The widowhood effect, and clapped out baboons
This month, male baboons pay a high ageing price for climbing the social ladder, evidence for the reality of the widowhood effect whereby breaking a pair-bond provokes cancer growth, a new way to track where vaccine antigens go in the body, an integrated model for Alzheimer's Disease, and better ways to predict pain and analgesia in newborns...
In this episode
00:32 - The higher they go, the faster baboons age
The higher they go, the faster baboons age
Jenny Tung, Duke University
For quite a few years, Duke University’s Jenny Tung has been studying baboons in Kenya. Recently she’s become particularly interested in how they age, and why some animals appear to be much older, biochemically speaking, than others that have lived the same number of years. As she explains to Chris Smith, it turns out that fighting your way to the top comes at a high biological price…
Jenny - We've been watching the same individuals, or their descendants actually for up to 50 years now - that's the Royal we! Just like all of us, chronological age goes at the same rate, but we were interested in why some of them seem to biologically age faster than others.
Chris - The phrase we use in the hospital is that "a person has a well lived in body", but it amounts to much the same thing. Doesn't it? Biochemically, a person is creaking at the seams a bit more at the same chronological age. And it's what lifestyle factors or other factors might've have risen that caused them to find themselves in that position?
Jenny - That's right. And we were particularly interested in whether aspects of their social environments, or their early life, might be the sorts of things that explain either sort of faster or slower biological aging in our paper.
Chris - How did you do it?
Jenny - Well, we looked at a measure of biological age that involves molecular changes on DNA. Most people are familiar with the idea that our DNA stays the same throughout our lives, but there are actual little chemical marks on the DNA that can change over time. And it turns out that, if you track some of those very specific marks, they're a really good predictor of both chronological age and biological age.
Chris - These are what we dub "epigenetic changes", aren't they?
Jenny - That's right. And in our paper, we are particularly focused on one type of epigenetic change known as a DNA methylation mark. So we have baboons data in the sense that we have blood samples and therefore DNA samples from animals who we've watched their whole life. So we know when they're born, we know what their chronological age is. We know how many actual years they've been on earth by the time we sampled them. What we did with the DNA is look very carefully at the level of these particular DNA methylation marks. We knew predicted age really well. And then we said, okay, if this is pretty predictive of age; if you're an eight year old baboon, we get a predicted output based on the marks on your DNA that you're about eight years old. But some of those eight year olds actually were predicted to be a little bit old for age. That is, they looked biochemically like they were maybe nine years old. So we took that difference, and we asked whether individuals that were either say high or low status or more socially integrated versus more socially isolated or who had more challenging early life environments, consistently looked old or young for age. So, we're taking social predictors that we know are important to the lives of these baboons and asking whether that translates into accelerated or decelerated biological or epigenetic aging.
Chris - And does it?
Jenny - Well, we were surprised to find that in some cases it does, and some cases it doesn't. The main thing that we found that did was actually the social status of males in our population. And this was a really sex-specific phenomenon. So that males who were high status, near the top of the social hierarchy in the groups who were studying, tended to look older than their actual age.
Chris - What about the females?
Jenny - We actually didn't observe any particular relationship between social status in female baboons and aging, but we think we might understand why, because females basically adopt the social status of their mothers. There's a really nepotistic pattern of status inheritance. Whereas males have to fight their way to the top. And so regardless of whether they were born to a high status mum or a low status mum, when they become adults, they have to move to new social groups and physically compete with other males to reach the top and then to stay there for as long as they can.
Chris - That's quite surprising, because when one looks at us humans, there've been a lot of sociological studies - I'm thinking of things like the Whitehall study - where people who are the underdog end up with more chronic stress, accelerated aging and a higher disease risk than the people who are perceived to be high-octane, high stress, top-of-the-pile people, but nevertheless seemed to, to come off better. So how do you reconcile the two?
Jenny - I think one of the things our study emphasises is that we use the same kind of terminology: we talk about social status in human socioeconomic status or, or rank in non-human animals. That doesn't always mean the same thing because of the differences in the way that you have to reach high rank, or if you even can reach high rank. The Whitehall study, of course, is this landmark classic examination of social gradients in British civil servants and its relationship with health outcomes like cardiovascular disease. I think one of the really key things that we have to keep in mind is that, as far as I know, in the British civil service, there's actually not physical fighting to reach the top, right?
Chris - I wouldn't assume that! You never know!
Jenny - Fair enough! Okay! I think that social status in humans often looks a lot more like social status in female baboons, where you have a lot of, uh, nepotism, right? You have a lot of social continuity between generations. You have other individuals who are helping to reinforce and maintain your rank and social hierarchies can be really stable over time because of it than they do in male baboons, where everything depends on you and your ability to fight off other, to literally fight off other males and then stay in that state. You know, nobody can do that. No baboons can do that for years and years on end. So you have very dynamic rank hierarchies where males are very unlikely to stay at the top of their whole lives.
Chris - Nevertheless, I suppose that if they can stay there for as long as possible, then that argues that they are endowed with some kind of genetic fitness or resilience, which wouldn't or would, which would only afford or lesser able individual, uh, less time at the top.
Jenny - You know? So I think that this is a really key point because it tells us something about the difference between health as an outcome, or even lifespan as an outcome and Darwinian fitness, right? So, uh, there's evidence from other work in the same baboons population that high ranking males may even experience a little bit higher risk of mortality, at least during the time that they maintain that rank. And of course, as humans, we think about elevated mortality risk as sort of pretty universally negative, but the only way that a male baboons is likely to leave offspring is to get to that high rank. So from an evolutionary perspective, there's a very, very strong motivation to fight for and attain high rank. Even if there might be costs to aging or health or longevity, um, as an exchange.
07:56 - The widowhood effect accelerates cancers
The widowhood effect accelerates cancers
Hippokratis Kiaris, University of South Carolina
Sociologists and psychologists will tell you that “life events” - like the loss of a lifelong partner - are associated with an increased risk in the aftermath of conditions like cancer for the survivor. But is this actually caused by the broken bond, or is it that the two shared risk factors and so it’s actually inevitable? Now, as he explains to Chris Smith, an intriguing set of experiments carried out by the University of South Carolina’s Hippokratis Kiaris confirms that something in the bloodstream of a bereaved survivor promotes the growth of cancers…
Hippokratis - It is designated actually as the widowhood effect, or the broken heart syndrome. And it is more prominent during the first few months after we lose a partner and the risk decreases after that.
Chris - How do you know, though, that birds of a feather don't flock together with a situation like this, whereby, you know, I've married my wife; we're of similar social class, similar education, similar background, similar lifestyle. So, therefore, the kinds of things that happened to me are likely to happen to her, at roughly at the same rate, give or take; how do we dissect away those confounders from this?
Hippokratis - This is a very important question and brings up the question of homogamy - the likelihood to marry individuals of similar health. These are the questions we wanted to address, because all these epidemiological studies, no matter how well they are being designed and controlled, they always have caveats. By remaining alone, one changes his or her diet, acquires or abolishes habits, all of which may have health impacts. So, we need to dissociate these effects and really explore if there is a biological basis to the widowhood effect.
Chris - Difficult to study though, isn't it, because humans aren't unique, but they're quite rare in terms of how long we live. And the fact we do form these long-term relationships with a single partner, and then do feel enormous grief when we lose that partner. How can you test that biologically?
Hippokratis - So this is the reason we turn to the deer mice - animals of the genus Paramyscus. These are monogamous. They establish long-term pair bonds based on matings, and they are ideal for our studies. So we did a few different experiments. We took these animals that have either established these pair bonds, or animals that these pair bonds were disrupted because the males had been separated from their female partners. Then we implanted these animals with cancer cells in order to develop tumours. When we took these tumours, we transplanted them into conventional laboratory mice, we recorded striking differences. Tumour growth was recorded predominately in mice that received tumours from the bond disrupted animals, but not from the bonded animals.
Chris - This would suggest, then, there is something in the biochemical milieu of a pair bond-disrupted mouse that in some way, re-patterns, the growth potential of pathological tissue, like a tumour. Can you recreate that in the dish though? Do you need a mouse to do that? Could you take out, for example, the serum - the plasma - that's in that animal, that's had its bond disrupted and grow tumours in the dish with that serum and recreate the effect that way?
Hippokratis - This is exactly what we did next! So we took serum from animals that were either bonded or bond-disrupted - separated - and we added cancer cells under conditions that the cancer cells form the so-called "organoids" or tumours spheroids. And we saw lung cancer cells that formed in the presence of the serum from bonded animals did not grow much as compared to the cancer cells that grew in the presence of serum from bond-disrupted, separated animals, that grew a lot.
Chris - Did you do the experiment where you took the serum from an animal before it bonded, then the serum from the same animal after it bonded and then serum from the same animal after that bond was disrupted and repeat the experiments across all three, to see if there was genuinely an effect and it wasn't just that animal. There was something about disrupting the bond in that animal that made the organoids grow differently?
Hippokratis - This is a very important experiment. We did actually such experiments. We really show these differences.
Chris - Putting all this together, then. It strongly suggests that, in response to pair bond disruption, something ends up going around in the bloodstream that has a pretty profound effect on the way cells that have the potential to be pathological, like cancer cells, will grow, but not just in the short-term while they're exposed, it must reprogram the growth potential of those cells or select for cells that are nastier inherently. So have you got any insights from this yet as to what those factors might be?
Hippokratis - Yes. This is actually a very important question, and it is on-going research we are currently performing in the lab. It is rather likely that certain hormones are associated with these effects and their activity should change in relation to both our bonding experience and status as well as to the stress that is induced when the bonds are broken. Such hormones, for example, can be oxytocin, can vasopressin. Both of these are hormones associated with bonding, as well as cortisol, for example, which is associated with the stress responses and all of these hormones and others that I didn't mention now are either directly or indirectly been linked to cancer and other pathologies before.
Chris - Would one logical kind of conclusion from this be that you need to investigate whether or not giving certain drugs even antidepressants, for example, or other agents acutely around the time that the pair bond is broken, would that be protective? And are you going to do those experiments to see if you can, you can stop this effect?
Hippokratis - Yes, it is possible for such drugs to function like that. And it is really in our interest to start exploring the effects of these drugs, that we know that they change our mood and, uh, mitigate in a way, the consequences of loneliness and start exploring whether they have real effect in our physiology acting directly on tissues and protecting us from disease.
15:13 - Tracking where vaccines go in the body
Tracking where vaccines go in the body
Beth Tamburini, University of Colorado
Vaccines are very much the talk of the town at the moment as the world strives to protect populations everywhere against the new coronavirus. And although we broadly understand that, when we immunise someone, the material we inject gets carted off to lymph nodes where it’s presented to the immune system and provokes the production of protective antibodies and T cells, the more fine-grained detail of what’s really happening isn’t clear. But now Beth Tamburini, at the University of Colorado, has developed a way to use special DNA tags that she can couple up to the antigens in a vaccine and then follow where the antigens go by looking for the DNA tag…
Beth - We were looking at different vaccination strategies, some of which we knew were better than others. And we were asking whether or not we could track these vaccines by taking this sort of molecular tag and conjugating it to a protein antigen, which is just a piece of pathogen we can inject into the body to make the immune system become educated that that is something that it should respond to.
Chris - And this therefore gives you an insight into when you put a vaccine into the body where it goes, but critically also how long it hangs around for, and who's looking at it?
Beth - That's right, because we can look at different time points after vaccination and tell whether or not the tag is still there.
Chris - What tags did you use and how do you make sure that they don't just fall apart?
Beth - We used DNA and we had to protect the DNA tag using these different types of bonds between the base pairs of the DNA. So that would protect the tag from degradation in the body.
Chris - Essentially, then, we've got, what, a protein, which is the vaccine molecule, and you've got coupled up to it, a hunk of DNA on the side, which is like a unique identifier, like a barcode effectively saying, this is the vaccine molecule.
Beth - That's correct.
Chris - And you can then go back in and read that DNA. So, you know, specifically it's the DNA, not just random DNA from around the body, that is the DNA corresponding to that vaccine molecule?
Beth - Yes, because it has this unique barcode and we can manipulate the barcode so that we can track different barcodes throughout the body. If we were looking at say multiple different types of vaccinations or boosting strategies.
Chris - So you've made a cluster of, of these things. What is it telling you? What have we learned through, through having this now quite neat tagging system, then that enables you to see where the vaccines go and how long they're hanging around.
Beth - We can use this vaccine and we inject it under the skin. And then we ask where the vaccine goes. And we're most interested in the lymph node, which is the place where the immune system becomes educated. There are different cells within the immune system that live within the lymph node. And so we can ask which cell types recognise this part of the pathogen and how they are responding and how they are holding on to the protein, antigen, or pathogen that we've tagged.
Chris - What did we learn? Because obviously that has been a central tenet of immunology for decades. That's how it works. That things get presented to the immune system in lymph nodes. And that's how we, we create the immune response. And that's why your glands swell up when you have an infection, let's be honest. So what did we learn from this that we didn't know before?
Beth - So what we've learned is that protein antigen that we've injected with the barcode stays in the lymph node for a longer period of time than we had anticipated. And this, we had some evidence for, from other studies, but we had some difficulty with tracking the antigen in the previous studies. With this new technique, the tag is actually quite a bit more stable. So we could detect vaccine antigen for a longer period of time and detect it in very small amounts. So the specific subset of cells actually could hold on to this protein antigen for over a month, which is far longer than the immune system takes, which is about a week, to respond and clear any pathogen.
Chris - And if we compare and contrast between vaccines we know produce a very potent response and those that are less good, is there any difference in how long the antigens from those vaccines hang around in the lymph nodes? Could that account for why some vaccines are really good and some are less good?
Beth - Yes. that is something that we're really trying to understand, which is why we're studying, how long the protein antigen stays in the lymph node. Based on our studies, it does appear that if you have the protein antigen staying within the cell type in the lymph node for a long period of time, it is beneficial if you become infected with the same thing later on, compared to if you didn't have the protein antigen there.
Chris - So we could use your technique then to investigate for the optimum latency in the lymph node, as it were, of whatever the stimulus is for the immune system to find something that will give a really good dwell time in the lymph node of that stimulus to also then translate into a really good memory potentially? So it could be used to sort of goal seek for superior vaccines of any type?
Beth - Yes, that is the goal is to try to understand what different types of vaccines cause this process of protein antigen retention, and how we can manipulate it so that we can make better vaccines.
21:22 - Modelling Alzheimer's Disease
Modelling Alzheimer's Disease
Quadri Adewale, McGill University
Alzheimer’s Disease is one of the most common forms of dementia; it causes progressive memory loss and cognitive decline. The pathological hallmarks of the condition are deposits of abnormal proteins, including beta amyloid and tau. But there are also a range of other factors that almost certainly contribute to the disease and might provide useful insights into the mechanism of the condition and act as a marker for its progression as well as the impact of potential disease-arresting treatments. And that’s what Quadri Adewale wanted to pull together: an integrated model of the imaging, metabolic profiles and underlying genetic expression patterns across the Alzheimer brain…
Quadri - There are a number of beliefs about the possible causes of Alzheimer's disease. For example, one of the beliefs is that Alzheimer's disease is caused by the deposition of a protein called amyloid. That is also another belief that the disease is associated with the formation of insoluble version of a protein called "tau". There are also other evidences pointing to the role of genes in the cause of the disease. So, in our research, we felt that if we could measure these biological processes, like the position of amyloid, abnormal function of genes, deposition of tau and so on, if we could measure these processes, perhaps we'll be able to understand the interactions between all these processes in causing disease.
Chris - Historically, the Alzheimer's field used to fall into two camps: "the BAPtists", who believed in beta amyloid, and "the TAUists", who believed in tangles of tau; you're saying actually, everyone needs to talk together and talk to the molecular biologists because, in fact, there might be a whole range of things all going on at the same time, which all interact. And we've got to unpick what the relationship is...
Quadri - Exactly! Apart from beta amyloid and tau, there are other processes, like inefficient usage of glucose, abnormal blood flow, and so on. So what we did in our study was to develop a method, using mathematics, and we applied this method to combine data obtained from Alzheimer's disease patients, as well as healthy people who are elderly. These data measure, those biological processes that we talked about earlier. Specifically, we looked at measurements of amyloid protein deposition, tau, blood flow in the brain, glucose breakdown and usage, the activities of the neurons, as well as death of neurons. Then we also looked at gene activities. Then we divided the participants into two. So we had those with Alzheimer's disease and those who are elderly, but healthy. We then use the healthy participants to study the process of healthy ageing while we use the Alzheimer's patients to study Alzheimer's disease progression. So using the mathematical methods that we developed, we asked which genes influence the interactions between all of that biological processes? And how does this interaction affect brain health in both aging and Alzheimer's disease?
Chris - I suppose it must be tricky to try to disentangle what is the healthy aging process from what then becomes pathological, because there's going to be a huge overlap. Did you manage to do that though?
Quadri - Yes! We found some overlap. To differentiate between the two, we discovered that Alzheimer's disease is a much more complex process than healthy ageing. So, for example, the number of genes that we found to underline healthy ageing were just eight, while the number of genes that we found for Alzheimer's disease were about 111. Which tells us that Alzheimer's Disease is a much more complex process. And, um, when we did the analysis of the biological parts with all the functions that are associated with these genes, we found that some of the functions in healthy ageing were also in Alzheimer's disease. But, uh, the functions we found in Alzheimer's disease were much more comprehensive than what we found in the healthy ageing.
Chris - Does this mean then, given that you've identified these genes, which, which appear to be so intrinsically linked to the process, that we can use them as some kind of diagnostic marker or that we could even use them as a progression marker to work out whether interventions, whether those are behavioural interventions, lifestyle interventions, even vaccines that people are coming up with to offset the progression of Alzheimer's disease, whether they're working?
Quadri - Yes. It's possible to use them as diagnostic markers. And I think the application area that's much more relevant to our work is using them for therapeutics, which genes are altered for each patient? And, um, if we could identify these, it's possible to design intervention for each patient. And as we know that, um, most of the drugs that we have out there, some of these drugs work for some groups of patients and they don't work for others. So in our study, we are able to disentangle these differences and we believe that if we apply these to the administration of basic interventions, uh, it will be very useful. So that's one part. The other part is that there are some beliefs that the cure for Alzheimer's disease might involve combination therapy. So what I mean by this is that instead of targeting beta-amyloid alone or tau alone, it might be more efficient to target as much as possible of the altered process in the disease.
Chris - And, of course, if you understand what genes are involved in the process, one has the opportunity to understand more about the mechanism of the disease and those mechanisms may vary between individuals and that sort of comes back to the point you're making about personalising the treatment.
Quadri - Exactly. Yes.
Chris - Does it throw open any avenues that we hadn't considered previously?
Quadri - Yes. Previous studies have only looked at which genes are altered or dysregulated in Alzheimer's disease. But in our study, we were able to - beyond identifying the genes that are implicated - we were able to know which other factors in the disease are being influenced by these genes? And, um, interestingly, most of the genes and the processes they've been reported in, in studies of animal models, and so mechanisms that we identify, a whole lot of them, have not been reported before. And this actually opens an avenue for the validation of these mechanisms that we identified.
28:24 - Measuring pain in neonates
Measuring pain in neonates
Maria Cobo, University of Oxford
Ensuring that infants undergoing medical procedures are not in pain is critically important, not least because we’ve learned in recent years that discomfort experienced early in life might have long term impacts on the brain and behaviour. Regrettably, we haven’t been very good at this previously, but now, as she explains to Chris Smith, Maria Cobo has developed a way to use brain activity to quantify pain and therefore the effectiveness of pain relief…
Maria - To give you some context, testing the effect of pain relief in newborns is very challenging because, unlike adults, they cannot report how much pain they are experiencing and understanding how much pain you are experiencing in the first place allows you then to test if a pain-relieving intervention is working or not. So, in our study, we wanted to find a way to reduce the sample sizes that we need, which can lead to a faster development of pain, relief interventions in babies.
Chris - Have people not already devoted a considerable amount of research effort to studying pain in neonates and infants for obvious reasons?
Maria - It is a very important topic. And, for sure, there are many groups investigating this area, but the metrics to assess pain have some limitations. So, for example, when a baby is monitored and experiences something painful, the heart rate may increase; the saturation may drop and you can see changes in the facial expression - a baby may start to cry. And this is usually how pain is assessed clinically. However, babies may also show the same type of responses, not necessarily when they are in pain. So these is why we have developed different methods to assess this.
Chris - And what were those?
Maria - So basically what we are using in our study is electroencephalography, which is a non-invasive technique. We place electrodes on the top of baby's head. And we basically are measuring the electrical activity when a baby experience, painful procedures.
Chris - And what are you comparing with what then? So just talk us through what you did to these infants, to get the data, and how you did the experiments.
Maria - What we did was a study, a total of 92 babies. And what we use is this EEG - or electroencephalography pattern of activity - that previously we have demonstrated that is present there when there is a painful stimulus, but not when we touch the baby or when a light or sound is presented to the baby. So we can say this measure is related to pain. In one set of babies we apply first a mild stimulus, which is just a gentle poke, and the way they respond to this mild poke allows us to predict how they will respond to a more intensive stimulus like blood test.
Chris - Right. So by doing the gentle prod, you can work out what particular fingerprint pattern of changes you get in the brain activity. So that is your pain signature. And when you do it more significantly with, as you say, a heel prick or blood test sampling, you see that same signature, but it's bigger and you can then standardize from that. So, you know, that is the signature of pain, that's our baseline. And when you extrapolate to other children with other interventions, you know, what you're comparing,
Maria - That's correct. Basically when we look at this response at baseline or to a mild stimulus, we can say how sensitive that baby is. So how intense is the response. And these also allow us to identify babies who are very high responders. So who, um, have a very intense response who may be actually those babies who can benefit most from the interventions. Uh, very interestingly, we found that interventions like gentle stroking of the leg before a blood test actually reduces the brain response to the blood test. And also in the last study we tested in a small group of babies paracetamol for immunisations. And we also found a positive effect.
Chris - Therefore, you can be both subjective and objective because you can, you can find individuals that are likely to respond more to a painful stimulus, and you can also therefore test how well you control the painful stimulus in those individuals. If we do this, it's painful. If we do this intervention, it makes it less painful.
Maria - That's correct. We are covering from the diagnostic tool itself of assessing if a baby is experiencing, uh, pain or the pain is subjective, we think we have a surrogate approximation of what is happening at the brain level. And, of course, this is then applicable when we are interested in testing interventions and things. Currently, there are no really medications or analgesics are not licensed to use in various small babies at the moment. So it could be a very important achievement if we can actually test these interventions faster and minimise the number of participants that we need.
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