Cold haemoglobin, and teaching old dogs new ethics
This month, how an extinct marine mammal made its haemoglobin work in the cold, how does learning compassion change the shape of the human brain, women publishing cautiously, how populations evolve to social distance in disease conditions, and can biochemical clocks accurately track ageing in children? Join Dr Chris Smith for a look at some of eLife's latest leading papers...
In this episode
00:37 - How Steller sea cow haemoglobin releases oxygen in the cold
How Steller sea cow haemoglobin releases oxygen in the cold
Kevin Campbell, University of Manitoba
To a biochemical detective story about an extinct species of giant sea cow - called the Steller sea cow - that inhabited the frigid waters of the Arctic until the mid 1700s. How did an animal closely related to a warm-water dweller like a manatee, survive in sub-zero climes? Part of the answer lies in a tiny switch in its blood haemoglobin structure, which enables it to more efficiently release oxygen to tissues despite very low temperatures. The discovery is the work of the University of Manitoba's Kevin Campbell. He spoke with Dr Chris Smith…
Kevin - The story of this creature actually goes back to 1741, when it was discovered by naturalist George Wilhelm Steller, who was actually the naturalist on the ship, captained by Captain Bering that you may have heard of the Bering Strait and Bering Sea. They were shipwrecked on an island off the coast of Russia, a really cloud shrouded cold desolate place where they discovered Steller sea cows, or which became known as Steller's sea cows after Steller himself. These animals are very interesting in that they're very closely related to manatees and actually more closely related to the dugongs, but they were quite different, in that they were immense. They were whale-sized. They could be up to 10 metres long and maybe up to 10 tonnes. They lived along the rocky, desolate cold, wavy shores of these Commander Islands. And this is the last known population, but they had lived previously in the Alaskan Archipelago. And there's not the same food that is usually eaten by manatees and sea cows, which is seagrasses. They actually became adapted to eating mostly kelp.
Chris - And where have they gone?
Kevin - They were actually probably on their way out. So estimates are that when Steller discovered them, and again, this is the last remaining population of this species, that there were maybe 1000 to 2000 individuals at most, at that point in the early 1740s. This species was probably on its way out already though. Sadly they were hunted to extinction only 27 years after the discovery, mostly by shippers, people that would stop off of the islands and get some very tasty sea cow meat.
Chris - And so how is it that 250 years later you are able to study them?
Kevin - The conditions on these Commander islands, they're rather cool. And so some of the bones have remained washed up on shore, and they're now in museums. They're good enough quality. We were able to start getting some DNA and of course we targeted haemoglobin genes. But now even the last couple years, there's been a complete genome of the species.
Chris - Why did you go for haemoglobin?
Kevin - Well, haemoglobin is actually a really interesting molecule in the sense that it's the molecule that carries all the body's oxygen from the lungs to the tissues. So it's actually one of the few molecules that really links animals with their environment. Like most enzymes or most other chemical reactions, it kind of works a little bit better at offloading oxygen at warm temperatures, but not so good at cold temperatures. At really cold temperatures, it tends to hold onto oxygen really, really tightly. And this can be a problem for Arctic animals or Arctic mammals or birds, specifically because they often let their extremities really cool down too close to zero degrees if possible, so that they can minimise heat loss. And by minimising heat loss, it actually lowers their overall energy budget, so they actually have to eat less, right? So it's kind of like, imagine your house in winter. If you kept the windows open, you could keep your house warm, but your energy bill would be enormous. But if you can modify your haemoglobin so you can lower the temperature at which it's still able to offload oxygen efficiently or efficiently enough, they can save a lot of energy.
Chris - And you have, through the genome, got the genetic sequence, the recipe effectively for their haemoglobin. And does it show adaptations or differences?
Kevin - We studied three different Steller's sea cows, and we found a very unusual mutation in their haemoglobin. And we found a change in the beta subunit at a site that is perfectly conserved in all other mammals. At this one position, it's a lysine, which is a very strong, positively charged amino acid, but in Steller's sea cows, it changed from a lysine to glutamine, which is a neutral charged molecule.
Chris - And what do you predict that would do to the haemoglobin in the Steller's sea cow?
Kevin - Well, fortunately, there are some humans that carry the same mutation. It actually causes an increase in the overall blood oxygen affinity.
Chris - The problem that the Steller's sea cows are grappling with is, in the cold, they want to give up oxygen from their bloodstream into their tissues, but without having to have a ferocious rate of blood flow to get enough oxygen in. So they want their haemoglobin to give it up readily. If it increases the affinity, this change of the haemoglobin for oxygen, does that mean the haemoglobin hangs onto it better? In which case, how does that serve their purposes?
Kevin - That's the one single big difference between human haemoglobin that has this change and Steller's sea cow haemoglobin that has this change. In humans, this effect causes the affinity to go up. But in Steller's sea cows, this change causes their blood oxygen affinity to actually go down. And the second thing is, it takes the same amount of heat to break this energy bond between oxygen and the haemoglobin, regardless of the haemoglobin type, right? Whether it's from a reindeer, a Steller's sea cow, a woolly mammoth, or a human. However, these cold adapted species tend to have some modifications in their haemoglobin. So, as I mentioned, it takes heat to break bonds, but haemoglobin doesn't only just bind oxygen, it's able to bind other molecules. And we have an organic phosphate in our red blood cells called phosphoglycerate. And it's also able to bind to this molecule. But these molecules tend to bind to haemoglobin when it is ready to offload its oxygen in the tissues. And the interesting thing is when these molecules bind to haemoglobin, it actually releases heat. So in colder temperatures, these haemoglobins from these cold adapted species tend to have these modifications where these other molecules can bind to haemoglobin, and that releases some heat, and then that heat can actually get donated or kind of shifted over to where the oxygen is found. And it's a little, almost a self heater to help break that bond between oxygen and the haemoglobin in the cold tissues of these species. But the change in the Steller's sea cow was really perplexing to us at first because it actually lowers the amount of phosphoglycerate binding to the molecule, which is what we think usually gives the heat. But this change, as I mentioned, is found right in the central cavity of haemoglobin. And so what this change does itself is it lowers the amount of heat required for this change. And so this kind of gives that energy itself to break the oxygen bond. So it's the precise opposite as what we find in most other mammal species. They're doing a different mechanism, but the end goal is they're able to offload oxygen. Pretty good at cold temperatures.
08:23 - Brain changes in response to learning social skills
Brain changes in response to learning social skills
Sofie Valk, Max Planck Institute
In the year 2000, Eleanor Maguire published a paper that caused a seismic shift in the neuroscience landscape: she scanned London taxi drivers as they completed “the knowledge” - the arduous task of learning every road through London. She famously found that the brain region called the hippocampus in these drivers enlarged as they progressed through their training, showing that even the adult brain has impressive powers of plasticity. So what about other aspects of behaviour, and in particular social skills and compassion? Can these be taught, and if so what changes, if any, are visible in the brain? Speaking with Chris Smith, and from the Max Planck Institute, Sofie Valk…
Sofie - Can we train social skills to adults? Can we learn to be more compassionate, more understanding for others? And if so, what would this do to the brain? And we had different types of mental training such as training from maybe yoga practice, mindfulness, social training where you speak with your partner about your emotions and the other person listens and then the other person speaks about their emotions. Or also that you learn that you have different perspectives in yourself. So for example, I'm a lab leader, but I'm also a mother and I'm also somebody that loves to watch crappy shows on Netflix when I'm tired. So I have all these different perspectives in me and as do you all, and learning about them helps you to understand the different roles we all have. And hence it may increase the understanding we have for other people and their perspectives.
Chris - It's sort of practice making perfect then. So by practising to be better at this, you in some way change the way your brain processes information and its structure and how it handles information does change in response to those stimuli.
Sofie - That's the idea, yeah. To let people increase awareness and also performance in emotional understanding and compassion, but also taking the perspective of others.
Chris - There's this old saying, isn't there, 'you can't teach an old dog new tricks.' And I suppose it's really relevant to the brain. We do learn much better when we are younger than when we're older. So who did you look at and how did you actually make these measurements?
Sofie - We recruited adult individuals between 20 and 55 years of age. Normal, healthy adults, willing to take part in this rather intense nine months training protocol. So it ended up being like both men and women. Average age 40, but distributed between 20 and 55.
Chris - And what did you do to establish the baseline? How did you work out how their brains were working before you did anything to them?
Sofie - For the beginning of the study, we did many behavioural tests to kind of establish a baseline and then we scanned them to understand the structure of their brain. So the anatomy is based on brain matter and white matter, but also looks at the function of the brain, namely looking at the activations that happen over a certain time period while you're scanned.
Chris - And then you subject your subjects to a fairly, as you put it, intense training over the nine month period. Did you look during that period or did you look just at the end to see whether anything had changed?
Sofie - Because it was three different types of training, because part of the study, the goal was also to understand if there's differences in learning to understand other people's emotions, further understanding their perspectives of thoughts. So we wanted to also compare different types of training to understand the specificity. So everything was a three month course and every three month training block was then evaluated by having a set of scans, also a set of behavioural measurements so that we kind of track how people changed over time.
Chris - And on average, we can look at how individuals might have performed differently in a minute, but on average, what happened over the course of the study?
Sofie - Many things happened. <laugh> I think focusing more on brain structure, you see over the course of nine months that particularly the structure on average changes. But function is more subtle and it seems to adapt more to the circumstances or the specifics of what you train. So here, what I observed in the functional measurements that I took, it wasn't something that just kept on adding, but something that kept on dynamically changing depending on what the needs of that certain training protocol were. So over nine months, brain anatomy changes in a more slow fashion or a gradual fashion. It builds up upon each other. Whereas function is something that you get a bit more of this if you train one thing, but then this reduces again if you train another thing.
Chris - We had an insight that this sort of thing happens because of the famous London taxi driver study with people developing larger sub regions of their hippocampus if they have to do the knowledge and learn the streets of London to navigate them very well. So what does this add? Does this tell us that it's not just the memory and navigational circuits, it's the emotional and other circuits in the brain that change as well when we use them?
Sofie - It depends on how you look at it, but for me it means that we can still also change as adults, right? So the brain is like a sponge and depending on the environment and the opportunities that we give ourselves, we can always learn and adapt to the circumstances, always within certain limits. And maybe over time with age and with certain habits or certain genetic predispositions to opportunities to change are more limited or different. So across individuals, but still, the context matters to the brain and the context is part of what shapes how the brain looks and functions.
Chris - Many would argue that's really encouraging to hear because some of your subjects were older, so we don't seem to be completely fixed in our ways. I mean maybe there were some subtle effects if you looked at just older people versus younger people. But what are the implications for people who have neurodevelopmental disorders? I'm thinking of people who might be on the spectrum, the autism spectrum, for example. If the brain can be, I don't want to use the word reprogrammed, but if it can be remolded in order to make it function better under certain circumstances, does this mean that we should be offering certain types of interventions to people with some of these particular developmental situations to help them?
Sofie - Yes. The question is to what extent you can support those who have neurodevelopmental conditions because it was like, obviously one should always stimulate somebody, right? Like if somebody is sick and starts feeling better, you should also encourage them to get out of bed, right? And get on moving after an operation. And probably this is the same that you find, you have to find a good way to stimulate people, but not all stimulation is right for whatever occasion or whatever person. And I think one of the take-homes also of the study is how differentiable it is so that you can also train different things depending on what you need, such as more emotional skills or more understanding of perspective skills, but also just more mindfulness, attentional skills. And now often these things are sometimes combined together in different ways and, and by unfolding them and seeing how these components actually contribute differently to the brain, but also to behaviour, I think is also a first step to maybe understand what components could then be best tested for a certain individual.
16:20 - Women take the cautious approach to scientific publication
Women take the cautious approach to scientific publication
Vincent Lariviere, McGill University
If you're a top scientist with an amazing discovery to tell everyone about, you send your manuscript to the world's top journals don't you? Well, apparently not, if you're a woman! As he explains to Chris Smith, McGill University's Vincent Lariviere has found that female scientists are much less well represented in the top tier publishing houses, favouring instead publication in worthy, but less “glitzy” venues…
Vincent - Many studies have shown that there's a gender gap in science; that there is less women than expected. And we also observe that women are less likely to receive, let's say, a lot of credit for the science that they do. So one of the markers of credit is citation. So is your research used in other papers that are being published afterwards? So what we try to do is to try to understand a bit more this gender gap in science by looking at women and men's publishing patterns. Where do they publish their findings?
Chris - And where do they publish their findings?
Vincent - Well, unfortunately they are globally submitting their findings in journals that are less prestigious. So, so in science where you publish matters and there's a premium in publishing in a certain set of journals that are very visible, very international, such as Science, Nature, and PNAS. And so what we try to do is looking at whether women were more or less likely to submit their findings to these very elite journals.
Chris - So it's not that the women are sending the work in to the journal and it's being bounced, it's that they're not sending it there in the first place, potentially?
Vincent - Exactly. So women and men's paper are actually accepted or rejected at the same rate. There's no differences in the proportion of women's paper that actually gets rejected. However, women are much less likely to send their work to these elite journals. And the reason for that, and this is actually quite depressing, is that they were considering their work to be of lower quality. So it's a self-perception of their work that makes them not submit their, their work to these journals
Chris - We're slightly put in the cart before the horse because I haven't asked you yet how you arrived at these findings, but it's not - just for clarity - that the women are doing science that's of less interest to these journals and therefore they're not sending them there. The work could be sent there; it's of a sufficient standard and interest, but they're just not choosing to send it to top tier journals?
Vincent - Exactly. And the main reason there is that they consider their work to be not as groundbreaking or sufficiently novel.
Chris - That's a pretty big claim that you are making. So how did you arrive at that conclusion?
Vincent - So we basically surveyed about 5,000 authors of scholarly papers, both men and and women. And we basically asked them, did you ever submit to those journals, which are Science, Nature and PNAS? We also asked them whether their papers were accepted there. And we also asked them whether they were in cases of rejection, whether they were just rejected or rejected after careful, let's say review from from the journal. So it's really true, a survey of, again, several thousand thousand researchers. And again, the finding that we had about submission was observed in every field. So in medicine, in the natural sciences, and as well as in the social sciences, women being less likely to submit to to these top journals.
Chris - And did you ask the women why they hadn't sent their work to these journals when it was worthy of being featured there?
Vincent - Yeah, exactly. Women were much more likely to say that their work was not of a quality that was as high. They were more likely to say that they considered their work to be not as groundbreaking.
Chris - Do you think though that to a certain extent this represents caution? Men traditionally are risk takers, especially younger men, and women tend to be on average a bit more cautious. So is it that they're thinking, well, I could go for the top tier journal, I might get rejected, there's a high rejection rate there, and then I'll end up wasting time having to send it again to somewhere else. So I'll take the cautious, surefire approach that will get me published; whereas the blokes will just say, no, I'll chuck it into the top tier journal. I might get lucky.
Vincent - Absolutely. So that's one of the main hypotheses that we have that would explain the results. But then we need to think about how to mitigate to improving this gender gap that exists.
Chris - And what sort of strategies might there be? What better mentorship, just encouragement, journals actually going out there on a PR exercise saying, hang on a minute, you should send your work here?
Vincent - Yeah, exactly. So, so there's on the one hand such such policies that aim at encouraging women to submit their best work to the best journals. But there's also another angle, which is to stop using the journal as an evaluation criterion. We now understand that there are biases in what these elite journals publish. And so by using indicators such as a journal impact factor, which is an indicator of the global citations and impact that their journal receives, so by using that, you're actually reinforcing the various disparities that exist in the system. So I would lean towards a decrease in the usage of journal level indicators to assess researchers and try to move to more holistic ways of evaluating scientists.
22:04 - How quickly can populations evolve to combat disease spread?
How quickly can populations evolve to combat disease spread?
Pratik Gupte, London School of Hygiene and Tropical Medicine
For more than two years during the Covid pandemic, the majority of us had to fight our natural instincts to socialise and instead stay away from those we love and like to mingle with to break the chain of disease transmission. Social behaviours evolve and become entrenched in populations because they confer great benefits: support, defence, food, growth. But if a disease emerges in a group, how quickly can evolved pro-social traits be shed to achieve nature's own equivalent of social distancing? Speaking with Chris Smith, Pratik Gupte is at the London School of Hygiene and Tropical Medicine…
Pratik - What happens to a population of individuals that have evolved rules for how to be social in the absence of a pathogen when an infectious disease then enters their population; how does that change their behaviour, especially in terms of being social when a disease first enters a population.
Chris - I suppose it's a balancing act, isn't it? Where you've got the benefits of being social, where there's learning from other individuals, there's safety in numbers, there's exploiting food, versus if an infection gets into that group, there's a price to pay and it's the balancing act of those two things?
Pratik - Yeah, absolutely. So what we've done is to say, well, each one of you can choose how you balance the costs and benefits of being social. And so what we found there is that you get a split. Some individuals will say, I want to be completely safe and I'll avoid everybody else. So that's very much like what you would think of as shielding during covid. But then there's other individuals that say there are serious benefits to being social, such as finding food. I will follow some of the other individuals that I can see, especially if they look like they've been successful in finding food themselves and risk it. I will take the costs. And the only reason that these two can exist sort of side by side is that the more social strategy pays a higher cost on average of infection, while the sort of safe strategy doesn't pay that cost. So on the whole they sort of balance out.
Chris - Before we talk more about the results, take us through how it actually works. How did you code this up? What does it do to model these scenarios?
Pratik - It's a computer simulation where every individual is just a little bit of computer code. Each individual is essentially just made up of a set of preferences. What's your preference for being near other individuals that have food? What's your preference for being near other individuals that don't have food and what's your preference for being near food itself? And this allows us to run lots of simulations sort of over and over again and then compare what happens in every instance and see whether there's any general patterns to be found.
Chris - Do you pre-specify those choices that each individual in your group that you're studying makes, or are those fluid, can they change?
Pratik - Well, we do pre-specify them in the sense that they can't change over an individual's lifetime. But because we take this sort of evolutionary approach, all the possible choices that exist in the population - and we allow every sort of combination that could exist to exist.
Chris - So that's like your gene pool effectively, you've got a range of possible behaviours in the population from which the selection may occur?
Pratik - Yeah, absolutely. So what we do then in the sort of evolutionary simulation, here, is to say, well, we've given the population all the possible options they could have. So we have initial phase of selection where that's whittled down to the preferences or let's say the genes, if you will, that are most suitable for moving and socialising when there's no infectious disease. And then once we introduce the infectious disease in terms of sort of randomly infecting a certain number of individuals and letting them spread the disease to others, we look to see how that whitling changes essentially so of the individuals that have made it thus far, which will continue to survive? And of course there's a mutational process here as well, which means that new combinations can always arise. So there's never a permanent loss of any of the genes or any of the preferences or any of the combinations as it were.
Chris - And so what emerges, and over what timeline, with the disease, when you introduce some sort of contagion into the group; what solution does the group settle on and how quickly?
Pratik - Yeah, so I would first start by saying that the group itself doesn't really settle on a single solution. And I think that's what's really interesting here. Every individual is making slightly different choices given the same information, even if they all at some point prefer avoiding their neighbours and they will avoid them to different extents. The two main things that we want to really focus on here is whether they avoid all their neighbours or whether they're willing to associate with some of them given some benefit. And that benefit is the social information as it were, the sort of information of who's been successful and where. In the main results of our paper, what we see is that the population essentially splits into two morphs - so two types of individuals - those that play it really safe, and avoid everyone else, and get infected much less. And then these others which are willing to take the risk of being infected given a certain sort of benefit, which is again, this useful social information and then pay the cost of being, on average, infected more frequently.
Chris - So bottom line then, what do you think this study adds and how does it change or influence our thinking?
Pratik - Yeah. So I would say that because this is a theoretical biology study that's really based on simulation models, what it does is that it adds another sort of toolkit to understanding potential scenarios for the future, especially long-term scenarios that can help with sort of not just management, but also understanding what the potential outcomes of letting an infectious disease spread to novel host populations might be. Which is not to say, of course this is exactly what will happen but rather it, it helps to set the, let's say, to set the tone for discussions around that sort of scenario. So again, to sort of come back to the avian influenza pandemicor panzootic, it's one of the things that perhaps people should consider when thinking about how to manage that, which is that there could be very long-term effects on how social these, the survivors of that, of this outbreak are likely to be and what that has, you know, what that means for sort of management of sort of populations of conservation concern. But again, I will emphasise that this is a theoretical study, which is really useful I think for setting the parameters within which one can interpret data that one collects from the real world in the future, or reinterpret data that have already been collected.
29:00 - Do biochemical clocks accurately age children?
Do biochemical clocks accurately age children?
Oliver Robinson, Imperial College London
In medicine, we often use a person's chronological age - how many candles are on their birthday cake - as a guide to disease risk. But what really counts is a person's biological age: how well "lived in" is their body? A person who eats a poor diet, smokes, and breathes bad air is likely to age faster than someone without those exposures. And we can read various biochemical clocks, such as chemical changes to DNA, that correlate well with these sorts of insults, at least in adults. But what about in children? Are these markers helpful in this context, or does the process of development and growth make them harder to interpret? Imperial College's Oliver Robinson has been trying to find out…
Oliver - We had a very nice study. And actually I was quite involved in the early part of my career in getting it off the ground, but it was a Pan-European cohort. So now these children have been followed - currently the data I looked at, they were between five and 12 years old, but we had information since, since the pregnancy of the mothers. Over a thousand children with all these different biological and developmental measures.
Chris - What were the measures?
Oliver - There are many aspects to development. We looked at their height; we looked at fat mass; we did a range of cognitive tests; general fluid intelligence; and another test, which I really enjoyed watching the children do, 'cause it's extremely boring, they basically have to look at a whole screen of fishes and click if they see a fish pointing the other way. And you can see the children starting to squirm and wriggle 'cause they're getting really bored. But that's the whole point is to measure their attention. We looked at behaviour, tantrums, bullying, are they kind to each other? And then finally we looked at lung function as well.
Chris - What about biochemical markers, DNA methylation marks and so on. Were you appraising that too?
Oliver - Yeah, so we had four different markers, actually, DNA methylation; telomere length. And then we measured RNA - basically which genes are being read. And finally we looked at a range of chemicals in the blood, big molecules. So we are talking about proteins and metabolites. We combined all of these circulating markers, the proteins and metabolites and used this to develop a sort of average profile of children at different ages.
Chris - And when you do this, what trends emerge? Can you see a clear ageing-specific pattern? Do the markers hold true to what we think is the genuine age and developmental pathway or track these children on, and does it line up with what we see and have learned about adult ageing?
Oliver - I would say in many ways it does actually. As we know from many, many studies that telomere length and DNA methylation age reflect unhealthy aging. And in some respects we do see that it is harmful for the development of children. When I say harmful, I mean that actually, if you look at their behaviour, so how often they have tantrums and so on, this was greater for the children with the advanced biological age from these measures, that is showing that it's not really very good for, for their development, 'cause they're actually quite immature, perversely, if they have a mature DNA methylation age. So I think actually what is really happening with these measures is unhealthy environment is causing changes to these chemicals. I say this because we see for DNA methylation clock, I mean if the children's parents are smokers, they have an older DNA methylation age. And similarly for telomere length, if the parents are less wealthy, which might reflect a less beneficial environment, they actually have an older telomere length. So for these markers it seems that, as in adults, it's probably not a very good for children to be older biologically. But for some of the other markers we looked at, the chemicals circulating their blood, here actually it seemed to reflect developmental maturity. So we saw a strong association between older biological age using these markers with their working memory and their fluid intelligence.
Chris - So you've got certain suite of markers that appear to be quite good at telling us about developmental progress. You've also got a set of, or a suite of markers that seem to be quite good at pointing to exposure to potentially deleterious environments. So actually you could integrate both of these and you can ask in the same way as we plot, say head size and body weight on a growth chart, you can ask, is this child developing according to where we would expect them to develop, but also what insults are they having to weather as they go through and are, are there any things we can therefore try to put right?
Oliver - Exactly. And I think this is what's intriguing is showing that if they're less affluent and maybe there's a lower education environment in the family, which is all not optimal for children's development, we find that actually it has a real biological impact. So it is showing that it's really important to make sure that all these children have the best start in life.