NATURE PODCAST

Podcast: Peering into a black hole, the dinosaur family tree, and finding drug combinations for cancer

This week, peering into a black hole, reorganising the dinosaur family tree and finding drug combination for cancer.

In this episode:

0:41 Dinosaur family

New research shakes up the branches in the dinosaur family tree. Research paper: Baron et al.; News & Views: Dividing the dinosaurs

8:28 Capturing a black hole

Astronomers around the world team up to attempt to snap an image of the black hole at the centre of our galaxy. Feature: How to hunt for a black hole; Event Horizon Telescope

14:16 Research Highlights

Ancient algae; and kingsnakes. Research Highlight: Oldest algal fossils found; Research Highlight: Kingsnakes go for the big squeeze

16:01 Cancer combination

Finding successful new combos of cancer drugs. Research paper: Han et al.; Research Highlight: CRISPR finds drug synergy

21:47 News Chat

What does Trump’s first budget proposal mean for research? News: US science agencies face deep cuts in Trump budget

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Transcript

This week, peering into a black hole, reorganising the dinosaur family tree and finding drug combination for cancer.

[Jingle]

Interviewer: Adam Levy

This week, after a century of consensus, the dinosaur family tree gets a shake up

Interviewee: Kevin Padian

A lot of people are going to be very surprised by this result and I think this is wonderful for the field.

Interviewer: Kerri Smith

And, astronomers’ ambitious plan to photograph a black hole.

Interviewee: Heino Falcke

So, you need a pretty large telescope. You actually need a telescope the size of the earth.

Interviewer: Adam Levy

Plus, finding successful new combos of cancer drugs. This is the Nature Podcastfor March the 23rd2017. I’m Adam Levy.

Interviewer: Kerri Smith

And I’m Kerri Smith.

[Jingle]

Interviewer: Kerri Smith

Just before we get started we have a little favour to ask. If you like what you hear in today’s show please vote for us to win the listeners’ choice at the British Podcast Awards. That’s britishpodcastawards.com/vote. Just search for Natureand fill in your name. Right, on with the show.

Interviewer: Adam Levy

Dinosaurs became celebrities in the Victorian era when loads of bones of these strange ancient reptiles were being found and studied. In 1888 Henry Seeley divided dinosaurs into two main groups based, among other things, on the anatomy of their pelvises. There were the ‘bird-hipped’ Ornithischians on one side (things like Stegosaurus, Triceratops and Iguanodons) and the ‘lizard-hipped’ Saurischia on the other (including giants like Diplodocus and teeth-gnashers like T-rex). This basic division is described in children’s books and museum displays across the world. Only now, almost 130 years later is a new paper starting to shake things up. To find out more, reporter Shamini Bundell went to meet author Matthew Baron at the Natural History Museum in London where he gave her a quick tour of one of their most popular galleries.

Interviewee: Matthew Baron

Interviewer: Shamini Bundell

Mathew Baron is, like many of the kids visiting the museum here today, really into dinosaurs. So he’s very familiar with the standard picture of their relationships. But his new research is completely shaking up what’s been a very longstanding and previously uncontroversial family tree. As any textbook will tell you, the Dinosauria are traditionally divided into the herbivorous Ornithischians on one side...

Interviewee: Matthew Baron

Interviewer: Shamini Bundell

Interviewee: Matthew Baron

This very large femur is the thigh bone from a Sauropod dinosaur, one of the long-necked tree-browsers.

Interviewer: Shamini Bundell

…And the famously terrifying Theropods.

Interviewee: Matthew Baron

So we’re now coming up to the very large animatronic Tyranasaurus Rex. It’s a particularly fearsome, two-legged, bone-crunching Theropod.

Interviewer: Shamini Bundell

And while the visiting school kids here at the museum might be mostly interested in the giant animatronic T-rex, if you look carefully you can also find a display showing this basic dinosaur family tree. Carnivorous Theropods and tree-browsing Sauropods, here, grouped under the name Saurischians and the herbivorous Ornithischians over here. Away from the noise of the dinosaur gallery I asked Matt how he ended up questioning this traditional division, especially since his PhD started out focusing only on Ornithischians.

Interviewee: Matthew Baron

While I was looking at all of these early Ornithischians I kept being struck by how unusual some of the elements of their anatomy were. They have lots of features which, when you look at them objectively, are remarkably like Theropod dinosaurs, the meat eating dinosaurs. The only explanation that I’d been given were, ‘oh, these are just coincidences’ and that just didn’t sit well with me.

Interviewer: Shamini Bundell

Matthew and his colleagues decided to step back and analyse lots of different dinosaurs in lots of groups. Many such analyses have been done before but this one was a bit more ambitious. Here’s palaeontologist, Kevin Padian, who wasn’t part of the study team.

Interviewee: Kevin Padian

There have been a lot of studies on the phylogenetic relationships – the family tree – of the dinosaurs but they’ve mostly focused on individual Dinosaurian groups but they haven’t really examined the entire dinosaur tree in such depth. So this analysis has the advantage of using a different and larger set of critters than most previous trees have used. They’ve analysed the characters used by people before and they’re also adding their own characteristics. And this, they think, is getting them quite different configurations… Radically different, in fact.

Interviewee: Matthew Baron

The tree that came out at the end of all of this was strikingly different to what we had been expecting.

Interviewer: Shamini Bundell

Back to Matthew Baron.

Interviewee: Matthew Baron

Our hints at close relationships between Ornithischians and Theropods were proven by the data but it was still quite striking to see and actually no matter what we told the computer programme to search for, how to treat the characters, how to treat the species, it kept producing this shock result which was Ornithischians and Theropods together.

Interviewer: Shamini Bundell

Putting Ornithischians and Theropods together leaves the Sauropods like Diplodocus alone on the other branch. Since the meat-eating Theropods are no longer in a group with the Sauropods, the name for that group – Saurischia – no longer exists in the new tree. And this rearrangement isn’t just about changing some names and re-drawing some trees… it could tell us more about what the common ancestor of all the dinosaurs looked like and it may hint that the almost feather-like spines found on the backs of certain Ornithischians could be closely related to the spines that did eventually give rise to feathers in the Theropods… that’s if other palaeontologists believe this complete shake up. Kevin Padian again…

Interviewee: Kevin Padian

A lot of people are going to be very surprised by this result and they’re going to be shaken up by it. And I think this is wonderful for the field because the importance of this paper is not whether it’s right or wrong, it’s how stimulating it’s going to be for other dinosaur researchers to re-analyse what we’ve got, what we’ve been thinking, how we think we know what we know. People have to take their analyses seriously because they used the same methods as everybody else. You add a few different animals; you add a few different tags and your scheme changes utterly. What does that mean? Does it mean that we don’t know anything? No, it just means that maybe we haven’t been analysing things as fully or comprehensively as we might, or this new analysis could just be way off track… time will tell.

Interviewer: Shamini Bundell

And if time does prove that this 130 year old idea has been wrong the whole time, will the Natural History Museum be updating the display in the dinosaur gallery?

Interviewee: Kevin Padian

Museums tend to be fairly conservative in their exhibits because they don’t like to redo them anymore than they have to. And so I expect that if this analysis stands the test of time, it may be modified a bit itself. It may shake up the existing structure. When the dust settles, then the museums and the children’s books will decide what they want to present.

Interviewer: Adam Levy

That was Kevin Padian of the University of California, Berkeley, who’s written a News and Views on the paper by Matthew Baron who you also heard from and is based at the University of Cambridge. Thanks to Shamini Bundell and the dinosaurs of the Natural History Museum, London, for that report. The paper and News and Views article can both be found at nature.com/nature.

Interviewer: Kerri Smith

Thanks to all the folks recommending us on social media using the hashtag ‘trypod’ – that’s ‘t-r-y-p-o-d’. All this month podcasters and listeners alike are sharing their favourite shows and introducing podcasts to people who didn’t even realise their phone had an app for that. Share the love; recommend you favourite show this month using the #trypod. It doesn’t have to be us but you know, if it is, that’s awesome too.

Interviewer: Adam Levy

What Kerri’s trying to say is that we’re desperate for your approval.

[Jingle]

Interviewer: Adam Levy

Astronomers around the world are teaming up. Eight observatories are joining forces with a single mission. I called up astrophysicist Heino Falcke who’s been involved in this plan since the very beginning.

Interviewee: Heino Falcke

We want to see a black hole. It’s as simple as that. And you want to know how we can see a hole? Well it’s a hole on a dark background – you’re not going to see anything obviously – but black holes are surrounded by a lot of light from matter that’s falling into it. You see, actually, the hole in a ring of fire.

Interviewer: Adam Levy

So it sounds like a fairly ambitious task. How do you actually make this happen and see a black hole?

Interviewee: Heino Falcke

Unfortunately, black holes are very small and compact objects so in order to see an event horizon of a black hole for the very first time you need to be able to see a mustard seed in New York from the Netherlands.

Interviewer: Adam Levy

Could you explain how – how do you actually do this?

Interviewee: Heino Falcke

You need a very sharp image of something and the bigger the telescope the sharper the view. So, you need a pretty large telescope – you actually need a telescope the size of the earth.

Interviewer: Adam Levy

Well a telescope the size of the earth seems like something that would be pretty much impossible to make.

Interviewee: Heino Falcke

I think most people would actually object if you would cover the entire world with a telescope, I agree. So there’s a trick where you combine telescopes distributed over large distances and then you create a large telescope which is, in terms of resolution, the size of the distance between those individual telescopes. So, if you have a couple of telescopes around the world where you record the data and you bring it together then you can actually reconstruct an image.

Interviewer: Adam Levy

Practically, how much of a challenge is it? What are the obstacles to actually making this happen?

Interviewee: Heino Falcke

To combine them all, you have to have good weather at all sites around the world and you need hi-tech digital equipment. We are recording petabytes of data.

Interviewer: Adam Levy

We’ve mentioned that we’re looking at a black hole. Where is this black hole? What black hole are we looking for? Do we know of lots to choose from or is there just one we know should be there?

Interviewee: Heino Falcke

Yeah, in principle there are lots of black holes in the universe. But we also know that the centre of galaxies, they are super massive black holes which are probably the collection of millions, sometimes billions, of stars or black holes and there is one in the centre of our galaxy. That is the closest one and it’s the biggest one in the sky and that’s why you have the best chance of seeing the event horizon there.

Interviewer: Adam Levy

Can you describe what we’re actually hoping to see? Is it going to be a really detailed picture and what will that picture look like?

Interviewee: Heino Falcke

I’m afraid the very first picture will be rather crappy. If you are lucky it will look like a peanut or something like that. The reason is that while this is the largest number of telescopes that has ever looked at these frequencies, it’s still at the edge of what will give us a very good image. However, we think, and we’ve simulated that, if we add multiple observations over a few years, in the end we should be able to get half a ring, a quarter of ring that we could see.

Interviewer: Adam Levy

That was Heino Falcke and joining me in the studio now is reporter Davide Castelvecchi who’s written a Feature this week all about this so-called event horizon telescope. Davide, what are researchers actually hoping to learn from taking a picture of a black hole?

Interviewee: Davide Castelvecchi

In part it’s about making sure that black holes actually exist and work as advertised because there is a lot of circumstantial evidence but so far there isn’t a smoking gun.

Interviewer: Adam Levy

Or a photo.

Interviewee: Davide Castelvecchi

Or a photo. The closest thing to a smoking gun is the gravitational waves that LIGO detected.

Interviewer: Adam Levy

Is it just to check that black holes exist or would having a picture of one tell us something about how they work?

Interviewee: Davide Castelvecchi

If the black holes appear the way that theory predicts then they are the black holes of general relativity. General relativity makes some very, very precise predictions. Any small deviation would be a huge discovery.

Interviewer: Adam Levy

Why is it only happening now? Has the technology only just go to the stage where it’s possible to do this?

Interviewee: Davide Castelvecchi

Yeah, so you need to detect and record data at a staggering rate. We are talking about faster than even the experiments in the large hadron collider. And they will record every little crest and trough of every electro-magnetic wave that arrives at these dishes to a precision of one tenth of a nanosecond.

Interviewer: Adam Levy

So, when do we actually get to see the picture? I know that later this year they’re hoping to run the experiment. Do we then see the output a couple of days later?

Interviewee: Davide Castelvecchi

Even to get to the stage where you see a few pixels, it will take probably a year because first of all they have to take all these petabytes of data through two central locations and then the real scientific work begins of figuring out what the data means.

Interviewer: Adam Levy

I actually asked Heino whether the prospect of having to wait for the results for so long made him at all nervous. Here’s what he had to say:

Interviewee: Heino Falcke

I’ve already been waiting almost 20 years for this. Another 1 or 2 years doesn’t make such a big difference.

Interviewer: Adam Levy

That was Heino Falcke who’s at the Radbound University in the Netherlands. I was also joined by reporter Davide Castelvecchi whose Feature you can find at nature.com/news.

Interviewer: Kerri Smith

Oh my god, it’s the Research Highlights next. From Boston, here’s Corie Lok.

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Interviewer: Corie Lok

In the snake world King Snakes rule. These mighty constrictors attack and kill other snakes – even ones that are bigger than they are. To find out what makes them such successful killers, researchers studied King Snakes and other snakes, comparing the size of their muscles and the forces they use to escape predators and constrict prey. They found that for all snakes, the bigger they got the larger were there muscles and the more force they used to pull themselves away from predators, but King Snakes had much higher constriction power relative to their body weight compared to larger snakes. This superior crushing ability may result from the snake’s distinctive posture during constriction. They wrap their bodies around their victims to form regularly aligned coils allowing them to apply large amounts of pressure. The study was published in The Journal of Experimental Biology.

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Researchers have discovered the oldest plant fossils. The findings suggest that algae might have been some of the first multicellular organisms to live on earth some 1.6 billion years ago. Using 3D X-ray microscopy the team found that the fossils had structures that are characteristic of red algae. Some of these structures may have been used in photosynthesis. The discovery could mean that the first plants might have evolved on earth about 400 million years earlier than previously thought. You can learn more about the work in the journal PLOS Biology.

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Interviewer: Adam Levy

A method based on the CRISPR gene-editing system is helping scientists identify pairs of cancer-killing drugs. Kerri has more.

Interviewer: Kerri Smith

There are lots of cancers for which we have good drugs – drugs that target particular genes or proteins to kill cancer cells, but here’s the first problem… [Drumming] Cancers find ways to resist these drugs. What scientists know they need is a pincer movement: combinations of drugs that act on different bits of the same process or pathway. [Drumming] These combinations are already used in therapy. For instance, one drug could damage the cancer cell and the second could stop it repairing itself. Here’s the second problem. There are so many possible combinations that it’s impossible to do enough experiments to test them all. This week in Nature Biotechnology, one Stanford University group reports the beginnings of a way around this problem. Mike Bassik and his team said to themselves… ‘we want to know how pairs of drugs could help kill cancers. Drugs act on genes so let’s take thousands of cancer cells, pick a different pair of genes in each cell, knock them out and see which cells die.’ [Drumming] I spoke to Mike Bassik about the technique they’ve used and whether they found any promising pairs. So here you’ve used a technique that’s commonly used to find out about the interactions between genes. This is kind of a proxy, right, for how the drugs might act?

Interviewee: Mike Bassik

Yeah, that’s exactly right. Yeah, so I should say we’re making a huge presumption which is that drugs work in a very specific way and target only one gene and of course, as anyone who has worked on drugs will tell you that many times they’re not as specific as one would like. They have many off-target effects but we’re making the assumption that if we target a gene which is itself the target of a drug and we find synergistic interactions between those genes then the corresponding drugs should be synergistic.

Interviewer: Kerri Smith

But if we just go along with your assumption for now… you sort of needed to create these maps first which you did using CRISPR. You had to make these pairs of mutations…

Interviewee: Mike Bassik

Yeah, so what we did was to design a very large pool of libraries of CRISPR guide RNAs that target the targets of FDA approved drugs and then basically stitch them together. We do this on mass so you have one pool that has about 21,000 drug pair combinations.

Interviewer: Kerri Smith

And then you could try and identify these synergistic combinations. And what you’re looking for essentially is for the cells, which are chronic myeloid leukemia cells, you’re looking for which ones are most affected – i.e. which ones are killed best by these combinations.

Interviewee: Mike Bassik

Exactly. The cells that kept the toxic pairs of deletions will drop out of the population.

Interviewer: Kerri Smith

One pair of genes that you found effective are involved in triggering cell suicide and there are already two drugs in different stages of development that target them but presumably for combinations of drugs, even though each drug has individually been approved, you still have to go through clinical trials to use them together in combination?

Interviewee: Mike Bassik

That’s right, although many of them have already been tested in patients, so there’s a huge barrier that’s already been crossed to show that this drug can be used in patients. But then you’re absolutely right; any new combinations would have to be investigated carefully by themselves and FDA approved for any combination.

Interviewer: Kerri Smith

And so next then, it strikes me you could go two ways. You could help test the combinations of drugs that you found looking promising here or you could, I suppose, do the same thing again with all different types of cancer cell.

Interviewee: Mike Bassik

Yeah, so that’s one of the things we’re really excited about for this technology is that we built a set of tools which are highly adaptable and can be used in a range of cancers and we’re doing that right now.

Interviewer: Kerri Smith

Did you find any surprises where you knew that two drugs worked for a different type of cancer but you threw them together here as part of your large screen and you found something working that you didn’t foresee?

Interviewee: Mike Bassik

We found a number of combinations which – if you look at the particular pair of genes that came out – they make pretty good sense, so, two different isoforms of a kind that’s often critically important for driving growth in a number of cancers, and we find if we knock out those two different isoforms and combinations those are highly lethal. The reality is cancers differ enormously in the particular constellation of genes that is required for maintaining their growth and so being able to take a library where you have a lot of likely pairs and scan it across many different cancers, we think should have a lot of potential for finding cancer-specific lethal pairs.

Interviewer: Kerri Smith

Even further into the future one presumes that because every patient’s cancer cells are different you could even take cells from a particular patient and personalise their treatment by running their own cells through some technology like this.

Interviewee: Mike Bassik

Yeah, I think that’s a really exciting possibility and something we’re interested to look into for sure. So having these libraries where you’re targeting combinations of drugs we think should be ideal for actually scanning across patient samples and I think really fantastic work has been done to model patient cancer cells in mice for example, or to grow them temporarily in culture and you can imagine coupling the technology we’ve built with that sort of model to really look for patient specific therapies. I think it will be very exciting.

Interviewer: Kerri Smith

That was Mike Bassik who’s at Stanford University in California and whose paper is in Nature Biotechnologyat nature.com/nbt.

Interviewer: Adam Levy

Only the news to go in this week’s show and last week for the News Chat we spoke about Trump’s changes to the Environmental Protection Agency in the US. Just after the podcast aired Trump announced his first budget proposal. We’re heading over to Washington DC where Lauren Morello is standing by to lay out how Trump’s proposed budget might affect science. Lauren, first of all, how surprising were the announcements in the budget?

Interviewee: Lauren Morello

Trump had signalled that he wanted to cut government spending and he and people in his administration have signalled that they’re not a great fan of research on climate change or environmental regulation but the budget does propose an 18% cut for the National Institutes of Health and I think that really shocked a lot of people. Biomedical research is traditionally a bipartisan thing in the United States.

Interviewer: Adam Levy

18% sounds like an awful lot. Have they specified where that money is going to be cut from or is it just 18% across the whole NIH?

Interviewee: Lauren Morello

So, we’re a little bit in the dark and I’ll explain why. Most presidents, when they first come into office, don’t have time to put together a full budget request. The actual legal deadline is the first Monday in February. So traditionally a new president puts together what is called a ‘skinny budget’ and then a fuller request later. So this is Trump’s skinny budget. I will say that it’s skinnier than most. For NIH it just lists an 18% cut which would take the budget down to 25.9 billion and says that the NIH should reorganise the 27 institutes that make it up and eliminate one of them – The Fogarty International Center. Other than there’s not much detail.

Interviewee: Adam Levy

You mentioned, of course, that it’s not just the NIH that’s getting hit by this. Who’s getting hit the worst?

Interviewee: Lauren Morello

So, interestingly science agencies faired both the absolute best and the absolute worst in Trump’s budget. The smallest cut was to NASA – that would be just under 1%. The biggest cut in the entire budget would be for the Environmental Protection Agency and that would be a 31% cut.

Interviewer: Adam Levy

Climate seems to have been dealt a pretty rough hand across the board, not just in the Environmental Protection Agency.

Interviewee: Lauren Morello

That’s true. At NASA Trump is proposing to decrease funding for the Earth Science Division from 1.9 to 1.8 billion. He’s also proposing a 17% cut at the Energy Department’s office of Science which funds climate and energy research along with some other things. So, as far as we can tell, climate is kind of taking it on the chin. One really clear sign of that, in case the budget document left anybody with any doubts, was comments made by Mick Mulvaney who directs the White House Office of Management and Budget. He was asked at a press conference the day the budget came out about the cuts to climate change and he told reporters, ‘we’re not spending money on that anymore. We consider that to be a waste of your money to go out and do that.’

Interviewer: Adam Levy

Wow. It seems really like there’s fighting talk almost. What’s the reaction been from the research community?

Interviewee: Lauren Morello

I think a lot of researchers are gutted, even if they thought this was coming. I mean, I don’t think this is a surprise to anyone who gets research grants from the EPA. I think the biomedical folks were legitimately surprised because, again, things like trying to cure cancer are usually not seen as political.

Interviewer: Adam Levy

Is there any good news for research funding in this?

Interviewee: Lauren Morello

We’ve heard from some people at NASA who say they’re relieved that this budget is not as bad as they thought it would be – even some people who deal with Earth Science at NASA. The other bright spot is that congress does not seem to be embracing this budget for a variety of reasons. We saw some early statements out the day the budget came out from key players in congress including high ranking Republicans who objected especially to the NIH cuts, others who thought the EPA plan went too far and it really just remains to be seen what congress is going to do with this, because remember, the President makes a budget proposal but congress actually formulates and approves spending bills. And the President needs to approve them before they become law but he can either approve the whole thing or veto the whole thing. There’s no line item veto, so congress is really in the driver’s seat when it comes to spending.

Interviewer: Adam Levy

What would it take for this to not pass congress?

Interviewee: Lauren Morello

Congress is going to start essentially from a blank state when they start drawing up spending bills this year. I think some elements of this are going to make it into those bills. Really the thing to watch for is that Trump is moving the goal posts here. He’s proposing a 31% cut at EPA so if congress only cuts EPA by 5% people are going to be relieved but, you know if this had started with somebody saying we’re going to cut EPA by 5% or 10%, people would be up in arms. I think one thing to watch for is the shifting goalposts.

Interviewer: Adam Levy

It’s quite telling that when I asked you for the best news, the best news you had to offer was that some cuts weren’t as bad as you might have thought.

Interviewee: Lauren Morello

There’s really not much for research in this budget and there are some big question marks still. The budget doesn’t include any proposed spending number or details for the National Science Foundation which is a glaring omission and I think if I worked there I’d be slightly nervous about that. It offers very little detail about the National Oceanic and Atmospheric Administration. It doesn’t include an overall number; it just says that Trump wants to cut the very successful, long-running sea grant programme and will fund the current generation of weather satellites but in the future wants to look to more commercial weather data. I think, you know, it’s not the final word so we’ll see this spring how congress deals with it and how it spools out.

Interviewer: Adam Levy

Lauren, thank you for breaking it down for us. For more on the budget and for other stories head to nature.com/news.

Interviewer: Kerri Smith

That’s all for this week. Come and say hello on social media. We’re @naturepodcast and remember to vote for us: britishpodcastawards.com/vote.

Interviewer: Adam Levy

Backchat is hitting the feed overnight so tomorrow get ready for predatory journals and time crystals. That’s all from us for now. I’m Adam Levy.

Interviewer: Kerri Smith

And I’m Kerri Smith.

[Jingle]

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