The team explores how temperature, rather than genetics, regulates limb length in mammals; the assumption that melanoma follows the usual cancer stem cell model challenged; the discovery of 11 new regions of genetic variation that are linked to cholesterol levels; nagging can save your life – single men are less likely to have prostate cancer screening; how X-ray crystallography has given an insight into the molecular mechanism that prevents eggs being fertilized by more than one sperm; new discoveries that may help control epilepsy and brain damage from a stroke.
Plus, in 'Stuff and Non-Science', does boiling water really freeze faster than cold water?
Chris Smith: Hello! Welcome to The Naked Scientists: Up all Night which is produced in association with the Open University. I’m Chris Smith. In this week’s show, scientists have turned up the heat on our understanding of how temperature controls the sizes of different parts of the body.
Kat Arney: They raised mice at either 7 degrees, 21 degrees or 27 degrees centigrade and then measured the lengths of their tails and their ears, and they found that they were significantly shorter in the mice that were raised in the cold, compared with the mice raised at warmer temperatures, even though their overall body weights were exactly the same.
Chris Smith: Kat Arney, who’ll be explaining how temperature can affect growth like that, in just a moment. Also on the way, we’ll be hearing from the scientist who’s cracked the problem of why the eggs of mammals, known as oocytes, only allow themselves to be fertilised by a single sperm.
Luca Jovine: The oocyte reacts to the binding of the first sperm by liberating some enzymes that cut this particular protein, and this creates a physical barrier to other sperm that want to penetrate and fuse with the egg.
Chris Smith: And that research could lead to new contraceptives and treatments for infertility. Luca Jovine will be talking to us in more detail about it very shortly. That’s all coming up on this week’s edition of The Naked Scientists: Up all Night.
First, let’s take a look at some of this week’s top science news stories from around the globe and bringing us up to speed is Kat Arney. So, Kat, shake a leg and tell us what have scientists discovered this week about the link between temperature and the size of your peripheries?
Kat Arney: Certainly. Well, there’s an old rule in biology known as Allen’s Rule which states that warm-blooded animals from cold climates are likely to have shorter legs and other appendages, such as ears and tails, than the equivalent animals from hotter climates. Now, a good example of this is the difference between Inuit people, basically Eskimos from the Arctic, who tend to be short and squat, compared with things like Masai warriors from Kenya who are much taller and rangier.
Chris Smith: So what do researchers think is the reason for that, though?
Kat Arney: Well, it’s been thought that this is hard coded into animals’ DNA. You know, animals evolve over time in certain locations and their genes have evolved to give them different length limbs. But now researchers at Pennsylvania State University have shown that temperature can directly affect cartilage growth providing perhaps a biological explanation for this rule.
Chris Smith: So what do they do and how do they do it?
Kat Arney: Well, it was quite a simple experiment. They raised mice at either 7 degrees, 21 degrees or 27 degrees centigrade, and then measured the length of their tails and their ears, and they found that they were significantly shorter in the mice that were raised in the cold, compared with the mice raised at warmer temperatures, even though their overall body weights were exactly the same.
Chris Smith: So these mice were all the same genetic stock. So it must be the temperature? It’s nothing to do with genes?
Kat Arney: Absolutely. They’re all genetically identical, just raised at different temperatures. And they found also that mice raised in the cold had less blood flow in their extremities, and when they tried growing bone samples at different temperatures in their lab, the researchers found that the samples grown in warmer temperatures had significantly more cartilage growth than those grown in colder temperatures.
Chris Smith: Well that’s interesting isn’t it because you’d have thought that if animals are all warm-blooded, as mammals are, that then their body would be at a constant temperature so why should there be a temperature-related effect?
Kat Arney: Well that’s very true but, as anyone will know, especially given the chilly temperatures that we’ve had at the moment, the temperature of your extremities, your fingers, your toes, your ears, can be a fair few degrees lower than your core temperature which is kept at 37 degrees.
Chris Smith: So what do you think the implications are of this on the grand scheme of things? To return to the example you gave earlier of people who live in the Arctic being quite short and squat, people who live on the Equator being lankier, how do you think this applies to human populations?
Kat Arney: Well, it seems that Allen’s Rule still holds. You know, if you come from cold areas, you’re more likely to be stumpy than if you come from somewhere that’s warm. But the research does tell us that the length of limbs, at least in response to temperature, isn’t necessarily hard-coded into our genes. It does also tell us that there’s still a lot more research to be done, for example, to find out if you can subsequently then inherit these changes in tail or limb length.
Chris Smith: Well talking of things controlling growth, one thing that is a growth that we often don’t like is cancer, and in recent years scientists have got very excited about stem cells in cancer because they thought they could be the things that are fuelling cancers to make them grow – that’s been cast into doubt a little bit this week. Tell us about that.
Kat Arney: Yes. Cancer stem cells are a very hot topic in science, and this is the idea that tumours are fuelled by a small group of immortal cells that are resistant to conventional treatment. Some people believe they’re at the root of all forms of cancer. But now scientists in the US are challenging that assumption, and writing this week in the journal, Nature, the researchers have found that melanoma, that’s the most dangerous form of skin cancer, doesn’t necessarily follow this conventional stem cell model.
Chris Smith: So actually what was the difference then? What have they done that says the previous theory was wrong?
Kat Arney: Well, this team led by Sean Morrison, they carried out experiments using human melanoma cells that were transplanted into mice. Now, if the stem cell model holds true, you’d expect only a tiny fraction of the transplanted cells to give rise to cancers in the mice, and they found that, in fact, these tumour-forming cells were very common, but hadn’t been picked up in the standard tests that they’d done before, and using their improved tests they showed that around a quarter of the melanoma cells had the capacity to grow into new tumours.
Chris Smith: That’s quite scary isn’t it, so what are the implications for cancer research then?
Kat Arney: Well the researchers say themselves that this doesn’t actually mean a complete failure of the stem cell model. We can’t throw it in the bin just yet, and it’s likely that probably for some types of cancer the stem cell model will hold true, but it suggests that certainly for melanoma stem cell-type treatments aren’t really the right thing.
Chris Smith: Well it’s, I suppose, good that we’ve found that out sooner rather than later, isn’t it, because otherwise we could have wasted more resources perhaps going down a blind alley. Now cancer kills about one person in three, so does heart disease, and one thing linked to heart disease is cholesterol, and scientists have got some interesting findings on the genes linked to cholesterol now?
Kat Arney: Absolutely. It is increasingly clear that our genes play a big role in our health, but now we’re starting to focus on the subtle genetic variations that make us all unique, you perhaps more unique than others, Chris, but also can increase or decrease our risk of various illnesses. And now an international research team has found 11 new regions of genetic variation that are linked to levels of cholesterol and triglycerides. Both of these are bad things and linked to heart and cardiovascular disease, and adding this to previous research it now means that we know about 30 such gene variations.
Chris Smith: And how did the researchers find the new set of genes that they identified in this study?
Kat Arney: Well, to start with, the researchers looked at the results of seven studies that are screened across the whole genome for genes that were linked to cholesterol and triglyceride levels, and then they looked at DNA samples from over 20,000 people and pinpointed this down to 30 gene sites that were really truly linked to cholesterol and triglycerides. Now, this included 19 genes that had been spotted before, suggesting that their methods were working, but also it threw up 11 new ones, which is obviously exciting, and although some of these new genes had previously been linked to cholesterol problems or diabetes, many of them, it’s not really clear what they might do.
Chris Smith: But having identified them, that presumably gives us new things to study in terms of making drugs to block the effects of these harmful genes and therefore reduce the risk of dying of heart disease?
Kat Arney: Absolutely, and this is really what this research is all about. The more we can understand about the genetic faults and variations that underpin diseases, then the more likely we are to be able to design more targeted effective treatments. And a really good example, I’m sure you know, is statin drugs, and they work by blocking the actions of a particular gene, and that’s one of the 30 gene variations that’s been picked up in this study.
Chris Smith: And, in that respect, what are they hoping to do next?
Kat Arney: Well, the researchers think that these 30 genes only account for around a fifth of the genetic contribution to cholesterol and triglyceride levels, so clearly there’s loads more genes out there that we need to track down that we don’t know about them yet. And also it’s going to be important to sequence these 30 genes, to really track down what are the differences that increase or decrease people’s risk.
Chris Smith: Encouraging stuff. Let’s hope that they make some breakthroughs soon given how many people actually die of heart disease in the UK, and the UK doesn’t do terribly well on that front, does it. Now, Kat, perish the thought that you could possibly nag your better half. You don’t do that, do you?
Kat Arney: I would never nag my better half, except when he leaves the toilet seat up. But here is a story that might be surprising to any man with a nagging partner because it could actually save your life. Now researchers at the University of Michigan have found that men with a wife or a significant other half living with them are more likely to go for screening for prostate cancer, and they did this because while there’s some evidence that prostate cancer screening can help in picking the disease up, we don’t really know about the reasons why men choose to go for screening or not.
Now it’s worth pointing out at this point that prostate cancer screening’s available from your GP here in the UK on request but there is no national screening programme because there’s not really enough evidence to show that screening really saves lives.
Chris Smith: This sort of reminds me of something that was put about in the time of about, well, it was about 8 years ago, and there was a poster campaign “His Life in Your Hands” and the idea was to try to get women to examine their partner’s testicles to cut down the risk of testicular cancer, which had shown a big increase in numbers. But how did the researchers actually go about studying, in this case, the beneficial effect of having a nagging partner?
Kat Arney: Well, they did this by looking at nearly 2,500 rather hectored men, obviously, in Minnesota, aged between 40 and 79, and they asked them to fill in questionnaires about their family history, their concerns about prostate cancer and their marital status.
Chris Smith: Do you read “under the thumbness” by martial status then?
Kat Arney: I think just whether they were married, single or living with a partner, that kind of thing, not whether she nags you or not. And first, they found that men who are worried about prostate cancer were twice as likely to go for screening, as you might expect, but also the likelihood to go for screening among men with a family history of the disease dropped if they lived on their own. And, in fact, these men were 40 per cent less likely to be screened than those who were married or had a significant other in their home too.
Chris Smith: Now, that sounds great but the thing is that people who are already married are getting the benefit already, people who aren’t married, well, they’re not going to go and get married just to reduce their risk of prostate cancer, are they, so how is this information actually going to help anybody?
Kat Arney: Well, the obvious answer is that health professionals should be targeting messages about screening to men’s partners, as well as to men themselves, but it does show that there’s quite a big challenge in getting through to single men, and maybe we need to find different, more subtle or maybe more kind of sledge hammer ways of getting through to single men that, you know, they should go and that your wife won’t necessarily push you into it.
Chris Smith: So a sledge hammer to crack a prostate cancer - ouch! Thank you, Kat. That was Kat Arney from The Naked Scientists with a roundup of some of this week’s top science news stories. And if you’d like to follow up on any of those items, the details and the references are all on the Open University’s website which is at open2.net/nakedscientists.
In just a moment, how scientists have uncovered the workings of a new nerve cell channel found in the brain which could lead to new treatments for epilepsy and stroke. But first to an enigma, or you could say an egg-nigma! It’s a question that’s had scientists baffled for decades, which is how does an egg prevent itself from being fertilized by more than one sperm? It’s essential that this doesn’t happen because otherwise an egg would end up with too many chromosomes and that could prove fatal.
To solve the mystery and find out how sperms and eggs recognise each other, scientists at the Karolinska Institute in Sweden have used X-rays to work out the three-dimensional structure of a protein called ZP3 which forms part of the zona pellucida, the outer coat of an egg. To tell us more, here’s Luca Jovine.
Luca Jovine: People have always been wondering about how binding between germ cells that is sperm and egg works, and there’s been lots of pictures that were taken from 1965 onwards, more or less, that showed this event but the actual molecular mechanism still remains a mystery. We wanted to use structure biology to kind of break through this barrier and try to get some detailed information on how this works.
Chris Smith: Crack into the egg, if you will?
Luca Jovine: Yeah, exactly.
Chris Smith: How did you do it?
Luca Jovine: So essentially we use a technique called X-ray crystallography, and this technique relies on the ability of convincing a certain protein to form crystals, and this is what we did with this protein ZP3, and after we obtained the crystals we could expose them to X-rays, and from that we could reconstruct a model of its three-dimensional structure.
Chris Smith: And this ZP3, this is one of the surface proteins on the egg which is presumably responsible for the interaction with sperm?
Luca Jovine: Yeah, correct, so essentially all eggs have several coats and in mammals there is a single coat which is called zona pellucida, and essentially it’s like a plastic bag which is wrapped around, completely, the egg. And this coat is very important for the egg to grow, it’s crucial for its binding to sperm, and this is where this protein comes into play.
Chris Smith: So when you put these crystals through the synchrotron beam of X-rays, what did that reveal about the structure of this protein?
Luca Jovine: So what we saw is that it has a particular arrangement in three dimensions which is similar to many other proteins that share a so-called immunoglobulin-like fold. It also showed, basically, the special arrangement of the most important amino acids of this protein.
Chris Smith: So, in other words, you could get some insights into how, given that this protein is repeated many times across the surface of the egg, how all the proteins lock together effectively?
Luca Jovine: Yeah, this is one of the things that we could at least start thinking about. The other thing was to make sense of almost 30 years of research that was done on this protein. So there was lots of biochemical data that was sometimes not so easy to fit together that suddenly we could visualise in terms of how the protein actually looks like, and this has kind of clarified several issues.
Chris Smith: So what do your measurements actually suggest goes on? So when one sperm locks onto the egg, how does that erect a barrier to stop other sperm coming in?
Luca Jovine: So what was known is that there is another subunit which is of this egg coat called ZP2, and this subunit, after the first sperm is bound, is modified. So what happens is that the oocyte reacts to the binding of the first sperm by liberating some enzymes that cut this particular protein, and somehow this specific cut makes the coat tighter, so that basically this creates a physical barrier to other sperm that want to penetrate and fuse with the egg.
Chris Smith: So once one sperm gets in, you end up with a sort of molecular domino effect where these proteins all change their shape, erecting this permanent barrier which stops any more sperm from gaining entry?
Luca Jovine: Yeah, it’s kind of like that. It’s not the whole zona pellucida that changes but the very inner layer which sits next to the plasma membrane. And this is of course the most important region because that’s where sperm has to go through in order to fuse.
Chris Smith: And now you understand a bit more about the surface of the egg and how it interacts with sperm. Presumably, that could be a brand new target for contraception?
Luca Jovine: Yeah, that’s right, so that’s the other side of this work. The part we saw the structure of actually is responsible mainly for allowing the protein to make this coat, so it probably does not bind sperm directly. However, experiments done in mice have shown that if you make mice that are engineered so that they don’t express ZP3 or the other subunit ZP2, these mice basically make eggs but these eggs are completely lacking the coat, and in vivo this results in complete infertility. So this observation can be used in the sense that if one were able to make a compound that would bind to ZP3 and block it from assembling into this egg coat, then this would act as a very specific contraceptive essentially.
Chris Smith: Luca Jovine describing his discovery of what happens to the outer coat of an egg cell when it’s fertilized by a sperm, and he’s published that work in this week’s edition of the journal, Nature. Now from egg cells to nerve cells and how scientists may have stumbled upon a new way to treat epilepsy and also to reduce the damage that’s done to the brain by a stroke. A number of years ago, researchers uncovered a pore in the membranes of nerve cells called the NMDA receptor, which when it’s activated makes nerve cells more excited. But if this NMDA receptor is over-activated, which can occur when nerve cells run out of oxygen like they do during a stroke, this can damage the cell. Scientists were therefore quite surprised when they gave drugs that could block the NMDA receptor but found that they weren’t very effective at reducing the damage done by a stroke.
Now two neuro scientists, Brian MacVicar and Roger Thompson, think they know why. They’ve found that the NMDA receptor is connected to another very large channel called pannexin, and when the NMDA receptor turns on, it also opens up the pannexin channel, and this floods the cell with potentially harmful substances. The same process could also trigger epilepsy. Here’s Roger Thompson.
Roger Thompson: So in this paper we were trying to discover how epilepsy can be initiated by the normal communication that the brain uses. So the brain normally uses a neurotransmitter called glutamate, which is a chemical signal that’s released from one neuron and binds to the next one on specific receptors; one subclass of them is the NMDA receptor. It has been known for quite some time now that when the NMDA receptor becomes over-stimulated it leads to a secondary current that was unidentified. So our goal was to identify this secondary current and then see if it played a role in any type of pathological situation.
Chris Smith: When you say there’s a secondary current there, what is that current? What does that mean and how might it be involved in pathological conditions?
Roger Thompson: So it was called the secondary current because when the NMDA receptor is activated, it itself carries an ionic current across the cell, across the neural membrane, and this leads to another ionic current, and it was named a secondary current. So what happens is when the secondary current is activated, the cells can then become overloaded with calcium, which is very detrimental to the health of a neuron and most cells, in fact.
Chris Smith: So if I could turn to Brian MacVicar who’s one of the other co-authors on this study. Brian, what did you actually do to try and investigate what was going on?
Brian MacVicar: So the strategy was to look at the effect of activating NMDA receptors on the nerve cells, and we had studied this other channel called pannexin a few years ago, and pannexin is a giant channel. We suspected this may be the secondary current that’s turned on by the NMDA receptor activation, and it could explain why treatments for stroke that block the NMDA receptor weren’t effective because this other channel which is much, much larger was actually activated.
Chris Smith: So how does it get turned on, Brian? So the NMDA receptor becomes active. How does it get a signal to this other channel so that this one, this pannexin, turns on too?
Brian MacVicar: This is actually still a mystery and I think this will be an important avenue to pursue in the future, to figure out exactly how this large channel, this pannexin channel, is turned on, because it may give us some mechanism to go in and prevent the activation and prevent the epilepsy or stroke damage.
Chris Smith: So how did you go about investigating this presumed link between NMDA and pannexin?
Brian MacVicar: So the first experiment was to apply the egenis, this artificial compound, that mimics glutamate, the natural transmitter, and we activate the characteristic current and look for strange unusual secondary currents that are turned on. We look for evidence of large channel opening so we can see large molecules cross the membrane and then to show that this is blocked by different agents that we know block this channel.
Chris Smith: Roger, when you set up these experiments, what did you actually see?
Roger Thompson: So the first thing that I did was to isolate neurons from a rodent brain and then use tiny electrodes to record their electrical currents. This is a technique called patch-clamping which has been around for quite some time. And when doing those experiments and we add the NMDA to the neurones, now, NMDA is a chemical mimetic of glutamate, the brain’s natural transmitter, we see activation of the NMDA receptor currents and then with some delay then the secondary current turns on.
Chris Smith: Now if you’re right and that these channels get activated when animals, such as humans, have strokes or damage to the brain, if you give these blockers of pannexin, do you then prevent damage to the brain when you try to trigger a stroke?
Roger Thompson: That is certainly the million dollar question, I think. The answer is we don’t know yet. Typically, these blockers are somewhat difficult to deliver to the brain without injecting them directly in the brain. There is currently a mouse model in which the pannexin channel has been genetically deleted, and in that situation the lesion area in a stroke has been reduced, so that’s at least consistent with our original proposal. So how this will affect epileptic-type behaviour, the subject of the latest paper, we just don’t know yet.
Chris Smith: What role do you think it might play in things like epilepsy?
Roger Thompson: I think it acts as, probably as a boost during the epileptic-type bursting, the aberrant electrical behaviour. So we have some evidence to show that if we inhibit the channel, we don’t prevent, in our model, the epileptic-type behaviour from occurring, but we can certainly reduce its amplitude and the frequency of these what are called interictal spikes or a regular pattern of electrical discharge in the brain.
Chris Smith: Roger Thompson from the University of Calgary and, before him, Brian MacVicar from the University of British Columbia. They’ve published their findings in this week’s edition of the journal, Science.
This is the Naked Scientists: Up all Night with me, Chris Smith, and time now for this week’s Stuff and Non-Science where we murder urban legends, and getting her muffler out in anticipation of a cold snap, here’s Diana O’Carroll.
Diana O’Carroll: This week’s Stuff and Non-Science was sent in by Steve Whitehead, and it’s the myth that boiling water freezes faster than cold water, or is it just a bit of misunderstood science? To set us straight, here’s Martin Chaplin.
Martin Chaplin: Many people believe that boiling water might freeze faster than cold water and other people believe that this is an urban myth and think it’s complete nonsense. The nonsense bit is much easier understood in that surely if something is hot then it has to become cold before it can freeze and therefore it must take longer; however, this is not what’s found in practice.
The particular effect was found by a schoolboy called Erasto Mpemba in Tanzania, who found that his ice cream froze quicker if he heated it rather than if it was cold ice cream when he put it in his freezer. Eventually, other people have done a number of experiments on it and they find that, in fact, quite often hot water will freeze faster than cold water. This is possibly due to the fact that it evaporates more because it was hot to begin with and it loses heat faster because the water is circulating much more if it was hot to begin with. Perhaps the best reason for this is because that the materials don’t actually freeze at 0 degrees.
Although water melts at 0 degrees, it usually freezes a few degrees below, and if the water is cold to begin with, it freezes even more below than if it was hot to begin with, so the hot water freezes first because it doesn’t need to get to such a low temperature before freezing sets in, and that really is the key to it. If it’s hot to begin with, perhaps you drive off the gas that’s dissolved and make, maybe, little bubbles in the water, and then when that cools down and it’s got to freezing point, these bubbles actually allow ice to form much quicker than if there weren’t bubbles there and the gas was actually still dissolved in the water. If the freezer was at just minus six degrees, the likelihood is that the hotter water would freeze first. Although if the water is very close to freezing point before you start and the other one’s very hot, then it’s probably unlikely to see the effect. But if one is, say, at room temperature and the other one is at 90 degrees, then you will see the effect.
Diana O’Carroll: Martin Chaplin, who’s Professor of Applied Science at the London South Bank University. So hotter water can freeze faster than cold water but only in a fairly specific set of circumstances. If you have a science myth of your own, then send it to me, firstname.lastname@example.org.
Chris Smith: So hot ice cubes are definitely the way forward. Thank you, Diana. That was Diana O’Carroll with this week’s ‘Stuff and Non-Science’.
That’s it for this time. We’re back next week with another round-up of the latest findings from the world of science. The Naked Scientists Up all Night is produced in association with the Open University, and you can follow up on any of the items included in the program via the OU’s website. That’s at open2.net/nakedscientists. Alternatively, you can follow the links from the BBC Radio 5 Live Up All Night webpage. Production this week was by Diana O’Carroll from thenakedscientists.com and I’m Chris Smith. Until next time, goodbye!
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Clare Sansom explores the chances of an individual human sperm fertilising an egg in Half a billion to one.
These are the sources used by the team in making the show:
In the news
'Temperature regulates limb length in homeotherms by directly modulating cartilage growth'
by Maria A. Serrat, Donna King and C. Owen Lovejoy
'Efficient tumour formation by single human melanoma cells'
by Elsa Quintana, Mark Shackleton, et al
'Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts'
by Yurii S Aulchenko, et al
in Nature Genetics
'Psychosocial factors associated with an increased frequency of prostate cancer screening in men ages 40 to 79 years: the Olmsted County Study'
by Wallner LP, et al
in Cancer Epidemiology Biomarkers & Prevention
Luca Jovine, 'Crystal structure of the ZP-N domain of ZP3 reveals the core fold of animal egg coats' by Magnus Monné, et al in Nature
Brian MacVicar and Roger Thompson, 'Activation of Pannexin-1 Hemichannels Augments Aberrant Bursting in the Hippocampus' by Roger J. Thompson, et al
Martin Chaplin for 'Stuff and Non-Science'