京领嘉宾 | 诺贝尔生理或医学奖得主解读基础科学在创新过程中的重要作用
2020年12月25日，
（点击榜单名称可进入链接观看完整榜单），
并且共邀请了五位主旨演讲嘉宾：诺贝尔经济学奖得主、哈佛大学校级教授马斯金教授；北京一零一中（教育集团）校长、国家督学陆云泉；剑桥大学终身正教授、院士卡德维尔教授；诺贝尔物理学奖得主巴里什教授；诺贝尔诺贝尔生理或医学奖得主谢克曼教授参与京领榜单发布会暨诺奖创新论坛，并在与会嘉宾共同见证下重磅发布2020中国国际学校系列排行榜。
诺贝尔生理或医学奖得主、美国国家科学院院士
兰迪·谢克曼（Randy Scheckman）
受邀在论坛上发表了精彩演讲。
嘉宾介绍
谢克曼教授
诺贝尔生理或医学奖得主
美国国家科学院院刊前主编
美国国家科学院院士
美国艺术与科学院院士
谢克曼教授是世界知名生物化学家和细胞生物学家，美国国家科学院院士，美国艺术与科学院院士。2013年，基于在细胞膜囊泡运输方面开创性的贡献，谢克曼教授与詹姆斯·罗思曼和托马斯·聚德霍夫共同获得诺贝尔生理学或医学奖。谢克曼教授还是美国细胞生物学学会2010年E. B.威尔逊奖、2011年亚瑟·科恩伯格和保罗·伯格终身成就奖、德国生物化学学会奥托·沃伯格奖的获得者。谢克曼教授积极倡导呼吁学术期刊出版改革和开放获取科学出版物，并担任由霍华德·休斯医学研究所、马克斯·普朗克学会、惠康基金会联合发布的开放获取期刊《eLife》的编辑。
谢克曼教授作为诺贝尔生理或医学奖得主、世界知名生物化学家和细胞生物学家，美国国家科学院院士，美国艺术与科学院院士，在本次论坛中进行了深刻的发言，阐释了基础科学在创新中的重要性。
京领在此独家放送谢克曼教授的精彩演讲，以飨读者。（扫描文末二维码可观看完整发布会回放）
以下是谢克曼教授的演讲内容：
谢克曼教授在京领榜单发布会暨诺奖创新论坛上的精彩演讲
01
大家好，欢迎来到京领榜单发布会暨诺奖创新论坛，我是Randy Scheckman，加州大学伯克利分校细胞生物学系的教授，我要欢迎我中国的朋友们、理工科的学生们、有抱负的年轻医学博士和他们的家庭成员们。因为今天我想要简单的讲述一下，为什么我觉得基础科学对过程的基本理解如此重要。
比如我的案例提到的是细胞是怎么工作的，这能引导我们从大方向了解我们所面对的问题，比如我们现在正在遭受的流行病以及衰弱性疾病，如神经退行性疾病，等下我会专门讨论一个的例子。
但在我讲述之前，我想先描述一下我的发现之路来引导大家理解，我想说明的基础科学的重要性。
当我在加州成长的时候，我开始对微生物感兴趣。我感兴趣是因为我那会有一个显微镜，我是通过我自己在周围邻居附近帮忙干活挣得钱买的，那是我高中时期一个博世伦的学生显微镜，我一直用它研究当地科学展会的项目。但我上大学的时候就把这个显微镜闲置了，再后来我就成为了加州大学伯克利分校的一名教职员工，并且我有继续研究微生物学。因为我觉得了解简单的有机体有助于我们探索更有难度的、和更复杂的有机体问题。
02
让我来通过展示酵母细胞的图片来给大家说明我的观点。
这些是用来烤面包和发酵酒精的细胞，但它们是可以帮助我们理解基本生命过程的强大实验有机体，因为就像大家看到的，酵母细胞使用的是与人类细胞制造蛋白质分子一样的过程机制，就是把它们打包并运输到细胞外，这个过程叫做蛋白质分泌，这对于我们身体里的每一个细胞都很重要。因为它们负责组织运送进入血液和进入淋巴系统，抗体分子以及胰岛素之类的激素里的蛋白质。这些全部都要被打包进细胞里，然后再运输到细胞外，所以我决定在面包酵母中研究这个过程，因为我相信它最终会和人类细胞共享相同的机制。
然而，从之前到现在，研究一个可以在实验室大量生长的有机体都要简单得多，而且也可以对它们进行简单的基因操作。
这是一个生长在葡萄表面的v簇细胞，当酵母细胞生长和分裂时，它就会从发芽开始它的生命，然后它的芽会越长越大，酵母细胞就会在90分钟左右的时间里分裂，最终芽会变的和母细胞一样大，然后细胞就会分裂成两半。如果培养基因中的营养条件良好，细胞就会继续这样，然后再多代中呈指数增长。
如果你看看酵母细胞的内部，会看到一些可以表明它和其他细胞一样的证据。
这些点叫做核糖体，它们就像缝纫机般的小机器一样把氨基酸缝合在一起形成蛋白质。但细胞中也有内膜，其中有一些非常类似于在人体细胞中看到的薄片。我们要注意的是这些叫做血管的小膜，我们在遗传实验和生化实验中都有呈现出，这些血管可以捕获细胞外分泌的，可以让它生长在葡萄表面的蛋白质。
现在我们从多年的工作中发现酵母细胞用来组织这个过程的基因也和我们体内的细胞做这个过程的基因是相同的，甚至与胰岛素这样制造和分泌的分子都一样，这也让酵母细胞有可能成为组织临床上重要蛋白质生殖和分泌的一个平台。
就比如说现在全球三分之一供应用来治疗糖尿病的重组胰岛素都是在巨大的发酵罐中制造的，成千上万的领导者在成长过程中把胰岛素分泌到这种生长介质中，然后从中分离出胰岛素并用于治疗糖尿病患者。
酵母细胞也可以用来制造我们使用的疫苗。像你们接种的乙肝疫苗在中国曾是一种可怕的传染病，世界上90%的肝癌都是由乙肝引起的，现在都可以有效地通过酵母颗粒进行免疫。因为我们的发现，或许它们也会在更广泛的临床环境中得到应用。
03
七年前，我也因此获得了诺贝尔奖,你们可以看见照片里我在斯特哥尔摩从瑞典国王手中接过证书，这是七年前的12月份了。
恰恰就在颁奖典礼之前，我向斯特哥尔摩的诺贝尔博物馆捐献了那个开启我科学之旅的显微镜。如果你们有机会去斯德哥尔摩，你们可以去看看我的那个显微镜，那还描述了这个显微镜在我对科学产生兴趣的过程中起了多么重要的作用。
04
现在我要说另一个话题，不过逻辑是相同的，这就是基础科学在理解像帕金森氏综合征等复杂疾病方面的重要性。
你们可能会认识帕金森的患者，它通常结合着行动困难或有时有语言障碍或咳嗽困难等症状，它通常伴随着认知功能的衰退和发展性痴呆症，这是一种非常严重的疾病，它可以持续发展很多年，并且有不可避免的致命性。当人们患上帕金森时会有各种各样的死亡原因，然而我们还不了解这种疾病的根本原因，我想跟你们讲讲我们知道的一点事情，以及我如何努力来获得这种疾病的分子和细胞。
首先，这种疾病在世界范围内都影响深远。这是一种流行病，和我们现在遭受的流行性新冠病毒没什么不同，但有一个区别就是，新冠病毒在之后的几年中肯定会因为疫苗的诞生被控制住，但帕金森会一直持续着，甚至是变得更加具有普遍性，数百万的患者都在遭受这种疾病。
据估计，在未来的十年左右，全世界将有近2000万人患上这种疾病，这种病虽然大部分都是因为老龄化，但并非全部都是因此。事实上，这种疾病不分国界，就像冠状病毒大流行一样。我要特别提醒你们，现在几乎有一半，并且在将来将会有超过一半以上的帕金森患者都会在你们国家，因此这是一个至关重要的问题，无论对于中国政府还是世界政府都要试图了解以及开发出更好的治疗方法。
现在我来告诉大家一些我们已知的成果和相关问题。200年前，这种疾病最初被认为是运动障碍，直到近100年来，这种疾病才被理解为是大脑内某个区域无法分泌出多巴胺这种化学物质而导致的。多巴胺是使神经细胞能够进行互相交流的物质，同时控制人体肌肉运动以及其他的情绪和认知能力。
看一下现在图中大脑的这一区域。因为其他原因死亡的人的大脑这部分区域是这样的在这一区域内，你可以看到在中脑有一小条黑带，这一部分被黑色素的存在突显了出来。这些黑色素由黑色素细胞构成，可以看到因为其他原因死亡的人的大脑这部分区域是这样的，然而在因患帕金森而死亡的人的大脑中，那条由黑色素构成的黑带大部分都消失了。那是因为在死亡的时候，那些黑色素细胞早就死亡了。
事实上，当某人出现早期帕金森的症状时，脑中有将近一半的黑色素细胞都已经死亡了，并且剩余的细胞还会继续死亡。目前为止，没有任何方法有助于控制黑色素细胞死亡。
一百年前左右,另一个名为路易（Frederick Lewy）的英国医生观察了大脑有这一区域有带状痕迹的帕金森患者的历史情况。他看到一些细胞是黑色的，现在那些细胞被称为路易氏体，那些似乎是损坏的蛋白质和膜的堆积，并且也许那就是这些细胞死亡的原因，或者是细胞和膜累积在一起只是细胞正在死亡的症状之一。
我们不知道是否是这样，不知道这样的症状是什么原因导致的，也不知道如何阻止这样的症状发生，因此，我们中的许多人共同研究了这些基本过程，我们可以在实验室培养生长这些大脑里的细胞。这是一个动画版的神经细胞，我们怎么来研究这些细胞呢？我们需要怎么样来了解帕金森这个疾病呢？
05
几年前，我同意领导一项叫做跨帕金森症的科学调整工作。这个项目是从美国开始的，现在变得越来越国际化。
我们召集了来自11个国家的调查人员团队和近100个不同的实验室，这些团队都共同从事研究同一主题，这样才可以帮助我们发现疾病的根本所在。我们还和一个组织一起研究，这个组织是美国的Michael J Fox基金会，我们在跨越国界，使人们参与协作其中，因为这不是某一个实验室就能解决的问题。
因此，你可以把这种疾病视为一个拼图，一个包括很多碎片的拼图，就像这只是一个有着少量碎片信息的拼图，但仅通过这些现有的碎片就能看出来它很复杂，这是属于路易聚集体中的一小部分。
众所周知，这种蛋白质以疾病的遗传形式在细胞内环变质。但我们也知道线粒体，也就是细胞的动力室必须要清洁，它们如果被破坏了就必须被清除，如果它们在正常的大脑细胞生长过程和营养过程中受损，那这些线粒体就被破坏了，然后这些被破坏的线粒体就要被重新认知并消除，否则线粒体的破坏会严重破坏细胞的正常功能。
因此，控制系统需要始终保持更新，免疫系统在切断大脑以确保消除伤害方面也有一定作用，但有时也可能会恶化情况，也可能会杀死那些不应该被杀死的细胞，并且有时候降解需要去除的蛋白质会失败。但无论怎样，我们已经有了很多碎片信息，现在这是看起来一个简单的拼图了。
但事实证明，这个拼图要复杂的多，有许多的不同的基因和途径已经在发挥作用了，现在的挑战是要解决一个可能包含数千个碎片信息的拼图，然后将它们放在一起创建成图片，这样我们就可以看到那些需要通过药物测试的链接，并且看看我们能否阻止此步骤。
现在我要介绍几种我们小组准备专注于的方法，因为他们似乎在分子和细胞的攻击上特别成熟。这其中包括基因，这个过程就是基因在起作用，这些基因在帕金森疾病中以牛顿家族的形式出现，这就是我所说的它对免疫系统起的作用。它可能对增强垂死的大脑区域的损害有关系，我们甚至都不知道那个连接神奇的神经元到其目标的接线图和电路，这些是即使在普通人脑中也需要被充分理解的。
这是一个漫长的阶段，在疾病发展之前就有数十年的时长，有些病人有一些症状，似乎预示着这种疾病的最终发展，我们还不知道这些症状的意义，我们不知道如何标记这个疾病的进展，也没有可以使用的生物标记，我们为了真正的了解这个疾病需要尽早地探索所谓的前驱期。
06
好了，我的幻灯片结束了，但我想再重申一次了解这些过程有多重要。
它在分子和细胞上都对帕金森疾病有害，但我相信我们可以解决它，因为与其它世界上更困难的疾病问题，像心脏病、癌症等，了解了它的分子和细胞并且了解是哪里出了问题就会让我们开发出更有效的药物和手术来控制疾病。尽管心脏病和癌症一直还是致命的疾病，但是因为我们有有效的治疗方案让越来越少的人会因此死亡，对于狭窄的退行性疾病，我们也需要同样如此，比如帕金森和阿尔兹海默症。
所以我希望你们能对我们对这个问题的热情有所了解，了解事物的基本工作原理，我希望你们也可以挑战自己，让自己也对未来感到兴奋。
祝你们好运！
演讲原文
English Version
Hello. Welcome to the Kinglead Christmas conference. My name is Randy Scheckman. I'm a professor in the department of molecular and cell biology at the University of California Berkeley. And I’d like to welcome my friends in China, students of science,aspiring young physicians, and their family members. Because today I'm gonna tell you briefly about why I feel so strongly that basic science of fundamental understanding of processes.
In this case of how cells work can lead us in tremendous directions in understanding the problems that we face,including, for instance, the epidemic that we now suffer and the debilitating diseases, such as nerve degenerative diseases. And I’ll focus on one particular in a moment.
But before I do that, I wanna lead in with a description of my own path to discovery. How that can help you understand the point that I wish to make about the importance of basic science.
So, when I grew up in California,I became interested in microorganisms. And I did this because I had a microscope that I received of that I purchased with earnings that I made with the chores that I did around the neighborhood.This was my Bausch and Lomb student microscope that I used throughout high school to work on independent projects that I entered in local science fairs.
But I put this microscope away when I went off to college. And later as I became a faculty member at the University of California, Berkeley,I continued to study microorganisms because I felt that understanding simple organisms could lend itself to discoveries that were much more difficult to do with more complicated organisms.
And let me make my point by showing you this image.
Which is of yeast cells. These are cells that are used to bake bread and to ferment alcohol,but they are a powerful experimental organism to understand basic life processes.Because as you'll see, yeast cells use the same mechanisms,the same processes that human cells use to manufacture protein molecules and to package them for export outside of the cell. This is a process called protein secretion that is very important for all the cells in your body,because they are responsible for organizing the shipment of proteins that go into the blood that go into the lymphatic system, antibody molecules, hormones like insulin.All these things must be packaged inside of the cell and then exported outside of the cell. And I decided to study this process in baker's yeast,because I believe that it would end up sharing the same machinery as a human cell.
And yet, it has been and still is much simpler to study an organism that you can grow in large quantities in the laboratory,and with which you can do simple genetic manipulations.
This is a cluster v cells that you might find growing on the surface of a grape, and as a yeast cell grows and divides,it begins its life by sending out a small bud. And this bud gets bigger and bigger during the 90 minutes or so that it takes the yeast cell to divide.Eventually the bud becomes the same size as the mother cell, and then the cells divide in half. And if the nutritional conditions in the growth medium are good,the cell continues to prost do this and can grow exponentially over many generations.
Now if you look inside a yeast cell,you can see some evidence that it's like other cells.
These dots are called ribosome, there the little machines like sewing machines that stitch amino acids together to make proteins.But the cell also has internal membranes, some of which are very much like those that are seen in thin slices through human cells.We were particularly interested in these small little membranes called vessels,and we showed in genetic and then in biochemical experiments that these vessels can capture proteins that are gonna be secreted outside of the cell to allow it to grow on the surface of a grape.
Now we discovered in the course of our work over many years that the genes that yeast cells use to organize this process are the same genes that we use in the cells in our body to do the same thing, even to manufacture and secrete molecules like insulin.And it became possible to use yeast cells as a platform to organize the production and secretion of clinically important proteins.
So for instance, now, 1/3 of the world's supply of human recombinant insulin that's used to treat diabetic patients is manufactured in giant fermentation vats,as you see here,tens of thousands of leaders growing up to secrete insulin into this growth medium,from which it can be isolated and used for treatment of patients who suffer from diabetes.It's also been possible to use yeast to manufacture the vaccine that you use when you're immunized against hepatitis b virus,which is a terrible endemic infection within China,90% of the liver cancer that arises in the world is as a result of hepatitis b infection.and that can now effectively be treated by immunization with particles that are made in yeast.Well, as a result of our discoveries,and perhaps also their application in broader clinical setting.
Now seven years ago, I was awarded the Nobel prize. And here, you see me receiving the diploma in the middle from the king of Sweden in Stockholm.on December now seven years ago.
Now, in addition, just before this award ceremony,I donated to the Nobel museum in Stockholm,that old microscope that began my journey in science.If you ever find yourself in Stockholm,please drop by to see that old microscope together with a description of how it was so important in my development of an interest in science.
Now I'm gonna turn to a different topic, but the same logic.And that is how important basic science can be in understanding even complicated diseases like Parkinson's.
You may know people who suffer from Parkinson's.It's often associated with difficulty moving,sometimes difficulty speaking or coughing.It often is accompanied by a decay in cognitive function, a developing dementia. It is a very serious disease.It can progress for many years.and it is inevitably fatal.And people die for various reasons when they are flipped with Parkinson's.And yet we don't understand the fundamental basis of this disease.I want to tell you what little we knowand how I'm organizing effort to try to get the molecular and cellular basis of this disease.
First of all, the diseases profound around the world.It's a kind of a pandemic,not unlikely the pandemic that we suffer from now from covid-19.The difference is that the pandemic will certainly be controlled in the next year with a vaccine,whereas Parkinson's continues to march on,it's becoming even more prevalent.Millions of patients suffer from this disease.
And it's estimated that within the next decade or so,almost 20 million people around the world will suffer from the disease,which is largely, but not always a disease of aging. In fact, the disease observes no national boundaries,just like the coronavirus pandemic.And a particular note to you,almost half now, and in the future,over half of the patients who suffer from Parkinson's disease will be in your country.So, this is something of vital concern to the Chinese government and governments around the world to try to understand this, to develop better treatments.
Now let me tell you a little bit about what's known about what goes wrong.The disease was first recognized as a movement disorder, now 200 years ago,it's only been in the last 100 years that the disease and understanding is focused on the inability of a region of the brain to manufacture a chemical called dopamine,which allows nerve cells to communicate with each other,and which, among other things, controls our bodies ability to move and other aspects of emotion and cognition.
Now this region of the brain can be recognized in a section of a brain,in this case, of a person who died for other reasons.And in that section, you can see a dark band that appears small region in the mid brain that is highlighted by the presence of a pigment called melanin,which happens to be produced also by these cells.And you can see this in the brain of someone who died for other reasons,in the brain of someone who died from Parkinson's disease,this band is largely gone.That's because by the time of death,almost all those cells have died.Indeed, when someone presents with the symptoms of the disease first some years earlier,almost half of those cells have already died and they continue to die.And nothing can be done yet to control that death.
Now, more recently, a hundred years ago,another British physician by the name of Frederick Lewy looked at history, logical stains of this region of the brain in patients who were suffering from Parkinson's.And he could see that some of these cells had dark bodies that are now called Lewy bodies.That seemed to be an accumulation of damaged proteins and membranes that stick together and may be the cause of death of these cells,or it may just be a symptom as they are dying, that these things begin to accumulate.
We don't know that. We don't know what brings this about.We don't know what can be done to arrest it. And so many of us have banded together to study these fundamental processes,In the cells of the brain, we can grow in the laboratory.This is a cartoon of nerve cells.Now, how do we study these cells?What can we do to try to understand Parkinson's disease?
Several years ago, I agreed to lead an effort called aligning science across Parkinson's.An effort started in the United States,but which has since become international,where we have brought together teams of investigators from 11 different countries,nearly a hundred different laboratories, teams who agreed to work together on common themes that will allow us to get to the basis of the disease.We work along with an organization called the Michael J Fox foundation in the United States.But we reach across borders to countries around the world to engage people in a collaborative effort.Because this problem is larger than any one laboratory can solve.
So you might look at the disease as a kind of a puzzle,the puzzle includes pieces.This is a simple depiction of the puzzle with only a small number of pieces.But already just looking at these pieces, you can see that the puzzle is complicated.,this is a protein that is part of those aggregates in Lewy bodies.
And it's known that in a genetic form of the disease, this protein goes bad inside the cell.But we also know that mitochondria, the power houses of the cell, must be cleanse.They must be removed if they are damaged in the normal course of a cell growing in the brain and being nourished,these mitochondria become damaged,and the damage mitochondria have to be recognized and gotten rid of,or else damage mitochondria can do a great deal of destruction to the normal function of a cell.
So that control system must be renewed all the time. There's also some role for the immune system in severing the brain to make sure that damages gotten rid of.And sometimes that may go bad,and may actually cause the death of these cells when they shouldn't be killed.And sometimes there's a failure in degrading proteins that need to be removed.Anyway, there are lots of these pieces.Now, this is a simple puzzle.
It turns out that the puzzle is much more complicated,there are many different genes and many different pathways that have been suggested to play a role.And the challenge now is to take a puzzle that may consist of thousands of pieces,and put them together to create a picture that will allow us to see these of links that need to be tested with drugs to see if we can block this step.
Now let me just say there are several approaches that our group has decided to focus on because they seem like they're particularly ripe for attack at a molecular and cellular basis.And that includes the genes.The process is the pathways that these genes play a role in.These genes have turned up in newton forms in families with Parkinson's disease.There is a role, as I suggested, for the immune system,that may be responsible for or enhance the damage to the regions of the brain that are dying.We don't even know the wiring diagram, the circuitry that connects a dope magic neuron to its targets.These need to be fully understood even in a normal human brain.
And finally, there's a very long phase,sometimes decades long that precedes the development of a disease.And some patients have some symptoms that seem to predict the eventual development of the disease,we don't know what those symptoms mean,we don't know how to mark the progress of the disease.There are no biological markers that we can use.And we need to explore this early so called prodromal phase, to really understand the disease.
Now I'm gonna stop these slides,and just finish by telling you again how important it is to understand this process.
It goes bad in Parkinson's disease at a molecular and cellular level,and I'm confident that we can do this,because with other diseases that have been even more of a big problem in the world,such as heart disease and cancer,understanding the molecules and cells and what goes bad in those diseases has allowed us to develop drugs and surgical procedures that are very effective now in controlling these diseases.And though heart disease and cancer continue to be a killer,fewer people are dying because we have effective treatments.We need that same thing for narrow degenerative diseases like Parkinson's and Alzheimer's disease.
So I hope you've gotten a flavor for the passion that we bring to these problems,understanding how things work at a fundamental level.And I hope you now can challenge yourself to be excited about that in your future as well.
Good luck to you.
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