us working in this area would think of these technologies as being the sole solution or a magic bullet. They are always going to be part of an integrated set of approaches which, for example with malaria, will include bed nets and insecticide treatments and everything else we can throw at it, but GM technologies might just add another range of tools. However these things are deployed, there is going to need to be monitoring and surveillance of how the genetic changes are faring in the natural environment. If there is evidence of some kind of breakdown, or a deletion or some kind of rearrangement that stops it working, I do not think that makes it necessarily any more risky; it just stops it working, so you have to have another release strategy in train to bring forward and help with the disease transmission.

Q52 Viscount Ridley: Can I change the subject to commercialisation? Professor Alphey, you have built up a very successful business around population suppression. How far away is the prospect of doing the same around population replacement? As a corollary to that, is there even a business model that works because one of the problems, as I understand it, with population replacement is that you only have to do it once. If you release it once you have solved the problem and you can go home. Is there a viable business model there?

Professor Luke Alphey: I doubt that we will do it once and solve the problem and go home. That does not mean there is not a viable business model—I do not think any of us is claiming that—I think there is, but in particular circumstances or for particular types of insect. Where you are looking at the more extreme invasive genetic systems where you are seeding them across an area and then they will spread through the whole species or species complex—Austin can talk about this better—it is hard to see anything other than a philanthropic or government basis for that. It is hard to see a conventional revenue-generation business model for that. There are other population replacement or gene drive-type systems which are anticipated to be more local, so you can treat one area and not another area, and it will persist in one area but not spread to another, at least in simulation models. There you might easily see a more conventional business case and therefore more private sector involvement. As you say, the one-time release big impact will still need monitoring and maintenance and perhaps the development of replacements and so on for it, if and when it breaks down, but I think it is hard to see a commercial business case for those more invasive genetic systems. However, that is not every case.

Viscount Ridley: Is someone going to be selling gene drive population replacement at some point, even if only for the Gates Foundation to apply or whatever? Is that going to be at the point where we are using it in the near future?

Professor Austin Burt: For those of us working on gene drive for population suppression for malaria, we do not see a business model where there can be a profit generated from it. We are not going down that route at all.

Viscount Ridley: But you do see application in the near future?

Professor Austin Burt: Yes.

Viscount Ridley: Give us a timescale, if you can.

Professor Paul Eggleston: Five to 10 years.

Professor Austin Burt: I think our Gantt chart gives a timeframe of 2028-30, something like that, when we might get rollout in a country. There is huge uncertainty on this. A lot of it is over the regulatory aspect and how long that is going to take. This is a long-term thing. It is not happening tomorrow.

Q53 Lord Patel: I will take my question in stages and it relates to safety issues. I am sure you are all familiar with the kind of concerns that are raised on safety issues, including horizontal gene transfer, damage to ecosystems, the production of virulent strains, et cetera. Which ones do you think should be of most concern?

Professor Luke Alphey: They are all legitimate issues to look at and all of these have to be looked at on a case-by-case basis. Not just in the case of a regulatory agency but, as developers of these technologies, we would ourselves look at as wide a range of risks, or potential hazards I should say, as we can imagine, and go through them one at a time and think how feasible they are and to what extent we can get around them by design. Resistance relates to that. Some designs would be less amenable to resistance evolution than others. One of the good aspects of some groups opposed to these kinds of technologies is that you get an external, sceptical eye cast on this which can potentially provide things that people who are more favourable to the technology may not have thought of, at least in principle. You get as large a list of these things as you can, which will include all the ones you have suggested and more, and then for your particular case or application go through them and think how feasible they are—if they are feasible—what you can do to mitigate them and how that relates to the benefits and so on. To go through such a list here is inevitably going to be rather superficial.

Horizontal gene transfer, which has been talked about a lot, is probably not such a big concern. A lot is known about natural horizontal gene transfer and it seems unlikely to be a major issue for any of the technologies that we are talking about here.

The impact on the ecosystem is probably the biggest area of discussion—and that is, “What if it works?” as well as “What if it does not?”, but especially, “What if it works?”

For population suppression, if you eliminate the target species from a particular location, is that a good thing? It is probably a good thing in some ways, such as reducing disease transmission, but does it open a niche for another intake to come in? Does it have some disruptive effective on the ecosystem? The answer could be dramatically different, even for the same species, in one place than in another. If you imagine an island over here where it is an alien invasive species relatively recently introduced, you might imagine eliminating it to be an environmental benefit, in addition to any reduction in disease transmission there might be. However, in this other place over here, in its native range where perhaps the same species is a more integrated part of the ecosystem and is providing some ecosystem functions, eliminating it might be much more of an issue from an ecosystem point of view than over there. It is very case-by-case for those things. You mentioned the evolution of virulence, and to my mind the suppression approach, where you are trying to take out the vector, will have only an indirect effect on the pathogen and is unlikely to cause issues in that direction, which is not to say we should not think about them. Certainly, where you are trying to modify the insect in a way that makes it less able to transmit, that brings in a third player in these multiple evolutionary responses, being the pathogen, and you certainly have to think about those issues.

Professor Paul Eggleston: The pathogens are very able to modify the virulence themselves, whether we are talking about normal or genetically modified insects. It does not change the risk profile there at all.

The other thing I would like to add is all of this is tied up with some of the regulatory issues that we might touch on later. My own view is that all of this is about a balanced approach to risk versus benefit, and people’s perceptions of risk versus benefit differ depending on where they live. In the work I did in Mali, for example, local people and scientists there had a slightly more balanced view than you tend to get in western Europe. The current regulatory system does not put enough emphasis on what the potential benefits might be. There is a risk that worrying overly about all of these risks means we will never ever be able to do anything. That is a personal view, but I think it is pertinent.

Professor Austin Burt: I would just reiterate that it has really got to be taken on a case-by-case basis.

Lord Patel: Can you put these worries about safety issues in the context of using alternative methodologies such as insecticides?

Professor Paul Eggleston: In the longer term they will not work.

Lord Patel: Do we not have examples of using insecticides, chemicals, to reduce the population?

Professor Paul Eggleston: Yes, but if you throw a poison at any natural population, in time it will develop resistance. We have populations of mosquitoes now that are multiply resistant to virtually everything that we have, and that situation is not going to get any better. It is one of the drivers for thinking about developing technology of this kind. Insects will become resistant to insecticides. Parasites will become resistant to the drugs you try to treat them with. We need more tools, not fewer, to be able to tackle the problem of disease transmission.

Professor Luke Alphey: One of the differences and perhaps benefits of genetic insect approaches relative to chemicals is specificity. Most chemicals have a relatively broad spectrum effect. In other words, they will be toxic to quite a wide range of insects. That varies from one to another, but they are unlikely to be specific to a single species, whereas for GM insect approaches, the control agent is now not a chemical; it is a modified insect, and it interacts with the wild population through mating. Modified males will only mate with females of the same species, so that initial contact and effect is very species-specific. That feature of these technologies is a real strength from an environmental point of view. When you go back to the question, “Where are they good and where are they not?”, it is a potential limitation in other areas. If you were a farmer whose crop was being eaten by a dozen different pests, you might prefer something a bit more broad spectrum than a dozen different species-specific interventions. That species-specific nature means that GM insect methods are likely to be more useful where you have a single dominant pest species—whether that is in agriculture, conservation, human health or wherever—than where you have whole slew of different things doing the same kind of damage, where something more broad spectrum might be more appropriate.

Lord Hennessy of Nympsfield: How difficult is the science that lies behind the forecasting of unintended consequences in your specialist fields? Is it the same as it is for most other scientific activities or are there particular perils here? As you said earlier, it goes to the heart of the confidence question on the spectrum of public confidence/public anxiety, around which the question of regulation always swells. Is it particularly difficult in your trade, because it still strikes me that what you are doing is wonderful stuff but it is very early days?

Professor Luke Alphey: It is relatively early days for gene drive systems, although even there, by analogy, there are some things you can look at. We know quite a lot about natural selfish DNA systems that have these sorts of properties. For sterile insects it is a little simpler because we have a 50-year history of the use of radiation-sterilised insects which are extremely similar operationally, so we perhaps know rather more about that. One of the big advantages when we started developing genetically modified sterile insects—although, obviously, we were going on a rather cautious step-by-step basis of lab, cage, small field trial—was that we could see these very large programmes using radiation-sterilised insects which told us about the operational issues, also some issues about resistance and managing that. For example, the New World screwworm was eliminated from a continent by a rolling programme of release of radiation-sterilised insects so we have vast experience of the field use of sterile insects.

The Chairman: Professor Eggleston, you make the observation that it is a question of assessing risks against benefits. Would it be more accurate to say it is a question of assessing potential benefits against potential disbenefits?

Professor Paul Eggleston: Yes, that is fair.

The Chairman: I think that is an important distinction.

Professor Paul Eggleston: It is, but most of the regulatory issues that we all battle with focus on perceived risks, many of which the scientists think are negligible, and there is not often that much emphasis put on what the benefits might be. As I was saying, if you are living in a disease-endemic country you might have a slightly different view on that balance of risk versus benefit.

Viscount Ridley: Following up on the risk/benefit balancing question, this is a theme we have heard from a number of witnesses and written submissions. It was taken up by a House of Commons Committee, and one of the responses from the Government was to say: “Ordinarily this would seem a sensible approach. However in the EU context it could result in a disproportionate requirement to assess the potential socioeconomic benefits of novel crops.” This is talking about crops. “This would add a further layer of complexity, burden and subjectivity to the regulatory process.” In other words, if you have to start enumerating the benefits you are stuck in the regulatory hell for longer.

Professor Austin Burt: I would not go to a Government in sub-Saharan Africa with this idea of a genetically modified mosquito and not talk about malaria. That does not make sense.

Viscount Ridley: Is this a slightly defeatist response from a government department?

Professor Austin Burt: I cannot talk about the crop situation.

Professor Luke Alphey: It has been suggested that the developers should say what the full socio-economic impact would be, which would be like asking developers of mobile phones to have predicted micro transactions and so on, which I think is ridiculous, frankly. I can see some things in the direction you are talking about that would be undesirable but, as Austin says, if you are developing mosquitoes to try to prevent malaria or dengue or crop pests or whatever, how could you not talk about the benefits? If you are not talking about the benefits and the reasons why you are doing it, how will you persuade anybody it is worth doing? At that level it does not make any sense.

Q54 Baroness Morgan of Huyton: Can I take you back to commercialisation for a minute? It is particularly appropriate to have Professor Alphey here because we have heard repeatedly, and certainly to my surprise, that your company was literally the only one in a UK context that has been involved in developing any of this technology at a commercial level. What we want to know, and we have heard some of this from previous witnesses, is whether the UK is supportive enough of the development at a commercial level of these technologies, particularly from the early stage to the next stage of development, where there seems to be a particular problem. Also—this is particularly directed to you, Professor Alphey—to what extent was the sale of the company driven by the business environment here, or was it the only natural partner?

Professor Luke Alphey: I should have said in my introduction that I am speaking in a personal capacity. I do not represent Oxitec or anyone else.

Baroness Morgan of Huyton: You are absolutely not, which is why it is handy to have you here because you understand the history, which is helpful to us.

Professor Luke Alphey: Oxitec is the only such company in the world, not just in the UK, so to that extent if the only such company in the world started in the UK, then there must be something good here.

Baroness Morgan of Huyton: The science might be good though, might it not?

Professor Luke Alphey: Precisely. I think the key benefit is the science base and the expertise in these general areas. Though perhaps not in this particular inquiry, I am sure this Committee is thinking about science funding going forward. What makes the UK attractive from this point of view is the strength of the science base, and I would say the BBSRC was the key to this, although other agencies were involved.

The key disadvantage is the lack of a local market. Business 101 would say start with a local market and expand from there, but we do not have a local market for GM insects. If we had set up Oxitec saying that we were going to sell GM insects in Europe, never mind in Britain, we would not have had investment—to the point that we would not have asked, I would not have asked, I would not have tried. One does not know how many other businesses have not started because of that. I do not see how one could know. The fact is it is impossible to sell this technology in Europe at the moment. Field trials, perhaps, but there seems to me no possibility of getting commercial registration in a reasonable time, or even having any idea how much time or money it would take. That is probably the biggest negative factor.

There are some things along the way. Although it is very small scale, the support of Innovate UK—the TSB as it used to be—for small companies is very valuable, and R&D tax credits are very helpful. For those relatively early stages, there is a good economic environment, albeit perhaps a little at risk at the moment. I feel I may not have answered every part of your question.

Baroness Morgan of Huyton: What needs to change? I suppose this is for Professor Burt as well, in a sense, because you were clear that yours had to be not for profit.

Professor Austin Burt: At the moment our core funding is from FNIH in the States—so it is overseas—which is part of a Gates Foundation programme. It is a complicated project that goes all the way from protein engineering and molecular entomology to field ecology and community engagement, specialists in risk analysis and things such as that. It is complex and not many funding sources are able to take on the challenge of funding something with so many moving parts. They have been very good to us over the years.

Professor Paul Eggleston: For any kind of commercialisation, there has to be a financial model that works for the business. Luke can correct me but Oxitec’s business model, essentially, is that they can get rid of these mosquitoes for the same or less than the cost of insecticides. It you are talking about endemic diseases in poor countries, there is no financial model, and why would a company get involved in developing these insects when they have got no market to sell them to? The situation in Europe might change, let us say with climate change; if some of the arboviruses we see in southern Europe start to spread dramatically, that could create at least a governmental market. Or let us say Bluetongue becomes an even bigger problem across Europe; again, Governments might then want to find the money to try to commercialise tools to combat those diseases. In Europe, it is hard to see where the business model currently would come for most of this, unless it is agricultural pests.

Professor Luke Alphey: It is not that there is a lack of credible targets or targets that would benefit from this technology in Europe. We do not have a lot of vector-borne disease that we worry about, although there is some in political Europe. However, for agricultural pests, yes, absolutely, there are many relevant targets, but it would not be economic to work through the regulatory processes at the moment. That was clear when I was looking for investment for Oxitec right at the beginning to start up the company. When we talked to European-based investors, they felt that the risks associated with developing and commercialising this technology were rather high and, correspondingly, were disinclined to invest.

Baroness Morgan of Huyton: Primarily because of the regulatory environment.

Professor Luke Alphey: Yes, even though we were not talking about selling the insects in Europe. It was the atmosphere, the environment in which they lived, not so much the market we were talking about, whereas I think the first US-based investor we talked to invested. It was not that we were making a different pitch to the two. It is the view of GM in Europe which has this chilling effect on the investor community as well, because they think, “You will never be able to do that”, or, “It will take too long or be too expensive”.

Lord Maxton: You mentioned cotton and that was almost the first of the insects released. That must have been commercial. If you can find an answer that stops an insect destroying a cotton crop and the cotton crop develops, that is a commercial argument, is it not?

Professor Luke Alphey: Yes, I agree. That trial was done in collaboration with the US Department of Agriculture. In the US, some of these big insect control programmes are run by the government effectively on an infrastructure basis. They would see that as infrastructure investment dealing with this, particularly if it is an invasive pest.

Lord Maxton: It was done by them and not by a private company, in other words.

Professor Luke Alphey: Correct—a collaboration between the USDA and Oxitec.

Q55 Lord Cameron of Dillington: I am a farmer and you mentioned various possibilities of applications in the agricultural world. I am interested also in the natural environment. Professor Burt mentioned that it is unlikely that we will see a rollout of the antimalaria GM insects until 2030, so I am asking you to take a big leap forward here. What other applications can you see in agriculture? We have a pollinator problem at the moment. Could insects be increased or maybe even vaccination of wild animals? Tuberculosis in badgers springs to mind. Equally, if you are talking about lots of long-term benefits, maybe there are disbenefits. What possibility is there that countries could use insects as weapons and release them? What are the possibilities here long term?

Professor Luke Alphey: There are many potential applications that might become available over different timescales. Drosophila suzukii—the spotted-wing drosophila mentioned in a previous session—is a recent invasive pest into the UK which attacks soft fruit. These sorts of things would be potentially amenable to the technology that Oxitec is developing. The technical strain could be available in the very short term. We discussed the regulatory issues but from a technical perspective a strain could be available in short order.

You mentioned pollinators—so on rather longer timescales, and we have not really talked about beneficial insects. We have all talked about trying to do bad things to bad insects, but, potentially, you could think about doing good things to good insects. On insecticide resistance, a simple idea is to protect pollinators against agricultural uses. For example, neonicotinoids in bees is quite a big issue in Europe at the moment. What if we could make the bees more resistant to those or other classes of chemical that they might contact? If we could protect them against particular chemistry, could we use that chemistry against the varroa mite, for example? That is another area you might think of.

There are some bumble bees that are very good pollinators, but there are restrictions on using non-native bumble bees because of the threat to native bumble bees. What if you could engineer some sort of reproductive isolation, the sterility type things we have talked about for other purposes, into a pollinator, so then you could use a non-native pollinator in a new area, knowing that it would not be able to establish? Invasive species are a huge problem for conservation and biodiversity in any number of different places and some of those are insects, so what about controlling those? Those might be the same technologies as we are talking about here, but for a conservation biology target rather than a human health target—so, a pretty wide range.

Lord Cameron of Dillington: The downsides, weapons, is that a possibility?

Professor Luke Alphey: That is pretty hard to see.

Professor Austin Burt: I am not clever enough to think of one.

Professor Luke Alphey: In anything other than the most invasive gene drive systems, deployment would be a very visible and continuous thing, where it is pretty hard to imagine it being done in any way. It would be much easier to move a wild, non-native insect around than it would be to use a modified insect in some way to intervene against a wild population, I think.

Professor Paul Eggleston: It is worth bearing in mind that any of those applications is some way off because the tools and technology for these other insects are nothing like as well developed as they are for mosquitoes.

Viscount Ridley: That feeds in nicely to what I was going to ask. Can you see this technology being used in invertebrates other than insects to control invasive species, particularly signal crayfish or killer shrimps, which are problems in this country? They are arthropods.

Professor Paul Eggleston: Transformation of prawns and shrimps is feasible. I can remember from years ago someone telling me how easy it was to make a transgenic prawn. I have not done it myself but in principle, yes, that could be done in terms of the signal crayfish.

Viscount Ridley: What about grey squirrels?

The Chairman: I think that is an interest you have not yet declared.

Professor Paul Eggleston: I am sure you could make a genetically modified squirrels using the mouse technologies that are quite well developed.

Professor Luke Alphey: There certainly is interest. When I mention conservation biology, of course invasive insects are a problem, but rodents on island populations cause devastation, and there are people certainly interested in controlling rodents. Currently that is done with toxic baits and the like, but there is certainly an interest in the application of genetic technologies in those areas as well, which would be analogous, although obviously the molecular detail might be a little different.

Lord Fox: Would RIDL not work?

Professor Luke Alphey: It would certainly be population suppression; we will have to see about the exact mechanism, but it would likely be some form of sterility, or sex-ratio distortion.

The Chairman: We have come to the end of the questions we wish to put to you. Thank you very much for the full and helpful way you have answered them. There will be an opportunity to correct the transcript. On behalf of the Committee, thank you once more for helping us this morning.