 Today, we have with us Dr. Satyajit Rat and we will discuss some new interesting findings how mammals have evolved. There is a new paper which has emerged, which has come recently on Cell, talks about evolution of mammals. What is this new finding that people are talking about? It's nice for us to be able to talk about problems such as evolution, which may or may not have anything to do directly with science and public policy occasionally. In public discourse in general, I would say, wouldn't you? In any case, it is an interesting finding. So the finding arises from the basic issue that we all take for granted, which is that a very small group of species ourselves included carry our young within our bodies, clearly not yours or mine, but women's bodies. But most species don't, most species lay eggs. So when you think about evolution of body design, how the way bodies function and are put together functionally has altered over evolutionary time. This is a major transition. Either you lay eggs in which the developing organism, the baby as it were, is separate from the mother's body or as in mammals. The baby is carried within the mother's body. I should be technically correct and say placental mammals, but we will come to that in a bit. What are the consequences of such a design alteration as with engineering principles? Every time you make one design alteration for an intended outcome, there is a whole host of unintended outcomes that need to be dealt with. And really what this paper tells us is how over the course of evolution, one of the unintended outcomes of this transition has been dealt with. So the unintended consequence of this transition has been that the baby's blood and the baby's tissues in humans or in proper mammals come into contact with the mother's blood, mother's tissues and the mother's immune system. Most of the times, since the baby expresses HLA types, tissue typing molecules where we know tissue transplant rejections happen, those molecules, those proteins are inherited in the baby both from the mother and from the father. So why does the mother's immune system not attack the embryo, that is the key issue. That has been a major issue for both reproductive biologists, immunologists and evolutionary biologists to understand for a very long time. This is as a problem, as a conceptual problem, we have understood this for a very, very long time. And a number of mechanisms have been invoked to explain how the mother's body tolerates what is effectively a foreign graft. The baby and the placenta through which the baby attaches to the mother's uterus is in a certain sense a half foreign graft. The mother's body for nine months tolerates that half foreign graft allows it to grow and then at a certain stage allows birth to take place. There are two separate categories of problems. One is how is the uterus engineered, how does the placenta form and so on and so forth and those are sort of nuts and bolts problems. The issue of why does the mother's body tolerate it in the first place, what are the mechanisms through which tolerance happens has always been a problematic issue. So what this paper that you are referring to in Cell a couple of months ago by Samstein Neta describes is an extremely peculiar finding. In our immune system, there are cells that normally suppress our immune responses to certain targets. So for example, we can all generate autoimmune, self-directed immune responses, but we have suppressor cells that normally don't allow us to generate those responses. There is some evidence that at least in some chronic inflammatory and autoimmune diseases, these suppressor cells may be defective. That can lead to things like lupus and so on. That can lead to things like rheumatoid arthritis, lupus, multiple sclerosis, diabetes, many of these diseases have an autoimmune component that may involve these suppressor cells not functioning properly. So for a long time there has been argument that these suppressor cells are also involved at the placenta between the mother and the baby in making sure that the mother's immune response doesn't function against the placenta and the baby and the fetus. So people have made this argument for a long time. One can argue that if that is the case, then in animals which don't have these suppressor cells, pregnancy should not happen and that's not what happens. Instead, the finding is a little more peculiar. The finding is that when you create suppressor cells, when the immune system during its development creates these suppressor cells, it creates two kinds of suppressor cells. One are suppressor cells from the beginning from when they are generated as suppressor cells. But the other category is a category where normal non-suppressor cells go and see a target. But the microenvironment is such that instead of becoming effector cells that begin to function against the target, they turn into suppressor cells. Now the same molecule is involved in creating both categories of suppressor cells. How that molecule is expressed is under regulatory control, instruction control, coding control that is different. And obviously the switch for expression is a different switch. So in the cells that are born as suppressor cells, a different switch is used for turning this molecule on. In the cells that are subsequently created and instructed to become suppressor cells, a different switch is used. What Samstein and colleagues show is that only in placental mammals is the second switch available in the genome. So the first switch is available in everybody, but the second switch is available only in placental mammals. That is a dramatic finding. In the first place, because remember marsupials are sort of betwixt and between egg-laying mammals such as duck-billed platypus and so on and so forth versus true placental mammals like us. Marsupials do not have the second switch, they only have the first switch whereas all true mammals have both the first and the second. All those who have placental mammals have the first and the second switch. And the second switch which is involved in suppressing the mother's immune system in a way that the embryo is not attacked. So the prediction would be that if the mother is carrying a pregnancy in which the father's genes have some differences from the mother's genes, then the role of these cells would be significant. And that is exactly what Samstein et al. have shown. What they do is they make a genetically engineered mouse where the second switch has been deleted. Now these mice of this strain if the females are mated with males that are genetically identical to the females, then the pregnancy is unaffected. But if the females are mated with males that are not genetically identical to the females, those pregnancies tend to fail much more if the second switch is not available. And even if they don't fail, the birth weights of this mice are much less and so on, which would seem to indicate that the immune system is still attacking the embryos in some way or has not been fully suppressed. And this happens even though the suppressor cells obeying the first switch are present. They don't seem to be good enough to mediate protection of the fetus. What is required for protecting a non-identical fetus is the second switch and the cells that are generated as a result of turning the second switch on. Now this is quite extraordinary because it has two implications. It says that when evolution happens, there are large building blocks of design alterations that take place and here is one major building block that has been altered. And very commonly during evolution, these building blocks seem to be carried by viruses. Viruses that get integrated randomly into host genomes seem to carry fragments back and forth. So, remember in GM crop related discussions, this issue of horizontal gene transfer very commonly comes up. Can non-species transfer genetic material to other species? When we discuss bacterial resistance to antibiotics, we repeatedly discuss horizontal gene transfer of antibiotic resistance genes between bacterial species. Even in us, horizontal gene transfer by viruses of this kind seems to have happened. And it is instructive that many of the major features of vertebrate and mammalian body design control are located and have sequences that seem to indicate a viral insertion. So, it is almost as though viruses have inserted something randomly and during evolution it has been accidentally found to confer a certain set of properties that have led to better survival in species. So, Saty, that opens up a completely different question that incremental evolution can take place through really small mutations taking place in a species. But if a major structural alteration takes place, then it is likely to be this kind of insertion. Is that a possibility? Well, it is certainly one possibility. I do not think there is any evidence for us to say that it is the possibility. So, at the moment it remains a curiosity that many of the regulatory features seem to be virus insertion related. But I propose of what you said, it is interesting that many of these insertions are major game changers in design terms. They are not incremental in the sense of changing only one small thing. They change a large set of downstream consequences in body design. And that, again, is interesting. That is the other issue. When you have incremental changes, then the large logic of evolution, small changes fitting into the environment takes place. When you have major structural shift like this, some of it can survive, most of it will not. But when it does, then the changes are likely to be such that they would not be just one small change, but a range of a set of changes, not just something small having changed, but a large number of things having changed. Some of them would give evolutionary advantage, some of them are just contingent. Would that be right? Oh, absolutely. So, two separate issues related to that. One, this notion that during evolutionary history, it is possible that we have had long periods without major structural change leading to speciation. And then short periods where lots of speciation with large structural change has happened fits very plausibly with what you just said. But it is also true that sort of by-product baggage of evolutionary history is clearly inherited alongside the advantages that confer survival. And in that context, the Samstein et al paper is very revealing about something that the authors do not quite, I think, discuss. And that is when they meet a genetically identical pair of male and female, whether the second switch is present or not doesn't make any difference. True. But the failure rate of pregnancies in such a situation seems to be a little more than the failure rate of pregnancies from a non-identical male and female pairing. So, it is almost as though non-identity carries an evolutionary advantage and in order to allow non-identical pairing to survive, this second switch has been terribly useful for us. You know, I am just going back to the other issue which was one of the major battles between evolutionary biologists. Gould, in particular, was the one who proposed the hypothesis of spandrels and contingent evolution and so on. In other sense, bogus that is really everything happens by effectively an incremental evolution hypothesis. So, this would seem to indicate that Gould had a point in what you were saying. Oh, absolutely. So, I will give you an example of this particular cell type itself that fits this. These are cells that are clearly useful for successful pregnancy where the mother and father are not genetically identical, which as you know, outbreeding has evolutionary advantages in terms of species survival. But it turns out that these are cells, these particular cells, second switch dependent cells are also cells that allow us to strike a harmonious balance with, for example, the microbial communities that live in our guts. That second switch being absent has consequences, not simply for pregnancy, but also for gut homeostasis and gut balances and gut equilibrium. Clearly, our gut contents protect us from a number of truly pathogenic bacteria. They also provide a certain kind of nutritional backup for us, whether by making vitamins, whether by making certain kinds of nutrients more accessible and so on and so forth. And currently, there is a great deal of interest in how our gut microbiota may actually be controlling a variety of our physiology ranging from obesity to diabetes to mood changes and so on and so forth. We are what we eat. We are what our gut contains. And it is possible that these cells have helped provide a much finer control for calibrating ourselves with our gut contents than non-placental mammals have. You are saying that our gut content is far richer in bacterial growth than other animals? Our equilibrium, our balance with our gut resident bacteria is far more complex perhaps than in the situation of animals which don't have these cells? Satyajit, last question. This is really a matter of a major scientific breakthrough in terms of understanding nature. May not have immediate medical or health other implications. Would that be right? As it happens, I would have loved to say yes, since I would argue that scientific understanding has value in and of itself. Fortunately or unfortunately, the answer is no. We actually have a situation where this finding in addition to being meaningful in purely scientific if you like ways may have consequences for our understanding of human pregnancy failure. So, I will give you an example. Toxemia of pregnancy, clamsia and preeclampsia are conditions that are life threatening to the mother and that have very bad outcomes potentially for the life of the baby that mothers carry. There is evidence that these conditions may be related to a failure of the mother becoming tolerant of the baby that she is carrying. And it is therefore possible. There is some very preliminary and very tentative evidence, but it is possible that a failure of this category of cells may be contributing to at least some of this major problem. Given our situation where our public health is poor in its provision particularly at point of care situations, given our situation where mothers have very low health status to begin with so that they are very prone not to be able to deal well with these kinds of situations. For us to understand mechanisms and to be able to eventually come up with an intervention would have public health consequences as well. Thanks, Satyajit. This has been very interesting and we will discuss hopefully more scientific breakthroughs in the future, not just public policy. Thank you.