Human birth trigger genes, and clam cancer
This month, the genes linked to human birth onset, signs hunter gatherers already had a taste for cereals before farming came along, how sunflowers balance UV protection, aridity resistance and attractiveness to pollinators, a contagious cancer that can jump the species barrier, and inside the eLife Ambassador Programme...
In this episode
00:36 - Genes that trigger human birth
Genes that trigger human birth
Vincent Lynch, University of Buffalo
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?
07:49 - Hunter-gatherers had a taste for cereals
Hunter-gatherers had a taste for cereals
Emanuela Cristiani, University of Rome Sapienza
These days, most of us are fed by farming. Previously, though, we lived a very different lifestyle: one dominated by hunting and gathering. How that transition to agriculture and urban living happened though isn’t well understood. Scientists have long suspected that early hunter gatherer communities already had a taste for many of the plant species they subsequently began to farm, but the evidence for this was limited to sites only in Greece. Now, speaking with Chris Smith, Emanuela Cristiani, from the University of Rome Sapienza, explains how she has found evidence - from tooth tartar and early tools - for precisely this transition also happening in the same way in parts of what is now Serbia and Romania…
Emanuela - There is a big unknown, which is whether foragers used plant foods in their diet before the arrival of farmers; before the introduction of agriculture.
Chris - When did farming actually get started?
Emanuela - In this region, it arrived around 8,500 years ago.
Chris - Before that time, what did we think life consisted of?
Emanuela - The diet and the subsistence was mainly focused on hunting and fishing and a very limited gathering of possible plans.
Chris - Is the evidence strong for that? Is that just our inference because we can see a line in the timeline where people start to gathering communities that are a bit more permanent and that goes with agriculture, or do we actually have rock solid evidence that we can point to, to say 'that's how people were living, and this is what they were probably eating'?
Emanuela - At that time, before agricultural societies were definitely more mobile. We are thinking that they were possibly hunting and gathering more than living in villages. But there is another problem here for the reconstruction of diet is that the evidence we get in archaeology is stronger for bones than for organic remains like seeds or plant remains, meaning there is a preservation problem.
Chris - Is there a way around that?
Emanuela - Yes, absolutely. We have to work with evidence that is in a way indirect. One is the actual use and consumption of plant foods that can leave the residues in the mouth, on the teeth. The other is the study of technology that is used for processing the plants and extract the nutrients from the plants.
Chris - When you say "residues in the mouth", is this plaque on teeth?
Emanuela - Yes. The plaque, the dental tartar which is a sort of mineralised plaque can survive for millennia on ancient teeth. We in archaeology consider it as a special treasure trove, because the plaque can trap particles of foods, but also can trap bacteria, particles of the environment that we inhale when we breathe, or when we use the mouth as a third hand.
Chris - Where did you get plaque to look at? Who have you been studying?
Emanuela - We have been working on a huge number of individuals that were buried in a number of sites in the Dream George in the central Balkans, which is a region where we have important documentation of hunter-gatherer communities in the period before the arrival of agriculture.
Chris - And so this is people from pre-8,000ish years ago.
Emanuela - Yes. People from 11,500 to around 8,500 years ago.years ago to the arrival of agriculture.
Chris - And the obvious question then is, when you look at what these people were eating based on what's trapped in their teeth, what do you find?
Emanuela - Starches, which is the most important energy reserving in plants. In particular, we found granules of this starch, which is the form in which the starch is preserved in specific organs of the plants, like roots or seeds. Those are the parts that we are interested in when we want to eat plant foods. The types of starches we found in the dental calculus, but also on the stone surfaces were typical of certain species of wild cereals and also other types of plants like oats.
Chris - This would tell us then that these hunter-gatherers definitely were gathering, and certainly a part of their diet comprised of cereal crops that were wild grown, presumably. Is this a stepping stone in some respects then, because agriculture didn't just suddenly spring up. Did people, do you think, become familiarised with these plants and then begin to domesticate them? What you are seeing here is that stepping stone, that early prelude to familiarity with the crops that we were going to start farming later.
Emanuela - Yes, exactly. The findings we found meant that these foragers in this region have been sharing knowledge they knew about this plant species for quite a long time, as we found some of these starches, even in individuals dated to 11,500 years ago. It means that at least for 4 millennia before the arrival of agriculture, these people knew and used these pieces in their diet. This also meant to us that this familiarity might have eased. It might have created a sort of taste palatability familiarity with a sweetness of, for example, the grains and eased the acceptance of these plants once they were brought in a domesticated form by the farmers.
Chris - And was it just the practice of farming that was then embraced? Or was it that prior botanical knowledge of those plants that they were also incorporating? Was it both? As in, they became familiar with eating those plants, they became familiar with the plants themselves, and then they domesticated them, or did someone else come along with the know-how and say, 'this is how you do it. This is what you grow.'?
Emanuela - I think that what was brought by was the knowledge of cultivating probably the seed, but not the familiarity and the taste of them, which was known for quite a long time.
Chris - Do your results broadly agree then with what we thought was the process through which farming was embraced in this area and more broadly, or are there any areas which don't quite line up and which might therefore be interesting avenues to pursue?
Emanuela - The results absolutely agreed with what was embraced for the area, for the arrival of agriculture, but also for what the connection between the farmers and the foragers were in this area based on other evidence. For example, we found on dental calculus, evidence that already the latest hunter-gatherers in this region were consuming domesticated plants and domesticated cereals at the end of their life as hunter-gatherers. This means that they probably exchanged domesticated species, domesticated grains with other communities that were farming communities living around 8,500 years ago in the region. In a way there was familiarity with the plant foods, but the results shed light on the way this change in our history happened.
15:50 - Sunflower genes for UV and pollination
Sunflower genes for UV and pollination
Marco Todesco, University of British Columbia
Native to North America, sunflowers are instantly recognisable. But, to pollinators, some are more eye-catching than others. And that’s because they have hidden pigment patterns that make the flowers look different to animals that can see in the ultraviolet part of the spectrum, like bees. It turns out that those patterns are down to a molecule produced by a single gene. And as well as making plants more or less attractive to insects, can also protect the seeds from UV and affect how the plant handles water and keeps itself cool. Making it comes at a metabolic cost though, so the plants out there in nature have to balance resistance to aridity and UV exposure against attractiveness to bees and other pollinators, as Chris Smith hears from Marco Todesco…
Marco - In this particular case we looked at flower colour, which might not be the first thing that comes to mind with sunflowers, because they all appear yellow to our eyes, but we knew that there are ultraviolet patterns in their flowers that we can't see, but that pollinators like bees can see. What we found is that there's a tremendous amount of diversity. We set out to figure out how they're able to have this diversity, what is the genetic basis, what are the genes that make this sunflower look so different from one another to bees, and why are they are so diverse?
Chris - When one looks at the relationship between the patterning and the behaviour of pollinators, does it make a difference? Do plants that have different patterns get different responses from the insects that pollinate them?
Marco - Yes, that's actually the case. We found all kinds of variations, UV absorbent in the middle and UV reflecting on the side and it's known that this is helpful to attract pollinators. We found plants that have completely UV absorbent flowers and completely UV reflecting flowers. We found out that pollinators tend to prefer plants that have intermediate patterns, a bit UV reflecting and a bit UV absorbing.
Chris - And were these just randomly distributed as part of a mixed population right across the geography you studied, or did you see that certain places have certain characteristics of these patterns?
Marco - That's the thing that really stood out. So, the first question was, if one pattern is better than the other for pollinators, why do you have this diversity? And then we started to look a bit more into this, and we found that the variation is not randomly distributed across North America, some patterns are more common in some areas and some in others. We tried to look at what might be driving this and we found that sunflower populations that came from very dry places had larger UV absorbing patterns.
Chris - And how do you tie that to the fact that they've become more common in those areas?
Marco - We try to look at what may be the reason as to why these different populations have different patterns of UV. We found that there is one gene that is controlling most of this diversity and this gene is responsible for the production of a class of chemicals which are called flavanol glycosides that are UV pigment - they create these patterns, but they're also important for the plant to resist different kinds of environmental stresses. One of the things that these flavanol glycosides do is help plants control how much water they lose from different tissues. Plants that had more of these UV flavanols, in dry environments, were able to retain more water from their flowers. That's, of course, something that is very important if there is not a lot of water to go around. That's probably one of the reasons why larger UV patterns, a higher level of accumulation of these chemicals, is selected in dry places.
Chris - Presumably there's a metabolic cost to doing that, which is why you get the diversity in other areas of the country where you don't have the same drive to defend yourself against desiccation?
Marco - Yes. That's a very common pattern that is seen in ecology, right? Things that are favourable in one environment might not be favourable in another one. There's probably a metabolic cost, which is why somewhere else won't have these smaller patterns.
Chris - It's interesting, isn't it, that one gene makes the pattern change and the pattern protects the plant at the same time against water loss, but also affects how attractive it is to pollinators? It just goes to show how rich the web of connections in any given ecosystem is in terms of how organisms all interreact and interrelate to each other and how they behave.
Marco - Yeah, absolutely. I mean, it shows that things are never quite straightforward, right? And that evolution can drift in any way. So, if it can get two things done with a single gene or with a single trait, it'll certainly try to do that.
20:32 - Clam contagious cancer jumps species barrier
Clam contagious cancer jumps species barrier
Alicia Bruzos, University of Santiago de Compostela
And now to the process by which cancer spreads - but we're not talking about within an individual, we're talking about between individuals - so called "transmissible tumours" - where cells physically move between individuals. And Alicia Bruzos, at University of Santiago de Compostela, explains to Chris Smith, she's discovered a new example of a transmissible cancer, this time among clams. But the twist here is that these tumours haven't just jumped ship from one clam to another, they've also jumped the species barrier. By using genetic sequencing, she's been able to show that cancer cells originating in a species known as striped venus clams are now cropping up in their cousins, the warty venus clams, and she suspects that the cancer may even be stowing away aboard ships, with obvious implications for the ecosystem…
Alicia - Usually cancers start in a person or in an animal. They develop and they are able to travel to other organs or tissues of the body, which is called metastasis. But, whenever that individual or that animal dies, the cancer dies with it. But that is not the case for contagious cancers. There are a few exceptions in nature, like dog cancer, Tasmanian devil cancer, and also some viral cancers that are able not only to spread among all the tissues of the individual, but also to jump to other individuals in the population. So, that's why we call it a contagious cancer.
Chris - Literally, then, a cell leaves one individual and gets into the body of another individual and carries the disease process with it. It becomes a new cancer in that new individual?
Alicia - Right.
Chris - In the case of Tasmanian devils, we are comfortable that when they fight and bite each other, they could perhaps inject cells from one animal into the other, and that could happen in the case of dogs, it's a vaneal tumor that's sexually spread. What's the bivalve (shellfish) equivalent?
Alicia - That's a very good question and it has not yet been answered, but we have some ideas of how it can happen. These contagious cancers in bivalves are a leukaemia-like cancer, a cancer that is found in the circulatory system of these animals. So, what we might be happening is that those cells are probably released to the marine environment, by death or by active breeding of the cells out of the body, and somehow these cancer cells are able to last in the marine water. As these animals are filtering the water, by chance, they take those cancer cells that are floating in the marine environment and, once they are inside the body, they start to divide and to make cancer.
Chris - The scientists that have investigated the Tasmanian devil transmissible tumors were able to show, genetically, that the cancer cells are quite distinct from the host they find themselves in, proving that it is the cancer that's spreading. Have you got evidence that the shellfish have done the same thing? Can you find cancer cells and show that they're genetically completely different to the host they're in? Therefore they must have come part and parcel from outside?
Alicia - Yes. When you look at the cells, they are already different from the healthy cells that other individuals have. But when you go and read the DNA and study the genetics of those cells, you find that the DNA of the cancer cells is not similar to the DNA of the healthy cells of that individual. So, yes, we find it is the same as with the Tasmanian devils.
Chris - Is it from the same species? Because the thing about the Tasmanian devils is it's a Tasmanian devil giving a cancer to another Tasmanian devil. When you look at the shellfish, is it the same species of shellfish giving a cancer to another shellfish of the same group?
Alicia - There are several contagious cancers described in bivalves and in some of them, like for instance in cockles, a cockle gave rise to a cancer which was then found spreading among cockles. But, in the case that we are talking about here, the cancer arose in a different clam, the striped venus clam, and now it is currently spreading among the venus clams and all these striped venus clams that we have screened have no cancer, although this cancer originated in them.
Chris - So, putting that another way, you've got one species of clam that spawned the cancer in the first place, and it seems to have not just jumped out of them, it's jumped ship entirely and got into a completely different species of clam and is causing a headache - or a blood problem - for those clams. And it's the difference in the genetics that tells you it's come from one species and into another?
Alicia - Yes, effectively.
Chris - Are you worried that we seem to have a cancer that can transmit between species?
Alicia - Yeah. That's something that we have to be careful with. I mean, if these cancers are able to spread to closely related species, that poses a threat for the environment of these species,.
Chris - I suppose one important vector for that happening is international trade and shipping because we know that boats pump out water from their builds that could contain marine life. We also know that they have, clinging to their hulls, various shellfish and other marine animals that they take on their journey with them. If those animals are discharged at a remote location, yes, they could become an invasive species, but they could also discharge cancer cells that could then infect the locals?
Alicia - You're right. And in this study, we found the same cancer in the Atlantic coast of Spain and also in the Mediterranean coast, more than a thousand miles away. It's difficult to imagine a cancer cell floating and travelling that far, so our suspicion is that yeah, maybe human activity has had some role.
Chris - What's the take home message from your study, then? You've confirmed that there is a transmissible tumour that can jump the species barrier, but it is in quite a limited repertoire of animals at the moment. Are we sort of reassured or alarmed off the back of your study?
Alicia - We are describing a new cancer and, if we are spreading them, we should be taking some measures to avoid that because this could reduce the quantity of species. It could bring disease to places where it was not originally found. And all these things are not good for the environment.
28:17 - eLife Ambassadors
Ailis O’Carroll, eLife, & Aalok Varma National Centre for Biological Sciences
eLife is more than just a ground breaking digital journal. Ten years on from when the initiative launched, eLife has continued to actively seek out ways to confront the challenges that science and research present internationally, right through from overhauling the peer review process to a focus on early career scientists and scientific careers. One strand of that is the Ambassadors Programme, which uses the journal’s international reach and standing to bring scientists together around the world and empower them to make beneficial changes to things they perceive as needing a shake up. So how are they getting on? Chris Smith spoke with Ailis O’Carroll, eLife’s Community Manager, and Aalok Varma, who previously participated as an Ambassador...
Ailis - eLife has an ambitious agenda to reform research communication. What we've realized is we actually have to look into what is going on with research culture and what we need is the voices from all of the research community around the world. We've decided to create an ambassador program where we invite early career researchers, from around the world, to get involved to see what is wrong with research culture, what can we change, and how can we make it more inclusive for everyone?
Chris - And once you've identified people to come on the program, what do they actually do?
Ailis - From the 350 applicants, we have 128 ambassadors. They're from 51 countries around the globe, the most diverse we've had so far. The ambassadors will engage in the training phase, which is 8 to 10 months of learning and community building, which we think is really crucial. The ambassadors have the drive and the passion to make change, but we will provide them with the tips, the tricks and the network. After those 10 months, which will bring us to around September this year, we'll do another 12 months a year of activism where we raise awareness about issues in research culture, the barriers that people may be experiencing and come up with solutions.
Chris - Tell us a bit about the kinds of people that applied. What level of their career were they at? Was it more women than men? Or about the same?
Ailis - Everyone from people who have just graduated, just starting their PhDs, right through to people who are up to 5 years. We had half women and half men. It's been a really diverse group and we've been able to select ambassadors who will bring forward experiences and voices to the table who haven't really had their voices heard before.
Chris - I know you've said that there's this phase of activism where they do community building, but what's actually involved in that? If I were on your program, what would you be empowering me to do?
Ailis - If you were extremely interested in sustainability in the lab for example, throughout the training phase, you would learn tips and tricks from different organizations and speakers who have come on board, you would connect to a network of like-minded people, your group then can push forward change based on your community needs. That can be so dependent on what is needed. It could be sending emails across to your university, it could be creating a resource sheet, it could be staging an event or a symposium. It will really depend on the group and Aalok can actually say a lot more about this as he was an ambassador.
Chris - Yes. What was your experience?
Aalok - When I signed up for the ambassador's program, I was actually going through a rough patch in my PhD and I didn't know what I was gonna do. I just took a chance and joined the program. There was a group, as Ailis was saying, which worked on sustainability and raising awareness of how research labs use up a lot of plastic, for example. Of course, it's important to try and control our plastic usage, and what they did was ambassadors got together and they did a #labplasticday on Twitter, where they urged everyone to just collect all the plastic that they have used on one day, and wait, and take a photo of themselves holding all the garbage that they produce in one day. Soon you realise that it's a staggering amount of plastic that we used in our lab spaces all the time. Another example was a meta research study that I was a part of. Meta research is all about studying how science is done. The project that we did was about looking at how papers report images. If you're looking at something, you want to know how big it is. Whether it's a cell or an elephant or a plant or whatever it might be, you need to have scale bars. Not everyone is colour sighted, there are people who are colour blind. We assessed papers that are published to try and ask 'how well are images reported in these papers?' We found that less than 20% of papers, regardless of field, actually follow good practices in reporting images. We try and find ways to look at an introspect as a community, to figure out what we are doing wrong and how can we improve it?
Chris - So Ailis in essence, you're using the international reach and power of eLife as well as the fact that science is an international language and a community to create a sort of hub that people can come to and really they're setting the tempo, by the sound of it. They're coming up with some of the priorities they're coming up also with the solutions.
Ailis - I think that remote working and virtual networking comes with its problems, but it also comes with this great advantage that we can connect all around the world and push forward solutions. I'm excited for this program because there are so many driven and passionate researchers around the world who are coming together. And the knock on effect of that, I think it'll really make a big change this year.
Aalok - Scientists are not one dimensional people, they're not just spending all their time in the lab. They have interests and hobbies to connect, not just on a scientific level, but on a personal level with scientists across the world, with something I managed to get an opportunity to do by this program. I'm really thankful for that.
Chris - Ailis, one of the things that's often levelled as a criticism at engagement programs is how you measure success. How are you judging whether this is working?
Ailis - Particularly in science, where we depend on tangible results, we can publish the various papers on awareness, create resources, we can make websites. But if the impact is not felt on the personal level of researchers, I think that we're not doing our job properly. What we've done is we've sent surveys and we'll send surveys every quarter of the year, just to check in on everyone. We'll also have social meetups where people can express how they're feeling and how they feel like the program is impacting them.
Chris - Any learning points? Anything that when you went into this, you thought you would do it a certain way, you ended up doing it a different way?
Ailis - I guess one big one was the fact that we knew that we couldn't select all 350 applicants. It felt very wrong to say, 'okay, thank you very much'. We've now set up another program called the 'open science champions' program. From us, seeing that we couldn't include everyone, we've now actually turned that on it's head to make a much more inclusive network now, which is great.