JoeDeRisi_2006[乔德.里西][解决医学难题].pdf

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1、www.XiYuS锡育软件Thank you.(Applause)How is it,how can we investigate thisflora of viruses that surround us,and aid medicine?谢谢你。（掌声）怎么说呢？我们应该如何来研究 那些围绕在我们身边，又同时帮助医学发展的病毒？962100How can we turn our cumulative knowledge of virology intoa simple,hand-held,single diagnostic assay?我们怎样才能把我们积累的有关病毒的知识 变成简单、可行

2、的方法运用到诊断中去？00:23I want to turn everything we know right now about detectingviruses and the spectrum of viruses that are out there into,lets say,a small chip.我想将所有我们现在已知的有关检测病毒 和病毒图谱的方法 变成，比如说，一块小小的芯片。00:31When we started thinking about this project-how wewould make a single diagnostic assay to scree

3、n for allpathogens simultaneously-well,theres some problemswith this idea.当我们开始思考这个计划时-我就在想我们如何通过一个简单的诊断 将所有的病原体同时检测出来-其实这个想法实施起来有一些困难。00:39First of all,viruses are pretty complex,but theyre alsoevolving very fast.首先，病毒是相当复杂的，同时它们的进化速度相当快。00:49This is a picornavirus.这是一种小核糖核酸病毒00:57viruses:n.病毒病毒;病霉

4、(virus的复数)cumulative:adj.累积的 virology:n.病毒病毒学,滤过性微生物学 hand-held:adj.手提式的,便携式的 diagnostic:adj.诊断的;特征的/n.诊断法;诊断结论 assay:n.化验;试验/vt.分析;化验;尝试/vi.鉴定;经检验证明内含成分 detecting:n.检测;检定/v.发现;探知(detect的现在分词)/adj.探测的 spectrum:n.光谱；频谱；范围；余象 pathogens:n.基医病原体;病原菌;基医致病菌 simultaneously:adv.同时地 First of all:adv.首先 evolv

5、ing:adj.进化的;展开的/v.进化;展开(evolve的ing形式)Picornaviruses-these are things that include the commoncold and polio,things like this.小核糖核酸病毒包括了 普通感冒和小儿麻痹症之类的病症。00:58Youre looking at the outside shell of the virus,and the yellowcolor here are those parts of the virus that are evolving very,very fast,and the b

6、lue parts are not evolving very fast.你们仔细看病毒的外壳 这些黄色的部分 进化得很快，非常快，而那些蓝色的部分则进化得相对缓慢。01:03When people think about making pan-viral detectionreagents,usually its the fast-evolving problem thats anissue,because how can we detect things if theyre alwayschanging?当人们想到制造泛用型病毒检测剂时 病毒的快速演变是个问题，因为我们如何能够对一直变化着

7、的病毒进行检测呢？01:12But evolution is a balance:where you have fast change,youalso have ultra-conservation-things that almost neverchange.但是进化是一种平衡：哪里有快速变化，哪里也会有超级保守-有些东西几乎是不变的。01:21And so we looked into this a little more carefully,and Imgoing to show you data now.所以我们要再看仔细些，现在我要向你们展示一些数据。01:29This is jus

8、t some stuff you can do on the computer from thedesktop.这些东西你在桌子的电脑上就可以完成。01:33I took a bunch of these small picornaviruses,like thecommon cold,like polio and so on,and I just broke themdown into small segments,and so took this first example,which is called Coxsackievirus,and just break it into smal

9、lwindows.我将一些小核糖核酸病毒 如普通感冒和小儿麻痹症等 分割成小的片段，第一个例子是柯萨奇病毒，我将它们放到小玻璃片上，01:36polio:n.小儿麻痹症(等于poliomyelitis);脊髓灰质炎 reagents:n.试剂试剂(reagent的复数)a bunch of:一群;一束;一堆segments:n.片段;段数(segment的复数);积弓形片模型/v.把分割成段;细胞分裂(segment的三单形式)And Im coloring these small windows blue if another virusshares an identical sequenc

10、e in its genome to that virus.然后我将这些小玻璃染成蓝色 如果有另一个病毒有着和那个病毒相同的 基因序列.01:49These sequences right up here-which dont even code forprotein,by the way-are almost absolutely identical acrossall of these,so I could use this sequence as a marker todetect a wide spectrum of viruses,without having to makesome

11、thing individual.这里的序列 顺便说一句，这些序列甚至没有同蛋白质编码-几乎完全与所有这些相同，所以我将这个序列做为一个标记物 来检测更多的病毒，不需要再进行个别实验。01:57Now,over here theres great diversity:thats where thingsare evolving fast.在那些进化迅速的地方 你会看到很大的差异，02:13Down here you can see slower evolution:less diversity.在这里你可以看到缓慢的变化和较小的差异。02:17TED演讲者：Joe DeRisi|乔德.里西演讲

12、标题：Hunting the next killer virus|解决医学难题内容概要：Joe DeRisi hunts for the genes that make us sick.At his lab,he works to understandthe genome of Plasmodium falciparum,the deadliest form of malaria.生物化学家乔德里西讲述了通过DNA诊断病毒（和治疗疾病）的新方法。他的研究可以帮助我们了解疟疾，非典，禽流感-以及日常生活中百分之六十的无法确诊的病毒感染。Now,by the time we get out her

13、e to,lets say,acute beeparalysis virus-probably a bad one to have if youre a bee-this virus shares almost no similarity to Coxsackievirus,现在我们再看看别的，比如说 蜜蜂急性肠道病毒这应该是蜜蜂界中最严重病毒-这种病毒和柯萨奇病毒几乎没有任何相似之处，02:21but I can guarantee you that the sequences that are mostconserved among these viruses on the right-h

14、and of thescreen are in identical regions right up here.但是我可以向你保证在右侧屏幕中的病毒中的 最保守的基因序列 都在相同的区域里。02:32coloring:v.着色(color的ing形式);出现颜色/n.着色;着色剂;配色;天然色;外貌 identical:adj.同一的；完全相同的/n.完全相同的事物 genome:n.基因组;染色体组 sequences:n.数计序列,顺序;继起的事(sequence的复数形式)marker:n.记分员;书签;标识物;作记号的人 diversity:n.多样性;差异 paralysis:n.麻

15、痹;无力;停顿 similarity:n.类似;相似点 conserved:adj.保守的/v.保存;保全(conserve的过去式)right-hand:adj.得力的;右手的,用右手的And so we can encapsulate these regions of ultra-conservation through evolution-how these viruses evolved-by just choosing DNA elements or RNA elements in theseregions to represent on our chip as detection

16、reagents.因此我们可以简述这些进化中的超保守区域-这些病毒如何进化的 仅通过选择这些区域的DNA或RNA片段 作为检测试剂在我们的芯片上表现出来。02:41OK,so thats what we did,but how are we going to do that?那是我们所做的，但我们如何去做呢？02:54Well,for a long time,since I was in graduate school,Ivebeen messing around making DNA chips-that is,printingDNA on glass.很长时间以来，自从我读研究生 我一直在

17、试验DNA芯片-即在玻璃上打印DNA。02:57And thats what you see here:These little salt spots are justDNA tacked onto glass,and so I can put thousands of theseon our glass chip and use them as a detection reagent.你们看，就是这个：这些小的盐点是DNA留在玻璃上的印记，同样我可以在玻璃芯片上放上千个盐点 然后把它们作为检测试剂。03:04We took our chip over to Hewlett-Packard a

18、nd used theiratomic force microscope on one of these spots,and this iswhat you see:you can actually see the strands of DNA lyingflat on the glass here.我们把芯片带到惠普公司，用他们的原子显微镜来观察其中的一个点，你们看到的就是这个：你们能很清楚地看到在玻璃上的DNA链，03:13So,what were doing is just printing DNA on glass-little flatthings-and these are goi

19、ng to be markers for pathogens.所以我们现在所做的就是将DNA打印在玻璃上，那些又小又平的东西是要作为病原体的标记物。03:22encapsulate:vt.压缩;将装入胶囊;将封进内部;概述/vi.形成胶囊 graduate school:研究所,研究院 messing:n.杂乱,弄乱(mess的动名词形式)tacked:水运抢风行驶/五金平头钉 reagent:n.试剂试剂;反应物 strands:n.线;绳索(strand的复数形式)/v.搁浅;使处于困境(strand的第三人称单数形式)markers:n.标记;记分员;书签;马克笔(marker的复数)O

20、K,I make little robots in lab to make these chips,and Imreally big on disseminating technology.我在实验室里用小机器人来制造这些芯片，我真的非常热衷于传播科技。03:29If youve got enough money to buy just a Camry,you canbuild one of these,too,and so we put a deep how-to guideon the Web,totally free,with basically order-off-the-shelfp

21、arts-you can build a DNA array machine in your garage.如果你刚好有钱去买一辆凯美瑞汽车，那你也可以制造一个这个，我们在网站上有个免费的如何做的指南，附带基本的组件订购部分-你可以在你的车库里生产一个DNA芯片机器。03:35Heres the section on the all-important emergency stopswitch.这部分是所有重要的紧急开关。03:49(Laughter)Every important machines got to have a big redbutton.（笑声）每个重要的机器都有一个大的红色

22、按钮。03:52But really,its pretty robust.但真的，非常坚固。03:57You can actually be making DNA chips in your garage,anddecoding some genetic programs pretty rapidly.Its a lot offun.你可以在你的车库里制作DNA芯片，快速解码一些遗传程序。非常有趣。03:59(Laughter)And so what we did-and this is a really coolproject-we just started by making a resp

23、iratory virus chip.（笑声）所以我们做的是一个非常酷的项目 我们是从制作呼吸道病毒芯片开始的。04:06I talked about that-you know,that situation where you gointo the clinic and you dont get diagnosed?我讲的是 你知道，那种情况，你进了诊所，但没有得到诊断。04:13disseminating:v.传播(disseminate的ing形式);宣传;散播 how-to:adj.指引的;解释作法的 all-important:adj.非常重要的;首要的 robust:adj.强健的

24、;健康的;粗野的;粗鲁的 decoding:n.通信解码;计通信译码/v.破译;译解(decode的ing形式)respiratory:adj.呼吸的 diagnosed:v.诊断;被诊断为(diagnose的过去分词)Well,we just put basically all the human respiratory viruseson one chip,and we threw in herpes virus for good measure-好，我们刚好把所有人类呼吸道病毒 放在一张芯片上，然后又加入疱疹病毒以更好的测定。04:19I mean,why not?为什么不呢？04:24

25、The first thing you do as a scientist is,youve got to makesure the stuff works.作为一个科学家第一件要做的事就是 确定你要做的工作。04:25And so we did is just take tissue culture cells and infectedthem with various viruses,and we take the stuff andfluorescently label the nucleic acid,我们所做的就是提取组织培养细胞，用不同的病毒感染它们，用荧光标记核酸，04:28th

26、e genetic material that comes out of these tissue culture来自这些组织培养细胞的遗传物质 大部分是病毒类的东西把它粘在芯片上。04:37the genetic material that comes out of these tissue culturecells-mostly viral stuff-and stick it on the array to seewhere it sticks.病毒类的东西把它粘在芯片上。04:37Now,if the DNA sequences match,theyll stick together,

27、andso we can look at spots.如果DNA序列是匹配的，它们就会粘在一起，我们来看这些点。04:44And if spots light up,we know theres a certain virus in there.如果它们发亮了，我们就知道那有某种病毒。04:48Thats what one of these chips really looks like,and these redspots are in fact signal coming from the virus.那是其中一张芯片的样子，这些红点实际上是来自病毒的信号。04:50herpes:n.皮肤

28、疱疹 for good measure:作为额外增添;另外 infected:adj.被感染的/v.传染(infect的过去分词)nucleic:adj.核的 viral:adj.滤过性毒菌引起的;滤过性毒菌的 sticks:n.棍;树枝;麻骨(stick复数形式)/v.用杆支撑;刺死;插入(stick的第三人称单数)stick together:在一起;团结一致;互相支持 light up:照亮;点亮And each spot represents a different family of virus or speciesof virus.每一个点代表不同的病毒家系 或者病毒物种。04:5

29、5And so,thats a hard way to look at things,so Im just goingto encode things as a little barcode,grouped by family,soyou can see the results in a very intuitive way.要看清它们是很困难的，所以我把它们编成小的条码，按家系分组，这样你可以直接看到结果。04:59What we did is,we took tissue culture cells and infected themwith adenovirus,and you can

30、see this little yellow barcodenext to adenovirus.我们所做的就是提取组织培养细胞，用腺病毒感染，你可以在腺病毒旁边看到这个小的黄色条码。05:07And,likewise,we infected with parainfluenza-3-thats aparamyxovirus-and you see a little barcode here.同样我们用副流感病毒-3感染 它是副粘病毒你在这看到小的条码。05:15And then we did respiratory syncytial virus.然后我们又用呼吸道合胞病毒。05:20Tha

31、ts the scourge of daycare centers everywhere-its likeboogeremia,basically.这是所有日托中心的灾难 大体上说就象是鼻粘膜病。05:23(Laughter)You can see-you can see that this barcode is thesame family,but its distinct from parainfluenza-3,whichgives you a very bad cold.（笑声）你能看到这个条码是同一家系的，但它与副流感病毒-3不同，它会使你患非常严重的感冒。05:27encode:v

32、t.(将文字材料)译成密码;编码,编制成计算机语言 barcode:n.条形码;条码技术 grouped:adj.分组的;化合的/v.分组,分类(group的过去分词)intuitive:adj.直觉的;凭直觉获知的 adenovirus:n.腺病毒 scourge:vt.鞭打;蹂躏;严斥;痛斥/n.鞭;灾祸;鞭子;苦难的根源 daycare:n.日托;日间照管儿童 distinct from:vt.与不同www.XiYuS锡育软件And so were getting unique signatures,a fingerprint foreach virus.所以我们要有独特的标记，每一种病

33、毒都有一种指纹。05:36Polio and rhino:theyre in the same family,very close to eachother.小儿麻痹症病毒和鼻病毒：它们是同一家系的，相互非常接近。05:39Rhinos the common cold,and you all know what polio is,and you can see that these signatures are distinct.鼻病毒是普通感冒，你们都知道小儿麻痹是什么，你们可以看到这些标记是不同的。05:42And Kaposis sarcoma-associated herpes vir

34、us gives a nicesignature down here.和卡波济氏肉瘤相关的疱疹病毒 底端有很好的标记。05:47And so it is not any one stripe or something that tells I have avirus of a particular type here;its the barcode that in bulkrepresents the whole thing.所以不是一条带或是什么东西 来告诉我说这里有一个特殊的病毒；是大量的条码代表整体。05:52All right,I can see a rhinovirus-and he

35、res the blow-up ofthe rhinoviruss little barcode-but what about differentrhinoviruses?我能看到鼻病毒，这是放大的鼻病毒的小条码，那么不同的鼻病毒呢？06:00How do I know which rhinovirus I have?我怎么知道我有哪种鼻病毒？06:06Theres 102 known variants of the common cold,and theresonly 102 because people got bored collecting them:thereare just new

36、 ones every year.已知普通感冒有102种变异，仅仅只有102种是因为人们已经厌倦去收集它们了，每年都有新的。06:08signatures:n.签名;鲜明特征(signature的复数)fingerprint:n.指纹;手印/vt.采指纹 rhino:n.犀牛(等于rhinoceros);钱;现金rhinovirus:n.病毒鼻病毒 blow-up:n.单相交;发脾气;放大 variants:n.计变体;变异型(variant的复数)And so,here are four different rhinoviruses,and and you cansee,even with

37、your eye,without any fancy computer pattern-matching recognition software algorithms,that you candistinguish each one of these barcodes from each other.这里有4种不同的鼻病毒，你可以看到，即使用你的眼睛就可以，而不用任何计算机模式匹配 识别软件，你就可以区分这些条码。06:16Now,this is kind of a cheap shot,because I know what thegenetic sequence of all these

38、 rhinoviruses is,and I in factdesigned the chip expressly to be able to tell them apart,but what about rhinoviruses that have never seen a geneticsequencer?这是某种划算的作法，因为我知道所有这些鼻病毒的遗传序列，并且实际上我设计了芯片 能够明确地区分它们，但对于还不知道遗传序列的鼻病毒怎么办呢？06:27We dont know what the sequence is;just pull them out ofthe field.我们不知

39、道它的序列，那就不要做它们。06:39So,here are four rhinoviruses for which we never knew这是4个鼻病毒 我们对此一无所知，没有人对它们做过测序，你也能看到 你得到了独特的且可识So,here are four rhinoviruses for which we never knewanything about-no ones ever sequenced them-and youcan also see that you get unique and distinguishablepatterns.们做过测序，你也能看到 你得到了独特的且

40、可识别的格局。06:41You can imagine building up some library,whether real orvirtual,of fingerprints of essentially every virus.你可以想象建立一个资料室，无论是真实的或是虚拟的，收藏基本病毒的指纹。06:50distinguish:vt.区分；辨别；使杰出，使表现突出/vi.区别，区分；辨别 barcodes:n.条形码;条码技术 expressly:adv.清楚地,明显地;特别地,专门地 sequencer:n.程序装置,计定序器 sequenced:数计序列 distinguish

41、able:adj.可区别的;辨认得出的;可辨识的 fingerprints:n.法特医指纹(fingerprint的复数)/v.取的指印(fingerprint的三单形式)But thats,again,shooting fish in a barrel,you know,right?但这又是瓮中捉鳖，对吧？06:55You have tissue culture cells:theres a ton of virus.你有组织培养细胞：有大量的病毒。06:58What about real people?那么人呢？07:00You cant control real people,as yo

42、u probably know.你控制不了人，就象你所知道的。07:02You have no idea what someones going to cough into a cup,and its probably really complex,right?你不知道某个人会往杯子里咳出什么东西，它可能非常复杂，对不对？07:04It could have lots of bacteria,it could have more than onevirus,and it certainly has host genetic material,so how do wedeal with this

43、?可能有许多细菌，可能有一种以上的病毒，它肯定有宿主遗传物质，对此我们怎么办？07:11And how do we do the positive control here?我们如何做阳性对照？07:17Well,its pretty simple.非常简单。07:19Thats me,getting a nasal lavage.要是我就做鼻灌洗。07:21And the idea is,lets experimentally inoculate people withvirus so we-this is all IRB-approved,by the way;they gotpaid.这

44、个想法就是我们实验性地用病毒给人们接种，这是经人体实验委员会批准的，他们是拿薪水的。07:23And basically we experimentally inoculate people with thecommon cold virus.简单讲我们用普通感冒病毒 给人接种。07:33cough:n.咳嗽,咳嗽声;咳嗽病/vt.咳出/vi.咳嗽 bacteria:n.微细菌 nasal:adj.鼻的;鼻音的/n.鼻骨;鼻音;鼻音字 lavage:vt.临床灌洗;清洗/n.临床灌洗;洗胃 experimentally:adv.实验上;用实验方法;实验式地 inoculate:vt.医接种;嫁

45、接;灌输Or,even better,lets just take people right out of theemergency room-undefined,community-acquiredrespiratory tract infections.或者更好的是我们把人们 从急诊室解救出来，未明确的群体获得性呼吸道感染。07:37You have no idea what walks in through the door.你不知道什么会从那个门进来，07:44So,lets start off with the positive control first,where weknow

46、the person was healthy.所以让我们以阳性对照开始，我们知道某人是健康的。07:46They got a shot of virus up the nose,lets see what happens.他们的鼻子受到病毒的袭击，让我们看发生了什么。07:51Day zero:nothing happening.当天：什么都没发生。07:54Theyre healthy;theyre clean-its amazing.他们仍然是健康的，清洁的很奇怪。07:56Actually,we thought the nasal tract might be full of virus

47、eseven when youre walking around healthy.实际上我们认为他们的鼻道会充满病毒，即使你是在健康人周围走动。07:58Its pretty clean.If youre healthy,youre pretty healthy.它相当清洁，如果你是健康的，你是相当健康。08:01Day two:we get a very robust rhinovirus pattern,and its verysimilar to what we get in the lab doing our tissue cultureexperiment.第二天：我们得到了很强的鼻

48、病毒模式，与我们在实验室做组织培养实验 得到的非常相似。08:03So thats great,but again,cheap shot,right?很好，这又是划算的作法，对吧？08:10We put a ton of virus up this guys nose.So-我们在这个人的鼻子里放大量的病毒，08:13undefined:adj.不明确的;未下定义的 infections:n.传染病;口腔病害(infection复数形式)start off:出发,开始 similar to:与相似;和相同(Laughter)（笑声）08:15-I mean,we wanted it to wo

49、rk.I mean,he really had a cold.我指，我们希望能这样。他真的感冒了。08:16So,how about the people who walk in off the street?走过这条街的人会怎么样？08:20So here are two individuals represented by their anonymousID codes.这里的两个人各自用他们的身份识别码代表，08:24They both have rhinoviruses;weve never seen this pattern inlab.他们都有鼻病毒，我们在实验室从未见过这种类型。

50、08:26We sequenced part of their viruses;theyre new rhinovirusesno ones actually even seen.我们做了部分测序，它们是新的鼻病毒，没人见过。08:30Remember,our evolutionary-conserved sequences wereusing on this array allow us to detect even novel oruncharacterized viruses,because we pick what is conservedthroughout evolution.记住