Transgenic mosquitoes, update Effective Altruism Policy Analytics

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