The placenta: a legacy inherited from ancient viruses 

Since their dis­cov­ery at the end of the 19^th Cen­tu­ry, virus­es have been asso­ci­at­ed with the notion of dis­ease. And with good rea­son: it was in the search to under­stand the ori­gin of some of them that these new kinds of infec­tious agents were iden­ti­fied. How­ev­er, as explained in a pre­vi­ous col­umn, virus­es can become our allies in the fight against bac­te­r­i­al infec­tions. But this is only a recent twist: long before any human mind had the idea of using these micro­scop­ic enti­ties to our advan­tage, the vagaries of evo­lu­tion had already unit­ed us in a par­tic­u­lar­ly inti­mate way.

While only 1–2% of the human genome con­sists of pro­tein-cod­ing sequences, between half and two thirds are made up of dif­fer­ent types of mul­ti­ple-repeat­ed sequences, the func­tions of which are dif­fi­cult to deter­mine. And virus­es have a lot to do with this.

Those belong­ing to the retro­virus fam­i­ly, the best-known mem­ber of which is HIV, which caus­es AIDS, have a very spe­cial abil­i­ty: they can inte­grate their own genome into that of the cells they infect. This inser­tion some­times takes place in a germ cell that even­tu­al­ly pro­duces gametes (sper­ma­to­zoa or oocytes in humans, for exam­ple). In this case, the squat­ting viral genome is passed on to the next gen­er­a­tion and is found in all the cells of these new indi­vid­u­als, who will in turn pass it on to their off­spring. Thus, over time and through infec­tion, retro­virus genomes have become well-estab­lished in the DNA of oth­er species – includ­ing our own.

In the human genome, there are about 500,000 of these retro­vi­ral genomes, which rep­re­sent about 8% of its total length… That’s much more than the length of our own genes (the 1–2% men­tioned above)! And these mol­e­c­u­lar com­pan­ions are not new: the most recent one is about 150,000 years old. So, they have had time to accu­mu­late many ran­dom muta­tions and most of these viral genes are no longer expressed today. They can be con­sid­ered as viral fos­sils, which are in fact among the objects of study of a dis­ci­pline called palaeovi­rol­o­gy¹.

But as always in biol­o­gy, there are excep­tions. Some viral reg­u­la­to­ry sequences still mod­u­late the expres­sion of our own genes, and some viral genes are still expressed in our cells. Is this a rea­son to pan­ic? Not real­ly. On the con­trary. Because we owe our birth to them. Literally.

In 2000, dur­ing a sur­vey of the pro­teins expressed by var­i­ous human tis­sues, researchers iden­ti­fied a viral pro­tein pro­duced in a sin­gle organ: the pla­cen­ta². It is a retro­virus enve­lope pro­tein, usu­al­ly found on the sur­face of viral par­ti­cles, which has two par­tic­u­lar­i­ties. On the one hand, when exposed to host defences dur­ing infec­tions, enve­lope pro­teins are able to decrease the effi­cien­cy of the immune response. On the oth­er hand, it is these pro­teins that, like mol­e­c­u­lar keys look­ing for their locks, inter­act with recep­tors on the sur­face of cells and cause the virus enve­lope to fuse with the cell membrane.

This viral enve­lope pro­tein is specif­i­cal­ly expressed in a tis­sue of the pla­cen­ta called syn­cy­tiotro­phoblast, which allows exchanges between the moth­er’s blood and that of the foe­tus. This tis­sue, which is essen­tial for the prop­er devel­op­ment of the preg­nan­cy, is formed by the fusion of sev­er­al cells and has immuno­sup­pres­sive activ­i­ty. This leads us to believe that the for­ma­tion of the essen­tial syn­cy­tiotro­phoblast is due to the action of a viral enve­lope protein…

The viral envelopes specif­i­cal­ly expressed in the pla­cen­ta and capa­ble of induc­ing the fusion of sev­er­al cells (to form tis­sues called syn­cy­tia) take their name from this last prop­er­ty and are now called syn­cytins. In the plur­al, because the dis­cov­er­ies have been made one after the oth­er since 2000.

Two human syn­cytins³ are now known, also present in oth­er Pri­mates⁴, and genes of the same type have been dis­cov­ered in many Mam­mals: Rodents⁵, Lep­ori­dae⁶, Car­ni­vores⁷, Rumi­nants⁸… And even Mar­su­pi­als⁹, which have lim­it­ed devel­op­ment in utero. And this list is nei­ther exhaus­tive nor detailed. In fact, syn­cytins have been found every time we have looked for them in a vivip­a­rous species (whose embryos devel­op inside the moth­er’s body, as opposed to oviparous species, which lay eggs). This under­lines the impor­tance of these viral genes in pla­cen­ta for­ma­tion! In mice, their indis­pens­able nature has even been direct­ly demon­strat­ed¹⁰.

The diver­si­ty of syn­cytins cur­rent­ly observed in mam­mals, which are descend­ed from the same com­mon ances­tor, is prob­a­bly explained by the pro­gres­sive acqui­si­tion of new endoge­nous retro­virus­es in each of the dif­fer­ent lin­eages. In a sort of evo­lu­tion­ary relay, the ances­tral syn­cytin would have giv­en way to a whole series of dif­fer­ent syn­cytins¹¹. Sev­er­al stud­ies have already iden­ti­fied ancient syn­cytins in some organ­isms and the link between syn­cytin diver­si­ty and vari­a­tions in pla­cen­ta mor­phol­o­gy is an open research question.

This close link between vivipar­i­ty and domes­ti­ca­tion of a viral pro­tein could be due to one of the main dif­fi­cul­ties of non-egg repro­duc­tion: the moth­er’s organ­ism has to tol­er­ate that of the foe­tus dur­ing the whole ges­ta­tion peri­od. If there is no spe­cif­ic adap­ta­tion, its pres­ence should trig­ger rejec­tion, as in the case of a trans­plant. Var­i­ous mech­a­nisms now com­bine to allow this feto-mater­nal tol­er­ance but, at the time of the appear­ance of vivipar­i­ty, it is pos­si­ble that viral pro­teins of the syn­cytin type were indis­pens­able because of their immuno­sup­pres­sive capacities.

In the absence of being able to go back in time to demon­strate this, we can look at the few vivip­a­rous ani­mals that do not belong to the mam­malian group¹². French researchers study­ing syn­cytins have iden­ti­fied one of them… in a South Amer­i­can vivip­a­rous lizard¹³! The role of these viral pro­teins in vivip­a­rous repro­duc­tion is there­fore not lim­it­ed to Mam­mals, and it remains to be seen whether their pres­ence is real­ly sys­tem­at­ic in ani­mals with a placenta.

The link between syn­cytins and vivip­a­rous repro­duc­tion is par­tic­u­lar­ly well stud­ied, but it is not the only exam­ple of func­tion depen­dent on the domes­ti­ca­tion of a viral gene. Beyond the syn­cy­tiotro­phoblast, ini­tial results indi­cate that syn­cytins may play a role in the for­ma­tion of oth­er tis­sues that require the fusion of sev­er­al cells, name­ly cer­tain mus­cles¹⁴, cer­tain struc­tures respon­si­ble for the regres­sion of bone tis­sue and cer­tain giant cells involved in the reg­u­la­tion of inflam­ma­tion¹⁵.

Anoth­er retro­virus pro­tein is expressed in our brains, where it is notably involved in mem­o­ry¹⁶¹⁷. Par­a­sitoid wasps have domes­ti­cat­ed whole virus­es, which they inject into the arthro­pods they par­a­sitise at the same time as their eggs, to pro­mote their immune tol­er­ance¹⁸. Con­verse­ly, var­i­ous retro­virus genes pro­tect the organ­isms that car­ry them from infec­tion by oth­er virus­es¹⁹.

Obser­va­tions of this type are mul­ti­ply­ing, and it is becom­ing nec­es­sary to rethink our vision of virus­es. In con­stant inter­ac­tion with oth­er bio­log­i­cal enti­ties, they are not only vec­tors of dis­ease, but also of genet­ic inno­va­tions that have turned the evo­lu­tion of life upside down²⁰.