Dad’s microbiome can affect offspring’s health — in mice

Nick Petrić Howe

Welcome back to the Nature Podcast, this week: uncovering why cancer rates vary so much worldwide…

Benjamin Thompson

…and how altering the gut microbiome could affect reproduction. I’m Benjamin Thompson…

Nick Petrić Howe

…and I’m Nick Petrić Howe.

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Nick Petrić Howe

Where you live can have a big impact on your risk of getting cancer. People in Malawi, for instance, have a much higher risk of esophageal cancer, even in comparison to neighbouring countries. In fact, even if you move from one place to another, you take on the risk of your new home. Now, some of this global variation is down to known factors like using wood burning stoves, or rates of smoking. But that only explains some of the differences. There's a lot scientists don't really know about why where you live affects the risk of cancer. Now a study in Nature is providing new clues by looking across the world at genomes for the most common type of kidney cancer: clear cell carcinoma. I called up one of the authors behind the new work, Paul Brennan, and — on a slightly wobbly phone line — he explained some of the regions that have particularly high levels of clear cell carcinoma.

Paul Brennan

In Central Europe, the Czech Republic traditionally have had a very high incidence of this cancer. Other countries that have very high rates include countries like Hungary, the Baltic countries, and we can't explain why this is. And it's not explained by factors such as you know tobacco, obesity, hypertension.

Nick Petrić Howe

So, what was your approach, then, in this study, to try and solve the problem and understand why there is such variation?

Paul Brennan

So, what we've been trying to do in this study, it's really to take quite a different approach to you know, the traditional epidemiological-type study. And it's to try and see if we can get the answer of why there is a high incidence in some populations and not in others, by looking at the human genome, and the patterns of mutations in the genomes. Because more recently, over the last 10 years or so, with whole genome sequencing of large numbers of cancers, it's become clear that specific causes of cancer often leave a specific pattern of mutations in the genome. So, tobacco smoking in lung cancer, for example, tends to leave a very specific pattern of mutations. So, we were hoping that by looking at the patterns of mutations in the genomes of individuals with this cancer between high and low-risk countries, we might see differences in in the mutation patterns that might lead us to understanding what the underlying causes might be.

Nick Petrić Howe

So, it's almost like working backwards, you start with the cancer, then look at the mutations underlying that cancer and then see what could have caused that.

Paul Brennan

Exactly.

Nick Petrić Howe

And so, this was a huge study, it was eleven countries on four continents that you had these cancer genomes from. What did you find by looking at the sort of differences between them?

Paul Brennan

So for example, we found in Japan a signature called signature 12 — It’s previously been reported. And this was present in about three quarters of the cases in Japan and was almost completely absent elsewhere. So, the signature had some of the characteristics of signatures that are caused by external agents. And we have no idea what it is, but this is pointing towards an exposure in the Japanese population.

Nick Petrić Howe

Do you think then this study will inform Japanese health authorities to try and investigate what's going on here?

Paul Brennan

Well, I think it's certainly going to lead to develop to try and understand what's underlying this, because we don't know if it's you know an environmental-type agent if it's something in food supply, or if some other you know lifestyle type habit, that's resulted in these mutations. We don't know to what extent it's restricted to Japan — because all of our cases in this region were from Japan — or to what extent it might be affecting countries in the East Asian region. We don't know it's affecting millions or tens of millions of people or potentially even hundreds of millions of people.

Nick Petrić Howe

Is it possible that this could be something to do with the genetics of the population in Japan? Or are you pretty certain this is coming from, as you say, like an external agent, some sort of environmental factor?

Paul Brennan

We've certainly tried to rule out that this was due to the genetic difference of the Japanese population. And we did not find any genetic variant that was associated with this, and we looked at some known type genes you know metabolite-type genes that are common in the Japanese population, we found no association with any of these. So, to the extent that we could, we ruled out that explanation.

Nick Petrić Howe

And another signature that seemed to crop up in quite a lot of the cases that you looked at, this signature 40. What do you think was the significance of this particular mutation?

Paul Brennan

So, this is a new signature. In fact, we call it 40B and the interesting thing about this signature was that it was far higher in the high incidence countries. We found evidence of it in every country, but it was a lot higher in the high incidence countries in particular, in countries like Czech Republic in–in Lithuania. And so this is the hallmark of something that could explain the geographical difference in renal cancer. So, you know, a clear challenge now is to try and pinpoint what is underlying this signature, assuming that it is some type of environmental agent, because that could really be the secret to understanding why renal cancer is so high in some countries and not in others.

Nick Petrić Howe

I mean, from the sort of discussion we've had, it seems like there are still a lot of unknowns here. But what do you hope this work will be used for in the future?

Paul Brennan

I think, firstly, it's showing that its approach to sequencing counters and sequencing tissue across different populations, is providing evidence for exposures that are causing mutations in large numbers of specific populations. So, this is providing a whole new angle on potential carcinogens and mutagens that traditional epidemiological studies have not been providing. So, I think we need to consider to what extent we should be doing this sort of study on a far larger scale. We included 11 countries here. We've found evidence for widespread mutagens across these 11 countries. So, question we're asking is what would happen if we looked at this in 50, or 60 countries? So, if we looked at it's really on a global level would we find evidence for a whole range of other mutagens that were existing in populations that, you know, we just don't know about at the moment. And then the second thing is, how you go back to the populations and identify what the underlying exposure might be, and what the source of the exposure is? And that will require a whole different type of study that would really obtain detailed information on individuals to try and trace where the exposure was coming from. If we are to do that, then that could potentially lead to cancer prevention.

Nick Petrić Howe

That was Paul Brennan, from the International Agency for Research on Cancer, in France. For more on that study, check out the show notes for some links.

Benjamin Thompson

Coming up, evidence that upsetting the gut microbiome in male mice could affect their reproductive organs. Right now, though, it’s the Research Highlights, with Dan Fox.

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Dan Fox

Sabre-toothed cats and the dire wolf are two examples of enormous extinct creatures with huge teeth. But have you heard of the sabre-toothed salmon? This salmon ancestor reached 2.7 metres long as it swam in the Northwest Pacific some 5 million years ago. Previous work had indicated that the salmon had sabre-like fangs but now researchers have done imaging scans on fossils which still had their teeth attached that suggest the fangs were really sideways-facing tusks, like those of a warthog. The snout-mounted spikes were not for hunting prey; the massive fish are thought to have dined on plankton. But the oversized tusks might have been used for self-defence, interspecies competition or digging out nests in the riverbed. Get your tusks into that research in PLoS ONE.

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Dan Fox

A common fungus has been found to simultaneously remove heavy metals and organic pollutants from its surroundings. Aspergillus niger was already known to take up heavy metals from contaminated soil in a process called bioremediation. But toxic metals are often found in the environment together with carbon-based organic pollutants like insect repellent. To test how organic pollutants might affect heavy-metal bioremediation, researchers exposed the fungus to toxic metals along with an organic dye. They found that the presence of both pollutants actually enhanced the uptake of metals and degradation of the dye. The results suggest that Aspergillus niger or similar fungi might be useful for cleaning soil and water tainted by complex mixtures of contaminants. You can soak up that paper in Current Biology.

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Benjamin Thompson

Our bodies are teeming with microorganisms. But these microbes aren’t just functionless passengers travelling in and on a human vessel. Many of them appear to play important roles in how our bodies operate. Especially those that live in the gut.

Disruption of the gut microbiota has been linked to issues with organs like the liver, kidney and the brain. But Jamie Hackett from the European Molecular Biology Laboratory and his colleagues wanted to know whether another set of organs should be added to the list: the reproductive organs. They also were interested in whether any disruptions could even have effects on future offspring. Here’s Jamie.

Jamie Hackett

The idea that the environment of a parent prior to conception may influence the phenotype or even a disease risk in offspring is something that's really kind of captured people's imagination over the last decade or so it's a really interesting idea. At the same time, I think there's been quite a lot of healthy scepticism about whether this is actually happening in a meaningful way in mammals.

Benjamin Thompson

And this is something that Jamie and the team have tried to shed some light on, and they've published a paper about it in this week’s Nature. In particular they looked at how disrupting the gut microbes in male mice prior to conception could affect their progeny.

Jamie Hackett

The initial way we chose to disrupt the microbiota was by using non-absorbable antibiotics administered at a fairly low dose. So we're not trying to ablate the microbiome here, we're just trying to perturb it.

Benjamin Thompson

By using antibiotics that aren’t absorbed by the body and only stay in the guts, the team could be confident that any effects they saw were down to disruption of the microbes living there. Mice that had their gut microbes disrupted were otherwise healthy, but when these males were mated with untreated female mice this wasn’t the case for some of their offspring. On average these pups had a reduced birth weight, but some had more significant issues.

Jamie Hackett

What we began to see that a fraction of these mice, they were severely underweight, we saw quite a severe growth restriction. And ultimately, many of those mice were not able to survive. And we just didn't see that when the fathers had that to say, an unperturbed microbiome, and it was in the range of 10% of the offspring. This is not a deterministic thing whereby if you perturb a prospective father's microbiome, there's going to be an effect. It's more that you're changing the risk of an adverse pregnancy or disease risk in the offspring.

Benjamin Thompson

But this could be reversed. Stopping antibiotics allowed the gut microbes of the treated mice to recover. When they subsequently went on to have more offspring, this increased risk of health issues wasn't seen, strongly hinting that these microbes were central to the phenomenon.

But it was possible that this effect could have been caused by the mice passing on their dysfunctional gut microbiome to female mice or their offspring, through contact perhaps. To rule this out the team turned to in vitro fertilization.

Jamie Hackett

In those circumstances, there's no parental contact whatsoever, we just use donor sperm and donor oocytes. And again, we saw that when the sperm is derived from a father with a microbiome perturbation, the offspring are born with an increased risk of severe growth restriction.

Benjamin Thompson

But how was the microbiome affecting the male mice’s reproductive organs? Well, the team showed that there were physical changes in the mouse testes — they were smaller, for example — but there were changes in levels of metabolites, and hormones known to be important in sperm production.

The sperm themselves also were affected. The team didn’t find any changes in their genomes, but they did find other changes, like alterations in levels of molecules that potentially influence how genes are switched on and off. Exactly what these changes are doing is unknown, but they appear to be having an effect post-fertilization.

Jamie Hackett

If you look during mid-gestation, there aren't a lot of changes in the embryo itself. But where there are clear changes in the placenta. What this was implying is that the status of microbiome perturbation in the father at the time of conception was influencing placental development, which means the placenta is unable to function appropriately. And we suspect this is what's actually causing the slightly lower birth weight and the increased risk for severe developmental events in offspring.

Benjamin Thompson

So, whatever these changes to the sperm are specifically doing, they can have an impact on placental development, but it’s not clear why. And the team have shown evidence that all this can be traced back to disruptions to the population of microbes living in the guts of male mice. Liisa Veerus from Rutgers University researches the effects the microbiome can have on health. She’s co-written a News and Views article for Nature and says she’s convinced by the huge amount of data the team present.

Liisa Veerus

I was incredibly impressed how, almost beyond the scope of this paper, the author's went to try and pinpoint what is happening, how they looked at sperm quality, how they looked at placental health, how they measured the health of offspring, how many different microbiome experiments they carried out to show that this effect is not because of the transfer of the microbiome itself, but through the indirect effects. So, they really included so many state of the art experiments. I was incredibly impressed.

Benjamin Thompson

However, there’s still some big unresolved questions: why is this happening, and why doesn’t it happen every time? After all, it’s only a fraction of the mouse offspring that experienced the severe growth impairments. To understand it, Liisa thinks that researchers need to look at what happens in the gut when antibiotics are administered.

Liisa Veerus

Because we can think of microbiome as a jungle of its own, right. And when we give it antibiotics, it's almost like a forest fire. And some strains survive, some don't; some increase in abundance, their gene expression and the way they live in the gut changes. So, I think looking at the bacterial gene expression, really trying to delve more into the bacterial side, not the host side, can also give us indication of what could actually participate in signalling in the reproductive tissue.

Benjamin Thompson

There’s also the question of whether the results in this paper translate into humans. Jamie cautions that that is currently impossible to know, and that there are likely many interconnecting and overlapping pathways to uncover. Both he and Liisa also stress that antibiotics remain a vital medicine and that this work shouldn’t put people off using them.

But even if this work doesn’t show exactly how this intergenerational disease risk is transmitted, it adds more evidence to the idea that heritability is about more than just the genes encoded in DNA.

Jamie Hackett

At present, I think it's, it's interesting from a biological point of view, it tells you that in the case of these mice, lifelong disease risk or phenotype more generally, is not purely dependent on the genes you inherit, but there is some component of, of parental environment that is having, albeit a relatively small effect, an effect on phenotype, so that that conceptually is really interesting. It also tells us that we need to consider perhaps a little bit more how the environments that were exposed to is affecting mammalian physiology, all the way through from the kind of molecular responses within the organism to a much bigger scale, which is intergenerational effects.

Benjamin Thompson

That was Jamie Hackett from the European Molecular Biology Laboratory in Italy, and Liisa Veerus from Rutgers University in the US to read Jamie’s paper and Liisa’s News and Views article look for links in the show notes.

Nick Petrić Howe

Finally on the show, it’s time for the Briefing Chat, where we discuss a couple of articles from the Nature Briefing. Ben, what have you been reading this week?

Benjamin Thompson

Well, I've got a story from Nature, and it's about an atlas, okay? And it's not about any old atlas – it's an atlas of the Moon. And in fact, it's the highest resolution one yet.

Nick Petrić Howe

So when you say an atlas of the Moon, is this just like, you know, where are the craters are or that sort of thing? Or is it you know, more in depth detail about what the moon is composed of? What makes up a moon atlas?

Benjamin Thompson

Well, a bit of both, actually. So, this was released by the Chinese Academy of Sciences, right. And it's taken 100 researchers over a decade to compile–

Nick Petrić Howe

–oh wow–

Benjamin Thompson

–yeah, and it reveals 12,341 craters, 81 basins, 17 rock types, and lots of other sort of geological info about the Moon's surface.

Nick Petrić Howe

So, the Moon has a lot of craters and rocks. Were scientist surprised at these findings?

Benjamin Thompson

I mean, newsflash, yes, the Moon has taken a bit of a battering over his lifetime. But what's interesting here, is that this new map is double the resolution of the previous one that was being used. And that one sort of dates to the 60s and 70s, and data from the Apollo programme. But this one, as I say, is a much higher resolution, you know, using newer tech, and specifically, the data comes mainly from China's lunar exploration programme, particularly the Chang’e 1 mission that surveyed the lunar surface from orbits and had info about the topography and the geological structures. And that was kind of verified by Chang’e 3 and Chang’e 4. And the researchers have combined that with data from other missions from NASA and India's ISRO to make this quite wonderful looking atlas, which has all sorts of different colours, we'll put a link to it in the show notes. And it really gives a sense of our nearest kind of space neighbour and what it looks like.

Nick Petrić Howe

So, on the podcast, we've talked a lot about various like missions to the Moon, like various scientific research that's going on, on the Moon. Will this help the sort of research that's going on there or point people towards the best crater to land on?

Benjamin Thompson

I mean, undoubtedly, that's the plan, right? So, if you're gonna go somewhere, it's useful to have a map of what it looks like. And so, what the researchers here are saying is that this updated atlas should really help researchers, you know, understand the history of the Moon, and identify, as you say, potential resources and landing zones. And this atlas is available in both Chinese and English and the team say that, you know, the maps will support China's lunar ambitions and will hopefully be beneficial to other countries, too, because — as we've covered a bunch — the Moon is big business, right? We've already had several missions go this year with varying degrees of success. And China, of course, has multiple missions planned. In fact, this week they were intending to send a craft to collect rocks from the far side of the Moon. But beyond that, there are plenty of future missions involving humans as well, crewed missions. And the idea was to try and put them on the surface too. So, I'm sure that having say a good map of where they can safely put their feet will be a very useful thing indeed.

Nick Petrić Howe

So, as you say, now we've got this incredibly detailed map, what is sort of next for this research?

Benjamin Thompson

Well, the team aren't resting on their laurels, that's what. So apparently, they've already started to improve the resolution of the maps, and will produce, you know, regional maps of higher accuracy on the basis of, you know, whatever the scientific and engineering needs might be. In the meantime, the completed atlas has been integrated into a cloud platform called the Digital Moon, which will eventually become available to the international research community.

Nick Petrić Howe

That is a very good name for that. I'm looking forward to seeing those bits of the Moon soon. For my story this week, coming back down to Earth, we are talking about AI for a change, we don't do that very much on the podcast. And this is a story I was reading in Nature, about a kind of ChatGPT but for CRISPR.

Benjamin Thompson

Right, an AI chatbot and a way of editing genomes. I mean, those aren't necessarily two things I'd initially kind of smush together.

Nick Petrić Howe

Exactly. And I'm slightly tongue-in-cheek here. This is a like a ChatGPT but for CRISPR. So basically, it's an AI that can help you design different CRISPR-based gene editors, and ChatGPT is based on a large language model, this is based on a protein language model. So, it's got millions of sequences of proteins, most of them like CRISPR-based proteins, that have been thrown in its training data. And from that training data, they've been able to design brand new CRISPR-type editing systems that people can try out.

Benjamin Thompson

And so, what's the kind of the aim of this to make gene editing easier or more efficient? What comes out the other end kind of thing?

Nick Petrić Howe

Yes and yes, really. So, I think the initial aim is to just make it easier for researchers to find new and different and hopefully better ways to edit genes. So, they can try and use this model to create new kinds of CRISPR, that may be more efficient, or maybe make less mistakes, because you know, CRISPR is slightly error prone. And I think their eventual aim is to make bespoke editing systems. So CRISPR works well in certain species and less well in others. So, you could potentially try and make a specific kind of editing system for whatever it is you're trying to do. And that could help it be again, more efficient and just work better.

Benjamin Thompson

And so, it seems then that the plan is to come up with — if that's the right word — CRISPR and CRISPR-adjacent systems, is this still very much just in a computer? Or has this been demonstrated to be actually a practical approach?

Nick Petrić Howe

So, in this article, there's a few different approaches that are discussed, but they're all based on preprints. So, none of this has been peer reviewed, just bear that in mind. But the bulk of the article focuses on one particular preprint. And in that one, they have actually tried it out in the real. So, they made 200 designs that the AI came up with, and they found that some of them worked really well. In fact, the most promising of them was something that they called OpenCRISPR-1, I'm assuming they think this is the first of many. And they found it was just as efficient, as you know, the sort of regularly used CRISPR Cas9, but it made fewer errors, it made fewer cuts in the wrong places. And they also span this out to make a base editor too, which we've talked about before on the podcast. But just as a reminder, a base editor is a gene editor that just swaps one particular nucleotide base. And it found this, again, was less prone to errors.

Benjamin Thompson

Of course, there are a bunch of systems like this that have evolved. I wonder if any of those that do exist haven’t been thought up by the AI and are yet to be discovered, or–or have been discovered, but–but not compared and contrasted kind of thing.

Nick Petrić Howe

I mean, it's entirely possible, it could be coming up with the same things nature's come up with but I guess the idea with this is to try and make ones that maybe work a bit better than nature. In nature. these are sort of bacterial defence mechanisms to prevent them getting invaded by viruses. And so instead of doing that, we can sort of tweak them towards our own purposes. And, you know, the people who were interviewed for this article seem pretty impressed by this, and also by the fact that this is an open tool as well. So, researchers can just freely use these tools to try and do it. Whereas some of the CRISPR technologies that many researchers use are actually patented. So, there are limitations on how and when you can use them.

Benjamin Thompson

Well, as you know, I have a particular fondness for anything that is ultimately related to microbiology, so that is an absolutely fantastic story. But let's leave it there for this week's Briefing Chat. And listeners for more on those stories and where you can sign up to the Nature Briefing to get more like them, check out the show notes for some links.

Nick Petrić Howe

And that's all for this week. If you want to keep in touch with us, you can, we’re on @NaturePodcast on X or you can email us podcast@nature.com. I'm Nick Petrić Howe.

Benjamin Thompson

And I'm Benjamin Thompson. Thanks for listening.