Class Supplement, Nature Podcast Digest 2012/03/22

The original script of this podcast: http://www.nature.com/nature/podcast/v483/n7390/nature-2012-03-22.html

The audio file of this podcast: http://www.nature.com/nature/podcast/archive.html

元グリーンピース活動家の研究者が、絶滅したタンパク質を再生し、タンパク質の進化の過程を証明。結果的にインテリジェントデザイン説（自然は偶然に進化してきたにしてはあまりにも巧妙・精緻につくられているため神によるものだとしか説明できないという考え）の論拠も崩した。現在はステロイドホルモン受容体の起源となる６～８億年前のホルモンを再生。これらのホルモンの中には公害に強く反応するものがあり、自然保護活動時代の課題とつながっている。

Helen Pearson: Well, Joe specializes in working out the sequence of ancient proteins, so ones that have been extinct for hundreds of millions of years which he goes and resurrects, so he brings them back to life. So he can study them in the lab.

Helen Pearson: It means he can experimentally test ideas about how these proteins evolved. So, his lab has become one of the leading ones in this field of ancestral protein resurrection and he has used this to workout in great detail, for example, how a hormone and receptor pair evolved to the point where he can actually workout the precise mutations that caused the receptor to switch many millions of years ago from one hormone to another.

Geoff Marsh: And through his work he uses it as a way to, sort of, refute the claims of intelligent design advocates.

Helen Pearson: He didn't set out to refute intelligent design but some of his work has ended up doing so. So, some of these complex systems he worked on and that we heard him talk about have been pointed to by proponents of intelligent design as being so complex that only a divine force could have created them but what Joe does is he goes in and works out in great detail in fact how evolution could have produced these systems step by step. So his work has been taken as a refutation of some of these ideas of intelligent design.

Helen Pearson: Many of his friends and colleagues describe him as very intense and he is in some ways. He thinks very carefully before he speaks. It was a pleasure to spend time with him in his lab – they're just this regular molecular biology lab, but at the same time they have this minus 80 degree freezer which is packed with proteins which were extinct which is kind of mind blowing. And the other thing which makes him very interesting as a person is that he had a very unconventional route into science so long before he was doing ancestral protein resurrection, he worked as an environmental activist for Greenpeace in which he campaigned against the release of toxic chemicals. He dropped out of Yale to go into activism. He didn't even take a molecular biology course until he was 30. So all in all a very interesting person to spend time with.

Helen Pearson: He has been interested in this family of proteins, the steroid hormones receptors for really long time since his Greenpeace days. So, these are receptors that bind hormones such as oestrogens and progesterones and androgens and they're crucial in driving these processes in development and the interesting thing is that particularly one of these receptors, the oestrogen hormone receptors exquisitely sensitive to pollutants as well. So there's an interesting mirror to his former life. So, one of the things he is working on now is looking at the common ancestor of this entire hormone family which is about 600 to 800 million years old and he has resurrected this protein. What's amazing is that he is studying proteins which are hundreds of millions of years old using some of the most sophisticated biochemical techniques you can think of to look at them and he has used this for example to understand how this ancient common ancestor of the family which were sensitive to oestrogens evolved step by step to certain mutations to become sensitive to other hormones.

ＩＣチップならぬ腸チップ：　コイン大の透明ポリマーチップに通した溝の中にヒトの腸細胞をはり、腸内細菌を繁殖させたり、組織を収縮させたりできる。薬品開発への応用が考えられている。

Corie Lok: You can put transistors on a chip, but how about a human organ. Harvard researchers have developed a chip that mimics the structure and physiology of a human intestine. The device, about the size of a coin, is made out of a clear polymer and has two microscopic fluid channels, separating the channels is a flexible membrane covered by human cells that normally line the gut. The researchers could grow a common gut bacterium on this layer of cells and they could even simulate the contractions of intestines by applying suction through two side chambers. The researchers say their device could be used in drug development to screen molecules. We at Nature like this paper because this gut on a chip appears to be a better intestinal mimic than static cell cultures. You can find the paper in the Journal Lab on a Chip. Nature 483, 376 (22 March 2012)

抗生物質を使用しても生き残る菌がいるのはなぜか？大腸菌の場合、抗生物質を使うとインドールという物質による細胞間の連絡が起こる。インドールはストレスに反応する遺伝子を活性化する。この発見は耐性菌研究に役立つ。

Switching our focus to microbiology, researchers have figured out why some bacterial cells can survive the onslaught of antibiotics even though they're genetically identical to ones that die. It turns out that at least in E. coli these so-called persister cells arise because of signalling between bacterial cells, using a chemical they normally produce called Indole. Cells treated with chemical were able to withstand higher levels of antibiotics than untreated bacteria. The researchers found that Indole activates genes that help cells respond to stress. This paper caught our eye because it sheds light on how persister cells come about which is important because these cells have been implicated in chronic infections such as tuberculosis. This paper was published in the Journal Nature Chemical Biology. Nature 483, 377 (22 March 2012)(Cry of an elk)

脳も免疫細胞によって守られている。　マウスの研究で、神経疾患のレット症候群の原因が、免疫細胞起源のミクログリア細胞の不全にもあるらしいことが分かった。レット症候群マウスと免疫不全マウスの症状に共通点があることが発見のきっかけ。レット症候群マウスは骨髄移植によりほぼ完治。ヒトのレット症候群治療に骨髄移植を使うかどうかはメカニズム解明を待ってから。現在、研究はミクログリア細胞の改善方法に向けられている。

Geoff Marsh: Rett Syndrome, a severe neurodevelopmental disease affects as many as one in ten thousand females. They have trouble learning to speak and coordinate their movements. Their growth is stunted and many develop serious breathing problems called apneas. Scientists have thought that these symptoms were due to malfunctioning neurons, but now research in a mouse version of the disease shows that immune cells in the brain may also be involved. These brain immune cells are called microglia, they are macrophages, cells that gobble up cellular trash. Jonathan Kipnis and his team at the University of Virginia have found that replacing the brain's microglia alleviates some symptoms of Rett Syndrome in mice. Ewen Callaway gave Jonathan a call.

Jonathan Kipnis: So the microglia are the macrophages of the brain. Every tissue has its own macrophages. Unlike every other cell in the brain, the microglia are not from the origin or neurons or other glial cells. They are coming from immune progenitors.

Jonathan Kipnis: Well, this goes back to our other work, where we showed the effect of immune cells on brain function and learning and memory and so the idea was because Rett mice manifest many of the symptoms that we see in immune-deficient mice. For instance they're cognitively impaired, they have reduced levels of BDMF which is Brain-derived neurotrophic factor and so we approached, we thought okay, we will just replenish the whole immune system.

Ewen Callaway: Tell me what effects you saw when you gave the Rett syndrome mice a bone marrow transplant from the mice that didn't have Rett syndrome.

Jonathan Kipnis: So, We take a male mouse at four weeks of age and we gave it him a full body irradiation to eliminate their own bone marrow in the immune system and we gave them an infusion of the wild-type bone marrow, in a hope to see a little bit of extension of life and hopefully improvement of some of the symptoms of the disease and then when we looked at mice at 8 weeks of age the mice looked much better than their counterparts which either received their own bone marrow or the intravenous treatments and were about to die and were actually dying and then at 10 weeks of age when most of the control mice have died, those mice with transplantation, they were almost perfectly normal, So the results were beyond and above anything we had expected from this approach.

Ewen Callaway: What about the symptoms? Did the bone marrow transplant correct any of those?

Jonathan Kipnis: Yeah, this is a very good question, so actually yes, apneas were almost completely abolished. So, the mice still have abnormal breathing pattern but there is no apneas and apneas are very severe in kids; so this is very important that the apneas have been eliminated. Also the mice's gait was substantially improved and probably most importantly is their activity in the open field. So usually when you put a sick mouse, red mouse it's not really moving but these mice were exploring and they were moving around. So they were overall looking and feeling better.

Ewen Callaway: Do you have any clues as to how the bone marrow transplant worked?

Jonathan Kipnis: When we did the irradiation in order to clean the endogenous bone marrow in the immune cells, we covered the brains of this mice, so the irradiation does not heat the brain and then we inject bone marrow there was no repopulation of microglia, because the brain wasn't affected by the radiation so there is no place for new cells to get into the brain and to repopulate the brain. So, we know that it's not the peripheral immunity that mediates the effect but rather we need the engraftment of microglia. They maybe, do not make neurons healthy but they make them, they make their environment much healthier.

Ewen Callaway: Could you think your study pinpoints these microglia cells and their role clearing this junk as the cause of Rett Syndrome?

Jonathan Kipnis: I would not claim that the microglia is the cause of Rett Syndrome. It just shows that it supports cells in the brain, the glia cells, even if the neurons don't have normal protein if the support cells are perfectly functioning then you could alleviate many aspects of the disease.

Ewen Callaway: And do you think doctors should look as to whether a bone marrow transplant may help children and adults even with this condition?

Jonathan Kipnis: So, we need to be very cautious when we're talking about moving from the mouse experiment to humans, but I am not sure that I can really if anything but in my mind we need to understand better what are these new microglia doing, .how bone marrow transplantation works, what are the cells that are important to be replaced and only then I think will be ready for the clinical trials.

Ewen Callaway: Are there other ways to make microglia work better?

Jonathan Kipnis: This is exactly where our research is heading right now, is to try understand how can we take a girl's own macrophages of the microglia and make them work better. Honestly as a scientist that's where my hope is. Not as much with the bone marrow transplantation but with now finding drugs that would circumvent the need for transplantation.

動物実験に反対する活動家たちが、北米等への実験用動物の空輸を止めている。この状況が続けば、実験用動物の産出国に研究所が移転し始めることも考えられる。

Richard Van Noorden: This is a new technique from animal activists, antivivisection people who seem to have found a new way to disrupt the transport of primates around the world. Now in the UK last week, it emerged that ferry companies had refused to transport all research animals including mice into the country and we have a wider story looking at disruption to flights around the world from places where primates are bred like Mauritius and China into the places that use them like Canada and America.

Richard Van Noorden: Well exactly, essentially this is disrupting the flow of primates into American labs and what's actually happening right now is a bit of a bottleneck where all the animals are being kept back in their breeding colonies and in the labs at the moment they're not quite feeling the pinch, because they've got a lot of experiments going on. The scientists are very worried about where their primates are going to come from and this isn't just US problem. Air France is facing mounting pressures, the last major European carrier to transport research primates and Air Canada is petitioning the Canadian Transportation Agency for permission to refuse the transport research primates.

Richard Van Noorden: There doesn't seem to be anything specific about the conditions; it's just that animal rights activists say this is a way to stop primate research happening, to stop the flow of primates around the globe. Now scientists say well, you know, our priority is humane treatment of animals and air travel is the fastest and least stressful way of transporting them and the other thing they say , as well suppose we do restrict transport of animals, what's going to happen, scientists will just go to Singapore, India, Malaysia, China, where you can basically drive animals, if you need to transport them which is not as good but you can do it and just do work there where the research is less heavily regulated anyway.

多くのホルモンの受容体となるタンパク質の結晶構造が分析できるようになった。これはノーベル賞レベルの進展。たとえばこの方法を用いて鎮静剤受容器の構造が分かり、薬と反応させることができるようになれば、副作用なしで鎮静効果のみを得ることが可能になる。

Richard Van Noorden: Well, this is a family of really massively important receptor proteins, the G protein coupled receptors which my biological lessons will immediately recognize as ubiquitous, cell surface molecules that basically many things activate hormones, neurotransmitters, smells, light they all do their work in the cell by activating these receptors In fact these are the targets of a third to half of all drugs. But incredibly up until 2007, we couldn't solve any of these crystal structures, because we just couldn't get the proteins to crystallize but then this incredible breakthrough happens and Brian Kobilka lab at Stanford published the first few structures which will probably win the Nobel prize and this week we have reports on two more crystal structures from Kobilka lab and from Ray Steven's group, at the Scripps Research Institute in La Jolla and that means that five of these structures have been published this year and in total we have 14 results, so there is a sudden wave of these critically important proteins being solved.

Richard Van Noorden: Well, the ones this week are the opioid receptors, so these are the targets of drugs like morphine, codeine, pain killing, sedative effects. These receptors basically mediate the effects like analgesia, euphoria sedation. So, we can understand what these receptors look like and have the drugs interact with them and we can work how to design drugs that do the things we want opioids to do without the unwanted side effects. So, we're already seeing for example that these proteins are very sort of large gaping binding pockets which may explain why the actions of opioids can turn on so quickly and be rapidly reversed because many different types of molecules can quickly bind in and out of the pockets.

ニュートリノは光より速くないことが、数メートルしか離れていない別の探知機による測定で確認された。別件だが、ニュートリノを岩盤を通して送受信し、”Neutrino”というメッセージ送信に成功。応用目的はないが基礎研究として重要。

Richard Van Noorden: We have reassuring news and exciting news and the reassuring news is the neutrinos don't travel faster than light as far as we know. We know new results with an Italian experiment called ICARUS and these experiments actually sit just a few meters away from each other talking about the OPERA experiment which last September found that neutrinos travelling from about CERN 730 km all the way to the Gran Sasso laboratory in Italy, travelled 60 nano seconds faster than light would have. Well the ICARUS experiment which is another box shaped detector just a few meters away well that's found that they don't. So it looks like there was some kind of glitch in the original experiment which to be honest we kind of already thought looks like, it's Einstein was right after all and the neutrinos are just travelling as fast as we expected.

Kerri Smith: Now the standard model can breathe a sigh of relief?

Richard Van Noorden: Exactly but in other exciting neutrino news, physicists have successfully transmitted a message from an accelerator to a detector using neutrinos through solid rock. So, that's kind of exciting solid rock in the way you couldn't transmit a message with light but these scientists have used a MINERvA detector of Fermilab and they've spelled out the word Neutrino by sending the neutrinos through the rock. Now this is completely useless. It's great news that we've have underground bunker aligned with the particle accelerator and loads of iron, lead, helium, water and plastic from the detector lying around and it took over two hours to send the message Neutrino but you know they've done it. This is Neutrino communication.

Kerri Smith: Well, here at Nature we love a good proof of principle right even if it is completely useless.

Richard Van Noorden: Exactly, that is the essence of blue sky science.

生態系の音をとり続けている人の話：　自然の音は互いに調和してオーケストラになっており、その中で暮らす人間の生活音も調和している。ある生態系の健康度はその場所を１０秒間録音して分析すれば分かる。更に、ある生態系の開発開始前と一年後の音を比較すると、視覚的には影響がないようでも音声的には大きく変化している。また、生き物の喜怒哀楽的瞬間をとらえることもある。

Bernie Krause: When I first started as a musician of course I was recording natural sounds and kind of decontextualising them abstracting them and taking them out of context and when you fracture the natural world that way you get a very limited perspective of what it shows. And so as I began to record I began to think well maybe there's something else happening here and we have to listen to and I began to record all habitats. Number one it was structured and number two that there were still human groups living closely connected to the natural world who understand this structure and use it as natural Karaoke Orchestra with which they perform. Because of this kind of proto-orchestration we learned our music from them and that's what we got it and we got our music first followed by language. I was sent by the California Academy of Sciences in San Francisco to Kenya to record and it was there that I first heard the organized sound of the natural soundscape.

Bernie Krause: First of all how much noise is there, secondly how the density and diversity of critter life has changed though with time and then the natural soundscape gives us feedback. Because we can then tell how things are changing within a given habitat very quickly by doing a 10 second recording and analyzing that 10 second recording we were able to tell exactly how healthy that habitat is. It's remarkable.

Kerri Smith: Some ecologists are using the method?

Bernie Krause: They are being used to evaluate certain habitats throughout the world and I was the first really to suggest this as a model for evaluation. The organizations that were collecting natural sounds, these sounds were abstracted and deconstructed. There are sounds taken out of context. Now I as a musician think of things in a much larger context. I think of orchestration, I think of the way that instruments fit together and so I came to natural soundscapes with that idea and I thought well how do these critters hear one another if they get in each other's way. Well, in fact they don't. In a healthy habitat they structure their voices in bandwidth that's unique to their particular biological status if would one call it that.

Kerri Smith: Krause has also recorded clips of the same environment years apart to show the difference that humans have had on these natural areas and soundscapes.

Bernie Krause: One of the examples that I use in the book to create animal orchestra is a site that is just a year apart, a year before and then after selective logging took place, a place called Lincoln Meadows. It's about a four-hour drive from east of San Francisco. In 1988,I went there to record and I was told by the logging company that selective logging, a new model for logging would have absolutely no effect on the biosphere. The sound is always under the radar where a visual culture in the west. However sound tells a very different story. You know a picture is worth a thousand of words but a soundscape is worth a thousand pictures.

Bernie Krause: Well, the most remarkable sound I have ever heard recorded by a colleague Curt Olson is the sound of a wounded beaver. Curt had been recording at this lake in Minnesota from many, many years and he always recorded there because there was a beaver dam at the outlet. Three springs ago he was recording there and a couple of hammock wardens came to the pond and stuck some sticks of dynamite down the dam and blew it up, destroying the female and offspring that had just been born and Curt captured that night the sound of this lone male beaver swimming in circles around this pond looking for its mate. It's the saddest sound I've ever heard.