Nick Petrić Howe
Welcome back to the Nature Podcast, this time: the difference a Y chromosome can make to bladder cancer...
Shamini Bundell
...and engineering artificial cartilage. I'm Shamini Bundell.
Nick Petrić Howe
And I'm Nick Petrić Howe.
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Nick Petrić Howe
First, up on the show, how the lack of a Y chromosome can make bladder cancer worse. Now, Y chromosomes are mostly talked about for their role in sex determination. But it seems this little stretch of DNA has other roles to play as well. It's been shown that as people age, the Y chromosome is often lost in some cells. Scientists aren't exactly sure why this happens. But what we do know is that this chromosome loss is associated with a lot of health conditions.
Dan Theodorescu
There has been a tremendous amount of evidence that suggests that loss of the Y chromosome is associated with some of the most serious and prevalent human diseases, such as cancer, neurological disease and cardiovascular disease.
Nick Petrić Howe
This is Dan Theodorescu, a urologist from the Cedars Sinai Cancer Centre. He’s got a paper this week in Nature about Y-chromosome loss, and how it relates to disease. As a urologist Dan found himself particularly interested in whether the Y Chromosome, or lack thereof, was having an effect on bladder cancer.
Dan Theodorescu
We noticed in the literature that the Y chromosome was also lost in a proportion of bladder cancers. And it was not clear what the role of that loss was. So we decided to test the hypothesis that Y chromosome loss is associated with more severe disease.
Nick Petrić Howe
To do this, Dan and his team assessed 300 male participants with bladder cancer to see if the amount of Y chromosome they had influenced their survival. And as it turned out, those that had very little Y chromosome, or none, in their bladder cells were less likely to survive than those who still retained most of their Y. The team then looked to further check this hypothesis with some experiments in the lab. They developed models of the disease, using cancer cells in a dish and mice. Some of these had no Y chromosome — Y-negative — or they had the Y chromosome — Y-positive.
Dan Theodorescu
To our surprise, when we tested this hypothesis in animal models that have an intact immune system — so basically, very normal, if you will, experimental mice — it was found that the cells that had lost the Y chromosome grew much faster than the cells that had an intact Y chromosome.
Nick Petrić Howe
But while the Y-chromosome-less cancer cells grew faster in the animals, the same thing wasn’t happening in the cells grown in a dish. They grew at the same rate regardless of how much Y chromosome they had. So what was it about the mice that was giving the Y-negative cells an advantage?
Dan Theodorescu
That was the A-ha moment. We realised that the difference in growth between the Y-positives and the Y-negative cells was really dependent on the immune system.
Nick Petrić Howe
With this in mind, Dan and the team looked to other mouse models, which had various bits of the immune system missing. The thinking being that they could identify which parts of the immune system were important for the more aggressive growth of the Y-negative cancer cells.
Dan Theodorescu
In fact, it was the T cells that drove this difference in growth between the Y-positives and Y-negatives.
Nick Petrić Howe
T cells are a kind of immune cell that can either kill cancerous cells directly, or can recruit other immune cells to fight the tumour. But something was amiss when the Y-chromosome was missing. As it turned out, in the Y-negative mice, the T cells were not doing so well.
Dan Theodorescu
The Y-negative cells cause an immune evasive environment in the tumour, and that, if you will paralyses the T cells, and exhausts them, makes them tired and ineffective. And this prevents the Y-negative tumour from being rejected, therefore allowing it to grow much better.
Nick Petrić Howe
Exhausted T cells have lost their ability to kill cancer cells and have lota of proteins on their surface known as checkpoints, which put the brakes on immune responses. But this exhausting environment made by the tumours could actually be their undoing.
Dan Theodorescu
What they also did inadvertently, I'm sure, is made themselves a lot more vulnerable to one of the most useful and prevalent therapeutics in cancer today, which is immune checkpoint inhibitors.
Nick Petrić Howe
Immune checkpoint inhibitors are a class of drugs that block those checkpoint proteins that sit on the surface of T cells, effectively taking the brakes off immune responses. Causing the T cells to become more aggressive. And when T cells are exhausted certain immune checkpoint inhibitors seem to be particularly effective. Overall this means that the bladder cancer is particularly vulnerable to the drugs.
Dan Theodorescu
So it turns out, while an untreated Y-negative cancer is more aggressive, and lethal, when you treat that cancer with immune checkpoint inhibitors it is more sensitive, than the Y-positive cells, when they're treated with the same treatment.
Nick Petrić Howe
Immune checkpoint inhibitors are already used in some cancers as treatments. But of course, this study is in mice and in cultured cells. And they'll be more tests to be done to find out whether the results of this work are relevant to humans. Also, this loss of Y may only explain why certain cancers are more aggressive. Different cancers show different responses to the absence or presence of Y chromosomes. Another study in Nature this week actually shows that when part of a Y chromosome, a particular gene, is introduced into mice without Y chromosomes, it makes colorectal cancer worse. Nonetheless, for bladder cancer, Dan is confident about the future.
Dan Theodorescu
I am very optimistic that in the next year or so we'll have identified additional therapeutics that could be used in combination with checkpoint inhibitors that could make the Y-negative — these very aggressive, stealthy tumors — even more susceptible to checkpoint inhibitors. So, I'm very optimistic of the future and the potential of these findings.
Nick Petrić Howe
That was Dan Theodorescu from Cedars Sinai Cancer Centre, in the US. To find out more about that story, check out the link in the show notes.
Shamini Bundell
Coming up, making cartilage from aerogels. Right now though, it's the research highlights with Noah Baker.
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Noah Baker
Fine particles of pollution can ferry influenza deep into the lungs, according to new research. It's known that exposure to air pollution can make viral infections more severe, but precisely how has been a mystery. Now, a team in China may have an answer, pollutant particles can attract and carry virus on their surface. The researchers infected mice with a mixture of flu virus and one of four types of fine particle. Pollutants collected from Beijing's air attracted the most viral particles, followed by soot made from burning either maize or fossil fuels. And finally, silica dust. The particles easily carried their viral payloads into lung cells in laboratory dishes, without the virus having to bind any cellular receptor. In cells infected with viruses attached to pollutants more viral progeny budded off to infect other cells, than in those infected with a virus alone. The virus-laden particles also travelled deep into the lungs of live mice, and to their spleens, liver and kidneys, causing system-wide inflammation and tissue damage. Read more on that study in Science Advances.
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Noah Baker
The glow worms come hither signal is being lost in the glare of human lights. Female glow worms emit green light from their bodies to lure their mates. But this behavior makes them vulnerable to light pollution. A team in the UK is seeking to understand the risk placed male glow worms at the bottom of a Y-shaped chamber. Then they used a green LED light to mimic a female's glow, secured at the top of one of the chambers arms. They recorded how long it took the males to find the light both in the dark and under increasing levels of white light pollution. Every male found the LED in the dark, but only 21% of them found it under the brightest light — about equivalent to the glare below a lamppost. However, even low levels of white light more than doubled the time it took the males to reach their target and caused them to hide the eyes beneath a shield shaped head structure. The researchers say that this effect could run the risk of driving the glow worms to extinction. Seek that research out in the Journal of Experimental Biology.
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Shamini Bundell
Next up, reporter Benjamin Thompson has been finding out about some new research looking to develop artificial cartilage that could help mend damaged joints.
Benjamin Thompson
The load bearing tissues found in our bodies, our mechanical marvels. For example, cartilage, the tissue that can be thought of as the body's shock absorber, has a range of properties that enable it to play its vital role as Hongbin Li, from the University of British Columbia in Canada, explains.
Hongbin Li
So, there is a very, very low friction, so very low wear. And it can kind of dissipate energy, dissipate impact so that the bone tissue or muscle tissue will not be damaged.
Benjamin Thompson
Cartilage has to withstand and dissipate the huge forces placed on it every time we take a hop, a skip or a jump. And although it's very good at doing this, sadly, it doesn't always last forever. So researchers have been trying to work out how it might be possible to replace cartilage.
Hongbin Li
So one of the ways that people envision is to use synthetic tissue. So, in that case, you want to get as close to the native tissue as possible, and then it can be integrated into the native environment so that you can restore those functions.
Benjamin Thompson
And developing a material with the potential to be used as synthetic cartilage is something that Hongbin and his colleagues have a paper about in Nature this week. But making a material that mimics cartilage is easier said than done. You see, it's a tissue that needs to be exceptionally stiff, so that it doesn't just collapse when weight is put on it. But it also needs to be exceptionally tough, which in material science terms essentially means it can be deformed, bent, or compressed, say many, many times without breaking. And these two characteristics, stiffness and toughness are in direct opposition. You can make a material that's incredibly stiff, for example, but it won't be very tough. It would likely be brittle, which wouldn't make for a good cartilage substitute. In the body, cartilage in the joints manages to be both stiff and tough, thanks, in part, to a tangled network of proteins and other molecules that help dissipate forces and give the tissue its shape. It was this network that Hongbin looked to emulate using a material called a hydrogel.
Hongbin Li
Yeah, hydrogels, it's a kind of a network of polymers that can hold water and so the polymers will not dissolve, but can swell, they can hold a lot of water in the network. And so hydrogel in that sense is kind of very similar to the biological tissues.
Benjamin Thompson
Researchers have successfully made hydrogels out of proteins that are tough, and can mimic the properties of muscles say, but it's been difficult to turn these materials into ones with cartilage-like capabilities. One way to make them stiffer, is chemically stick sections of the different protein chains together, known as cross-linking. However, there's a limit to how far you can take this, add too many cross links, and the chains are no longer able to move with negative effects on the material.
Hongbin Li
You can make it stiff, but they are brittle, they can no longer dissipate energy effectively.
Benjamin Thompson
Hongbin was looking for a way to get the protein chains in his hydrogel to stick together in a way that would increase the stiffness without making the material brittle. And he and his team did this by jumbling them up using a process called entanglement, which he likens to something that happens when you're eating spaghetti.
Hongbin Li
Because the individual spaghetti strands when you try to pull one, so probably going to get a few together and because they are kind of entangled, so they are not kind of isolated individual ones.
Benjamin Thompson
To achieve this entanglement, Hongbin took the protein chains that his hydrogel was made of and unfolded them, making long spaghetti like strands with no 3D structure. These strands tangled up and this entanglement was locked in place with a smattering of chemical crosslinks. Finally, in areas where they weren't entangled, the protein strands were made to refold back into their original shape. This three-step process led to a lot more points of contact between the proteins in the hydrogel helping stiffen the material. But these entanglements aren't as permanent as the chemical crosslinks that can make everything brittle. Instead, proteins can slide across each other. Also, the refolded sections of protein are free to unfold once again when the material is squeezed.
Hongbin Li
So, this will allow the energy to be dissipated quite effectively. So, when you remove the stress, the unfolded protein can reform.
Benjamin Thompson
The team put their hydrogel through its paces to see what it could do.
Hongbin Li
Its stiffness is much higher than previous protein-based hydrogel. So, by almost an order magnitude. So now we can get to a range that is close to cartilage. And this is tough. So, you can really compress this hydrogel to more than 80% its original dimension without cracking.
Benjamin Thompson
While cartilage has a number of properties that make it good at doing its job. There is one thing this tissue is not so good at, and that's repairing itself. Damage to cartilage can take a long time to heal or require surgery to fix. So the team wanted to see whether their hydrogel could help. To find out they implanted small sections into damaged cartilage in an animal model to see whether the hydrogel can act as a scaffold for new tissue to grow on and around.
Hongbin Li
So, after three months implantation, we see the newly grown tissues from the appearance from the histology and other tests. They are very similar to the native cartilage and that at the end of the three months implantation, the protein hydrogel scaffold is completely degraded.
Benjamin Thompson
Because Hongbin's hydrogel is based on protein. He says it's biodegradable, leaving behind only the new tissue. But while this result appears positive, Hongbin cautions that three months isn't long enough to say that this early tissue regrowth would result in mature cartilage later on. There's also a lot to understand about the healing process. For example, The team tested hydrogels of different stiffnesses and found that, confusingly, the one with properties closest to real cartilage didn't perform the best.
Hongbin Li
So, the highly stiff one is a closer to cartilage. But in the animal experiment, they didn't give the best results. The hydrogel gave the best results. It's stiff, but not that stiff. So this was a little bit to our surprise. So this really points to the complexity of a biological system.
Benjamin Thompson
There's clearly lots to learn before the team's work could translate into treatments in humans. And Hongbin's approach isn't the only one being developed and tested. But right now he and his colleagues are working to tune the mechanics of their hydrogel to see if they can improve it by incorporating some of the molecules that make cartilage cartilage. And although it might be a long road, Hongbin is excited to see where it leads.
Hongbin Li
In the field people call this one of the unsolved challenge. So compare it with bone repair, cartilage is much more difficult. So it's not the end, but rather more exciting, so this is a beginning.
Shamini Bundell
That was Hongbin Li from the University of British Columbia in Canada. To read his paper, head over to the show notes where you can find a link.
Nick Petrić Howe
Finally on the show. It's time for the Briefing Chat, where we discuss a couple of articles that've been featured in the Nature Briefing. Shamini, what have you got for us this time?
Shamini Bundell
So I've been reading this really interesting article in Science. And I'm going to do the really mean thing, Nick, where I've read this if you haven't, and I'm going to ask you to kick us off.
Nick Petrić Howe
Oh, no.
Shamini Bundell
Do you think, yeah sorry, do you think you can explain the concept of chirality? When molecules are chiral?
Nick Petrić Howe
This is the one that I seem to remember from organic chemistry where some things are right-handed and some things are left handed. So chiral things have like mirror reflections, like reflections of each other, but some have in the right-hand way. And some have in the left-hand way. I think like, I think DNA is right-handed or something like that.
Shamini Bundell
Yes, exactly. So as you say, DNA is an example. And in fact, loads of organic molecules are sort of chiral in one way. So for example, DNA and the sort of DNA bases are right-handed amino acids and proteins are left-handed. And this is quite common in life. But it's actually a bit of a puzzle, because a sort of normal chemical reaction will tend to produce a sort of 50/50 split of left-handed and right-handed versions of chiral molecules, whereas life, it tends to be this really strong, what they call homochirality. So it's all kind of one type or another, depending on the molecule. And apparently, one of the puzzles of life is where this sort of originated from. How do you when you're, you know, evolving into a living thing, how do you start off getting this bias towards one side or another? And that is what this particular paper has a potential and promising suggestion for.
Nick Petrić Howe
So, if this is happening in life, and in not-life it's sort of a 50/50 split, why is there this bias when things are alive?
Shamini Bundell
Okay, so this article starts with in 1848, French chemist Louis Pasteur, you may remember Louis Pasteur from other exciting episodes of science, but in this case, he had a theory for this homochirality, which could explain it. And he thought that it must have something to do with magnetic fields. And now there's three new papers, which suggests that yes, magnetic minerals that would have been found on the early Earth could in fact, have sort of accumulated certain molecules on their surface and favoured one form over another, setting off a sort of positive feedback loop for that particular version.
Nick Petrić Howe
So, paint me a picture here, because I'm not quite sure I fully get how magnetic minerals lead to life preferring one way or another. So how is it that magnetic minerals lead to, say, DNA being right-handed?
Shamini Bundell
Okay, so the link here between the molecules and the magnetic field is all about the spin of electrons. So, there was a paper from 1999, which found that molecules with the opposite chiral forms have contrasting patterns of spin, electronic spin, which is in fact a magnetic property. And further research showed that this can mean that they interact differently with magnetic materials. And some later research by the same group sort of experimented with this and found that peptides, so like short amino acid chains, they found that they could make one form — left-handed peptides — bind to a magnetic surface, while the right-handed ones were repelled. So that was one way that you could get an initial bias in whether it's right- or left-handed forms of a molecule because they could accumulate on this surface. Now, the thing about that is that there are other explanations for this sort of initial skew, for example, so cosmic rays — polarized light — they can also cause this initial bias. And the question after that was like, okay, you've got a bias, but how is this bias amplified? How is that sort of built up to create this sort of large reservoir of chiral molecules that you would probably need to make the first cells and that's where this new research comes in. And it's based on a molecule called ribo-aminooxazoline — RAO, I'm going to call it RAO, much easier — which can help form some of the building blocks of RNA, which is like one of the probably key things in the sort of evolution of life RNA, as opposed to DNA. And this RAO molecule forms these crystals. And once a crystal starts to grow from either a left- or right-handed version of the molecule, only the same chirality molecule can then bind. So that's how you get this amplification. And these new researchers have basically combined this sort of previous research and taken magnetite, a magnetic mineral from the Earth's crust, applied a really strong magnetic field and exposed it to a mixture of different RAO molecules of different chiralities, and showed that there was a bias in the ones that settled on it. And that this bias could then sort of self-propagate and eventually form pure, single handed RAO crystals.
Nick Petrić Howe
Wow. Okay, so just a quirk of the Earth's magnetic field interacting with these materials then led to crystals, which then may have led to certain molecules being a certain way in life. But is this it now do researchers think? Have we got to the nub of why it is the molecules in life seem to be either right-handed or left-handed?
Shamini Bundell
Well, no one's yet going back in time to sort of prove anything that happened. One expert interviewed for this article said that they thought it was a sort of very likely solution. Another researcher says, well, the magnetic field that they used was sort of actually several times stronger than the Earth's magnetic field in their experiment. So not very realistic conditions, they seemed a bit more doubtful. But the team has done some further work that's currently on a preprint server under more realistic conditions showing a sort of slower, smaller bias, but still a bias existing towards one form of a chiral molecule over another. And another sort of slight sort of loose end is that RAO, this particular molecule, very important for RNA but it's actually only been shown to make two out of the four RNA nucleotides. Not yet the other two, so maybe it will be maybe that's still a little bit of a gap. But this solution, certainly according to one of the researchers, solves more sort of steps of the problem than other solutions that have been proposed. And once you have got this sort of basic chirality in RNA, say, chemical reactions, we then pass on that chiral bias, so that other molecules, amino acids, proteins are then sort of templated. And then you get perhaps the full chirality of life as we see it today.
Nick Petrić Howe
Well, I'll be interested to see if Louis Pasteur was actually right or not then with this one, thanks for that one Shamini. For my story this week, I've been reading about how groundwater pumping may have actually affected the Earth's axis.
Shamini Bundell
Wait. So, you mean groundwater extraction as in people taking water out of the ground to, to use for various things?
Nick Petrić Howe
Yeah, essentially humans, drilling wells or digging down to get water out of the Earth to then use in... mostly agriculture and that sort of thing. So, so I've been reading about this in a news article in Nature. And this sort of redistribution of water from the ground, to eventually the oceans, may have actually affected how the Earth's axis is tilted by a few centimeters.
Shamini Bundell
That sounds really unbelievable, though, because, you know, the Earth is a big planet relative to you and me with like this huge mass and like, sure, there's a lot of water, but it's just kind of around the outside, like, how can just us moving bits of water around have such an impact that the entire planets tilt can change?
Nick Petrić Howe
Well, I will say is a lot of water; between 1993 and 2010, is about 2 trillion tonnes. So it's a significant amount of mass that has been moved around. And the Earth's axis actually moves quite a bit already due to mass moving around. So during seasonal and weather changes, the atmosphere moves around. And this massive shift of air, basically, also will shift the axis because as a object spins around, if its centre of mass moves, the tilt at which it is spinning, will also move.
Shamini Bundell
I see. Okay, so these 2 trillion tonnes of groundwater that we've been redistributing, has quite a big impact, how would you go about measuring that and figuring out the sort of link between us moving water around and the Earth's tilt, changing?
Nick Petrić Howe
Well it's quite difficult, because it's still a relatively small change. So the change of the atmosphere moving around is much bigger than this, but it's still measurable. So what researchers do is they use quasars, which are bright centres of distant galaxies that are so far away that they're essentially immobile from our perspective, and using them, they can sort of figure out like how the axis is changing. And by using this information and other information about sort of the Earth and the various waters on it, some researchers were trying to figure out how much water may have tilted the Earth's axis, because they thought maybe, you know, sea level rise due to glaciers melting, and that sort of thing, may be changing it. But when they were doing this, they found sort of a few centimeters they couldn't quite explain. And so there's a quote in the article from the researchers that says, "so I just scratched my head and said, probably one effect is groundwater." And then when he included groundwater in the calculations, they had a model, it seemed to agree with the observed change in the Earth's axis tilt.
Shamini Bundell
So as you say, the weather and over the different seasons, the Earth's axis is tilting quite a lot. So this isn't a sort of example of like, humans are ruining the planet yet again, you know, this is this isn't like a problem, right?
Nick Petrić Howe
No, but I think it is an indication of just how much we are influencing the planet, you know, you think of things like the Earth's axis as being this enormous thing that we could possibly affect. But then because we have shifted so much groundwater, especially in North America, and in India, predominantly for agriculture, it has had an actual measurable effect. And yeah, it's only a few centimeters and the earth is quite big, but it's still pretty impressive, or quite sad depending on your perspective, that humans can have such a huge influence on the planet that we live.
Shamini Bundell
Wow, that's a really interesting one. Thank you so much, Nick, and listeners. If you want to find out more about these stories and find out where you can sign up for The Nature briefing, and get more stories like these, then check out the show notes where we'll put some links.
Nick Petrić Howe
That's all for this week. If you want to get in touch with us. You can reach us on Twitter, we're @Naturepodcast, or you can send us an email to podcast@niche.com. I'm Nick Petrić Howe.
Shamini Bundell
And I'm Shamini Bundell. Thanks for listening.