Host: Benjamin Thompson
Welcome back to the Nature Podcast. This week, we look at the legacy of the sequencing of the human genome…
Host: Nick Petrić Howe
And how the immune system helps muscles repair. I’m Nick Petrić Howe.
Host: Benjamin Thompson
And I’m Benjamin Thompson.
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Interviewer: Benjamin Thompson
This week marks the 20th anniversary of a momentous scientific milestone – the publication of the first draft of the human genome in papers in Nature and Science. To mark this achievement, we’ve got a wealth of content in this week’s edition of Nature, and to get a sense of its legacy, I spoke with Nature’s editor-in-chief, Magdalena Skipper. Magdalena is a geneticist by training and in previous roles has worked as chief editor of the journal Nature Reviews Genetics, senior editor for genetics and genomics at Nature and a bunch more besides, so she knows the field pretty well. I started our chat by asking Magdalena to cast her mind back to the turn of the millennium and give her recollections on what the field of genome sequencing was like when she was in the lab.
Interviewee: Magdalena Skipper
What I remember best in relation to the Human Genome Project and these sort of heady days of genome sequencing was in fact when I was back in Cambridge. I was doing my PhD at the end of the 90 and I was studying C. elegans, which is this little model organism worm that geneticists love, and its genome was also being sequenced at the time. We were very close to the Science Centre as it was called then, and of course that centre plays an important part in the sequencing of the human genome as well. And in fact, one of the leaders of the public effort of the Human Genome Project, John Sulston, was the examiner of my PhD thesis, so I was very close to that community. And one of the things that I remember the most was that feeling of coming to the lab, in my case to work on C. elegans, turning on the computer and going to the database to see if ‘my favourite part’ of the genome had been sequenced overnight. That was an amazing feeling which I think is hard to imagine today.
Interviewer: Benjamin Thompson
Well, Magdalena, in your time working as an editor you obviously saw a lot of genomics and genetics papers come across your desk. How have those fields changed and maybe more broadly how has science changed, do you think, as a result of the Human Genome Project?
Interviewee: Magdalena Skipper
Thinking about what it was like back then from today’s perspective, I’m not even sure that we could say that there was a field of genomics back then as we understand it now. The publication itself was of course a true landmark, but in many ways it was the project was doing as it was going along, the fact, most notably to me actually, that the decision was made by the project to share the data as the data was being generated without any restrictions. In fact, there was an agreement, the Bermuda Agreement, which set out the fact that the data were going to be shared immediately, without exceptions, without restriction. But at the same time, it protected the data generators, if you like, so that they would be able to publish first, and that definitely influenced the whole field as it was being born, if you like, in the sense that we understand today. That was to me the most fundamental influence. But of course there were other related aspects and that is that in a project like the Human Genome Project, so many researchers from different parts of the globe had to come together to work together. And so genomics in general, today when we think about the field, we think about multi-lab efforts coming together, collecting the data, analysing the data together often in that distributed but collaborative way. And so, the project and the publication really set the stage and the bar, if you like, for this type of work.
Interviewer: Benjamin Thompson
If we can talk about the legacy of the publication then, what are some of the key areas that emerged as a result, would you say?
Interviewee: Magdalena Skipper
If you think about it, we understand so much more about biology, so much more about population dynamics, so much more about ecology, and then of course there is the very human focused aspect of the legacy, our understanding of human biology and indeed human disease. Armed with the genome, we are much better able to diagnose so-called monogenic diseases, so these are the diseases which are caused by single genes. There’s a whole pool of so-called undiagnosed diseases which are phenotypically very complex but there is no obvious underlying molecular diagnosis, and sequencing has been invaluable in diagnosing these diseases. They’re often diseases that are diagnosed in very young children. And finally are the so-called genetically complex diseases, and here the whole field, the whole approach of genome-wide association studies – only possible because we have the sequence of the human genome – has absolutely blossomed, enabling us to understand which variation in which areas of the genome contributes towards phenotypically complex diseases such as cardiovascular disease or cancer and of course metabolic diseases and many others.
Interviewer: Benjamin Thompson
Well, if we’ve learnt so much about disease and the potential is there, of course, to learn a lot more, how can we make sure that the information that is gained benefits everyone? I mean, if we think back to the original publication of the genome, certainly it was skewed in favour of those of European descent, so how can we make sure that genomics is equitable and can really benefit humanity as a whole?
Interviewee: Magdalena Skipper
That’s a very important question. So, the community is beginning to realise that there has been an inequity, and much needs to be done to adjust for it. Over the past few years, there have been some really impressive efforts, for example in Asia, to understand actually population history and dynamics, so that incidentally informs us about how the world has been peopled, populated, but very importantly in the context of medicine, to provide tools so that individuals of non-European descent can be better diagnosed and the drugs that are prescribed for them, conditions, can be more effective and have fewer side effects. There are other part of the world which continue, unfortunately, to lag behind. Again, one effort that I can specifically mention is H3Africa, for example, that specifically aims to characterise genetically and genomically populations in Africa, and of course there’s a great diversity of human populations in Africa. Another example is that of indigenous populations for which very few studies have been done. And of course these studies need to be done in an inclusive way not just in the sense of including samples from these populations. We need to see more scientists who belong to these populations who themselves drive these projects and engage with them, but also we need to engage the communities themselves. So, indeed, those studies can be designed better to fit their particular needs.
Interviewer: Benjamin Thompson
Finally then, if we think back to the year 2000, there was a press conference with the then US president Bill Clinton and UK prime minister Tony Blair when the sequence was first presented before the publication of the papers, and that was such an exciting time. I mean, it was likened to the Moon landings in terms of its importance. Do you think the promise of the Human Genome Project that was assumed, that was hoped for at the time, has been realised?
Interviewee: Magdalena Skipper
If you consider how many contributions at many different levels, some of the ones we’ve spoken about in terms of, I would say, almost kickstarting the whole field of genomics as we know it today, how much has come from that information. And then also there is this social aspect of the way that science is done itself. In the life sciences, in biological sciences, the Human Genome Project was really the first template, if you like, for these large, multi-centre, multidisciplinary collaborations because you have to share, because you have to work with those whose forte lies in a type of analysis or discipline that may not be so familiar to you. So, in that sense, I think it’s not only just delivered but it has gone beyond it. There were promises that were made which verbatim have not been fulfilled, but I would argue that always is the case in science. When we arrive at a certain goalpost, so many new questions and new complexities come to light that the next goalpost that we might have established previously suddenly appears to be ill-defined. New questions, new challenges arise and that’s actually a really beautiful and wonderful thing.
Interviewer: Benjamin Thompson
That was Nature’s editor-in-chief, Magdalena Skipper. To coincide with the 20th anniversary of the publication of the human genome sequence, we have two new films up on our YouTube channel. One looks at the field of ancient DNA, while the other investigates how work on the genome of the C. elegans nematode worm led to the open science approach of the Human Genome Project. Find links to those and all of Nature’s other human genome content in this week’s show notes.
Host: Nick Howe
Coming up, we’ll be finding out the particulars of how the immune system is involved in muscle repair. Right now, though, it’s time for the Research Highlights with Dan Fox.
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Dan Fox
You might have thought that there was some sort of evolutionary reason that certain cultures favour spicy food, but according to new research, probably not. It’s been suggested that the reason people in many hot countries have a predilection for hot food could be due to spices having protective antimicrobial properties, perhaps creating a selection pressure to prevent food-born infection which is more likely in warmer regions. But after analysing over 33,000 recipes from around the world, researchers discovered that spice use is not associated with how hot a country is but is better explained by socioeconomic status. There was also no association between where spices grow, cultural diversity or risk of infection. Instead, the researchers suggest that its more coincidence that warmer countries have spicier food and they just happened to generally have lower incomes. Sample that spicy research in Nature Human Behaviour.
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Dan Fox
Having a strong group of female friends may be one of the most important things for survival in giraffes. A study of more than 500 giraffes has found that when females are more sociable with one another, forming larger groups, they have far better chances for survival than more socially isolated giraffes. When female giraffes form a tower – the collective noun for a group of giraffes – they benefit from cooperative childcare, increased foraging success and they even seem to be less stressed. These benefits outweighed negative effects of the environment or even the impact of humans. Tell your girlfriends about that research over at the Proceedings of the Royal Society B.
Host: Nick Petrić Howe
Next up, Shamini Bundell has been finding out how the immune system can help regenerate damaged muscle cells and whether doctors could one day use the same pathway to treat muscle injuries. To find out more about the new research, Shamini spoke to one of the researchers involved, Dhanushika Ratnayake.
Interviewer: Shamini Bundell
Why were you interested in understanding what happens in our muscles when they’re injured?
Interviewee: Dhanushika Ratnayake
So, I was always really fascinated by regeneration, and there’s a lot of tissues that have the ability or don’t have the ability to regenerate, and the thing with muscle is you need to be able to regenerate it. So, I was really interested to take an animal model that regenerates really, really well and kind of study how it does that.
Interviewer: Shamini Bundell
And when you started off this project, what was the basic understanding of how muscle repair works and how we deal with injuries to muscles?
Interviewee: Dhanushika Ratnayake
Muscle regenerates by the stem cell population that is present in the muscle, and this stem cell population has been known for decades. However, you really can’t just take those stem cells and transplant them into muscle, and it will not work. So, at the start of this project it was just to get a fundamental understanding on how these stem cells were able to function, and particularly to try and find out the external signals that were required to allow these muscle stem cells to function properly.
Interviewer: Shamini Bundell
And how do you go about doing that? I mean, it must be pretty hard to find out what’s going on in a living muscle inside a body?
Interviewee: Dhanushika Ratnayake
So, that is where the zebrafish larvae comes in and they’re amazing, they regenerate their muscles super well, and the best thing about them is that they’re transparent as larvae. So, what we do is we use genetic engineering to introduce fluorescent proteins, we just tag what cells we’re interested in, what tissues we’re interested in, carry out an injury, and we just watch.
Interviewer: Shamini Bundell
And did you have any clues as to what to look for when you were trying to look for the external factors that are going to stimulate these stem cells?
Interviewee: Dhanushika Ratnayake
We obiously knew that the immune system was very, very important, and we knew that macrophages, which is the main player in this story, was a key component of that response, so we did just start looking at that.
Interviewer: Shamini Bundell
So, what did you see in your transparent zebrafish?
Interviewee: Dhanushika Ratnayake
Well, the first thing we did was we carried out an injury, and we had these fluorescently labelled macrophages and we had the muscle as well fluorescently labelled, and we saw, as expected, a whole bunch of macrophages coming in to the wound site. But at about 12 hours, we saw that some of them, about 50%, started to leave the wound site. However, 50% decided to stay, and then we saw that the macrophages started to interact or cuddle the stem cells, and they kept cuddling them for about six hours, and at the end of that time period we saw that the stem cell undergoes division. And what was really interesting was inside the wound, no muscle stem cells division without a macrophage that was kind of cuddling it and hanging out with it, so we were like, okay, there is something going on here.
Interviewer: Shamini Bundell
So, whatever the macrophages are doing, they are able to trigger the stem cells to do all the things that they need to do to heal that wound, so what exactly is going on during these cuddles between these two cells?
Interviewee: Dhanushika Ratnayake
So, what we found out was that the macrophage is releasing a protein that goes and interacts with a receptor that is on the muscle stem cell, and this two-way communication was done by NAMPT from the macrophages’ side, or nicotinamide phosphoribosyltransferase, and the receptor on the muscle stem cell was CCR5. And then we went on to do quite a lot of genetic studies in the larval zebrafish to really confirm that the communication was done by these two parts, and all our studies confirm that you really need NAMPT and CCR5 on these two types of cells to be able to get muscle stem cell proliferation.
Interviewer: Shamini Bundell
So, this is kind of the first time that we’ve understood these macrophages being able to use the specific NAMPT molecule to trigger this sequence which means we could then potentially take that and use it maybe in a healthcare setting.
Interviewee: Dhanushika Ratnayake
We really wanted to see, could you just take NAMPT and add it into an injury site and would that allow that injury to heal better? So, we wanted to look at an injury type that normally is quite hard to heal. So, if, for example, you lose quite a lot of muscle in a certain area, it’s very, very hard even for your stem cells to build it up. So, we did what we call a volumetric muscle loss injury in a mouse leg and then we introduced NAMPT in a gel-like substance that allows NAMPT to stay in the wound site, and then we went back ten days after and we looked at the injury, and what we were really amazed by was that at a certain dose of NAMPT, which is not very high, the full muscle was completely regenerated.
Interviewer: Shamini Bundell
So, the control mice would really struggle and a lot of those fibres wouldn’t be regenerated, but your NAMPT-treated mice looked pretty much normal.
Interviewee: Dhanushika Ratnayake
Exactly, so that particular result was really… I mean, we were amazed, I would say.
Interviewer: Shamini Bundell
So, what you’re doing is stimulating a sort of already existing process within our natural immune system. Is there any concern that by sort of pushing it further than it usually goes that there could be some downsides that we don’t know about?
Interviewee: Dhanushika Ratnayake
I mean, that’s always a possibility, of course, but what I think is in these big injuries where you don’t get proper repair, the whole immune environment is completely different to the immune environment you would have in a healthy, well-healing system. So, maybe the macrophages that actually secrete or produce NAMPT are not even present or have not even been able to reach that state, so we think we’re just going try and revert it to the proper response that should happen.
Interviewer: Shamini Bundell
And you’re thinking about medical applications for this and being able to actually use this to treat muscle injuries in human patients?
Interviewee: Dhanushika Ratnayake
Definitely, we would be very interested to develop this further as well, and especially, I mean, coming from such a fundamental question of trying to understand regeneration and then being able to find something that could be applied in an actual human, I find that really amazing and really what science should be about.
Host: Nick Petrić Howe
That was Dhanushika Ratnayake of the Hubrecht Institute in the Netherlands and formerly of Monash University, Australia. You can find her paper linked in the show notes.
Host: Benjamin Thompson
Finally on the show, it’s time for the weekly Briefing chat, where we discuss a couple of articles that have been highlighted in the Nature Briefing. Nick, what’s caught your attention this week?
Host: Nick Petrić Howe
Well, Ben, I was reading an article in the Washington Post which is all about various legislation and court rulings that are affecting how environmental policy will go forward in the Unites States.
Host: Benjamin Thompson
Right, and what’s the background to this then? What was sort of brought in and how is it affecting how things might go?
Host: Nick Petrić Howe
Well, a couple of weeks before Biden became president, the Trump administration brought in a rule that was supposed to aid transparency in the sort of data that is used by the EPA (Environmental Protection Agency) in making its regulations and public health recommendations. And this rule said that they would have to assign higher weight to scientific studies that had all the raw data available and there to be scrutinised, and lower weight to those studies that do not do this, which may sound like a good thing, like there’s a lot of advocates of open data and more access to the underlying data within science. However, this was criticised by many people because it was seen as maybe sort of a trojan horse that would prevent some sort of good science being used in making environmental policy. And the reason for that is a lot of what the EPA does is they make legislation about public health, and that relies on things like patient data which is confidential, so studies that had that sort of thing would have less weight than those studies that didn’t, where the raw data was available.
Host: Benjamin Thompson
Well, Nick, you said that these rules were brought in at the end of President Trump’s administration and of course, US politics has moved on as we’ve discussed on the podcast before. Now President Biden has come in, has he looked to maybe reverse some of these decisions?
Host: Nick Petrić Howe
Yeah, so that’s part of what’s happened here, but also the rule was challenged by several environmental groups, and a district judge made the decision that actually this rule wasn’t a thing that was possible because it was a substantive change rather than a procedural change and for various reasons that meant that it wasn’t okay. And then the Biden administration has waded in and said, ‘Okay, in that case, can you vacate this,’ which is a term that basically means overrule this, and that’s what’s happened now.
Host: Benjamin Thompson
So, we’re back to where we were before then where all of the evidence can potentially be used.
Host: Nick Petrić Howe
Yes, and the outgoing Trump administration officials who were part of this have said that this rule was just brought in to make sure that everything is transparent and to enhance public trust, and they hope that that is something the Biden administration will carry forward, and they think it’s somewhat of a knee-jerk reaction from the environmental groups. However, critics are quite happy because they think this will enable more of the Trump-era regulations to be pulled back because there were many concerns throughout the presidency of Donald Trump that the environment was taking a backseat to a lot of other issues, and there were deregulation of things like how much carbon emissions power plants and things can make, and that sort of stuff is also being taken back now with the Biden administration. So, there is hope that there’ll be more positive legislation in terms of the environment and things like climate change, which was not, shall we say, a darling of the Trump administration. But, Ben, what have you found this week?
Host: Benjamin Thompson
Well, Nick, I’ve been reading a story this week about a study on blue whales which was reported in The Independent, and it’s having a look at their ability to sort of move freely around the ocean.
Host: Nick Petrić Howe
Right, okay, and what is happening to their ability to move freely around the ocean? I’ve got a funny feeling it’s not going to be good news.
Host: Benjamin Thompson
No, sadly not, Nick. Well, in particular then we’re talking about an area of the South Pacific off the coast of Chile, and this is a very important foraging and nursery ground for blue whales, but there’s something that appears to be really affecting their ability to be able to move freely, and that is sadly, once again, human activity, but specifically in this case maritime activity, fishing boats and the like, which creates a lot of noise and often collisions as well.
Host: Nick Petrić Howe
Right, okay. I mean, this doesn’t sound great but is there anything that we can do about it? What has this new finding uncovered?
Host: Benjamin Thompson
Well, Nick, researchers tracked 15 blue whales over 4 years and combined that with data on where ships sailed, right. So, they combined these two datasets to get an idea of some priority areas for conservation, what areas were really important to the whales and what collisions might happen. And there was one video from this research that was doing the rounds – maybe you saw it yourself, Nick, but I’ll certainly put it in the show notes – and it shows a sped up week in the life of a blue whale as it tries to navigate around 1,000 different boats and ships.
Host: Nick Petrić Howe
Wow, okay. Is this a thing that happens often? It’s a huge area, the ocean, are they having to dodge and weave all the time to try and avoid human influence?
Host: Benjamin Thompson
Well, Nick, the answer to that is absolutely, yes. So, this video looks a bit like a video game but it’s quite harrowing when you realise what it is. So, it’s kind of a square of a map of the ocean of this area, and there’s a blue dot that represents this blue whale, and there’s a bunch of other orange dots which are the ships moving about, and you can kind of see this whale trying to get to a place and then a ship comes towards it and it has to suddenly veer off to a different direction, maybe it has to sort of swim very quickly in front of a bunch of other ships to get to where it’s trying to go, and it’s going backward and forwards. It must be quite harrowing to be a blue whale in this area of the ocean.
Host: Nick Petrić Howe
Yeah, and you mentioned sort of conservation areas and things, does this work sort of show where might be good places to do this? Do they need like corridors to get to different breeding grounds and things like that?
Host: Benjamin Thompson
Well, the authors of this paper, Nick, are saying that actions are required. Particularly in some cases you don’t know how many collisions happen between boats and these blue whales, and what’s interesting as well is that 89 of the ships that were tracked as part of this study were involved in the region’s very extensive salmon farming industry, so I guess there’s the hope that things can be changed to really give more of a safe space for these magnificent mammals to be able to move freely and get where they need to go.
Host: Nick Petrić Howe
Well, hopefully there’ll be more in the way to protect these beautiful and enormous mammals in the future. So, thank you for telling me about that, Ben, and listeners, if you’d like to know more about all the stories we discussed, you’ll find links to them in the show notes. And if you’re interested in more stories like this but instead as an email, then make sure you check out the Nature Briefing. Again, we’ll put a link in the show notes where you can sign up.
Host: Benjamin Thompson
That’s all for this week, but don’t forget to check out our new videos and all the other content on the sequencing of the human genome. As usual, head over to the show notes where you can find links to all of that, and keep an eye on your podcast feed for the next edition of Coronapod coming out later this week. I’m Benjamin Thompson.
Host: Nick Petrić Howe
And I’m Nick Petrić Howe. See you next time.