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Interviewer: Charlotte Stoddart
Welcome back to the Nature Podcast. This week we find out about a very peculiar dwarf planet, and take a look at how DNA sequencing has transformed biology.
Interviewer: Adam Levy
Plus, the grieving families contributing to a huge genetics project. This is the Nature Podcastfor October 12th2017. I’m Adam Levy
Interviewer: Charlotte Stoddart
And I’m Charlotte Stoddart.
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Interviewer: Charlotte Stoddart
First up, we’re looking at a bundle of papers out this week from a big genetics project known as GTEx. Here to tell us more is Shamini Bundell.
Interviewer: Shamini Bundell
The Human Genome Project which started in 1990 and took over a decade to complete aimed to map out a full human genome. Obviously every person’s DNA is different but sequencing a complete genome was a vital step in understanding how our genes make us who we are. Some papers from another big project are being published this week. It’s called GTEx which stands for the Genotype Tissue Expression Project and its aim is to map out gene expression. In other words, how the DNA is expressed as RNA to find out which genes are active in which tissues across the body. Studying the DNA alone is valuable but the RNA can provide a different part of the picture particularly when it comes to links between genetics and disease. I got reporter Ewen Callaway into the studio to tell me a bit more.
Interviewer: Ewen Callaway
Scientists have done a fantastic job of finding tens of thousands of DNA letter variations that differ between people that increase their risk or protect them from diseases. The problem is that a lot of these variants that are linked to disease – they’re not in genes that make proteins – they’re in these so-called non-coding regions and what we think is that these non-coding regions are influencing the expression of genes, sometimes in different tissues or in particular tissues. So GTEx is trying to connect these dots between the Human Genome Project and the biology of disease susceptibility which is what we really want to understand if we’re going to come up with cures or treatments for diseases.
Interviewer: Shamini Bundell
So if you’re going to sequence a bit of DNA, you can extract it and work out what the order is. When you talk about gene expression, you kind of want a snapshot of what’s being expressed at a particular moment and that’s really hard to get isn’t it.
Interviewer: Ewen Callaway
So the idea is to get a read out of what a cell is doing you need to look at these RNA molecules. The problem is they break down really quickly. They’re not super stable in many cases. So as soon as a cell dies, as soon as a cell stops getting oxygen which happens really quickly after somebody passes away, these RNA molecules start breaking down, so you need to find a way to collect them as quickly as possible after death if you’re going to get an accurate snapshot of what genes are active in that tissue.
Interviewer: Shamini Bundell
And in this GTEx Project they did need samples from dead donors. They needed to be able to take tissues you wouldn’t be able to take from a living person so how did they arrange that?
Interviewer: Ewen Callaway
Yeah, you’re exactly right. They looked at, I think, up to 44 different tissues across 960 people, nearly a thousand people. So, yes it necessitated going to deceased donors and what the researchers who were leading this project did was they worked with organizations that procure organs for transplants, so people who sign up to be organ donors and if somebody was an organ donor and then they passed away, in some cases they would ask their next of kin, their family, would you be interested in participating in the GTEx project: here’s what it’s about.
Interviewer: Shamini Bundell
One such family member who was approached about the project was Jim Walls.
Interviewee: Jim Walls
I am Jim Walls. I am 76 years of age. I have a son – Peter – and two grandsons, Ben and Matt and my wife was taken away by an aneurism in 2012. I’ve since remarried. My wife’s name now is Linda. She’s delightful and has four grandchildren.
Interviewer: Shamini Bundell
For Jim, despite the tragedy of his wife’s death, the decision to participate in the GTEx program was not that difficult.
Interviewee: Jim Walls
Well, my wife years ago said that she was already part of a donor program: kidneys, heart, lungs, whatever body part that could be used to restore other people’s lives. She was a willing donor. And so it was a very simple step to accept the request of becoming a tissue donor for research.
Interviewer: Shamini Bundell
At the time, Jim tells me, he only had a vague idea of what the tissue samples might be used for. Since then he’s been involved in helping researchers consider the ethical implications of how potential donor families are first approached. This was actually one of the big concerns when the project was first getting under way.
Interviewee: Tuuli Lappalainen
So I think there has always been a lot of excitement about the scientific goals but of course in the early days there was also a lot of uncertainty of is this actually going to work.
Interviewer: Shamini Bundell
This is Tuuli Lappalainen who was a postdoc when she first got involved in GTEx in 2011.
Interviewee: Tuuli Lappalainen
A project of this scale had not been done before so there were big questions of data quality and also how easy would it be to recruit close to a thousand donors. Will people consent to these things? Will people want to donate tissues when their loved one has just deceased? But luckily it became clear quite quickly that actually, this is going to work.
Interviewer: Shamini Bundell
And work it did. The papers being published this week only represent the first half of the final data set from around 450 donors. But there are already fascinating associations being uncovered between genes, gene expression and disease which could help researchers figure out the cellular processes involved in various conditions, and the data from the GTEx project is being made available to scientists all over the world and from all sorts of fields.
Interviewee: Tuuli Lappalainen
There are probably thousands of researchers that are using the research – all kinds of research actually. Here in the lab next door to mine they study neurodegenerative disease and in particular ALS and we are collaborating with them to use GTEx data from the brain and spinal cord as a reference so that we can compare samples and data from individuals with ALS or Lou Gehrig's disease to the healthy donor data from GTEx.
Interviewer: Shamini Bundell
The GTEx database will undoubtedly have a lot of value to researchers going forward. Other upcoming projects like the Human Cell Atlas will look at the interplay between genes and expression and disease in even more detail. But GTEx has also expanded frontiers in how scientists access this kind of sensitive data.
Interviewee: Tuuli Lappalainen
GTEx is a bit of a unique project in the sense that the GTEx researchers have stayed in contact with many of the donors’ families and discussed with them how they felt about the process and why did they decide to donate so it’s been really rewarding for a researcher to see this side of the process because none of GTEx would ever exist unless these people gave this hugely valuable, generous donation.
Interviewer: Shamini Bundell
And while a tissue donation might not have as obvious an immediate impact as organ donation, the value of the data is clear, not just to the scientists but to the families who have allowed this research to take place.
Interviewee: Jim Walls
So I’m waiting for that discovery where these tissue samples say QED – this causes Parkinson Disease and these genes cause it and this is how we remedy it. Boy oh boy that will be a glorious day.
Interviewer: Charlotte Stoddart
That was Jim Walls finishing up that package, where you also heard from Tuuli Lappalainen and Ewen Callaway in a report from Shamini Bundell. You can find out a lot more about GTEx in this week’s Naturewith a news story, an editorial, a News and Views article as well as all the papers.
Interviewer: Adam Levy
Still to come in the Research Highlights: the sun’s scorching atmosphere and the brain’s waste disposal system. But now… For a number of years, exoplanets have been among the trendiest topics in astronomy. One of the easiest ways to spot an exoplanet is to look for the subtle dimming of a star’s light as the planet passes between it and us. So far, thousands of exoplanets have been discovered. But this trick could also be useful to study objects in our own solar system. If astronomers wait patiently for objects in our solar system to cross in front of stars in the sky, it can reveal all sorts of information about that object. And now a team have done exactly that for a dwarf planet – called Haumea - orbiting the sun beyond Neptune. Jose-Luis Ortiz led the study and was also among the first to spot Haumea, a little over a decade ago. I called him up and asked what we can learn from studying distant dwarf planets like Haumea.
Interviewee: Jose-Luis Ortiz
This subject holds important clues on the formation of the solar system because they are the remnants of the formation of the solar system.
Interviewer: Adam Levy
Now these are objects within our solar system but one of the approaches you used to look at that might sound familiar to people who’ve heard about exolpanet research.
Interviewee: Jose-Luis Ortiz
Yeah the technique is similar to the transit technique used for exoplanet science and in this case what we do is to wait for a planet or a solar system object to pass in front of a star, causing an eclipse, blocking its light – sort of a transit which we can measure with our telescopes so we can determine the length of time that the star was occulted compared to exoplanet transit which are very brief events because exoplanet transits take one or a few hours typically, but this is just a matter of a few seconds – maybe a minute.
Interviewer: Adam Levy
For this technique you don’t just use one telescope, you use quite a few telescopes around the world, right?
Interviewee: Jose-Luis Ortiz
Right. Usually we have uncertainties over where the shadow of the object falls on earth so we have to use several telescopes to make sure that we cover the exact area of the world where this occultation is going to happen. But also we need to determine the length of the occultation from several sites on earth so we that can project those lines on the sky and then derive the exact shape of the body.
Interviewer: Adam Levy
Does it take a lot of planning for one of these eclipses? How often does it happen that a dwarf planet or any other object out there happens to eclipse a star?
Interviewee: Jose-Luis Ortiz
It takes a lot of planning because usually this happens maybe one, two or three times per year so it’s really challenging.
Interviewer: Adam Levy
In this study you were specifically looking at a dwarf planet called Haumea, found a little over a decade ago. What was already known about this dwarf planet?
Interviewee: Jose-Luis Ortiz
Well we knew quite a lot of things. For instance, we knew that it spins very quickly and it rotates around its axis in less than four hours. We knew that Haumea was highly non-spherical. It has a shape which might be similar to a melon or also a rugby ball. We knew quite a lot of things but some of the important stuff was not really well known, for instance like density – so we needed to improve on that.
Interviewer: Adam Levy
So there were some things we knew about this little dwarf planet, some things we didn’t, so you set out to use this approach where it eclipses a star and what did your team find out using this technique?
Interviewee: Jose-Luis Ortiz
We found out that the size of Haumea is bigger than we thought it would be so Haumea turned out to be less dense. This is important but probably the most remarkable finding from our investigation was the fact that Haumea has a ring revolving around and this was quite a surprise because we were not expecting to find a ring system around a dwarf planet.
Interviewer: Adam Levy
You mention that studying objects like Haumea tells us something about the early solar system. Does Haumea specifically tell us anything about where the solar system came from and what its origins were?
Interviewee: Jose-Luis Ortiz
The fact that Haumea has a ring can tell us about the collisional scenarios and the collisional processes that took place in the early processes of the solar system because the ring could have been caused by collisions with Haumea. But this is currently a speculation because so far we cannot really tell what the origin of the ring is.
Interviewer: Adam Levy
How do you feel when you do studies like this, that there’s so much coordination involved that there’s this potential to find out some quite fundamental things.
Interviewee: Jose-Luis Ortiz
Yeah it’s such a huge effort that we get nervous, excited… it’s a lot of fun when you finally find something interesting. Sometimes we have failed and that is also sad. But fortunately in this case, we had huge success and we were very excited.
Interviewer: Adam Levy
That was Jose-Luis Ortiz who's at the Institute of Astrophysics at the CSIC in Andalucía in Spain. Check out his paper in the usual place.
Interviewer: Charlotte Stoddart
Later in the show, we’re looking at mouse ‘avatars’ and an upcoming battle between publishers and ResearchGate. That’s in the News Chat. But now we’re joined by the newest member of the Nature Podcast team, Benjamin Thompson, for this week’s Research Highlights.
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Interviewer: Benjamin Thompson
The sun’s surface is a toasty five and a half thousand degrees Celsius. Strangely, it seems that its own atmosphere is even hotter. The corona can in fact be several million degrees hotter. Gigantic solar flares release a lot of energy from the surface but they’re too rare to explain the corona’s excessive heat. Now, X-ray observations of parts of the sun hint at a plethora of tiny plasma pulses reaching a roasting 10 million degrees. These fleeting Nano-flares which went undetected by regular satellite imaging, could explain the corona’s colossal heat. Hot foot it over to Nature Astronomyto read the full paper.
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Interviewer: Benjamin Thompson
The brain’s waste disposal system has been observed in humans for the first time. Lymphatic vessels, which carry waste products away from damaged tissues were first hypothesized 200 years ago but weren’t actually seen in brains until 2015. And that was in mice. In the new work, researchers were using magnetic dye to study blood vessels in the brains of healthy human volunteers in an MRI scanner. The dye leaked into a neighboring network, illuminating the camera shy lymph-vessels. Tweaking the dye molecules to dim the blood vessel signals enabled the first snapshot of these discreet drainpipes. This technique could help study neurological disorders where waste products might not be suitably washed away. Scan the full paper over at eLife.
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Interviewer: Charlotte Stoddart
This year commemorates the 40th anniversary of DNA sequencing, a technique that has transformed biology. Reporter Anand Jagatia takes a look at how far we’ve come in that time, and what the future of DNA sequencing might hold…
Interviewer: Anand Jagatia
A, T, C and G: letters that represent the base pairs which code for life on earth… DNA. The earliest attempts to read this sequence of letters in DNA molecules were painfully slow. In 1973 it took researchers two years to sequence the gene for a binding site that was a mere 24 bases long. But then, 40 years ago in 1977, two papers were published that gave methods for DNA sequencing, allowing researchers to read hundreds of bases in an afternoon. Since then, sequencing technology has improved at and incredible pace – becoming faster, more reliable and less expensive. And today, the latest generation of machines can sequence an entire human genome, that’s three million bases, in just one hour.
Interviewee: Eric Green
Really over the past decade or so we’ve essentially reduced the cost of sequencing DNA by about a million fold and that has just changed everything in terms of what you can use DNA sequencing for.
Interviewer: Anand Jagatia
This is Dr. Eric Green, director of the National Human Genome Research Institute at the US National Institute of Health. Eric has been working in genomics since 1987 and was involved in the Human Genome Project throughout its duration. He told me that it’s hard to think of an area where DNA sequencing has had a bigger impact than in health and in medicine.
Interviewee: Eric Green
Well in terms of sheer numbers the most widespread clinical applications have been in the arena of prenatal genetic testing for abnormal numbers of chromosomes such as trisomy 21: three copies of chromosome 21, which causes Downs Syndrome. This is a practice that has been going on for many, many years but has previously required invasive methods to access fetal DNA, but these new DNA sequencing technologies are so exquisitely sensitive that they now allow the detection of the small amounts of fetal DNA that float around in the internal bloodstream – in mom’s blood. In fact it’s now estimated that something in the order of 4 to 6 million women who are pregnant will get that test worldwide each year now and it’s expected to grow over time.
Interviewer: Anand Jagatia
This growth in prenatal testing isn’t the only growth in how we do testing. DNA sequencing has also transformed the diagnosis and treatment of cancer.
Interviewee: Eric Green
Cancer is a disease of the genome and so we could use these new methods to sequence the genome of a tumor, of a cancer sample and tailor the care of that patient with that cancer based on what you learned and that will help guide many aspects of the patient’s care. Another exciting development, especially looking towards the future is something that’s referred to as liquid biopsies. In other words if a patient has cancer their tumor will often shed small amounts of its DNA which has some abnormal signatures in it into the bloodstream and so one is now able to sequence the DNA in the blood, looking for signatures of cancer.
Interviewer: Anand Jagatia
In the research arena, as the technology behind DNA sequencing has improved, scientists have become increasingly hungry for sequence data. The Human Genome Project successfully sampled the first human genome in 2003 and since then researchers have gone on to complete the Thousand Genome Project and are soon set to complete the One Hundred Thousand Genomes Project. But generating such vast amounts of sequence data has its problems.
Interviewee: Eric Green
We are now able to generate prodigious amounts of DNA sequence data and then we immediately hit a blockade of being able to interpret it and understand it as effectively as we’re able to generate it. We need very large data sets, not just the genome sequence; we need to know many other aspects of their lives to tease out all the complexities of human health and disease which of course is a choreography between our genome, I mean our blueprint, but also our lifestyle, our environmental exposures, social context and so forth.
Interviewer: Anand Jagatia
But it’s not just in the lab or the clinic that DNA sequencing has changed things. Smaller, cheaper devices have democratized sequencing technology which no longer means it’s just big rich labs who can use it.
Interviewee: Eric Green
There are instruments that are coming online now that can be basically operated with a laptop out in the field to basically look for certain types of microbes. And increasingly as one can imagine as more mobile devices become available and prices go down, maybe people in the food industry will be monitoring specific foods by DNA analysis and so forth. One can imagine using it in your home. There may be applications where you want to read out some DNA in your home for various personal reasons.
Interviewer: Anand Jagatia
These reasons could be very personal indeed. Perhaps you have a DNA sequence installed in your toilet to monitor the health of you and your family in real time. And according to Eric, this could just be the tip of the iceberg.
Interviewee: Eric Green
What is very clear is that we probably can’t accurately predict all the applications for DNA sequencing in the future. One of the analogies I sometimes make is a smart phone. I mean I never anticipated 10 years ago, all the different ways I’d be using a smart phone. I thought it was just going to be used for phone calls. Now I barely use my smart phone for phone calls. I use it for all sorts of other things. I think we’ve already seen a similar circumstance with DNA sequencing.
Interviewer: Charlotte Stoddart
Dr. Eric Green from the US National Institutes of Health talking to Anand Jagatia. You can read a Comment on the future of DNA sequencing technology at nature.com/news. And there’s also a review paper that looks back over the past 40 years of sequencing.
Interviewer: Adam Levy
Time now for this week’s News Chat and Nature’s new European Bureau Chief – Alison Goddard – joins us in the studio. Welcome Alison.
Interviewee: Alison Goddard
Hello.
Interviewer: Adam Levy
So first up there’s been a new look at something called mouse avatars. Now, before we get to what this new study is showing… what is a mouse avatar?
Interviewee: Alison Goddard
I’m afraid it’s rather a grim thing but it’s a mouse which has been edited, has been interfered with in order to mimic a human so that diseases which occur in humans can be implanted into the mouse and their development can then be studied in the hope that that will then then treat disease in humans.
Interviewer: Adam Levy
So what kind of diseases are we often looking at for these kinds of studies?
Interviewee: Alison Goddard
In this particular case its cancer. You have many, many different forms of cancer and what the researchers are doing is removing the cancer from a human being, implanting it into a mouse that’s had its immune system knocked out then watching how that cancer develops in the mouse and then you’re using that information then to tailor the treatment which is given to the human patient.
Interviewer: Adam Levy
It seems like something where there might be some issues. Firstly a mouse is not a human. Secondly, getting rid of the immune system in this way might cause other issues. Were there already concerns that this might not match up?
Interviewee: Alison Goddard
There are always concerns with using animals in these experiments. Clearly it’s an imperfect model but it is also a better model than not having a model but yes, there are long standing concerns with using animals in research and this paper is identifying another one which is that it may be that by implanting the human cancer into the mouse, the cancer is developing in a different way in the mouse than it would do in a human and that’s what this paper is raising.
Interviewer: Adam Levy
So what actually was the discrepancy between tumor development that they saw between these mouse models and between what we’d see in human patients.
Interviewee: Alison Goddard
So in humans who’ve got brain cancer, the tumors tend to gain extra copies of chromosome 7, left untreated. If those human brain tumors are planted into mice, the mice lose those extra chromosome 7s, so that’s a discrepancy between the mouse model and what would happen in a human being.
Interviewer: Adam Levy
Is this difference something that completely derails this approach or are people saying they’re still going to use it and it’s still a useful thing?
Interviewee: Alison Goddard
No it absolutely doesn’t derail this area of research. It does raise a question mark but others are confident that the mouse model, though it’s not perfect, it’s still useful.
Interviewer: Adam Levy
Well, one tool that is certainly useful for researchers across the board is the online website ResearchGate. It’s a very popular tool, not least for avoiding pay walls so that people can often read papers which they otherwise might have to pay for. Perhaps unsurprisingly some organizations are quite unhappy about articles being posted there.
Interviewee: Alison Goddard
Yes and I should say at the outset that clearly I’m employed by Springer Nature and I would also like to say at the outset that yes, Springer Nature, big publisher of journals but the Natureeditorial line is very much independent of Springer Nature, so I just need to clarify that at the outset.
Interviewer: Adam Levy
Thanks.
Interviewee: Alison Goddard
So, yes, so ReseacrhGate… It’s a big publisher of papers. It’s based in Berlin. It’s got 3 million members and has raised more than 80 million dollars from investors including Microsoft founder, Bill Gates, and the Wellcome Trust which is a big UK based biomedical researcher.
Interviewer: Adam Levy
So it’s a very big organisation but they’ve now got some, I suppose, quite powerful enemies.
Interviewee: Alison Goddard
Yes, so what has happened, and it’s been a long time coming. Five publishers have formed what they call a consortium. They are about to imminently send out a batch of take down notices to ResearchGate, asking them to remove some of the 100,000 articles which are currently on the site for reasons of copyright infringement.
Interviewer: Adam Levy
100,000 is a huge number of articles; do we have any idea of what kind of percentage might be infringing on some form of copyright?
Interviewee: Alison Goddard
Nobody has gone through them line by line individually but a spokesperson for the coalition of publishers has estimated about 40% of the papers could be in breach of copyright.
Interviewer: Adam Levy
Is there any room for some kind of compromise for this or is it just ResearchGate want to post these things and these publishers don’t want them to be posted.
Interviewee: Alison Goddard
I think there always has to be room for compromise doesn’t there? So, Springer Nature at least has said that it has been in serious discussions for some times about sharing journal articles with ResearchGate.
Interviewer: Adam Levy
Is it actually ResearchGate that is breaching copyright in this case, or is it the people who are using it who are posting these things.
Interviewee: Alison Goddard
So, ResearchGate sees itself as a platform and says that it doesn’t want people to upload papers for which they don’t own the copyright, however it isn’t individually checking what’s going on in the site so the publishers are saying they need to take more responsibility for what’s being published.
Interviewer: Adam Levy
When do we expect that this will all come to a head? When will legal action formally be taken?
Interviewee: Alison Goddard
We’ve been asking the coalition on a more than daily basis and the answer is always imminently.Interviewer: Adam Levy
Alison Goddard, thank you very much for joining us. For more on those two news stories, go to nature.com/news.
Interviewer: Charlotte Stoddart
That’s all for this week. But if you haven’t already, make sure to check out last week’s Podcast Extra. To celebrate our 500thepisode, it features 8 podcast contributors introducing their favourite pieces since the start of the show, including one of my earliest segments from a full decade ago.
Interviewer: Adam Levy
Give it a listen at nature.com/nature/podcast or on your favourite podcasting app. I’m Adam Levy.
Interviewer: Charlotte Stoddart
And I’m Charlotte Stoddart.
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