Genes that trigger human birth

Most mammals reproduce the same way, except for animals like us humans, where there are some important differences. One of them is how the baby - or the mother, or both - know that it's time to be born, and that's what intrigues Vincent Lynch, at the University of Buffalo, where he's been using the power of genetics to try to home in on what that signal might be...

Vincent - The early process in the part of reproduction is basically the same between most animals. There's some population that happens, then fertilization happens, then the embryo implants into the wall of the uterus. But near the end of pregnancy, things get very different. If you were to pick a random mammal, I could tell you what the signal is that says 'pregnancy's over, it's time to start the process of birth.' But I can't tell you what that is in humans, because humans have a different signal and we don't actually know what that signal is.

Chris - Do we know why it's different? That's a different question than 'what is the signal?' Do we know why different animals have different triggers?

Vincent - We don't, but there's some theories about why that could be. There's this idea that it's in the best interest of the father to have pregnancy last as long as possible, so that his foetus can extract as much resources from mom. Mom doesn't want to give up all of her resources though. She wants to save some of those resources for future pregnancies, it's in her best interest to keep pregnancy as short as possible. This battle gets played out through the foetus; It's called maternal foetal conflict. There's this challenge going between the mother and the foetus and the father for how long pregnancy should last.

Chris - And how have you sought them to attack this enigma?

Vincent - We know a lot of these changes have to be genetic because they're common to every human, and they're common to every ape, or they're common to every rabbit. What we were able to do is collect a whole bunch of pregnant uterus samples from a whole bunch of different animals and simultaneously determine all of the genes that are turned on and off. Then we can find the ones that are uniquely turned on and off in humans compared to the other animals. Presumably those are the ones that are responsible for the human specific pregnancy traits.

Chris - Were you using biopsies of uteruses? How did you get human samples that you could use to do this?

Vincent - For a lot of animals, these were collected from slaughter houses. For some animals, people were interested in other things, but they were collecting the uterus, so we were able to politely ask, 'can you please send us some uterus?' For humans it's a little more challenging. For a lot of these samples, these are elective terminations of pregnancies or pregnancies where something has happened and there needs to be a termination.

Chris - So you've got this data from across a whole raft of mammals and you are presumably gonna find a core bunch of genes, which just reflect the state of a pregnant uterus. Then there are gonna be animal specific differences. Do you see those in humans?

Vincent - We do. What we end up with is a giant spreadsheet where the rows are all of the genes and the columns are all of the animals. We look to see where the genes and where the gene rows and the column animals have turned on in humans, but not in everybody else. If you do that, you see that there's about 800 genes, which look like they have unique on or off patterns in humans compared to every other animal, which is a lot of genes considering that there are, depending on how you count, 20,000 or 22,000 genes in your genome.

Chris - When you look down that list, which is very sizeable, are there any surprises because obviously we've been studying this process for a long time. There are already some genes which are well defined so you must have already ticked those off the list. Are there any in there that we never even considered might be on the list related to pregnancy?

Vincent - Yeah, there's a lot of genes that we wouldn't have previously thought were related to pregnancy that show up on these lists. For example, there are genes which typically play a role in serotonin signalling in the brain. They show up as being turned on in the uterus during pregnancy. There's also, not surprisingly, a lot of genes which seem to play a function in regulating the immune response, the kinds of immune responses that you might normally think of being associated with parasitic infection, which makes a lot of sense because the uterus during pregnancy is a place where there's a foetus and that foetus is half-mom and half-dad. The maternal immune system should recognize the half-dad part as a foreign entity in the uterus and mount an immune response against it. But that doesn't happen. We see a lot of genes that play a role in contributing to that immune response. There's also a whole lot of genes which play a role in the development of the placenta. The help the mother and the foetus make this very intimate connection between them, which is important for all aspects of pregnancy.

Chris - Are there any in there that might be that key trigger?

Vincent - It depends on which camp you belong in. Because we don't know the answer to the question of what causes labour and delivery in humans, some people speculate that there's gonna be one signal from one gene. Because that's what it is in almost every other animal. Other people have speculated, 'It might not just be one. It might be the sum effects of very, very many genes.' I'm somewhere in between. I think that there's probably only a handful of genes which are important for integrating maybe one or two signals. If we look in our data, it seems like what those signals might be are related to inflammation, which is the process by which you normally would think of getting an immune response. It could be that at the end of pregnancy, when labour and delivery are starting to happen, the mother is no longer willing to tolerate the presence of the foetus and the uterus, so her immune system starts to mount an immune response against it, which causes an inflammatory response.

Chris - How are you going to take this forward then? Because presumably you've now got a shopping list with 800 genes on it that you can begin fishing through things like 'what happens to those genes individually', 'their level of expression', 'whether they're on', 'whether they're off', the temporal, the timing dynamics of how they change during pregnancy is. Is that the way forward now to start going through them with a brute force process of elimination?

Vincent - That's exactly right. That's also the most challenging part. Because that means you have to study each of those genes and there's a long list of them. It's also really challenging to do these kinds of experiments because you can't manipulate pregnant women. To get around that, what we can do is do cell culture work in the lab, where we can grow uterine cells in a dish, and grow foetal cells from the placenta and see how they interact with each other. The other way that you can start to study the effects of these genes is to look at women who have challenges during pregnancy. Maybe they have infertility or they have recurrent spontaneous abortion, or they have preterm birth. We can sequence these genes in those individuals and see if they have normal, healthy functioning copies of these genes, or do those genes include mutations, which might have an adverse effect on their function?