Babies cry in utero, and pushing preprints

Developing babies learning to cry, brain structures that underpin speech proficiency, and the power of the preprint...
11 November 2022
Presented by Chris Smith
Production by Chris Smith.


This month, what ultrasound scans are revealing about how primates learn to cry before birth, the new imaging technique highlighting brain structural changes linked to speech and language impairments, why eLife is breaking the publishing mould to prioritise the preprint in future, and how evolution turn a single lung into a pair...

In this episode

Common marmoset, callithrix jacchus

00:38 - Babies learn to cry in the womb

Scans during pregnancy show marmoset babies making crying faces...

Babies learn to cry in the womb
Darshana Narayanan, Princeton University

When infants are born, some aspects of behaviour are ready to go right away while others take time to develop. Clearly embryogenesis is prioritising the maturation of some processes and neurological pathways over others. Crying and vocalising is one of them, because it's critical for soliciting care from a parent, signalling distress and in the bonding process. But most of the work on this has been carried after birth, so relatively little is known about what goes on during the pregnancy. As she explains to Chris Smith, Darshana Narayanan was at Princeton University when she embarked on a study using marmoset monkeys, which develop in a very similar way to human babies, to get some insights into how and when language development begins...

Darshana - Often, particularly when people are studying development, behaviours that are found at birth are thought to be hardwired. And so what we wanted to do is dig a little deeper. So these behaviours that are found really early in life, are they appearing mysteriously, or is there a time period before that these behaviours are developing?

Chris - What sorts of behaviours, specifically?

Darshana - In this case, it was communication behaviours. So babies cry on the day they're born. All babies do, human babies do, monkey babies do. And so our question was, how is it that they can cry at birth? What is happening before birth that allows them to cry?

Chris - Is crying something that's hard to do?

Darshana - It is. It requires coordination across many different systems. Your brain, all of your face musculature, your lungs, your vocal chords. And so yes, it is I would say it's a hard thing to do! Often when we think about young animals, we start thinking about them as soon as they're born, but there's a lot happening before they're born. And it turns out that much is developing before birth.

Chris - How did you study it?

Darshana - We worked with the monkey called the marmoset. They're little monkeys that are found in, primarily in Brazil, but now also in parts of Argentina, I think. They are very vocal. They reproduce quite prolifically, have multiple sets of babies a year. We can house them since they're tiny and sort of gregarious in family units. And so we bred these monkeys and then studied the foetuses by doing ultrasounds on the pregnant mothers.

Chris - This is a bit like having a baby scan for a human who's pregnant, isn't it? So what would you, what would you be looking at specifically when you were doing your ultrasounds?

Darshana - We would ultrasound them regularly. We were first looking for indication of pregnancy. Again, very similar to what's done with humans. The system looks very similar. The setup looks very similar except we bribe the mothers with, with marshmallow fluff, which I don't think we need to do with pregnant mothers to get them to lie still! And then once we saw that there was a baby, we trained the ultrasound wand in a way that we could always watch the face of the baby. And then did that almost every day for months and months to study how the facial movements of the baby were changing, and whether we could recognise the vocalisations of the baby marmoset in the foetus.

Chris - So it's basically crying in utero!

Darshana - So it is some form of crying. Where marmosets are a little different from humans is that they produce some adult-like sounds in their infancy. They're kind of contact calls. So when separated from the rest of the group, they produce this sound to make contact with parents or siblings or friends in some case, I guess. And that was the call that we tracked. It's a very distinct call. It can be very easily identified by length, by the number of sequential syllables that happen in the call. And so that is the call that we tracked.

Chris - And you can see that reflected in particular sequences and movements of the facial musculature?

Darshana - Yes, very much. Yeah. We could see that in the infant. We saw that in and to our surprise, and this was what the results of the study was, we saw that in the foetus and increasingly so as the foetus got older.

Chris - Now, when did that behaviour begin to manifest in the foetus when in its development?

Darshana - In this case, I cannot make a very firm statement because we, you know, we start seeing the face musculature at about the face, the architecture of the face at about ninety five days into gestation. And it's hard to tell whether that's because that's when the ultrasound picks it up or that's when you know the baby's actually making these movements. So that's when the first movements can be observed using the ultrasound.

Chris - And how far through pregnancy is that?

Darshana - The pregnancy in total is 146 days.

Chris - We've also done sort of similar scans on human babies. Do they show similar meaningful movements at a similar level of development? Or are these marmosets a bit ahead of what we see with humans?

Darshana - So with humans tracking them continuously, the way we've done in the marmoset is hard, which is why working with a primate is important. But there have been in the last trimester very, very clear evidence that that babies are making cry-like movements and smiling and frowning and doing lots of things that we recognise as expressions of sound or emotion in in infants.

Chris - Presumably this means then that there's, there's some kind of coordinated connection between the nervous system and the facial musculature in order to make those movements in the right sequences in the right sort of way to do this?

Darshana - Yes, absolutely. Absolutely. And the way and the way it happens is a coordination between the brain, the body, and the environment. In this case, space constraint is something that we hypothesised plays plays a huge role in in allowing certain muscles to move and others not. And that prunes the network body plan, tactile receptor distribution, and then of course the networks in the brain. And then it's the dance between these three elements that that for, you know, move development forward.

Chris - Do these movements just begin to happen spontaneously or are they provoked by something? If you play the sound of the mother's call, for example, does that make the infant more likely to make these sorts of movements? Are they reactive or is it just practising?

Darshana - <Laugh> It's it's funny you asked that. We did try, we tried to play play the sounds of mothers to the babies. It, it was, it didn't, we didn't see anything clear. It was hard to do because the mothers themselves would call back <laugh> the sounds and so sort of muddled. But there is good indication in, in all sorts of animals, humans included, that there's a lot of spontaneous movements happening that are not triggered by a stimulus of any kind.

Chris - And what conclusions did you draw from this? I mean, how does this move us forward? Apart from confirming that these sorts of complicated movements that are going to be very useful once a baby is born are being developed early during development. They're not just manifest from birth. Apart from that, what are the implications of what you've found?

Darshana - One of the big takeaways here is the importance of foetal life. We often forget that when a baby is born, it is not zero. There's nine months of development that has happened before. There's a lot happening during foetal development in humans. Almost every sense we have develops in utero. We even have some visual development. We can, you know, we see the, I think our visual system, the development is accelerated much more after we're born. But much of our development happens in utero.

A brain surrounded by vivid colours.

08:27 - Brain structure and speech impairments

Do reproducible differences in the density of the myelin that insulates nerve connections explain the gift of the gab?

Brain structure and speech impairments
Saloni Krishnan, Royal Holloway, University of London

Some people, without doubt, have the gift of the gab. They can almost speak in poetry, it seems. Others, on the other hand, struggle and find language a chore. Hitherto, we've tended to give individuals affected like this labels such as "dyslexia"; and indeed dyslexia can cause some language difficulties. What we haven't had was objective data on why this is happening to some people. Until now, at least. Because by using newer brain imaging techniques that can quantify the numbers of cells and their white matter axonal connections in different parts of the brain, as she explains to Chris Smith, Saloni Krishnan, at Royal Holloway, University of London, has found reproducible differences in the density of the myelin that insulates nerve connections, in regions of the brain concerned with executing things in the correct sequences and at the right times. These are key aspects, of course, of stringing a sentence together…

Saloni - I'm really fascinated by spoken language and how our brains kind of evolved to have spoken language, because I'm really interested in children who struggle to speak; to learn the words in their native language; they might struggle with aspects of the grammar; they might struggle to kind of tell you a story. Many of these children you probably think of as, say, dyslexic, as half of the children with dyslexia actually end up having language disorders as well. And I'm really interested in kind of what's going on in their brains. Surprisingly, actually, we know quite a lot about what happens and say autistic brains, or the brains of people with ADHD, but despite the kind of fundamental importance of communication, we actually know very little about what might be the kind of systems we need to kind of configure a talking brain, if you will.

Chris - So how did you attack trying to understand more about the process of development? Because there are several things sort of wired together in this, aren't there? There's the kind of how the human brain puts itself together and then how it acquires information from the environment to do things. And that's really what language involves...

Saloni - When we talk about language, in the adult brain, we kind of know what systems we use to speak language. There's been beautiful work from a number of labs that has really given us insight into how we process speech around us, how we actually speak and so on. And one thing that really pops out there is that the left hemisphere particularly areas in like the frontal bit of the brain and the temporal bit of the brain are very important. One thing that's really interesting though is that if children have a stroke really early on in life, like as they're being born, we don't find that they have the same kind of debilitating language difficulties that an adult would have. There's this kind of paradox that sort of set up, which is, we know these systems are really important in adulthood, but they don't seem to have the same importance or the same configuration in infancy or childhood. Kind of relating to that, we have this big population, so about 7% of children or about two children in every classroom, who fit that profile of children who have spoken language problems that I was talking about earlier. And given that when we just look at brain scans from these children - like a regular MRI scan - we actually can't see any differences with the naked eyes. So it's not like they've got a little bit of their brain missing or there's something really obvious. So whatever's happening is happening at a much more subtle level and that's the kind of thing we're trying to understand.

Chris - And what did you do?

Saloni - We actually used this really exciting new technique. So most people have probably seen a picture of an MRI scan and if you get an MRI scan of the brain, it's, it's fundamentally really, really exciting. But these brain scans generally tend to be quite simplistic in that you can can see grey matter, which is sort of neuronal bodies the, the kind of bits that we think are doing the kind of calculations and computations that we need. And then there's white matter which is like axons of the neurons. So kind of making up the connections between different parts. However, the kind of meaning of those numbers is like it's not meaningful. You're just saying, "is that a bit more grey, or is that a bit more white?" and that's how we've been making conclusions. There's been a new technique that kind of really flips this on its head, which basically means that you can put someone in an MRI scanner in London, you can put them in an MRI scanner in Oxford and you could actually get the same numbers. And we call this quantitative MRI. And the reason this is really powerful and exciting is that it means that instead of just talking about a bit more grey and a bit more white, we're actually talking about quantitative hard numbers. So we recently used this protocol to study children who have this profile of spoken language impairments and compare them to children who don't have any spoken language impairments. And one of these things that the quantitative scans can really tell us about is myelin. And what myelin tends to do is to make information transfer between neurons much faster. And so, generally, as you grow older, you get kind of more myelinated neurons. And here we were kind of able to look at, in children with language disorder and those without, what were the differences in kind of myelination across their brains,

Chris - What were the differences and what did that reveal?

Saloni - We've had a hypothesis for a little while that children with language problems, they really struggle with making things habitual, or sequencing things. Because, inherently, what you have to do in order to learn language is actually sequence sounds together. So, for example, let's take a word you might have never heard before, like "geckizeissacad", and you suddenly have to hold onto those sounds. And the order of those sounds is also particularly important. And as you do it over time, you just say right there are these patterns in language and they become almost kind of default. And you do this of course with grammar as well where you might have things like, you know "walk, walked" and you kind of have all of these configuration and rules. And again, the sequence there is very, very important. So we've had this idea that perhaps in children with language disorders, the parts of the brain that might be really responsible for learning those kind of habits or sequences might be different. Using this new technique, what we were able to show is that myelin in these regions that might have to deal with kind of sequencing, habit formation, and so on seems to be reduced in children with language disorder.

Chris - Do you think that that's persistent, or is there an opportunity to intervene?

Saloni - Well, we don't know yet. And I think one of the difficult things about these kind of correlational studies almost where we say it, this group has this and this group doesn't have it, is we also don't know if this is a cause or a consequence, right? So it could be - because the children we worked with were between 10 to 15 - so it could be that a consequence of having a language problem for a long time is that you don't develop the same kind of myelination profile. And if it's a consequence then it's not necessarily a target for intervention. However, if it's a cause it could be an interesting target for intervention. So basically we need more research to fine tune that.

Chris - Overall, what do you think the implications of this are? It's a very useful observation. It gives us some, some numbers now as well. But what can we do with this data? What's the next logical step for this?

Saloni - From a research standpoint? I think I've kind of hinted that this already we need to establish if this is a cause or a consequence. And the way we could do that is by having longitudinal studies where we would follow up children to say like, what's happening when you had these low levels of myelin, and we saw you say three or four years later what happened to you? Another way we could establish this is by, you know, doing training studies. So for example, if we gave people lots of language training, what might happen and then we've got some really interesting ideas about kind of genetics and how that also might be influencing these kind of myelination patterns.

A person makes notes on a manuscript

16:30 - eLife Changes Gear to Prioritise Preprints

Executive Director Damian Pattinson explains why this is the future of scientific publishing...

eLife Changes Gear to Prioritise Preprints
Damian Pattinson, Executive Director, eLife

On the 20th of October, eLife made the following announcement: “From next year, we will no longer make accept/reject decisions at the end of the peer-review process; rather, all papers that have been peer-reviewed will be published on the eLife website as Reviewed Preprints, accompanied by an eLife assessment and public reviews. The authors will also be able to include a response to the assessment and reviews. The decision on what to do next will then entirely be in the hands of the author; whether that’s to revise and resubmit, or to declare it as the final Version of Record.” So why is this happening, how will it work, and how will it shake up the dissemination of science, something that eLife prides itself on having done already? Speaking with Chris Smith, Damian Pattinson, eLife’s Executive Director…

Damian - Really what we're doing next puts pre-prints at the centre of research communication. Pre-Prints are something that we are extremely excited about. We see them as solving many of the problems that have really plagued research for, for many years. Most notably the issue of access in that they are fully available for anyone to read, and of speed in that they are immediately available. So, pre-prints have been really growing a great deal in volume over the last two years. And the pandemic, I think, really showed how important they were that that research could be shared immediately. So essentially all they are is an a, a version of a paper that is put online as soon as the author is ready to share it.

Chris - And why are you going down this road at all? Other places are doing this and you can be the beneficiary of it. So why do you need to go down this road?

Damian - It's more that we are sort of following a route that we are seeing the world go down, which is that, you know, if pre-prints do become the norm - and we do strongly hope that they do - then the whole publishing model needs to change because essentially they are published at that point. You are putting work online and therefore the publication process has already happened. So then the role of the publisher changes dramatically in that world. So in a preprint world, the, the question that the readers want to know is is this paper correct? And is it worth my time to read it? And so that's what our new model is seeking to address. We'll continue to perform our expert consultative peer review process that we've been developing over the last 10 years, and that will help us answer the question of whether this paper is correct. But then we're also sort of changing the bit around answering the question of whether someone should read it. So at the moment, that question is really answered by the venue that the paper is published in. So if it's an eLife paper, you can assume that it's going to be quite interesting and it's going to be maybe a sort of broader audience piece. So our model replaces the title of the journal with something much more nuanced and much more detailed. So we have these, what we're calling eLife assessments, and essentially they are short summary of the peer reviews, and they indicate both the significance of the findings and also the quality of the methods. And we think it will really reduce the wastefulness that happens in the peer review process at the moment where great reviews are often just discarded if a paper gets rejected by a journal. And this whole notion of a sort of accepted or rejected in a journal, which really doesn't work in a, in a pre-print world, is replaced with something much more nuanced and, and hopefully useful.

Chris - You're really redefining what pre-print means though, aren't you? Because at the moment, pre-print means I put something somewhere in a sort of what I think is vaguely completed form while a journal like eLife considers it. You're saying actually what we now call a pre-print is just the beginning of the scientific publishing journey, where there has been some value added by experts looking at it, providing peer oversight of that piece of work, and it can then subsequently be considered or, or adapted, adjusted in a dynamic way going forward. But that is the research as it stands at that point in time with you adding a star rating almost in terms of whether someone should trust it.

Damian - Yeah, that's broadly right. I mean, you know, in this system you start with what the scientist puts out there as their best attempt at explaining what they've done, and then we then enhance that. So the process does become much more dynamic. You know, the peer review process is then there to make corrections, to make suggestions for changes if necessary, and alert people to the importance of that work and the sort of significance of it. So in a world where the author is in control, and essentially that's what we're talking about here, the author is now the one who decides when they're ready to post, they're ready to, you know, what changes they want to make or, or, or anything. Then the role of the publisher does become one around making recommendations and suggesting to their readers that this is something that maybe of interest to them. So it's an extremely different world that we are envisaging here.

Chris - Does this get round one of the problems that people have traditionally said is an issue with peer review, which is that if a particular person is a bit unpopular in the field, or, or they're coming at the field from a direction where it's not aligned with the dogmatic view of how that field works, that they've traditionally found it very hard to publish. Whereas if you can do this, then you can get the community behind it rather than just a small pool of, of reviewers who might give you negative reviews.

Damian - It's interesting. That's, that's not a way I'd thought about it before. But yeah, I think certainly there is something much more kind of leveling about preprints. You know, anyone can post one there. I mean, there are checks that preprint servers do their own checks, but broadly, you know, if you are posting something that is, you know, robustly reasonable, then it will get posted online. And so all of a sudden you have this incredibly sort of equitable system where the journals then come in and provide review in a world where everything is already out there. So yeah, it does, I think certainly improve the kind of equitability of the system.

Chris - How about the reaction from the supporters, the scientists that are sending you their manuscripts and people who, who now highly value eLife and regard as one of the world's leading science journals? How's this going down with them?

Damian - I mean, the reaction has been amazing. When we announced a couple of weeks ago Twitter really set a light and we had more engagement than I think we've ever had on social media and beyond in our entire existence. So it has been extraordinary, and I think that's what sort of 10 years of, of, of building e Life has allowed us to do. The reaction has been incredibly mixed. I think some people see this as a complete game changer and a genuine alternative to the current journal system. Others are more cautious and they are waiting to see how it will play out, what these reviews, these new reviewed pre-print will look like how we will handle these sorts of workflows and things. And there's obviously apprehension from people who feel that this is too different, it's too dramatic and radical, and that's all fine. I mean, that's exactly what we're expecting. But overall, there was a clear feeling from Twitter at least, that this is a sort of revolutionary change and people did really understand the scale of it. So from that point of view, I think it's really successful and extremely exciting.

Chris - I wonder what Elon Musk will have to say about it, now he owns Twitter <laugh> one's always very cautious about what the Twitter sphere says, cuz we know that can go in either direction. What's the business model? How much does this cost? And who pays what?

Damian - So the business model is changing as well. Obviously, in a world where we are posting these reviewed preprints for everything we review, then it doesn't make sense to to only charge a subset of the authors. So the, the previous system, we were only charging publication fees to accepted authors. And obviously now that we're moving away from a kind of binary accept, reject decision, we are changing our model so that we would then charge a publication free to everyone who we post a review preprint for. So essentially every paper that we send for review, we will then charge the author for for the, the work that we do to to review and to to post the reviewed pre-prints.

Chris - Does that - sorry to interrupt -does that include everyone everywhere? Because one of the other attractions of eLife in the past is that some countries, and for instance, our colleagues in Africa who've published an amazing sequence of palaeo papers in eLife did so because they wanted to make sure that other poorer African countries could still access effectively heritage data that would otherwise be snatched away and put behind a firewall with some of the other publishers.

Damian - So yes, we are still continuing with our waiver policy, which we, which we've always had, which is essentially to say that if you can't afford to pay for a publication fee, then we won't ask for one. We'll continue to do that. The other thing I just wanted to say was, because we're obviously charging authors we send for review, that means that there are more authors to charge and it means that we can reduce our fee to any one author. So it used to be $3,000 and with this new model it will be $2,000. So it's a dramatic saving for any individual author.

Chris -
And parting thoughts on what you want to do next?

Damian - I think this is going to take some time for people to really understand and to get behind. So I think the next few years for us will be around learning how things change, what, what we need to do differently, and, you know, to continue to kind of support all our authors and readers to make sure that this, this system still works and gives them everything they need. So I think we're going to be very busy with that. But I think what we have now is a kind of clear direction of travel. It's been amazing to finally announce this work so that we can really sort of start engaging with the community on how it really works in practice. So so that's going to be all of our work for the next few years.

Australian lungfish (Neoceratodus forsteri)

26:10 - How one lung became two

Primitive fish that invaded the land had a single lung; so why have terrestrial animals all got two?

How one lung became two
Camila Cupello, University of the State of Rio De Janeiro

Look inside the chest cavity of a land-living vertebrate, like one of us, and you find a pair of lungs. But life on land owes its origins to animals that evolved first in the water and then, about 400 million years ago, came ashore. The animals that did that were fish, and the fossil record, understandably patchy as it is from this era, suggests that these species developed primitive lungs to enable them to breathe air at the surface so that they cold survive in oxygen-poor water. But based on species that still survive today, these lungs were all unpaired single structures, not the paired entities in you and I. So, how, and why did one turn into two? Speaking with Chris Smith, Camila Cupello, at the University of the State of Rio De Janeiro, has been scanning embryos of different groups of lunged fish, and salamanders that spend part of their lives in the water yet also have two lungs. What the developmental patterns reveal is that the switch to a pair of lungs seems to have coincided with the exit from the water and appears to be a critical part of the adaptation to life on land, probably by boosting the efficiency of the respiratory system…

Camila - Fish are the first group that have a lung, that have the same origin as our lung. So we can trace the evolution of this organ.

Chris - Are we talking here about primitive fish that develop lungs so they could breathe air from the surface? So they would live in water, but they would breathe air from the surface. And they did that by having some kind of lung structure?

Camila - Yes, we are talking about this kind of fish that can breathe air.

Chris - And so which fish have you studied to get at this question then?

Camila - We studied very primitive fish. We can say like that. All the groups of fish that have a lung.

Chris - And are their lungs like our lungs? If you look at those fish and look at their descendants today, do they have lungs that if I saw them I would recognise as the same as mine? Or are they different?

Camila - They are a little bit different because they are paired and they have less compartments. So they are a little bit different, but they have the same origin, the same evolutionary origin. The lung.

Chris - When you say unpaired, I've got a right lung and a left lung. So, hopefully have you! But these fish would've had a single lung, is that what you're saying?

Camila - Yes. They have only one lung.

Chris - So does that mean the question becomes how that one lung turned into two lungs?

Camila - Exactly. We try to understand how this single lung, this one lung turn into a paired lung.

Chris - And so how did you study that? How did you attack the problem?

Camila - When we scan embryos, we can understand the evolutionary pattern of the development of the lungs. So we made some tomographies to understand this.

Chris - And what did that tell you? Did it reveal how you got from a single lung in these fish to two lungs in animals like us?

Camila - Yes. This was very important to understand and to reveal. How was the lung during evolution, during the water to land transition. Because the paired lung appeared in groups that live out of water.

Chris - How do you know that? What was it that told you that the lungs only became a pair once the animals were out of the water?

Camila - When we studied the groups, we could see that single lungs were present in groups that were in in the water and paired lungs were present in groups that are out of the water. So we can trace back this.

Chris - Do you have any way of narrowing the gap between the water and the land? Do you think that the change happened into a pair of lungs only after they were on land, or do you think having paired lungs helped animals get onto land out of the water.

Camila - Groups that had a paired lung when they were inside the water so they could go out of the water because they had already a lung, a paired lung.

Chris - How do you know that though? Because you, you just told us that, that the animals that were on land had these paired lungs and the animals in the water had a single lung. So how do you know that the paired lungs evolved in those fish first?

Camila - I'm not saying that paired lungs evolved in fish first because fish, all the fish, all the groups of fish that have unpaired lungs - have a single lung - but salamanders are amphibious, and this group live sometimes inside the water yet. So they make this transition during their life. And when we see that paired lungs were present in groups that make this transition for water to land when they are during their life, we can understand this.

Chris - And, presumably because paired lungs have become the way to do it because all these animals around us do it this way pretty much these days. Why does it give them an advantage? There must have been some kind of advantage of having lungs like that or animals wouldn't have done it. What's that advantage, do you think?

Camila - They have that advantage to have a paired lung is that they have more surface to make gas exchange. So it's better, it's more efficient to breathe air.

Chris - And you think that was the main driving force? It was a more efficient respiratory system?

Camila - Yes, certainly it was more efficient to have a paired lung out of the water.


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