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我很高兴能来到艾莫利大学 I'm delighted to be here at Emory
而且很荣幸能够以教职工演讲者的身份 and it's an honor to participate in this marvelous lecture series
参与到这个很棒的系列讲座中 as a faculty lecturer
今天我要向大家汇报我个人的…… I'm here to present an individual...
或者说用半学术的视角 or say a semi-scholarly perspective
探讨一下此次讲座的选题 of my selected topic
对药物治疗的探索 which is the search for pharmaceutical remedy
在开始之前 but before I do that
我想花几分钟简单介绍一下 I wanna spend a few minutes sketching the larger outline
艾莫利大学神经科学创新计划的概况 of Emory's neuroscience initiative
估计大多数在座的人都知道 so the Neuroscience Initiative
神经科学创新计划 as probably most people here know
是由詹姆斯·瓦格纳校长领导的 grew out of a strategic planning process
战略计划发展而来 led by president James Wagner
目前有很多从事神经科学研究的教职工 and currently encompasses the efforts
参与到其中 of a large number of faculty neuroscientists
具体人数目前还无法确定 the exact number is still pinning down
但是…… but it's...
根据海顿的调查 based on Heiden's efforts
人数肯定超过400 certainly more than 400
考虑到艾莫利大学 it's a really significant number of faculty
只是一个中等规模的学校 given especially Emory is not...
这个数字的确很可观 it's a medium-sized university
这个计划包含了 and this initiative encompasses
现行的几个重要项目 我都在这里列举出来了 several strong existing programs which are illustrated here
包括一个研究生培训项目 including a graduate training program
目前该项目中大约有将近 that currently trains approximately
100位博士和医学博士研究生 100 PhD and MD/PhD students
还有大约250名参与培训的教职工 and has around 250 training faculty
此外还有一个保罗·雷纳带的 there is a very successful undergraduate major
非常成功的本科专业 led by Paul Lerner
该专业目前有大约350个学生 that currently has about 350 undergraduates in the pipeline
还有一个建立在学院基础上的 there is a college-based
心灵 大脑与文化中心 Mind, Brain, and Culture Center
目前也在积极地发展 which is currently under active development
另外还包括重要的临床研究工作 and there is a substantial clinical effort
这些临床工作都下属于神经科学综合研究中心 subsumed under the rubric of the Comprehensive Neuroscience Center
该中心又被亲切地简称为CNC or affectionately referred to as CNC
它下面又能分出许多特定疾病的研究中心 which is home to a number of disease-specific centers
幻灯片的字体有些小 we get a little bit thin on top up there
其中有阿伦·列维领导的老年痴呆症研究中心 but the ADRC led by Allan Levey
神经再造中心 the Center for Nerve Regeneration
富科晚年抑郁症研究中心 the Fuqua Center for Late-Life Depression
帕金森症研究中心 中风研究中心 the Parkinson Center, Stroke Center
睡眠研究中心 Sleep Center
学校级别的心理分析研究所 Psychoanalytic Institute which is actually university-based
还有脑肿瘤研究中心等 and the Brain Tumor Center as well as others
神经科学综合研究中心大力致力于 the Comprehensive Neuroscience Center is home to a substantial effort
通过转化型研究 that is directed towards translational research
利用基础神经科学的最新进展 harnessing some of the recent advances in basic neuroscience
开发亟需的 to develop needed therapies
治疗脑和脊髓疾病的方法 for diseases of the brain and spinal cord
我待会儿要介绍的的个人看法就是 and the individual perspective that I will present in a few moments
针对这个领域的 lies in that zone
这张幻灯片也描述了 this slide also depicts the relationship
艾莫利大学神经科学计划 between Emory's Neuroscience Initiative
与区域内重要的学术机构的关系 and importantly regional academic partners
特别是乔治亚理工学院 莫尔豪斯学院 in particularly Georgia Tech, Morehouse
乔治亚州立大学 and Georgia State
它们由国家科学基金会资助的 that in part have been linked through the NSF-funded
行为神经科学研究中心即CBN联系起来 the Center for Behavioral Neuroscience, CBN
该计划还与艾莫利地区的医院 as well as important partnerships
和其它医院建立了重要的合作关系 with Emory's and other hospitals
其中包括亚特兰大儿童医院 including Children's Healthcare Atlanta
这个计划的名称是 the title of this initiative
我把它打到上面了 which I put up there
它的正式名称是 formal title is
神经科学 人性和社会 Neuroscience, Human Nature, and Society
我认为这个名称非常好 it's in my view a marvelous title
它是从一个基于社区的方案发展而来 it grew out of a community-based planning effort
早在我来这里之前就存在了 that predated my arrival here
它的发展是由阿兰·沃克和阿伦·列维带领 and this effort was led by Alan Walker and Allen Levey
它的名称揭示 this title telegraphs the intended
它是一个宽领域 包容性的计划 very broad and inclusive scope of the initiative
许多人都为了完善它的宗旨 a number of people have been working
而付出了艰辛的劳动 to refine the mission statement
我认为现在它的宗旨目标定得很好 which currently I think is at the excellent state
能够体现出它宽广的雄心和远大的目标 that captures this broad ambition and scope
我们艾莫利人认为这个计划 so we at Emory see our initiative
是要为理解人类的心智做出独特的贡献 as dedicated to making our contribution to understanding the mind
这具体意味着 and that means specifically
它以大脑为出发点 its emergence from the brain
研究如何通过神经网络 how you get from the web works
钠通道 还有细胞膜等等 the sodium channels and membranes and all of that
最后抵达神奇的人类心智 to the marvelous entity the human mind
但这个计划不仅如此 but it's not just that
如果只是这样就是神经生物学了 that's neurobiology
这个计划超越于此 the initiative goes beyond that
它致力探究人类心智的本质 to ask questions about the fundamental nature of the human mind
其目的不仅仅是为了纯知识的积累 and it asks that not just for the purposes of pure knowledge
纯知识当然很重要 which are strong purposes
但是更重要的目标是贡献社会 but also for the purposes of contributing to society
这是为了强调这个宗旨 so that's emphasizing the statement
具体来说就是为大众健康服务 and specifically society's health
我们在这里就是尽我们所能 and we are here to do our part
支持艾莫利大学的教学任务 to support Emory's teaching mission
当今人们跨进了日新月异的跨学科研究时代 now we are in an increasingly interdisciplinary time
重要的科学发现在不同学科的合作下 where important discoveries are emerging routinely
层出不穷 鳞次栉比 at the interfaces between established fields
神经科学也是如此 this is certainly true in the neuroscience
我们已经能够从系统的层面 we are beginning to learn enough about the brain and the mind
从分子的层面 神经回路的层面 at a system's level, at a molecular level
认识我们的大脑和心智 at a circuit level
并已经就人类成就的其他领域 to begin to gain useful insights
取得了一些有用的见解 into many other areas of human endeavor
包括传统的人文社会学科的领域 including in the traditional social sciences and humanities
神经科学创新计划的使命就是 The mandate of the neuroscience initiative is
沟通和连接起 to bridge and to crosscut
神经科学领域内各个模糊不清的边界 towards the attractively fussy boarders of the neuroscience field
作为对这项探究的支持 in support of the inquiry
神经科学创新计划不应该成为未来的事情 The neuroscience initiative should not be tomorrow's silo
而是需要和艾莫利大学其他的单位 but needs to work in partnership with the other components
合作努力 of Emory university
特别是和其他重要的战略创新计划 and in particular with the other major strategic initiative
包括伦理学研究中心 which are illustrated here
我把它们都列举在上面了 as well as the Ethics Center
我愿意把这些研究中心比作 metaphorically I'd like to think of these as analogues
理查德·费曼所说的的电子云 to Richard Feynman's electron cloud
所以可以把这个计划的目的理解为 so one way of saying what the initiative is here to do
通过与其他创创新计划的合作 is here to leverage existing resources
把现有资源进行集中进行战略投资 and to identify high-impact areas for strategic investment
以形成一种积极而无缝的合作关系 in a dynamic and seamless partnership with the other initiatives
我们对大脑了解得越深刻 as we learn more about the brain
我们对自身观念的大脑基础 即自我与他人 we learn more about the brain basis of our concepts
就会有更深的理解 of us versus them
我们也就能更深入了解根植于人类大脑中 we learn more about our innate spirituality
与生俱来的精神性 which is hardwired in the human brain
以及人类的同情 利他 as well as our capabilities for empathy for altruism
以及亲社会行为的能力 for pro-social behaviors
和与之相关的 and related to that
我们也会更深入认识人类的是非观 we learn more and more about the human sense of right and wrong
以及这种观念是怎样在社会中 and how that becomes systematized
以及在我们对伦理和法律的理解中 into our social systems
慢慢地系统化的 and into our understandings of ethics and law
当然神经科学 Of course the neurosciences would be
通过神经科学综合研究中心的工作 through the Comprehensive Neuroscience Center
会成为其他健康创新计划的重要助手 a key partner for the other health-based initiatives
神经系统疾病不仅仅是美国要面对的问题 diseases of the nerve systems are not the problem in the United States
它们是一个全球性问题 they are major world-wide problem
世界卫生组织曾经做过一个全球调查 and in fact when the World Health Organization did a survey
调查人们被疾病掠走的时光 of years-lost-to-disability across the world
调查结果的前10种 their top ten list of disorders
剥夺人们健康和幸福的疾病中 which created this loss of human health and happiness
好几种都是神经系统疾病 included several diseases of the nerve systems
实际上排位前10的疾病中 in fact six of the top ten
有6种都是神经系统病 were diseases of the nerve systems
其中抑郁症排在第一位 with depression far and away on the top of the list
当然医疗保健的目标 Of course the goal of all health care
不仅仅是有病治病 is not just to treat diseases when they occur
还应重在预防 but to keep people healthy in the first place
预防工作上 and that would be something
我们很愿意与防治创新计划联手合作 we will eagerly join forces with Predictive Health Initiative
最后我想介绍一下 and finally I wanna illustrate the potential
在神经科学计划 just a comment or two
与计算机生命科学计划强强联合后 for a very powerful bi-directional partnership
将会带来的非常强劲的潜力 between the neuroscience initiative
我只简单的介绍几句 and the Computational Life-Science Initiative
非常明显 it's intuitively obvious that
要进一步了解大脑怎样工作 learning more about how the brain goes about
需要计算机的参与 is computing tasks
反过来这也会为开发更先进的计算仪器 might be useful and providing insights
提供有益的洞见 in how to build better computational devices
对于神经科学领域之外的人来说 may be a little less obvious
这一点或许有些难以理解 to people outside the neurosciences
这也是一种研究方向 it's the other vector
随着设备运算能力的不断提高 which is the ability of increasingly powerful computational devices
计算机会成为大脑活动建模的平台 just serves as platforms for modeling brain function
并用于检验关于大脑如何工作的理论 and testing concepts about how the brain actually works
当前我们就有一些很好的例子 good examples of this at present
比如瑞士的深蓝大脑项目 can be found in the Swiss-based Blue Brain Project
深蓝是指IBM公司的深蓝计算机 and the Blue comes from IBM blue
这个项目与IBM合作 its partnership with IBM
试图用软件建构出 that's attempting to construct
一个虚拟的大脑 essentially a software version of a brain column
还有杰拉德·艾道曼的很了不起的成就 Gerald Edelman's beautiful work
就是模拟出丘脑皮层系统 modeling thalamocortical systems
还有杰夫·霍普金斯卓越的假设 or some of Jeff Hopkins' brilliant hypothesis
他提出 大脑如何完成模式识别 around how the brain goes about achieving pattern recognition
然后对该模式进行分层处理 and then hierarchical processing of this pattern
这样许多事件 so that many things
可以在低水平的大脑回路上得到处理 are handled at low levels of brain circuits
而那些在低水平大脑回路上 and only the things that don't quite make sense
难以处理的事件 at lower levels of brain circuits
会逐渐上升到高层次大脑回路中处理 get bumped up to increasingly higher levels of brain circuits
最终到达我们的意识 and finally even our "consciousness"
这些都是两个学科的合作 these are samples to the future
组成的具有巨大潜力的例子 of this potentially very powerful partnership
现在我就谈谈我自己的任务 So now to my own individual task
我们把视线缩小到…… and we are gonna cone down...
还记得那张图吗？ remember the map?
现在开始聚焦到…… zooming in now...
转换与…… translational and...
具体点说 now specifically
我花费精力研究的课题是 the thing I spend some my own time thinking about
药物开发 which is drug development
我想把这个课题 and I would put it in the context
放到大脑本身这个背景下来讨论 of thinking now about the brain itself
而大脑仅仅是一只三磅重的大脂肪团 which is a rather unassuming three-pound lump of fatty tissue
令人惊奇的是 and it is truly stunning that
人类的智识 our intellectual being
也就是 我们的本质 或理想的本质 all that we really are or hope to be
就存在于这块三磅重的脂肪团里 somehow resides in this three-pound lump of fat
当一个人的大脑运作时 wonderful things happen at the individual level
就会创造出美好事情来 when these brains function
同样 当几个大脑合作 wonderful things happen at the group level
也会创造出伟大的事情 when several brains get together
但是不幸的是 but unfortunately
这块三磅重的脂肪团很脆弱 this three-pound lump of fat is very fragile
容易受到各种疾病的伤害 and subject to many, many disorders
这一点单在美国国内的统计数据中就能体现 and that's captured in this single US-based statistics
我还会让大家看看世界数据 I'll give you a glimmer of world-wide impact
但还是先看看限于美国的数据吧 but just look at it at a US-centric level
神经系统疾病是目前美国国内 nervous system diseases are today the leading cause
造成住院治疗和成人残疾的罪魁祸首 of hospitalization and adult disability in the United States
折磨着1亿美国人 affecting 100 million Americans
每年造成的经济损失 and costing over 600 billion dollars annually
高达6000亿美元 taking that out of our economy
这是个很大的影响 This is a rather large impact
从有记录的历史以来 so since certainly recorded history
很有可能从人类诞生以来 and very likely back to the origin of our species
人们就不停地尝试治疗 people have been interested in trying to treat
大脑和心智的问题 problems with the brain and the mind
如果回到古代 If one goes back to ancient times
回到有记录历史的最初时期 really at the very beginning of recorded history
是可以找到清楚的记录的 one can find clear records
记录当时的人类就使用了许多草药 indicating the use of a number of medicines in plant form
包括尼古丁 咖啡因 吗啡 麻黄和可卡因 including nicotine, caffeine, morphine, ephedra and cocaine
而且这只是有记录的历史 and very likely that's just recorded history
是苏美尔人和古希腊人流传下来的历史 back to the Sumerians and ancient Greece and all that
我们完全有理由认为 there is every reason to believe that
人类有史以来就在不停地寻找 humans have always tried to figure out ways of remedying
治疗各种大脑和心智疾病的方法 the many ways that the brain and the mind go south
比如大脑疲劳了 that three-pound lump of tissue fatigues
大脑变得悲伤了 抑郁了 that three-pound lump of tissue gets sad and becomes depressed
这个三磅重的组织团 that three-pound lump of tissue
在变老后 会混乱不清 if it gets older, gets plex and tangled
失去认知能力 and loses its cognitive ability
或者丧失了它 or that three-pound lump of tissue
控制移动系统的能力 loses its ability to control its motor system
这样就会造成身体僵硬麻木 and people freezes up and get stiff
或者大脑的某些部分不听使唤 or parts of that tissue start sparking on their own
就会引起癫痫病 and generating epilepsy
或许从人类诞生以来 people have been working empirically
就不停地通过经验在尝试试图治愈这些病症 probably since the origin of the species to ameliorate these conditions
艾莫利大学里的很多人 now there are people in Emory
在这一点上都比我更有见解 who know much more about this than me
他们提出的一些东西使我很感兴趣 but I've been intrigued by even some suggestions
比如一些灵长类动物 that non-human primates
已经能够凭借经验 has made use of empirically
使用一些原生药物进行治疗 derived medicinal therapies
我是从霍夫曼那里知道这点的 I found this note from Hoffman
他观察到一只黑猩猩咀嚼斑鸠菊树枝干 who observed a chimp chewing on a vernonia tree
而那其中就含有一种物质能够杀死体内寄生虫 which apparently contains a substance which is anti-parasitic
霍夫曼认为 and makes several arguments
黑猩猩吃那些枝干不是为了填饱肚子 that wasn't a food-use of that pith
而是为了治疗 but really a medicinal purpose
所以如果这些记录…… So if those kinds of records...
如果说对这些观测到的现象的解释是正确的 if those observations are interpreted correctly
那么毫无疑问 it's then unquestioned
从古代开始人类就在凭借经验尝试寻求 that human have sought on an empiric basis treatments for disorders
治疗疾病的方法 since the origin of the species
所以我们将那一时代称为古代 so we call that the ancient times
对它还有一种称呼 草药时代 there is another way to call it the age of the plant
或者是 尝百草观疗效时代 or the find-a-plant-chew-see-what-happens age
通过对长期以来 now in my view in thinking about
药物发展的历史的观察 drug development over the years
我将其划分为五个阶段 列举在这里 you can see here. I've identified 5 eras
我的中心论点就是…… and my central thesis...
鉴于有些人可能有事需要提前离场 if you want to leave early or whatever
我把重要部分提到现在来讲 I'll give you my punch line here and now
而剩下的时间 and basically the remainder of my talk
我只会讲一些 will just be presenting a little bit of additional
事例和支撑我观点的其他证据 anecdotal and other support for the hypothesis
我的论点是 Here is the hypothesis
纵观人类开发药物的历史 that if you look at the human development of drugs
从所谓的草药时代开始 that's starting from this age of the plant
总共有5个时代 there have been 5 eras
我的中心理论是我们已经经历过4个时代 and my central thesis is that we really have only traversed 4 these eras
而第5个时代还没有真正到来 and this last era isn't here yet
我一个一个讲 so let's move down
先讲接下来的时代 and see what's the next era
我将此时代称为药剂时代 the next era I would call the age of apothecary
这可以说是草药的系统化时代 that's just the systematic age of the plant
人们无需再在荒山野岭里 you no longer have to wander the wilderness
寻找柳树枝干 looking for willow bark
顺便说一下 柳树干是阿司匹林的原料 which by the way is the source of aspirin
应该说是水杨酸的原料 不能说是阿司匹林的 or salicylic any way, not quite aspirin
当时人们所做的 But people have done what people should do
就是开始系统性地思考 which is to start thinking about
和收集草药和治疗方法并将其组合 systematically collecting herbs and treatments and putting them together
在早期的一些人类文明中 in some early civilizations
就已经出现了一些逻辑性的组合 there's a bit of logical convergence
比如将药物或者说是草药与香水混合 putting drugs or medicinal herbs together with perfumes
这很有逻辑性 that makes sense
或者将草药与香料混合 or putting drugs or medicinal herbs together with spices
这其中同样有一种逻辑性 there is a certain logic to that as well
但是随着时间的进步药房出现了 but gradually and progressively the pharmacy emerges
药剂师这个职业也诞生了 and the pharmacist as the medicine man
也就是那些了解不同草药作用的人 the person sort of knows what different herbs might be used for
这是个重要的时代 so that's an important age
这可以说是草药的系统化时代 it's sort of the systematic age of the plant
接下来的时代 Then the next age
始于19世纪 是合成时代 which begins in the 19th century is the age of synthesis
它与工业革命息息相关 随着工业革命的发展 in the course and in common with the Industrial Revolution
制造人造药物成为可能 it becomes possible to start making drugs de novo
而不是像以前一样嚼树皮治病 not simply chewing on bark
基本上可以说 but basically saying
只要掌握化学分子的基本知识 well we have an idea of a chemical molecule
就可以制造它 I'm gonna make it
大多都是从煤焦油开始的 mostly initially from coal tar
然后制药产业就开始兴起 and hence the origin of the pharmaceutical industry
在该时代诞生的制药公司 and the companies that were born during this time
大多数仍然存在 are largely still with us
并且成为当今制药业的巨头 now are the giant pharmaceutical companies today
它们中有很多都是 many of those companies were born from work
从合成化学起家 in synthetic chemistry around...
最初研制染料 search for dyes
所以是从事生产煤焦油和染料的一些生物公司 so coal tars, dyes, some of the organic companies around that
那时人们开始合成新的物质 substances start to be developed
人们会去尝生产出来的新物质 And these new substances were essentially chewed on
以观察它们的功效 with people looking to see what the effect was
因此合成时代与草药时代 really no difference between the age of synthesis
真的没有什么区别 and the age of the plant
唯一的不同是 人们不再局限在草药上 just that now we are not limited to plants
开始制造新的化合药品 we can start making novel compounds
然后有一些勇士会以身试药 以观效果 and some brave souls stick it in and see what happens
然再沿着这个方向研究下去求得答案 and we start moving ahead that way, we'll soon be there
请注意第四个时代 Now notice this fourth age
它在时间上离我们最近 就在20世纪70年代 which is very recent, only the 1970s
已经不是古代了 that's no longer ancient history
它有明确的史载 this is recorded history
我们直到70年代 it's only been the 1970s
才算实际上进入了疗效证明时代 that we actually entered the age of proven value
不学药物的人对这一点觉得非常惊奇 that's quite remarkable for people outside the medicine profession
人们觉得…… to sort of see the...
人们常常会认为 people tend to think that
孜孜不倦的科学家和医生 we've always been vigorous scientists and doctors
总是强调他们的治疗方法会有效果的 have always insisted that their treatments work
事实并不完全如此 well not exactly
实际上食品药物管理局 actually the FFDA
直到1966年才与国家科学院建立工作合约 only in 1966 contracted with the National Academy of Sciences
这太荒唐了 this is crazy
市场上有那么多的药品 with all these drugs out there
但人们根本不知道它们到底有没有药效 and we have no real knowledge about whether they work
当然一些有效果一些则没有 some of them work but some of them don't work
所以食品药物管理局才与国家科学院 so they contracted with an independent agency
这个独立的机构建立工作合约 National Academy of Sciences
开始从事审查药品 said let's start working it
系统地研究数据 let's look at the data systematically
在需要时进行研究 let's request study if necessary
看看当前的药品到底有多少种有效果 let's see how many of our current medicines work
这个过程很漫长 and this process took a long time
大约于1984年完成 不能算很久以前的事 and finished around 1984, scarcely a long time ago
结果是在大约3000多种 and of the approximately 3000-plus
市场上的商业药品中 commercial treatments on the market
大约有三分之一没有疗效 about a third were found to not work
所以这项工作是很有意义的 so this is a very worthwhile effort
而我认为我们现在也处在这个时代之中 and I think this is roughly where we are today
以上就是我的中心论点了 that's basically my central thesis
如果把这四个时代合在一起 and if you put these 4 eras together
可以把它们统称为经验主义时代 they are still in era of empiricism
不管某种药品的疗效物质 whether the putative therapeutic substance
是从树皮中提取的 comes from the bark of a tree
还是在化学实验室合成的 or whether it comes from a chemist lab
有一个过程必不可少 there is still this point
即人们必须通过实验 where one has to go into man to see
检验它是否能达到期望疗效 whether it produces the desired effect
现在慢慢地 我们都会知道 now increasingly we are informed about
一种药品的期望疗效是什么 what the desired effect might be
所以现在不再是漫无目的了 so it's not a random walk
但对药物的理解在本质上还是经验性的 but it's fundamentally empirical
接下来的一个时代就很明显了 now the next age is obvious
有很多人认为 and to many people
我们已经进入了这个时代有一段时间了 we've been in this age for some time
但我却不这么想 but I personally don't think we are there yet
我所说的这个时代当然就是设计时代 and that's of course the age of design
在这个时代 and that's the age
人们充分了解目标疾病 where we know enough about the target
以及其病理学原理 and disease pathophysiology
然后可以对应地制造药品 that we can purposefully create drugs
满足治疗需求 to serve needs
这才是制药产业真正的使命 that's what the pharmaceutical industry is all about
我的观点是 My thesis is that
我们确实能够充分了解目标疾病 we actually do know enough about target
在大多数情况下制药企业也明白 so the pharmaceutical industry does know
它们所生产的化合物的作用 what it's making a compound for in most cases
但是我们对生物学知识的掌握并不充分 but we don't yet know enough about biology
包括神经系统生物学 including nerve system biology
所以我们无法把现有知识完全整合 to actually connect all the dots
所以目前 and so at the end of the day
我们还身处实验主义时代 it's still part of the empirical era
就和前四个时代一样 spanning the first 4 sub-eras
而这…… and that in fact are...
对于社会来说 by which I mean societies
盲目地认为 hoovers in believing that
人类已提前进入真正的设计时代 we are now in the point of true design
进入理性的药物设计时代 rational drug design ahead of time
是造成最近几年药物开发工作 is actually responsible for some of the lower performance
成效不大的原因所在 of the drug development system in recent years
以上就是我的观点 so that's my thesis
接下来我会讲讲个人的看法 I'll give you some personal notes
和一些详细阐述 作为对我论点的支撑 and a little bit of elaboration around the thesis
你们应该都发现了 First as you can tell
我刚才的观点有些扫兴 my message is somewhat downer
所以我想先讲一件令人振奋的事情 I want to start with an upper message
我先讲一个成功故事 so I want to start with a success story
这个故事事发生在现代 and this is a modern era success story
这是是一种神奇的药品或者说一类神奇的药 so this is a marvelous drug, marvelous class of drugs
苯二氮平类药物 the benzodiazepines
这种药帮助治疗了很多人 hat have helped many, many people
而它不是从草药中提取出来的 it did not originate from some root
而是人工合成的新药 but were synthesized de novo
我现在就讲讲有关它的故事 so let's look at the story
这个故事很吸引人 it's a marvelous story
和所有吸引人的故事一样 它也有一个主人公 like all marvelous stories, it has a hero
这个主人公的名字是莱奥·斯坦恩巴赫 the hero's name is Leo Sternbach
在波兰攻读博士后时 as a post-doctoral fellow in Poland
作为一名药物化学师 he began to make some lead molecules
他合成了一些先导分子 as a kind of medicinal chemist
对他来说 那些不过就是新分子 as far as he was concerned, they were new molecules
他觉得这是很酷的合成品 he just said this is really cool synthesis
他想把它们合成在一起 I like the way the molecules are coming together
所以他就研究这些化合物 so he started working on the class of compounds
后来 他的能力被罗氏公司发现 his talent was later recognized by Hoffmann-La Roche
就聘请了他 that hired him first in Switzerland
刚开始在瑞士工作 and later they brought him across
后来把他带到新泽西纳特利的公司总部工作 to their Nutley New Jersey headquarters
他在所属的医学化学部门中屡有升迁 and he rose in the ranks in the medicinal chemistry department
并发起了很多研究项目 and did many projects
我认为这些项目肯定是得到上级管理层授权的 I'm sure under instruction from the upper management
但是他在自己最宝贝的项目中 his own personal pet project however
一直在做苯二氮平 was always making benzodiazepines
所以他进行的实验中 so when he has experiments when he's going
也会合成苯二氮平 make benzodiazepines
实际上制药公司管理层 he was actually instructed by pharmaceutical company management
是指示他去做这些合成和分子的 to synth and assist making these molecules
因为管理层认为这有用 that they then think were useful
我对这些历史背景记得很清楚 that was a little historical note that I kept firmly in mind
因为我曾经 when for a period of years
在一个制药公司管理层工作过一段时间 I joined a pharmaceutical company management
从各个方面了解问题总是一件有益的事 it's always good to keep all perspectives
不管如何 but anyway
他的成功的确不是他故意为之的 he did this truly as a skunk work
是在业余时间完成的 on his spare time
罗氏公司年鉴和其他一些文件明确记录了 and there was a moment which was well documented
一个具有历史意义的事件 in Hoffmann-La Roche annual etc.
当时他要换到另外一个实验室 要清理实验室 he was asked to move clean up his lab and go to another lab
所以 那些装有这些化合物的箱子 and basically the boxes of these compounds
即将被扔掉 were all being thrown away
但那时在罗氏公司内部 but by then he was sufficiently an influential figure
他已经颇具影响力 in the Roche organization
所以他用自己的威望或者人脉 that he was able to resort to his own authority or own friendship
说服了一个同事 to convince a colleague
允许他将他最喜欢的一种分子化合物带出来 to take one of his favorite molecules
当时所有的分子都被编了号 which all molecules get assigned a number
那种分子的编号是 Ro 5-0690 this is Ro 5-0690
后来世人将之称为甲氨二氮 which the world would later recognize and call chlordiazepoxide
他拿到这瓶白色粉状物体 which he take this bottle of white powder
很酷的化合物 which is really cool entity
然后用它进行动物实验 and test it in an animal
这没什么问题 so it's ok and sure for you
把它注射到实验鼠体内 they injected it in a rat
实验鼠就表现出一些行为变化 and the rat shows some behavioral changes
他们如果注射入大量的该药物 in fact if they inject a lot of the drug into the rat
那只鼠就会被催眠 the rat actually would fall asleep
所以他们报告说这种物质对神经系统有作用 so they reported back this was a neuro-active substance
这毫无疑问 no question about it
该化合物进入实验鼠体内后 you administer it into rat
这只鼠的行为会发生明显变化 you get distinct behavioral changes
这引起了罗氏公司管理层的注意 so that picked Roche management interest
他们觉得这很不寻常 they said ok it's kind of interesting
所以开始进行研究 开始进行一些临床试验 let's start to explore, they started to do a couple of clinical trials
之后他们发现效果很不理想 they found that it was really pretty sad
甚至所有人都认为 这东西没有什么前途 and even all said this is not going anywhere
此时它又逃过一劫 and then it was saved again
这次是一个心理学研究者挽救了它 this time is by a academic psychiatrist
来自德克萨斯州的尤因·科恩 Irving Cohen in Taxes
科恩和他的同事们 who at that point of time
在当时的条件下 of course didn't have a whole lot
在治疗患有各种精神疾病的病人时 of different options in trying to help the many patients
实际上并没有其他 that he and his colleagues were treating
很多的方法 with a variety of psychiatric disorders
所以他认为 既然有一种对神经有作用的化合物 he said look you've got a neuro-active compound
那么就拿来 give it to me
至少让我们做一些研究 let us at least explore
所以科恩医生和他德克萨斯的同事们 so Doctor Cohen and colleagues in Taxes
拿到了一些那种化合物着手研究 got a bit of that stuff started to explore
之后就获得了重要的观测成果 and made the pivotal observation
即在少量剂量情况下 that at lower doses
这种药不会让人催眠 long before you put somebody to sleep
而是让人放松 it has a very relaxing quality
自此该药一举成名 and a star was born
这时 罗氏公司意识到 so at that point, Roche management figured out
他们手上握有一种重要药物 that they had something important
你们可以看到之后的速度 you see the speed
制药公司在速度上从来不含糊 there is nothing that a pharmaceutical company does well lest...
执行力非常的快 executed fast and follow
1960年利眠宁诞生了 so Librium was born in 1960
安定在三年后也研制成功 valium followed a mere 3 years later
这两种药分别成为全球药品销量的 these two compounds become the NO.1 and NO. 2
第一名和第二名 world-wide best selling pharmaceutical drugs
使罗氏公司成为国际巨头 driving Roche to international giant size
另外这些药还影响了流行文化 and these drugs entered our popular culture
滚石乐队发行过 as evidence by the Stones' release
一张很流行的专辑《花》 of their famous Flowers album
其中就有一首歌叫做 妈妈的小助手 which has the song "Mother's Little Helper"
我认为指的就是安定 which refer I believe to valium
所以这是一个巨大的成功 So it's a success story
目前在临床治疗中 and there are plenty benzodiazepines
还大量用到苯二氮平类药物 in active clinical use today
首先 它们对于治疗焦虑症很有效 they are useful for the treatment of anxiety disorder first and for most
而且对其它的一些病症也有疗效 but are also useful for a number of other conditions
比如癫痫病 肌肉痉挛 失眠症等等 including epilepsy, muscle spasms, insomnia, etc.
这些药救治了无数患者 These drugs are helping an enormous number of people
但它们不是没有副作用的 they have not been without side-effects
它们有一些副作用 so these drugs have had side-effects
还有一些死亡病例 there have been deaths
也与使用苯二氮平类药物有关 associated with benzodiazepines
但大多数属于蓄意寻死也就是过量服用该药 in a large part intentional deaths as people have taken overdoses
服用苯二氮平类药物自杀不是易事 it's not that easy to kill yourself with benzodiazepines
但是如果摄入的量够大也会致命 but if you take enough you can do it
所以它的效果并不都是正面的 so the profile will not be all good
会有一些副作用 there would be a set of side-effects
甚至会造成死亡 and even deaths associated with these drugs
但我觉得医学圈里没有人会 but I don't think anybody in medicine
因此而质疑这些药物的功用 would question the utility of these drugs
没人会认为没有这种药人们会活得更好 nobody would say we would be better off if we took these off the market
它们都是很棒的药 这就是一个成功的故事 these are marvelous drugs, this is a success story
不仅是科学的成功 scientific success story
也是医学和商业上的成功 medical success story, commercial success story
当这些药还是数一数二的畅销药时 So actually when these drugs were NO.1 and NO.2
也就是在70年代 and in fact even into the 70s
实际上没有人清楚它们的作用原理 nobody had any idea of how they worked
人们只知道它们是药 they were just drugs
人们只管服用它们以减轻焦虑 they just took them and they relieved anxiety
这还不算最让人惊奇的 so if that surprises you
要知道 阿司匹林的作用原理 the mechanism of action of aspirin
直到1971年才被揭开 was only delineated in 1971
阿司匹林可是19世纪最先合成的药品之一 aspirin was one of the first 19th century synthetic drugs
是拜尔公司在1899年 it was produced by the Bayer company
首先开始出售粉状阿司匹林药剂 released in powder form in 1899
它令拜尔声名大震 it drove Bayer's success
成为最大的德学化学公司 to become the largest German chemical company
阿司匹林是一种非常有价值的药物 unquestionably invaluable drug
但是请注意 keep in mind
它同样也有许多副作用 有很多死亡病例 unquestionably lots of side-effects, lots of deaths
但是没人会说阿司匹林这种药不好 but nobody would say aspirin was a bad thing for medicine
但是这种神奇的粉状药剂 后来的片状药剂 but the mechanism of action of the marvelous white powder later tablet
它的作用机理直到1971年才被维恩揭开 was completely unknown until Vane's work in 1971
人们才明白它的作用原理 identifying the mechanism of action
70年代我在杰里·费什堡的实验室读研究生 so I was a graduate student in Jerry Fishbough's lab in the 70s
我必须承认 我交了好运 and I would have to say through good luck
遇到了一个非常适合研究 kind of tumbled on a system that was perfect
苯二氮平类药物作用机理的研究环境 for asking the question how do the benzodiazepines work
杰里的学术研究建立在 Jerry has developed his academic career
当时的一个先进技术上面 around at that time new technique
就是把中枢神经元移植到一个二维平面上 of taking central neuron and growing them on two-dimensional surfaces
这样就能充分体现药物作用 so they are freely accessible to drug application
我们没有只是猜想苯二氮平类药物 so instead of wondering what benzodiazepines did
对大脑的作用效果 in this black box of brain
我们已经能够完成一些技术上容易些的实验 we were able to do some technically easy experiments
我们观测可视化单个神经元上的 we actually started looking at transmitter actions
递质作用 on these visualized single neurons
然后对其使用苯二氮平类药物 观察效果 and put benzodiazepines on them and see what happened
我作为研究生在杰里的指导下 so I did these experiments under Jerry's direction
做了这些实验 as a graduate student
通过实验我发现当对培养皿中的中枢神经元 I learned that when you put benzodiazepines
使用苯二氮平类药物时 on cultured central neurons
这些神经元 That the responses
对抑制类的伽马氨基丁酸递质的反应 of these neurons to the inhibitory transmitter GABA
被利眠宁加强了 was enhanced by chlordiazepoxide
利眠宁本身 chlordiazepoxide itself
不会对细胞膜的性质有直接的影响 didn't have a direct effect on membrane properties
它只是增强了伽马氨基丁酸的效果 it simply enhanced GABA action
我还记得 and I still remember the discussion
当我还在哈佛药理学系念研究生时 when I was a graduate student in pharmacology
曾经就我的这一发现有过一次辩论 in Harvard's pharmacology department around this finding
一位老师认为这很新奇 a faculty found it interesting
其实有些老师对此有些困惑 and in fact some of them were perplexed
因为那时神经药理学还比较初级 because at that time neuro-pharmacology was very simplified
还在讨论兴奋剂和拮抗剂 it was sort of agonist and antagonist
而利眠宁两者都不是 and this was of course neither
不能称之为拮抗剂 you can't say it's agonist
因为它本身没有直接作用 cause it didn't do anything by itself
但是它调节了其它物质的作用 but it modulated the actions of another substance
这个例子中 调节了神经元递质伽马氨基丁酸 in this case the neuron transmitter GABA
这听起来有些荒诞 it seems a little quaint
因为现在多数药品都被看作 because nowadays most drugs actually are thought
是通过调节作用生效的 to work through modulatory effects
而且 多数设计药物的项目都瞄准了调节功能 certainly most design programs are aimed at modulatory actions
但是在70年代的药理学中 but modulation was not the watchword
调节还不那么流行 in pharmacology in the 70s
不管如何 and anyway
我得承认这个发现有些运气成分 and I have to say this was a chance finding
但我对此还是很高兴 but I was very happy about it
对于我来说 这个发现对我的好处是 and the major good effect, as far as I was concerned
它使我完成了博士学位 was it got me through my PhD program
并赢得了荣誉 and honor with life
我觉得挺满意的 which I thought was a good thing
我当时考虑 but I did sort of reflect on this
就像我说的 我运气比较好 as I said, I've been lucky
所以必须完成研究 这个研究很有益 so I have to finish, which is good
然后继续努力 and go on
也许未来能凭借它找到工作 这可是件好事 maybe someday I should like to get a salary that will be good
我还觉得 but I also said
这种开发药物的工作很酷 this drug discovery stuff is really cool
而且也不难 and it's really easy
当时我还在学校实验室呢 I mean I'm just in a school laboratory
就能研究出来苯二氮平类药物的工作原理 I figure out how the benzodiazepines work
靠这项工作吃饭可不错 I could do this for a living
后来 当我在斯坦福大学有自己的实验室后 So later when I have my own faculty laboratory at Stanford
还有后来在华盛顿大学 and then subsequently at Washington University
我开始对一种机理感兴趣 I became interested in a mechanism
利用那种机理 and around that mechanism
也许可以设计出一类新的亟需药物 in the possibility of designing a new class of needed drugs
那个机理被称作谷氨酸毒性 so the mechanism was called Glutamate toxicity
它是首先被华盛顿大学的约翰·欧内发现的 it was discovered by John Olney at Washington University
我采用了与他相同的方法 and I used the same sort of approach
将这个机理过程分离出来 of isolating this process
并简化了细胞培养基 and simplified cell cultures
以分析谷氨酸递质的作用 to dissect the ability of the transmitter glutamate
通常它是用来传递神经信号的 which is normally used for signaling purposes
但是在病理条件下 but which under pathological conditions
比如中风和癫痫 它会过量分泌 like stroke and epilepsy, can be released excessively
所以该模型到现在还有不少人研究 so the model which most people still buy today
也就是在病理条件下 is that under these pathological conditions
谷氨酸递质不再像传递信号时那样 instead of being released in the small package
只分泌很少的量了 appropriate for signaling
相反 这种递质 也就是氨基酸谷氨酸 this transmitter glutamate, just amino acid glutamate
会大量分泌 充斥神经终端 floods all of nerves terminals in inappropriate amounts
造成过量的谷氨酸浓度 creating inappropriately high and sustained concentrations
长期聚集在神经元周围 of glutamate surrounding neurons
而这会过度刺激神经细胞的受体 that this over-stimulates the receptors on nerve cells
也就是能够识别谷氨酸的蛋白质受体 protein receptors that recognize glutamate
受体所受到的刺激再不是用于信号传递的 instead of being stimulated in this little physic fashion
那种合理的刺激了 appropriate for signaling
而是被激活到大大敞开的程度 they are stimulated wide open
特别是 and in particular
有一类谷氨酸受体叫做NMDA受体 a class of glutamate receptors called NMDA receptor
它们与具有高度的 which is systematically linked
钙渗透性的通道紧密连接 to channels with high calcium permeability
这种受体也被激活 致使过量的钙进入细胞 got activated allowed too much calcium to flood into cells
在某些病症条件下 it's actually a key cause of nerve cell death
比如中风和癫痫 under some of these conditions
这是造成神经细胞死亡的重要原因 like stroke and epilepsy
这是一种已有的理论 so this was a theory
我们为这种理论做了一些贡献 and we contributed to this theory
在我们研究出了NMDA受体和钙的作用后 and we worked out the role of NMDA receptor and calcium
越来越多的人开始研究这种理论 more and more momentum started to go around this theory
看起来就像自然而然的事 it seems like natural
我们掌握了一种新的机理 we have got a new mechanism
我们进入了设计治疗学时代 we are in a wonderful age of design therapeutics
这是一种新的机理 we have a new mechanism
当你想要阻断这个机理的运转时 when you want to break this mechanism
只需要阻滞NMDA受体就能保护神经细胞了 block the NMDA receptor thereby protect nerve cells
这也就是一个治疗大脑损伤 thereby have a new treatment for brain damage
比如中风的新疗法了 in signs like stroke
听起来很合理 made a lot of sense
它在动物实验中取得了成效 it work in animals
取出一只实验鼠 让它中风 so if you took a rat and produce a model stroke
这并不难 which is easy to do
而且会获得很多的表面有效性 with a lot of face validity
只要把那实验鼠的大脑中动脉阻断 simply clip off the rat middle cerebral artery
切断大脑中的血液流动 and deprive original rat brain of blood flow
这就跟人类典型中风时的情况一样 much as happens to human who has a typical stroke
鼠大脑中发生的情况与人类一样 what happens in the rat brain is just what happens in human brain
就是有一块组织阻断了动脉血管 which is a chunk of tissue which is perfused by that artery
然后组织死亡 也就是梗死 Dies, so-called infarcts
我们认为谷氨酸毒性 and we believe that glutamate toxicity
是造成这些组织损伤的原因 was a driver of some of these tissue damage
你们也能做这个实验 so you can do this experiment
使用一只实验鼠或者一组实验鼠 you can take a rat or a series of rats of course
阻塞它们的大脑中动脉 and subject them to middle cerebral artery occlusion
然后它们就会出现脑梗现象 and they will develop these infarcts
然后你用能够阻断NMDA受体的 and you can treat them with a probe drug
探针药物治疗这些老鼠 designed to block the NMDA receptor
制药公司现在正在开发这种药物 which is being developed now by pharmaceutical companies
它们都认为这种机理是有道理的 they are all buying into this mechanism
认为这种新疗法 或者说系列药物 Ok, we could make this new treatment
保护神经的药物是行得通的 new class of treatments, neuro-protective treatments
默克公司是一家领先制药公司 Merck actually was a lead pharmaceutical company
它开发出一种化合物 名字是MK-801 it made a compound called MK-801
这种药物是第一种广泛使用的…… which is the first widely used...
在实验室中广泛使用的科学探针性 meaning widely used in laboratories widely used scientific probe
NMDA拮抗剂 NMDA antagonist
如果你把某种NMDA拮抗剂 so if you put in some NMDA antagonist
随便哪种 take your choice
注射到另外一组同样引发了脑梗的老鼠体内 in another series of rats who were treated with the same insult
你会发现它们的中风症状会减轻 you would see they would develop a smaller stroke
这个现象给人们很大的鼓舞 so it looks very promising
很多制药公司都开始 and a whole bunch of companies
把NMDA拮抗剂投入临床试验 started moving NMDA antagonist in the clinical trial
试图开发出治疗中风的药物 seeking treatments for stroke
我讲一个很有代表性的例子 and this is a representative example
这个临床试验是做得比较好的一个 from one of the better done clinical investigation
是由一个叫做汽巴嘉基的公司做的 this was run by a company called Ciba-Geigy
该公司后来被现在的诺华公司兼并 which later became part of current Novartis
他们开发出一种很好的NMDA拮抗剂 and they developed a very nice NMDA antagonist
编号是19755 which was known by its number 19755
这个实验是人体实验 and this is a human trial
你们可以看到 and you can see
他们让患者服用CGs 19755 they treated people with CGs 19755
阻隔NMDA受体 to block the NMDA receptors
试图降低作用在突触后神经元上的谷氨酸毒性 to reduce glutamate toxicity on postsynaptic neurons
然后观察患者在接受治疗后 and if you look at how the people were doing
3个月内的反应 3 months after this treatment
接受治疗的用红体字表示 and you look at the treated in red
没有接受治疗的…… and the not treated...
或者是安慰剂治疗的用白体字表示 or placebo treated in white
最后 实验结果并不令人满意 you can see that there was no encouragement
如果我们在进行事后分析时 and in fact if you did a post-hoc analysis
认为也许是有其它因素 and say maybe the therapeutic effects
掩盖了治疗效果 have been washed out by something else
那么我们看看因大脑疾病死亡的实验者人数 let's just look at brain related mortality
也许有借鉴意义 really maybe it's relevant
不去管那些人是有心脏病还是其它的疾病 whether somebody has a heart attack or something later on
其结果更是令人沮丧 you get even less encouragement
其实在接受治疗的那组人中 in fact there is a trend
有更多的人因脑疾病而死 towards more brain-related mortality in the treated group
而目前在这个领域内情况没有改观 so that's where things basically stand today in this field
今天的人们都认为 everybody agrees that NMDA antagonists
虽然先前希望很大 despite their early promise
但NMDA拮抗剂不再值得人们继续投资 are not the way people should continue to invest
无望试图从中开发出急需的 in developing a needed treatment
治疗中风和其他疾病的保护神经的药物 for stroke and other diseases and neuro-protective treatment
为什们 在目标病症明确 why did the NMDA antagonist idea
从未受到过质疑的情况下 there were well-defined targets
NMDA 拮抗剂 reasonable idea
这个在老鼠试验中取得成功的概念 an idea that has not been refuted that actually works in rats
不能成功地运用到人体中 failed to translate usefully in the humans
这是一个值得深思的问题 that's a topic of considerable discussion
我想给大家讲讲我自己的一些观点 I'll just give you a couple of my own favorite ideas
当然问题的正确答案没人知道 of course the answer no one knows
我只是想说这种拮抗剂未能成功 I simply state that it has not translated
转化为人类药物 into human medicine
我个人认为造成转化失败的 my personal belief as to one of the major reasons
主要原因之一是 for this lack of translation
随着对神经细胞死亡的另一种方式的 is that with the subsequent delineation and recognition
理解不断加深 of prominence of another way the nerve cells die
即在局部缺血的条件下 under ischemia conditions
甚至在血液流动被阻断的情况下 even the blood flow is cut off
实验的结果显示 so it does appear to be true that
局部缺血会使神经细胞分泌谷氨酸 the ischemia causes glutamate release
引起谷氨酸中毒 and causes glutamate toxicity
这种情况被称为兴奋性中毒 which is also called excitotoxicity
也会杀死神经细胞 to kill nerve cells
但是 同样的 一些神经细胞 but it also appears that some nerve cells
在受损到一定程度后自己崩溃 receive a degree of injury and implode
实际上相当于启动了内部的自杀程序 they basically triggered an internal suicide program
致使细胞死亡 这种情况叫做细胞凋亡 and undergo a cell death, called apoptosis
NMDA拮抗剂并不能对细胞凋亡起作用 this apoptotic process is not sensitive to NMDA antagonist
在实验条件下 and in fact under experimental conditions
可以表明 you can demonstrate that
NMDA拮抗剂实际上加速了细胞死亡 NMDA antagonists actually worsen the death
而且很可能是钙的原因 most likely around calcium
对生物学家们来说 他们还需要深入研究 and for the biologists, they will go one step deeper
但我知道大家不是生物学家 I know this gets a little too detailed
所以这有点太过专业了 for non-biologists
请原谅我 but if you bear with me
我特别感兴趣的一个理论是 the theory that I'm particular fond of is the idea
NMDA拮抗剂这种战略 that the NMDA antagonists strategy
虽然说对于顶级分支来说是合适的 while being the right thing for that top limb
顶级分支是指抗兴奋性中毒分支 i.e. the anti-excitotoxic limb
它会帮助降低谷氨酸毒性 usefully reducing glutamate toxicity
减低NMDA受体的受激以及减少钙的积聚 NMDA receptor stimulation and calcium overload
制药公司积极地应用了 was essentially applied with maximum of vigor
上述的这点理论 by the pharmaceutical companies
我之所以知道这一点 and I know this
是因为我曾经在很多制药公司工作过 because I worked with several of them
可是 这不知不觉地 and unknowingly at that time
会导致细胞以另外一种形式死亡 favored the other death
即通过一些理论性的设计中点 by driving cell calcium
将细胞中的钙含量降得太低 through some theoretical desired midpoint to too low calcium
这样也会导致细胞的自杀或凋亡 which promoted this suicide or apoptosis
如果能重点关注这种细胞死亡模式 accentuating this death pathway
填补上这个逻辑漏洞 which to close the logic loop
人和老鼠之间的转换理论的可信度也许会增强 their reasons to believe might be more prominent in man versus rat
所以只是通过数量的变化 而不改变理论基础 so a mere quantitative shift, all the principles being intact
但是这个机理 在当时并没有被人们重视 but having this mechanism not quite as well recognized by people
反正我当时没有重视 certainly not by me at that time
而制药公司的工作仍然在继续进行 that this kind of work was going on
后来的局面就是 and later oh what about this
人们会认为这类药物对大脑的好处多于坏处 then saying mostly in human brains this is a bigger contributor
于是就使用NMDA拮抗剂 then you deliver NMDA antagonists
特别是大量地使用那些拮抗剂的时候 and especially if you deliver them with maximum vigor
不知不觉间你也许做的是好事 unknowingly you sort of do the good thing
但是也许也是干了件坏事 but you also do the bad thing
也许功大于过 也许得不偿失 maybe you break evener even a little worse
所以这是一种可能的解释 so that's potentially an explanation
对于这次讲座来说 the details of the explanation don't really matter
解释的细节并不重要 for the purposes of this lecture
真正重要的是获得的经验 what matters is really just the experience
还有作为一种想法的本身 and totally of an idea
它作为一篇论文很完美 which looks awfully good on paper
甚至在动物测试时也取得成功 even good on animal models
而在向人类用途转换时却失败了 and fails to translate into man
后来 我的实验室继续研究 so later my laboratory continued to study
神经系统中的信号传递基础上的细胞死亡 trans-signaling based cell death in the nervous system
这是后期的一张图 and this is a later cartoon
所以你们看 so you see the pictures
这些图的比刚才的那张复杂多了 got progressively more complicated
我们发现在这个受到过度刺激的神经终端 we identified that not only was glutamate being released
不仅分泌出谷氨酸 from this over-stimulated nerve terminal
还分泌出了锌元素 but actually the metal zinc was coming out
锌元素本身就能够阻断信号传递 that zinc itself had an ability to be a signaling killer
即阻断递质 i.e. a transmitter killer
锌毒性与谷氨酸毒性一起作用 zinc toxicity was acting in parallel with glutamate toxicity
所以当我发现这一点时 so when we first found this out
我们认为这是个新的靶点 oh a new target
所以我们要攻击锌元素 减少分泌出来的锌 we'll hit zinc, we'll reduce the amount of zinc that's released
或者消除锌 or we'll delete the zinc
但当我们深入研究后才发现 but then we started to study it more we said oh look at this
锌也能调节NMDA受体 zinc has an ability to modify NMDA receptors
实际上就是阻滞它们 it actually blocks them
也就是说锌是大脑的自我保护机理的一部分 so it's part of the protective mechanism of the brain
能够降低谷氨酸毒性 to reduce the glutamate toxicity
还没完呢 oh wait a minute
还存在另一种机理 there is actually another mechanism
它通过信号激酶运作 更复杂了 which operates through signaling kinases, more complex
它能够上调NMDA受体 这是件坏事 that up-regulate the NMDA receptor, so that could be bad
但是也许 如果在后期的某个时间段内 but maybe if the cells are undergoing calcium starvation
细胞缺钙 那么这种上调就是好事 in a later and time-dependent fashion this up-regulation is good
还有这些亲代谢性谷氨酸盐受体 and then there are all these metabotropic glutamate receptors
也能对NMDA受体的刺激进行正或负的调节 that modify NMDA receptor stimulation either negatively or positively
虽然说这张图已经够复杂了 and as complex as this map is
但它还只是我自己的图 this is really just a Dennis map
我的意思是 这不过是我的实验室的研究成果 I mean this is just what my lab is working on
还有很多实验室在研究这个领域 there are lots of labs working in this field
人们还发现了许多其他的信号传递方式 and many more signaling pathways have been identified
在这里我没有一一给出来 that I'm not graphing
这个只是我们的内部的工作图 this is our internal working diagram
仅限于我们自己的实验 for our own experiments
然后我们就退一步想 and we stepped back and said
那么合理的靶点是什么呢？ ok where is the logical target?
答案就是 and the answer is
不知道 I haven't any clue
所以这是一个案例 and so this is an example
基本上我觉得 这就像通过一个虫洞的过程 basically I felt like we've sort of come through a wormhole
刚开始觉得一切都很顺利 where a little knowledge sounded really good
但是随着知识的增加 情况越来越复杂 but a little bit more knowledge made things so complex
以至于根本无法发现 that one could no longer easily identify
一个合适的制药靶点 an appropriate pharmaceutical target
我刚才说过 so I said well when I got this chance
当我有机会进入制药公司工作时 that I've mentioned to join the pharmaceutical companies
我就觉得光搞学术无法回答这个问题 so maybe the thing is I'm working as academia
我要做的应该是与业内人士一起工作 what I really need to do is work with professionals
或许能够对这个问题有更好的理解 and then I'll get a better sense of how this is done
所以我在2001年毫不犹豫地进入默克公司 so I eagerly accepted the opportunity to Merck labs in 2001
我开始阅读大量的期刊 I started reading different journals
然后发现这边的情形也不像我想象的那么好 and I started seeing that the grass wasn't greener
就连制药领域里的人 that people even in the pharmaceutical world
他们想的也是大型概念 碰运气和经验主义 talked about mass concepts and serendipity and empiricism
而我对这些太熟悉了 in a way that was all too familiar to me
而药物的工业开发的过程是…… the industry process of drug development...
我努力就用一张幻灯片来描述它 I try to sketch here on a single slide
这里没法讲太细 and I can't go into it in any detail
但我想让那些不了解药物开发的人们 but I want to capture some of the sense to people
能够搞明白其中的一些过程 who weren't familiar with pharmaceutical drug development
这个过程就像漏斗状 I think of it as a funnel
我说的这个漏斗是…… and the idea of funnel is...
这就是制药企业攻击药物靶点的一个过程 now this is how a drug company hits a target
如果一个企业有了一个靶点 so if you could figure out what it is gonna hit
那么最通常的做法就是 eventually what a company often does
让它的拳头部门开始工作 is take its crown jewels
也就是它的化合物实验室 which are its compound laboratory
通常在一个大型制药企业 which in a large pharmaceutical company
会有6到10个这种的实验室 number in the 10 to 6 range
很多…… multiple...
制药企业 some millions of selected compounds
会拥有数百万计的化合物 are used by pharmaceutical companies
它们被严密看管 保密措施很严格 garded very carefully, very proprietary
通过第一道筛选 选出最可能对靶点有效的 and it uses this initial screen to identify lead compounds
先导化合物 that could potentially hit a target
这就是不断筛选化合物的过程 now this shows how progressively things are winnowed down
但是这种过程不是一种线性的 but don't think this winnowing happens over a few weeks
只持续几个星期的过程 in a linear fashion
这里是时间轴 the timeline is here
艰难的临床前阶段工作一般为3-8年 3-8 years of hard preclinical work
接下来的临床试验也要持续7年 followed by 7 years of clinical study
这就是通常情况下从靶点到成药所需要的时间 it's usually what's required to go from a target to a drug
这么长时间才能制成一种药 甚至制不出来 tendered 0 or one drug
花费这么长时间的原因是…… and the reason why so much time takes place...
再考虑到成功的几率 and notice the probability of success
在投入如此长的时间和人力后 and the time you actually put into man
只有10%的几率能生产出新药 you only have a 10% chance of coming out with a drug
造成这么大消耗的原因是 the reason for this attrition and time is that
这种过程不是线性的 而是反复的 this is not linear, but actually is iterative
当取得一种先导化合物后 so a lead comes out
化学家们 像斯坦恩巴赫一样 and then chemists, likely a Sternbach's guy
会制造出它的衍生品 制出相关的化合物 derivatizing this lead and making related compounds
然后检验哪种衍生品 and thus to examine to sort of see which kinds of modification
能够提高靶点功效 seem to improve target finity or efficacy
在一段时间之后 and over a period of time eventually
大约会合成10的四次方这么多的化合物 ten of the fourth compounds were made
也就是10000多种化合物 so maybe 10,000 compounds were made in the campaign
其中会有100种作为候选药品 something about 100 candidates
它们也不是同时进行 而是往复进行 again not all at once but iteratively
也就是说先测试一种化合物 反复测试 meaning a compound goes forward, forward
但是最后它被证明是毒性的 and then it turns out to be toxic
那么就得回到起点 back to square one
再试下一个 循环往复 Next, go on a ultimate branch
一个典型的药物开发阶段中 when it's all said and done in a typical campaign
一般会仔细研究100种化合物 100 compounds would have been studied in considerable detail
对它们进行毒理学等试验 would have been subject to the toxicology and alike
很多情况下 many times advanced until...
一开始进展顺利 it was really great
后来却发现 服用了一年大剂量的实验鼠 until we administered high doses for a year to a lot of rats
现在它们的情况不是很好 now their lyrics don't seem so good
试验出现问题了 in fact there seems to be a problem
那么这一类的化合物都要从头再来 this whole class of compound back to square one
如此反复 so this is going on...
如果一切顺利的话 最后也许就能合成一种新药 if it all goes well, eventually a drug comes out
这就是制药过程 that's the process
不幸地是 这个过程效果并不理想 unfortunately this process isn't working very well
所以说这张幻灯片挺令人沮丧的 so this is a real downer slide
但它表现的确实是整个产业的现状 and it's hard, objective and across the board
也就是不光一家公司如此 so this is not one company's experience
整个生物制药产业 but if you look at the entire biomedical industry
生产药物的能力 and its ability to produce needed treatments
都是这样 it's shown here
这张幻灯片显示的是…… so what this graph shows is that...
数据截止到2006年 most recent number I add here is 2006
我觉得07年的数据也好不到哪儿去 I don't believe things get any better in 07
因为 现在在全世界注册的 That the number of new active substances
对治疗疾病有效的新的有效物质数量 being registered world-wide for the treatment of diseases
大约是在30左右 is on the order of 30
这跟幻灯片上这个数字差不多 which is approximately that are named here
也就是说和人们在70年代 it's actually where things were
刚开始记录这些数据时的数字差不多 when people first started tracking this in the 70s
在90年代巅峰时期时 it's not as good as the heyday in the 90s
这个数字能到达40或者50 when things got up the order of 40 and 50
而这种生产力的滞后 and this lack of increased productivity
应该可以理解为…… must be interpreted...
首先是 first an understanding that
拥有一种新型的有效物质 just because you have a new active substance
并不意味着就有了一种新型的药物 doesn't mean you have an exciting new drug
大多数这种新型有效物质 many if not most of these new active substances
都是复制已有药物 are truly meant to copy on drugs
只做了少许改变 just a little modification
然后就成了化学意义上的新物质 and it makes it a chemically novel substance
被统计进这个表单 gets you on this list
所以真正突破性的 so the actual number of
新型药物原理和具有影响力的新药 real breakthrough novel mechanism
数量其实远远低于这些数字 big-impact drugs is way smaller than this
还有一个不好的消息 and here's the other bad news
就是说 是因为如果没有人对研发投资 one thing is that if nobody had invested in the R&D
才造成这种局面 and the contribution could be the light bulb
那么也许我们应该加大研发投入 well maybe we need to increase our R&D effort
但实际上 全世界范围内对研发的投入 but in fact, the world has increased the R&D effort
已经增至500亿美元之高 to the tune of 50 billion dollars world-wide
所以制药产业的的处境十分不好 so the tune of pharmaceutical industry being quite bleaker
你们应该都知道 and you know this
制药企业的股票表现都不太好 I mean pharmaceutical companies' stocks are not riding high
处境每况愈下 things are hitting harder and harder
而这种低下的生产力还有…… and this lack of productivity coupled with...
我们必须肯定制药产业如此巨大的投资 you have to give this industry credit for very considerable spent
它们对研发模块的投入 the fractional spent into R&D
一直处在很高的水平上 is actually at high watermark for industries
但这种投入不可能持续下去 this is not sustainable
这种花费一直在成指数性增长 you have a cost which is increasing exponentially
而生产力和商业模式并没有得到相应地发展 a productivity and business model which is not concurrently rising
这样公司就陷入两难境地 and a business pincer is forming
这就是问题所在 so that's the problem statement
事实就是如此 that's just the way things are
为什么制药工作总是失败呢？ why are our drugs failing?
一个还不错的方面是 there is a little bit of good news
随着科学进步 as science progresses
现在制药工作的失败原因与90年代时的原因 drugs now are failing for somewhat different reasons
已经不尽相同了 that they failed back in the 90s
这个图显示了这一点 so this graph shows this
好的方面用绿颜色表示 basically says that, the good news is right here in green
比如说 在1991年 有些药物 that many drugs that used to fail back in say 1991
由于没有应用正确的药物动力学原理 because they turn out not to have the right pharmacokinetics
和生物原理没有体现出疗效 or the right bio-availability
这些药在理论上很好 the drugs look good
但是在应用到人身上后或者动物体内后 until you actually start giving it to people or sometimes animals
发现它们不被吸收 and turn out not to be absorbed
或者说没有被成功的代谢 or distributed or metabolized properly
那么就不得不从其他理论入手研究 and you have to go back to another theories
而这种情况现在少多了 that's not happening so much now
因为现在人们有更好的技术能够预测相关参数 because there are better techniques for predicting these parameters
目前的瓶颈仍然是药效 but the wall is efficacy
各种化合物被合成出来 so basically still compounds go all way out
但是的效果并不好 and then they just don't work right
有时候有些疗效 但是本身毒性又太 or sometimes they seem to work but they are too toxic
而且在现今科技越来越发达的世界里 and in our increasingly complex modern world
商业失败案例也越来越多 business failures are rising
换句话说 一些项目成本实在太大了 in other words, they just take so much to do
我们把所有事情都考虑到了 but at the time we find we add that all up
却没有得到任何回报 can't make a dollar doing this
前一段 针对全部注册的药物做了一个调查 of currently registered drugs there was a survey a while ago
也就是经过前面讲的艰难过程 the drugs actually make it
幸存下来的药品 out of this long obstacle course
只有30%能够收回最初的开发成本 only 30% actually bring back their development cost
那30%的药必须要挣很多钱 so those 30% have to make it big time
才能使制药公司生存下去 to essentially float the entire enterprise
70%的注册药物都根本收不回开发成本 70% registered drugs don't ever recoup their own development cost
至于动物实验模型…… so then you go to the world of animal models...
我刚才谈的是整个治疗领域 these earlier comments are really across therapeutic areas
还有整个产业的情况 and across industry
我想把话题缩小到 I wanna cone down a bit
人们在开发 on the special challenges
治疗脑部疾病的药物时所遇到的困难 faced by people who want to make treatments for brain diseases
大脑疾病的研究门槛很高 brain diseases are especially hard to access
因为大脑的结构很复杂 because the brain is especially complicated
加里·拉尔森为人们了解这些疾病 the fundamental insight is well captured
做了奠基性的贡献 by Gary Larson here
如果你从事神经科学研究的话 and if you work in the neurosciences
你就会了解 存在很多种动物实验样品 you are very familiar with a variety of models
大多数情况下是老鼠 耗子 which have rats, mice in most cases
有时也有大型动物 occasionally in larger animals
用它们做各种实验 scouting around doing various tasks
然后人们从人的角度 and we anamorphically interpret what's going on
主观地分析情况 in terms of human perspectives
认为这是抑郁症 that's depression
那只老鼠焦虑了 that rat is anxious
因为它把头伸到暗盒里了 它肯定是焦虑了 it's sticking its head in the dark box, it must be anxious
最好的动物实验也只能到这水平了 and that's the best we have
然后就直接进入临床实验 sure to go into clinical trials
现在制药产业 now the pharmaceutical industry
把很多资源都投入到这种模式的实验中 tended to put a lot of stocks in these models
然后轻易地认为 and tended to believe in this earlier hoovers
人们已经达到了相当的科技水平 that we've got to a scientific point
只要知道分子靶点 where we could really get the line aside
再根据接受过加里·拉尔森实验的动物的表现 between molecular target
就能得出结论 and action in a Gary Larson behaving animal
并明确了解亟需治疗的疾病 and know what disease we are gonna treat
当我在默克公司的时候…… so when I was at Merck...
我现在向大家讲一下我经历过的一个实验项目 I'll tell you about a one single program that I watched
那个项目在我去默克公司前就开始了 it was launched before my arrival
但我坐在第一排目睹到了这个过程 but I certainly have the front-row seat
这个项目很有趣 this was a very exciting campaign
看这里 这是时间轴 that you can sort of see, it's a timeline
可以回溯到1931年 it goes all way back to 1931
那年人们发现了脑部中的一种物质叫做P物质 the discovery of a brain substance called substance P
提取出来是白色粉状 a white powder that basically when extracted
它对运动能力和血压 and had pharmacological actions
有药理反应 in test of motility and blood pressure
之后苏珊·李曼和同事发现 and later Susan Leeman and colleagues found
它的生物性质表明 that its biology suggests that
它或许是疼痛的主要信号传递物质 it might be a primary signaling substance for pain
当时 制药公司觉得 so at that point, the pharmaceutical industry said
那太好了 great now we got it
现在知道P物质 受体和疼痛的关系 substance P, receptor, pain
那么可以破坏它们间的作用 we'll break that
可以制造一种分子去阻断那种联系 we'll make a molecule to block that
这样就能研制出一种不含鸦片的止疼药了 and we'll have a non-opiate analgesic
这正是全世界急需的 which the world desperately needs
默克公司就开始大力研发这种药 so Merck set out on this
从化学角度来看 这个工作很难 it's really hard from a chemistry's standpoint
几乎没有所谓的肽受体 there are very few so-called peptide receptors
能够被小分子当成靶点 that can be successfully hit with small molecules
很多专家组花了非常长的时间 large teams of expert people worked for a very long period of time
希望能研制出一些有可能 to come up with candidate molecules
阻断P物质关键受体的分子 that were capable of blocking a key receptor for substance P
那些关键受体被称作 NK 1受体 called NK 1 receptor
结果是 随着这个项目的推进 it turned out that, as this program progressed
原来人们寄予希望的 that the original idea
能够充当止疼药的分子 最后失效了 that such a molecule would be analgesic, failed
它不具有止疼功效 it did not have analgesic properties
但是这个项目当时还没完全起步 but the program barely started-stepped
因为在那个时候 各种生物学现象表明 because at that time, a lot of biology was emerging
尤其在人脑内 suggesting that in the human brain in particular
NK 1 受体和P物质是抑郁症的中介物 NK 1 receptor and substance P were mediators of depression
当时有一种逻辑 认为 and that was a logic
疼痛是低级抑郁症 抑郁症是高级疼痛 pain is low depression, depression is high pain
话差不多就是这么说的 that's the way they say it
所以说 我们会觉得 如果说一种理论 so if we are thinking about a certain principle
可以应用到低等的动物身上 that would extend to lower animals
那么也许 一旦用于人体 这个传递机制 but maybe in man, this signaling mechanism was
就会上升到更高级的大脑皮层功能 subsumed into higher cortical functions
会具体表现成抑郁症而不是以初始的疼痛表现 more subtlized into depression rather than primary pain
所以默克公司很看重这个工程 so Merck got really serious around
希望能开发出一种新型抗抑郁药物 the development of a novel anti-depressive
如果看过一些医药领域的文献 that if you followed the pharmaceutical literature
你就会知道 you are probably well aware of this
这个项目在当时很轰动 this was a very high-profile campaign
希望研制出一种NK 1受体的拮抗剂 to make an antagonist to the NK 1 receptor
很有可能成为一种新型抗抑郁化合物 that could be new anti-depressive compound
当我 进入默克公司后 at the point, where I joined the company
该项目已经进入大规模试验阶段了 this was moving into large-scale trials
这是因为项目取得了一些鼓舞人的试验结果 basically driven by some encouraging results
基本上 就是当把一些小豚鼠 with the guinea pigs that would make a little screaking noises
从它们妈妈那里分开时会发出尖利的叫声 when separated with their mothers
但是在注射过这种化合物后 就不再叫了 and didn't do so when treated with this compound
在进行小规模人体实验时 to small series of humans
患者的抑郁症病情在注射过NK 1拮抗剂后 who seemed to have their depression ameliorated
也有所减轻 when treated with NK 1 antagonist
通过这次动物和人的实验转换 Merck through the switch
默克公司开始进行第三阶段大规模实验 did a large-scale phase 3 trial
来验证它是否就是抗抑郁药物 to see if this was an anti-depressive
这次实验规模很大 this was a huge trial
可以说是花钱如流水 it cost literally a zillion dollars
我就眼看着这些钱花出去 and I sort of watch it go
它的生物原理很完善 and as good as this biology was
我认为这次实验的原理 the rationale is as good as anything you see
可以跟任何生物学原理相媲美 that is seen as biology in my view
我把实验结果打在下面了 I've put the outcome down here
这次实验其实做得很漂亮 this was actually a beautifully done trial
很多抑郁症实验都因为无法区别 many depression trials actually failed
已知抗抑郁化合物和安慰剂而失败 to discriminate a known active anti-depressive compound from placebo
因为在抑郁实验会很大程度上 because there was so much placebo effect and noise
受到安慰剂的影响和干扰 in depression trials
而默克公司的这个实验设计得很好 the Merck trial was very well done
他们区分出了所有的阳性对照组 they all discriminated positive control
但还是根本无法检测到 and rather resoundingly failed to detect
这种著名化合物具有任何抗抑郁效果 an anti-depressive effect of this designer compound
我可以就此打住了 so the story could end here
但是大家刚才看到了我的漏斗图表 except that you sort of sensed my funnel diagram
图表上至少有个好结局或者至少算个安慰奖 there was a happy ending or at least a consolation prize
看这儿 so here
这是我从默克公司网站上剪切的一种化合物 which I popped off Merck's website, a compound
公司内部命名是阿瑞匹坦 which is called internally aprepitant
现在它有个商标 叫Emend now has a brand name Emend
在市面上可以买到 is on the market
而它不是作为一种抗抑郁药面市的 it's not on the market as an anti-depressive
因为它没有抗抑郁的效果 because it didn't work to treat depression
好消息或者说是安慰奖是 the good news and the consolation prize was that
在开发该分子的过程中 in the development of this molecule
默克公司的科学家发现了 Merck scientists figured out exactly
能够阻断人类大脑NK 1受体的准确剂量 what doses were needed to block human brain NK 1 receptors
这让他们在一些英国科学家做了一种试验后 positioning them very well when a chance of observation emerged
有了很好的观察机会 from some scientists in the UK
那些英国科学家用了一样的方法 who has taken this approach
他们说 我们注意到老鼠不会呕吐 they said we have noticed that while rats don't vomit
而白鼬会 ferrets vomit
那么我们可以通过给它们服用某些物质 and we can actually cause them to vomit
让它们以工业规模呕吐 on an industrial scale by giving them certain substances
我们可以让一些白鼬 so we'll set up a bag of vomiting ferrets
不停地吐啊吐啊 just set them vomiting, vomiting
然后拿一些药物 and then we'll grab anything we can get
然后给这些白鼬服用 and we put it into these ferrets
看看它们的呕吐反应是否改变 and see if the vomiting behavior is altered
得出的结果很好 the data was beautiful
这边是呕吐的白鼬 you basically have all these vomiting ferrets
然后服用了这种化合物都不呕吐了 and got this compound, zero vomiting
这促使人们开始进行一个副试验 so that provided the impetus for a side trial
看看有没有用得上这种化合物的地方 to see if there is any chance this compound could help
当然只有相对少的人 of course now there are smaller number of people
患有化学疗法诱发的恶心和呕吐症 who have Chemotherapy-induced nausea and vomiting
这种病很严重 which is a terrible problem
如果你见过这种病的患者就会知道 if you know anyone has that problem
在Emend出现前最好的药物 and even the best current therapy prior to the Emend
药效也不敢恭维 leave a lot to be desired
好消息是这种药成功了 the good news was it worked
在服用过Emend后 so these people are found significant released
大部分患者都大大减轻了病症 in many cases by taking Emend
它就是因为这个疗效才出现在市场上的 and it's on the market for this purpose
这也算是个成功的案例 and so it is a success story
当然这不是默克公司 but of course it is not a commercial success
在大力开发抗抑郁药物时 that Merck kept in mind
所预想的那种商业成功 when set out to build an anti-depressive
还有一个发生在最近的例子是…… one other recent example is...
它也可以说明这一点 just to illustrate the same point
大家应该都熟悉研制万络药的故事 you are well familiar with the Vioxx story
研制起步前 制药靶点就已经了解清楚了 you couldn't ask for a better prospective target
清楚得不能再清楚了 for drug design
人们知道有一种酶叫做环氧化酶 people knew about the so-called enzyme called COXes
以下是制药企业的一个经典案例 and this is a classic pharmaceutical industry playbook
人们发现了该酶的子类型 when the sub-types of the enzyme were identified
也将环氧化酶一型和二型区分开了 COX-2 was separated from COX-1
生物学现象表明 the emerging biology suggests that
如果不像阿司匹林那样把这两种酶都阻断 instead of blocking both which aspirin does
而是只阻断二型酶 if you just block COX-2
那么就能获得理想的抗发炎药效 you would have the desired ant-inflammatory effects
不阻断一型酶的原因是 you wouldn't block COX-1
它能保护胃肠道 which has a protective effects on the gut
也就能避免发生消化道出血现象的发生 and therefore you would peel away the propensity for GI hemorrhage
因此这是个经典的选择性制药法 so this is a classic selective approach
而且取得了效果 it worked
默克公司选择性地阻断二型酶 the company hit COX-2 selectively
这样的话二型酶抑制剂 the COX-2 selective inhibiter was still
在止痛和抗发炎的同时 analgesic and anti-inflammatory
很少会引起消化道出血 they had less propensity for GI hemorrhage
这种药已经面市 they are put on the market
默克公司把它称为万络 Merck struggled to call it Vioxx
大家应该都知道后来的事 and you know the end of the story
也就是在大量患者实际使用后 which is that only a large patient experience
人们发现 then was able to detect that
这种药有诱发心脏病 there was a liability in terms of enhanced risk for heart attack
和中风的风险 and stroke
后来宾夕法尼亚大学的加利特·菲斯杰拉德 after the fact Garret FitzGerald from the University of Pennsylvania
给出了一个我认为很有道理的原因 came up with a... I think a very plausible explanation
来解释这一现象 for why this is the case
他认为虽然理论都正确 he said actually, while this is all true
但环氧化酶一型还有一个负面效果 there is another effect of COX-1 which is a bad effect
他研究了这一点 and he played with this
他合成了一种叫凝血烷A2的东西 he made substance called thromboxane A2
它促进凝血的能力很强 which is actually really pro-coagulant
当我们不阻断环氧化酶一型 so when we spared COX-1
看似对肠胃有好处 we did some good for the gut
实际上却造成了一个问题 but we actually created a problem
因为它会使很多 by allowing more
促进血液凝固结块的成分持续存在 pro-coagulant clump-favoring mode to persist
这可能算是从事后角度解释为什么万络 and that may explain retrospectively why Vioxx
会使心脏病和中风的几率增高 was associated with increased heart attack and stroke
而这也是另外一个例证 maybe another example
告诉我们有时候一个研究最初很有希望 of that sort of early insight looking really good
但是经过生物机理一系列复杂的检验 and then the grandeur and complexity of biology
最后证明事实并非那样简单 later showing that things aren't quite simple
这是最后一张幻灯片 so this is my last slide
不 是倒数第二张 next to last slide
我认为现在是建立新的制药模式的时候了 I basically think this is the time for a new model
而且现阶段也是 and this is a place
类似艾莫利大学的学术医学研究中心 where academic medical centers such as Emory
参与其中的好机会 may be able to step in a very important way
让我们带着更严肃更谦虚的态度 and inherently return a little more vigorously and humbly
重新回到经验主义时代 to the era of empiricism
在人体上多做一些早期筛选工作 and basically do more early screening
当然 是符合医学伦理的工作 of course ethically in man
不要总认为 less of an idea that
一个明确的药效靶点 a known target is gonna have a known effect
会对确定的一类患者起作用 to a known population of patients
而要知道一个明确的治疗靶点 more of an idea that a known target
也许会对不同种类的人起不同的作用 might help the following several groups of people
而且要有一种深入探索研究的意愿 and willingness to go in and begin to explore
这种探索 that kind of exploration
只靠制药企业是无法完成的 can't be really accomplished by industry operations
因为他们接触不到患者 because they don't have patients
但是这种探索非常适合学术研究来进行 but it's very well suited for academic operations
而且我认为 and I think that is possible that
如果我们真能建立起这种平台的话 if we are to develop such a platform
我们也许可以与企业合作 that we might be able to partner with industry
甚至可以挽救一些非常有前途却被雪藏的 and even rescue some of the very interesting molecules
分子制剂 that are sitting indoors now
人们通常了解这些分子的标靶 with known molecular targets
但不了解其临床效用 and unknown clinical utility
现在我介绍艾莫利大学自己实验的一种化合物 I give you one cool local example of a compound
它叫做黄体酮 this is progesterone
在动物实验中它能起到保护神经的作用 which in animal models has neuro-protective effects
这是唐纳德·斯坦恩做的实验 work of Donald Stein
如果你把黄体酮 which if you look at it in comparison
与其他的具有保护神经作用的化合物 to the many different kinds of compounds
做一个比较的话 that ultimately end up having neuro-protective effects
你会发现它们没有什么区别 It would be hard to pick out
那么如果我是一个制药企业的老板 in a sense if I were a pharmaceutical head
我就会说 I would say
我的公司没有什么必要 there probably would not be any basis for a company
把宝都压在黄体酮上 saying the progesterone is where they put the big bet
在它身上花费巨资 and spend gazillions of dollars
但是唐纳德·斯坦恩对这种分子很有信心 but Donald Stein having a sense of confidence in this molecule
他与急诊医学系的一些医生 and together with physicians in Emergency Medicine Department
比如大卫·怀特和亚瑟·凯勒曼 such as David Wright and Arthur Kellerman
他们一起把这项实验推进到了实际的第二阶段 basically advanced it to a true phase 2 trial
而格雷迪医院内的脑外伤患者数量 and the volume of patients seen in Grady with traumatic brain injury
足够支持他们的第二阶段单边实验 was sufficient to support single side phase 2 trial
这就是实验结果 很鼓舞人心 and this was the result, it's very promising
人们接受…… people treated...
患有脑外伤的人在接受黄体酮后 humans with traumatic brain injury treated with progesterone
死亡率降低了 had lowered mortality
这个结果真的很鼓舞人 so this is indeed a very encouraging result
它是学术平台的直接应用 it's an application of academic platform
从根本上是经验性质的 fundamentally empiric
这个结果出来后 with this result in hand
国家卫生研究所现在对其很感兴趣 the NIH is sufficient interested now to get serious
目前正在进行进一步的商讨 there are very advanced discussions ongoing
考虑是否进行多中心参与的第三阶段试验 about a multi-center phase 3 trial
我们期待能够真正地生产出第一种 that we can all hope to actually produce the first
人脑神经保护类药物 human brain neuro-protector
谢谢大家 thank you
我对你的问题的理解是 So the question as I understand
你问的是 you are asking
关于药物对生命作用的多样性 about heterogeneity in drug action in the biology versus
以及在目标人群中的多样性 heterogeneity in the target population
也就是说患上一种疾病的不同变异的人群 people who have different variations of a disease
学生:不仅仅是患者 Student: Not only the people
还有不同病症发作的情况…… but the situations that they will show up...
教授:好的也就是说在一段时间内 Prof: Sure, different places
不同地点 不同发病过程 等等 in the time course trajectory, etc.
这个问题问得很好 it's a very good question
这两个因素在任何临床实验中 and the both factors both are generally complicating factors
总体上都是很复杂的 across the board in any clinical trial
但是第二个问题 that second issue though
即 患有相同疾病的人体现出的病症多样性 the heterogeneity in people with ostensibly the same disorder
也开始受到越来越多的关注 is increasingly recognized
也是预防创新计划的核心 really at the heart of Predictive Health Initiative
等到我们能够搞清楚 the era of individualized medicine will gradually come
每个人之间的差别之后 as we are able to understand
不管是基因区别 person to person differences
还是发病时间过程的区别 到那时 whether they are based on genetics
量体裁药的医药治疗时代会慢慢到来的 whether based on differences in time course
到那时就能根据个体的特殊情况对症下药 and we can begin to adjust our therapies to tailor to the individual
那样就能提高有效疗效 that would bring in increasingly better effects
而减少副作用 with increasingly less side-effects
目前我们吃的药片都是一样的 right now we just take the average pill
所有的药片都一样大小 对吧？ it's always the one size, right?
而不考虑成人患者体型的区别 even look at the range of the body size of the adult population
我们不得已才让药片都统一大小 we really do have a one-size-fits-all mentality by necessity
而随着时代进步 and progressively
我们会有为个体量身打造的药物 we will move to individualized medicine
而这个目标 and that would be something
就是艾莫利大学的防治创新计划所努力的方向 which the Emory predictive health initiative will help spear ahead
最后一个问题 one more question
学生:我的问题是 Student: My question is
关于高等大脑功能的疾病 in terms of higher brain function
比如精神疾病的范围内 for example like psychiatric disease
你是怎么看待 what is your opinion of the extent
药物与安慰剂影响患者行为的不同？ which drugs can affect behavior over placebo?
药物的作用比安慰剂的作用大多少呢？ how much stronger is the drug's effect than placebo effect?
教授:你是在问 Prof: So the question is
精神治疗药物的作用与安慰剂作用的比较 how does psychotropic drug effects compare with placebo effects
这很难一概而论 it's hard to generalize
因为有太多种治疗精神疾病的药物了 there are so many classes in psychotropic drugs
但是我认为现有的精神药物…… but I think the known psychotropic agents...
神经医药学有很多药物 neuro-pharmacology is populated with drugs
都可以对中枢神经系统起显著作用 with considerable actions on the central nervous system
但是 不可以低估安慰剂的作用 However, the placebo effect is never to be underestimated
它的作用很有可能是有生物学根据的 and it's probably very biology-based
当人们相信他们的病能治好时 when people begin to believe that they are gonna get better
脑部的相关机理会被激活 brain mechanisms are triggered
能够促使脑部 that actually shift brain biology
和其他器官的生物活动 as well as potentially other organism biology
达到人类的极限 towards the human most
安慰剂不是没有效果 placebo effect doesn't mean non-existent effect
这种效果是基于信念的 it's the effect based around conviction
但是这是个很大的…… but that's very large...
我觉得可以说现在的神经药物 I think it would be fair to say current neuro-pharmacological agents
是能够与安慰剂区别开的 are able to distinguish against placebo
否则它们也不能够通过临床试验 otherwise they wouldn't have been registered
也就没法注册了 through clinical trials
谢谢大家来听我的讲座 appreciate your attention
谢谢 thank you
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