Are trends in modern living helping or harming our ability to reproduce? And how do factors affecting fertility differ between men and women? Plus, fighting brain tumours with artificial antibodies and are internet filters really keeping children safe?
In this episode
00:52 - Fighting Brain Tumours with Artificial Antibodies
Fighting Brain Tumours with Artificial Antibodies
with Samuel Cheshier, Stanford University
A new way to tackle brain tumours has been tested successfully in mice by researchers in the US. The team at Stanford, in California, have found a way to trigger the immune system to selectively attack cancer cells but leave healthy brain tissue untouched. The discovery hinges on a signal called CD47, which brain tumours display on their surfaces. This is an immune off-switch, which sends out a kind of “don’t eat me” signal that prevents the dangerous cells from being destroyed. But an artificially-produced antibody that blocks this CD47 signal can save mice with otherwise lethal human brain tumours. Chris spoke to neurosurgeon Samuel Cheshier to hear how…
Samuel - Brain cancer is the number one killer of children of all cancers and it’s tough to treat because one: a lot of times we can’t operate to take out the cancer tissue mainly because the brain is a very sensitive organ and there’s lots of it you can’t touch. And the other issue is the brain greatly regulates what gets in it from the outside so it’s very difficult to get drugs into the brain.
And finally, some of the treatments that we do have that can treat brain cancer effectively, they’re all just a little bit more poisonous to the cancer than it is to the person. They have a lot of toxic side effects because children are growing and developing they're even more susceptible to the side effects than adults. So you can treat a brain cancer, but take a child who would be going to Oxford and Cambridge and change that person to someone who can’t even ever hold a job.
Chris - I’m glad you didn’t name any other rival institutions because they would feel second best. But what is the approach that you think we might be able to take then if surgery isn’t an option and current chemotherapy regiments are just too vicious? What could we do instead?
Samuel - What we can do instead is to get your own body to fight the cancer, and the main part of the body that is really capable of doing that is the immune system. Now normally your immune system actually fights colds, and flu, and fevers, and bacteria, and germs, and things of that nature, but what you might not know is your immune system actually fights cancer cells as well. There are some estimates that every single day your immune system takes care of one to five cancer cells and gets rid of them. But what happens when your cancer is able to grow is that the cancer sends out signals that trick the immune system into leaving it alone. And what we’re doing here is we’re using special proteins to subvert the cancer tricking in order to get your own immune system to go ahead and attack the tumour again and kill it.
Chris - Effectively the cancer is disguising itself and saying “look, I’m healthy, don’t eat me, I’m harmless”?
Samuel - That’s exactly what’s going on. The immune system can kill a cancer in three ways - one is to target it like a smart missile and explode it. The other one is to touch it and kill it sort of like what Dr Spock does in Star Trek, where he hits you with the Vulcan death grip and then you just fall down. T cells do that. And the cells that we use in our experiments are called macrophages. They’re really like the Pac-Mans of the immune system and they’re capable of eating cancer cells. But what happens is cancer express a special protein on the surface of the cell that says “don’t eat me,” and when we subvert that process by a protein called anti-CD47, the “don’t eat me” signal becomes unreleased and the Pac-Man can now eat the cancer cell. So, if you think about it, if anyone’s ever played Pac-Man, the anti-CD47 is that big power pill that Pac-Man eats and now can eat the ghosts.
Chris - So talk me through the experiments that you’ve done then to show that this can work and how you actually came up with something that’s capable of masking that “don’t eat me” signal?
Samuel - This was actually a collaboration between a number of scientists at Stanford University. We took actual pediatric brain tumours from patients that we had operated on and we put them in brains of mice that were genetically engineered to be capable of receiving human tissue. The tumours grew in the brains of the mice and we gave them the drug and the tumours went away. The other thing that was really cool is that we put normal human brain cells with the brain tumours and even with active eating of the brain tumours, the normal human brain cells that weren’t cancerous continued to grow and thrive in the setting of excellent tumour killing.
Chris - So what actually happened in the mice then, were they completely cured?
Samuel - Our mice, if you had received the treatment, they all lived and they lived for a very long period of time. Every mouse that didn’t receive the treatment died.
Chris - One of the things that cancers notoriously do is spread. Presumably, because you’re bringing the immune system to bear against the tumour, it doesn’t matter if it’s spread because this drug will go to wherever it’s spread to and make the immune system active in that place too?
Samuel - That’s absolutely true, and one of the tumours that we treated was called a medulloblastoma. This brain tumour has a very big propensity to spread all around your brain, and what we learned is not only can the anti-CD47 treat the primary tumour growing in the brain, but all the spread up and down the brain and the spinal cord was also treated as well.
Chris - Is it relatively easy to now translate this antibody that you’ve made, this artificial antibody that hits this “don’t eat me” signal to human patients to try it in them?
Samuel - Absolutely. Actually, we are using this particular monochromic antibody in patients with cancers in the very earliest stages of clinical trials.
06:46 - Are Internet Filters Really Keeping Children Safe?
Are Internet Filters Really Keeping Children Safe?
with Victoria Nash, University of Oxford
Internet filters that screen what can be accessed over the web are becoming commonplace in people’s homes. They block access to online content that might be unsuitable, like pages that contain blacklisted keywords, as well as games and videos. The purpose is to protect children from being exposed to inappropriate material. But now a new study suggests that, in fact, these filters are not very effective, they may also lull us into a false sense of security and could even be having a negative effect because of blocking or ‘overblocking’ of useful content. Tom Crawford spoke to Oxford University’s Victoria Nash…
Victoria - Our most recent study takes some data from some “Ofcom” surveys, that the communications regulator in the UK. And we carried out some analysis on that data to see whether or not there was any connection between parents that have household filters installed and the likelihood that their children, in this case 12-15 year olds, would have experienced any negative experiences online.
Slightly contrary to my expectations, unfortunately, we didn’t find strong evidence that installing these household level filters in the home provided effective protection in stopping children from having nasty experiences online.
Tom - How did you assess how effective these filters were with this data?
Victoria - The data that were using was a survey data set, which was rather nice because a lot of the time we only actually interview say children, if we’re interested in children’s responses. In this case there were interviews carried out both with the 12-15 year olds and their parents.
The data set asked the parents whether or not there were filters installed in the household and, amongst other things, it asked the children whether or not they’d experienced anywhere between one and seven different types of what we call “adverse experiences online.” What it means is just nasty, unpleasant things. The analysis that we carried out - I won’t go into the statistics, thankfully. But, effectively, it was looking to see if there was any correlation between those two factors, and what we found was that for those that had filters at home they were no less likely of experiencing things online than those that didn’t.
Tom - How common was it for a child to experience something aversive or negative on line?
Victoria - The most common experience that they’d had on line, which was experienced by about 8% of people, was being contacted by somebody they didn’t know who wanted to be their friend. Interestingly, much more common for girls than for boys.
I suppose that’s one to be a little bit careful about because certainly I know a lot of parents and carers might think that that’s alarming; it’s often presented as such in policy discussions. But certainly from a teens perspective that could also mean they’re just being contacted by somebody with their interests, in their age group who they want to talk to.
Other things that were slightly less common were seeing sexual content, or being cheated out of money, or feel under pressure to share information.
Tom - The example you gave about meeting strangers online, I would imagine that’s very difficult for a filter to block, because, as you said it could be positive, you could make friends online right? But then filtering out sexually explicit images, or things about drugs or something that, I would guess, would be much easier to block out with a filter and, as you said, you would definitely expect with a filter present that kind of material would be less available than when the filter wasn’t there?
Victoria - That’s right. Obviously we can’t be sure about what the explanations for that might be. Once suggestion certainly is that these days so much of children’s internet use is actually outside the home that, obviously, a filter only controls a portion of their experience. It’s also the case that so much these days can be exchange, for example, on a peer to peer basis. It’s essentially quite straightforward for this material to be exchanged and seen.
Tom - I guess, of course, the kids could be lying; they could be bypassing these filters?
Victoria - Absolutely. Again, we did want to check this out because this is concern often raised that the more technically able children will simply just be able to work around filters and this will expose them to more risk. Luckily for us this was again a question that was asked in the Ofcom survey.
Again we had to be a bit careful about the result because, as you can imagine, some children would not be happy saying they had tried to circumvent filters. But certainly on the basis of findings in that survey, there seems to be no difference between those that say they circumvented the filters and those, again, that didn’t.
Tom - So what would be the way forward?
Victoria - Personally, I am not saying we shouldn’t use filters. I recognise that certainly for parents, they represent one useful tool that they would like to have in their repertoire but I think, for me, it would suggest that we should be doing an awful lot more to educate children, to educate parents. This is a very difficult message to get across, for example, to parents saying yes, you should let your children use the internet and here’s how to help them not see things that you might find worrying or how to deal with it, but I think we need to focus more on that.
I also think that there’s an awful lot more to be done around what we might term “building resilience,” so ensuring that if children do encounter risky material or experiences online, that they know how to get away from it, or how to ensure that the risk is not significant.
12:16 - Mythconception: There are more people alive today than have ever lived
Mythconception: There are more people alive today than have ever lived
with Tim Revell, New Scientist
On the subject of reproduction, Tim Revell gets stuck into this week's mythconception...
Tim - Did you know that there are more people alive today than have ever lived before a myth pusher might ask? But there is only one response to this myth and it’s not a delicate one. No, I didn't know that because it’s wrong. You simply could not be further from the truth, and here’s why…
If you go back in history, the population of Earth was pretty tiny compared to today. There are over 7 billion people alive right now, but at the height of the Roman Empire in around 1 AD, there were only 300 million people on Earth in total. So there is, perhaps, some logic to this myth even if it is very wrong.
Counting everyone who has ever lived is really not an easy task. Modern day humans, or homosapiens, first started walking the Earth around 50,000 years ago. But, unfortunately, it took us supposedly wise creatures a long time to develop good book-keeping skills. So, for the majority of the time humans have been on Earth, we have no written records of how they lived or who was living. For cavemen and women, there were more pressing things to do than create and store birth certificates.
But despair not, we do have some approximations of the number of people that have ever lived. In 2015, the Population Reference Bureau in Washington, USA, did a detailed analysis of all the information we have about the number of humans roaming Earth over the last 50,000 years. This included archaeological evidence and modern day birth records, as well as extrapolating from the general trends, and they came up with a conservative estimate.
They reckon that, since the first Homo sapiens, there have been 108 billion humans on the planet. That’s around 15 dead people for every one of the 7 billion living people alive today. In fact, we passed 7 billion dead way back in 8000 BC. OK, OK, but worlds population is growing so maybe one day we will have more people alive than dead… a Myth-sapien might say.
Nope again. The population is rising, but not fast enough, and the rate is actually slowing.
Working out the maths, the United Nations say that it’s unlikely that the world’s population will double it’s current size, and they estimate that the population will stabilise at around 10 billion people sometime after the year 2200. This means that the living do not outnumber the dead and they will never outnumber the dead. So, hopefully, this mythconception will die out soon.
15:08 - The World's First Certified Contraceptive App
The World's First Certified Contraceptive App
with Raoul Scherwitzl, Natural Cycles
Last month the fertility app Natural Cycles became the world's first app to be certified as a method of contraception. Chris Smith spoke to co -founder Raoul Scherwitzl...
Raoul - With Natural Cycles a woman measures her temperature in the morning then enters it into the app, and then the algorithm crunches the data and returns a “red” or a “green” day. On a red day there is a risk of pregnancy and the couple need to use protection or abstain, and on a green day there’s considered no risk of pregnancy so they are good to go.
Chris - Tell us, what is the physiology or the way the body works, the principle on which this is founded?
Raoul - The medical basis is actually a hundred years old. It’s known that after ovulation, the temperature rises because of an increase in progesterone and so by tracking your temperature what you can do is identify that ovulation has happened. If you take sperm survival into account and the ovulation day, you can compute the days where there is a risk of getting pregnant and the days where there’s not.
Chris - Does this work straight out of the box or does the person have to teach the machine about them. Because, obviously, everyone’s different and if you talk to different women they will say that, broadly, that their cycle is a month long, but it varies.
Raoul - Yeah, I would say that cycles are generally irregular, and the good thing with the algorithm that we’ve developed is that it adapts to every woman’s unique cycles. So the woman just needs to get started with measuring and Natural Cycles takes care of the rest.
Chris - Now when you say “get started,” as in how many cycles would a woman have to go through before she could rely on your tool?
Raoul - Oh, she can rely on the tool from day one. But the app, in the beginning, will be very conservative when it gives a green day because the algorithm simply doesn’t know yet whether the woman is fertile or not. So, in the beginning, she’s likely to start with red days, days where she needs to use protection and then. In the first cycle, generally, the algorithm finds the first ovulation and then gives green days for the rest of the cycle where she’s not fertile. That fraction of green days per month, or per cycle gradually increases over time and stabalises roughly after three cycles.
Chris - How many people have you tested it on?
Raoul - The app is being used by more than 200,000 women worldwide as of today, basically. It’s a lot of women using the app. The clinical studies that we have done, however, were done of 4,000 women using the app for a total of 2,000 years.
Chris - When you say 2,000 - as in 2,000 women years. So the number of people using it added up to the equivalent of 2,000 years of use?
Raoul - Exactly.
Chris - What’s it’s success rate? How reliable is this?
Raoul - Contraceptives effectiveness are generally measured in pearl index, so they tell how many women get pregnant in a year when using this certain contraceptive, and in our case it showed that seven women out of a hundred get pregnant in a year for all possible reasons; that’s a typical use pearl index. And five women out of a thousand get pregnant in a year because we give a wrong green day because the algorithm falsely attributed a green day within the fertile window.
These results are extremely promising it definitely already improves the use of natural family planning which, so far, has always been considered less effective. With the algorithm now and with the automation behind it it improves the use to the level where it becomes comparative to the contraceptive pill.
Chris - Now you say you’re the first app every to be certified for this use. I’m aware of many people that have published similar sorts of, or invented similar sorts of things in the past, so what sets you apart that enables you to get that certification?
Raoul - Contraception is a serious thing. It’s very important that you get that right and so if you want to bring an app onto the market for contraception, then you need to not just convince women of it, and doctors with it, but you also need to convince regulators that this is safe for the public to use. And, therefore, we underwent conformity assessment that you need to do if you want to bring a contraceptive product onto the market.
Chris - And in 30 seconds, if someone is interested in trying out this product, how do they find out more about it?
Raoul - They go to a website on naturalcycles.com or they download it from the app store.
20:02 - Decoding Bird Song
Decoding Bird Song
with Dr Dan Stowell, Queen Mary University of London
Some people say that there’s nothing like the sound of birdsong, particularly during an early morning dawn chorus, and many of us are pretty good at identifying a number of species by their distinctive calls. But our understanding of what birds are are actually saying to each other when they sing is still very limited. Jane Reck has been along to Queen Mary University of London to hear about some research that is changing this...
Dan - The timing’s really important; it’s not just some notes but it’s some notes with a particular sequencing, it’s about 200/300 milliseconds gap between each of them.
Jane - Dr Dan Stowell is a research fellow in machine listening at Queen Mary University of London. His work has already been used to develop an app called “Warbler” which identifies a UK bird from the recording a user makes. Now he hopes to take the computer analysis of the sounds birds make to a new level to discover more about the social interaction that’s going on.
Dan - Traditionally you would take explicit measures such as: how long is this sound, what frequency is that sound? But, in order to go beyond that, we use modern machine learning methods where you don’t necessarily know how a computer has made a decision about a particular sound. But by training it, which means showing it lots of previous example, we can encourage a computer algorithm to generalise from those.
Jane - At the university’s laboratory aviary, female zebra finches provide plenty of audio examples for Dan’s research.
Dan - We’ve put the timing of the calls together with acoustic analysis of what is the content of that call. Is it a short call or a long call, for example? So with the zebra finches that we’re working with, to some extent there’s knowledge about what the calls are and what there purpose is. When the birds are just hanging around together, they very often make short calls to each other just in the ordinary course of business so they just sound a bit like “ma.”
If one of them gets separated a little bit - it doesn't have to be too far, maybe it gets separated a couple of metres from its partner and then it would do a distance call which sounds more like “maaa.” A little big longer, a little bit more emphasis. It’s quite clear from the content that it’s for re-establishing contact and making sure that you’ve not lost your partner or your group.
We’re starting by taking small groups of birds and record all the calls, and use the timing of those calls to decipher: is this bird when it calls influencing another bird, so are it’s calls causing another bird to call? It’s very difficult to tell that just by listening to the recording but if we apply an analysis that says does the probability of one bird calling increase after this bird calls, or does it decrease, or is there some more subtle interaction? Then we can work out how strongly each bird influences each other and that gives us a kind of picture of the communication network in that group of birds.
Jane - All of Dan’s research has been supported by the Engineering & Physical Sciences Research Council. In the longer term it could be used in a wide variety of areas…
Dan - Deciphering the dawn chorus is certainly one of the long term goals of this kind of work. Certainly something I’m very interested in. But the general application of automatic bird detection or automatic monitoring has a lot of significance in terms of monitoring populations and we know, for example, that bird populations, the latitude that they migrate to depend, at least in part, on the effects of climate change and so monitoring these things is important.
Looking at the detail of bird vocalisations and how birds interact with each other is important in the long term for understanding animal communication, which includes human communication. People working on these things are looking at birdsong, at least in part, because it’s an analogy to human language. Songbirds learn to sing in an analogous fashion as humans learn to speak a language. And so we can improve the monitoring of animal sounds, we can improve the understanding, decoding of animal sounds.
More generally, we actually have quite a lot of applications in which machines are going to need to understand the world around them through sound as well as through vision. Whether that’s self-driving cars, whether that’s your mobile phone, whether it’s monitoring CCTV, for example. Although people have been working on speech recognition and speech technology for a long time, what this work can feed into is a more general understanding, a more general sound analysis of an ordinary sound environment.
Jane - There was also an unforeseen, but very welcome addition to Dan’s research, which has come from the thousands of sounds collected by the great British public through the Warbler app. This big data citizens science aspect will contribute to the machine learning work to help a computer analyse whether a particular sound is, or isn’t, made by a bird.
Dan - One thing that we didn’t quite expect was that people would like to test the recognition quality for themselves by making funny noises into the phone and seeing what decision it came up with. So, as a result, we have an unexpected extra benefit of this collection of bird impressions, and whistling, and squawking children, and other things.
Part of what’s motivating this is, essentially, the big question: what is birdsong? How can a computer know this is birdsong; this is a squeaky door; this is a small child? Those kind of questions you have to try and really address if we’re going to be able automate this kind of detection. There are people creating projects right now where they have unattended microphone systems in the forest recording, and trying to identify which birds occur where. In order to be able to do that, in any sort of scaleable way, we’re going to need algorithms that can say “yes, that is a bird” or “no, that’s just a tree creaking in the wind".
27:08 - The Nuts and Bolts of Fertility
The Nuts and Bolts of Fertility
How do you make a baby? Tom Crawford and Georgia Mills have been finding out; here’s the “nuts and bolts” about the cells that make reproduction possible…
Tom - Men produce sperm non-stop throughout their life. It takes about two months per sperm cell from beginning to end.
Georgia - Women are very different. They start making eggs nine weeks after fertilisation and by the time they’re born they have all of their eggs already in their ovaries that they will ever produce.
Tom - Males make loads of sperm - half a teaspoon contains about 200 million. Each sperm has a lifetime of between 40 and 70 days.
Georgia - In comparison, females only release about 500 eggs during their entire reproductive life.
Tom - Sperm are tiny. The head is 1/2000th of a centimetre, but if you lined up all 200 million head to tail, they would extend over six miles.
Georgia - Eggs, on the other hand, are one of the largest cells in the human body at about 0.2 millimetres in size. They can just about be seen with the human eye.
Tom - Sperm can survive for about two days inside a woman and swim towards an egg by following chemical signals that they sniff out.
Georgia - Eggs ensure that only one sperm can enter and fertilise them by transforming their surface coat into an impenetrable outer shell immediately after fertilisation.
Tom - Both eggs and sperm have only half of the DNA that’s found in all other cells. Sperm have either an X or a Y chromosome.
Georgia - Eggs can only have an X chromosome so, if they meet a Y carrying sperm a male baby is formed, and an X bearing sperm results in a female. So sperm, in other words Dad, determines the sex of a future baby.
29:05 - What are the Worldwide Trends in Fertility?
What are the Worldwide Trends in Fertility?
with Professor Tim Child, Oxford Fertility
One in seven couples currently experience problems when trying to conceive; so the question is are fertility rates declining? Georgia Mills spoke to Professor Tim Child from Oxford Fertility...
Tim - There’s certainly some controversy, but it may be that male sperm quality is reducing - there’s some controversy around that. It’s certainly true that women tend to be leaving it later in life to be trying to conceive and so we’ve noticed quite a significant shift actually in age of first childbirth. And also there have been increasing rates of chlamydia and other problems that could affect the woman’s tubes.
Georgia - Is the fertility going down? Are we seeing this across the world?
Tim - Again, some controversy. From a UK perspective it can be difficult to work out. There’s increased awareness because, for instance, programmes such as this on fertility issues and potentially treatments for fertility. So certainly within the UK we are seeing that more people are coming forward and looking for fertility treatment.
Georgia - What about elsewhere in the world?
Tim - Again, in Africa for instance, there are data suggesting that infertility rates are increasing. Again, the difficulty is that there are such huge social changes going on around the world that it can be hard to know the extent to which changes are due to social changes or actual pathology affecting fertility.
Georgia - You mentioned earlier this might be due to people having children later in life. So how does this affect fertility?
Tim - As you mentioned in the intro, women are born with a couple of million eggs in their ovaries and for some reason, we’re not entirely sure why, the eggs that are released as women get older are more likely to have genetic or chromosomal problems within. They’re more likely to have the wrong number of chromosomes. The same is true for men as well but it happens at a later age. What that means is that on a monthly basis, as couples get older, they’re less likely to get pregnant and, unfortunately, are more likely to have a miscarriage.
Georgia - You can see this month by month?
Tim - Yes, certainly. So as you go through a woman’s reproductive life, and you look at her chance of getting pregnant year by year, then roughly up until her early 30s it appears to be fairly stable. But as she goes into her mid and late 30s then her monthly chance of conception does go down and the unfortunate double whammy is the chance of miscarriage does increase.
Georgia - What about other environmental factors that might be having an impact on impact on fertility rates? Do we have any possible suspects?
Tim - Well, I know that one of the later speakers is going to be focussing more on the sperm side of things, but there have been various environmental, perhaps chemical, suspects from a sperm perspective. The same is true from a female perspective, there’s been some suggestion that some chemicals may be increasing the risk of conditions such as endometriosis, which is a common condition that 20% of women have that can affect fertility. But again, the quality of sa lot of this data is very, very poor so we’re not entirely sure.
Georgia - There’s a lot of things out at the moment where we’re not eating very well, we may be a bit fatter than we should be. Has that been linked with fertility?
Tim - Certainly BMI has been linked with both male and female infertility. We know that as a woman’s BMI increases after the 20s into the 30s, then her monthly chance of getting pregnant goes down, and again the chance of miscarriage does go up. We’re not entirely sure why, and this why, for instance, those people that are lucky enough to qualify for NHS IVF funding if they need it, in nearly all areas of the UK, women will have to have a BMI of less than 30, and that’s really based on the very strong evidence that BMI does matter.
Georgia - OK. So we’ll be probing a bit more about the male and female effects that might be causing this but, just briefly, what are people doing who are having trouble conceiving? What kinds of things are they doing to try and help them?
Tim - One of the most important things is if couples are worried about their fertility, then the first port of call would be to have a chat with the GP. That could be after 6 to 12 months of trying for instance. In general, if a woman’s having regular cycles, she’s probably going to be ovulating, but there are some quite straightforward blood tests that can check for ovulation. The man can do a sperm test, again, via his GP.
Once they get to 12 months of trying if those tests are normal, then usually the third test would be a check of the woman’s fallopian tubes. It can be quite a straightforward test and often that would need to be arranged in hospital. If we see then that the woman’s ovulating, the man’s got normal sperm and the woman’s tubes are open, then very often the suggestion would be to continue trying for a bit longer.
Georgia - Very briefly, is this drop in fertility, are we seeing it mainly in that people just are unable to conceive or is it problems later on that are popping up?
Tim - It tends to be that couples have perhaps a delay in conception, so it’s not common we would see a couple where there’s no chance of conceiving. Very often we would be able to say that their monthly chance of conception may be much less than they would like. But often the suggestion would be to continue trying, perhaps optimise lifestyle and, if necessary, move on to some treatment such as IVF or some drugs to get the woman ovulating.
33:55 - What Determines Male Fertility?
What Determines Male Fertility?
with Professor Allan Pacey, University of Sheffield
It seems that modern living might make us less fertile as a species, but what about males in particular? Sperm counts on the whole seem to be in decline but what is it that determines the number of sperm produced by a man, and what role does aging play? Chris Smith spoke to Allan Pacey, a Professor of Andrology at the University of Sheffield...
Allan - There’s some controversy about whether or not sperm counts have declined or not. In 1992, there was a famous paper published in the B.M.J by Elizabeth Carlson suggesting that sperm counts from the 1930s to the 1990s had seen a year on year decline. It gets a little bit fuzzy as we go further forward from that because some studies say that there hasn’t been a change, some studies say that there has. But it’s certainly clear that couples are having fewer children; more men are seeking infertility diagnoses and treatment, but I think we’ve got to remember that some of that may be social as much as it might be biological.
Chris - So if we assume for a minute that sperm counts might be on the move, what factors might account for them dropping?
Allan - Well there’s two stages in a man’s life where sperm counts might be affected. The first might be a surprise and that is processes that happen before he’s even born. As a foetus, the developmental processes that develop his reproductive system and, ultimately, will influence the size to which his testicles will grow will have an effect on his sperm counts as an adult, but they’re processes that occur before he’s born.
Then when a man is an adult, we have to take into account all of the things that may impact on his life at that moment in time that may affect his sperm production. So, for example, there are certain drugs and medications that we know will decrease sperm production and may do so permanently. But, similarly, there are temporary effects such as temperature and we know, for example, that men who wear pants that are too tight are more at risk of poorer sperm counts.
So, when we’re studying male fertility, we almost have to take a two step look at processes that might have occurred before he was born and those that are occurring now.
Chris - So, there’s a developmental predisposition to your maximum fertility, and superimposed on that is how you live your life. What’s the reason for that developmental predisposition towards testicular size and fertility? Why should that effect be there?
Allan - I think it’s just part of the developmental programme, and external things that may affect that might be aspects of maternal diet, aspects of maternal hormonal environment in the womb. If you’re to build a factory, how big do you build the factory will depend on how many cars, for example, you may make when the factory opens, and the developmental processes define how big the factory gets. Whereas, you don’t know how efficient the factory will be until the production line starts rolling, and that only occurs as puberty.
Chris - When the production line does start rolling, tell me a bit more about the kinds of factors that do influence sperm count? You eluded to temperature, that’s one of them, and people wearing tight pants, but there are others?
Allan - There are others. We know that temperature has an effect, as I’ve said, and there are many studies both from epidemiology, but also experimental studies in animal models that show that if you elevate the temperature of the testicles you decrease sperm production.
But then there are subtle influence of aspects of diet. We know that men who are eating more processed, refined foods generally have a poorer sperm production that men who are eating five portions of fruit and vegetables a day and are eating more mediterranean diets, for example. There are also temporary issues to do with alcohol to some extent, I think you really have to be in the realms of going into binge drinking before we see an alcohol effect.
But then there’s also an impact of things like smoking and the compounds within cigarette smoke. Smoking doesn’t alter the efficiency of the sperm production process, but what it does is it allows the introduction of damage at the genetic level so the sperm that are produced are, ultimately, less functional because their DNA is a bit more chopped up and a bit more mashed up. So I think, when we think about sperm production, we not only have to think about the efficiency in the speed of it, but we also have to think about the quality of the sperm that come out at the other end.
Chris - I was going to ask that. Because one aspect of this is how many sperm can you physically make and that’s going to be important, but then equally, if all those sperm that you make, you make millions, and they’re all defective, you’re not really any better off than someone who makes none?
Allan - Indeed. And there is a theory that men whose sperm production process is too quick also, generally, makes poorer quality sperm simply because - to take the analogy, there isn’t enough time to put the wheels on.
Chris - So timing really is everything? What about ageing though because, increasingly, people are deferring having a family till they’re older. There are lots of people now who are on their second family. Are there effects there?
Allan - Yeah. There are subtle effects in ageing. But it does become a little more interesting actually because there are slight changes in how many sperm an older man produces, and how well they swim, but they're really quite subtle. But at the genetic level when you look at the health of the children born to an old man, compared to the health of children born to a younger man, you see that there are increased risks of having a child with a genetic disease. The kind of things that we see are increased risks of schizophrenia, down syndrome. Things like achondroplasia, which is a form of shortening of the bones which leads of a form of dwarfism. So that’s probably indicative of the fact that as a man gets older then the quality of the genes in the sperm that are produced is not as good.
40:07 - What Determines Female Fertility?
What Determines Female Fertility?
with Francesca Duncan, Northwestern University
As men age, the genetic quality of their sperm falls and this might also affect fertility. But what about women? The general trend in many countries is that couples are starting families later, which appears to be driven by financial, educational and career pressures. So how does deferring motherhood affect a woman’s fertility? Georgia Mills spoke to Francesca Duncan who is the Executive Director of the Center for Reproductive Science at Northwestern University...
Francesca - As women age there is a dramatic decline in both the number of the eggs within her ovaries as well as a decline in their quality. What people may not realise is that reproductive ageing in females begins when they reach their mid 30s, and continues all the way until menopause around age 50. So really, female reproductive ageing is one of the first organ systems in the human body to show signs of overt ageing.
Georgia - Do we know why this is?
Francesca - My laboratory and others around the world study what happens to egg quality with age and we really look at it from multiple angles. So what’s happening to the DNA inside of the egg, and what happens to other structures within the egg, and then what happens to the environment of the ovary where the egg is developing.
Georgia - So how did these three things affect the quality of an egg?
Francesca - We know that as women age their is an increase in the chromosomal abnormalities in that egg. The egg has to undergo a process of cell division called meiosis, and this process is really necessary for the egg to have its chromosomes so that when it unites with sperm, it can have the correct chromosomal complement in the embryo. With age, there is an increase in the abnormalities in this segregation process and this leads to incorrect chromosome numbers.
Georgia - These are kind of too much DNA in a cell?
Francesca - Yes, exactly. Or the incorrect number so it can have too much or too little and that can be bad for the outcomes of the embryo. Again, with age, the ability of that egg to undergo this process correctly deteriorates.
Georgia - What about the other items in the cell?
Francesca - There are also lots of things in the cell. The egg is one of the largest cells in the body and there are lots of structures called organelles, and you can think of these as little factories within the cell. Mitochondria, one of the organelles that we think about, especially with regards to ageing in the egg. Mitochondria is really the energy producing organelles of the body and they’re important for supporting the energenic demands of the egg as it develops and later the early embryo. With ageing, researchers have shown that there’s a decrease in the functional capacity of these mitochondria, as well as increase in the mutations in mitochondrial DNA, and this can negatively impact reproductive outcomes.
Georgia - I guess for an egg to get to a baby it’s going to take a lot of energy so, if something’s gone wrong in the energy factory of the cell, that’s kind of a big deal?
Francesca - Absolutely. And then the final part that we’re really interested in is what’s happening to the environment in which that egg is developing. Because there’s this complex environment of protein networks, as well as different cell types, where the egg develops in that ovary.
Our work has shown that there is really striking changes in that micro environment, so it become fibrotic or stiffer with age. You can actually physically feel this if you touch an animal ovary or a human ovary as it ages that it becomes tougher. This is also corresponding with a highly inflammatory environment which can damage the egg indirectly. So we’re really interested to see how we can study the mechanisms that underlie these changes in the environment.
Georgia - So to sum up: we’ve got a problem in the coding in the DNA of the cell; the energy factories are messing up, and the environment the egg is living in is worse. So what can we do about this; can this be mitigated?
Francesca - Yes. I think, as you just highlighted, it’s complex and it’s multi-factorial and so I think there’s unlikely to be just be one “catch all” intervention that will cure egg quality with age. But there are a lot of efforts underway now to figure out if there are ways we can target one or more of these pathways.
One example is supplementation of the animal or the impending mother with antioxidants, or mitochondrial nutrients that will improve the mitochondrial function. This has shown tremendous promise in mouse models in terms of extending fertility and improving fertility outcomes, but the data is less clear in humans.
Georgia - Something I’ve heard mention quite a lot is this idea of egg freezing. Could you just quickly explain what that is and then tell me does it work?
Francesca - Egg freezing really refers to the idea of undergoing a process of assisted reproduction to stimulate the ovaries to produce eggs that are then retrieved and frozen. What you’re probably referring to is this concept in relationship to ageing is “social egg freezing,” where younger women who want to sort of freeze their biological age in time. Or another way to think about this is for fertility insurance and will have this process of oocyte freezing done when they’re young with the hopes that later one when they’re ready to start a family and they’re older, they will have young eggs to use to start their family.
Georgia - But you mentioned earlier, one of the problems her is that the environment itself is harsher?
Francesca - Right. There’s actually fairly compelling data from assisted reproductive technology cycles that shows from a egg donor studies, so eggs are obtained from women who are young and then they’re transferred back into women of advanced reproductive age. You can, in fact, have very high fertility rates in these older women when they use eggs from younger individuals.
But what the real big problem is with this process is that embryos are then being transferred into an older woman and we know that pregnancies in women of advanced maternal age have their own complications for both the mother and the offspring. This can include gestational diabetes, low birth weight, preterm birth, and stillbirth. So, basically, there’s some problems of having an older mother carrying the pregnancy to term.
46:34 - How do Chemicals in the Environment affect Fertility?
How do Chemicals in the Environment affect Fertility?
with Professor Paul Fowler, University of Aberdeen
There are many things that men and women can do individually to maximise the fertility, but what about the environment in which we live and the air we breathe? Chris Smith spoke to Professor Paul Fowler from Aberdeen University who looks at how these factors play a role...
Paul - Well, in the modern world, we’re exposed to a very large range of chemicals all at the same time. So, what interests me is models where the exposure is to the foetus, which is a sensitive life stage, is also an exposure to a complex cocktail.
One of your previous speakers already alluded to smoking and I study the effects of maternal smoking on the human foetus because, really, there is no totally adequate animal model for that. When you look at the effects on the foetus you can see changes in the liver and also defects in both the developing testes and the developing ovary. This matches to increased risk for the offspring of having reduced fertility in adulthood.
Chris - The thing is, ever since Walter Raleigh and all his pals went and got tobacco off of the Americas and brought it back and got us all hooked on it, people have been smoking, but populations have not declined. Populations have grown and they’ve grown faster and faster until more recently, so it can‘t just be smoking. There must be something else which is also affecting people’s fertility?
Paul - Well, that is a very good point to make, although taking one of the other points your speakers mentioned, increasingly leaving your fertility till later will exacerbate the problems. But we’re also exposed to a very large range of both natural and synthetic chemicals, some of which are persistent, some of which are not persistent.
But some of these chemicals are what we call “endocrine disrupting” compounds, and what they can do is to alter how the body’s endogenous hormones, our own hormones, our own endocrine system works. So, an example would be something like phthalates which may block the effects of the androgen receptor…
Chris - These are in plastic bottles, aren’t they?
Paul - That’s correct, yes. And the effect of that in the developing male foetus would be reduced masculinisation.
Chris - Essentially, we’re living in a world which is more polluted than previously; we’ve made more artificial things than we ever had in the past, and we’re basted in these substances - the environments full of them. We’re being exposed, and because they might look chemically a bit like some of the hormones that we naturally have in our body, there might be a knock-on effect to our own physiology, the way our body works. Because of exposure to these chemicals, one of those consequences could be affecting our reproductive development?
Paul - That is correct. Although the thing to bear in mind is that some of these compounds do indeed have close relationships. One would be bisphenol A, which looks like oestrogen and, indeed, bisphenol A can act like an oestrogen, but it’s a much weaker oestrogen than the oestrogen in our own bodies.
Chris - How are you looking at this; how are you attempting to study this?
Paul - The other model we use is a sheep exposed to sewage sludge which contains if I may be it this way, a rich digestion of the modern world. Right from pharmaceuticals, to agricultural run off, to air pollution.
Chris - But sheep don’t eat sewage do they, so how do the sheep get in contact with the sewage sludge?
Paul - Well, sewage sludge is a wonderful fertiliser. So it is widely used in many European countries, including the UK, as a fertiliser. We found that if you pasture pregnant sheep on sewage sludge fertilised fields, then you can get defects in development of the foetus. So smaller testes, lower testosterone, reduced numbers of eggs, and some of those defects persist in some of the animals into adulthood.
Chris - Are they transgenerational? In other words, if an animal is affected in this way, when itself then comes to breed, do it’s offspring suffer similarly?
Paul - There is some evidence of that in other studies. We’ve not been able to do that with the sheep model. If you think about how long it takes to breed successive generations of sheep, and the patience of funders, that’s difficult to do. There is evidence of transgenerational effects of smoking, for instance.
Chris - It’s a worry though isn’t it because if we’re exposed to these chemicals because we’ve messed up the environment? And, obviously, you’re looking at sheep, and that’s one example, but you can see how with these things being in the environment we may ourselves also be being exposed. But if the effects don’t go away, or we’ve done something to ourselves and we can pass those effects onto our offspring, that’s a real concern.
Paul - It is a concern. Although one of the things to, perhaps, just take a little bit of comfort from is given that we’re exposed to very complex cocktails of chemicals, the net outcome for the individual is very difficult to predict. That said, it’s only sensible that proper risk assessments are done on the chemicals that are used in order to determine their likely risk both to humans, and to economically important species.
Chris - Just very briefly in 30 seconds, actually what evidence have you got that what is happening in the sheep could be happening in us?
Paul - Allan Pacey did say the data on falling sperm counts is controversial and some of the studies are very poor, and I agree utterly with that statement. However increasingly, the series of publications recently suggest that the decrease in sperm counts in humans probably is genuine.
52:48 - Can HIV be Transmitted by Mosquitoes?
Can HIV be Transmitted by Mosquitoes?
Ricky Nathvani put Mehran's question to Peter Bull at the Department of Pathology at the University of Cambridge...
Peter - The short answer to this question is very clearly stated by The Centre for Disease Control in Atlanta on their website. No, HIV is not transmitted by mosquitoes, ticks, or any other insects.
Ricky - Phew! Well that’s a relief... but why?
Peter - Several viruses are transmitted by insects. For example: dengue, zika, yellow fever, and the parasites responsible for malaria and sleeping sickness. If all these diseases are transmitted by insects, why not HIV?
What all these infections have in common is the ability to reproduce and multiply within specific insects and then be reinjected into another person. By contrast, HIV is immediately rendered harmless once it gets digested in the insect’s gut.
Ricky - So, it turns out that HIV in infected blood just gets digested inside mosquitoes and can’t do much from there. But how do all those other nasty diseases end up surviving?
Peter - Viruses like dengue, that I just mentioned, are all in the same biological group called flaviviruses. They can all reprogramme insect cells to manufacture copies of themselves. This is an enormous feat of nanoengineering involving specific interactions between many virus and insect molecules. And the viruses genetic software, if you like, only works with compatible insect’s cellular hardware.
Similarly, the parasite responsible for malaria has evolved to infect insects over millions of years. Instead of being destroyed by mosquito digestive juices, which is what happens to HIV, the parasite’s sex cells picked up from an infected human fuse to form a new immature form of the parasite. After escaping through the wall of the gut, this divides to produce thousands of new malaria parasites which make their way to the mosquito's salivary glands ready to be injected with saliva through a dedicated tube into another human when the mosquito next takes a blood meal.
Ricky - So certain diseases can hijack the mosquito cells to make thousands of copies of itself. But thankfully, other blood borne viruses like HIV can’t really do this…
Peter - There are a lot of stages a virus or a parasite has to go through to be transmitted between humans. HIV isn’t capable of surviving and replicating in a mosquito so it can be transmitted because it gets destroyed in the mosquito’s gut. Nor is it able to infect or multiply in insect cells. Insects are not like flying syringe needles or blood bags, and only a handful of infectious agents have evolved the specialised ability to reproduce in insects and then spread to another person.
Ricky - So malaria and yellow fever might find it’s way into you from a mosquito, but at least HIV won’t. Cheers for the answer Peter.