In March 2016, the U.S. Food and Drug Administration posted a draft of its environmental assessment on the potential impact of testing OX513A mosquitoes in the Florida Keys. OX513A mosquitoes are genetically modified to pass genes to their offspring which result in offspring death. They are used to suppress Aedes aegypti mosquito populations, which are known for spreading dengue fever, chikungunya, Zika fever and yellow fever viruses, as well as other diseases.

Following this post, Jack Newman from Amyris and Zagaya alerted Tessa Alexanian of the opportunity and she organized a team with Matthew Gentzel to submit a public comment addressing the risks and benefits of testing OX513A as proposed. You can find the comment we submitted to the FDA here.

Summary of comment:

If OX513A mosquitoes are released as described in this proposal, there appears be little risk of relatives of released mosquitoes spreading further than intended during testing because of their low survival rates. Even if they did, there is very little risk of harm to anything except populations of Aedes aegypti mosquitoes close to the release site. The potential benefits of future use of this and related technologies in the fight against mosquitoes and disease make it well worth conducting the study.

Oxitec will be releasing OX513A transgenic male Aedes aegypti mosquitoes. Male mosquitoes do not blood-feed. This will be an instance of Release of Insects with Dominant Lethality (RIDL), which means that the offspring of these males will die in a controlled fashion. The method of death is the overproduction of a protein encoded on the inserted sequence called tTAV. If there is any tTAV in these mosquitoes, the modified genes will make them create more tTAV unless it is cancelled out by the presence of tetracycline. Although the mechanism is different, the results should be comparable to an application of a widely-used method called Sterile Insect Technique (SIT). In SIT, the sperm of male mosquitoes is rendered inviable via radiation before release into the wild. In RIDL, the parents are reared with tetracycline and their offspring will die without it.

This is not a gene drive. Offspring of these mosquitoes are expected to die out within a couple of generations after release. The offspring of the modified mosquitoes have, by design, far lower rates of survival than the wild type. Only about 3-4% make it to adulthood. The nearest hospital (and the only nearby place that could plausibly have enough of the tTAV antidote, tetracycline) is more than 300 meters away, and beyond the typical lifetime flight distance for Ae. aegypti males. This method of death is not pesticide-based or mutagenic. The end result is that survivors are no more likely to carry dangerous mutations than the wild-type, and will have far fewer surviving offspring.

OX513A mosquitoes are also non-toxic, dead or alive. Without the introduced genes, tTAV is non-toxic. Predators fed on a diet consisting almost entirely of modified mosquitoes suffered no adverse effects. With the sorting methods used, less than 0.03% of mosquitoes released are expected to be female and potential blood-feeders. Even if someone was bitten by one, it is unlikely to be any different from a normal mosquito bite. The only unusual proteins in these mosquitoes - the lethality protein (tTAV) and the glowing red protein used to identify these modified mosquitoes (DSRed2) - weren’t detected in transgenic mosquito saliva.

A major environmental disturbance seems unlikely. Aedes aegypti are an invasive non-native species, and so are probably not an important part of the local ecosystem.

The trial is short in duration, and the chosen location is remote. The site of release is an area of the Florida Keys far from the mainland, and mostly surrounded by ocean. Considering their low survival rates, these modified mosquitoes are unlikely to spread without the help of tetracycline, and would be no more hazardous than their wild cousins if they did. The result of the release will probably only be a reduction in the size of mosquito populations in the local area, which is exactly the result intended.

Going forward:

The FDA has approved trials with OX513A, though local government could still prevent the trials from being performed. A nonbinding referendum is taking place in the Florida keys to inform local government decisions. A national survey in February indicated 78 percent of the 964 participants supported the introduction of genetically modified mosquitoes to fight the Zika virus, however this sample was not representative of the Florida Keys population, and is out of date. Nevertheless, it does seem likely trials will proceed, especially given that the referendum is nonbinding and Florida’s mosquito board ultimately has decision authority.

To follow up on comments submitted last year by Effective Altruism Policy Analytics, Richard Bruns and Matthew Gentzel will be searching the Federal Register for agency responses later this August.

Special thanks to Tessa Alexanian, Eric Yu, Anjali Gopal, Linchuan Zhang, John Min, Olivia Schaeffer, the Scientists at Zymergen and others for helping produce our policy comment!

-Megan Crawford and Matthew Gentzel