Interviewer: Adam Levy
Coming up: a proposal to shake up biomedical research.
Interviewee: Malcolm Macleod
So what this does is it shifts the burden of non-rigorous science from the community to the scientists themselves.
Interviewer: Shamini Bundell
And, a whole new system for controlling gene expression in our cells.
Interviewee: Chuan He
In that second when the students showed me the data, I knew this was a potential paradigm shifting breakthrough.
Interviewer: Adam Levy
Plus some highlights from the meeting of the American Association for the Advancement of Science. This is the Nature Podcastfor February the 23rd2017. I’m Adam Levy.
Interviewer: Shamini Bundell
And I’m Shamini Bundell.
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Interviewer: Shamini Bundell
At our Nature Podcastteam meeting last week we spotted an upcoming feature entitled, ‘A new twists on epigenetics’. It sounded very cool but none of us could guess what it might be about so I rang up Cassandra Willyard who wrote the feature. She started by giving me a quick epigenetics catch up class.
Interviewee: Cassandra Willyard
So, epigenetics is basically the reason that you have the same DNA in every cell but you have more than 200 different cell types, because it’s controlling which genes are expressed and which genes are silenced.
Interviewer: Shamini Bundell
Switching genes on and off is vital for the body to be able to control which proteins are produced in each cell, and therefore how each cell functions. That’s because genes, i.e. our DNA, get copied into RNA which then get used to make proteins. The genes can be switched on and off by chemical marks like methyl groups which bind to specific sections of DNA. They effect which bits of DNA get transcribed into RNA and which don’t.
Interviewee: Cassandra Willyard
So, DNA has a series of chemical marks and these collectively are known as the epigenome and people have known for a long time, for decades, that there are also many marks on RNA. They didn’t really know what these marks were doing.
Interviewer: Shamini Bundell
Although marks on DNA, the epigenome, have been studied for a while, these marks on RNA have only been investigated relatively recently.
Interviewee: Cassandra Willyard
Around 2008, there was a chemist named Chuan He. He was studying enzymes that repaired DNA damage by removing a specific chemical mark from DNA and he wondered if they might also work on RNA.
Interviewee: Chuan He
There are all kinds of modifications people know are on RNA.
Interviewer: Shamini Bundell
This is Chuan He at the University of Chicago.
Interviewee: Chuan He
But in 2008 nobody had thought about that these marks could be dynamic and really could alter gene expression.
Interviewer: Shamini Bundell
Chuan He and his colleagues wondered if the marks on RNA could be important for gene expression just like the marks on DNA are. But how could they investigate this possibility?
Interviewee: Chuan He
Eventually we decided that the key is to discover an enzyme to remove RNA modifications. So imagine if we have a dedicated enzyme; its function is to reverse RNA modifications. That would be the strongest indication that RNA modifications play critical roles in gene expression.
Interviewer: Shamini Bundell
If they could find an enzyme which removed the RNA marks it would mean that these RNA modifications are dynamic rather than fixed and so could change in response to the environment just like the marks on DNA do. Because a lot of RNA and DNA modifications involve the addition of a methyl group, Chuan He looked for a de-methylating enzyme.
Interviewee: Chuan He
So we set out to discover a RNA de-methylation. We were lucky; in the winter of 2010 we found an enzyme called FTO. It’s really a major factor associated with obesity, with diabetes: a fascinating enzyme.
Interviewer: Shamini Bundell
FTO is a very well-known gene because mutations in FTO lead to such major problems. It was already being studied in Chuan He’s lab as part of their work on DNA methylation but no-one had ever considered that it might work on RNA.
Interviewee: Chuan He
What we found is this enzyme is RNA de-methylate. What it does is it removes methylation from RNA. In that second when the students showed me the data I knew this was a potential paradigm shifting breakthrough.
Interviewer: Shamini Bundell
It now looks like Chuan He was right about the significance of that first discovery. Cassandra Willyard explained why this find was so important to our understanding of how our cells work.
Interviewee: Cassandra Willyard
One of the central dogmas in biology is that DNA gets transcribed into RNA and that RNA gets translated into proteins. So if you have some DNA, they can control which genes get transcribed and which don’t. If you have marks on RNA, they can control which transcripts, which pieces of RNA, get translated into proteins or how much protein they make or how long those little bits of RNA stick around – that sort of thing. It opened up this whole idea that maybe it’s this whole new way of regulating gene expression.
Interviewer: Shamini Bundell
Since that first discovery, Chuan He’s lab has figured out a lot more elements of the system. After finding enzymes that removed a particular mark they wanted to know how the marks are placed there in the first place, how he cell then reads those marks, and how the marks can actually change gene expression.
Interviewee: Cassandra Willyard
They found different readers for these and depending on what reader binds to it, it does different things. So, one of the readers appears to affect the stability of the RNA: so how quickly it decays. Another reader appears to affect how much protein gets made. And there’s a third reader that seems to do both those things.
Interviewer: Shamini Bundell
These discoveries of complex systems involving RNA marks led to a whole new field of research, called epitranscriptomics, and this has raised questions for loads of other areas in biology. In particular, there are medical conditions such as those associated with the FTO enzyme that could be affected by RNA marks. And understanding the epitranscriptomic system could even lead to new therapies for some conditions.
Interviewee: Chuan He
It’s been a really exciting time. Every day, or every week, you see a different story come out connecting RNA modifications with a different biological process. And frankly, back in 2010, I realised that it was a paradigm shifting discovery, potentially, back then, but I did not realise the breadth, the broad impact, to almost all biology.
Interviewer: Shamini Bundell
That was Chuan He from the University of Chicago, as well as freelance journalist Cassandra Willyard. Her feature is out in this week’s issue and at nature.com/news. For more on epigenetics, check out the Nature Video, ‘Epigenome: the symphony in your cells’ at youtube.com/NatureVideoChannel.
Interviewer: Adam Levy
Before we continue with the show, we’d just like to issue a quick apology. In last week’s show we misnamed the director and chief curator of the National Churchill Museum. The curator is in fact Tim Riley. Sorry Tim.
Interviewer: Shamini Bundell
Still to come: an eagle-eyed camera and an ancient pregnant reptile. Those stories are in the Research Highlights.
Interviewer: Adam Levy
But first, over the last week the American Association for the Advancement of Science, or AAAS, has been holding its annual meeting. Scientific American’s reporter and podcast host, Steve Mirsky, has been embedded in the meeting. I gave him a call to find out about his highlights and see whether the election of Donald Trump had changed the tone of the meeting.
Interviewee: Steve Mirsky
Yeah, there’s been a lot of discussion about science in this new era and there have been sessions on the role of fact in the post-fact era.
Interviewer: Adam Levy
It sounds very different from the last AAAS meeting that I went to which seemed, not apolitical, but politics definitely wasn’t at the heart of it.
Interviewee: Steve Mirsky
Well politics is never at the heart of the meeting but it always comes up because there are funding issues that are clearly related to politics. One of the sessions I went to was about research into gun violence and how difficult it is to get funding for such research. One of the speakers that I heard, David Hemenway who’s a professor of health policy at Harvard School of Public Health, talked about what an outlier the US is in terms of gun deaths, especially among kids.
Audio Clip:David Hemenway
Since I graduated from college there have been more civilian deaths from guns in the United States than combat deaths in the battlefields in all the wars in the United States’ history, including the Civil War and World War II. Compared to the other two dozen high income countries, kids in the United States are much more likely to die from gun homicide. It’s not 50% higher or twice as high or four times as high… it’s eighteen times higher.
Interviewer: Adam Levy
It paints a really staggering picture but it’s obviously still a very polemic issue in America. Did the response to that talk reflect that deep divide in America?
Interviewee: Steve Mirsky
The response here didn’t because this is an audience of scientists for the most part and the scientists want to be able to get better data and get funding to do this kind of research.
Interviewer: Adam Levy
Last year there was a big buzz about gravitational waves. In fact, the announcement of gravitational waves happened just right at the start of the meeting. Is it still a talking point a year on?
Interviewee: Steve Mirsky
Yeah, most definitely. There were sessions on LIGO here and there were sessions on talking about being able to detect different wavelengths of gravitational waves. And one of the interesting sessions that I went to was given by a young researcher named Sarah Burke Spolaor who is with the National Radio Astronomy Laboratory in New Mexico. LIGO can detect relatively short wave gravity waves that are produced by interactions between objects of about a stellar mass, like our sun’s mass, and what Sarah Burke Spolaor was talking about were PTAs: Pulsar Timing Arrays. So look for really, really long wavelength gravitational waves.
Interviewee: Sarah Burke Spolaor
Just like we can scale the stellar mass black holes that LIGO can detect, Pulsar Timing Arrays will probe the most massive – so the billion to even 10 billion – solar mass binary black holes in the universe. Of course, gravitational waves does not stop at detection. What we really want to do is astrophysics with gravitational waves and use it as a new tool to observe the universe and understand our place in it.
Interviewer: Adam Levy
There’s always plenty at the AAAS meeting on health. Were there any particularly surprising bits of news coming out of it this time around?
Interviewee: Steve Mirsky
I went to a session on medical marijuana and what kind of data we have there and again that’s another area where politics comes into play because it was very difficult in the US for many, many years to do any research on medical marijuana. But in recent years, with the legalisationof marijuana in various states it’s become easier to do the research. And a pain researcher and clinician at McGill University named Mark Ware talked about some of the interesting, cascading effects of legalizing marijuana. He started by talking about a 2014 study in the Journal of the American Medical Association.
Audio Clip: Mark Ware
And they found that there was about a 25% reduction in opioid mortality in those states which had medical cannabis laws compared to those that did not. We’ve seen another type of follow up study looking at patients in dispensaries – this is in Washington – where Kevin Bonacker and his colleagues followed patients, or actually looked retrospectively at patients attending a dispensary and found that over 6 months they were reducing not only their opioid doses but their anti-depressants, their anti-convulsants, their anxiolytic medication. So, again suggesting that patients who are using cannabis are able to, or seem to be willing to reduce the use of their other medications.
Interviewer: Adam Levy
Yeah, it’s interesting to think of all the other knock on effects that might come of this quite big change in legislation. And were there any other pieces of health news coming out of the meeting this year that you particularly took note of?
Interviewee: Steve Mirsky
Yeah, well, there’s a lot of study on microbiomes still and there will be for years to come. One of the speakers was a fellow named Brett Finlay from the University of British Coluimbia and he was talking about the hygiene hypothesis which says that maybe we’re actually too clean in our… especially infants are being raised in environments where they’re not exposed to enough of an immune challenge. Well, I’ll let him say it…
Audio Clip: Brett Finlay
Get a dog. That certainly dogs play in the environment… it’s well known that dogs bring in microbes to the house. I think dogs do two things: they contact environment and they contact the kids.
Interviewee: Steve Mirsky
And the presence of a dog is associated with a lower asthma rate.
Audio Clip: Brett Finlay
The presence of a dog in a house is a 20% decrease in asthma, which is weird because it used to say, don’t have dogs because they’re allergic and they cause more asthma, which is a ‘180’ in that sense.
Interviewer: Adam Levy
Is it still worth doing once you’re in your late 20s or have I missed my chance?
Interviewee: Steve Mirsky
I’m afraid the data isn’t really suggestive of any good effect there as far as I understand it.
Interviewer: Adam Levy
Thank you, Steve. I’ll let you get back to the final little bit of the meeting now.
Interviewee: Steve Mirsky
Thanks very much. Good to talk.
Interviewer: Adam Levy
That was Steve Mirsky on the line from Boston where the AAAS meeting was held this year. For more from Steve make sure to check out the Scientific AmericanPodcast. You can find it at the memorable address scientificamerican.com/podcasts.
Interviewer: Shamini Bundell
Stay tuned for the news on the CRISPR gene editing legal battle, and, a giant fracture in Antarctica. Now though, it’s time for this week’s Research Highlights read by Noah Baker.
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Interviewer: Noah Baker
Researchers have built an eagle-eyed camera. The tiny 3D printed device uses an image sensor just a few millimetres long with 4 different lenses. Each lens is zoomed in a little more than the last so the camera captures 4 images at the same times. It then combines them into 1 image which is more detailed in the middle. This mimics the way that predators like eagles focus their view to help pick out prey. This kind of technology could one day be used in drone cameras. Find that paper in Science Advances.
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A fossil find shows that an ancient reptile gave birth to live young. The 245 million year old fossil was found in China and was identified as a marine reptile called Dinocephalosaurus. And, it was pregnant. Its relatively large offspring was curled up in a very similar way to the embryos of other vertebrates. Live birth has evolved dozens of times in various vertebrate groups but this is the first evidence of live birth in an Archosauromorph, the group which includes crocodiles, birds and other dinosaurs. Read about that ancient mother in Nature Communications.
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Interviewer: Adam Levy
We love hearing your thoughts about the Nature Podcastas much as you love hearing the Nature Podcast.
Interviewer: Shamini Bundell
Hmmm, a bit presumptuous.
Interviewer: Adam Levy
Well they’ve made it this far through the show.
Interviewer: Shamini Bundell
Well, regardless of your opinion of the show, we’d love to hear from you. Mary McCade let us know that the show helps distract her when she’s busy dissecting. Plus, she gets a gold star for spotting our not so subtle nod to Destiny’s Child in last week’s episode.
Interviewer: Adam Levy
To let us know what you think of the show, email us at podcast@nature.com, tweet us @NaturePodcast…
Interviewer: Shamini Bundell
…Or just write a review on your favourite podcasting app. Now, on with the show.
Interviewer: Adam Levy
You shouldn’t trust everything you read in research papers. In the last few years there’s been a slew of replication studies and the results have unsettled scientists. In a psychology replication study over half the findings tested didn’t hold up. And an effort to reproduce cancer studies has returned mixed first results. So that raises the important question: how is research going to improve? Although there’s been plenty of hand wringing, the ideas for reforming research have been few and far between. In this weeks’ Naturea Comment piece comes up with a suggestion: something described as preclinical trials. One of the piece’s authors, clinical neurologist Malcolm Macleod, joined us in the studio to give us a better sense of the problem and his suggested solution.
Interviewee: Malcolm Macleod
Over recent years it has become increasingly apparent that some of the things that we thought we believed, because they came out of laboratory research, have turned out not to be true. There’s a number of examples where drug companies, for instance, have taken things from the scientific literature and said, ‘hey, you know, we could make a drug out of this that could treat some diseases’. But when they do the first step which is trying to reproduce, replicate, those findings in their own labs, they don’t work. Just now, I wouldn’t take a drug to trial on the basis of one or two or even three of four studies.
Interviewer: Adam Levy
So looking at the current situation, how many conclusions are wrong and why are they going wrong in the first place?
Interviewee: Malcolm Macleod
Well that’s the $64,000 question and the answer is that we don’t really know. If you do a back-of-the-envelope calculation and people have tried to do this, so for instance, John Ioannidis has estimated that perhaps as much as 85% of biomedical research is wasted because the answer’s wrong, or the answer’s not relevant, or the work isn’t published. There’s a number of what people have called dubious research practices that people are forced into doing to get the result that they require to get them published. They might repeat the experiment a couple of times until they get the right answer. They might use different statistical analysis, plans, depending on which drops them under the magical ‘0.05’. I’m not saying that any scientist gets up in the morning and decides to go into the lab to do bad research; I’m just saying that this is one of the things that creates the ecosystem, creates the incentive system, which discourages people from doing the highest quality research. So what Doctor Morgan and I were keen to do was see if we could do a bit of brainstorming, a bit of thinking, about what our scientific ecosystem, if you like, would look like that had the opposite effect, that encouraged people to do good quality research.
Interviewer: Adam Levy
In this Comment piece that you are publishing this week, you call for something called preclinical trials. How would this work in practice? What is a preclinical trial and what does it hope to achieve?
Interviewee: Malcolm Macleod
So, the trick is to combine the standards of rigour that we’re used to requiring to demonstrate that a new drug is effective with the scientific flexibility to allow science to still be fun, to allow people to be inventive, to allow them to explore interesting ideas. And so instead of requiring that every part of the story has a result that is statistically significant and holds up, we say, judge the work as a whole. And so for the preliminary experiments, for the experiments done in support of the overall hypothesis, we don’t want to see ‘p-values’, we don’t want to see statistical significance. We want those to be good enough to convince the investigator that there’s something worth looking into, something worth testing. And then they move onto the second stage which is the formal hypothesis testing of the experiment and that goes the other way. So instead of being less rigorous than done at present, it’s much more rigorous. And then they publish all of that together in one paper. So what this does is it shifts the burden of non-rigorous science from the community where it is just now, to the scientists themselves.
Interviewer: Adam Levy
Perhaps a bigger question than how this would work in theory is how we actually get people to use this approach in practice. Are you optimistic that people might adopt this, and how do you think you could encourage them to adopt it?
Interviewee: Malcolm Macleod
At an immediate stage what I’d like to see first of all is journals saying that a paper of this shape would be something that they would consider as a submission. If it was done explicitly in this way, and I’d like funding agencies to say that they thought that this was a tangible and valuable output from a programme of research and might even be prepared to set aside some money, some funds, explicitly to test out whether this system does indeed lead to more generalized – more research.
Interviewer: Adam Levy
Does this just add a lot of extra work for researchers to have to do?
Interviewee: Malcolm Macleod
No, I think that’s exactly the opposite of our intentions. The challenge we set ourselves was to find a system that was not additionally burdensome and we think that this will create greater flexibility in the early stages. It will reduce the requirement for further animals to be used in the early stages. That effort and work can be transferred to the later stages and of course the great advantage is that if we can reduce that proportion of research which it turns out was wasted, from 85% to 65% or 45%, it doesn’t really matter if this new approach takes a little bit more time or is a little bit more expensive because the value of the information that we get out of it at the end will be so much better.
Interviewer: Adam Levy
That was Malcolm Macleod from the University of Edinburgh. Read his Comment piece at nature.com/news. And, speaking of news, it’s time for this week’s News Chat and Heidi Ledford joins us in the studio. Hi, Heidi.
Interviewee: Heidi Ledford
Hi. Thanks so much.
Interviewer: Adam Levy
Now, the patent battle over the famous CRISPR gene editing technique has finally ended. Before we come to the conclusion of this trial, what was the trial actually about?
Interviewee: Heidi Ledford
Well, so there are two groups and we tend to refer to them loosely as Berkeley and the Broad Institute, although there are more institutions than just those two that are involved, but they’re on two teams. And they were fighting over who had rights to key patents that would cover a lot of uses of CRISPR–Cas9 for genome editing, for making changes to the genome. So they were duking it out over patent rights to those key patents.
Interviewer: Adam Levy
And, who won and is it surprising that they won?
Interviewee: Heidi Ledford
Well, so technically the Broad won but that doesn’t mean that it’s over because Berkeley can appeal, for one thing, and even if Berkeley didn’t appeal, whoever wins this fight is going to end up being challenged later on by lots of other would-be patent holders. I’m sure it will end one day but not for a while.
Interviewer: Adam Levy
You look quite fatigued by the whole event.
Interviewee: Heidi Ledford
I think a lot of people sort of have CRISPR patent fatigue on this. There’s been a lot of… it’s very unusual, I think, for academics to be quite as interested in a patent battle as they tend to be in this one, in part because the technology is so interesting and in part because the two teams are these really leading institutions in biomedical research, and some of the researchers involved are household names if you’re a biomedical researcher. So, it’s been a very interesting case but it has dragged on for a while and it’ll keep dragging on. Berkeley can appeal and Berkeley has even said, also even if it doesn’t appeal, it has said that it believes it can still assert its patents over all uses of CRISPR–Cas9 for genome editing. There’s a bit of a division… the Broad definitely has rights to use in eukaryotic cells like plants and animals, humans, so the uses that are likely to be quite lucrative. Berkeley’s patents it’s not as clear – the way they’re written – that they would apply to those uses. So that’s some of the battle but Berkeley was saying that it believed that that patent would hold for those as well.
Interviewer: Adam Levy
Of course it matters a lot to those two institutes. Does it matter to researchers who are using CRISPR in their day to day work in the lab?
Interviewee: Heidi Ledford
Thankfully, no. So for academic researchers it should not matter that much. Both sides – more than these two institutions – but both sides have been freely licensing the technology to academic researchers for some time now. There’s every expectation that would continue. It’s more of an impact for the companies who want to eventually sell some sort of product that they’ve made based on CRISPR–Cas9 genome editing. It’s really interesting: those companies have already lined up to license these patents even though the situation has been very unclear. Berkeley’s patent hasn’t even been granted yet. And then there was this fight going on between the two teams. So primarily it impacts them and how much they’re going to have to pay for their licences and so forth.
Interviewer: Adam Levy
What’s the next thing to watch out for? Will there be a bit of quiet on the legal front or…?
Interviewee: Heidi Ledford
Well we could get a few days of quiet. If I remember correctly I think Berkeley has maybe 60 days to appeal.
Interviewer: Adam Levy
You’re only hoping for a few days of quiet… that’s as optimistic as you can be.
Interviewee: Heidi Ledford
Probably so. If they appeal – quite a few people think they probably will appeal and if they do we should know – I would guess – within the next couple of months. Beyond that, Berkeley still has to get its patent granted as well so we could keep an eye on that and see if it is granted and in what form.
Interviewer: Adam Levy
Let’s turn now to our second story of the week which is a little bit further south, all the way in Antarctica, where there’s some pretty ominous news.
Interviewee: Heidi Ledford
Yeah, it’s amazing to me as someone who doesn’t often cover these sorts of geologic scale events, I guess. But there’s a massive crack; it’s in one of the largest ice shelves in Antarctica called Larsen C. I think the crack is something like 175 kilometres long. It could set loose, eventually, an iceberg that’s twice the size of Luxembourg into the sea.
Interviewer: Adam Levy
So this is the Larsen C ice shelf. Presumably there was a Larsen A and a Larsen B as well?
Interviewee: Heidi Ledford
There were, that’s right. So, Larsen B – if I remember – broke loose in 2002. Larsen A, I believe, was 1995.
Interviewer: Adam Levy
Do these two prior examples give us an understanding of what might happen with C?
Interviewee: Heidi Ledford
They really do. So particularly, I believe, with Larsen B it illustrated this effect where these ice shelves can serve as kind of a cork and once they pop out then the glaciers that are behind them are free to come out into the sea at a higher rate.
Interviewer: Adam Levy
How much do they actually accelerate by?
Interviewee: Heidi Ledford
So the speed at which the glaciers can flow into the sea can increase by up to a factor of 8.
Interviewer: Adam Levy
And in terms of the impact of course, ice flowing into the sea – that implies sea level rise. How big a contribution would the loss of this Larsen C actually have?
Interviewee: Heidi Ledford
So this one would cause… it’s enough for global sea level to rise by about a centimetre. And to put that into perspective, right now global sea levels are rising at about 3 millimetres a year due to climate change and so forth.
Interviewer: Adam Levy
So, a centimetre, it might not sound like a lot but it is actually quite a bit compared to what else is going on right now.
Interviewee: Heidi Ledford
Exactly. That’s quite a bit more than usual.
Interviewer: Adam Levy
Well we’ll have to keep an eye out for what the coming weeks and months hold for Larsen C. Heidi, thanks very much for joining us. For more on those stories and others, head to nature.com/news.
Interviewer: Shamini Bundell
That’s all we’ve got time for this week but keep an ear out for this month’s Backchatwhere we’ll be discussing various news including countries’ climate ambitions.
Interviewer: Adam Levy
And next week we’re bringing you a special show with 3 pieces centered around a common theme. Stay tuned for that. I’m Adam Levy.
Interviewer: Shamini Bundell
And I’m Shamini Bundell.
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