Does Vaping Inflame the Brain?
Signs that some vapes inflame the brain and other organs, how a whiff of CO2 puts mosquitoes into feeding mode, how long, at present rates, it will take before science reaches gender parity, and how babies get their vitamin D. Chris Smith looks inside some of the latest papers in eLife...
In this episode
00:32 - Vaping inflames the brain
Vaping inflames the brain
Laura Crotty-Alexander, UCSD
Rates of eCigarette and vaping product consumption have risen dramatically in recent years. In the UK over just the 5 year period from 2012 to 2017 it climbed by several hundred percent. Many users are former smokers who regard vaping as a healthier option and have switched for that reason. But there’s also a - for the moment small but - growing cohort of “never smokers” who vape because it’s perceived to be low risk. Could it be though that, in the same way that it took decades of following up smoking doctors before Richard Doll could categorically say that smoking causes health harms, vaping - being a relatively new phenomenon - just doesn’t have the data yet for us to know what the health risks are? This is very much the view of UCSD’s Laura Crotty-Alexander…
Laura - In terms of whether the e-cigarette aerosol mixture is safer than conventional tobacco smoke, it looks like it is going to have fewer health effects, but it will have its own set of health effects.
Chris - Which could be different and remote and, in fact, manifest in a different part of the body, presumably, if they're different chemicals than what's in cigarettes?
Laura - Absolutely. Cigarette smoke contains about 7,000 chemicals, and that use of cigarettes leads to damage across the body - everywhere from your lips, where it first makes contact, all the way down to the GI tract and out to the skin and to the brain. And what we sought to find was whether e-cigarette aerosols could also impact all these different organs across the body.
Chris - How did you do it?
Laura - We used a mouse model. So we have this special setup where we take the mice and we put them in a little pie-shaped wedge container where they can move around. And then we use e-cigarettes that we have bought on regular websites and we give them a puff of e-cigarette aerosol and then regular air. And we have them breathe that in for 30 minutes, three times a day.
Chris - And is the mouse dose equivalent to what a human consuming these products would get? Or are the mice getting a much bigger impact and a bigger dose? Because obviously a human breath would be massive for a mouse...
Laura - We do try our best to design these mouse models to mimic human use, which is why we expose the mice multiple times a day, because a lot of humans use e-cigarettes throughout the day. And when we take one puff that's more human-sized, we actually put it into a large chamber where it diffuses. So 16 mice are breathing in that aerosol.
Chris - And how do you then marry up what that intake is doing in different parts of the body?
Laura - We actually harvest the mice and then we take all the different body parts. And we look at them using special tools that look at gene expression or levels of protein. And we actually even look at organ function. And so we use these different measures to try and determine whether inhaling these e-cigarette aerosols over months leads to changes in these organs.
Chris - And what crops up when you do this? Do you see systemic effects?
Laura - Yes. So I was very surprised that we found profound changes in the brain in particular of these mice that inhaled JUUL mint and JUUL mango, which are two flavours that were very popular at the time we started this study. And both of those aerosols led to inflammation in the brain, which is shocking because the brain is a protected compartment. So it was very worrisome that inhaling the e-cigarette aerosols for just a month led to very impressive levels of inflammation in a part of the brain that controls mood and behaviour and memory.
Chris - Are you saying that it's specifically the flavours that are doing that? So this is an effect beyond the addictive qualities of the nicotine and so on?
Laura - In the brain, the fact that we saw similar changes in both flavours indicated more that it was the nicotine and the other substances at the core of these e-liquids that were driving the changes. But, for example, in the heart, we found that the mint flavour really changed and drove inflammation, whereas the mango flavour did not. And so that comparison helped us to understand that maybe the heart effects are maybe particularly driven by the mint flavour and not the nicotine and other components.
Chris - We'll come on in a second to what the impact of that might be, but just considering for a minute the fact you've got this effect, how does it compare in scale with if the mice were just (if mice could) smoking normal cigarettes?
Laura - If I were to look back at the historic data, I would say that the neurologic effects are of a scale that appears to be either equal to, or greater than, what is seen in conventional tobacco, and that the effects are different.
Chris - We believe that chronic inflammation might be linked to at least the progression, if not in some cases the cause, of certain neurodegenerative conditions and probably also degeneration in other organs. So do you think then that this is indicative of the fact that people doing this could be speeding up the ageing process of their brain? They're effectively bringing forward the age at which they may well succumb to degenerative conditions of the nervous system?
Laura - I absolutely agree that that is a concern. And, in addition, the changes in these parts of the brain suggest that people who are using e-cigarettes may have more anxiety and depression and might have sort of permanent changes to their behaviour patterns.
07:10 - What makes mosquitoes hungry
What makes mosquitoes hungry
Trevor Sorrells, Rockefeller University
Many regard mosquitoes as the world's most dangerous animals because of the diseases that the females transmit when they feed on us. They need blood to provide protein to support their egg laying. But other than the fact that they are attracted to the CO2 in our breath and the heat from our bodies, we know relatively little about how their feeding behaviour operates. And that's what Trevor Sorrells, at Rockefeller University, has been studying. He's been using the technique called optogenetics to fool mosquitoes into thinking they've just smelled a whiff of carbon dioxide. This, he's found, puts them into a "feeding mode" that seems to control a host of other downstream behaviours...
Trevor - Mosquitoes are micro-predators: they attack small quantities of their prey at a given time. And so this gave us inspiration to understand this behaviour that they use to find humans. And we wondered whether it had some similarities with larger predatory animals that hunt their prey over long periods of time. And this question of timing hadn't been examined. So we set out to understand whether mosquitoes have a sort of hunting state in their brain.
Chris - Is that in the way that if I felt hungry and I thought, "right, dinner time", I would lock myself into dinner mode and then my goal would be, "I'm going to make dinner." And I wouldn't stop until I'd eaten. Is that what you're saying? That they have a sort of default mode they go into that says, "Right, it's dinner time and I've smelt a human, now I'm on the scent of a human. I'm going to go and find them."
Trevor - Yeah, exactly. So if you were very hungry and you were walking down the street and smelled pizza, you might search around to try and find where the pizza smell is coming from. And until you locate your pizza shop and have a slice, then you'd be in this hunting mode.
Chris - Would that be indefinite? Would I carry on in hunting mode until something turned it off or would there be a time clock running?
Trevor - Yeah, exactly. And this is the question we set out to answer. It is also an important question because it has a lot of implications for how mosquitoes are able to find humans and bite us so effectively.
Chris - Obviously they're dubbed flying hypodermics and also the world's most dangerous animal, aren't they, in terms of the disease burden that's linked to them. How did you actually go about looking at this?
Trevor - We used a technique called optogenetics, which gives us the ability to activate neurons using light. And this is an advantage because it gives us really great control over the timing of when the neurons are activated. We used it to activate the carbon dioxide sensory neurons - carbon dioxide being a major component of our breath. So we put this channel that responds to red light in the neurons that respond to carbon dioxide. And so when we shine red light on them, it causes these neurons to activate and simulates the experience of carbon dioxide for the mosquito. And so we refer to this as fictive carbon dioxide.
Chris - I suppose one of the advantages of doing that is that you can be very precise in terms of when you give the stimulus and how much stimulus. It's not like blowing some CO2 at a mosquito and not knowing how much it's really smelled. This way, you actually know what the stimulus was when it was presented and in what sort of amplitude.
Trevor - Yeah, that's exactly right. And it's very hard to control gases because you don't know exactly where they are. And so we know exactly where, how much and when the mosquitoes are receiving this fictive carbon dioxide stimulus.
Chris - So that simulates a mosquito running into a human or an animal that's just breathed out. So what happens next then once it gets that stimulus?
Trevor - So mosquitoes respond to the fictive carbon dioxide stimulus by flying, which is well known as the response of mosquitoes to carbon dioxide. They also showed a lot of walking and this behaviour called probing, which involves the insertion of their proboscis into small crevices. So if a mosquito has landed on your clothing, then they show this behaviour of probing. So you would be very familiar with this, but what was surprising about our results is how long they do it for. They have this response for up to 15 minutes after just a brief fictive CO2 stimulus.
Chris - So that would be like flicking some kind of switch. It basically is the master switch that says, "right, feeding time" and activates all those other behaviours.
Trevor - That's what it appears to do. So these are a number of behaviours that the mosquitoes exhibit, but they have also altered responses to subsequent stimuli that occur later in time, or while they're in this hunting state. And these include additional cues that they use from the human host, like heat and the taste stimuli, that are present in our blood.
Chris - The one thing that we haven't discussed with this is the difference between males and females, because it is the female mosquitoes that do the blood meal feeding and the males don't do they. So if you do the experiments on males, what happens to them?
Trevor - So male mosquitoes do not feed on blood because they don't need to produce eggs. However, the males, when we tested them, they showed a strong response to fictive carbon dioxide. But the response was about 1/10th the duration of the female's response. This was interesting to us because it showed that males, while they have the ability to detect the carbon dioxide stimulus, they do not have this persistent state that we think is associated with blood feeding specifically. So males, it has been shown, do respond to carbon dioxide in order to get closer to humans and to mate with females in their vicinity. So we think that this time scale of the response of males and females is one of the reasons that the state we've discovered is specific to the goal of feeding on blood.
Chris - Does that also potentially give you a way to find out how this works? Because if you can look what is happening in the female brain, but absent from the male brain, that perhaps might be whatever that platform is that's subserving this timing mechanism.
Trevor - Yeah, that's one really interesting way to get at the neurons that control this persistent state, which is my goal for future research. Exactly as you said, to compare males and females and to understand which neurons are different in the male and female brain, because we would expect that if not the neurons that control the persistence of the state, it would identify the neurons at least that are somewhere in the circuit that control the persistent state.
14:40 - How long before science is gender neutral?
How long before science is gender neutral?
Lindy Barrett, Broad Institute
Considerable efforts have been made in recent years to achieve a more even balance of men and women in science, and particularly at senior levels. So how effective have those interventions been, and if we continue along the same trajectory of change, how long will it be before we arrive at gender parity? Surprisingly, this is not well delineated, so the Broad Institute’s Lindy Barrett set out to find out…
Lindy - The first thing that I did was really to take some data sets that had been collected by an organisation called the AAMC. This is the Association of American Medical Colleges because they have historic data on gender at different career stages going back for over a decade. And so the first thing that I did was look at how much change we've seen in a recent 10 year period and the number of both male and female full professors and department shares. Assuming we have the same rate of progress, I wanted to project how long it would take to get to gender parity, which is that 50 50 split between men and women. And the second question was, how do we actually get to 50/50? And I wanted to probe more deeply how getting to gender parity really might or might not impact men because so much attention in the area of gender imbalance is focused on women and how to promote and retain women. But we don't hear as much about how this will impact men.
Chris - Well, let's take those two things in turn. The first point you said was how long it would take. So how long will it take before we see an academic landscape which is about 50/50?
Lindy - At the leadership levels at tenured faculty and at department chairs, the short answer is that if really nothing changes, we're looking at another 30 to 40 years.
Chris - Where are these people going? Because if you look at the bottom end, the trainees, there's not that disparity. So where is the jumping off point and where do these women go?
Lindy - It's really interesting. I've kind of gone into this assuming that there was a slow attrition all along the way. But, at least in the case of US academic medicine, men and women are receiving the relevant degrees, which are MDs and PhDs in biomedicine, in roughly equal numbers. So we've a highly trained workforce of both genders and it's actually pretty equal at the assistant professor level. I think it's roughly 46% women and 54% men at that level. And then the attrition is really happening between the assistant professor and full professor level. So that was really striking that we're really getting a pipeline of women all the way to the assistant professor level, and then we're getting the drop off.
Chris - Dare I speculate that that might happen to also be the age at which women end up having children, because that I know from personal experience and talking to my colleagues brings enormous pressure and is a huge tension for people where they're having to choose between a career and a family very often. And in the US it's even intensified because there is much less provision for maternal leave and so on and family and parental leave, isn't there.
Lindy - Absolutely. It's really the age at which women are seeking tenures: the childbearing years, essentially. As you mentioned in the United States, there's no paid parental leave policy, there are a lot of difficulties that women specifically face because of their role as mothers. There are several studies suggesting that the gender disparity is a disparity of parenting, but I think parenthood is certainly not the only factor. I think that many of the issues are cumulative over time and they may reach a culmination when you're talking about that critical stage of promotion and retention at the faculty level.
Chris - The other point you mentioned is, what about when we flip this round and say, well, okay, we want to change this. So what does this mean for men? How did you investigate that? And what did you find?
Lindy - I essentially looked at two different ways to get to gender parity. So assuming we're going to get to a place of 50/50 between men and women, there are a couple of different ways that we could do this. One strategy would be to keep the number of men in these positions constant and just add more women. The second strategy would be to keep the overall number of positions constant and add women while also decreasing the number of men. And I think this is a bit more consistent with data over the last 30 years, showing that the absolute number of faculty positions has remained rather static. So if we take the first example, if we keep the number of men constant and we just add women, we would need to add nearly 20,000 new full professor positions just for women in order to get us to that 50/50. And so that would be an enormous increase. It would be going from just over 38,000 to nearly 58,000 positions. Alternatively, if we were to keep the overall number of positions constant, we actually need to double the number of women in these positions, but we also would need to reduce the number of men in these positions by at least a third. So we would be looking at taking about 10,000 of the current full professor positions that are held by men and essentially replacing those positions with women in order to get to the 50/50.
Chris - Hmm. It may also not go down very well if you take scenario two, mightn't it, because, to give you an example, which is a totally different situation but is similar in terms of its impact: there was a report written recently, some sentiment expressed by Stephen Toope who's the vice chancellor of Cambridge University. He was saying that, people who send their children to private school are going to have to get used to the fact that Cambridge, Oxford, other leading institutions, are going to take fewer people in future from private school. And they're going to bais admissions more towards people who are not at private school. Now his intentions are good ones, but the message that's coming through is, as a child, you will be discriminated against for a decision that your parents have made. So the men in your scientific scenario are effectively being discriminated against for a decision that history hands to them, not of their own making, which sounds a little bit unfair.
Lindy - Yeah. And I think when we look at the numbers, and that's why it's so important to do so, it really gets to questions of fairness. And I think a lot of people would have a gut reaction of, well, we can't do that. I think the point where we start to impact the position of men is the point where some people may feel very uncomfortable with some of the gender equality initiatives. But I think that really gets to the question of how do we think about fairness and advantage and who deserves a seat at the table? So I think the closer that we can look at the position of men and gender equality, that deserves some attention to get us toward more realistic solutions. And it may be that the field is sufficiently uncomfortable in reducing the number of men that we need to be looking at some of these alternative scenarios. But how do we think about additional resources? How do we think about restructuring power? These are conversations, I think, we really need to be having if the numbers are going to make people uncomfortable.
21:37 - How does a developing baby get its vitamin D
How does a developing baby get its vitamin D
Jane Cleal, University of Southampton
Vitamin D is a crucial hormone that helps to regulate calcium levels as well as playing a role in inflammation and immunity. We get it from what we eat and also, in large part, through the action of UV light on our skin, which produces the precursor molecule from which active vitamin D is then made, when it’s needed, elsewhere in the body. So what does this mean for a developing baby? Because it doesn’t eat, and it’s growing where the sun doesn’t shine. Of course, it’s dependent on a supply from mum, but what she needs might not be what the baby needs. And that’s where the placenta comes in. It picks up vitamin D precursors and activates them, at the right rate, and also uses vitamin D to regulate some of its own functions. Jane Cleal explains…
Jane - For most nutrients, the baby in the womb has to rely on transport from the mum. So the placenta is really important. It's like a really key organ for the baby. It provides its food, it provides its oxygen and it gets rid of wastes. So all the vitamin D to the baby has to be transported by the placenta, from the mum.
Chris - One of the things about the way vitamin D works in our body is that we make an inactive form of it, which we then activate when we want it. Is that the same in the baby, then? Or does the baby end up with the same vitamin D signal that mum's seeing?
Jane - So we took the main circulating inactive form of vitamin D and we saw that that is transported across the placenta to the baby. And we know that the baby has the enzymes in its body, so they can actually activate the vitamin D itself.
Chris - So it was the precursor, the inactive vitamin D that's going across, rather than active vitamin D.
Jane - Well, interestingly, we didn't know that. And we actually saw that, yes, the inactive one goes across, but the placenta does something to it itself, so that can use some of it. And then we saw that actually the placenta was releasing active vitamin D to the baby itself.
Chris - How does the placenta know how much vitamin D the baby needs?
Jane - People just think the placenta is a passive conduit. That stuff just goes across. But we are finding out that it perceives signals, it will perceive the vitamin D levels, and it will switch on genes, and it will carry out processes so that it can regulate what is transported across.
Chris - Is its role linked purely to calcium, because in adults, for example, you can find vitamin D having a hand in a range of other processes, including things like inflammation and immunity. So does it do other things in the placenta beyond just regulate how much calcium the baby sees?
Jane - So in the mum, it's regulating calcium levels and that calcium is being transported across to the baby. The vitamin D is going into the placenta and the placenta is using it itself. And so it's actually regulating the immune function of the placenta. It's helping the placenta implant and become bigger. So it's having lots of key functions on the placenta itself, and therefore all of these functions can also happen to the fetus. So it can have non calcium effects as well.
Chris - Well, I was thinking, as you were talking, we know the placenta is bound up in problems like preeclampsia when mothers get very high blood pressure and so on. Does this mean that vitamin D might be implicated in processes like that?
Jane - Yeah. Studies have looked at the vitamin D levels in women with preeclampsia and they do have lower vitamin D levels. So that's obviously an association. We don't know the relationship, but that's another example of why this work is really important because we're thinking vitamin D is affecting how the placenta grows and therefore it's affecting the placental function as well.
Chris - So in a nutshell, then, you have been able to show that the thing that gives rise to vitamin D in the mum's bloodstream is picked up by the placenta, it's activated by the placenta, and then fed to the baby, and certain signals coming from the baby regulate that. How did you do all of this? Because one of the problems with studying humans is there are ethical considerations. There are also practical considerations. So how did you manage to get hold of placenta that you could look at?
Jane - We have an established link with a maternity hospital, and we've got all of the ethics set up. We then wait in the labour ward and we have to collect the placenta when they're fresh because we keep them alive. So we collect the fresh placenta and we take it back to our lab where we can study it and study how it functions.
Chris - That though relates to babies being born at a certain stage of gestation. What about earlier on in the developmental process where most babies are not being born the normal way. Can you gain access to that tissue as well?
Jane - We could do. We haven't for this study. So we've only taken placenta from what are sort of deemed normal pregnancies, which are delivered at term. We can look at data from placenta collected earlier in gestation, and we have related that information as well. And we see the same things are expressed in those placenta.
Chris - So this is not a developmental kind of stage? This is happening right the way through pregnancy?
Jane - We think it's right the way through pregnancy, because in Southampton we also have some studies of women where we get their consent to be on our study before they become pregnant. And we get information on their lifestyle and diet, and we've been able to see relationships with the vitamin D levels earlier in pregnancy and the effects on markers in the placenta at birth.
Chris - We know that some winter babies are more prone to certain conditions - I should know I'm one of them. It's an intriguing association between being born in the winter, higher risks of certain conditions. We know that the population's level of vitamin D is an all time low in the height of winter, isn't it? So could there be consequences through this?
Jane - So in the data where they've studied populations, they see seasonal effects of vitamin D levels. It's surprising. We were shocked to find that a lot of women have low vitamin D levels. And what we did find that was when we gave the women vitamin D supplements, it was those that were due to give birth in the winter months that the supplement had the biggest effect on improving their vitamin D levels.
Chris - So would this argue then that actually we should encourage everyone to have more vitamin D and especially women who are pregnant in wintertime, or could there be consequences? If a person takes vitamin D when they're pregnant, does that have potentially negative consequences for the baby, given its unique role in what the placenta's doing?
Jane - There have been studies in America that have looked at higher doses than we use in the UK. And they've seen no harmful effects. It is advised to all women during pregnancy. I've literally just had a baby and I was told to take vitamin D and I did take my vitamin D throughout pregnancy because we know that it has beneficial effects.
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