卡尔·赫鲁普，《如何不研究一种疾病：阿尔茨海默症的故事》（麻省理工学院出版社，2021年）

大家好。

Hello, everybody.

我是马歇尔·坡。

This is Marshall Poe.

我是新书网络的创始人兼编辑。

I'm the founder and editor of the New Books Network.

如果你正在收听这个节目，你应该知道新书网络是全球最大的学术播客网络。

And if you're listening to this, you know that the NBN is the largest academic podcast network in the world.

我们的听众覆盖全球200万人。

We reach a worldwide audience of 2,000,000 people.

你可能已经有一个播客，或者正在考虑开设一个播客。

You may have a podcast or you may be thinking about starting a podcast.

如你所知，这其中存在挑战。

As you probably know, there are challenges.

主要分为两类。

Basically, of two kinds.

第一类是技术问题。

One is technical.

你需要掌握相关知识才能制作和分发你的播客。

There are things you have to know in order to get your podcast produced and distributed.

第二类，也是最大的问题，就是你需要获得听众。

And the second is, and this is the biggest problem, you need to get an audience.

在播客领域建立听众群体是当前最难实现的事情。

Building an audience in podcasting is the hardest thing to do today.

请记住，我们NBM已经启动了一项名为NBN制作的服务。

Put this in mind, we at the NBM have started a service called NBN Productions.

我们的工作是帮助您创建播客、制作播客、分发播客，并托管您的播客。

What we do is help you create a podcast, produce your podcast, distribute your podcast, and we host your podcast.

最重要的是，我们会将您的播客分发给NBN的听众群体。

Most importantly, what we do is we distribute your podcast to the NBN audience.

我们已经为众多学术播客多次提供这项服务，很乐意为您效劳。

We've done this many times with many academic podcasts, and we would like to help you.

如果您有兴趣与我们探讨如何协助您的播客项目，请联系我们。

If you would be interested in talking to us about how we can help you with your podcast, please contact us.

只需访问新书网络首页，您就能看到NBN制作的链接。

Just go to the front page of the New Books Network, and you will see a link to NBN productions.

点击填写表格，我们即可展开对话。

Click that, fill out the form, and we can talk.

欢迎来到新书网络。

Welcome to the New Books Network.

大家好，欢迎回到新书网络。

Hello, everybody, and welcome back to New Books Network.

我是Galina Lemorenko，瑞士洛桑联邦理工学院神经科学博士生，专注于神经退行性疾病的生物化学与分子生物学研究，今天将由我担任主持人。

I'm Galina Lemorenko, doctoral candidate in neuroscience with a focus on biochemistry and molecular biology of neurodegenerative diseases at EPFL in Switzerland and will be your host today.

今天我们将与Carl Hareb探讨他的新书《如何不研究一种疾病：阿尔茨海默症的故事》。

Today, we'll be talking to Carl Hareb about his new book, how not to study a disease, The Story of Alzheimer's.

一位阿尔茨海默病领域的权威学者，将带我们回顾过往的失败历程，并为治愈之路指明新方向。

An authority on Alzheimer's disease offers a history of past failures and a roadmap that points us in a new direction on our journey to a cure.

几十年来，我们最优秀的一些医学科学家致力于寻找阿尔茨海默病的治疗方法。

For decades, some of our best and brightest medical scientists have dedicated themselves to finding a cure for Alzheimer's disease.

发生了什么？

What happened?

治疗方法在哪里？

Where is the cure?

最大的突破发生在二十五年前，此后进展甚微。

The biggest breakthroughs occurred twenty five years ago, with little progress since.

在《如何不研究一种疾病》中，神经生物学家卡尔·赫洛普解释了为什么九十年代对阿尔茨海默病的发现未能结出果实，并为未来研究指明了方向。

In How Not to Study a Disease, neurobiologist Karl Herop explains why Alzheimer's discoveries of the nineteen nineties didn't bear bear fruit and maps a direction for future research.

好的，卡尔，欢迎来到节目。

Well, Carl, welcome to the show.

谢谢。

Thank you.

在我们经历全球疫情这一前所未有的时期时，我想请你先谈谈这对你及你的工作产生了哪些影响，以及你从这段经历中收获的主要经验。

So as we're living through the unprecedented times of the global pandemic, I was wondering if you could start by telling us how has it influenced you and your work and maybe some main takeaways that you have gathered from this experience.

疫情无疑在各个层面都造成了重大干扰。

The pandemic certainly has been a major disruptor, at just about every level.

显然在实验层面，我们不得不缩减许多正在进行的工作，并完全暂停了数月之久。

So obviously at the bench level, at the experimental level, we had to wind down a lot of what we were doing and put it on complete pause for many months.

虽然我们已恢复工作，但至今仍未达到满负荷运转。

We're back up again but not even still at full capacity.

在学术交流方面也遇到了巨大问题，因为我们所有的线下会议——无论是访问学者的研讨会还是参加国内外会议——都被完全搁置了。

And intellectually it was also a tremendous problem because all of the in person meetings that we would have, either seminars of visiting scholars or attendance at national and international meetings, all of that was completely put on hold.

而且，虚拟会议也不错。

And, virtual meetings are fine.

它们确实有其存在的价值，总比没有强。

They certainly have their place and they're better than nothing.

但我觉得，充其量只能说这是段艰难时期。

But, I would say it's been a difficult time at best.

这影响到你的出行了吗？

And has it affected your travel?

你觉得你会进一步限制出行吗？

And do you think you will limit your travel further?

噢，完全会。

Oh, completely.

唯一参加过的会议——现在回想起来仍然后悔——是七月份在丹佛举办的国际阿尔茨海默症会议。

The only meeting I've gone to, and I still look back and regret it, was I went to the International Alzheimer meeting in July in Denver.

我并不后悔参会本身。

I don't regret the meeting itself.

会议很棒且令人振奋，但我觉得自己与数百甚至上千名国际旅客接触的行为有点鲁莽。

It was wonderful and very exciting, but I think it was a little bit reckless on my part to, mingle with, hundreds, if not thousands, of other international travelers.

所以是的，在可预见的未来我没有任何参会计划。

So yes, and I have no plans for any meetings, for the foreseeable future.

能多介绍一下你自己吗？

So can you tell us a bit more about yourself?

嗯，我认为自己是个对人类疾病生物学基础感兴趣的基础科研工作者。

Well, I guess I would characterize myself as a basic scientist interested in the biological basis of human disease.

在学术层面上，我的兴趣在于神经退行性病变的过程。

At a scholarly level, my interest is in the process of neurodegeneration.

我研究过从影响幼儿的罕见病如共济失调毛细血管扩张症，到我职业生涯中投入最多时间的阿尔茨海默病及其他晚发性痴呆症。

And I've studied diseases from rare ones like ataxial telangiectasia that affects young children to the one where I've, I think, spent most of the time on my career and that is studying Alzheimer's disease and other late onset dementias.

我曾在世界各地实践这门技艺，自认为对科学持有国际视野，并非常重视科学的国际性特质及其对整个事业的强化作用。

I have plied this craft, literally all over the world, and think of myself as having a somewhat international outlook on science and very much value, the international complexion of science and how that strengthens the entire enterprise.

你是怎么对科学产生兴趣的？

And how did you get interested in sciences?

如果你真想知道，我想可以追溯到我大学二年级时上的一门遗传学课程。

Well, if you really want to know, I think I could trace that back to a course in genetics that I had the second year of college.

我常把那门课程比作植入我脑海的种子，从此生根发芽。

And I often attribute that course to planting the bug in my brain that has stayed there ever since.

我放弃医学院转而攻读博士学位这件事，让我父母非常失望。

It was a great disappointment to my parents that I was diverted from going to medical school and ended up doing something worthless like becoming a PhD instead of an MD.

不过现在看来结果还不错。

But it seemed to have made out all right.

在你的职业旅程中，有没有遇到过特别支持你的导师？

And along your career journey, were there any mentors that you find really supportive?

哦，当然有。

Oh, absolutely.

他们来自不同年龄段，风格各异。

And they come in at all ages and all flavors.

我喜欢说，我最好的导师中有些是学生，因为在努力以他们能理解的方式教学时，我反而对自己的专业有了更深理解并提升了知识水平。

I like to say some of my best mentors have been students where I feel that in struggling to teach them in ways that can reach them, I actually learn a lot more of my own craft and improve my own knowledge.

毫无疑问，我在布兰迪斯大学遗传学课程的那位教授钱德勒·富尔顿，将成为我的人生导师之一。

But certainly that professor from that genetics course at, Brandeis University, Chandler Fulton, would be one of my mentors.

我非常感激我的研究生导师埃里克·舒德，以及博士后导师迪克·马伦和汉斯·特南。

I'd give great stock to my graduate advisor, Eric Schuder, and postdoctoral advisors, Dick Mullen and Hans Ternan.

这一路上，有无数人影响过我，他们既引导了我的思考，也磨砺了我的思维。

And along the way, just countless people have influenced me and both guided my thinking and sharpened my thinking.

对于那些正在考虑从事科研而非医学事业的年轻听众，您会给他们什么建议？

And what would you tell our younger listeners who might be considering career in research instead of medicine?

我想说，我发现这是非常美好的人生，但你必须过自己的生活，而不是我的。

I would say it's I have found it to be a wonderful life, but you have to live your life, not me.

我认为你需要自己做出决定。

And I think you need to decide for your own.

这不是一条轻松的路，但我觉得人生没有哪条路是轻松的。

It's not an easy path, but I don't think any path in life is easy.

我发现这是世界上最棒的工作之一，任何东西我都不愿交换。

I have found it to be one of the greatest jobs in the world and wouldn't trade it for anything.

但这完全是个人的选择。

But it's a very individual decision.

我只想鼓励年轻人，无论选择哪条道路，都要保持好奇心，不断提问。

I just would encourage younger people to, no matter what path they choose, to always stay curious and keep asking questions.

即使你进入更定向的领域如医学，或发现自己身处产业界而非学术界，又或是从事更应用型的科学领域。

Even if you go into a more directed field like medicine or find yourself rather than an academic industry academic pursuits, find yourself in industry or, an area of science is perhaps more applied.

保持好奇心，永远要提出问题。

Stay curious, always ask questions.

即便在医学和工业领域，培养好奇心也能让你在工作中表现得更好。

And even in medicine, even in industry, you'll do better at what you do for nurturing that curiosity.

哦，这些观点非常精辟。

Oh, these are excellent points.

感谢分享。

Thank you for that.

那么你的新书是《如何不研究一种疾病：阿尔茨海默症的故事》。

So your latest book is How Not to Study a Disease, the Story of Alzheimer's.

能谈谈你是怎么开始写这本书的吗？

Can you tell us how did you come to writing it?

当然可以，这其实正好与我刚才关于好奇心的观点相呼应。

I can, and it actually follows nicely from the comments I just made about curiosity.

我觉得自己很难不加质疑地接受某个领域的教条。

I guess I find it difficult to just, unquestioningly accept the dogma of a field.

而我是在职业生涯中期才涉足阿尔茨海默症研究的。

And, I came to Alzheimer's research sort of in the middle of my career.

就像开头提到的，我最初的研究兴趣是细胞死亡。

So think I said in the beginning, my interest had been in cell death.

过去主要专注于儿童疾病的研究。

I had been focused mostly on, childhood diseases.

但像阿尔茨海默症这样具有显著神经退行性表型的疾病，很快引起了我的注意——事实也确实如此。

But clearly, with a major neurodegenerative phenotype, such as you find in Alzheimer's disease, it wasn't going to be long before it captured my attention and it did.

于是我转职到克利夫兰的西储大学，加入了那里的阿尔茨海默症研究实验室。

So I made the move to the Western Reserve University in Cleveland and joined the Alzheimer's Research Lab there.

作为一名已到职业生涯中期的科学家，我很快意识到，该领域许多被认为是既定艺术或教条的内容其实根本说不通。

And it very quickly became apparent to me, coming to it as a now sort of mid career scientist already, that a lot of what was purported to be settled settled art or settled dogma in the field just didn't make sense.

这些早期疑虑逐渐演变成一种挥之不去的怀疑：我们是否在以最佳方式——甚至合理方式——应对这种疾病。

And from those very early concerns, grew a nagging doubt that we were approaching this disease in the best way possible or even even a sensible way.

所以我常说这本书经历了异常漫长的孕育期。

So I like to say this book sort of had a very long gestation period.

确切地说始于2000年代初我在克利夫兰的时期。

It literally began when I was in Cleveland, which was in the early 2000s.

最终，正如我在书中描述的'第三次膨胀'事件，我彻底受够了。

And then finally, and I describe these events in the book with the event that I call the third inflation, I had simply had it.

我实在无法再保持沉默。

I just couldn't not speak up.

这促使我在专业期刊上发表了一系列文章。

And that led to a series of articles that I wrote, in the professional literature.

但我仍感到沮丧，认为需要不仅联系那些可能已厌烦我的同事们，更要面向更广泛的受众，解释我的挫败感来源，以及为何我认为阿尔茨海默病的故事实际上适用于整个行业，其教训远超对该疾病本身的研究。

But I remained frustrated and felt that I needed to reach out not just to my colleagues who were probably tired of hearing from me, but to a broader audience, and to try and explain where my frustration was coming from and why I thought that the story of Alzheimer's actually applied in an industry wide fashion and had had lessons beyond the study of Alzheimer's itself.

那么让我们深入探讨您书中讲述的科学发现和故事。

So let's delve into some of the science and the stories that you tell in your book.

让我们从最基础的内容开始。

And let's start from the very basics.

您能描述下什么是阿尔茨海默病吗？

Could you describe what is an Alzheimer's disease?

哈，你第一个问题就直指最难回答的核心。

Well, you've really hit the, the most difficult question for your first one.

那么让我说明一下，我会通过临床症状来定义阿尔茨海默病。

So let me just say I would define Alzheimer's disease by its clinical symptoms.

这是一种渐进性痴呆症，其特征表现为一系列特殊症状，受过训练的神经科医生能够识别。

So it is a progressive dementia that is characterized by a series of of peculiar symptoms, that a trained neurologist would be able to recognize.

其中最著名的症状当然是逐渐丧失形成和保留短期记忆的能力。

The most famous of these, of course, is the gradual loss of the ability to form and retain short term memories.

但除此之外，还有行为表现方面的症状。

But there are, in addition, behavioral manifestations.

比如攻击性、冷漠、抑郁，这些都是病情发展的症状。

So, aggression, apathy, depression, all symptoms of the progress of the disease.

最后，似乎大脑几乎没有任何区域能幸免于病变。

And finally, it appears that almost no region of the brain is spared.

在疾病末期，患者几乎总是需要住院治疗。

And at the end stages of the disease, an individual is institutionalized almost always.

他们甚至无法照顾最基本的需求，并且非常容易受到各种机会性感染。

They're unable to care even for their most basic needs and and are very susceptible to all sorts of opportunistic infections.

当然，我在书中提到的一个巨大悲剧是，这种疾病的病程异常漫长。

And, of course, one of the great tragedies, which, I mentioned in the book, is that it's an extraordinarily long disease.

从首次确诊到死亡通常需要超过十年时间，患者及其家人和护理人员承受的负担是巨大的。

It it takes, over a decade, from first diagnosis to, to death and, the burden borne by both the person with the disease and also their family and caregivers is, enormous.

那么阿尔茨海默病和痴呆症有什么区别呢？

And what is the difference between Alzheimer's disease and dementia?

官方定义中，痴呆症是更广泛的晚发性退行性脑疾病类别。

Officially, dementia is the broader class of, late onset degenerative brain disease.

但就目前定义而言，阿尔茨海默病无疑是痴呆症的主要类型。

But as it's currently defined, Alzheimer's is by far the major type of dementia.

所以阿尔茨海默病属于痴呆症的一种，但只是众多类型之一。

So Alzheimer's is a dementia, but it is only one of several types.

这让我非常震惊——我在您书中读到，当患者意识到自己正在丧失记忆时，他们更可能患的是其他类型痴呆症而非阿尔茨海默病。

And that's something that really strikes me, when I was reading in your book that quite often, more often than not, if the person recognizes that they are losing their memory, they're likely to have other dementia rather than Alzheimer's.

而阿尔茨海默病患者往往对此毫无察觉。

And with Alzheimer's, a person is quite often unaware.

是的。

Yes.

这种疾病有个非常奇特但持续的症状：患者对自己身上发生的变化毫无觉察。

It is a very strange but persistent symptom of the disease that, the person is unaware, of what's happening to them.

或者至少，他们无法表达这种觉察。

Or at the very least, they can't articulate their awareness.

但患者的变化对其家人朋友而言却相当明显。

But the change in the person is quite apparent to their family and to their friends.

那么现在，让我们从不同角度来谈谈对阿尔茨海默病的认知。

So now if we, talk a little bit about the perception of Alzheimer's disease from all of these different points of view.

比如从医生、像您这样的研究者，以及患者和家属的角度？

So for example, from physicians, from researchers like you, and also from patients and their families?

我希望能最终实现这三种视角的统一融合。

My hope would be that in the long run, those three views would be a unitary view that they would be united.

我们应改变现状——目前患者关注点与医生描述的病症存在差异，而医患双方的描述都应使用基础研究者能理解的术语，这样像我这样的实验室工作者才能开展有效工作，实现阻止病情恶化、甚至从根本上预防疾病发生。

And that we would leave the situation we find ourselves in now where what the patients care about is different than what the physicians, describe as the disease and that both the physicians and laypersons description would be couched in terms that basic researchers such as myself could go into the laboratory and actually begin to do productive work that would either, arrest the disease, and prevent it from progressing or even prevent it from starting in any significant way.

那么，为何这些实体之间会存在这样的鸿沟，如果我可以这样说的话？

So why are there such gaps between, all these sort of entities, if I can put it this way?

举个例子，为什么患者对疾病的认知与基础研究人员不同？后者可能专注于他们想要干预的特定点。

So why, for example, patients perceive the disease in a different way from basic researchers who might be looking at a very specific points they want to intervene with?

我认为我们面临的最大问题是，在试图为疾病创建生物学定义时，我们搞砸了，不仅定义不准确，而且实际上阻碍了任何有成效的研究。

I think the biggest problem we face is that in attempting to create a biological definition of the disease, we've messed up and created something that is not only inaccurate but, really inhibitory to any sort of productive research.

对于患者及其家人来说，显然他们不是科学家，也没有接受过医学培训。

So with a patient and their families, obviously they're not scientists and they're not trained in medicine.

对他们来说重要的是家庭发生了什么，患病的亲人发生了什么，必须照顾他们的人发生了什么。

What matters to them is what is happening to the family, what is happening to the loved one with the disease, what is happening to the people who have to care for them.

这些症状就是我们所说的临床症状。

Those symptoms are what we would call clinical symptoms.

你知道，他们能记住多少？

You know, how much can they remember?

我们得多小心才能防止他们走失？

How careful do we have to be that they're not wandering?

诸如此类。

So on and so on.

然而，对于医生和科学家来说，这些症状清单并不代表治疗的路线图。

For physicians and scientists, though, those list of symptoms don't represent a roadmap to treatment.

我们需要理解其生物学机制。

We need to understand what is the biology.

这就是我们陷入困境的地方，因为这种疾病从20世纪初阿尔茨海默和克雷特林为其命名开始，就几乎不可逆转地将大脑中这些奇怪沉积物的出现与疾病的成因联系在一起。

And here is where we got caught because the disease beginning with its naming by Alzheimer and Kretlin back in the early 1900s almost irretrievably linked the appearance of these funny deposits in the brain as causative elements in the disease.

一百年前，这曾是一个高尚甚至值得称赞的假说。

And it was a noble and even laudable hypothesis one hundred years ago.

但在此期间我们收集了大量数据，这些数据与该假说根本不相符。

But we've collected a lot of data in the interim and the data is simply inconsistent with that hypothesis.

我们需要摒弃它，但正如我在书中探讨且至今仍未完全理解的原因，这个领域始终不愿放弃病理学与行为之间的这种关联。

We need to abandon it, but for reasons that I explore in the book and honestly to this day don't fully understand, the field has been unwilling to give up on that linkage between pathology and behavior.

结果我们陷入了一片混乱。

And we've ended up in a mess.

那么目前关于阿尔茨海默症成因的主流假说有哪些？

So what are the leading hypotheses that we have for what causes Alzheimer's?

主流假说被称为β淀粉样蛋白级联假说。

So the leading hypothesis is known as the amyloid cascade hypothesis.

该假说预测：从β淀粉样蛋白这种小肽沉积开始的一系列事件，会触发最终导致阿尔茨海默症痴呆症状的级联反应。

And this is a a prediction that a series of events beginning with the deposition of this small peptide known as beta amyloid is the trigger for a cascade of events that ultimately leads to the dementia that we find as Alzheimer's disease.

这个观点长期主导着该领域，实际上压制了其他所有原本完全可行的假说，导致它们被边缘化且得不到验证。

And that idea has dominated the field and really squeezed out all other, perfectly viable hypotheses that then become discouraged and not tested.

这些被忽视的假说包括氧化损伤假说、神经元及脑细胞DNA损伤导致的基因组完整性丧失假说。

So these other hypotheses include, oxidative damage, they include, the loss of genomic integrity through DNA damage in the neurons and other cells of the brain.

还包括tau蛋白病理沉积假说——这也是阿尔茨海默症大脑病变的特征之一。

It includes, pathological deposits of tau, which are, also part of the picture of Alzheimer brain.

还包括髓鞘丧失假说。

It includes loss of myelin.

以及线粒体功能障碍假说。

It includes, mitochondrial dysfunction.

这包括一种被称为细胞衰老状态的影响。

It includes, the impact of a cellular state known as senescence.

这包括存在的许多、许多、许多替代方案。

It includes the many, many, many alternatives exist.

它们并非互斥，但不知怎的，这已成为该领域的一种要求——你必须将任何假设与之关联。

They aren't mutually exclusive and yet, somehow it's become the sort of the requirement of the field that you must, relate whatever your hypothesis is.

你必须用β淀粉样蛋白来解释它。

You have to explain it in terms of beta amyloid.

而且，这纯属无稽之谈。

And, is simply nonsense.

你认为这是我们难以找到治愈方法的主要障碍之一吗？

Do you think this is one of the major hindrances to our ability to find a cure for it?

我完全同意。

I absolutely do.

是的，毫无疑问。

Yes, unequivocally.

那么如今研究阿尔茨海默病的方法是什么？

So how is studying Alzheimer's disease approached nowadays?

我们采用与研究任何疾病相同的方法。

It's approached as we approach any disease.

你从一个假设开始，进行实验，根据该假设分析数据，然后调整假设并重新开始整个过程。

You start with a hypothesis, you perform an experiment, based on that hypothesis, you analyze your data, and then you adjust your hypothesis and start the process over again.

我们陷入的困境是：我们提出了假设，进行了实验，分析了数据，结果与假设不符，但我们却不改变假设。

And where we're stuck is that we formed a hypothesis, we did the experiments, we analyzed the data, they don't agree with our hypothesis, and we don't change the hypothesis.

这有点像用头撞墙。

So it's kind of like beating your head against a wall.

只有停下来时才会感觉好些。

It only feels good when you stop.

那么你认为为什么淀粉样蛋白级联假说如此难以被改变？

So why do you think this hypothesis, the amyloid cascade is so resilient to being changed?

这是个非常有趣的问题。

That's a really interesting question.

我真希望能给你答案，但我做不到。

And I wish I could answer it for you, but I can't.

在书中我尝试解释，并探讨了阿尔茨海默病研究在不同时期的心理状态。

I try and explain and in the book, I try and go into what I think was the psychology of the different epochs in which Alzheimer's research, emerged.

我追踪了一些战略决策，这些决策与其说是科学性的，不如说是政治性的。

I track some strategic decisions that I described as more political in nature than scientific.

当时这些决策看起来都很明智，但回顾起来，它们实际上扭曲了我们领域的发展，阻碍了进步。

They all seemed, smart at the time, but looking back, their impact, has been to really distort our field in a way that, just precludes us from from making progress.

在很多方面，我必须道歉，因为我希望能有个答案。

And in many ways, I just I need to apologize because I wish I had an answer.

我同样感到沮丧——可能比任何人都更沮丧——因为我无法为这种可怕疾病提供一条明确的替代治疗路径。

And, I'm as frustrated, probably more frustrated than anyone that I can't give a clear alternative path, to a cure for this horrible disease.

我写这本书以及进行其他写作和教学的主要目的，是希望人们能够重置思维，重新开始，用我的话来说就是'开始倾听我们自己的数据'。

Mostly what I'm trying to do by this book and in my other writings and teachings is just to get people to reset, to go back and, as I put it, start listening to our own data.

希望由此我们能到达需要去的地方。

And hopefully from there, get to where we need to go.

好的，请继续。

Yeah, go ahead.

不，一点也不。

Yeah, not at all.

这正是关键所在——彻底革新这个领域，促使人们思考所有这些替代方案，以及我们可以将智力投入何处进行探索。

That's, that's exactly the point to really shake up the field, to get people thinking about all of these alternatives and where can we put our brainpower to explore.

确实如此。

Exactly.

那么在你看来，生物技术和制药行业在我们寻求治愈方法的过程中具有怎样的意义和潜力？

So what think do is the significance and perhaps potential of the biotech and maybe pharma industries in our quest of finding a cure?

我认为它们非常重要。

I think they're really important.

而且我在书中提到，我承认刚开始时，我试图将制药行业描绘成这个故事的主要反派之一。

And, I say in the book, that I admit when I started, I was looking to, you know, try to paint the pharmaceutical industry as one of the major villains of the, of the story.

但事实根本支持不了这个观点。

But the facts just simply don't bear that out.

通过写这本书和整理相关数据，我不仅认识到了这一点，更对此产生了深刻的理解与赞赏。

And what I, came to not just realize but appreciate in writing the book and in getting the, you know, the, the data together for it.

如果我们想要有任何机会对抗这种疾病，我们真的、真的、真的需要制药行业。

We really, really, really need the pharmaceutical industry, if we're ever going to have any chance of combating this disease.

像我这样的基础研究者，我们解决了一个问题后，就只想继续前进。

It's, you know, basic researchers like myself, we solve a problem, we just want to move on.

但仅仅在智力上解决问题，并不能让任何药物或疗法真正进入临床使用。

But solving a problem intellectually doesn't get a pill or a treatment into anybody's clinic.

正是制药行业填补了这一空白，而且他们在这方面效率极高。

And it's that gap that's filled by the pharmaceutical industries and they're extraordinarily efficient at it.

最近我开始强调我们在病毒疫苗研发方面取得的巨大成功。

And I have recently begun to highlight the immense success of the of the of the virus back of the viral vaccines we've been able to develop.

没错，这是建立在扎实的基础科学研究之上的。

Yes, that was built on a solid foundation of basic science.

但说实话，如果没有生物技术行业，甚至包括一些大型制药公司的全力投入和推动，疫苗研发根本不可能实现。

But boy, it just would not have happened without the biotech industry and even some of the and including the major pharmaceutical houses, putting their shoulder to the wheel and making vaccines happen.

然而他们也要为我们当前的困境承担一定责任。

And yet they too bear a certain responsibility for our being stuck.

原因多种多样，包括自负心理，也包括我认为那些与科学判断脱节的财务激励。

For a variety of reasons having to do with ego, having to do with, I think financial incentives that, are divorced from scientific judgment.

这个领域一直支持阿尔茨海默病的β淀粉样蛋白假说占据主导地位。

The field has been a party to the dominance of the amyloid model of Alzheimer's disease.

正如我在书中所说，这其实是不负责任的行为。

And as I say in the book, that's not really responsible behavior.

他们掌握数据，清楚数据质量，还拥有全球顶尖的统计学家。

They have the data, they know how good it is, they have some of the best statisticians in the world.

但他们没有用这些资源来真正指导财务风险决策，反而用来事后粉饰那些失败的风险投资，这很可悲。

And rather than use them to truly guide the financial risks that they take, they use them to paper over in retrospect what have been bad risks and that's sad.

我相信很多听众都听到了今年夏天关于阿尔茨海默病药物阿杜卡奴单抗的新闻。

So I'm sure many of our listeners, heard heard the news over summer about Alzheimer's drug aducanumab Mhmm.

该药物获得了FDA的批准。

Being approved by FDA.

能否请你简单介绍一下情况并分享你的观点？

So could you tell us a little bit about it and what is your perspective?

嗯，我相信这对你或任何听到现在的人来说都不足为奇。

Well, I'm sure it'll come as no surprise to you or to anyone who's listened this far.

我认为那个决定是灾难性的，事态发展正如我们所预料的那样。

I think that decision was a disastrous one, and it has been playing out in much the way that we expected.

统计数据被用最激进的方式重新计算，只为寻找一丝微弱的可能性。

The statistics were reworked in the most aggressive way possible to find a shadow of a possibility.

基于此，FDA做出了我认为近乎不负责任的决定，继续推进并批准了该药物。

And on the basis of that, the FDA made what I think was an almost irresponsible decision to go ahead and approve the drug.

而业内的反对声浪非常强烈。

And the outcry in the field has been very substantial.

我发现不仅是我这样的人在反对——我们并不认为减少淀粉样蛋白对治疗该疾病有任何作用，这当然是批评的一部分。

And I find it coming from not just people like myself who don't feel that amyloid reduction of amyloid is going to do anything for the disease, which is certainly part of the criticism.

但我想即便是那些仍以淀粉样蛋白为主要研究模型的人，也对药物获批的流程提出了批评。

But I think even people for whom amyloid is remains, their top model, the process by which the drug was approved, still comes up for criticism.

正如我所说，事态发展正如预料的那样，这种药物并未被广泛采用。

So and I it's playing out, as I said, as one might have predicted, the drug is not being adopted.

欧洲监管机构现已明确表示不会开具该药处方。

The European regulators have now said they're not going to, prescribe it.

日本方面也表示不会使用该药。

The Japanese have said they're not going to prescribe it.

在美国FDA批准后仍存在争议——我们的公共医疗体系（如果还能称之为体系的话）即医疗补助和医疗保险，至今尚未决定是否批准使用。

There's still debate in The United States after the FDA approved our public health care system met well, what passes for public health care system Medicaid Medicare has not decided whether or not they're going to approve it.

他们面临巨大压力不能批准该药物，部分原因是它无效或至少效果甚微。

There's a lot of pressure on them to not approve it, in part because it is not efficacious or at least not very efficacious.

我会说它无效。

I would say not efficacious.

部分原因是存在明确风险，包括脑肿胀及其带来的短期和长期后果。

In part because there are clear risks involved attributable to brain swelling, and both short and long term consequences of that.

从最基础层面看，其成本过于高昂，而患病人数及潜在用药人群如此庞大，这将迅速拖垮整个医疗体系。

And just at a very basic level, the cost is so exorbitant that and the number of people with the disease the number of potential people who would use the drug is so enormous, that it would quickly bankrupt our entire healthcare system.

你觉得

What do

其他公司寻求FDA批准其可能清除淀粉样蛋白的抗体药物会带来什么连锁反应？

you think the ramifications would be for other companies seeking the FDA approval for their antibodies that might be clearing amyloid?

你认为它们可能会压低价格吗？

Do you think they might be driving price down?

是的，我认为它们肯定在压低价格。

Well, yes, I think they're definitely driving price down.

实际上我虽未持续关注，但前两天确实看到头条新闻说百健已将其药物Aduhelm的价格减半。

In fact, I haven't followed through, but I did see a headline a day or two ago that, Biogen had taken the step of reducing the cost of what they call Aduhelm, by half.

所以没错，我认为激烈的竞争压力确实是部分原因。

So yeah, I think the hot breath of competition certainly is part of that.

但我认为部分原因在于他们未能说服医学界这是种值得开具的药物。

But I think part of it is that they just, are they have not convinced the medical community that this is a drug worth prescribing.

作为基础研究者，我担心的是——如果现在仅凭降低某种生物标志物（我认为是未经证实的标志物）就足以获得FDA紧急批准，那么将有一大批公司和产品排队要求FDA批准，声称自己降低了tau蛋白水平就该获批。

As a basic researcher, what I worry about is that now if reduction of amyl if if reduction of a biomarker, and I would argue an unproven biomarker, is now sufficient to get emergency approval from the FDA, well, there is a long line of companies and a long line of products that's going to be forming at the FDA's door saying, well, look, we reduced tau, you should improve our drug.

你好，我们也通过不同方法减少了淀粉样蛋白。

Hello, we also reduced amyloid using different method.

你们应该批准我们的药物，很快市场上就会出现这些毫无疗效的药物。

You should approve our drug and pretty soon we'll have all these drugs that don't do anything, out on the market.

我认为公众和世界各国政府很可能会开始对生物医学机构失去信心和信任。

And I think the risk is substantial that the public and the governments of the world will begin to lose lose confidence and lose faith, in the biomedical establishment.

哦，这确实是个关键点，要让人们明白即使从生物分子层面清除了淀粉样蛋白，也不一定转化为临床效益。

Oh, that's such a key point to really bring across, to people that even when the amyloid itself, so from biomolecular perspective, is being cleared out, it might not translate into clinical benefits.

所以即使从基础科学角度，我们也不能直接跳到对人类临床效益的结论。

So even from the basic science, we cannot just go straight to clinical benefits in humans.

正确。

Correct.

是的。

Yeah.

现在更多考虑从监管的顶层设计角度来研究阿尔茨海默症。

And now thinking about more of a top down approach of regulation and also studying Alzheimer's, really.

那么大学或政府在这类研究中扮演什么角色？比如研究经费补贴方面？

So what are the roles of universities or governments in how this research is, being subsidized, for example?

嗯，好问题。

Yeah, good question.

我思考了很多，我认为这是个可以富有成效地长期辩论的领域。

I've thought about it a lot, and I think this is an area where we could debate productively, for quite a while.

我个人认为现代医学进步大多建立在扎实的基础研究之上。

My personal opinion is that most of modern, medical advance has been built on the shoulders of strong basic research.

所以现在，我当然也参与其中了。

So now, of course, I have skin in this game.

我绝非中立观察者，但我坚信世界各国政府应当大力投入基础研究的资助。

I'm far from a neutral observer on this, but I do believe that, the governments of the world would be well advised to put, substantial effort, into the funding of basic research.

我要特别强调‘基础’而非‘应用’，因为正如我常说的，你永远不知道下一个好点子会从何而来。

And I I emphasize basic, rather than applied because, as I like to say, you just don't know where your next good idea is going to come from.

要知道，我们现在正经历一场基因编辑革命，而这完全基于一群无人知晓的奇特细菌中晦涩难懂的酶系统。

And, you know, we are now having a revolution in gene editing based on an absolutely arcane set of enzymes in a bunch of weird bacteria that no one had ever heard of.

但这正是CRISPR Cas9技术的全部基础。

But that's the whole basis of CRISPR Cas9.

若在二三十年前试图根据‘是否该资助这些奇特生物研究’来做资金决策，包括我在内所有人都会说‘还是算了吧’。

If you tried twenty years ago or let's say thirty years ago to make a funding decision based on, whether or not you should fund research into these odd creatures, I think all of us, including myself, would have said, Well, no, I don't think so.

但看看，看看发生了什么。

But look, look what happened.

事实就是如此。

So there's that.

因此我认为，这应当成为大学和研究所工作的基石。

I do think then there is a role in so this is where I would put sort of the I think that would be the cornerstone of the university and research institute work.

但在此基石之上，基础转化研究也扮演着重要角色。

But building on that cornerstone, there is a role for basic translational work.

也就是说，研究细菌虽然有趣，但最终必须将其与哺乳动物生理学——特别是人类生理学联系起来。

That is to say at the end of the day, the bacteria are really fun, but you've got to begin to connect that to mammalian physiology and in particular to human physiology.

因为在世界上的奇特生物与人类生物学之间，存在着基础研究的鸿沟。

And because there is a basic research gap between the odd creatures of the world and, you know, the human biology.

而这正是临床医学将发挥最大效益的地方。

And that's where clinical medicine is going to achieve its most benefits.

因此我会将这一理念贯穿到临床试验的初始阶段。

So I would extend that all the way through the, initial stages of clinical trials.

所以无论是基于新发现的药物安全性（一期临床试验），还是早期疗效迹象（早期二期临床试验）。

So whether a drug, based on a new discovery, is safe, Phase I clinical trial, or shows early signs of being effective, phase early phase two clinical trials.

我认为政府和大学技术转移部门都可以在其中发挥作用。

I think there's a role for, government, and I think even university tech transfer groups, have a role there.

但我会在此处划下明确界限。

But I would put a very hard stop right there.

而我认为更昂贵、临床强度更大的三期试验，这些成本应该由产业界自行承担。

And then I believe that the more expensive clinically intense, phase three trials, those need those are expenses that need to be borne, by industry itself.

我认为这将使生物技术产业和生物技术机制更具生产力。

And I think that that would make for a much more productive bio biotech industry and biotech machinery.

那么现在从宏观角度来看，当今的政治、经济和社会力量如何影响我们对阿尔茨海默病的认知和理解？

So now thinking about the bigger picture, in what ways are we thinking and understanding Alzheimer's is being shaped by the political, economic and also social forces of the day?

哦，这是个棘手的问题。

Oh, I would tough question.

我的意思是，所有事物当然都会受到当下政治和社会问题的影响。

I mean everything is of course influenced by the politics of the day and social questions of the day.

我认为阿尔茨海默病的问题在于，在试图快速推进的过程中，我们变得鲁莽而非承认自身知识的不足。

I think the problem with Alzheimer's disease is that in trying to move quickly, we've moved rashly rather than sort of accept our own lack of knowledge.

我几乎要称之为一种谦逊。

I would call it almost a humility.

要知道，面对对这种疾病认知的匮乏，我们非但没有保持谦逊，反而变得傲慢，声称‘不，我完全清楚是怎么回事’。

You know, rather than being humble in the face of of our lack of knowledge about the disease, we've instead become arrogant and said, Oh no, I know exactly what's going on.

我们只需要这样做。

We just have to do this.

如果行不通，就意味着我们只需选择稍有不同的患者群体，或者需要在疾病更早期介入——这种态度，我要说，本质上是政治和社会性的。

And if it doesn't work, it means we just need to select a slightly different group of patients or maybe we need to go a little bit earlier in the disease or so that attitude is, I would characterize it as political and social.

可悲的是，这其中并没有多少科学价值。

It has sadly, not a lot of scientific merit to it.

提出这些问题对更广泛的社会意味着什么？尤其在人口老龄化和寿命延长背景下，疾病负担会如何演变？

And what are the implications of raising these issues for the wider society, especially in terms of more aging population and people living much longer about the burden of the disease?

是的，这至关重要。

Yeah, it's critical.

再次强调，我真希望自己能有个答案，某种成功秘诀。

And here again, I sure wish that I had an answer, you know, a recipe for success.

但我没有。

I don't.

我在书中专门用一章阐述我们对衰老生物学的认知——因为阿尔茨海默病恰似个典型例证：公共卫生的进步使人类寿命远超史前时代，但这一成功也带来了悖论，让我们暴露在祖先们根本无缘知晓的疾病中，因为他们活不到发病的年纪。

I devoted a whole chapter in the book to what we know well, sort of an introduction to what we know about the biology of aging because Alzheimer's is sort of a poster child for the fact that the successes in public health that have extended human lifespan to well beyond what it was, back when we were, in prehistoric times, that success has led to the paradox of exposing us to diseases that our 10,000 year old ancestors would never have known about because they never got old enough to get them.

正因如此，我在书中极力呼吁要加倍乃至更多地投入衰老生物学研究——因为无论最终答案是什么，它都不仅是攻克阿尔茨海默病的关键，更是解决从心脏到关节、骨骼到肌肉、肾脏到肝脏等全身系统疾病的核心。

So we need, and it's why I make such a big push in the book to redouble and more, our efforts to understand the biology of aging because whatever that turns out to be, it's the key to not just Alzheimer's disease but a host of diseases that afflict all of our body systems from our hearts to our joints, to our bones, to our muscles, our kidneys, our livers.

这关乎我们每个人。

It affects all of us.

我在书中提出了一个问题：我们能否阻止衰老？

I raised the question in the book about whether we'll stop aging.

我认为我们不会。

I don't think we will.

我相信我们所能做的就是尽可能延长所谓的'健康寿命'。

What all we can do I believe is to keep what's called our health span as long as possible.

通过理解生物学，你可以尽可能长久地保持肌肉健康，尽可能长久地保持大脑健康。

So in understanding the biology, you can keep our muscles as healthy as they can be for as long as possible, keep our brains as healthy as they can be for as long as possible.

但你知道，虽然很遗憾，但死亡是无法避免的。

But, you know, it's sad but death is not optional.

这个观点非常棒，实际上让我想起你书中开头讲述的那个阿尔茨海默症患者的故事。

This is such a great point and actually, brings me back to the beginning of your book when you were telling a story of one of the Alzheimer's patients.

你在书中写到，他们在运动和饮食方面'做对了一切'，却仍然患上了这种疾病。

And something that you wrote about them is that they've done everything in quotes right in with regards to exercise and the diet and still ended up with this disease.

所以我在想，我们应该在多大程度上考虑预防措施，但也许不要把所有的鸡蛋放在一个篮子里？

So I wonder to what extent should we be thinking about preventative measures, but maybe not putting all of our eggs in one basket?

我完全同意这个观点。

I would definitely agree with that point of view.

预防、生活方式选择，说实话真的很无聊。

Prevention, lifestyle choices, I mean, it's really boring.

从生物技术和制药的角度来看，这不仅无聊，而且无利可图，因为没有知识产权涉及。

And from biotech point of view, from a pharmaceutical point of view, it's not only boring, it's unprofitable because there's no intellectual property involved.

但你知道，没人能靠开'每日散步'的处方赚大钱。

But, you know, no one's going to make a whole lot of money prescribing a daily walk.

但从衰老和阿尔茨海默症等疾病的整体角度来看，这完全合理。

Yet it makes perfect sense from a more holistic view of aging and of diseases like Alzheimer's.

我提到了控制血压的问题，道理相同。

And I mentioned keeping blood pressure under control, same thing.

那里有些药片可以出售，但知识产权所剩无几。

There's some pills to be sold there, but, not a lot of intellectual property left.

所以你知道，你永远无法为一年期的降压治疗收取56,000美元的费用。

And so not, you know, you'll never be able to charge $56,000 a one year treatment of keeping blood pressure down.

因此，我想如果退一步看，我真正主张的是我们的制药模式需要改变。

So, I think I guess if if you take a step back, what I'm really arguing is that our pharmaceutical models need to change.

在你撰写《如何不研究一种疾病》这本书的过程中，哪些发现最让你感到惊讶？

So what discoveries along your journey to writing your book, How Not to Study a Disease, surprised you the most?

我想是阿尔茨海默病中丧失的脑部特征的多样性。

I guess the diversity of brain features that are lost in Alzheimer's disease.

我的意思是，每当我回头观察大脑先天免疫系统的细胞，每次看到制造髓鞘的少突胶质细胞的行为，甚至只是看到大脑中本不应受阿尔茨海默病影响的区域的神经元时，我都对这种疾病的影响感到震惊——我犹豫地说出这句话是因为我想把衰老也列入病因清单。

I mean, it just seems like every time I turn around and look at the cells of the brain's innate immune system, every time I look at the behavior of the oligodendrocytes that make myelin, every time I even just look at neurons in regions of the brain that are not supposed to be affected by Alzheimer's, I'm just astonished that the effect of this illness, and I don't and I say it hesitantly because I want to include aging in the list of causes.

但功能的丧失异常广泛。

But the loss of function is extraordinarily widespread.

我认为这最终就是我们要传达的信息，人们正逐渐意识到这一点。

And I think that in the end is the message, that slowly coming around to realizing.

你自己遵循地中海饮食吗？

And you yourself, do you follow the Mediterranean diet?

说实话可能没完全做到，但我确实在注意。

You know, probably not as well as I should, but I do try and watch.

我想我们毕竟都是人类，作为一个物种，我们在延迟满足方面存在很大困难。

I think all of us are human and we as a species have a great deal of trouble with delayed gratification.

既然这种情况下的延迟可能长达三十年、四十年甚至五十年，确实需要钢铁般的意志才能做到尽善尽美。

And since the delay in this case can be thirty, forty, fifty years, it takes a real iron will to be able to, live perfectly.

但正如你刚才指出的，多萝西的故事鲜明地提醒我们，即便做到尽善尽美，也依然无法保证万无一失。

But as I think, as you pointed out just a moment ago, the story of Dorothy is a stark reminder that even if you were to do everything perfectly, it's, still not a guarantee.

是啊。

Yeah.

偶尔也可以来一勺意式冰淇淋。

Can allow a scoop of gelato now and then.

我甚至要推荐这么做。

I would even recommend it.

好的，我们占用了您不少时间。

Well, we've taken up a lot of your time.

能请您谈谈当前的研究方向和下一个项目计划吗？

So can you tell us what are you currently working on and what will be your next project?

老实说，我暂时没有写新书的打算。

Well, I don't plan to write another book, I have to say.

写书是项大工程，我不确定自己还能再写出一本。

It was a major effort and, I'm not sure I've got another book in me.

我的实验室主要研究髓鞘、炎症和DNA损伤，以及这三者之间的关联机制。

My lab is interested in myelin and inflammation and DNA damage as and in fact, how those three things relate to each other.

这是个复杂的网络。

It's a complex web.

我努力将研究聚焦在具体实验上，但这始终是个挑战。

I try and keep it reduced to specific experiments, but it's a challenge.

说实话，我在这行已经待得够久了，差不多是时候把接力棒传给其他人继续奋斗了。

And I'll be honest, I've been in this game long enough that I'm sort of going about ready to pass the torch to others to keep up the fight.

或许如果我能早些进入这些领域开拓，就能为后来者照亮前行的道路。

And maybe if I can make a few early entrees into these fields, I can light the way for others to carry on.

是啊，你确实是许多年轻学者的榜样。

Yeah, you're truly an inspiration to many of the younger scholars.

希望如此

I hope So

听众们在哪里可以了解更多关于您工作和著作的信息呢？

where can our listeners find more information about your work and also your book?

这本书呢，你可以直接去麻省理工出版社的官网上购买。

Well, the book, you can just, head to MIT Press, when pick it up on their website.

所有线上商业书店都有售。

It's available on all the commercial booksellers, online.

我非常期待你们能阅读它。

And I just would be delighted to have you read it.

我也很乐意收到反馈，哪些内容容易理解，哪些比较难懂，说不定有朝一日我还会出第二本书。

I'm also delighted to get feedback, things that are easy to understand, hard to understand, and maybe there will be a second book in me one day.

噢，希望如此。

Oh, let's hope so.

非常感谢您今天参与节目，带来这场令人耳目一新的讨论。

Well, thank you so much for joining me today and for this refreshing discussion.

荣幸之至。

Pleasure.

感谢邀请我。

Thank you for having me.