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.