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[ARVO2013]转化医学的意义
——美国威斯康星大学医学院Paul L.Kaufman博士专访

眼科基础研究  作者:  P.L.Kaufman  2013/7/2 15:54:00
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内容概要:《国际眼科时讯》:您认为眼科研究转向转化医学模式的意义何在,尤其是当您认为其已经成为世界性模式的时候?

  <International Ophthalmology Times>:What do you think is the significance of the ophthalmology study turning to a more translational medicine model, especially when you consider that that’s becoming a worldwide model?

  《国际眼科时讯》:您认为眼科研究转向转化医学模式的意义何在,尤其是当您认为其已经成为世界性模式的时候?

  Dr. Kaufman:We think of translational as being something that goes from the dish in the lab to the patient in the clinic, and the translation are between basic scientist to hardcore basic science research related to the disease process and the person in the clinic, in the office, in the operating room actually dealing with the patient one on one. There is a gap there. It’s hard for those groups to communicate. And this isn’t because some are speaking in Chinese and some are speaking in English, it’s because they really are very different items. And sometimes the clinician can’t really understand what the basic scientist is doing or even why and the basic scientist doesn’t really understand the disease and doesn’t understand what the clinician means. And we are getting better at bridging those gaps, and the most important thing is that there is recognition that those gaps must be bridged because otherwise medicine will advance very slowly and very poorly.

  So, what we mean by translational research is research which, it’s basic. It takes on basic concepts like let’s say the rho kinase concept which was worked out in the cells and by people who had even no interest in glaucoma or didn’t even know where the eye was let alone what glaucoma was but were just interested in cells. They may have been cancer people who are interested in what makes some cells spread and divide and others not. Because the scale of mechanisms are tracked down. Mechanisms are involved in adhesion and cell spreading as well.

  Somebody from the eye recognizing that same process could be important to the tissue like trabecular meshwork not because of tumor genesis but because of the fluid conductivity issues that occur from manipulating those processes in a tissue that’s configured a certain way and that’s function is to let fluid go through or not let it go through.

  So the idea of somebody being able to take basic science piece of information say, "I think that could apply in the disease that I am working on, treating, and let’s do some research in the appropriate cell type, and then let’s go to analyst and make some measurements and see if the outflow is affected in the way we think from the way we know that these compounds are acting. And if it’s yes and yes, then let’s go with gingerly and demand and again do some kind of proof of concept study to see if the idea is right and this actually can work and then let’s go to a pharmaceutical lab to get a drug  with a preservative and a vehicle and a dose with a molecular modification if necessary so that it’s tolerated by the eye, and so the penetration of the eye into the tissue that you are interested in."

  That whole process is called translation. Translation from basic science into the clinical world. And the research is done that is called translational research. I’m not a living basic scientist. I trained as an ocular physiologist as well as a clinician but I am not a hardcore card-carrying PhD level physiologist and I am not a cell biologist, people who work on the set of skeleton. But I know enough to say when I see that stuff, This looks really interesting. This could apply to the clinical world, and I have a laboratory that is set up to work at the interface, we are working at those. But we measure the same things that would be important to same parameters that would be important in the drug that would be used for treating glaucoma.

  We can get another information that either confirms or denies that hypothesis that can say no, that isn’t going to cut it or this looks really good. It has the effect that’s going on that the animal seems to tolerate it pretty well. And then of course, you get into the real development. Some company has to take this whole, “We will do the important tax  work,” and all the things you have to do to get the drug to the FDA and into the marketplace and really within that interface between clinical and basic scientist world.

  Kaufman医生:转化医学引导我们从实验室走向患者,涉及基础科学家和临床医师双方,前者握有与疾病过程相关的核心基础科学研究成果,而后者身处医院办公室、手术室,能够一对一地接触患者。这当中存在隔阂,导致两个群体很难互相沟通。这不是因为谁说中文或者谁说英文,而是因为他们根本就是截然不同的群体。临床医生有时不能真正理解基础科学家正在做什么,同时基础科学家也不是真正了解疾病,因而不能理解临床医师的真正用意。我们正在努力搭建二者间的桥梁,以消除二者间的隔阂,更重要地是,消除这一隔阂已经成为全球医师的共识,否则新药的研发进展将异常缓慢,异常艰难。

  因此,我们口中的转化医学,是基础研究。它立足于基本概念,比方说让那些对青光眼毫无兴趣或者一无所知的人来谈论细胞中的Rho激酶,但别指望这些只着眼于细胞的人能弄明白青光眼是什么。可能他们当中有人曾经患过癌症,因此对于细胞扩散转移、分裂增殖这些问题感兴趣,但其他人不是这样。因为机制研究的方方面面都会被跟进,也有机制参与细胞的黏附和扩散。

  从眼球结构而言,同样的一个途径,有人可能说这对小梁组织是很重要的,不是因为其与肿瘤发生相关,而是因为流体传导性的问题,通过某种方式在组织中调节了一定的通路,这些通路其实拥有控制流体通过与否的功能。

  所以,看了一些基础科学资料后,有人提出,“我认为这可以应用到我现在正在治疗的疾病中,让我们使用合适的细胞来进行一些研究,让分析员做一些测定,看流出方式是否正如我们所预计的那样受到化合物影响。如果的确如此,那么就小心求证,重复试验,完成概念研究中所谓的验证试验,看这个想法是否正确有效,然后让药物实验室制作这种药,加入防腐剂、载体,必要时进行一定程度的分子改造,保证眼部能耐受这种药物,然后如你所愿地,药物穿透眼表到达你感兴趣的那部分组织发挥作用。”

  这整个过程就是转化。从基础科学到临床工作,研究圆满了,这就叫转化医学。我也不是基础科学家。我实际上是一名眼科医生,同时也是一名眼科生理学家,但我没有PhD的职称,我也不是致力于结构研究的细胞生物学家。但当我参与到这些研究时,我有足够的知识,对这些研究感兴趣,认为其适用于临床。于是我建立了自己的实验室,并以此为平台进行研究。但是,虽然我们测定同样的事物,拥有相同的参数,但都能够有助于青光眼治疗药物的研发,这是非常重要的。

  我们可以得到另外的信息,无外乎肯定或是否定假说,像是这方法行不通,或者这不可能阻断,或者这看起来不错,它确实有效,发挥作用了,动物们耐受良好。然后,理所当然地,你进展到真正的研发关键阶段。有些公司想全盘接受,“我们会完善所有重要的税收工作,”然后你只需要把药物提交到FDA,引入市场,真正构建了临床和基础研究之间的平台。

  <International Ophthalmology Times>:So your lab is the translator?

  《国际眼科时讯》:所以您的实验室从事转化研究吗?

  Dr. Kaufman:We are the translator. That is what we do and that’s generally what clinician scientists do. A lot of them are trained as basic scientists. They all have some level of clinical involvement. In fact to lose that, we lose the advantage of knowing what it is that you need, knowing what it is that the field needs, and being able to properly evaluate something that comes up. If you are not trained as a clinician, you don’t even know what to look for in the clinical world to see if a drug is effective and say how do you measure effectiveness, how you measure safety, you kind of have to know these things and there has to be also an infrastructure somewhere to do the clinical trials. And those could be the academic centers, they can be contract research centers, but you have to get into that intermediate basic science knowledge here, there is clinical need here, somebody needs to be able to navigate that space in-between.

  It works the other way too. You have to have some input from the clinical world into the basic science world. Clinician should be able to go to a cell biologist and say, “Do you know I need something for the treatment of this disease that does this? I can tell you what membrane it has to works on but I know I need to make this tissue more porous.” And then you have to be able to explain the tissue to a basic scientist. Basic scientist will turn around and say, “Aha, if that’s what you want to do, then I know five ways, five biological pathways that can accomplish that. So, let’s look at your cell type if this cell type is relevant to the disease and see if I can induce those changes in that cell type, in a culture dish. And if I can’t, then I know that that I am not competent enough to be able to help you. If I can, then you begin to have that pathway that I just described.”

  So, it’s not just clinical, it’s not as basic, the clinical translation. It’s clinical to basic, clinical need to basic development of something based on that need and then back to clinical again, so the translational cell can be a back and forth translation or it can just be something that’s already growing up in the basic science world for some other reason. It’s harder and harder to do that because the people who sit in middle, the physician-scientists are really an endangered species. The economics of the scientific side, that is, the monotonous competition for grants as well as small amounts of money available, and the relentless economics of the clinical side where it isn’t just the people who paid less for clinical work.

  That means that an entire academic department is being paid less which means that it’s hard to support the person who wants to spend half of their time to the clinical work and the other half of the time to the research and how do you pay for that other half of the time, and there is less extra money around in the system to do that. And that’s why we are in danger. And so, the NIH tries to help a particular grant set aside for clinician scientists, and per year you have to repeat for those dollars too, but at least the dollars that can only be used from that pool. So, it gets harder but translational medicine is what you hear now and it doesn’t mean translation between Japanese and English, that’s not the translation I am talking about. It’s a translation between basic and clinical scientists.

  Kaufman医生:我们是转化工作者。这是我们的工作,就像一般临床科学家所做的那样。他们当中许多人原本是基础科学家,又都某种程度上参与了临床工作。实际上,如果没有这样的经历,我们也就失去了优势,不知道临床医师需要什么,不知道临床工作中究竟需要什么成果,不能正确评估新生事物。如果不是一名临床医师,你甚至不会知道该如何在临床工作中判断药物有效性和安全性,你多少得知道这些,同时还需要有进行临床试验的基础研究机构,可以是学术研究中心,合同研究中心等,但这里有基础科学家,也有临床医生,所以你得有一个中间人,能够调和这两个群体之间的差异。

  反过来也一样,你必须从临床工作中汲取知识代入基础科学研究的领域。临床医生应该能够和细胞生物学家交流,说“你知道我需要一种治疗这种疾病的药物,这可行吗?我可以告诉你它需要作用于哪些膜结构,但我知道这些组织应该倾向于多孔结构。”然后,你必须能够向基础科学家解释这些结构,然后他会转身过来告诉你,“ 啊,原来如此,如果那就是你想要的,我有五个方法,五条生物学途径可以做到这一点。所以,让我看看你的细胞类型是否与这种疾病相关,还有是否能在体外培养的这些细胞中诱导这些改变。如果我做不到,那我还真没法帮到你了。如果我成功了,那你就能开始做我刚说的那些通路。”

  所以,这不仅限于临床,也不完全是基础,而是临床转化,这是从临床延及基础的过程,基础研究的发展以临床需要为根本,再回到临床,所以转化流程实际就是一个来回往复转化的过程,或者说它是从基础研究中为其他原因而衍生的。转化医学越来越困难,因为身为中间地带的这类人,身兼临床医师和科学家身份的人员越来越少。从科学界的经济学方面来看,研究项目和少量研究基金的审批竞争激烈,而临床界的经济学也很残酷,不仅是人均收入少的问题了。

  也就是说,整个学术部门收入低,难以支持那些想要各分一半精力进行临床和研究工作的人们,你想,如何支付那一半时间所付出的工作,而同时系统可用余额又那么紧缺,这就是转化工作者越来越少的原因。所以,NIH想通过帮临床科学家单独设定特别基金,每年重复申请资金,并只能专款专用。因此,又难上加难。但是转化医学,正如你所听到的,并非日语和英语之间的翻译,那不是我现在所说的“转化”。转化医学是基础和临床科学家之间的转化。

  <International Ophthalmology Times>:Dr. Kaufman, I thank you very much for your time. It’s delightful.

  《国际眼科时讯》:Kaufman医生,非常感谢您抽空接受我们的采访。实在是非常高兴。

  Dr. Kaufman:Okay, I appreciate it.

  Kaufman医生:好的,我非常感谢有这个机会。


 
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