Nature Podcast

This is a transcript of the 4th September 2014 edition of the weekly Nature Podcast. Audio files for the current show and archive episodes can be accessed from the Nature Podcast index page (http://www.nature.com/nature/podcast), which also contains details on how to subscribe to the Nature Podcast for FREE, and has troubleshooting top-tips. Send us your feedback to mailto:podcast@nature.com.

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Kerri Smith: This week reviving Aristotle's reputation as a scientist.

Armand Leroi: I actually think that Aristotle is bigger than Darwin. After all Darwin just gave us the theory of evolution by natural selection which is I agree usually thought to be no small thing but Aristotle gave us science itself.

Thea Cunningham: And efficient genome editing is just like drafting a document.

Feng Zhang: Like the search and replace function that you would find in Microsoft Word.

Kerri Smith: Plus growing more food without ruining the environment. This is the 350th episode of the Nature Podcast, it's September 4th 2014. I am Kerri Smith.

Thea Cunningham: And I am Thea Cunningham.

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Kerri Smith: Aristotle was a star student at Plato's Academy in Athens. When Plato died Aristotle seemed to shoe in for the top job of the academy, but he was overlooked. The job went to Plato's nephew and Aristotle left travelling east from Athens to Lesvos marrying an 18-year-old woman called Pythias and then the story gets a little hard to verify discovering a beautiful lagoon. It was this lagoon that prompted Aristotle to wonder about the natural world. He began his scientific work. Evolutionary biologist Armand Leroi in his latest book dives into Aristotle's life and the lagoon and argues that Aristotle invented science. Noah Baker caught up with Leroi for more. Nature 512, 250–251 (21 August 2014)

Noah Baker: This book is called The Lagoon: How Aristotle Invented Science. Aristotle inventing science is a big claim, you know how, do you back that up?

Armand Leroi: It's a big claim. Science, what is science what do you even begin. I mean you want some sort of definition that embraces everything from coleopterous to, you know, particle physicists but excludes astrologers. It's kind of difficult to pin down. But let's say something like science is the systematic investigation of the empirical world. By that criteria Aristotle is a scientist and he is the first person to do it. Before him there were people who investigated the world in the sense they speculated about it. But they didn't ever get out of their armchairs to actually look to say the way it was. This is all literally armchair speculation. Aristotle says uh-uhh, we need to investigate this and we have to do so by actually getting our hands dirty, building causal models explaining that world. That to me is the core of the scientific activity, the scientific ethos, the scientific attitude and he is the first person to do it.

Noah Baker: And this sort of observation and exploration of the natural world brings us on to the other half of your book's titled “The Lagoon.” Can you tell us a little bit about The Lagoon?

Armand Leroi: It's a magical place. It's a body of water which bisects the island of Lesvos in the Eastern Aegean. And it is where we believe Aristotle actually began his empirical work where he turned away from Plato's concern with metaphysical questions and actually began to get his hands dirty and I don't know if it is exactly where Aristotle began his work. Aristotle doesn't leave us a diary but it's a symbol kind of like what the Galapagos is to Darwin.

Noah Baker: And you talk about this place with a lot of sort of passion and that's because this book is more than a biography. This is your own exploration of the place and the man.

Armand Leroi: Yes absolutely. I first went to Lesvos oh it must be 14 years ago when Greece still had the Drachma, you know, it was poor and cheap and since then it became rich and expensive and now it's poor and cheap again. So I have been at this for a long time going to Lesvos and what I wanted to do was to bring my background as a biologist to Aristotle because the thing is he is a real hands' on man, he cuts up a cuttlefish. And I don't say that the classical philosopher is who read him don't know what they're doing, but if you read Aristotle on cutting up a cuttlefish it's good if you've actually cut up a cuttlefish yourself and you know something about that anatomy and the zoology and I know something about that and so it became a very intensely personal exploration of his world and his way of looking at the world in the place where we looked at it.

Noah Baker: How did you first discover Aristotle, was he always a guiding light, a hero as it were in your scientific work?

Armand Leroi: No I came to Aristotle very late. And that was actually the reason for writing the book. It comes out of the personal revelation. It was in a book store in Athens I found a few of the volumes of Aristotle's works translated into English and not very interesting Aristotle at all, actually I don't know anything about him, not interested in classical philosophy certainly I mean I am a scientist, a evolutionary biologist. Well anyway I take this book down, and opened it up and it's a complete revelation. Aristotle is writing about snails, the insides of snails and cuttlefish and I know exactly what he is talking about and how remarkable after all the guy is writing 2300 years previously. So he spoke to me and then I read the story about the Lagoon and I knew that if I didn't know this story and if he was so great then actually nobody knew this story except for a possibly handful of classical philosophers. My contemporaries don't know this story, so I thought, you know, here's a great story that this has to be told. At least it's better than writing another book about Darwin.

Noah Baker: Yeah, you mentioned Darwin and Darwin has been clearly someone that has really inspired you in the past. Is Aristotle pipping him to the post now?

Armand Leroi: I will run into trouble if I said that were true. But in a way I actually do think it is. I actually think that Aristotle is bigger than Darwin. After all Darwin just gave us the theory of evolution by Natural Selection which is I agree usually thought to be no small thing but Aristotle gave us science itself. Now of course Aristotle's theories especially his notions of how the body work, when considered in detail are clearly wrong after all they run on a four-element chemistry. Right, so if you're trying to do physiology starting off with earth, air, fire and water, it's just not going to take you terribly far. That said he gives a very clear account of how stuff is taken in by animals, transformed, turned to its various ends and then excreted. In other words, he has the concept of a metabolic network and then there's his conception of the soul. Now I know what you're thinking the notion of a soul can have no scientific value whatsoever but that's because we are familiar with the soul as some theological notion but that's not what it is for Aristotle. For Aristotle the soul is the system that keeps a creature alive. It's all wrong, the physiology is wrong, the physics is wrong, the chemistry is wrong' the anatomy is not even that great. He thinks for instance that we've got three chambers in our heart. He seems to have missed the fourth. Never mind, but the structure of the argument is brilliant.

Kerri Smith: That was Armand Leroi talking to Noah. There's soon to be a longer version of that conversation available on the Nature Podcast feed and our website http://www.nature.com/nature/podcast and the book is out now and is called The Lagoon: How Aristotle Invented Science.

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Thea Cunningham: Coming up in the research highlights mysterious moving rocks and a Neanderthal masterpiece. But first being able to edit the genetic code could help scientists study what goes wrong in genetic diseases and even lead to corrective treatments that rewrite mutated genes. Scientists are playing around with the new gene editing technique called CRISPR. The latest effort is a paper in this week's issue and Kerri has been asking the experts where the field is headed. Nature 513, 120–123 (04 September 2014)

Kerri Smith: Nobody would introduce typos to text on purpose unless they were sabotaging your homework but scientists have been trying to put typos in the genome for ages. They'd like to change precise letters of the code and then watch the effects. It could give them a handle on what happened in disease. Here's Feng Zhang, a geneticist at the Massachusetts Institute of Technology.

Feng Zhang: As we sequence a lot of patient or even just individual genomes, we are uncovering a lot of genetic variations, thousands or even millions of them. We don't understand the function of many of these mutations and so being able to very rapidly introduce these different genetic variations within a very controlled genetic background will allow us to start to figure out which one does what.

Kerri Smith: The newest and the most precise method for doing this is called CRISPR. Zhang was one of its creators. He compares it to efficient text editing.

Feng Zhang: Like the search and replace function that you would find in Microsoft Word. So suppose you're typing a document and you made a typo to actually go from a printed copy to the electronic version and make corrections to that typo you would in Microsoft Word type in the search phrase and then you will go in and replace it, that's what CRISPR/Cas9 allows us to do. It allows us to use a short ordinary guide which is basically the search phrase and it will help the enzyme search through the genome and then land to the site where you want to make the change.

Kerri Smith: Traditional gene editing methods are more scattergun, more like inserting the new phrase willy nilly into the document in the hope that in one version you get it to the right place. The reason CRISPR is so efficient might be because it evolved to do this job. It's actually a piece of machinery borrowed from bacteria with the search module and a kill module. Here's George Church of Harvard University.

George Church: CRISPR cuts make double stranded breaks in the mammalian DNA without huge modifications from what it normally does in bacteria that protect them from invading bacterial viruses or phages where it's primary focus is to make double strand breaks in those invading viruses.

Kerri Smith: So, it recognizes a specific genetic phrase and then sends in an enzyme called a nuclease to chop it in half and because DNA has two strands that's the double stranded break. Pioneered in mammalian cells only in the last few years, CRISPR has already been used to edit code in a variety of human and animal cells and even in whole animals. George Church again.

George Church: So, once the RNA-protein armed with the CRISPR host scanned along the 6 billion base pairs of human looking for the right place to cut, it makes a double strand break and then the nuclear cell machinery is waiting for a donor piece of DNA to come along and seal that break.

Kerri Smith: Which brings us to the latest paper. A team at the University of Washington in Seattle used CRISPR to edit the hell out of two genes. The first author Greg Findlay is actually just beginning several years of medical degree and PhD training. So in between running to and from lectures, Greg took the two genes and made all possible changes to their codes to see which mutations cause problems and which were inert.

Gregory Findlay: So, what we are trying to do here is make a process where in a single experiment we can make hundreds or even thousands of mutation and then assess what all of them are doing in the genome at once. The advantage of using the gene editing approach is that we actually make all the mutations at the natural site with the gene live in the endogenous locus it's called.

Kerri Smith: It's like taking this sentence “the cat sat on the mat” and making every possible mutation, “the hat sat on the mat,” “the cat hat on the mat,” “toe cat sat on the mat,” “the fat sat on the mat”, to see if the phrase can still be read. One of the genes they chose, BRCA1 or B-R-C-A-1 is linked to breast cancer. Scientists know that mutations in BRCA1 can cause breast cancer, but they don't know which mutations and there were lots of possibles. This technique could help sort out which ones are which.

George Church: It doesn't necessarily guarantee you know whether a particular real cause will cause cancer and at what rate but, it's a huge step in that direction.

Kerri Smith: Using CRISPR for correcting gene mutations in humans is still a way off. Though it has been used to cure liver disorder in mice and one other gene editing technique has made it into human clinical trials for combating HIV. When Zhang and his colleagues developed the technique these clinical applications weren't far from their thoughts.

Feng Zhang: We definitely thought about the long term potential using these nucleases to actually correct in any mutations. I think that's a very exciting direction forward but there are still a lot of immediate challenges that we need to figure out for example we need to understand how specific these nucleases are. We want to go in the genome and fix the mutation that causes the disease but we don't want to introduce other mutations at the same time.

Kerri Smith: Outside the clinic CRISPR could find totally different uses, Church proposes in conservation. Church imagines a package of genes and CRISPR which he calls a gene drive that inserts itself into the genome of something like a mosquito not only makes it resistant to malaria but also passes that trait on to its offspring.

George Church: Another one that we just published three papers recently on was using CRISPR's as part of the gene drive which you can use to alleviate problems with invasive species or with disease vectors that can spread malaria and other diseases.

Kerri Smith: All this in just a few years. It was only in 2012 after all that CRISPR was first shown to work in human cells.

Feng Zhang: It has been pretty amazing to see how rapidly this technology has been adopted by many, many scientists around the world.

Kerri Smith: Feng Zhang and before him George Church and Greg Findlay. Find Findlay's paper in this week's Nature at the ever obvious link http://www.nature.com/nature.

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Thea Cunningham: There's more than just a podcast from us this week. Check out our newest video all about the Galactic Super Cluster where we live which astronomers have finally mapped. That's over at http://www.youtube.com/naturevideochannel. And if you didn't check out the walking fish video then 400,000 people have beaten you to it, head on over to glimpse that too.

Kerri Smith: Coming up agriculture under pressure. Could more thoughtful methods help feed more hungry mouths but first it's time for the best science from outside Nature. It's Research Highlights read by Noah Baker.

Noah Baker: Some of Europe's oldest art could've been created by Neanderthals. The art isn't exactly a masterpiece just a few straight grooves, carved into the wall of a cave in Gibraltar. It looks a bit like a tic-tac-toe board. Its discoverers are convinced that Neanderthals were behind it because of the age of the sediment they found covering it. It dates to around 40,000 years ago, a good 10,000 years before humans arrived at the cave. If it was a Neanderthal commission, it adds support to the idea that they were capable of abstract symbolic thought. Find the paper in the Journal PNAS. NatureIn a dry lake bed in the mountains in California, rocks have been mysteriously moving. Turns out they're nudged along by large ice sheets. Geologists have long speculated about the wandering rocks in Racetrack Playa suggesting some combination of wind, rain and ice pushes them about. So scientists tagged the rocks with GPS markers. One morning in December last year, pools of ice in the lake started to crack in the sunshine, then a gentle breeze bumped the ice sheets against the rocks, moving them at breakneck speeds for a rock of up to 5 meters per minute. By the end of the winter, one rock had wandered over 200 meters. Find that paper in PLoS One. Nature

Thea Cunningham: Agriculture is under pressure. A growing population and an increasing fondness for animal protein in our diets means it's likely that the demand for crops in 2050 will be twice what it is today. To feed us and our meat habit. In China, yields of crops like rice, wheat and maize are already quite high thanks to green revolution technologies like fertilizers and better crop varieties. But some of this progress comes at a cost to the environment. For instance, nitrogen from fertilizers can run off into rivers. So, a group of researchers looked at farmland across China to see if they could boost yield while staying green. They combined information that farmers always need to consider like the local environment, sowing dates and nutrients and put them together in a methodical way. And it turns out using traditional techniques in the right proportions are all you need. The system increased yields for rice, wheat and maize without any need for more nitrogen fertilizer. I phoned Gordon Conway, Professor of International Development at Imperial College, London to find out more. Nature (2014)

Gordon Conway: We've got to feed the world by 2050, which means probably doubling food production by then and we've got to do it more or less on the same amount of land and with the same amount of water and at the same time, we've got to make it environmentally sustainable. It means, we've got to cut green house gas emissions, we've got to increase natural capital, that means we've got to increase the soil and water conservation of existing soils, we've got to make it more resilient and we have to make it more sustainable. That's a really tall order.

Thea Cunningham: And how has this team produced more grain, but minimized the damage to the environment?

Gordon Conway: Yeah, it's a very interesting experiment. They've conducted over a 150 experiments around the country on wheat and rice and maize. They've taken what the farmers naturally do, as it were and replicated that in one of their plots. They've taken an improved version of what farmers do. They've taken a version, where they apply the highest nitrogen to get the highest yield and then they've done something which they call ISSM - Integrated Soil Crop System Management in which they really have studied the particular crop, in that particular environment and they've done what they regard as being the best that could be done in that environment. The best yield of course comes from applying as much fertilizer as the plants can take up. But the integrated system produces over 90% of the yield of that very high yielding plot and nearly as good as if you just apply a lot of fertilizer.

Thea Cunningham: And how does this compare with current Chinese crop yields?

Gordon Conway: That's what is interesting. The yields that are reported in this paper, the farmer's average for maize in the areas they were looking at is 7.6 tonnes per hectare and that's about the European average. So they were already doing very well because it's a great deal more than the one tonne per hectare that we're getting in Africa and I'm talking to you from Ethiopia. So it's already a quite advanced system, but it's probably not as well planned and as designed as they are doing in their experiment.

Thea Cunningham: How robust is this practice?

Gordon Conway: Well, it's being repeated, in these experiments across China, so this is a quite robust result, but there are two questions. One is exactly how much labour and how much skills go into it. In other words if it's replicable outside of China and the other question is more about sustainability. How sustainable are each of these different systems. There's no mention of as far as I can see of addition of organic matter into the experiment. It could be either manure or it can be waste and I think we all know that applying nitrogen, gives you high yields, but if you want to continue to get high yields sustainably you've got to add organic matter for sustainable, that is long-term yields.

Thea Cunningham: Do these increases in yields that the researchers have seen, does this mean the systems has the potential to meet food demand in China.

Gordon Conway: That's what they've calculated. If farmers could achieve their 80% of the best yields in their experiment by 2030, they could produce enough grain for direct human consumption and domestically produced animal feed by 2030. That assumes you can get all farmers to adopt this and my guess is it's practically feasible under considerable degree of Chinese direction and control of agriculture. It wouldn't' be feasible in Africa, of course because the yields are so low at the moment and I wonder whether it would be feasible in India, I'm not sure. The big question of course in all of this is the huge demand for livestock feed for animals, diets are changing rapidly, places like China, India, Brazil and Korea and so on are consuming large amounts of livestock products and to produce that for the market means you've got to produce a great deal of grain, and that's where increasingly our grain is going to be going into the future. What made me think was that perhaps we need the same kinds of approach and experiments to livestock as these Chinese scientists have done to rice, wheat and maize.

Thea Cunningham: Gordon Conway there. He wasn't involved in the research. But you can find the paper at http://www.nature.com/nature.

Kerri Smith: Finally this week, it's the news chat and I'm joined on the line from San Francisco by our reporter Erika Check Hayden. Hi Erika.

Erika Check Hayden: Hi Kerri.

Kerri Smith: Now you've been doing a lot of Nature's legwork on the Ebola outbreak. We had Celeste Beiver in to tell us about last week's story by you which was efforts to, you know, subdue the outbreak and what's going to happen on that front. Now since then, two papers have been published one in Nature and one in Science. Why don't you tell us about the Nature paper first of all? Nature; Nature

Erika Check Hayden: Sure. So for the Nature paper, the researchers examined a drug that's been really discussed a lot in this current outbreak and the drug is called ZMapp, it's made by a San Diego based company and what it is, is a cocktail of three different antibodies and antibodies are just immune proteins that are found in the body and these are purified forms of those antibodies. And so what the researchers did was they tested these antibodies in monkeys and they found that the antibodies protected the monkeys completely from dying from the virus. The important result from the paper is just that the researchers were actually able to save the monkeys even after the monkeys already had noticeable symptoms of Ebola and this is really important because in the field in an outbreak like this, it's really hard to use the drug to save a life if you don't actually know that the person has already been infected. If they're not showing symptoms like a fever or bleeding under the skin, you wouldn't necessarily know that they needed to be treated with the drug.

Kerri Smith: Encouraging news then from this monkey trial which I guess they'd done before the outbreak really had reached the peak that it's at now.

Erika Check Hayden: That's right and it's just sort of fortuitous that they were able to get these results out now because later this week the World Health Organization is going to be meeting to discuss whether interventions like this might be used in the current outbreak. Now unfortunately, there is no more ZMapp available. The existing supplies of the drug were used to treat seven people who were infected with Ebola in this outbreak. Five of those people did survive and two of them died, but it's really not possible to say very much from that result because the people received different levels of care, they were, you know, one was very old, the others were younger, really without further research, it'll be hard to know how effective this drug could be in people.

Kerri Smith: Right. So they're working now, are they on trying to get the stores of these antibodies and of this drug back up?

Erika Check Hayden: They're working really hard. Obviously they want this drug to be used. It's just not an easy process to make these types of purified antibodies.

Kerri Smith: So that's the Nature paper that came out at the end of last week. In Science, there was also a paper centering on the sequence of the Ebola virus or perhaps we should say viruses by now, virus strains.

Erika Check Hayden: Right. This paper is interesting because it's an example of how with high throughput sequencing researchers can do almost real-time analysis of the way that a virus is changing in the middle of an outbreak. And so the researchers, they were based at Kenema Government Hospital in Sierra Leone which has been one of the, unfortunately one of the kind of focal points of this outbreak and the researchers there in the course of diagnosing patients would draw their blood for diagnostic tests. After the blood was used in the tests, the researchers would collect what was left over, decontaminate it and send it to Cambridge Massachusetts, where it could be sequenced. The really tragic thing about this paper is that six of the co-authors who worked on it died before it could be published. Five of them died from Ebola and one died from a stroke that his colleagues believe was induced by this stress of fighting Ebola. So it really speaks to the toll that this outbreak is taking on the healthcare workers who are fighting it. They were able to collect 99 samples from 78 patients - the first 78 patients that they saw in Sierra Leone during the outbreak. They were able to sequence the viruses from all of these individual people. So what they can gain by looking at this is a really deep and thorough picture of how the virus is mutating as it passes from person to person. One really important thing from this paper is that they were able to confirm that the first case brought into Sierra Leone was likely brought by people who visited the funeral of a person who died from Ebola in Guinea. So they were able to trace that transmission. They were also able to show that the whole outbreak likely comes from one event in which an animal transmitted the virus to a human. So that's important to know that we're not seeing a lot of different transmission events happening during the course of the outbreak. It's also important to know that the virus is mutating again as it spreads from person to person.

Kerri Smith: So taking together these two types of result then because they're quite different papers, we've got the sequencing on the one hand and the experimental drug being trialled very successfully in monkeys on the other hand. I mean, is there any way that these two things mesh together, I mean, is having the sequence information going to be able to make the drugs that we do have the experimental drugs more effective?

Erika Check Hayden: That is the hope. So the researchers behind the sequencing efforts say they want this data to inform in real time, the efforts against the outbreak and the first way they're saying that'll be possible is by checking the sequences of the viruses that are mutating and making sure that the mutations aren't happening in regions of the virus that are targeted by drugs or vaccines or diagnostics. And so far it doesn't seem like that's happening, so for instance the makers of ZMapp have looked at this data and it doesn't seem like it would reduce the efficacy of ZMapp at all, same with the vaccines that are the ones sort of most discussed as possibilities to be used in the outbreak. It doesn't seem like this would reduce the efficacy of those vaccines at all. The virus is mutating in some areas that are targeted by diagnostics that are used in the current outbreak. There's no suggestion yet that this is making the diagnostics less effective, but it is definitely something to keep an eye on.

Kerri Smith: Thanks to Erika Check Hayden and for more all Nature's Ebola coverage is freely available at http://www.nature.com/news and that includes the paper about treating monkeys with ZMapp.

Thea Cunningham: That's all for this week. Next time, the genes that make gibbons so comfortable in the trees. I'm Thea Cunningham.

Kerri Smith: And I'm Kerri Smith.