if you think for a moment about the way mammals reproduce you'll realize that the placenta is actually where the rubber really meets the road that is the place where the fetus is interacting with the mother and where fetal nourishment and gas exchange is taking place an interesting feature of placentas is that in many mammals they are invasive and that has consequences when the embryo implants it actually aggressively attacks the endometrial tissue it invades it and this pattern has very old the degree of invasiveness varies among mammalian groups invasion is something that should give the fetus an advantage early in life and it would do that by giving the embryo increased control over nutrition and therefore growth but there's a trade-off there is an association between the degree of placental invasion and the risk of preeclampsia and metastatic cancer preeclampsia is abnormally high blood pressure life-threatening ly high blood pressure during pregnancy and of course metastatic cancer is a problem in aging in many systems the properties of invasive stem cells are actually very similar to the properties of metastatic cancer cells in other words the idea here is it was a great idea from the point of view of the embryo to develop an invasive stem cell so that it could take control of growth and nutrition but in so doing it created something that would hang around in the body and then years later the pre adapted to become a metastatic cancer cell so the pre embryo implants aggressively the outer embryonic cells are called the trophoblast and they bore into the uterus by secreting enzymes that dissolve tissue and that allows them access to maternal blood vessels the endometrium which is produced by the mother both enables this but it also resists it and limits the invasion the trophoblast that's coming from the embryo becomes part of the placenta and there those cells secrete hormones that mimic maternal hormones those hormones influence maternal blood sugar and the dilation of the maternal arteries in the placenta helping to regulate delivery of nutrients so one of the ways for the baby to get more nutrient out of the mother is to increase the level of sugar in her blood and it can do that by regulating the level of insulin in her blood and if that regulation goes off then you get pregnancy related diabetes for our purposes the features of placental morphology are the ones that determine how many layers of cells and tissue separate the fetal blood from the maternal blood and then how intimately intermingled our fetal and maternal tissue over how large a surface area prior to placenta formation there are six layers of tissue separating the maternal in the fetal blood during Classen tation one two or three of the maternal layers can be lost and the shape of the placenta can either be diffuse meaning that it occupies most of the surface of the embryonic sac it can be what is called cotyledon re with multiple discrete attachments zone are' forming a band around the fetus or discoid attaching at one point and smaller than the fetus humans have discoid placentas and they have placentas in which three layers of maternal tissue have been lost so let's take a look at the fetal and the maternal layers the fetal extra embryonic membranes all go into forming the peseta that's the endothelium that lines the alan toi capillaries the connective tissue and what's called the corrió alan toi mesoderm and the chorionic epithelium the outermost layer from the trophoblast so these are all part of the outer layers that are surrounding the embryo the maternal tissues can be endothelium that lines the endometrial blood vessels the connective tissue in the endometrium and the end meet real epithelial cells so three layers of fetal tissue and three layers of maternal tissue now if a veterinarian looks at this and makes classifications based on layers what they see is this if you look at how many maternal layers are retained it can be one two or none okay and this would be three layers retained one layer retained and none retain there are other organisms where you have the other possible combinations the type of placenta is then called epithelial Coryell if all three of the mother layers are retained you find that in horses pigs and in cows if you have just the endothelium of the mother retained that's the situation and dogs and cats that's called endothelial Coryell and hemo Koryo that's the most invasive kind of placenta where none of the maternal tissues are retained all of them have been dissolved away by fetal enzymes giving maximum access to maternal blood supply that's what happens in humans and in rodents so in humans and rodents the growing villi which are coming in from the fetus into the placenta erode through the maternal endothelium and in that Hema Coryell placenta the fetal chorionic epithelium is bathed directly in maternal blood so it's a way of gaining direct access to the maternal blood supply now when and why did that evolve and what are the consequences the other major thing is the overall macro shape of the placenta this is a diffuse placenta it is all over the embryonic sac a discoid placenta is just in one small part of the wall of the uterus that's what the human placenta looks like a cotyledon Airy placenta is formed all over the uterus but in little blotches and a zone or a placenta wraps like a ring around the growing fetus so a diffuse placenta can be found in horses and pigs a cotyledon Airy placenta in cattle and in sheep a zone or placenta in things like dogs and cats and a discoid placenta like this in humans apes monkeys and rodents the point is that's being made here is that placenta is very a great deal among mammals and there is interesting information to be gathered about the sorts of evolutionary conflicts that are going on when you study both the macro and the micro morphology of placentas so let's take a look at the evolutionary history of shape we have a discoid placenta okay so this is human and this is human here and here we have information on whether or not that is a discoid to Center or not black is discoid okay and what we see here on the phylogenetic tree is that black is an ancestral condition it looks like the first you therians had discoid placentas the zona replay santa has evolved a few times its present in foxes and then cats and then things like elephants and rock hyraxes and aardvarks of the BI discoid placenta is in tree shrews and the cotyledon re placenta is in cows so the human condition is an ancient one the discoid placenta is something that hasn't changed for 150 million years what about whether it is folded or lamellar or villas or trabecular or so forth well the human placenta is villus and a villus placenta basically is one that penetrates into the end of into the metrium with villi okay finger-like projections that are invading that space the villus condition is something that has happened in humans and other primates it has also happened in cows and foxes and in cows and pan golems and tapers and things like that okay so it is a derived condition so the uterus is the human placenta is a mosaic of attributes that have different evolutionary ages what about layers okay so here are the humans right here again this has been moved over a little bit this is a human right here and what you see on this is the same phylogenetic tree but there are different traits there that are plotted on it the Hema Coryell placenta that is the maximally invasive placenta is in white the epithelial Coryell placenta which is the least invasive placenta is in black and the endothelial is in green the take-home point here is that the invasive placenta is ancient that hasn't changed for about a hundred and fifty million years so invasiveness is not derived in humans there are other aspects of the placenta and of the interaction that are derived in humans but that is not one of them now what happens if there are fewer layers so what happens as you go from kima Coryell to endothelial Coryell basically the fewer layers of tissue there are between the mother and the fetus the shorter the gestation period okay so basically that is the difference between this line up here and this line down here this is a hundred and nine species from all mammal orders the data or log transform so this is how big the mom is this is how long gestation is in log scale yeah epithelial Coryell is up here it's non-invasive and these are all of the relatively invasive types intermediate to highly invasive so it seems as though invasive embryos managed to shorten their gestation this is about 35 days now what did happen in humans and in chimpanzees and gorillas but not in Gibbons was deep invasion and remodelling of the spiral arteries okay so this is something that primary interstitial implantation is occurring only in in great apes it does occur in guinea pigs that seems to be a rather different situation in humans there are two routes of trophoblast invasion and there is deep trophoblast invasion that reaches the inner third of the myometrium part of the endometrium this is shared only by great apes okay so this is something now that's that's unique in humans and great apes it is especially deep invasion we now can take a look at the genes that are controlling that process okay so genes that are involved in the risk of preeclampsia and of trophoblast invasion experience positive selection at two points one was at the origin of the humidity that would be here that's before the group of gibbons orangutangs and gorillas chimps and humans and the other is at the origin of the home in aney that is the smaller group that is just gorillas chimpanzees and humans at this point we have Hema Coryell placentas that are discoid and villus deep invasion extensive spiral artery remodeling in Gibbons they also have a Hema Coryell placenta but invasion is shallow and there's very little remodeling of the spiral arteries so we can look for signatures of selection in the gene that are controlling that shift out of 18,000 genes that were checked for the synonymous nonsynonymous ratio this is a measure of how many selective changes have taken place 295 signaled positive selection on the branch going to the hominoid e 264 positive selection on the branch leading to the home inin e so that's all genes but these sets of genes were enriched for genes that function in the risk of preeclampsia and trophoblast invasion so there is a correlation between risk of preeclampsia and how invasive the placenta is now that is one potential trade-off the other is between fetal nourishment and the risk of cancer there are striking similarities between these invasive placental cells and invasive cancer cells when these stem cells are invading the placenta they are using capacity that is probably used by cancer cells to invade during metastasis they have particular cell adhesion molecules their extracellular matrix and matrix metalloproteinases are of a particular sort they are involved in angiogenesis that is in generating beds of arteries and veins and capillaries and that is a feature of both implantation and the spread of cancer so understanding the maternal mechanisms that control trophoblast invasion might be one route to understanding how to control metastasis here is a list of genes and I'm not going to go through them basically what I want you to notice is that there are a lot of them I'll talk a little bit about what kinds of things that are involved in but these are genes that are expressed both in trophoblast and in metastasis so there are some smoking guns here is the case where we say if we want to rea up regulate stuff in cell that will allow it to invade those are the same things we would up regulate to allow it to become a metastasis these have been found in colorectal cancer breast cancer testes cancer lung cancer kidney cancer colon cancer cervical cancer endometrial cancer leukemia and so forth liver cancer so it's quite a battery of evidence that has started to accumulate that establish at the genetic level this connection between invasion and cancer so to summarize the mammalian placenta evolved in many different ways they vary widely and tissue layers separating fetal and maternal blood they vary in the shape of structures that mediate exchange and they vary in how much the fetal tissue invades the maternal tissue human placentas are a mix they have some very ancient features and they have some derived features very deep invasion is derived it is shared with chimpanzees and gorillas and it's associated with preeclampsia that is dangerously high blood pressure during pregnancy trophoblast invasion pre adapts cells for metastasis it's an early life Fitness benefit trading off with a late life risk it is a classical case of antagonistic pleiotropy